Handbook of Macrocyclic Supramolecular Assembly [1st ed.] 9789811526855, 9789811526862

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Yu Liu Yong Chen Heng-Yi Zhang Editors

Handbook of Macrocyclic Supramolecular Assembly

Handbook of Macrocyclic Supramolecular Assembly

Yu Liu • Yong Chen • Heng-Yi Zhang Editors

Handbook of Macrocyclic Supramolecular Assembly With 1098 Figures and 32 Tables

Editors Yu Liu College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry Nankai University Tianjin, China

Yong Chen College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry Nankai University Tianjin, China

Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) Tianjin, China

Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) Tianjin, China

Heng-Yi Zhang College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry Nankai University Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) Tianjin, China

ISBN 978-981-15-2685-5 ISBN 978-981-15-2686-2 (eBook) ISBN 978-981-15-2687-9 (print and electronic bundle) https://doi.org/10.1007/978-981-15-2686-2 © Springer Nature Singapore Pte Ltd. 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Foreword

As a result of the significant development of supramolecular chemistry, the Nobel Prizes were awarded to supramolecular chemists in 1987 (Donald J. Cram, JeanMarie Lehn, Charles J. Pedersen) and 2016 (Jean-Pierre Sauvage, Sir J. Fraser Stoddart, Bernard L. Feringa). Within the field of supramolecular chemistry there is an increasing interest focused on the supramolecular assemblies based on macrocycles, including ionic crown ethers, ionic macrocyclic arenes, cyclodextrins, cucurbiturils, etc., and these macrocycles are extensively used as not only excellent receptors for molecular recognition but also convenient building blocks to construct nanostructured functional materials, especially bioactive materials. Looking back, many scientists made a solid foundation for the development of macrocyclic supramolecular assembly. At the same time, we are also delighted to see that a group of young chemists have grown and started to show their prominent abilities in this area. These years witnessed a significant harvest in the macrocyclic supramolecular chemistry. However, we believe that, with the joint efforts of all supramolecular chemists, the exciting findings are only beginning to be discovered. To further present these research achievements, Springer Nature decided to publish the Handbook of Macrocyclic Supramolecular Assembly, and I was invited to act as an editor of this handbook at the time of The 100th Anniversary of Nankai University. The main purpose of the handbook is to provide educators, scientists, and graduate and undergraduate students with a relatively comprehensive set of knowledge and recent developments covering macrocycle-based supramolecular chemistry, biochemistry, functional material, and nanotechnology. I wish that the publishing of this handbook will be helpful to the chemists who are interested in the

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macrocyclic supramolecular chemistry. I also wish to thank the editorial team at Springer Nature and co-workers, in particular Ms. Haiqin Dong, Ms. Lijuan Wang, and Mr. Stephen Yeung, for their tremendous work. Finally, it is my honor to thank all the contributors of this handbook who presented so many excellent works and made the publication of the handbook successful. College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry Collaborative Innovation Center of Chemical Science and Engineering Nankai University

Yu Liu

Preface

From the 1960s to the 1980s, Pedersen reported the discovery of crown ethers as host molecules, Cram incorporated host-guest chemistry, and Lehn created supramolecular chemistry. From then on, supramolecular chemistry becomes one of the most popular and fastest growing areas of chemistry, leading to numerous achievements in molecular recognition, molecular assembly, molecular machine, and so on. Most of these works are based on macrocyclic compounds, and these macrocycles act as good receptors for molecular recognition and convenient building blocks for molecular assembly and molecular machine. Therefore, providing a comprehensive set of knowledge on recent developments of macrocycle-based supramolecular system, especially functional supramolecular assembly, to educators, scientists, and students who are interested in supramolecular chemistry becomes necessary. With this aim, Prof. Yu Liu, Prof. Yong Chen, and Prof. Heng-Yi Zhang from Nankai University jointly edited a handbook of macrocyclic supramolecular assembly, which is now being published by Springer Nature. The handbook mainly focuses on works in the field of macrocyclic supramolecular assemblies, with an emphasis on their construction, structural characters, and biological functions. All 59 chapters of the handbook cover a wide variety of topics on macrocyclic supramolecular assemblies including: (1) construction and structure of macrocyclic supramolecular assembly (key building block, construction method, structural motif, and stimuli responsive control); (2) approach and technology (controllable synthesis, molecular recognition, spectral and thermodynamic study, supramolecular assembly at interface, orthogonal self-assembly, supramolecular organic framework, molecular induced aggregation, theoretical calculation, and molecular simulation); (3) application (chemical and biological sensing, theranostic tool, molecule/ion channel, drug/gene delivery, supramolecule-assisted biomolecule production, supramoleculeassisted transmembrane transport, supramolecule-assisted immunity regulation, and supramolecule-based medicinal drug.). Each chapter in this handbook is written by active experts in the research field of macrocyclic supramolecular assembly and has a high academic level. Together they form a handbook that may become very important in the bibliography of supramolecular chemistry. I am glad to participate in this project by recommending this

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handbook to scientists interested in the research of supramolecular assembly and application, to engineers interested in the use of supramolecular techniques, and to undergraduate and graduate students who intend to begin their research in supramolecular chemistry. Nankai University Jin-Pei Cheng

Contents

Volume 1 Part I Supramolecular Assemblies Based on Crown Ethers and Cyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

1

Water-Soluble Aromatic Crown Ethers . . . . . . . . . . . . . . . . . . . . . Ling Chen and Yu Liu

3

2

Polypseudorotaxanes Constructed by Crown Ethers . . . . . . . . . . . Hong-Guang Fu, Yong Chen, and Yu Liu

27

3

Host-Guest Chemistry of a Tetracationic Cyclophane, Namely, Cyclobis (paraquat-p-phenylene) . . . . . . . . . . . . . . . . . . . . . . . . . . Hao Li, Tianyu Jiao, and Libo Shen

49

4

Mechanically Self-Locked Molecules . . . . . . . . . . . . . . . . . . . . . . . Sheng-Hua Li, Yong Chen, and Yu Liu

83

5

Photoluminescent Crown Ether Assembly . . . . . . . . . . . . . . . . . . . Yan Zhou, Bang-Tun Zhao, and Yu Liu

107

Part II Supramolecular Assemblies Based on Macrocyclic Arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

137

6

Triptycene-Derived Macrocyclic Arenes . . . . . . . . . . . . . . . . . . . . . Ying Han and Chuan-Feng Chen

7

Emerging Macrocyclic Arenes Related to Calixarenes and Pillararenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dihua Dai, Jia-Rui Wu, and Ying-Wei Yang

181

....

201

8

Supramolecular Medicine of Diverse Calixarene Derivatives Jie Gao and Dong-Sheng Guo

139

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9

10

Preparation of Biosensor Based on Supermolecular Recognization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jingjing Jiang, Xinyi Lin, and Guowang Diao

231

Application of Anion-π Interaction on Supramolecular Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . De-Xian Wang

253

11

Functional Rotaxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cai-Xin Zhao, Qi Zhang, Gábor London, and Da-Hui Qu

277

12

Biphen[n]arenes: Synthesis and Host–Guest Properties . . . . . . . . . Bin Li, Yiliang Wang, and Chunju Li

311

13

Pillararene-Based Supramolecular Polymer . . . . . . . . . . . . . . . . . . Xuan Wu, Yong Chen, and Yu Liu

341

Part III 14

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16

Supramolecular Assemblies Based on Cyclodextrins . . . . .

383

Functionalized Cyclodextrins and Their Applications in Biodelivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jiang Liu, Peng Yu, Matthieu Sollogoub, and Yongmin Zhang

385

Cyclodextrin Hybrid Inorganic Nanocomposites for Molecular Recognition, Selective Adsorption, and Drug Delivery . . . . . . . . . . Wenting Liang and Shaomin Shuang

425

Photoresponsive Supramolecular Polymers Based on Host-Guest Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fan Gu and Xiang Ma

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17

Cyclodextrin-Based Supramolecular Hydrogel Qian Zhao, Yong Chen, and Yu Liu

...............

483

18

Supramolecular Photochirogenesis with Cyclodextrin . . . . . . . . . . Jiabin Yao, Yoshihisa Inoue, and Cheng Yang

509

19

Construction and Applications of Cyclodextrin Polymers in Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yao-Hua Liu, Heng-Yi Zhang, and Yu Liu

537

Construction and Biomedical Application of Magnetic Supramolecular Assemblies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Qilin Yu, Yong Chen, Bing Zhang, Ying-Ming Zhang, and Yu Liu

559

Supramolecular Assembly Constructed from Multi-charged Cyclodextrin-Induced Aggregation . . . . . . . . . . . . . . . . . . . . . . . . . Pei-Yu Li, Yong Chen, and Yu Liu

573

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Contents

22

Cyclodextrins-Based Shape Memory Polymers and Self-Healing Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sheng Zhang, Shi-Lin Zeng, and Bang-Jing Li

Part IV 23

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Supramolecular Assemblies Based on Cucurbiturils . . . . .

Stimuli-Responsive Self-Assembly Based on Macrocyclic Hosts and Biomedical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Weipeng Mao and Da Ma Modulation of Chemical and Biological Properties of Biomedically Relevant Guest Molecules by Cucurbituril-Type Hosts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hang Yin, Ziyi Wang, and Ruibing Wang Self-Assembled Two-Dimensional Organic Layers in Solution Phase Based on Cucurbit[8]uril-Mediated Host-Guest Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Shu-Yan Jiang and Xin Zhao

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603

647

673

26

CB[n]-Based Coordination Chemistry . . . . . . . . . . . . . . . . . . . . . . Rui Han Gao and Zhu Tao

695

27

Biological Systems Involving Cucurbituril . . . . . . . . . . . . . . . . . . . Fengbo Liu and Simin Liu

731

28

Cucurbiturils-Based Pseudorotaxanes and Rotaxanes . . . . . . . . . . Zhi-Yuan Zhang, Yong Chen, and Yu Liu

759

29

Fabrications and Applications of Cucurbit[8]uril-Based Supramolecular Polymer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cai-Cai Zhang, Heng-Yi Zhang, and Yu Liu

787

Volume 2 Part V Supramolecular Assemblies Based on Other Macrocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Supramolecular Catalysis Using Organic Macrocycles . . . . . . . . . Qi-Qiang Wang

31

Constructions and Properties of Covalent Bonds Linked Porphyrin Arrays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ling Xu, Kaisheng Wang, and Jianxin Song

32

Protein Self-Assembly: Strategies and Applications . . . . . . . . . . . . Shanpeng Qiao and Junqiu Liu

827 829

877 915

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Contents

Covalent Connection Dictates Programmable Self-Assembly of Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Xinmou Wang, Shaofeng Lou, and Zhilin Yu

34

Naphthol-Based Macrocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Huan Yao and Wei Jiang

35

Construction of Glyco-nanostructures Through the Self-Assembly of Saccharide-Containing Macrocyclic Amphiphiles . . . . . . . . . . . Guang Yang and Guosong Chen

957 975

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36

In Vivo Self-Assembly of Polypeptide-Based Nanomaterials . . . . . 1023 Man-Di Wang, Yan-Qing Huang, and Hao Wang

37

Construction of Well-Defined Discrete Metallacycles and Their Biological Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045 Xu-Qing Wang, Xi Liu, Wei Wang, and Hai-Bo Yang

38

Fabrication and Application of Cyclodextrin-Porphyrin Supramolecular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073 Feng-Qing Li, Yong Chen, and Yu Liu

Part VI Some Important Approaches in Macrocycle-Based Supramolecular Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1105

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Molecular Simulations of Supramolecular Architectures . . . . . . . . 1107 Wensheng Cai and Haohao Fu

40

Thermodynamic Studies of Supramolecular Systems Nan Li and Yu Liu

41

Spectroscopy Studies of Macrocyclic Supramolecular Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1161 Zixin Yang, Hao Tang, and Yu Liu

42

Artificial Host Molecules Modifying Biomacromolecules . . . . . . . . 1195 Tian-Guang Zhan and Kang-Da Zhang

43

Controllable Synthesis of Polynuclear Metal Clusters Within Macrocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1223 Siqi Zhang and Liang Zhao

44

Molecular Recognition with Helical Receptors . . . . . . . . . . . . . . . . 1253 Dan-Wei Zhang, Hui Wang, and Zhan-Ting Li

45

Supramolecular Interface for Biochemical Sensing Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1277 Xu Yan, Wenwei Pan, Hemi Qu, and Xuexin Duan

. . . . . . . . . . 1135

Contents

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Supramolecular Functional Complexes Constructed by Orthogonal Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317 Tangxin Xiao, Xiao-Qiang Sun, and Leyong Wang

47

Application of Macrocycle-Based Supramolecular Assemblies Based on Aggregation-Induced Emission . . . . . . . . . . . . . . . . . . . . 1345 Jing-Jing Li, Yong Chen, Heng-Yi Zhang, Xianyin Dai, and Yu Liu

48

Construction and Application of Lanthanide Luminescent Materials Based on Macrocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . 1369 Weilei Zhou, Yong Chen, Lei Chen, and Yu Liu

49

Supramolecular 2D Nanostructures Mediated by Macrocyclic Host: Cyclodextrin, Cucurbituril, and Pillararene . . . . . . . . . . . . . 1393 Ni Cheng and Yu Liu

Part VII

Biological Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1411

50

Responsive Supramolecular Vesicles Based on Host-Guest Recognition for Biomedical Applications . . . . . . . . . . . . . . . . . . . . 1413 Mingfang Ma, Pengyao Xing, and Yanli Zhao

51

Host-Guest Sensing by Nanopores and Nanochannels . . . . . . . . . . 1439 Siyun Zhang and Haibing Li

52

Drug/Gene Delivery Platform Based on Supramolecular Interactions: Hyaluronic Acid and Folic Acid as Targeting Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1465 Yang Yang

53

Self-Assembling Peptides for Vaccine Development and Antibody Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1497 Zhongyan Wang, Youzhi Wang, Jie Gao, Yang Shi, and Zhimou Yang

54

Macrocycle-Based Synthetic Ion Channels . . . . . . . . . . . . . . . . . . . 1519 Harekrushna Behera and Jun-Li Hou

55

Construction and Biomedical Applications of MacrocycleBased Supramolecular Topological Polymers . . . . . . . . . . . . . . . . . 1555 Wenzhuo Chen, Chengfei Liu, Xin Song, Xuedong Xiao, Shuai Qiu, and Wei Tian

56

Supermolecules as Medicinal Drugs . . . . . . . . . . . . . . . . . . . . . . . . 1587 Cheng-He Zhou and Yan-Fei Sui

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57

Nanoscaled Cyclodextrin Supermolecular System for Drug and Gene Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1635 Xianyin Dai, Yong Chen, and Yu Liu

58

Immunity Regulation by Supramolecular Assemblies . . . . . . . . . . 1655 Qilin Yu, Yong Chen, Bing Zhang, Nali Zhu, Hangqi Zhu, Henan Wei, and Yu Liu

59

Industrial Applications of Cyclodextrins Qian Wang

. . . . . . . . . . . . . . . . . . . . 1665

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1699

About the Editors

Yu Liu is a professor at Nankai University. He received his Ph.D. from Himeji Institute of Technology, Japan, in 1991. Then, he spent about 2 years (1991–1992) as postdoctoral fellow at Lanzhou Institute of Chemical Physics. In 1993, he moved to Nankai University as a professor and got the special government allowances of the State Council. Prof. Liu obtained the support of National Outstanding Youth Fund in 1996 and is now the specially appointed professor of Cheung Kong Scholars Programme. He has made a great deal of contribution to the supramolecular chemistry of crown ether, cyclodextrin, and calixarene, and is the contributor of 8 books and more than 500 articles (h-index: 61). Prof. Liu won a Second Class Award of Natural Science from Chinese Academy of Science in 1990; a Second Class Award of Scientific and Technological Progress from Ministry of Education in 1998; three times First Class Award of Natural Science of Tianjin in 2000, 2005, and 2015; a Second Class Award of State Natural Science Prize in 2010, and a Special Grade Award of Baogang Outstanding Teacher in 2003. Yong Chen obtained his Ph.D. degree in 2001 from Nankai University (China), majoring in physical organic chemistry. From 2002 to 2003, he was an assistant professor at the Institute of Chemistry, Chinese Academy of Science. Subsequently, Prof. Chen went to Ecole Normale Superieure (ENS, France) as a post-doctor in 2002 via invitation from National Scientific Research Center of France (CNRS). At the end of 2003, he joined the Supramolecular Chemistry Laboratory of Nankai University as an associate professor and became a xv

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About the Editors

professor in 2009. Prof. Chen’s research interests are mainly focused on supramolecular chemistry of cyclodextrins and cucurbiturils. Heng-Yi Zhang born in Anhui Province of China, in 1965, is a professor of Nankai University (Tianjin, China). He received his M.S. degree from Anshan Research Institute of Thermal Energy in 1994 and his Ph.D. from Nankai University in 2000. In the same year, he became a lecturer of Nankai University and a professor in 2005. His current research interests focus on molecular recognition and molecular assembly based on the macrocyclic compounds including crown ether, cyclodextrin, and cucurbituril. Prof. Zhang is the contributor of 4 books and more than 130 research papers. In addition, He won one Second Class Award of State Natural Science Prize in 2010, two First Class Award of Natural Science Prize by Tianjin in 2005 and 2015, and one Second Class Award of Natural Science Prize by Ministry of Education in 2002.

Contributors

Harekrushna Behera Department of Chemistry, Fudan University, Shanghai, China Wensheng Cai Research Center for Analytical Sciences, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China Chuan-Feng Chen Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China Guosong Chen The State Key Laboratory of Molecular Engineering of Polymers and Department of Macromolecular Science, Fudan University, Shanghai, China Lei Chen College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China Ling Chen College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, China Wenzhuo Chen MOE Key Laboratory of Material Physics and Chemistry under Extraordinary Conditions, Shanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi’an, China Yong Chen College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China Ni Cheng College of Pharmacy, Weifang Medical University, Weifang, China xvii

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Contributors

Dihua Dai State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), College of Chemistry, Jilin University, Changchun, China Xianyin Dai College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China Guowang Diao School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu, China Xuexin Duan Tianjin University, Tianjin, China Haohao Fu Research Center for Analytical Sciences, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China Hong-Guang Fu College of Chemistry, State Key Laboratory of ElementoOrganic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China Jie Gao State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, China College of Chemistry, Key Laboratory of Functional Polymer Materials (Ministry of Education), State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Rui Han Gao Key Laboratory of Macrocyclic and Supramolecular Chemistry of Guizhou Province, Guizhou University, Guiyang, China Fan Gu Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, China Dong-Sheng Guo College of Chemistry, Key Laboratory of Functional Polymer Materials (Ministry of Education), State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Ying Han Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China

Contributors

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Jun-Li Hou Department of Chemistry, Fudan University, Shanghai, China Yan-Qing Huang Beijing Academy, Beijing, China Yoshihisa Inoue Osaka University, Suita, Japan Jingjing Jiang School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu, China Shu-Yan Jiang Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China Wei Jiang Department of Chemistry, Southern University of Science and Technology, Shenzhen, China Tianyu Jiao Department of Chemistry, Zhejiang University, Hangzhou, China Bang-Jing Li Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China Bin Li Key Laboratory of Inorganic-Organic Hybrid Functional Material Chemistry, Ministry of Education, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, College of Chemistry, Tianjin Normal University, Tianjin, China Center for Supramolecular Chemistry and Catalysis, Department of Chemistry, Shanghai University, Shanghai, China Chunju Li Key Laboratory of Inorganic-Organic Hybrid Functional Material Chemistry, Ministry of Education, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, College of Chemistry, Tianjin Normal University, Tianjin, China Center for Supramolecular Chemistry and Catalysis, Department of Chemistry, Shanghai University, Shanghai, China Feng-Qing Li College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China Haibing Li Key Laboratory of Pesticide and Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, China Hao Li Department of Chemistry, Zhejiang University, Hangzhou, China Jing-Jing Li College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Nan Li School of Textile Science and Engineering, State Key Laboratory of Separation Membranes and Membrane Processes, Tianjin Polytechnic University, Tianjin, China

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Contributors

Pei-Yu Li College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China Sheng-Hua Li College of Chemical Engineering and Materials Science, Tianjin University of Science and Technology, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, China Zhan-Ting Li Department of Chemistry, Fudan University, Shanghai, China Wenting Liang Shanxi University, Taiyuan, China Xinyi Lin School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu, China Chengfei Liu MOE Key Laboratory of Material Physics and Chemistry under Extraordinary Conditions, Shanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi’an, China Fengbo Liu The State Key Laboratory of Refractories and Metallurgy, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, China Jiang Liu Centre National de la Recherche Scientifique (CNRS), Institut Parisien de Chimie Moléculaire (IPCM), Unité Mixte de Recherche (UMR) 8232, Sorbonne Université, Paris, France Junqiu Liu Department of Chemistry, Jilin University, Changchun, China Simin Liu The State Key Laboratory of Refractories and Metallurgy, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, China Xi Liu School of Chemistry and Molecular Engineering, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University, Shanghai, China Yao-Hua Liu College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Yu Liu College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China Gábor London Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok kürútja 2., Budapest 1117, Hungary

Contributors

xxi

Shaofeng Lou Key Laboratory of Functional Polymer Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, China Da Ma Department of Chemistry, Fudan University, Shanghai, China Mingfang Ma Key Laboratory of Colloid and Interface Chemistry of Ministry of Education and School of Chemistry and Chemical Engineering, Shandong University, Jinan, China Laboratory of New Antitumor Drug Molecular Design and Synthesis of Jining Medical University, College of Basic Medicine, Jining Medical University, Jining, China Xiang Ma Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, China Weipeng Mao Department of Chemistry, Fudan University, Shanghai, China Wenwei Pan Tianjin University, Tianjin, China Shanpeng Qiao Department of Chemistry, Jilin University, Changchun, China Shuai Qiu MOE Key Laboratory of Material Physics and Chemistry under Extraordinary Conditions, Shanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi’an, China Da-Hui Qu Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai, China Hemi Qu Tianjin University, Tianjin, China Libo Shen Department of Chemistry, Zhejiang University, Hangzhou, China Yang Shi State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, China Shaomin Shuang Shanxi University, Taiyuan, China Matthieu Sollogoub Centre National de la Recherche Scientifique (CNRS), Institut Parisien de Chimie Moléculaire (IPCM), Unité Mixte de Recherche (UMR) 8232, Sorbonne Université, Paris, France Jianxin Song Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province, Hunan Normal University, Changsha, China Xin Song MOE Key Laboratory of Material Physics and Chemistry under Extraordinary Conditions, Shanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi’an, China

xxii

Contributors

Yan-Fei Sui Institute of Bioorganic and Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, China Xiao-Qiang Sun Jiangsu Province Key Laboratory of Fine Petrochemical Engineering, School of Petrochemical Engineering, Changzhou University, Changzhou, China Hao Tang School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, China Zhu Tao Key Laboratory of Macrocyclic and Supramolecular Chemistry of Guizhou Province, Guizhou University, Guiyang, China Wei Tian MOE Key Laboratory of Material Physics and Chemistry under Extraordinary Conditions, Shanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi’an, China De-Xian Wang Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China Hao Wang CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, China University of Chinese Academy of Sciences (UCAS), Beijing, China Hui Wang Department of Chemistry, Fudan University, Shanghai, China Kaisheng Wang Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province, Hunan Normal University, Changsha, China Leyong Wang Jiangsu Province Key Laboratory of Fine Petrochemical Engineering, School of Petrochemical Engineering, Changzhou University, Changzhou, China Key Laboratory of Mesoscopic Chemistry of MOE, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China Man-Di Wang CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, China University of Chinese Academy of Sciences (UCAS), Beijing, China Qi-Qiang Wang Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China

Contributors

xxiii

Qian Wang School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, China Ruibing Wang State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China Wei Wang School of Chemistry and Molecular Engineering, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University, Shanghai, China Xinmou Wang Key Laboratory of Functional Polymer Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, China Xu-Qing Wang School of Chemistry and Molecular Engineering, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University, Shanghai, China Yiliang Wang Center for Supramolecular Chemistry and Catalysis, Department of Chemistry, Shanghai University, Shanghai, China Youzhi Wang State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, China Zhongyan Wang State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, China Ziyi Wang State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China Henan Wei Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, China Jia-Rui Wu State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), College of Chemistry, Jilin University, Changchun, China Xuan Wu College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Tangxin Xiao Jiangsu Province Key Laboratory of Fine Petrochemical Engineering, School of Petrochemical Engineering, Changzhou University, Changzhou, China

xxiv

Contributors

Xuedong Xiao MOE Key Laboratory of Material Physics and Chemistry under Extraordinary Conditions, Shanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi’an, China Pengyao Xing Key Laboratory of Colloid and Interface Chemistry of Ministry of Education and School of Chemistry and Chemical Engineering, Shandong University, Jinan, China Ling Xu Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province, Hunan Normal University, Changsha, China Xu Yan Tianjin University, Tianjin, China Cheng Yang Sichuan University, Chengdu, China Guang Yang The State Key Laboratory of Molecular Engineering of Polymers and Department of Macromolecular Science, Fudan University, Shanghai, China Hai-Bo Yang School of Chemistry and Molecular Engineering, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University, Shanghai, China Yang Yang School of Chemical Engineering and Technology, Hebei University of Technology, Tianjin, China Ying-Wei Yang State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), College of Chemistry, Jilin University, Changchun, China Zhimou Yang State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, China Zixin Yang College of Science, Huazhong Agricultural University, Wuhan, China Huan Yao Department of Chemistry, Southern University of Science and Technology, Shenzhen, China Jiabin Yao Sichuan University, Chengdu, China Hang Yin State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China Peng Yu China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China Qilin Yu Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, China

Contributors

xxv

Zhilin Yu Key Laboratory of Functional Polymer Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, China Shi-Lin Zeng Sichuan University, Chengdu, China Tian-Guang Zhan College of Chemistry and Life Science, Zhejiang Normal University, Jinhua, China Bing Zhang College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Cai-Cai Zhang College of Chemistry and Materials Science, Hebei Key Laboratory of Organic Functional Molecules, Hebei Normal University, Shijiazhuang, China Dan-Wei Zhang Department of Chemistry, Fudan University, Shanghai, China Heng-Yi Zhang College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China Kang-Da Zhang College of Chemistry and Life Science, Zhejiang Normal University, Jinhua, China Qi Zhang Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai, China Siqi Zhang Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, China Sheng Zhang Sichuan University, Chengdu, China Siyun Zhang Key Laboratory of Pesticide and Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, China Ying-Ming Zhang College of Chemistry, State Key Laboratory of ElementoOrganic Chemistry, Nankai University, Tianjin, China Yongmin Zhang Centre National de la Recherche Scientifique (CNRS), Institut Parisien de Chimie Moléculaire (IPCM), Unité Mixte de Recherche (UMR) 8232, Sorbonne Université, Paris, France China International Science and Technology Cooperation Base of Food Nutrition/ Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China Zhi-Yuan Zhang College of Chemistry, State Key Laboratory of ElementoOrganic Chemistry, Nankai University, Tianjin, China

xxvi

Contributors

Bang-Tun Zhao College of Chemistry and Chemical Engineering, and Henan Key Laboratory of Function-Oriented Porous Materials, Luoyang Normal University, Luoyang, China Cai-Xin Zhao Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai, China Liang Zhao Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, China Qian Zhao College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China Xin Zhao Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China Yanli Zhao Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore School of Materials Science and Engineering, Nanyang Technological University, Singapore, Singapore Cheng-He Zhou Institute of Bioorganic and Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, China Weilei Zhou College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China College of Chemistry and Chemical Engineering, Inner Mongolia University for the Nationalities (IMUN), Tongliao, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China Yan Zhou College of Chemistry and Chemical Engineering, and Henan Key Laboratory of Function-Oriented Porous Materials, Luoyang Normal University, Luoyang, China College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China

Contributors

xxvii

Hangqi Zhu Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, China Nali Zhu Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, China

Part I Supramolecular Assemblies Based on Crown Ethers and Cyclophanes

1

Water-Soluble Aromatic Crown Ethers From Molecular Recognition to Molecular Assembly Ling Chen and Yu Liu

Contents 1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 The Binding Behaviors of Crown Ethers in Aqueous Solution . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3 Sulfonated Aromatic Crown Ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4 Carboxylated Aromatic Crown Ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5 Molecular Assembly Based on Water-Soluble Aromatic Crown Ethers . . . . . . . . . . . . . . . . . . 1.6 Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.1

3 5 6 15 18 24 24

Introduction

After the serendipitous discovery by Pedersen [1], crown ethers have been widely applied as brine separators, phase-transfer catalysts [2], and chiral sensors [3]. The simplest crown ethers are heterocycles with cyclic oligomers of ethyleneoxy. Although dioxane is compliant to this definition, it is not realized as a crown ether due to small cavity. The other crown ethers with simple chemical formula of (–CH2CH2O–)n in which n
3 are soluble in both water and organic solvents, they can bind small guests containing metal ions,

L. Chen College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, China Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_2

3

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L. Chen and Y. Liu

ammoniums, and diazonium [4]. To broaden the range of molecular recognition of crown ethers, lots of crown ethers with aromatic backbones have been developed which can associate with π-electron-poor guests like organic ammonium [5], pyridinium [6], pyromellitic diimide [7], and naphthalene diimide with the aid of π-stacking interaction [8]. During the past three decades, a lot of supramolecular architecture based on molecular recognition of aromatic crown ethers has been developed [9]. Almost all the neutral aromatic crown ethers are insoluble in aqueous environment. To increase the solubility in aqueous solution, a common method is introducing negatively charged groups to the aromatic backbone of crown ethers. To date, different synthetic strategies have been developed by many research groups to synthesize negatively charged crown ethers with versatile guest binding ability (Fig. 1). Many different recognition motifs, which are based on crown ethers with electrostatic interactions, have been reported, and their properties and molecular assembly have been studied extensively. All these efforts have resulted in a collection of host-guest pairs, thus providing a valuable resource for their design and application in molecular assembly. In the following section, we are going to summarize the related investigations concerned on the binding properties and structures of water-soluble crown ethers, which will be applied in a more extensive area in chemistry and material.

O

O

n

O

O

O

O

n n = 0, 1

O

O

Negatively charged aromatic crown ethers

SO3

O

SO3

O O3S O

O

O

CO2

O

CO2

O

O

SO3

O

O

SO3 O

O O2C O

O

SO3

CO2

CO2 O

O2C

O

Fig. 1 Some of the most commonly used building blocks in water-soluble aromatic crown ethers

1

Water-Soluble Aromatic Crown Ethers

1.2

5

The Binding Behaviors of Crown Ethers in Aqueous Solution

The molecular recognition and binding behaviors of crown ethers are highly dependent on the solvent environment. One of the most common crown ethers, 18-crown-6, has a value of exactly zero for the partition of solutes between higher alcohols and water, indicating an ideal balance between hydrophilicity of oxygen atoms and lipophilicity of ethylidene. However, the binding strengths of 18-crown-6 vary from a low level of 1  102 M1 to a high one of 1  106 M1 in different solvents (see Table 1). A comparison of the X-ray crystal structures between free 18-crown-6 and its K+ complex reveals that in K+ complex, all the oxygen atoms are directed inward to generate an entirely hydrophobic exterior and an electronegative cavity [10]. In contrast, in crystal structure of free 18-crown-6, partial oxygen atoms are directed outward [11]. It has been widely known that crown ethers such as 18-crown-6 are flexible enough to change its molecular conformation in various solvents, allowing

Table 1 A comparison of binding behaviors and noncovalent interaction for 18-crown-6 and several aromatic crown ethers Guests K+ K+ K+ NH4+

Solvent MeCN MeOH H2O MeOH

Binding constants (M1) 5.2  105 1.1  106 1.1  102 1.8  104

NH4+

H2O

17

CH3NH3+

MeOH

1.7  104

bis-pphenylene -34-crown10 H2 a

G8a

MeCN

2.4  102

G9a

H2O

7.0  102

H6 a

G9a

H2O

7.0  102

Host 18-crown-6

a

Noncovalent interaction Ion-dipole interaction Ion-dipole interaction Ion-dipole interaction N–H  O Strong hydrogen bond Ion-dipole interaction N–H  O Strong hydrogen bond Ion-dipole interaction N–H  O Strong hydrogen bond Ion-dipole interaction π-Stacking C–H  O Weak hydrogen bond Ion-dipole interaction Electrostatic attraction πstacking C–H  O Weak hydrogen bond Ion-dipole interaction Electrostatic attraction πstacking C–H  O Weak hydrogen bond Ion-dipole interaction

The molecular structure of H2, H6, G8, and G9 is present in the following section

Ref. [12] [13] [14] [15]

[16]

[15]

[17]

[18]

[18]

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L. Chen and Y. Liu

H

H

H

H

H

H

H H O H

H H O

H

H

conformational readjustment

O

H

H

H

H

O

(a)

H

H

H

K+

O

H H

H O

O

H H

H

H

O O

H H

O H

H H H

H H

H H

H H

H H H

H

H H

O H

H

O

H

H H

(b)

H

O O

O

H

K+

H

H O

O

H H

H H

O H

H H H

H H

(c)

Fig. 2 Conformation of 18-crown-6 in (a) aqueous solution, (b) organic solution, and (c) bound state with K+

them to present a conformation of lipophilic ethylene outside and hydrophilic oxygen atoms inside in organic solution or hydrophilic oxygen atoms outside and lipophilic ethylene inside in aqueous solution (Fig. 2). In aqueous solution 18-crown-6 has to undergo remarkable conformational readjustment to arrange oxygen atoms inward which is in the fashion most complementary to guests. This process consumes extra energy and lowers the binding strength of guests, which is ubiquitous for all aliphatic crown ethers and aromatic crown ethers in aqueous solution. Water-soluble aromatic crown ethers could be essentially realized as the ethylene glycol chains extended by negatively charged aromatic groups. While the hosts are complexation with π-electron-poor guests, the main noncovalent interactions involved in the association are electrostatic attraction, π-stacking, hydrogen bond, and dipole-dipole interaction. The hydrogen bond and dipole-dipole interaction mainly occur between ethylene glycol chains and cationic guests, as well as 18crown-6. Thus, the ethylene glycol chains on water-soluble crown ethers should show similar behaviors like 18-crown-6 in aqueous solution. The association constant of NH4+  18-crown-6 is only 17 M1 in aqueous solution; thus it is reasonable to declare that the hydrogen bond and dipole-dipole interaction contributed far smaller than a value of 17 M1. The other factors containing electrostatic attraction and π-stacking play the dominant role in the binding process. A large collection of cationic guests have been reported by several groups. To generate strong electrostatic attraction and π-stacking with water-soluble crown ethers, the complementary guest should be π-electron-poor aromatic cations. Some of the most common cationic guests, containing pyridiniums, bipyridinium, phenanthroliium, 2,7-dimethyldiazapyrenium, pyromellitic diimide, naphthalene diimide, NAD+, and stilbazolium dye, are listed in Fig. 3.

1.3

Sulfonated Aromatic Crown Ethers

Back in 1997, Shigeo et al. discovered that, by reacting sulfuric acid with benzocrown ethers in acetonitrile, monosulfonated benzo-12-crown-4, benzo-15-crown-5, benzo-18-crown-6 were obtained in good yields (Fig. 4) [19]. These sulfonated

1

Water-Soluble Aromatic Crown Ethers

7

EtOOC N

N

N

N

COOEt

N

N

N

EtOOC

N

N

N

COOEt

G1

G3

G2

N

COO

N N

N

N

HOOC

G7

G6

G5

N

N

N

N

N

N

n

n = 0, G8 n = 1, G9 n = 3, G10

N

N

N

OOC

N n

COOH

N

N

N

N

G4

G12

G11

N

N

N

G14

G13

NH2

O O

O

O

N

N

N

N

N

O

G15

O

N O

O

G16

G17

N N

G19

N

N N

N

O

G18

N

S n

N

G22

G21

G20

N

OHOH

OHOH

N

O

O P O P O OH O

S

N N

N

N

NH2

N

O

O

O N

N

N

n = 1, G23 n = 2, G24

O OH HN O NH N

O

N

G25

Fig. 3 The structure of most common guests that associate with water-soluble aromatic crown ethers

O O3S

O

O

O

O

O3S m

O

n O O

O

SO3

O n

m = 1, 2, 3

n = 1, 2

Fig. 4 Molecular structures of sulfonated benzo-crown ethers synthesized by Shigeo et al.

crown ethers showed moderate binding strengths toward alkali earth metal ions and lanthanide ions. This is acceptable because alkali earth metal ions and lanthanide ions have two or three positive charges, which are favorable to form electrostatic attraction to increase the binding strength. Shigeo et al. even synthesized disulfonated dibenzo-18-crown-6 and dibenzo-24-crown-8, but they never investigated the host-guest interactions between sulfonated crown ethers and π-electronpoor organic cations, which is achieved by Loeb et al. 10 years later.

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Different from sulfonated crown ethers with small cavity that can only bind small inorganic cations, sulfonated crown ethers with more than 20-membered rings are suitable to bind a variety of organic cations like pyridiniums (Fig. 5). In 2008 Loeb et al. and Nikitin et al. reported the synthesis and molecular recognition of antidisulfonated dibenzo 24-crown-8 (H1) and anti-disulfonated bis-p-phenylene-34crown-10 (H2), respectively (Table 2) [18, 20]. Loeb et al. have succeeded in synthesis of pseudorotaxane and rotaxane based on 1,2-bis(pyridinium)ethane axles and dibenzo-24-crown-8 wheels, in which the host and guests interact with each other through noncovalent forces: π-stacking, C–H  O hydrogen bond, and ion-dipole interactions [21]. In 2008, Loeb et al. reported such type of [2]pseudorotaxanes assembled in aqueous solution by introducing two sulfonate groups to the dibenzo[24]crown-8 wheels. The two negatively charged sulfonate groups allow the [2]pseudorotaxanes to be stabilized by additional electrostatic attraction. Association constants of the host-guest complexes are relatively high in less polar solvents as methanol (Ka > 105 M1). Binding is also sufficiently strong in less polar solvent such as CD3OD. In aqueous solution, the association constant is determined to be ranging from a low level of 1  102 M1 (G4  H1) to a high level of 2.3  103 M1 (G5  H1) depending on the substituent groups on

O O

O O3S

O

O

O

O

O

O

O3S

O

O

O

O

SO3 O

SO3

O

O

O O

H1

H2

Fig. 5 Molecular structures of H1 and H2 Table 2 Association constants for intermolecular complexation of H1 and H2 Hosts H1

H2

Guests G2 G3 G4 G5 G6 G7 G9

Ka (M1) 2.0  102 3.0  102 1.0  102 2.3  103 1.2  103 1.3  103 7.0  102

Ref. [18]

[35] [20]

1

Water-Soluble Aromatic Crown Ethers

9

axles. They reported the X-ray crystal structures of the host-guest complexes of G2  H1 and G3  H1 (Fig. 6), as can be seen in Fig. 5. Both crystal structure of G2  H1 and G3  H1 have 8 C–H  O hydrogen bonds (dH  O < 2.8 Å) as the complexes with neutral dibenzo-24-crown-8. The authors declared that the array of C–H  O hydrogen bonds and N+  O iondipole and p-stacking interactions that are normally identified as important driving forces do not sustain an interpenetrated geometry in a very polar solvent such as water, owing to the highly competitive water molecules. Instead, in π-stacking and electrostatic attraction, especially when the guest G5 with four positive charges is bound by H2, the associate constant of G5  H1 is 11 times larger than that of G2  H1. At the same time in 2008, Nikitin et al. reported another disulfonated benzocrown ether H2 by reacting bis-p-phenylene-34-crown-10 with chlorosulfonic acid (Fig. 7). In crystal structure of G9  H2, the bipyridinium plane of G9 stacks with two p-phenylene units with interplanar distance of 3.5 Å, indicating the existence of π-stacking interaction. Although the recognition motif of cations/disulfonated crown ethers has been successful in aqueous solution, its low binding strength is still worthy to be

Fig. 6 Crystal structures for intermolecular complexes of G2  H1 and G3  H1 Fig. 7 Crystal structures for intermolecular complex of G9  H2

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L. Chen and Y. Liu

improved. Consequently, introducing more sulfonate groups to the aromatic skeleton of benzo-crown ethers is an ideal strategy to this approach, in which stronger electrostatic attraction is generated. Unlike the o- and p-diaryoxy benzene that can react with only one sulfonato reagent, 1,3-diaryoxy benzene has better orientation-directed effect for sulfonation, so it can easily react with two sulfonato reagents on 4,6-position to obtain 1,3-diaryoxy-4,6-disulfonic acid [22]. Thus, Liu et al. reported the tetrasulfonated bis(m-phenylene)-26-crown-8 which was prepared by the simple reaction of bis(m-phenylene)-26-crown-8 with chlorosulfonic acid (Fig. 8) [23]. They investigated the binding behaviors and thermodynamic parameters for the host-guest complexation of G1  H3 and G8  H3 by method of isothermal titration calorimetry (ITC) measurements (Table 3). In the case of G1  H3, the binding process is mainly contributed by positive entropy change. In another case of G8  H3, the binding process is governed by both negative enthalpy and positive entropy changes. The distinct thermodynamic nature of the two complexes reveals they should have different binding modes. Crystal structures of G1  H3 and G8  H3 (Fig. 9) give direct evidence for their different binding behaviors. Due to the intensive positive charges of G1, in crystal structure of G1  H3, the guest G1 is located outside the cavity of H3 and is in close contact with the sulfonate groups to form more exclusive electrostatic attraction. On the other hand, the guest G8 interpenetrated through the cavity to form π-stacking, hydrogen bonds, and electrostatic attraction with H1, which is attributed to the πelectron-poor aspect of G8. Although the tetrasulfonated crown ether H3 is a successful water-soluble aromatic crown ether, its weak binding ability indicates that it is still possible to improve its molecular structure to enhance the binding strength toward cationic guests. In this context, Liu et al. synthesized two tetrasulfonated naphtho-crown ethers, which are named tetrasulfonated 1,5-dinaphtho-38-crown-10 (H4) and tetrasulfonated 1,5dinaphtho-32-crown-8 (H5) (Fig. 10) [24]. Possessing more extended π-electronFig. 8 Molecular structure of tetrasulfonated crown ether H3

O3S

O

O

O

O

SO3

O3S

O

O

O

O

SO3

H3 Table 3 Association constants (Ka, M1), enthalpy change (ΔH , kJ/mol), and entropy change (TΔS , kJ/mol) for intermolecular complexation of H3 Hosts H3

Guests G1 G8

lgKa 2.4  102 1.8 103

ΔH 3.03 10.18

TΔS 11.46 7.80

Ref. [23]

1

Water-Soluble Aromatic Crown Ethers

11

Fig. 9 Crystal structures for intermolecular complexes of (a) G1  H3 and (b) G8  H3

O O O

O

SO3

O O

SO3 O

SO3

SO3 O O

O

O O

SO3

SO3 O

O

SO3

SO3 O O

O

O

H4

H5

Fig. 10 Molecular structure of tetrasulfonated crown ethers H4 and H5

rich conjugation and additional anchoring points offered by ethylene glycol chains and sulfonate groups, H4 and H5 display especially high binding strength and molecular selectivity for given organic cations, which originates mainly from the cooperation of π-stacking and electrostatic attractions. Up to now, more than 18 kinds of organic cations have been investigated in the complexation with H4 or H5. Table 4 lists their Ka values and enthalpy and entropy changes for these host-guest complexation. In 2012, Liu et al. studied the highly affinitive complexation of bipyridinium (G8–G10) and monopyridinium ions (G17) with H4 and H5 in aqueous solution by ITC experiments [24]. The thermodynamic parameters clearly indicate that the complexation of H4 with the four guests was mainly driven by the negative enthalpy changes accompanied by a little entropic gain. Although the lengths of flexible alkyl group on G8–G10 are different from each other, it shows little influence to the

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Table 4 Association constants (Ka, M1), enthalpy change (-ΔH , kJ/mol), and entropy change (TΔS , kJ/mol) for intermolecular complexation of H4 and H5 Hosts H4

H5

Guests G8 G9 G10 G11 G12 G13 G14 G15 G16 G17 G8 G9 G10 G15 G16 G17 G18 G19 G20 G21 G22 G23 G24 G25

Ka 3.2  105 1.8  105 1.9  105 7.1  105 2.5  106 1.1  108 2.2  108 8.1  104 2.3  106 4.2  102 4.0  107 5.2  107 4.7  107 5.8  105 9.8  105 1.1  105 2.2  103 8.1  105 1.6  106 2.8  106 1.8  106 4.9  106 4.3  106 7.9  106

-ΔH 30.13 27.20 27.27 30.99 29.80 47.84 40.06 20.59 36.31 14.71 38.93 41.54 43.92 24.85 23.17 29.23 67.90 39.37 40.54 35.47 41.42 33.38 41.39 –

TΔS 1.33 2.86 2.83 2.54 6.84 1.96 1.87 7.40 0.01 0.38 4.47 2.50 0.17 8.05 11.01 0.39 48.87 5.65 5.08 1.34 5.89 4.82 3.54 –

Ref. [24]

[25]

[26] [24] [24]

[26] [24] [27]

[28]

association constants. Crystal structures show that the positively charged bipyridinium units are located nearby the negatively charged sulfonate groups of H4 and stacked with naphthalene planes (Fig. 11). The flexible glycol chains do not play a major role in the association progress, only few weak C–H  O (d H  O > 2.5 Å) hydrogen bonds are found in a typical complexation crystal structure like G9  H4. For the case of G17  H4 the association constant is really small due to the single charge and lack of π-conjugation size. Therefore, the binding process between H4 and pyridinium guests should be governed by electrostatic attraction and π-stacking. For the complexation of H5, the Ka values are obviously different from that of H4. Both bipyridinium and monopyridinium guests form more stable of two orders of magnitude complex with H5 than that of H4, which is accompanied by even more negative enthalpy change. The dominant enthalpy changes are mainly contributed by the π-stacking and electrostatic interactions, and the favorable (or slightly unfavorable) entropy changes generally originate from the positive contribution of desolvation effect accompanied by π-stacking and electrostatic contact as well as the slight positive entropy change for H4 complexes. The entropy change slightly decreases upon increasing the N-substituted aryl chain length on guests, in

1

Water-Soluble Aromatic Crown Ethers

13

Fig. 11 Crystal structures for intermolecular complexes of (a) G9  H4 and (b) G8  H5

which the long-chain guests lose more conformational freedom in complexation. Although entropy contribution in binding process of H4 makes little difference as H5, the higher association constants of H5 are mainly governed by inner repulsion in the cavity of H5. Although there are flexible triethylene glycol chains in H5, the four sulfonate groups in small cavity produce considerable inner charge repulsion to preorganize the flexible crown ethers in a certain degree, resulting in a favorable negative π-acceptant cavity. In this context, H5 is a specific host compared with the other sulfonated crown ethers (H1–H4). In addition, it should be mentioned that in solid state only one pyridinium unit interpenetrates into the cavity of H5, indicating that the small cavity of H5 tends to accommodate only one pyridinium group. This could explain why the singly charged G17 can form five orders of magnitude complex with H5. A surprising detail revealed by crystal structures is all the sulfonate groups are located on 4- and 8-position despite the strong steric hindrance from alkoxy on 1- and 5-position. The steric hindrance generates huge inner repulsion which distorts the naphthalene rings. Such sterically disadvantaged sulfonation positions indicate that the reactivity of 4- and 8-position is higher than 2- and 6-position in naphthalene ring. On the other hand, the inner repulsion compels the alkoxy groups keeping away from the sulfonate groups, which rigidifies H4 and H5 in some extent. Although sulfonated crown ethers prefer to bind guests containing pyridinium groups, it is not the crucial factor. In 2013 Liu et al. studied two nonpyridinium guests consisted by ammonium, pyromellitic diimide (G15) and naphthalene diimide (G16) (Fig. 12) [26]. ITC experiments were performed in aqueous solution to obtain Ka values and thermodynamic parameters for the inclusion complexation of H4 and H5 with G15 and G16. It was found that the complexation was well in accordance with the 1:1 binding stoichiometry, which is mainly enthalpy-stabilized. Unlike the low entropy change in complexation of bipyridinium guests (G8–G10), entropy change played important role in complexation of G15 and G16 with H4 and H5. Size-fit relationship is another important factor affecting the binding strength of G15 and G16. Pyromellitic diimide guest of G15 with smaller molecular size prefers to form eight times more stable complex with H5 than H4, and naphthalene diimide

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Fig. 12 Crystal structures for intermolecular complexes of (a) G15  H4 and (b) G16  H42K+

guest of G16 with larger molecular size prefers to form three times more stable complex with H4 than H5. Both guest selectivity and host selectivity are observed due to size-fit relationship. This selectivity was adopted to construct a specific binding system containing four host-guest components. The mixture containing equivalent molar of H4, H5, G9, and G16 in D2O solution shows only resonances corresponding to G9  H5 and G16  H4; no resonances of G9  H4 and G16  H5 were observed, which were also proven by high resolution mass spectrometer. 2,7-Dimethyldiazapyrenium (G13) is an important π-electron-poor cation, which has four more π-conjugation electrons than bipyridinium guests. Stoddart et al. firstly investigated interactions of G13 and 2,7-dibenzyldiazapyrenium (G14) with unsulfonated 1,5-dinaphtho-38-crown-10 in organic solution [29]. They found that G13 and G14 formed stoichiometric 1:1 complexes with Ka values ranging from 104 to 105 M1. In 2013 Liu et al. investigated the complexation of G13 and G14 with corresponding tetrasulfonated host (H4) by ITC experiments [25]. G13 forms highly stable complex with H4 which reaches up to 108 M1 in aqueous solution. Thermodynamic parameters show that the complexation is driven by very large entropy change (ΔH = 47.84 kJ/mol) that are attributed to electrostatic attraction and extensive π-stacking. The Ka value of G13  H4 is 350 times higher than that of G8  H4, indicating the large scale of π-stacking contributed to the most portion of Ka. However, the complex of G14  H4 is smaller Ka, giving positive entropy changes. The binding strength of G13 with H4 is five times stronger than G14 because the N-substituent benzyl group on G14 is too large to hinder the complexation with H4 associated with less negative enthalpy change and more positive entropy change. In comparison with G13 and G14, the guest G12 has similar molecular size and small scale of π-conjugation; its binding strength with H4 is smaller than G13 and G14, accompanied by lower enthalpy change. Crystal structures of G12  H4 and G13  H4 (Fig. 13) show that the guests G12 and G13 parallelly stack with naphthalene plane of H4, only few hydrogen bonds are found between host and guests, indicating π-stacking is the dominant noncovalent interaction in their complexation.

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Water-Soluble Aromatic Crown Ethers

15

Fig. 13 Crystal structures for intermolecular complexes of (a) G12  H4 and (b) G13  H4

In comparison with H4 which prefers to bind guests with large π-conjugation size, H5 has smaller cavity and more intensive anionic electrostatic field; it prefers to bind guests with only small positive groups like pyridinium and quinolium. In 2013 Liu et al. reported that G18, which acts as important coenzyme NAD+ in biological process, was included into the conformationally rigid cavity of H5 at neutral pH to show moderate binding strength of 103 M1 [24]. In contrary, the host H4 with larger cavity has no intermolecular interaction with G18. In 2016 they consequently investigated the interactions of several stilbazolium dye guests (G19 and G20) containing pyridinium moiety. The obtained data show that the two guests have strong binding strength with H5 (Ka = 105–106 M1). On the other hand, G19 and G20 usually show very poor emission in aqueous solution due to the relaxation of twisted intramolecular charge transfer (TICT) on locally excited state. DFT and TDDFT methods revealed that free dye guests are not coplanar but twisted by large twist angle. The twist angle increases in the excited state, which quenches the dye emission through TICT relaxation path. The binding in cavity of H5 lowers twisted angle of dye guests to a small value which leads to increase of fluorescent intensity. More dyes with TICT relaxation (G21–G24) were studied to associate with H5, in which the fluorescent emissions of dyes were enhanced to high intensity, as well as G19 and G20 [27]. Association constants of G19–G24 were determined by ITC experiments. It can be seen that the Ka values were mainly located in the range of 105–106 M1; the variation of structures of dyes exerts only small influence to the Ka values.

1.4

Carboxylated Aromatic Crown Ethers

Besides the aforementioned conventional disulfonated and tetrasulfonated crown ethers, carboxylated aromatic crown ethers (Fig. 14) also have good water solubility and guest binding ability like sulfonated crown ethers. Moreover, the negative charge of carboxylate group can be removed by acidifying, which makes the complexation to be controlled by change of pH. Several association constants of carboxylated aromatic crown ethers are listed in Table 5.

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O O

O

O O

O

O O

O

O

O

O

O

CO2

O O CO2

CO2 O2C

O O

O2C

O2C O

O

O

O

O

O

O

O

O

O

O O

O H7

H6

H8 O

O

O

O

O

O

O

O CO2

O2C

O O

O

O

O

O

O

O

O

CO2

O O

O2C O

O H9 O

H10

Fig. 14 Molecular structures of several aromatic crown ethers with carboxylate groups Table 5 Association constants (Ka, M1) for intermolecular complexation of H6–H10 Hosts H6 H7 H8 H9 H10

Guests G9 G8 G8 G9 G9

Ka 6.0  102 1.0  103 4.5  103 1.7  103 2.0  104

Ref. [17] [30] [30] [31] [31]

Nikitin et al. also studied bis-para-phenylene-34-crown-10 (H6) bearing one carboxylate group on each phenylene unit as well as the sulfonated crown ether (H2) [17]. They found that the complex of G9  H6 gave small Ka due to high flexibility of H6 and small aromatic size of phenylene moiety. In crystal structure of G9  H6 (Fig. 15), the position, orientation, and internal dihedral angle of bipyridinium guest inside H6 are similar to those in common [2]pseudorotaxanes containing neutral bis-para-phenylene-34-crown-10. The Ka value of G9  H6 is only 6  102 M1 in aqueous solution but increases to a range of 105–106 M1 in less polar media like methanol and acetonitrile, indicating that the electrostatic attraction is lowered by high polar solvents like water. Huang and co-workers reported bis-p-phenylene-34-crown-10 and 1,4-benzo1,5-naphtho-36-crown-10-based dicarboxylate water-soluble aromatic crown ethers, in which two carboxylate groups are located on the 2,5-position of one phenylene (Fig. 16) [30]. Both H7 and H8 are colorless in aqueous solution; the complexation of H7 and H8 with G8 turns out yellow in color by charge transfer between

1

Water-Soluble Aromatic Crown Ethers

17

Fig. 15 Crystal structures for intermolecular complexes of G9  H6

O

O

O

O

O O O

O

N

O COO

O O O O

H+

O O

N

OOC O

OH -

O

N O

O

COOH

O O

HOOC

O O

N

O

H10

G9

Fig. 16 The pH-controlled complexation between G9 and H10

π-electron-rich aromatic rings on hosts and π-electron-poor pyridinium rings of G8. The inclusion properties were studied by this charge-transfer absorption. The Ka of G8  H7 was determined to be 1.0  103 M1 by analyzing the change of chargetransfer absorption, which is slightly higher than that of G9  H6 reported by Nikitin et al. The Ka of G8  H8 is 4.5  103 M1, revealing that naphtho unit on H8 provides stronger π-stacking contributing to the host-guest complexation. The Ka value of G8  H8, 4.5  103 M1, is about 3.3 times higher than that of G8  H7. This is due to that there is stronger π-stacking interaction in G8  H8 because of the existence of a naphthalene unit in H8. Besides water-soluble aromatic crown ethers of H7 and H8, Huang et al. also reported bis(m-phenylene)-32-crown-10-based cryptand (H10) bearing two carboxylate units on the third molecular arms [31]. It is well known that three-dimensional cavity of cryptand is much more rigidified and preorganized for binding cations than that of corresponding crown ether analogue. To evaluate the contribution of the third arm on H10, the common dicarboxylated bis(m-phenylene)-32-crown-10 (H9) was employed to compare with H10. Both H9 and H10 form charge-transfer absorption band upon complexation with G9. By using titration method to the collected

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absorbance data, the corresponding Ka values was determined to be 2.0  104 M1 for G9  H10 and 1.7  103 M1 for G9  H9. H9 and H10 have similar crown ether moiety and the same negative charge, but the Ka value of G9  H10 is about 11 times higher than that of G9  H9, indicating that the third arm contributed about one order of magnitude to its binding to G9. Huang et al. also performed the assembly and disassembly of G9  H10 controlled by acid/base treatment. When complex of G9  H10 is treated by adding HCl solution, the carboxylate groups on the third arm are protonated, and H10 loses its negative charge and water solubility. The protonated H10 can also be turned back to negatively charged H10 by adding NaOH, making the cryptand H10 be controlled in aqueous solution.

1.5

Molecular Assembly Based on Water-Soluble Aromatic Crown Ethers

In the preceding sections, we have gained a deep insight into structural features and molecular recognition process of water-soluble aromatic crown ethers, which endowed them significant applications in several fields, including supramolecular metalorganic frameworks (MOFs), amphiphilic aggregations, controlled release, nanoassembly, and so on. Loeb and co-workers prepared and characterized a large collection of supramolecular MOFs with rotaxane linkers. These MOF systems usually employed a pseudorotaxane templating motif involving 1,2-bis(4-pyridyl-pyridinium)ethane axles and dibenzo[24]crown-8 wheels [32]. To eliminate independent counter anions and increase the stability of pseudorotaxane templating containing G4, the disulfonated crown ether H1 is more beneficial to be used as a wheel to form a neutrally charged [2]pseudorotaxane of G4  H1. To this end, G4(BF4)2 and [Me4N]2H1 are used as reagents to synthesize MOFs containing [2]rotaxane linkers (Fig. 17). This ligand forms reaction mixture one-periodic coordination polymer consisting of [Cu2(BnO)] with formula [Cu2(BnO)4(G4  H1)] (MeOH)2(DMF) [33]. The MOF is a one-periodic coordination polymer consisting of Cu(II) paddlewheel nodes and [G4  H1] inkers. The negative charges of the sulfonate groups on H1 counteract the positive charge of G4 to form an independent bipyridine ligand. Each [Cu2(BnO)4] cluster acts as a binuclear complex to coordinate to pyridine groups of G4  H1 to form one-periodic polymer chain in crystals. Besides the one-periodic polymer chain of copper MOFs based on [2]pseudorotaxane ligand of G4  H1, Loeb et al. also reported one-, two- and three-periodic MOFs using G4  H1 ligand and zinc ions (Fig. 18). By mixing G4  H1 with one equivalent of Zn(NO3)2(H2O)6 in methanol, MOF crystals with formula [Zn (G4  H1)2(H2O)2(MeOH)][NO3]2MeOH were obtained [34]. Each Zn(II) adopts an octahedral geometry to coordinate with two pyridine groups on G2  H1 and two water molecules. A methanol molecule and a sulfonate group from H1 wheel occupy the remaining coordinating site. H1 is stopped on the G2 axles during the coordination process. The neighboring linear chains are joined together through a head-totail fashion by coordination of a sulfonate group to neighboring Zn(II) center on each

1

Water-Soluble Aromatic Crown Ethers

19

Fig. 17 Crystal structures of (a) G4  H1 and (b) corresponding Cu MOFs containing G4  H1

Fig. 18 Crystal structures of (a) one-, (b) two-, and (c) three-periodic Zn MOFs containing G4  H1

other. Voids between the one-dimensional chains are occupied by one nitrate counterion and two methanol molecules. By mixing two equivalents of [G4  H1] with only one equivalent of Zn (NO3)2(H2O)6 in methanol, two-dimensional MOFs based on [2]rotaxane linkers were obtained. Crystal analysis shows that the formula is [Zn(G4  H1)2(H2O)2]

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(H2O)(MeNO2)2, indicating that each zinc core would coordinate with four pyridinyl groups, and these MOFs are two-periodic coordination grid polymers. Each Zn(II) center adopts an octahedral geometry and two water ligands coordinating to the remaining axial sites by hydrogen bonds. The grid layers are expanded in two dimensions and stacked in an alternating AB fashion along with the axial dimension by coordinated water molecules. The space of neighboring grid layers is 7.82 Å. Large voids in the grid layers are filled with solvent molecules. Treating the MOFs under mild vacuum at room temperature results in a porous solid with 42% void space, which could be applied to adsorb small molecules. Three-periodic MOFs were synthesized using the same reaction conditions as above but in the presence of [Me4N]2[SO4] with formula [Zn(G4  H1)2][(Zn(SO4)(H2O)2(MeOH)2)2] (MeNO2). The MOFs are three-periodic coordination polymers consisting of Zn (II) metal ions and [G4  H1] linkers as well as ZnSO4-based clusters pillaring the layers. As in two-dimensional periodic MOFs, the three-periodic MOFs contain neutral square grids consisted of [Zn(G4  H1)2] units, that is, each Zn(II) core coordinates with four pyridinyl groups of G4  H1 and each G4  H1 coordinates with another two Zn(II); the coordinate layers repeat in two dimensions to form a square grid. In contrast to the two-dimensional MOFs above, the two-periodic grids in this MOFs are no longer spaced together by hydrogen bonds, but are pillared by inorganic clusters of (Zn(SO4)(H2O)2(MeOH)2)2, which make the MOFs be stabilized in the third dimension. Initial investigations of Loeb and Tiburcio had revealed that H1 prefers to associate with guests containing 1,2-bis(pyridinium)ethane moieties due to the electrostatic attraction between guests and H1. Therefore, it seems that an extension of this concept would be to change the positive charge numbers which could remarkably affect the threading binding process. Thus, Tiburcio et al. designed a new axle guest containing one aliphatic carboxylic acid group on each side of 1,2-bis (bipyridinium)ethane (G6) (Fig. 19) [35]. As end units on G6 axles, the acid group on each side can be reversibly switched between neutral and anionic states when the

O O O3S

O

H1

O O

O

SO3

SO3 O

O

O

O

O

N O

N

N

O

N O

O N O

O

O

O N

O O

N

O O

O3S

N O

-1 -1 pH = 1, k = 9.0 x 104 s *M -1 -1 pH = 7, k = 1.0 x 103 s *M

Fig. 19 Schematic representation of the [2]pseudorotaxane of G6  H1 at pH = 7 and G7  H1 at pH = 7

1

Water-Soluble Aromatic Crown Ethers

21

pH of the media changed between 1 and 7. On the other hand, the acid group is far away from the recognition site of G6  H1; the reversible change of acid group shows limited influence to the binding strength. By using UV-vis spectrophotometry titration, the Ka values are determined to be 1.3  103 M1 and 1.2  103 M1 at pH = 1 and 7, respectively. However, the deprotonation at the end group of acid, affected mainly to the kinetic of binding process. The negative charge on each end of the G6 axle would generate a strong electrostatic repulsion to threading process of G6  H1. By using stopped-flow methodology, the energy barrier of G6 is determined to be 44.5 kJ/mol at pH = 1, but the energy barrier increases to 56.4 kJ/mol at pH = 7, revealing that the deprotonated acid group of G7 electrostatically hindered the threading of H1. The threading/dethreading rate can be finely tuned through pH of the solution, achieving an 100 times acceleration. Recently, “supramolecular amphiphiles,” which are generated by noncovalent synthesis, have emerged as a smart strategy to construct supramolecular nanoarchitectures [36]. Huang et al. reported novel supramolecular amphiphilic polymer constructed by crown ether-based molecular recognition. A water-soluble crown ether, named (m-phenylene)-32-crown-10 dicarboxylate, has moderate associated constant of 1.5  103 M1 to associate with bipyridinium guests. Poly(ethylene oxide) is linked to a bis(m-phenylene)-32-crown-10 dicarboxylate to further increase the hydrophilic property [37]. When H11 forms host-guest complex with guest N-ethyl-N0 -decyl-bipyridinium (G26) in aqueous solution, the complex self-assemblies into supramolecular micelle in water (Fig. 20). This supramolecular micelle can encapsulate hydrophobic dyes like nile red. When the water-insoluble nile red is encapsulated into the supramolecular micelles, it can reach up to a concentration of 5.0  104 M1, showing an emission band at 660 nm. Furthermore, the negative carboxylate groups of H11 can be converted into neutral carboxylic acid by adding acid, which remarkably weakens the complexation between H11 and G26 and destroys the micellar structure. This made G26  H11 to be considered as a pHresponsive supra-amphiphiles system, which can control the release of small hydrophobic molecules from the micelles. Benefiting from the intrinsic advantages of supramolecular chemistry, amphiphilic assembly can be obtained by reversal of external surroundings of amphipathic molecules. The amphiphilic aggregation in aqueous solution of guest N-methyl-N0 n

O NN N

O O

N

O

O N

O

O

O

O N

O

O

O O

H11

G26

O

O

O O N CO2 O2C

O

O

O O

O

NN N

O O

N

O O O

N

Micell

O O

O

N N

O

O

O CO2

O

O

O

N

O

O

O2C

O

O N

O

O

N

CO2 O2C

N

O

O

N

O

O

O

O

O2C

N

O

O

N

O O

O CHO2

O N

n

Fig. 20 Schematic representation of amphiphilic assembly of G26  H11 in aqueous solution

O n

CO2 O

O

O

n

O

O2C

n

O NN N

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L. Chen and Y. Liu

dodecyl-4,40 -bipyridinium (G27) bearing hydrophilic head groups and a hydrophobic tail is pronouncedly weakened by the mutual electrostatic repulsion between dicationic bipyridinium units [38]. UV-vis spectroscopy shows that the transmittance of free G27 at 450 nm hardly changes versus their concentration from 0.01 to 0.15 mM and no critical aggregation concentration is observed, indicating that G27 cannot aggregate into assembly at low concentration individually. Recently, “supramolecular amphiphiles,” which are facilitated by noncovalent interaction, have emerged as a smart strategy to construct supramolecular nanoarchitectures. Benefiting from the intrinsic advantages of supramolecules, when equivalent molar of G27 is associated with H5, the external surroundings were changed to adjust to amphiphilic assembly (Fig. 21). At a concentration of 0.1 mM, the transmittance of G27  H5 dramaticly change at 450 nm, indicating amphiphilic aggregation is formed. The aspect of aggregation of G27  H5 is also as observed from its TEM and SEM experiments. As expected, nanorods with the width of about 180 nm are observed in TEM images. Moreover, the supramolecular amphiphilic aggregation of G27  H5 is switchable by introducing extra host to bind with G27  H5. It is well known that α-cyclodextrin (α-CD) can bind long alkyl chain and 4,40 -azodibenzoic acid (AZA) with associate constants of 103 and 104 M1, respectively. By adding one equivalent complex of AZA  α-CD to the solution of G27  H5, nearly no amphiphilic change is observed to the four-component system because α-CD prefers to bind more with AZA to form a more stable complex rather than the alkyl chain of G27 . Upon irradiation of the four-component solution with 365 nm, most of AZA guests were transformed to the cis-AZA, and free α-CD is associated with the alkyl chain of G27  H5 to form a [3]pseudorotaxane of G27  H5α-CD. The newly formed G27  H5α-CD is absolutely hydrophilic, and the amphiphilic aggregates disassemble to free G27  H5α-CD. After subsequent irradiation of the fourcomponent solution with 450 nm light, the system recovered to G27  H5 and trans-AZA  α-CD, and amphiphilic aggregation phenomenon is reappeared and confirmed by UV-vis spectroscopy and TEM imaging. Benefiting from the inherent photoisomerization of AZA guest, the four components can be reversed between [3] pseudorotaxane and [2]pseudorotaxane by photoinduced interconversion to conduct the amphiphilic aggregates. Nanosupramolecular assemblies with controlled topological features have important applications in functional materials. Liu and co-workers present a novel way to obtain supramolecular nanosutructures via host-induced supramolecular aggregation of bipyridinium-modified diphenylalanine peptide (G25) through host-guest interactions with water-soluble macrocycles; benefiting from that, bipyridinium guests can form inclusion complexes with a variety of common water-soluble macrocycles [28]. Different macrocycles binding on the bipyridinium unit of G25 can provide diverse hydrophobic external surrounding to induce G25 complex to implement the specific nanosupramolecular assembly. Four water-soluble macrocycles contain H5, cucurbit[7]uril (CB[7]), cucurbit[8]uril (CB[8]), and water-soluble pillar[5]arene (WP5A) were selected in this system. Spectroscopy titrations determine the association constants to be 7.9  106, 5.3  104, 8.1  104, and 8.2  104 M1, respectively. Although all the four water-soluble macrocycles have strong interaction

SO3

H5

O

O

SO3

O

O2C

SO3 O

O

N

N

CO2

G27

light

α-CD O2C

O

O O3S

ON

O

O3S

O

O SO3 O N O

SO3

O

N

O

SO3 O

O

CO2

O2C

CO2

O SO3 ONO3S O O O O SO3 O3S O N O O N O SO3 O S O3 O O O3S SOO 3 O N O ON O O3S O SO3 O

SO3

O3S O ON O O3S

amphiphilic assembly

O3S O

O O SO O 3 N O

Water-Soluble Aromatic Crown Ethers

Fig. 21 Schematic representation of amphiphilic assembly of G27  H5 in aqueous solution

SO3 O

O

O

1 23

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L. Chen and Y. Liu

with G25, they form quite different nanostructures which differ considerably from each other observed by TEM and SEM imaging. Free G25 spontaneously assembles into fine nanofibers with a diameter of 20 nm. When G25 is associated with H5, rectangular nanosheets with the length ranging from 200 to 700 nm are found by TEM and SEM experiments. In the case of G25  CB[7] complex, nanorods with the length of about 500 nm and width of about 200 nm are observed; this is also investigated by DLS experiments to show distribution of 672 nm for their hydrodynamic diameter in solution. In contrast, G25  CB8 forms rarely reported octahedron-like nanostructure, and G25  WP5A forms left-handed helical nanowires.

1.6

Conclusions and Outlook

In conclusion, we have summarized the binding strengths and properties of watersoluble aromatic crown ethers with various cationic guest molecules, their thermodynamic aspect, inner noncovalent interaction, and applications. Possessing negative charges, π-electron-rich cavity, and additional binding sites on ethylene glycol chains, water-soluble aromatic crown ethers can extensively form inclusion complexes with a variety of cations, showing distinguishable binding characteristic and selectivities. Furthermore, these pronounced binding properties endow them broad applications in material fields, including MOFs, supramolecular amphiphilic, and so on. However, we believe that more structures of water-soluble aromatic crown ethers with powerful binding ability are still attractive field in the years to come.

References 1. Pedersen CJ (1967) Cyclic polyethers and their complexes with metal salts. J Am Chem Soc 89:7017–7036 2. Jane YS (1994) Crown ether phase-transfer catalysts for polymerization of phenylacetylene. J Mol Catal 89:29–40 3. (a) Cram DJ, Helgeson RC, Peacock SC, Kaplan LJ, Domeier LA, Moreau P, Koga K, Mayer JM, Chao Y (1978) Host-guest complexation. 8. Macrocyclic polyethers shaped by two rigid substituted dinaphthyl or ditetralyl units. J Org Chem 43:1930–1946; (b) Merten C, Hyun MH, Xu Y (2013) Absolute configuration and predominant conformations of a chiral crown ether-based colorimetric sensor: a vibrational circular dichroism spectroscopy and DFT study of chiral recognition. Chirality 25:294–300 4. Gokel GW, Leevy WM, Weber ME (2004) Crown ethers: sensors for ions and molecular scaffolds for materials and biological models. Chem Rev 104:2723–2750 5. Ashton PR, Campbell PJ, Chrystal EJT, Glink PT, Menzer S, Philp D, Spencer N, Stoddart JF, Tasker PA, Williams DJ (1995) Dialkylammonium ion/crown ether complexes: the forerunners of a new family of interlocked molecules. Angew Chem Int Ed 34:1865–1869 6. Barin G, Coskun A, Fouda MMG, Stoddart JF (2012) Mechanically interlocked molecules assembled by π–π recognition. Chem Plus Chem 77:159–185 7. Kaiser G, Jarrosson T, Otto S, Ng Y-F, Bond AD, Sanders JKM (2004) Lithium-templated synthesis of a donor–acceptor pseudorotaxane and catenane. Angew Chem Int Ed 43:1959–1962

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Polypseudorotaxanes Constructed by Crown Ethers Hong-Guang Fu, Yong Chen, and Yu Liu

Contents 2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 2.2 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

2.1

Introduction

In 1967 Pederson reported dibenzo-18-crown-6 as a molecular host for cationic guests, which opened the gate of supramolecular chemistry [1]. Crown ether, a traditional macrocyclic host, is composed of oxygen atoms linked by alkyl chains and plays a vital role in supramolecular chemistry. A unique structure makes them have a strong binding with secondary ammonium and leads them to be appealing building blocks in fabricating intriguing assemblies. Supramolecular devices including pseudorotaxane constructed by crown ether were very fascinated as it embedded multistimuli-responsive features (thermo-, pH-, and chemo-) [2]. Much attention has been given to the design and synthesis of macrocyclic molecules in science. These molecules could form mechanically interlocked molecules (MIMs) such as pseudorotaxanes [3], rotaxanes [4], catenanes [5], and cryptands [6] with appropriate guest, which acts as a potential candidate for molecular devices, molecular switches, and machines. In the past decades, various template strategies have been developed to construct topologically intriguing supermolecules. The topology or shape of a polymer is one of the most essential factors on determining its property. H.-G. Fu · Y. Chen · Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected]; [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_3

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A variety of polymer structures, such as cyclic, linear, grafted, and branched polymers, have been reported so far. Compared with traditional polymers, supramolecular polymers show some advantages in the fabrication of responsive or reversible materials. The development of supramolecular polymers also offers a platform to construct complex and sophisticated materials via a bottom-up approach. Supramolecular polymers can be prepared in solution, in gel, and in the solid state. A dynamic polymer system without cleavage of the covalent bond that undergoes a topological change is required to transform the polymer topology with sufficient structural stability similar to that of a covalent compound. Bu and coworkers [7] synthesized a crown ether-functionalized poly(tetraphenylethene) (AP-TPE) and successfully restricted the rotation of the tetraphenylethene (TPE) group via the complexation of organic ammonium salt and crown ether, leading to a stepwise enhanced fluorescence emission accompanied by a morphological transition from micelle to vesicle (Fig. 1). In comparison with 1,2-bis(4-ethynylphenyl)-1,2-diphenylethene, the absorption of AP-TPE showed a big red shift from 329 nm to 378 nm, showing no difference with the high conjugation of AP-TPE [8, 9]. 1H NMR spectroscopy was used to investigate the complexation between guest groups and AP-TPE. The size of the polymer was much smaller than the length of AP-TPE, which may be caused by the aggregation of AP-TPE under the present solvent condition. After the binding with C12-2H_PF6, the Dh band of supramolecular complexes increased to 294 nm with a much broader signal. Upon addition of the guest, the fluorescence emission band of

Fig. 1 Chemical structures of host molecule AP-TPE and the guest molecules: C12-1H-X and C12-2H-X, X = Cl, and PF6


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AP-TPE at 525 nm showed a clear increase. The host–guest recognition restricts the intramolecular rotation of AIEgens, and thus non-radiative pathway is blocked, which further causes a visible fluorescence enhancement [10, 11]. In this case, after the first acidification, dibenzylammonium salts (DBAs) bound with dibenzo24-crown-8(DB24C8) to form polar groups. Benefiting from the solvophobic effect, the host–guest complex formed a micelle with the polar groups located on the inner side. The subsequent reaction product further promoted the aggregation named salting-out effect. Recent studies showed that ammonium and its derivatives have been utilized as proton conductors in ionic liquids [12] and metal–organic frameworks [13], respectively. Bu et al. reported some supramolecular connection mode forms with twodimensional ionic channels that show controllable and appreciable proton-conducting behaviors. The starlike polymer of poly(E-caprolactone dibenzylammonium salt (PCL-DBA) contained four DBA-terminated poly(E-caprolactone (PCL) arms. The supramolecular network (Mo132-PCL and W12-PCL) was also obtained using PCL-DBA and DB24C8, where their molar ratio was controlled as 1:1. Considering that the present proton conductivity is originated from the NH2+ group, the increases in the proton conductivities of both W12-PCL and Mo132-PCL should arise from the aforementioned formation of [2]pseudorotaxanes between DBA ion and DB24C8 group, leading to the formation of supramolecular networks. Conductive AFM images showed that the patterns were electrically pronounced in a pA range. This is the first report that secondary dialkylammonium salt/crown ether [2]pseudorotaxanes were utilized as proton conductors (Fig. 2) [14]. Yan et al. reported a bis(p-phenylene)-34-crown-10 (BPP34C10) derivative bearing two pyridyl groups and studied its binding to paraquat and 2,7-diazapyrenium derivative (DAP) (Fig. 3) [15]. Upon the addition of di-Pt(II) acceptor, poly[2]pseudorotaxanes were formed. The themes of coordinationdriven self-assembly, host–guest interactions, and supramolecular polymerization are unified in an orthogonal manner. It was found that the binding ability of DAP to the crown ether is stronger than that of paraquat. Interestingly, after DAP was added into polypseudorotaxane, the more stable polypseudorotaxane was formed. The dynamical and reversible supramolecular polymer backbone with reversibility and adaptability makes it potentially useful in areas such as stimuli-responsive materials. During the past two decades, the Gibson team has been working on polypseudorotaxanes based on crown ethers. In 1998, they reported a polypseudorotaxane by threading linear paraquat through the cavities of cyclic repeated units of polymacrocycle. The change of color and proton NMR spectroscopy could validate the formation of polypseudorotaxane. With increasing amounts of paraquat, m/n value of polypseudorotaxane increased, as well as with decreasing temperature. The values of ΔS, K, and ΔH provided the foundation for predicting the m/n values for the preparation of analogous systems [16]. To further expand the research, they built the first supramolecular comblike graft copolymer based on pseudorotaxane constructed from two polymeric building blocks: a paraquat-terminated polystyrene and a main-chain crown ether polyester (Fig. 4) [17]. Introduction of appropriate

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Fig. 2 Encapsulation of the [2]pseudorotaxanes cluster of Mo132 by the DB24C8 group with a cationic surfactant. The resulting encapsulated complex containing 40 DB24C8 groups cross-linked PCL-DBA stars

blocking groups onto the paraquat units of this system after complexation will produce a mechanically interlocked comblike graft copolymeric rotaxane. A dramatic viscosity increase in solutions of two components, NMR chemical shift changes in solution, the lack of phase separation by both optical microscopy and small-angle laser light scattering (SALLS), and the observation of a single Tg by DSC jointly proved the formation of graft copolymer. Huang et al. endeavor to utilize a multicomponent self-assembly strategy to achieve hierarchical and more complicated supramolecular polymers. Therefore, by integration of the “self-sorting” concept, they prepared alternating supramolecular copolymers. Early studies demonstrated that secondary dialkylammonium salts bound DB24C8 strongly and resided within the macrocyclic cavity [18]. Luckily, they found that DBA/DB24C8 complex and paraquat/ BPP34C10 complex are a pair of building blocks with “self-sorting” recognition behavior in solution [19–21]. Based on this self-sorting organization, they constructed an alternating supramolecular copolymer (Fig. 5) [22]. They demonstrated that self-sorting organization of two AB-type heteroditopic monomers could result in the formation of supramolecular alternating copolymers in solution which was confirmed by DLS, CV, 1H NMR, SEM, and viscosity measurements. The degree of polymerization was dependent on the initial concentrations of two

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Fig. 3 Metal coordination and host–guest interaction-driven formation of metallosupramolecular poly[2]pseudorotaxanes and compounds used in their study

monomers. Morphology control of suprapolymers is essential for their future applications. Supramolecular polymers using dynamic assembled chains with low molar mass monomers by reversible highly directional noncovalent interactions have shown traditional polymeric properties in solution and in the bulk. Further, they used the self-sorting organization principle to prepare a supramolecular pseudopolyrotaxane with monomer and two BPP34C10 macrocycles and a DB24C8 ring linked by covalent bonds. By exclusively forming pseudorotaxanes between BPP34C10 host moieties and paraquat guest units, the supramolecular polymer backbone would be afforded (Fig. 6) [23]. The DB24C8 units were left free until the addition of dibenzylammonium salt. After the cavities of DB24C8 units were filled by dibenzylammonium salt, the DB24C8 units became more rigid, and the properties of resulting polymer were obviously different from the unfilled ones, such as specific viscosity, rheological properties, and critical polymerization concentration (CPC) values. Although supramolecular alternating copolymers prepared from self-sorting organization of two heteroditopic monomers were reported, supramolecular polymer

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Fig. 4 Illustration of the formation of polypseudorotaxane by poly(ester crown ether) host and paraquat-terminated polystyrene guest

Fig. 5 Formation of supramolecular copolymers from self-sorting of two heteroditopic monomers

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Fig. 6 Cartoon representation of the construction of supramolecular polypseudorotaxanes from the simple compounds

gels formed from small molecules by crown ether-based molecular recognition have been few reported. Shinkai and coworkers have developed gelators comprised of crown ethers [24–26], where the driving forces for the gelation were largely attributed to the appended groups. It is still a big challenge to design and synthesize novel stimuli-responsive gels completely based on the host–guest interactions between crown ethers and its complementary guest moieties. In 2011, benefiting from crown ether-based molecular recognition, a dualresponsive supramolecular polymer gel was built (Fig. 7) [27]. The system has thermo- and pH- responsive abilities. Long flexible alkyl chains play an important role as physical junctions in supramolecular gels which were found to contribute to the formation of linear supramolecular polymers. The supramolecular polymer gel showed excellent reversible phase transitions by cooling and heating or by adding acid and base. Benefiting from the relatively low activation energy required for breaking weak bonds, supramolecular gels can respond to external stimuli (pH, temperature, electric/magnetic fields, and solvent composition), and thus they can serve as functional membranes, smart devices, and drug delivery carriers [28–31]. Owing to the difficulties encountered in synthesizing well defined polymer precursors embedding multiple crown ether hosts at predetermined positions. Liu and Huang co-built supramolecular gels on the basis of reversible molecular recognition between dibenzylammonium salt (DBAS) moieties and DB24C8, with

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Fig. 7 Formation of a supramolecular polymer gel through self-assembly of crown ether monomer

biodegradable poly(e-caprolactone) (PCL) scaffold (Fig. 8) [32]. Two-arm PCL–DBAS and four-arm star PCL–DB24C8 incorporate complementary molecular recognition moieties. Pseudorotaxane formation between dibenzylammonium moieties and crown ether will form supramolecular networks and an increase of size of polymer chains. The growth of supramolecular networks with increasing polymer could be confirmed by the dramatic increase of reduced viscosity. At even higher polymer concentrations, the formation of supramolecular gels and reversible pH- and thermo-induced gel–sol transitions can be visualized macroscopically. The DSC thermogram of the mixture revealed a broad endothermic peak in the temperature range 55–80  C compared with those of the two separate components, which can be attributed to disruption of the interactions between DBAS and DB24C8 moieties. This result kept consistent with that obtained by 1H NMR spectroscopic studies. Although much progress has been made in the preparation of cross-linked supramolecular gels based on host–guest interactions [33], the study of their properties was mainly focused on their self-healing, and stimuli-responsive supramolecular gels have been rarely reported [34]. Huang et al. prepared two noncovalently cross-linked polymer gels by mixing pendent dibenzo[24]crown-8 (DB24C8) with a poly(methyl methacrylate) (PMMA) polymer groups and two bisammonium crosslinkers with different end-group sizes under different conditions (Fig. 9) [35]. Because of the larger size of the cyclohexyl unit, it took longer time to achieve equilibrium. Viscometry gave direct evidence of the existence of polymer networks in these two gels. Both the specific viscosities and reduced viscosities of the two gels are larger than those of polymer. To further investigate the formation of supramolecular gels and supramolecular networks, we considered the extent of cross-linking and calculated that the mean numbers of elastically active cross-linkers per chain

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PCL-DB24C8

Base or heating

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PCL-DBAS High concentration

High concentration Adding base or heating

Four-arm star PCL-DB24C8

Two-arm PCL-DBAS

Fig. 8 Cartoon representation for the construction of responsive supramolecular networks from two-arm PCL–DBAS and four-arm star PCL–DB24C8

Fig. 9 Self-healing supramolecular gels formed by crown ether-based host–guest interactions

(f*) of gels were 3.49 and 1.01, respectively. From these data, it is inferred that 48.5% and 14.0% of DB24C8 units are complexed to form elastically active crosslinkers in gels, respectively. Moreover, the gels exhibit excellent self-healing properties, which not only can be seen visually and directly, but also were fully studied

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using rheological measurements, showing 100% recovery even under 10,000% strain in less than 10 s over several cycles. Nowadays, on account of their high selectivity and sensitivity, much attention has been given to supramolecular cross-linked network-based fluorescent sensors, especially those whose polymeric backbones are fluorescent conjugated polymers [36–38]. Thus, the disassembly of the conjugated polymer network could be triggered by multiple stimuli. Huang et al. prepared a cross-linked polymer supramolecular network simply by mixing a bisammonium salt cross-linker and a poly (phenylene ethynylene) (PPE) polymer decorating pendent DB24C8 groups (Fig. 10) [2]. When the secondary ammonium salt moieties interact with DB24C8 units, the network will form, causing the aggregation of polymer main chains and leading to a sharp decrease of fluorescence emission intensity compared to that of the PPE polymer. After treatment with Cl
or K+, collapse will happen to the network, and the recovery of the fluorescence intensity will occur. Moreover, the supramolecular network is also responsive to temperature and pH changes. Therefore, this system could be used as types of sensors: an anion sensor, a cation sensor, a temperature sensor, and a pH sensor. The system can be used in thin film and solution. Exposure of a film made from this network to ammonia leads to an increase of fluorescence intensity from the film, which makes it a good candidate for gas sensing.

Fig. 10 Cartoon representation of the formation of the cross-linked polymer and its disassembly induced by different stimulate

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Triptycenes are a class of compounds with a unique paddle wheel structure and have wide applications in material science, supramolecular chemistry, and other research fields [39]. A variety of triptycene-crown ether fused multicavity hosts have been developed by integrating various sized crown ether rings and the threedimensional paddle wheel-like triptycene scaffold. Chen and coworkers reported the first triptycene-based tris(crown ether) host in 2005. Connecting triptycene units through crown ether rings resulted in multicavity macrocyclic hosts with three-dimensional central cavities. The interacting surfaces of the phenyl planes in triptycene enabled such hosts to recognize a range of diversified guest species by the formation of supramolecular assemblies which were further used in the construction of complex molecular machines. Chen et al. reported a triptycene-derived powerful host for complexation with different guests bearing different topology macrotricyclic which contained two DB24C8 moieties. Interestingly, they found that the new macrocycle formed a 1:2 complex with 2 equiv. dibenzylammonium ions, which inspired them to further design and synthesize two dibenzylammonium ions and a self-complementary monomer. They synthesized the monomer and proved its self-assembly into supramolecular polymer networks, which was the first example of supramolecular polymer networks formed by the self-complementary low-molecular-weight monomer assembly, based on intermolecular host–guest interactions. To their delight, they found that the supramolecular networks showed gel properties in chloroform/acetonitrile or acetonitrile solution, and the supramolecular gels exhibited reversible pHand thermo-induced sol–gel transitions (Fig. 11) [40]. Followed by the above work, they reported a supramolecular polymer gel formed by the host–guest interactions between a copolymer containing dibenzylammonium moiety and a DB24C8-based bis(crown ether). The gel showed both thermo- and pH-responsive behaviors. Moreover, the gel exhibited excellent self-healing property, which could occur under static state and without the input of external energy (Fig. 12) [41]. The formation of the supramolecular networks was supported by viscometry. It was found that specific viscosity of both the complex and the separated polymer changed almost linearly with the concentration demonstrating that no obvious physical interactions occurred. When the concentration reached

Fig. 11 Supramolecular gel formed from the monomer in CH3CN and its thermoinduced sol–gel transitions and in CD3CN/CDCl3 and its pH-induced sol–gel transitions

Fig. 12 Cartoon representation for formation of the polymer gel from copolymer and bis(crown ether) and specific viscosity of DB24C8 derivative (•), copolymer (■), and gel (~) versus secondary ammonium salt unit or DB24C8 derivative concentration

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22.5  10
3 M, specific viscosity of the gel displaying nonlinear increased which was continuously larger than polymer. It was also well documented that the anthracenyl group is not small enough to thread DB24C8. On the basis of the result, they deduced that if 1,10-(anthracene9,10-diyl)bis(N-benzylmethanaminium) and crown ether host could form a 1:1 “pseudosuitane”-type complex, to introduce a convenient and new method for the synthesis of polyrotaxanes could be developed by just connecting the “pseudosuitane” with an appropriate linker. So, they reported the formation of a “pseudosuitane”-type complex between the host and guest in both solution and the solid state, followed by the synthesis of a linear polyrotaxane by an effective copper (I)-catalyzed azide–alkyne cycloaddition reaction. Formation of the “pseudosuitane” complex encouraged them to further construct a linear polyrotaxane. It was found that the Mn of the polyrotaxane was about 11.9 kDa with a PDI of 1.27, indicating that each polymer chain of polyrotaxane was composed of about seven “pseudosuitane” repeating units (Fig. 13) [42]. To develop more sophisticated molecular machines, new kinds of tristable [2]-, [3]-, or [4]rotaxanes were obtained (Fig. 14) [43], which featured host containing an anthracene unit as the moveable part and pyromellitic diimide, anthraquinone, and N-methyltriazolium as the three stations. In the [2]rotaxane molecular shuttle, the macrocycle M can be controllably and reversibly switched among the three stations using stimuli. Moreover, the motion mode could be extended to the oligorotaxanes, creating a synchronous behavior for M and producing an original and visual prototype – molecular cable car for artificial molecular machines (AMMs). The study presented here also heralds the feasibility to control the submolecular motion at the polymer level and design novel stimulus-responsive polymers based on the tristable shuttle. So far, limited examples were reported on the dibenzylammonium salt/DB24C8 recognition motif suffering from tedious multistep synthesis toward A2B4- or A2B2type complementary monomers. Hence, researchers are keeping pursuit to exploit a more energy-saving and economical route to the desired supramolecular cross-linked Fig. 13 Graphical representation of structures and synthesis of linear polyrotaxane

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Fig. 14 Structures of the tristable rotaxanes and schematic drawing of [4]rotaxane molecular cable car

networks bearing novel crown ether-based building blocks. Secondary ammonium salt/benzo-21-crown-7 (B21C7) recognition motif is an appealing choice exhibiting easier availability and the enhanced binding property [44]. Wang et al. involved the interchain interactions between the complementary homoditopic benzo-21-crown-7 cross-linking agent and the secondary ammonium salt-functionalized graft polymer. Such strategy could avoid the stepwise incorporation to significantly simplify the synthetic procedures onto the scaffold. By increasing the concentration of the monomer to a high level in acetonitrile, the resulting cross-linked networks could immobilize the solvent and lead to the formation of supramolecular gel, which exhibits chemo-, pH-, and thermo-responsive gel–sol transition behaviors. Moreover, the gel would be an excellent candidate for the development of smart materials with desired functionalities embedding multistimuli-responsive features (Fig. 15) [45]. The [c2]daisy chain involved in the structures suffers from low reaction yield and tedious preparation. High structural symmetry of the [c2]daisy chain further restricts the formation of functional supramolecular architectures. To solve this problem, an alternative way is to use [2]rotaxane as the basic building monomer. Interestingly, kinds of functional groups could be introduced asymmetrically into the axle and wheel sites of the [2]rotaxane scaffold, facilitating the subsequent polymerization steps [46]. Wang et al. have successfully constructed supramolecular poly[2] rotaxanes via the hierarchical self-assembly strategy. The integration of two orthogonal noncovalent interactions into the [2]rotaxane monomer further facilitates the chain extension. The new types of mechanically linked supramolecular polyrotaxanes are regulated in a controlled and facile manner which motivate them to explore their potential applications in the future (Fig. 16) [47]. Hyperbranched supramolecular polymers (HSPs) possess not only the advantages of traditional hyperbranched polymers but also novel properties, such as self-healing and stimuli responsiveness. Hydrogen bonding, one of the most useful interactions to hold supramolecular networks together, is ubiquitous in many systems such as the double helix DNA structure. By employing host–guest interaction and triple hydrogen bonding, Qu et al. have constructed a hyperbranched supramolecular polymer.

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Fig. 15 Formation of supramolecular cross-linked networks from the homoditopic B21C7 host and secondary ammonium salt-functionalized polymer

Fig. 16 Schematic representation of main-chain poly[n]rotaxanes, poly[c2]daisy chains and hierarchical construction of poly[2]rotaxanes

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This result was confirmed by the combination of various techniques, such as viscosity measurements 1H NMR, AFM, DLS, and SEM (Fig. 17) [48]. Zheng et al. reported a low-molecular-weight gelator. Gels could form both in organic medium and water using this gelator. Each part of the unsymmetric bolaamphiphile of the gelation property was carefully investigated by designing a series of analogues. In order to get further understanding of the crown-based gelator, two new gelators were successfully prepared with better gelation properties. This simple framework can be seen as a new way to construct new low-molecularweight gelators (LMWGs), which can gelate in organic solvents and water (Fig. 18) [49]. Takata et al. have reported the synthesis of a challenging target polymer in one-pot way in the polyrotaxane (PRX) family. They found that chain-type PRXs (CE-PRXs) are soluble in typical organic solvents (DMF, etc.), ignoring their polyionic structures. Another method enables the controlled synthesis of PRXs involving polymerization of pseudo[2]rotaxane monomers, possessing the desired rotaxanation ratios. Complete neutralization promotes the crown ether (CE) translation remarkably. So far, a variety of CE modifications enable versatile

Fig. 17 Cartoon representation of the supramolecular oligomer and the hyperbranched supramolecular polymer from monomers

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Fig. 18 Synthesis of monomer and gels self-assembled from crown ether

functionalization of polypseudorotaxane (PRX). Thus, their study heralded rapid progress in the fabrication and application of CE-PRXs (Fig. 19) [50]. Supramolecular polymers constructed by metal-directed self-assembly via host–guest association and metal–ligand interactions attract more and more attention owing to their numerous interesting properties and potential applications. The strong binding between terpyridines and metal ions (Zn2+, Fe2+, etc.) can enable the easy construction of supramolecular polymers through the intermolecular coordination of ditopic hosts bearing two terpyridine terminals with metal ions, and the resultant supramolecular polymers can be reversibly disassembled through the addition of competitive ligands or metal ions We have fabricated a supramolecular gel with a three-dimensional network structure following the pathway of the primary assembly of bis(terpyridyl)dibenzo-24-crown-8 by metal coordination polymerization, grafting of anthryl-dibenzylammonium guests, and photo-induced secondary assembly. This supramolecular gel can reversibly convert to the soluble 1/Zn/2 assembly under heating and recovered under light irradiation. The stimuli-responsive sol–gel transformation property, along with the ease of preparation, will make this supramolecular gel well suitable for a variety of important biomedical and industrial applications (Fig. 20) [51].

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Method A

DB24C8

NH2+

threading

End-capping

Method B

threading

polymerization

Fig. 19 Two different strategies for preparing chain-type-based main-chain-type PRXs

Fig. 20 Schematic representation of the formation of supramolecular polymer and its reversible conversion with supramolecular network

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45

Conclusion

In this chapter, the development of pseudorotaxanes based on crown ether was introduced comprehensively. We discussed their synthesis, stimuli-responsive movement, and their function and applications. Given the unique structures and stimuli-responsive properties of crown ether and DBA, the dissociation and association of pseudorotaxanes makes them to be good candidates for molecular switches, molecular locks and keys, and molecular logic gates. Chemists also have studied their molecular machines in gels, which enable the functions of ion sensing, nanovalves, and single-molecular imaging. Up to now, studies on pseudorotaxanes have been widely explored. However, it is just the beginning. Acknowledgments We thank NNSFC (21432004, 21672113, 21772099, 21861132001) for the financial support.

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Host-Guest Chemistry of a Tetracationic Cyclophane, Namely, Cyclobis (paraquatp-phenylene) Hao Li, Tianyu Jiao, and Libo Shen

Contents 3.1 3.2 3.3 3.4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structural Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Guest Recognition Ability of CBPQT Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1 Guest Recognition Ability of CBPQT4+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2 Guest Recognition Ability of CBPQT2(•+) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Mechanically Interlocked Molecules Containing CBPQT4+ Ring . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1 Catenanes Containing CBPQT4+ Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.2 Rotaxanes Containing CBPQT4+ Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6 Molecular Machines and Molecular Switches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7 Extended Derivatives of CBPQT4+ Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8 Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

Since Pedersen’s seminal report [1] of the synthesis and guest recognition behaviors of crown ether in the year of 1967, the research on host-guest recognition began to represent one of the major focuses in the field of supramolecular chemistry [2]. In the early stage, supramolecular chemistry was often referred to as host-guest chemistry [3], because of the following reasons. On the one hand, host molecules often exist in the form of macrocycles, which have many convergent binding sites that point into their cavities. The implication is that the host is able to accommodate a guest within its pocket where multiple noncovalent interactions could occur simultaneously in a cooperative manner. These supramolecular driving forces include labile coordination bond [4], π-electron interactions in the form of either donor-acceptor H. Li (*) · T. Jiao · L. Shen Department of Chemistry, Zhejiang University, Hangzhou, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_4

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interactions [5] or aromatic radical-pairing interactions [6], solvophobic effect often in the form of hydrophobic forces [7] expressed in aqueous solutions, hydrogen bonding [8], electrostatic forces [9], anion binding [10], as well as a variety of van der Waals interactions [11]. On the other hand, host molecules often have preorganized conformations. As a consequence, host-guest recognition could occur without too much entropy loss in the cases when the guests have complementary sizes and geometries to fit within the host cavities. Host-guest recognition enables many tasks to be accomplished, including labile guest stabilization [12], accelerating reaction rates [13], as well as developing mechanically interlocked molecules [14]. Besides crown ethers, a few other macrocyclic molecules including cyclodextrins [15], calixarenes [16], cucurbiturils [17], and pillararenes [18] have been playing important roles in supramolecular chemistry. In the year of 1988, Sir Fraser Stoddart, the chemistry Nobel Laureate [19] of 2016 for his contribution in the development of molecular machines, designed and developed a rectangle-shaped host molecule, namely, cyclobis(paraquat-p-phenylene) (CBPQT4+) [20] (Fig. 1). This tetracationic cyclophane represents another milestone in the river of supramolecular chemistry, because (i) CBPQT4+ is relatively synthetically accessible and (ii) CBPQT4+ can recognize a variety of π-electron guests in both fully oxidized state and biscationic diradical state, driven by donor-acceptor and radical-pairing interactions, respectively. In this chapter, we are going to make a rough discussion of the following issues of CBPQT4+, including (i) the structural feature of CBPQT4+; (ii) its preparation including the template-directed synthesis; (iii) its binding behavior in its oxidized and radical states, namely, CBPQT4+ and CBPQT2(•+), respectively; (iv) mechanically interlocked molecules including rotaxanes and catenanes containing CBPQT4+ as a macrocyclic building block whose switchable features have been taken advantage of in the design of molecular switches and machines; and (v) the extended derivatives of CBPQT4+. Even although a few other groups also employed CBPQT4+ ring for self-assembly and molecular recognition, in this chapter, we mainly focus on the works of the group led by Stoddart, the inventor of this tetracationic cyclophane.

Fig. 1 Structural formula of the tetracationic cyclophane CBPQT4+ and its single-crystal X-ray structure. Counterions are omitted for the sake of clarity

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51

Structural Features

CBPQT4+ has been referred to as “Blue Box” in the community of supramolecular chemistry including the group of Sir Fraser Stoddart. Two major reasons might account for this “nickname.” First, the two 4,40 -bipyridinium (BIPY2+) units in CBPQT4+ can easily undergo reduction, producing blue-colored solution of CBPQT2(•+) containing two BIPY•+ moieties that absorb red wavelengths of light [21]. Second, the color of blue is often used to represent electron-deficient part in a molecule in the community of chemistry. The tetracationic CBPQT4+ ring has a πelectron-deficient nature. We therefore often employ blue color to draw the rectangular molecular structural formula of CBPQT4+, in order to indicate that this ring is electron-poor. This might be another origin of the name of “Blue Box.” In the solid-state framework of CBPQT4+ [20] (Fig. 1), two BIPY2+ units are bridged in a face-to-face manner by two p-xylyl linkers. The rigidity of the building blocks, including both the BIPY2+ and the p-xylyl spacers, affords the cyclophane a preorganized and rigid cavity. The distance between the two BIPY2+ in their middle parts is around 6.8 Å, which is twice of π-π interaction distance. The implication is that, when a π-electron guest inserts into the macrocycle cavity, the interplane distances between the guest and each of the two BIPY2+ moieties would be around 3.4 Å, an optimized distance for the occurrence of π-π interactions. As a consequence, both of the two BIPY2+ units are able to undergo π-π interactions with the guest in the host cavity in a cooperative manner. This feature explains the phenomena that CBPQT4+ is highly promiscuous in binding a variety of π-electron-rich guests with complementary geometries. It is also noteworthy that the BIPY2+ contains a few acidic protons, including the pyridinium protons in four α-positions with respect to the two pyridinium nitrogen atoms, as well as the methylene protons in the p-xylyl linkers. Their acidity results from the electron-withdrawing nature of the nitrogen atoms, on account of either conjugation or inductive effects. The consequence is that these protons represent promising hydrogen bond donors in host-guest recognition. More specifically, CBPQT4+ can provide larger binding affinities for those πelectron-rich guests that bear ethylene glycol side chains, whose oxygen atoms are considered hydrogen bond acceptors. This issue is discussed in more detail in the coming section. The rectangle architecture of CBPQT4+ introduces ring strain. It is well-known that a sp3-hybridized carbon atom should have an optimized bond angle of around 109.5 in order to minimize the repulsion between the four bonding electron pairs. Considering each of the four methylene linkers in CBPQT4+ framework contains two less steric bulky protons, the optimized C–C–C bond angle (i.e., the central carbon is the methylene one) is supposed to be even larger than 109.5 . This value significantly deviates from 90 in a regular rectangle framework. This deviation indicates that in a CBPQT4+ framework, either the C–C–C bond angle is smaller than the optimized value, namely, 109.5 , or the BIPY2+ moiety or p-xylyl linker undergo bend. Both of these two behaviors introduce ring strain. In fact, in a solidstate structure of CBPQT4+, the C–C–C bond angle is observed to be around 108 . In addition, the two pyridinium moieties in a BIPY2+ are not in the same plane,

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which supports our aforementioned hypothesis that these aromatic building blocks in the CBPQT4+ framework have bent conformation. The CBPQT4+ ring has an amphiphilic nature, i.e., its cationic BIPY2+ and the neutral p-xylyl building blocks are hydrophilic and hydrophobic, respectively. Therefore, the solubility of this tetracationic cyclophane is often determined by its counterions. When the counterions are less polar and hydrophobic PF6 or BF4, the salts, namely, CBPQT4+•4PF6 or CBPQT4+•4BF4, are soluble in polar organic solvents, such as MeCN, DMF, and MeNO2. When the counterions are changed to those that are highly solvated in water, including Cl, Br, or NO3, the cyclophane becomes soluble in water.

3.3

Synthesis

The design of CBPQT4+ was based on the discovery [22] (Fig. 2) of the group led by Stoddart that a BIPY2+ derivative 12+ could be recognized by a crown ether containing two π-electron-rich hydroquinone (HQ) units, namely, bis-para-phenylene[34]crown-10 (BPP34C10). The driving forces for the formation of the complex 12+BPP34C10 include charge-transfer interactions between the 12+ guest and the two HQ units in the host, which act as the π-electron acceptor and donor, respectively. The Stoddart research group thus envisioned that it might be possible to

Fig. 2 Structural formulaes and the corresponding single-crystal X-ray structures of BPP34C10 and CBPQT4+, before and after they recognize π-electron-deficient and rich guests 12+ and 2, respectively. Counterions are omitted for the sake of clarity

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53

reverse the constitutionally roles of the host and guest, by introducing two BIPY2+ units into a macrocycle, namely, CBPQT4+, which was supposed to bind a πelectron-rich guest including a HQ derivative 2. The synthesis (Fig. 3) of CBPQT4+ relies on the SN2 reaction in which pyridine and benzyl bromide act as nucleophile and electrophile, respectively. The Stoddart group firstly synthesized compound 3•2PF6, which has been referred to as “horseshoe” on account of its half-macrocyclic geometry. Combining 3•2PF6 and stoichiometric amount of α,α0 -dibromo-p-xylene in dry polar organic solvent such as MeCN produced a yellow solid-state product including CBPQT4+ (counterion could be either Br or PF6), as well as other polymeric and oligomeric byproducts. Water has to be avoided during the reaction, because water might result in hydrolysis of benzyl bromide. By using chromatographic purification followed by counterion exchange, the Stoddart group obtained CBPQT4+•4PF6 in 12% yield, assuming that the salt was not solvated. This 12% yield of CBPQT4+ is relatively low, compared with other [1+1] cyclization reactions. This low yield results from two major reasons. First, SN2 reaction is generally irreversible in most cases. The implication is that, if the reaction between 32+•2PF6 and α,α0 -dibromo-p-xylene yields oligomeric or polymeric byproducts, the “errors” could not be corrected. Second, the ring stain of CBPQT4+ makes the cyclization less favored in the context of both thermodynamics and kinetics. The effort to increase the yield of CBPQT4+ was performed [23] (Fig. 4) by using template-directed approach. The Stoddart group firstly prepared a guest 4 bearing a HQ moiety on which two ethylene glycol chains were grafted. The first SN2 reaction of 12+ and α,α0 -dibromo-p-xylene yielded a triscationic reaction intermediate 53+. This π-electron-deficient pseudo-macrocycle “warp around” the guest 4, by which the terminal pyridine and benzyl bromide units orientated close to each other, favoring the occurrence of SN2 reaction in an intramolecular manner. In MeCN, the yield of CBPQT4+•4PF6 increased to 36% in the

Fig. 3 The non-template protocol for the synthesis of CBPQT4+•4PF6 by performing SN2 reaction of 32+•2PF6 and α,α0 -dibromo-p-xylene in MeCN, followed by counterion exchange

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Fig. 4 The template-directed protocol for the synthesis of CBPQT4+•4PF6 by performing SN2 reaction of 32+•2PF6 and α,α0 -dibromo-p-xylene in the presence of a template 4 in MeCN, followed by guest removal and counterion exchange

presence of 4, which is almost three times compared to that in the absence of template. It is noteworthy that when the solvent was switched from MeCN to DMF, the yield increased from 36% to 45%, which might be explained by the fact that the triscationic reaction intermediate 53+•2PF6–•Br has better solubility in DMF. The same group also discovered that the yield of CBPQT4+ was dependent on the electron-donating ability of the guest. For example, when the guest 1,5-bis-[2-(2methoxyethoxy)-ethoxy]naphthalene (BMEEN), an analogue of 4, was employed to template the formation of CBPQT4+ in DMF, the yield underwent further increase to 62%. This higher yield is attributed to the 1,5-dialkoxy-naphthalene (DNP) unit in BMEEN, which introduces stronger π-electron donor-acceptor interactions to the intermediate 53+, compared to the HQ unit in 4. One of the disadvantages of using templates for the synthesis of CBPQT4+ is that template removal is technically demanding and time-consuming, especially in the case of high binding constant of guestCBPQT4+. In fact, when the guest 1,5-bis[2(2-hydroxyethoxy)ethoxy]-naphthalene (BHEEN) was employed to template the ring formation, it took a few days or weeks to remove the template from the ring cavity by performing liquid-liquid extraction. This problem was resolved (Fig. 5) by Stoddart group in the year 2010, by using a guest exchange strategy [24]. After the

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Fig. 5 The template-directed protocol for the synthesis of CBPQT4+•4PF6 by using BHEEN as the template. The guest removal is accomplished by means of guest exchange strategy. BHEAN is used to replace BHEEN in the ring cavity. In acidic condition, BHEAN is protonated and driven out from the ring cavity

ring formation reaction, another guest 1,5-bis[2-(2-hydroxyethoxy)ethylamino] naphthalene (BHEAN), which contains a 1,5-diamino-naphthalene unit, was added into the aqueous solution of the reaction mixture to drive the template BHEEN out from the ring cavity, forming BHEANCBPQT4+. In the presence of acid, BHEAN undergoes protonation and exists in a cationic form, namely, BHEAN•2H+, thanks to the basicity of the amino functions in BHEAN. The cationic BHEAN•2H+ is no longer π-electron-rich and exhibits no binding affinity within the cavity of CBPQT4+. Adding NH4+•PF6 into the mixture in water could precipitate CBPQT4+•4PF6, leaving the water-soluble BHEAN•2H+ in the aqueous solution. More recently, the Stoddart group developed [25] (Fig. 6) a pseudo-dynamic approach in the synthesis of CBPQT4+, as well as its extended derivative. Addition of tetrabutylammonium iodide into the ring closing reaction mixture of the 4,40 -bipyridine and a so-called reverse horseshoe compound 62+•2PF6 in refluxed MeCN could accelerate the reaction, producing CBPQT4+•4PF6 in 20% yield. The C–N bond formation is somewhat reversible, given that I anion is both a good nucleophile and a good leaving group. This dynamic nature allows the system to perform error checking to some extent, producing more CBPQT4+, which is more thermodynamically favored in terms of entropy compared to those oligomeric byproducts.

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Fig. 6 The non-template protocol for the synthesis of CBPQT4+•4PF6 by performing SN2 reaction of 62+•2PF6 and 4,40 -bipyridine in MeCN in the presence of tetrabutylammonium iodide catalyst, followed by counterion exchange

3.4

Guest Recognition Ability of CBPQT Ring

3.4.1

Guest Recognition Ability of CBPQT4+

As we mentioned before, CBPQT4+ is able to recognize a variety of π-electron-rich guests within its cavity. The driving forces for the host-guest recognition include: (i) π–π donor-acceptor interactions. This noncovalent force is also referred to as charge-transfer interactions. It is noteworthy that the width of CBPQT4+ ring, namely, 6.8 Å, allows the guest to be able to undergo π–π donor-acceptor interactions with both of the two BIPY2+ units in the host. However, in a given instant, only one of the two electron acceptors is strongly engaged in the noncovalent interactions. This proposition is supported by the observation that upon recognition of a π-electron-rich guest, the two BIPY2+ units in the CBPQT4+ ring have different reduction potentials on the cyclic voltammetry (CV) timescale, i.e., one BIPY2+ unit in the CBPQT4+ ring is easier to be reduced than the other one, in the cases when the dissociation process of the complex is slow or prohibited. Charge-transfer interactions lead to the optical absorption of the complexes in the visible light region, which brings about various colors of the complexes in solution. This is because when the complex absorbs a photon with a specific wavelength, electrons undergo transfer from the HOMO of the π-electron-rich guests to the LUMO of one of the two BIPY2+ units in the CBPQT4+ ring, leading a charge-separated excited state. For example, upon complexation with the CBPQT4+ ring, guest-bearing dioxyarene functions are typically orange to red [26], while diaminoarenes and TTF derivatives have green colors [27]. The difluorobenzidine-contained guest produces a blue color in solution [28].

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In addition, the difference in binding constants (Ka) for the guests bearing different π-electron moieties also reveals the occurrence and importance of π–π donor-acceptor interactions in guest recognition. For example, Ka of the guests containing a DNP unit are often a few order (two or three) of magnitude larger (Fig. 7) than that containing a HQ, on account of the fact that the former guest is generally more electron-rich than the latter. Tetrathiafulvalene (TTF), which is even more electron-donating than DNP, is used to synthesize guests with larger Ka. Introducing electron-withdrawing functional groups into the guest weakens the π–π donor-acceptor interactions and therefore reduces Ka. For example, the guest 4 bearing a HQ unit has a Ka of 2220 M1 [26], which is nearly two order of magnitude larger than that of the analogue guest 7 bearing two fluorine atoms [29] (Fig. 8a). The guest 8 containing four fluorine atoms demonstrates no binding affinity. TTF undergoes reversible redox process. The oxidation products, including the monocationic TTF•+ and the dicationic TTF2+, are π-electron-deficient and therefore lose its ability to associate with the CBPQT4+ ring (Fig. 8b). This switching behavior was taken advantage of in the design of molecular switches and machines in the form of catenanes and rotaxanes. We will discuss it in more detail in the coming section. (ii) As we mentioned previously, the BIPY2+ in the CBPQT4+ ring contains a number of acidic protons that are considered as hydrogen bond donors. The implication is that, when the guest bears hydrogen bond acceptors such as glycol oxygen atoms, the host-guest recognition could be enhanced by

Fig. 7 Association constants, Ka, of two series of pseudorotaxanes, in either MeCN or H2O. The guests contain either HQ or DNP units in the middle part

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Fig. 8 (a) Association constants, Ka, of a series of pseudorotaxanes in MeCN. When more fluorine atoms are grafted onto the HQ in the guest, Ka undergoes significant decrease. (b) A pseudorotaxane TTFCBPQT4+ undergoes dissociation after the TTF guest undergoes oxidation

hydrogen-bonding interactions in the form of [C–H•••O]. The occurrence of relatively strong hydrogen-bonding interactions for glycol chain relies on the gauche effect. That is, the two vicinal oxygen atoms in an ethylene glycol unit orientate in a manner that the O–C–C–O torsion angle is round 60 , instead of 180 that occurs in the case of C–C–C–C in a n-butane molecule. The gauche effect results from an orbital mixing between a C–H bond in a methylene and the empty anti-bonding orbital of the adjacent C–O bond. The gauche conformation of the glycol chain allows the glycol chain to wrap around a BIPY2+ unit, as a consequence of which, the multiple oxygen atoms in the former could form hydrogen bonds with one or a few acidic protons in a BIPY2+ unit simultaneously. This proposition is supported by the observation that when mono or di(ethylene glycol) chains are grated onto the guests bearing HQ or DNP moiety, Ka values of these guests to bind with CBPQT4+ could raise up by one or two orders of magnitude [26, 30] (Fig. 7). (iii) When some aromatic guests bearing HQ and DNP insert into the cavity of the host, the aromatic protons in the guests point toward one of the phenyl moieties in the p-xylyl linker of the host (Fig. 9). This orientation allows the occurrence of C–H•••π interaction, which, in some cases, act as the secondary driving force to strengthen the host-guest recognition. The occurrence of C–H•••π interaction could be convinced by the remarkable upfield shifts of the guest resonances in the corresponding 1H NMR spectra, given that the aromatic surfaces provide a shielded magnetic environment. Short contacts (e.g., 2.5 Å) between the protons in the guest and the phenyl moieties in the host also reveal its occurrence in solid state, as inferred from the single-crystal X-ray diffraction analysis. (iv) When the CBPQT4+ accommodates guest in water, in the case that the counterions were Cl, Br, or NO3, hydrophobic effect might occur and enhance

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Fig. 9 Structural formulaes and the corresponding single-crystal X-ray structures of two pseudorotaxanes. The guests contain either HQ or DNP units in the middle. C–H•••π interactions are clearly observed

the host-guest recognition, even although hydrogen-bonding interactions are weakened in these cases. This hypothesis is supported by the stronger Ka for the macrocycle to accommodate the guest BHEEN in water than that in MeCN (see Fig. 7).

3.4.2

Guest Recognition Ability of CBPQT2(•+)

One of the reduced states of CBPQT4+, namely, the bisradical dicationic CBPQT2(•+), contains two BIPY•+ radical cations. Different from the BIPY2+ contains an empty LUMO that affords BIPY2+ the ability to function as a π-electron acceptor, the SOMO of a BIPY•+ already contains an electron. As a consequence, BIPY•+ is not capable of undergoing donor-acceptor interactions with π-electron donors. Instead, BIPY•+ undergoes a type of homo-loving interactions, namely, radical-pairing interactions [31]. That is, the two SOMOs of two BIPY•+ undergo efficient overlapping, forming a set of two larger delocalized molecular orbitals of a (BIPY•+)2 dimer. The two radical electrons thus occupy the newly formed HOMO of the (BIPY•+)2 dimer and therefore get spin paired. The formation of the diamagnetic (BIPY•+)2 dimer could be proven by the observation that a solution of BIPY•+ has clear EPR signal in the condition of low concentration and/or higher temperature, while in the condition of higher concentration and/or lower temperature, the EPR signal becomes weaker or even silent in some cases. The behavior that two identical aromatic radicals get spin paired by means of π-π stacking was also observed in a few of other aromatic radical systems, including TTF•+ radical cation [32] and naphthalene-1,8:4,5-bis(dicarboximide) (NDI•) radical anion [33]. In the case of CBPQT2(•+), spin pairing does not occur to its two BIPY•+ units, because their distance, namely, 7 Å, is too large to allow the occurrence of radical spin pairing by means of π-π interactions, given that the efficient π-π interaction distance is around 3.5 Å. Instead, when a BIPY•+ guest inserts within the cavity, the guest is able to undergo spin-pairing interactions with both of the two BIPY•+ units in the macrocycle simultaneously, forming a BIPY•+CBPQT2(•+) complex [21, 34] (Fig. 10). Because the formation of BIPY•+CBPQT2(•+) is driven

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by the formation of “dual” (BIPY•+)2 dimers or a (BIPY•+)3 trimer, the binding constant Ka (i.e., 105 M1) is generally significantly larger than that of the (BIPY•+)2 dimer. The formation of BIPY•+CBPQT2(•+) has been convinced both experimentally and theoretically. The single-crystal X-ray diffraction analysis (Fig. 10) clearly demonstrates the formation of BIPY•+CBPQT2(•+) in the solid state. In solution, the formation of BIPY•+CBPQT2(•+) could be convinced by the following observations. First, the solution of BIPY•+CBPQT2(•+) exhibits an absorption band in the near-IR (NIR) region in the UV-Vis-NIR absorption spectra, a characteristic absorption band indicating the formation of a (BIPY•+)2 dimer. This NIR absorption band is not observed in the solution of either BIPY•+ or CBPQT2(•+), ruling out the possibility of the occurrence of side-on dimerization of either (BIPY•+)2 or (CBPQT2(•+))2. Second, in the CV spectrum of a 1:1 mixture solution of BIPY•+ and CBPQT2(•+), BIPY•+ has a less negative reduction potential compared to that in its individual solution. This is because the formation of BIPY•+CBPQT2(•+) acts as a driving force, making the reduction of BIPY2+ to BIPY•+ easier to occur. The discovery of the complexation of BIPY•+CBPQT2(•+) represents a milestone in the field of host-guest chemistry. First, radical-involved interactions begin to be employed as a driving force in host-guest recognition, even although for years radicals have been considered as labile species and infeasible to use in supramolecular recognition. Second, when this driving force is employed in the synthesis of mechanically interlocked molecules followed by oxidation, each of the latter molecules could contain a CBPQT4+ interlocked by a dumbbell or a ring containing a BIPY2+ unit. These interlocked components thus are repulsive to each other on account of Coulombic repulsion between these cationic building blocks, defying the commonly received viewpoint that mechanically interlocked molecules should contain mutually attractive components.

Fig. 10 Structural formulae and the corresponding single-crystal X-ray structures of BIPY•+ CBPQT2(•+). Counterions are omitted for the sake of clarity

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Mechanically Interlocked Molecules Containing CBPQT4+ Ring

Mechanically interlocked molecules (MIMs) [14a] have been considered as a type of nonclassic molecules. On the one hand, different from those normal or “classic” molecules whose atoms are all connected covalently with the molecular moiety, MIMs contain multiple components, between which covalent bonds are absent. When some noncovalent interactions occur between the interlocked molecular components, these MIMs might exist in some specific co-conformations. The preference of these co-conformations could be switched by using some external stimuli to tune these intercomponent intramolecular noncovalent interactions including either weakening the primary one or strengthening the secondary one, which results in mechanical movement of these molecular components with respect to each other. This behavior affords MIMs the ability to develop smart materials whose physical properties could be reversibly controlled. On the other hand, these molecular components are mechanically interlocked with each other, in reminiscence of the many interlocked rings in a necklace or metal chain. Without destroying at least one covalent bond, the architecture of a MIM would remain intact. This feature distinguishes MIMs from those supramolecular complexes, whose molecular components can undergo reversible association/dissociation. The often studied MIMs include rotaxanes and catenanes, both of which contain a macrocyclic component that encircles either a dumbbell-shaped or another ring component, respectively. When a linear molecule is encircled by a ring, this system is called a pseudorotaxane, which is a type of supramolecular complexes. Pseudorotaxanes are often used as the precursors in the synthesis of rotaxanes and catenanes, when the terminal groups of the former undergo reactions with larger and bulky molecules, or each other, respectively. We are going to discuss it in more detail in the coming section.

3.5.1

Catenanes Containing CBPQT4+ Ring

The often used approach to obtain catenanes is the template-directed synthesis. Some noncovalent interactions are employed to drive a macrocycle to encircle a thread-shaped molecule, forming a so-called pseudorotaxane. The supramolecular driving forces are of importance, given that they lead to enthalpy release to compensate the entropy loss during the association of the supramolecular complex. When the two groups undergo reaction with each other or another molecule containing two reacting units simultaneously, which has been called “clipping,” a catenane is generated. The formation of the donor-acceptor catenanes containing CBPQT4+ ring relies on the supramolecular interactions between a π-electron-rich ring and a CBPQT4+ ring. The driving forces include donor-acceptor interactions, hydrogen bonding, C–H•••π, as well as hydrophobic effect in aqueous solutions, as we mentioned before. The π-electron-rich ring thus often contains π-electron-rich unit such as

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DNP and TTF grafted with ethylene glycol chains. One approach to synthesize catenanes is by clipping a CBPQT4+ ring around a π-electron-rich unit in a crown ether template. That is, combining a π-electron-rich crown ether BPP34C10, α,α0 -dibromo-pxylene, and 32+•2PF6 in polar solvent, the latter two compounds would produce a CBPQT4+ ring around the π-electron-rich templating unit (Fig. 11) [35]. The overall yield of the catenane 94+•4PF6 was reported to be around 70%. It is also possible to clip the π-electron-rich ring around a BIPY2+ in a CBPQT4+ template. That is, a thread containing a central π-electron-rich unit bearing two ethylene glycol chains is recognized within the cavity of a CBPQT4+ ring. The two terminal groups undergo some high-yielding reactions, including EglintonGlaser-Hay coupling [36] (Fig. 12), Cooper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) [37], as well as esterification [38].

Fig. 11 The template-directed synthesis for the synthesis of a catenane 94+•4PF6

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Fig. 12 Synthesis of a series donor-acceptor [2]catenanes, by clipping via Eglinton-Glaser-Hay coupling

A few reversible reactions were also employed in order to prepare the catenane in a reversible manner, such as imine bond formation [39], as well as metal-catalyzed olefin metathesis [40]. These dynamic approaches often resulted in higher yields, compared with those in the condition of irreversible ones. This is because (i) dynamic bond undergoes reversible forming/cleavage processes, which allows the systems to perform error checking, and therefore the MIMs are synthesized in a thermodynamic control and (ii) the guest recognition ability of CBPQT4+ acts as the driving forces, making the MIMs more thermodynamically favored compared with other byproducts. Even although CBPQT4+ is considered as a macrocycle containing only irreversible covalent bonds, it has been discovered that one of the four C–N bonds between the pyridinium nitrogen and the methylene carbon could become reversible, by using

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iodide anion as both the nucleophile and leaving group. One of the methylene units in CBPQT4+ undergoes nucleophilic attack by an I anion, forming a linear-shaped intermediate whose two terminal groups are benzyl iodide and pyridine, respectively. The driving force is the release of ring strain of the CBPQT4+ ring. In the presence of a π-electron-rich crown ether BPP34C10, the thread could be recognized within the cavity of the former, followed by an intramolecular SN2 reaction between the benzyl iodide and pyridine. The latter process recovers the ring and yields a catenane. The leaving group, namely, the I anion, could undergo another attacking-followed-by-leaving cycle, catalyzing the transfer from CBPQT4+ to catenane 94+ [41] (Fig. 13). After the discovery of BIPY•+CBPQT2(•+) complexation in reduction state, MIMs including catenanes containing CBPQT ring could be driven by radical-

Fig. 13 Synthesis of a donor-acceptor [2]catenane 74+, by using a dynamic approach in which an I anion acts as both the nucleophile that opens the CBPQT4+ ring and the leaving group that yields the catenane

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pairing interactions. In the year of 2013, Stoddart group reported (Fig. 14) the synthesis of a homo-catenane 108+, which is composed of two mechanically interlocked CBPQT ring [42]. A reverse horseshoe-shaped guest 62+ containing a central BIPY•+ moiety was recognized by a CBPQT2(•+), by using Zn dust to reduce the corresponding BIPY2+ units to radical states. The two benzyl bromide terminal groups in the former undergo SN2 reaction with the two pyridine functions in a 4,40 -bipyridine molecule simultaneously. After oxidation by using a strong oxidant, a catenane 108+ bearing eight positive charges could be obtained. Different from those donor-acceptor counterparts, this catenane contains two CBPQT4+ rings that are highly repulsively to each other, on account of

Fig. 14 Synthesis of a homo-[2]catenane 102+ composed of two mechanically interlocked CBPQT4+ ring by radical-pairing interactions. Counterions are omitted for the sake of clarity

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the Coulombic repulsion between the cationic building blocks. This feature also brings about a unique property of this catenane. That is, in order to decrease the Coulombic repulsion, one or two of the BIPY2+ units in the catenane prefer to stay in the radical state, namely, BIPY•+. As a consequence, the radical is highly stabilized, opening up opportunities to develop purely organic paramagnetic materials.

3.5.2

Rotaxanes Containing CBPQT4+ Ring

The donor-acceptor rotaxanes are obtained in a similar approach as their catenanes counterparts, relying on the ability of a CBPQT4+ ring or its precursors to recognize the π-electron-rich guests. Clipping reaction of α,α0 -dibromo-p-xylene and 12+ occurs in the presence of a dumbbell, yielding the corresponding rotaxanes [43]. Because the C–H•••O hydrogen bonds play an even more important role than that of donor-acceptor interactions, it was observed that the dumbbells containing more ethylene glycol units often produced rotaxanes in higher yields. The threadingfollowed-by-stoppering strategy is also often used in the synthesis of rotaxanes containing a CBPQT4+ ring. Here the CBPQT4+ ring encircles a thread on its πelectron-rich binding station. The two terminal OH groups of the thread react with two larger bulky silicon derivatives whose volume should be larger than the cavity of CBPQT4+ ring to trap the corresponding rotaxane architectures [26] (Fig. 15). CuAAC [44], which has been referred to as click reaction, is an ideal reaction for rotaxanes synthesis [45], because of (i) high yield and (ii) room temperature condition that favors complexation. The capability of CBPQT2(•+) to recognize a guest containing BIPY•+ was also taken advantage (Fig. 16) of by the Stoddart group in the synthesis of rotaxanes [46]. A complex 11•+CBPQT2(•+) was self-assembled. Tris(2,20 -bipyridine) dichlororuthenium(II) was used as a sensitizer, which reduces the BIPY2+ units in both CBPQT4+ and 112+ to their radical states, in the presence of amino sacrificial reductant under visible light. The two azide terminal groups in 11•+ were introduced to undergo a type of click reaction, namely, azide-alkyne cycloaddition. An electron-deficient alkyne 12 was chosen, because it has a low-lying LUMO and therefore can undergo azide-alkyne cycloaddition without Cu(I) catalyst. Avoiding Cu(I) catalyst is of importance, due to its oxidative nature that might quench the BIPY•+ radicals. After the click reaction was accomplished, a rotaxane 136+ was obtained, whose dumbbell and ring components are repulsive to each other. A few years later, the Stoddart group also discovered [47] that the length of rotaxane could determine the stability of BIPY•+ radicals in the rotaxane against oxidation. In a shorter rotaxane, the distance between the CBPQT4+ ring and the central BIPY2+ unit in the dumbbell is smaller, which introduces larger Coulombic repulsion. The unfavorable repulsive interaction increases the tendency of the BIPY2+ unit to be reduced, as a consequence of which, the radical state of the short rotaxane is remarkably stabilized.

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Fig. 15 Synthesis of rotaxanes by using a threading-followed-by-stoppering strategy. A 2,6lutidine catalyzed Si–O bond formation is used for the stoppering reaction to capture the rotaxane structures

3.6

Molecular Machines and Molecular Switches

As mentioned before, MIMs could be switched between different co-conformations by tuning the noncovalent interactions between the interlocked molecular components. First, these different co-conformers, whose covalent structures are essentially the same, might have dramatically different physical properties, such as color, luminescence, electric conductivity, hydrophilicity, as well as viscosity. This

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Fig. 16 Synthesis of a rotaxane 136+ by using radical templation. The counterions are omitted for the sake of clarity

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switching behavior could be used to design smart materials, whose properties could be controlled by employing external stimuli. For example, when a bistable rotaxane whose two co-conformers have remarkable difference in electric conductivity, it has the potential application in the design of molecular computer [48], i.e., the two co-conformers could represent “0” and “1,” respectively, for information storage. Second, switching between different co-conformers allows the components of a MIM to undergo intramolecular machinery mechanical movement, which could perform work on the surroundings and influence their properties. This potential ability opens up the opportunities for human to precisely control the microscopic world. The early trials include the nanoelectromechanical systems [49], in which the switching behavior of a MIM is employed to control the shapes and properties of an inorganic component. Using molecular switches to develop mechanized silica nanoscopic particles [50] for precisely targeted drug delivery represents another example of their potential applications. In the year of 2016, the Nobel Prize in Chemistry was awarded to three chemists, including Jean-Pierre Sauvage [19a], Sir Fraser Stoddart [19b], as well as Bernard Feringa, on account of their contributions in the field of molecular machines. The former two chemists, namely, Jean-Pierre Sauvage and Sir Fraser Stoddart, employed MIMs in the design of molecular machines. In order to shed light on the underneath mechanism how a molecular switch or machine works, we use a bistable rotaxane as a model compound. In the dumbbell component, two binding stations are introduced. This bistable rotaxane thus has two co-conformations, determined by which station the ring encircles. The ring is doing random Brownian movement along the dumbbell between the two stations, even although the energy barrier could be controllable by introducing a steric or electronic “speed bump” in the dumbbell between the two stations. When the macrocycle encircles the stronger or primary binding station, the rotaxane adopts a co-conformation that has been called ground state co-conformation (GSCC). In contrast, the co-conformation in which the ring sits on the weaker or secondary binding station has been called metastable-state co-conformation (MSCC). The ratio of the two co-conformations could be determined by the energy gap (ΔG) between the two co-conformations, as claimed by Boltzmann distribution, i.e., ΔG = RTlnK (K is ratio of GSCC to MSCC). A molecular switch and machine based on a bistable catenane has a similar working mechanism, except that the dumbbell in a rotaxane is replaced by a macrocycle containing two binding stations in a catenane. When an external stimulus is introduced, which either weakens the binding between the primary binding station (i.e., station A) and the ring or strengthens the binding provided by the secondary binding station (i.e., station B), the preference of the macrocyclic component to encircle the two stations would change. That is, more macrocycles would prefer to encircle the station B, after addition of the external stimuli, which implies that it is a net effect that the ring is “moving” from station A to station B. This mechanism is different from its macroscopic counterparts, in which a macroscopic object undergoes direct change of its physical position. Removing the stimuli might recover the noncovalent bonding, and therefore the ring might move back to station A as a net effect.

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In the year of 1994, the first molecular switch in the form of bistable [2]rotaxane 144+ containing CBPQT4+ as the macrocyclic component was synthesized [51] (Fig. 17) in the group led by Stoddart. The dumbbell component bears a benzidine as the primary station and a biphenol unit as the secondary one. The stronger binding affinity of benzidine compared to biphenol results from the fact that the two amino nitrogen atoms on benzidine represent better electron donors than the oxygen atoms on biphenol function. Either oxidation or protonation of the benzidine introduces a positive charge, which diminishes its binding affinity with the ring. As a consequence, the CBPQT4+ moves and encircles the biphenol station. Performing reduction or deprotonation of benzidine recovers its binding affinity, and therefore the ring moves back to this station. TTF, whose switching behavior under redox stimuli is more reversible than benzidine, was also employed in the design of molecular switches in the form of both multi-stable rotaxanes [52] and catenanes. For example, in the catenane 154+ (Fig. 18), TTF and DNP act as the primary and secondary binding station for the ring, respectively. The ratio of GSCC to MSCC is around 150:1 determined by using slow scan rate cyclic voltammetry [53], in which the ring encircles the TTF and DNP unit, respectively. Oxidation of TTF would drive the ring to reside on the DNP station [54]. When the secondary binding station is a di-alkyne linker that has no binding affinity with the CBPQT4+ ring, a so-called push-button molecular switch

Fig. 17 The bistable [2]rotaxane 144+, which could be switched between two co-conformers by using redox or acid/base stimuli

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Fig. 18 The bistable [2]catenanes 154+ and 164+, in both of which, TTF acts as the primary binding station. In 154+, DNP acts as a secondary binding station. The ratio of GSCC to MSCC is around 150:1. Counterions are omitted for the sake of clarity

[36a] in the form of a catenane 164+ was obtained. That is, in the neutral state, the catenane 164+ adopts (Fig. 18) a co-conformation that the CBPQT4+ ring encircles the TTF unit almost exclusively, on account of the absence of any binding affinity between the di-alkyne linker and the CBPQT4+ ring. Upon oxidation of the TTF unit to its cationic forms, either TTF•+ or TTF2+, CBPQT4+ ring chooses to reside on the di-alkyne exclusively, in order to avoid Coulombic repulsion introduced by the cationic TTF•+ or TTF2+ unit. This all-or-nothing switching behavior is even more obvious in the molecular switch whose switching behavior is driven by using the radical-pairing interactions. A bistable rotaxane 178+ was designed [21] (Fig. 19), containing a CBPQT4+ ring threaded onto a dumbbell that bears a DNP and a BIPY2+ unit. In the fully oxidized state, the tetracationic ring resides on the former station, driven by donor-acceptor interactions. The preference of the ring to encircle DNP is close to exclusive, given that DNP is the only π-electron-rich unit that has binding affinity with the ring. In the reduced state, the CBPQT2(•+) resides on the BIPY•+ station exclusively, driven by radical-pairing interactions. Introducing oxygen into the system could oxidize the radicals to the dicationic state, resetting the rotaxane. A few years later, the same group developed a light-stimulated “version,” namely, a bistable rotaxane 178+ [55] by introducing a photosensitizer as one of the two stoppers onto the rotaxane 178+. The light-stimulated excited state of a photosensitizer, namely, a tris(2,20 -bipyridine) dichlororuthenium(II) stopper, is able to reduce BIPY2+ units in the rotaxane into BIPY•+ in the presence of amino sacrificial reagent, namely, tri(ethanol)amine. It is noteworthy that the aforementioned molecular switches produce the ring movement in a reciprocating manner. That is, when a stimulus is used to drive the movement of the CBPQT4+ ring, the work produced by the macrocycle would be

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Fig. 19 The light-stimulated bistable [2]catenanes 178+. In oxidative conditions, the ring encircles the DNP station. Under visible light, the tris(2,20 -bipyridine)dichlororuthenium(II) stopper can reduce the BIPY2+ units in both the ring and the dumbbell components with the assistance of N (CH2CH3)3 as a sacrificial reagent. After reduction, the ring shuttles and encircles the BIPY•+ station

cancelled or neutralized when we reset the molecular switch, because the ring returns to its original position by using a reversed pathway. Or expressed in another way, the net energy produced by the molecular switch is nothing after a full switching cycle. In order to produce a real artificial molecular machine that is able to produce useful work to the surroundings, a pseudorotaxane 18+CBPQT4+ that produces unidirectional motion was designed [56] (Fig. 20). A CBPQT4+ ring encircles a DNP unit in a dumbbell-shaped molecule 18+ bearing two terminal units, namely, a neutral 2isopropylphenyl group and a positively charged 3,5-dimethylpyridinium unit. The formation of the pseudorotaxane 18+CBPQT4+ is again driven by donor-acceptor interactions. However, due to the Coulombic repulsion introduced by the 3,5dimethylpyridinium, the association of the pseudorotaxane occurs in the manner that the ring passes the 2-isopropylphenyl unit. Reduction of the ring diminishes its binding affinity for the DNP station and therefore results in the dissociation of the pseudorotaxane. At the same time, the Coulombic repulsion between the reduced ring and the 3,5-dimethylpyridinium unit undergoes significant decrease. In order to avoid the steric hindrance introduced by the 2-isopropylphenyl group, the CBPQT2(•+) ring chooses to pass the 3,5-dimethylpyridinium unit to finish dissociation. These switching behaviors enable the ring to perform unidirectional movement from one end of the dumbbell to another, generating useful work.

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Fig. 20 A pseudorotaxane 18+CBPQT4+ which can perform unidirectional association and dissociation motion under redox stimuli

3.7

Extended Derivatives of CBPQT4+ Ring

A number of extended “versions” of CBPQT4+ rings were also designed and synthesized, which acts as larger counterparts of the small Blue Box. These extended derivatives are able to host either larger guests or in some cases, multiple guests simultaneously. In the year of 1996, a wider counterpart of CBPQT4+ ring, namely, cyclobis (paraquat-4,40 -biphenylene) (CBPQB4+) [57], was obtained (Fig. 21), by using ferrocene, a relatively “thicker” guest to template its formation. The two BIPY2+ units are bridged by two 4,40 -bitolyl spacers, instead of the p-xylyl linkers in the synthesis of CBPQT4+. The distance between the two BIPY2+ units in CBPQB4+ is around 11 Å, enabling the ring to recognize two π-electron guests within the cavity, where both of the two guests undergo donor-acceptor interactions with the two BIPY2+ units in CBPQB4+ ring in an A-D-D-A manner (A, acceptor; D, donor). This recognition behavior opens up opportunities to use CBPQB4+ to synthesize [3] catenanes. In fact, the [3]catenane 204+ (Fig. 22) containing CBPQB4+ was even synthesized [58] before CBPQB4+ itself. The two crown ether rings in the 204+ act as the intrinsic templates for the ring closing reaction. A few years later, [3]catenane 214+ (Fig. 23) containing two TTF recognition sites was obtained [59]. Both the two TTF units in the two crown ether rings locate within the cavity of CBPQB4+. Interestingly, upon oxidation of TTF units into cationic TTF•+ radicals, the two TTF•+ units continue to reside within the macrocycle cavity, undergoing radicalpairing interactions. This behavior indicates that radical-pairing interactions within a (TTF•+)2 dimer are strong enough to overcome the Coulombic repulsion between

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Fig. 21 Structural formulaes of the extended derivatives of CBPQT4+

Fig. 22 Structural formula of a [3]catenane 204+

the TTF•+ units and the tetracationic cyclophane. It is also strong enough to compensate the potential enthalpy release that results from the donor-acceptor interactions between the DNP unit and the CBPQB4+ ring. Further oxidizing TTF•+ to TTF2+ diminished the (TTF•+)2 radical-pairing interactions, leading to a co-conformation that the ring encircled the two DNP stations. Different from CBPQT2(•+) that can recognize a BIPY•+ guest, the ability of CBPQB2(•+) to accommodate two BIPY•+ guests in the cavity is relatively weak. This is probably because encapsulation of two BIPY•+ guests within the cavity of CBPQB2(•+) simultaneously leads to too much entropy loss. However, when the two BIPY•+ units are connected by two m-xylyl linkers, the macrocyclic 222(•+) could be

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Fig. 23 Structural formula of a [3]catenane 214+ and its redox-switching behavior

Fig. 24 Structural formulas of the ring-in-ring complexes, including (a) 222(•+)CBPQB2(•+) and (b) Guest CBPQT2(•+)192(•+)

recognized within the CBPQB2(•+) ring (Fig. 24a). The complex 222(•+)CBPQB2(•+) [60] contains two (BIPY•+)2 dimers, as a consequence of which, it is diamagnetic and can be characterized by NMR spectroscopy. This ring-in-ring recognition is taken advantage of in synthesizing a rotaxane [61], whose dumbbell component contains a macrocyclic binding station. In a recent report, by introducing an ethyne unit between the two phenyl rings in the 4,40 -bitolyl spacer, the Stoddart group obtained a wider cyclophane 194+. This ring in its radical state is able to accommodate a CBPQT2(•+), which, again, is driven by radical-pairing interactions. Within the cavity of 192(•+), the CBPQT2(•+) ring can still act as a host to recognize a variety of guests forming a series of supramolecular architectures that are reminiscence of the Russian dolls [62] (Fig. 24b). The extension of CBPQT4+ could also be performed in the BIPY2+ part. By introducing a phenyl unit between the two pyridinium moieties in the BIPY•+ functions, a so-called Exbox4+ [63] was obtained. The central phenyl moiety is rather electron-deficient, due to the electron-withdrawing effect from the two pyridinium either by means of inductive effect or conjugation. Exbox4+ is thus able to recognize a few π-electron-rich aromatic hydrocarbon compounds, such as anthracene, phenanthrene, pyrene, etc. Introducing two phenyl units in each of the two BIPY•+ functions in CBPQT4+ could produce an Ex2box4+ [64]. In the Ex2box4+, each of the central phenyl units is

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connected with only one of the two pyridinium units. The consequence is that the central biphenyl units do not have good π-electron-accepting ability. Instead, the cavity of Ex2box4+ has a dual feature. In the terminal part, the cavity is rather electron-poor and can recognize electron-rich guest, which is reminiscent of CBPQT4+ ring. In the middle part, the cavity of Ex2box4+ is able to recognize electron-deficient guest. Ex2box4+ is even able to accommodate two trichlorobenzene guests. A few other extended boxes, including TVBox8+ [65], Ex2.2Box4+ [66], as well as ExBox24+ [67], were also synthesized, whose structures are illustrated in Fig. 21. In addition, now cage-shaped versions of CBPQT4+, namely, Excage6+ [68] and BlueCage6+ [69], were also obtained. These prism-shaped cages are composed of two triangular π-electron acceptors that are bridged by three spacers. Given that the triangular π-electron acceptors are triscationic and have better π-electron-accepting ability, these two cages often have larger binding affinity for π-electron-rich guests, compared to the ring counterparts (Figs. 23 and 24).

3.8

Conclusions and Outlook

In sum, the CBPQT4+ ring represents one of the most important macrocyclic hosts in the field of supramolecular chemistry and host-guest chemistry. It can recognize a variety of aromatic guests, most of which are π-electron-rich. These capabilities are based on (i) the rigid macrocycle framework of CBPQT4+, resulting in little to no entropy loss during guest accommodating, (ii) the distances between the two pyridinium moieties are optimal to allow the guests to undergo donor-acceptor interactions with both of them in either A-D-A or A-D-D-A manner. This hostguest recognition ability allows CBPQT4+ ring to be used as the building block to synthesize a variety of supramolecular or mechanically interlocked architectures. The driving forces for CBPQT4+ to recognize guests including donor-acceptor interactions, hydrogen bonding, electrostatic forces, C–H•••π interaction, as well as hydrophobic effect are expressed in water. In the condition of reduction, the CBPQT2(•+) ring becomes attractive to BIPY•+ guests, driven by radical-pairing interactions. By tuning these driving forces, the host-guest complexation could be controlled, in the form of either dissociation of pseudorotaxanes or co-conformation switching in the case of bistable rotaxanes or catenanes. These switching behaviors of the CBPQT4+ ring based on supramolecular or mechanically interlocked architecture are taken advantage of in the design of molecular switches and machines, which could potentially be used in developing smart materials. The dream of human beings to precisely control the microscopic world might come true. In order to allow the recognition of some larger guests, or realize multiple guest recognition, extended versions of CBPQT4+ ring were developed. These macrocycles demonstrate different guest recognition behavior from that of CBPQT4+ ring. Their recognition abilities enable more complex architectures to be synthesized.

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4

Mechanically Self-Locked Molecules Sheng-Hua Li, Yong Chen, and Yu Liu

Contents 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Pseudo[1]rotaxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1 Cyclophane-Based Pseudo[1]rotaxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2 Crown Ether-Based Pseudo[1]rotaxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3 Cyclodextrin (CD)-Based Pseudo[1]rotaxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Pseudo[1]catenanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Molecular Figures-of-Eight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5 Pretzelane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6 Double-Lasso Macrocycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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S.-H. Li College of Chemical Engineering and Materials Science, Tianjin University of Science and Technology, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, China Y. Chen · Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_5

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Introduction

The dream of the “Gluttonous Snake” not only inspired Friedrich Kekule with the structure of benzene ring but also led chemists to begin to understand the macrocyclic molecules. Interesting and biologically active circular natural molecules, like terpenoids, not only enlightened chemists to develop a variety of methods to synthesize them [1, 2] but also prompted the designation and synthesis of organic compounds with novel structures that are not naturally existing [3]. In the 1960s, Wasserman first synthesized and discovered a mechanically interlocked molecule ring and named it catenane using the latin etymological catenof the chains and put forward the concept of “chemical topology” with Frisch later [4, 5]. However, due to the low synthesis efficiency of this kind of mechanically interlocked molecules, the research of which had always been ignored until the year of 1983. That was the year, Savage et al. [6] proposed a new synthesis strategy using metal ion as template, which greatly simplified the synthesis route and improved the synthesis efficiency of the mechanically interlocked molecules. Subsequently, the research on mechanically interlocked architecture exploiting supramolecular template strategy developed rapidly. And the construction of various organic molecules with novel and complex topologies greatly promoted the research on molecular machine. Pseudo[1]rotaxane and pseudo[1]catenane could be simply prepared from a pseudo[2]rotaxane by connecting the axle with the macrocyclic part. The most important feature of this kind of structure is that it includes mechanical bond in a single covalent component. Pseudo[1]rotaxane is the simplest mechanically selflocked molecular architecture. When a molecule contains a macrocycle covalently linked to a molecular chain, it will have two interesting molecular conformations. One is the chain segment lies behind the macrocycle like a tail, and the other one is that the chain part bends back threading through the cavity of the macrocycle, which is given the name – self-inclusion complex. When the other end of the chain molecule in its self-included conformation is connected with a large molecular fragment (also known as the end-capping group), we call it [1]rotaxane. When the chain part penetrates through the macrocyclic molecule and both ends are connected to the same segment of the macrocyclic molecule, we call it [1]catenane. If the two ends of the chain part link to two different segments of the macrocyclic molecule, we call it molecular figure-of-eight. Therefore, based on the topology structure of the mechanically self-locked molecular architecture, we classify this kind of architectures into pseudo[1]rotaxanes, pseudo[1]catenanes, molecular figures-of-eight, pretzelanes, and double-lasso molecules to discuss.

4.2

Pseudo[1]rotaxanes

Compared to pseudo[1]rotaxanes, [1]rotaxane has an bulky end-capping group and it seems that it can keep the self-included conformation. However, due to the reverse of the macrocyclic fragment, the axial part that passes through the macrocycle could escape from the macrocycle and change its conformation as shown below

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(Fig. 1). According to the macrocyclic components of pseudo[1]rotaxanes, we summarized pseudo[1]rotaxanes from three parts as cyclophane, crown ether, and CD-based systems.

4.2.1

Cyclophane-Based Pseudo[1]rotaxanes

In 2000, Busch [7] and Vogtle [8] proposed the concept of pseudo[1]rotaxanes in a review and a research paper, respectively. Vogtle has been devoted to the study of constructing novel mechanically self-locked molecules with chirality. In 2000, he reported a structurally stable [1]rotaxane system through covalently linking the wheel part (cycloaromatic amide units) and the axle part (amide units) of a [2] rotaxane. This class of mechanically self-locked structures could be synthesized in preparative yields and their circular dichrograms depending on the lengths of the bridge were systematically studied. Stoddart [9–11] has been committed to the study of photoelectric behaviors of host-guest complexes based on viologen-contained macrocycles and electron-rich aromatic compounds. Since 1997, his group [9, 10] designed and synthesized several pseudo[1]rotaxane systems (which is always called self-complexes by Stoddart) and conducted systematic studies on the photoelectric behaviors of such simple molecular shuttles by changing the structure of the electron-rich aromatic rings (Fig. 2a). In general, when an electron-rich aromatic ring as electron donor shuttled through an electron-deficient cyclophane containing viologen (cyclophane cyclobis (paraquat-p-phenylene), CBPQT4+), the strong π-π noncovalent interaction began to play a vital role in stabilizing the structure. However, when viologen was reduced to an electron-rich aromatic ring, the π-π effect was greatly weakened, resulting with the separation of the axle part from the cavity of the macrocycle. The color of the system also changed significantly from the macro point of view. Until 2017, two potential viologen-based pseudo[1]rotaxane both containing a 4,40 -bipyridinium unit as part of the chain appended to a CBPQT4+ ring also have been reported to mimic the mechanical motion of a lasso peptide (Fig. 2b) [12]. By treating this pseudo[1]rotaxane with Zn dust, due to strong intramolecular radical-pairing, a self entanglement process could be triggered to form a noose-like conformation. Interestingly, Becher et al. [13] also reported a series of pseudo[1]rotaxane based on CBPQT4+ in 1998, while exploiting tetrathiafulene (TTF) as the electron donor. Then in 1999, they [14] reported the conformation transformation of the above mentioned [1] rotaxane. They found that when the “decomplexed conformation” was triggered by fractional crystallization, the rigid compound (Fig. 3a) was not able to recomplex to any significant degree, while the relatively more flexible [1]rotaxane (Fig. 3b) could Fig. 1 Conformation tautomerism of [1]rotaxane

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Fig. 2 (a) Pseudo[1]rotaxanes based on CBPQT4+ [9, 10]; (b) conformation transformation of CBPQT4+-viologen-based pseudo[1]rotaxane upon the addition of Zn dust [12]

Fig. 3 Pseudo[1]rotaxanes based on CBPQT4+ and TTF with (a) rigid or (b) flexible linkage; (c) pseudo[1]rotaxane based on cyclophane containing TTF as host and pyromellitic diimide as guest [14]

reestablish an equilibrium between the complexed and uncomplexed states in solution. Therefore, Fig. 3b could be seen as a “thermal switch” though the response was very slow. Taking advantage of the multivalency of TTF, Becher et al. [14] also synthesized a cyclophane containing TTF as electron-rich macrocycle and linked the pyromellitic diimide as electron acceptor to the cyclophane, thus resulting with the corresponding pseudo[1]rotaxane (Fig. 3c). And the mechanical behavior of it was systematically studied. In 2006, Cooke et al. [15] reported a self-complexed donor-acceptor pseudo[1] rotaxane system using CBPQT4+ as acceptor and wheel part, and the electron-rich pyrrole unit connected with CBPQT4+ as the axle part (Fig. 4). This pseudo[1] rotaxane system possessed excellent photoelectric property. The self-complexed conformation of this pseudo[1]rotaxane could be disrupted thermally,

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Fig. 4 Conformation transformation of pseudo[1]rotaxanes using CBPQT4+ as acceptor and wheel part, and the electron-rich pyrrole unit connected with CBPQT4+ as the axle part [15]

electrochemically, or by the addition of a guest with more effective binding ability with the cavity of CBPQT4+. When lowering the temperature of the pseudo[1] rotaxane, the uncomplexed conformation turned to the self-complexed conformation due to the enhancement of the π-π interaction at a relatively low temperature, and this phenomenon could be clearly observed on NMR time scale. When the viologen part of the cyclophane unit was reduced to a diradical dicationic state electronically, the flexible arm – pyrrole unit – dethreaded from the cyclophane’s cavity. When the competitive bonding agent TTF was added to the system, an emerald-green solution was obtained immediately due to the charge-transfer process of the newly formed TTF-CBPQT4+ complex. Broadly defined, resorcinarenes and pillararenes also belong to cyclophanes. Pseudo[1]rotaxanes and self-complexes based on such macrocyclic systems were also investigated by supramolecular chemists, and the novel structures and stabilities of pseudo[1]rotaxanes were preliminarily studied [16, 17]. Rebek et al. [16] constructed a series of self-complexed tetrabenzimidazole cavitands with alkyl chains of different lengths appending to the upper rim. As shown in Fig. 5a, when in the appearance of hydroxylic solvent or cosolvent, these cyclophanes could fold into a “vase-like” conformation due to hydrogen bonding between the benzimidazole groups. One of the alkyl chains could helically coil into the cavity of resorcinarenes to form [1]rotaxane architecture in CDCl3 solvent (which also acted as a competitive guest). These flexible alkyl chains could exchange with each other via a CDCl3-containing intermediate process proven by 2D NMR, and the exchange rates could also be determined on the NMR time scale. This type of self-complexed resorcinarene could be potentially used as sensors or triggers for external stimuli. Recently, Yang et al. [17] reported a pillar[5]arene-based [1] rotaxane (Fig. 5b) and proved its catalytic performance in Knoevenagel reaction.

4.2.2

Crown Ether-Based Pseudo[1]rotaxanes

As the first generation of macrocycle, crown ether has always been the research focus of supramolecular chemists due to its easy modification. Based on the

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Fig. 5 (a) “Vase-like” conformation of resorcinarene-based [1]rotaxane [16]; (b) self-complexed conformation of pillar[5]arene-based [1]rotaxane [17]

molecular chameleon system discovered in 1998 by Stoddart et al., they also designed and synthesized a pseudo[1]rotaxane system containing naphthalene ring-based crown ether and the electron-deficient viologen structure in 2001 [18]. The 4,40 -bipyridinium unit could undergo reversible threading and dethreading motions in the cavity of crown ether when dissolved in solvents of different polarity or acidity. When this pseudo[1]rotaxane was in CH2Cl2, the viologen tail tended to thread into the macrocycle due to the hydrogen bonds between the hydrogen atoms of bipyridinium and the oxygen atoms of crown ether; while in CH3CN, the dicationic viologen moiety was well solvated by the polar solvent. Similarly, when in acidic condition, the bipyridinium was protonated and complexed by crown ether; while in basic environment, the viologen part would more prefer to lay outside. Also, the spectroscopic and electrochemical properties were studied (Fig. 6). In 2004, Hiratani et al. [19] reported a structurally stable [1]rotaxane, which could keep the self-complexed conformation even after heating for 5 h at 100  C. As shown in Fig. 7, an anthracyl unit was linked to the macrocycle by a long alkyl chain, which threaded through the cavity of the crown ether containing naphthalene ring. Then the optical property of the stable [1]rotaxane was systematically investigated. Fluorescence resonance energy transfer (FRET) occurred between the naphthalene group of the macrocycle part and the anthracene group of the axle part, due to the efficient overlap of the emission spectra of naphthalene and excitation spectra of anthracene. When lithium ions were added to the [1]rotaxane system, fluorescence emission of anthracene group enhanced greatly because lithium ion closed the distance between naphthalene and anthracene efficiently through host-guest complexation thus resulting with the increasement of FRET efficiency. Feringa et al. [20] have been engaged in the research of light-controlled molecular motors. He introduced the photoinduced double bond isomerization switch into the [1]rotaxane system containing crown ether structure (Fig. 8). When in acidic

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Fig. 6 Conformation transformation of crown ether- and viologen-based pseudo[1]rotaxane upon the addition of acid or base [18]

Fig. 7 Schematic illustration of the conformation stable [1]rotaxane and its optical properties (increase of fluorescence) upon the addition of Li+ [19]

Fig. 8 Conformation transformation of molecular motor based on crown ether upon the addition of acid or base [20]

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condition, the molecular motor stayed at its shuttered state because of the existence of strong supramolecular complexation interaction between secondary ammonium salts unit and crown ether group. While upon the addition of base, the acid proton of the secondary ammonium salt was neutralized resulting with the decreasing of the host-guest bonding between amine and crown ether, thus further triggering the sliding out of the axle from the crown ether’s cavity. Then the molecular motor was switched to a open state. This process is reversible through repeated adding of acid or base. Finally, through reduplicative exposure, this [1]rotaxane system to ultraviolet light, a directional rotation of molecular motor, was successfully constructed. In 2012, Qu group [21] introduced ferrocene unit into the crown ether-based bistable [1]rotaxane system. As shown in Fig. 9a, a linear chain was grafted to one of

Fig. 9 Conformation transformation of pseudo[1]rotaxane based on crown ether as host and ferrocene as linkage upon the addition of acid or base [21, 22]

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the cyclopentadienyl ring of ferrocene unit and complexed by dibenzo-24-crown8 which was connected to the other cyclopentadienyl ring of the ferrocene unit. Then they investigated the relative mechanical motion of the chain part to the crown ether. When pH value of the system was changed, the dibenzo-24-crown-8 unit would slide on the axis of rotaxane, thus changing the electrochemical behavior of the molecular system. When in acidic condition, the macrocycle bound with the secondary ammonium salt unit, and the pseudo[1]rotaxane system was electrochemically reversible; while upon the addition of DBU, the triazole rings fell into the cavity of the dibenzo-24-crown-8, resulting with an electrochemically irreversible system. In 2013, a continuous work was reported by them [22]. In this work, they introduced a fluorescent naphthenyl imide group at the end of the [1]rotaxane system, so that a fluorescent emission “active” or “silent” mode of the system could be controlled by simply changing the pH (Fig. 9b). These systems laid a solid foundation for the construction of advanced logic circuits with memories or sequential functions. As shown in Fig. 10a, in 2014, Qu et al. [23] also synthesized a class of [1]rotaxane with star-shaped structure by using some bifunctional end-sealing agents. In these systems, when external base or acid was added, the crown ether would do an uniform relative mechanical movement along with the arms of the [1]rotaxanes. Then they investigated the energy-minimized structure of the [1]rotaxanes in acetone via molecular dynamics simulations. The results showed that a complexed molecular structure which resembled the muscle’s extension and contraction was successfully constructed (Fig. 10a). Similarly, Coutrot [24] also designed and synthesized a star-shaped [1]rotaxane through a covalent template strategy in 2015 (Fig. 10b), which could not be constructed by classical straightforward strategies. In this system, the “macrocycle transporter” played three key roles: first to bind a dibenzo-24-crown-8, second to link a triazolium-containing axle temporarily, and third to deliver the dibenzo-24-crown-8 around the newly formed axle as a molecular machine. Finally, the extended encircled thread was cut off and a [1]rotaxane was obtained. As shown in Fig. 11, Mayer et al. [25] connected the crown ether ring containing 1,10-phenanthroline unit to a long alkyl chain which also contained 1,10phenanthroline group. This compound could dynamically change between the selfentangled and disentangled conformations. The change of the morphology could efficiently influence the size and length of the pseudo[1]rotaxane molecules, suggesting a potential application in the area of molecular actuators’ construction. Amazingly, upon the addition of metal ions, this pseudo[1]rotaxane could keep its conformation as self-entangled due to the complexation of a copper ion with two phenanthroline units on both the macrocycle and alkyl chain in the same molecule. While treated with an excess of KCN, the copper ion could be cleared from the system, thus recovering to the equilibrium of a self-entangled and disentangled state. In this way, they obtained a pseudo[1]rotaxane structure that could response to chemical stimuli. As shown in Fig. 12, Takata et al. [26] used a polymer chain (loaded with terminal agent) to connect with a pseudo[1]rotaxane structure which contained crown ether

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Fig. 10 (a) Extension and contraction conformation transformation of [1]rotaxane with star-shaped structure upon the addition of acid or base [23]; (b) synthesis of a star-shaped [1]rotaxane through a covalent template strategy [24]

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Fig. 11 Cu2+ modulated self-entangled and disentangled conformation transformation of a crown ether-based pseudo[1]rotaxane [25]

Fig. 12 Conformation transformation of a [1]rotaxane structure based on crown ether and secondary ammonium [26]

as macrocycle and a secondary ammonium salt as axle. Then they partially acetylated the secondary amine, thus resulting with the decomplexation of the crown ether and secondary ammonium, along with a relative mechanical movement at the axle making that the conformation of the whole polymer changed from line to ring. Through this conventional simple protection-deprotection method, they realized the adjustment between linear and cyclic transformation reversibly, obtaining a new type of dynamic system that could pave the way for novel stimuli responsive polymers. From another perspective, this new synthetic strategy for

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cyclization provide a new idea for the synthesis of cyclic polymers at a large scale, regardless of the concentration or side reactions (macrocyclization and polymerpolymer reactions).

4.2.3

Cyclodextrin (CD)-Based Pseudo[1]rotaxanes

As the first discovered macrocyclic host molecule, CDs and their single modified derivatives have been extensively studied due to their easy synthesis and more importantly the complexation interaction with hydrophobic guest. When the size and shape of the unit modified on CD matched with the CD’s cavity, the molecule tended to form a self-included complex. While the modified unit could pass through the cavity of CD, a [1]rotaxane based on CD would be significantly constructed.

4.2.3.1 Pseudo[1]rotaxanes Related to Pyranose-Based CDs In 2003, the first pseudo[1]rotaxane structure based on CD was reported by Easton et al. [27] Several [2]rotaxanes were firstly prepared, including α-CD as the rotor and stilbene as the axle, and trinitrophenyl group as terminal agents. Then α-CD-based pseudo[1]rotaxanes were successfully fabricated through a tactful linkage (succinamide) of the rotor and the axle (Fig. 13). They investigated the pseudo[1]rotaxanes system through the application of 2D NMR by performing TOCSY, DQF-COSY, ROESY, HMQC experiments. And finally they made the conclusion that the relative intramolecular rotation was limited due to the steric hindrance effect between the methoxy group on stilbene and the side chain portion of the α-CD, which was much similar to the ratchet and pawl elements. Azobene, as a photoisomeric switch that can be efficiently bound by α-CD and β-CD through host-guest interaction, could change to its trans-conformation upon the irradiation of 365 nm light and to its cis-conformation under 430 nm light reversibly. Tian et al. [28, 29] developed a series of pseudo[1]rotaxane based on the complexation of CD and azobene. In 2007, they reported a light-driven pseudo[1]rotaxane which was prepared conveniently and directly via self-included complexation interaction of azobenzene modified β-CD, and this pseudo[1]rotaxane was capped with fluorescent naphthalimide type terminal agent through Suzukicoupling. This direct method, for the first time exploiting the subtly intramolecular Fig. 13 Mechanically selflocked conformation of the α-CD-based [1]rotaxane resembling ratchet and pawl [27]

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self-inclusion to make the intriguing [1]rotaxane conveniently and provided a novel idea for the preparation of amazing mechanically self-locked architecture. In 2013, they investigated the photophysical and induced circular dichroism (ICD) properties of a [1]rotaxane system much similar to the above mentioned one through both experimental and computational methods (Fig. 14a) [30]. Taking advantage of the DFT calculation and molecular dynamics simulations, they rationalized the magical ICD signal with the interconversion of a number of conformers in the aqueous system. Based on the research foundation of ICD and room temperature phosphorescence (RTP), they designed a similar pseudo[1]rotaxane and studied its INHIBIT logic operations upon the addition of α-bromonaphthalene (α-BrNp) in 2014 (Fig. 14b) [31]. In this β-CD-azobene pseudo[1]rotaxane and α-BrNp system, photoisomerization of the pseudo[1]rotaxane could be reversibly controlled and then the host-guest association was adjusted due to the binding constants (β-CD, trans-azo>β-CD, α-BrNp>β-CD, cis-azo). The authors utilized ICD and RTP signals as output addresses respectively and thus conveniently achieving the INHIBIT logic operations. 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), a compound with single electron, processes obvious paramagnetism and can give strong electron paramagnetic resonance (EPR) signal. When TEMPO was reduced, the diamagnetism disappeared due to the inexistence of the single electron, along with the disappearence of the EPR signal. As shown in Fig. 15, Lucarini et al. [32] attached the TEMPO unit to β-CD to form pseudo[1]rotaxane and found that the conformation of the pseudo[1]rotaxane had strong influence on its EPR signals. When the TEMPO group was self-included in the β-CD’s cavity, the pseudo[1]rotaxane gave a persistent EPR signal of nitroxide under reductive condition (in the presence

Fig. 14 (a) Conformation transformation of β-CD- and azobene-based [1]rotaxane using naphthalene imide as terminal agent upon the irradiation of UV or visible light [30]; (b) conformation transformation of a pseudo[1]rotaxane structure based on azobene modified β-CD upon the irradiation of UV or visible light at the existence of α-BrNp [31]

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Fig. 15 Synthetic route of pseudo[1]rotaxanes based on TEMPO modified β-CD [32]

of glutathione). While upon the addition of the competitive guest – sodium dodecyl sulfate – the TEMPO was extruded from the cavity, and the single electron in this system was gradually consumed by glutathione, leading to a fast decreasement of the EPR signal. The experimental data suggested a potential application of pseudo[1]rotaxane for the protection of free radical in the reductive environment.

4.2.3.2 Pseudo[1]rotaxanes related to altro-pyranose Based Altro-CDs CDs are versatile macrocyclic oligosaccharides composed of α-(1,4)-linked d-glucopyranose units in the 4C1 chair conformation. Different from traditional α-CD, the altropyranose-based altro-α-CD’s secondary rim is more convenient to be modified with functional groups. Compared to the cavity size of the traditional α-CD, Harada et al. [33, 34] found that altro-α-CD had a slightly larger cavity which could allow the pass of the amantadine fragments. They synthesized a series of altro-α-CD-based pseudo [1]rotaxanes and studied their conformations in detail by systematic NMR experiments. They grafted two altro-α-CD macrocycles at both ends of an alkyl chain first, and then the alkyl bridged altro-α-CD dimer reeled its decamethylene chain into the cavity of the α-CD and thus forming a pseudo [1]rotaxane dimer through simple tumbling (Fig. 16). They described this highly variable pseudo [1]rotaxane system as a molecular puzzle ring. Similarly, the conformation of β-CD-based pseudo [1]rotaxane was studied by Desire [35]. They synthesized a series of novel β-CD dimers linked through their primary faces by different glycerol-like moieties via “click” chemistry. The unusual behavior of the above-mentioned glycerol bridged β-CD dimers in aqueous solution had been investigated by NMR. They found that the β-CD dimers could adopt two very different conformations in water, the symmetrical one and the pseudo[1]rotaxane one which was formed through the tumbling of one glucopyranose unit in a β-CD group. This phenomenon was totally depending on the length of the linking arm between the two CDs. Tian

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Fig. 16 Conformation transformation of the altro-α-CD-based pseudo [1]rotaxane [33]

et al. [36] also synthesized a β-CD-based [1]rotaxane and studied its light response behavior. Cai et al. [37] reported a pseudo[1]rotaxane containing an altro-α-CD derivative bearing an adamantyl end group tumbling of its arm into the altro-α-CD’s cavity, as shown in Fig. 17. They used molecular dynamics simulations and free energy calculations explained the formation of the pseudo[1]rotaxane through the tumbling process via an altro-α-CD conformation rather than threading of the adamantyl unit across the α-CD’s cavity.

4.3

Pseudo[1]catenanes

Various mechanically self-locked and interlocked molecules can be synthesized conveniently through pseudorotaxane. As just mentioned, when one end of the axle is linked to the macrocycle in one molecule, we call it pseudo[1]rotaxane. Comparing to pseudo[1]rotaxane, when two ends of the axle are both linked to the same region of a macrocycle in one molecule, we call the self-complex pseudo[1]catenane. In 1998, Stoddart et al. [38] designed and synthesized molecules of this structure for the first time. Two dipyridyl units were first connected with the phenyl segment of a crown ether containing both naphthyl and phenyl units. Then the two dipyridyls were chained up by a phenyl to form a cyclophane (Fig. 18). Due to the strong π-π interaction between the electron-rich naphthyl-contained crown ether and the electron-deficient viologen-based cyclophane, a [1]cantenane was successfully fabricated. Upon the addition of electron-rich guest TTF, the naphthyl was squeezed out of the cyclophane, along with a change of the conformation from mechanically interlocked structure to a spiro-macrocycles structure. Therefore, the optical property

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Fig. 17 Conformation transformation of the pseudo[1]rotaxane structure based on adamantyl unit modified altro-α-CD [37]

Fig. 18 Conformation transformation of the cyclophane- and crown ether-based pseudo[1] cantenane upon the addition of electron-rich guest TTF [38]

(UV-Vis absorbance) could be efficiently adjusted through the addition of competitive guest. Hence, Stoddart et al. named it as molecular chameleon. In 2013, Ogoshi et al. [39] reported a chiral pseudo[1]cantenane based on pillararene. They synthesized and separated the pseudo[1]cantenane with optical activity using chiral column chromatography. Rotation of the phenyl unit connected with the alkyl chain could cause the conformation transformation between inclusion and dethreading of the alkyl chain (Fig. 19a). In 2017, Yang [40] reported a pseudo[1]cantenane based on pillar[5]arene and crown ether, of which planar chirality switching could be driven by temperature (Fig. 19b). Upon the addition of competitive guest molecule – adiponitrile – the conformation of the pseudo[1]cantenane changed from the inclusion one to the spiro macrocyclic structure. And when 24-C-8, a macrocycle can bind with adiponitrile more tightly, was added, the pseudo[1] cantenane could reverse back to its intramolecular complexed conformation. Therefore, supramolecular interaction could be designated as driving force for the inversion of chirality. In 2018, a chiral pseudo[1]cantenane also reported by Lee (Fig. 19c) [41]. This pillararene- and thiacrown ether-based pseudo[1]cantenane’s chirality could be efficiently triggered by metal ions (e.g., Hg2+) and controlled by anions (e.g., I, ClO4). The investigation on the inversion of the planar chirality of pseudo[1]

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Fig. 19 (a) Conformation transformation of a chiral pseudo[1]cantenane upon the addition and removal of the competitive guest [39]; (b) structure of pseudo[1]cantenane based on pillar[5] arene and crown ether [40]; (c) conformation transformation of a chiral pseudo[1]cantenane upon the addition of ClO4 and S2 [41]

cantenane via host-guest interaction, temperature, and ions could be potentially applied in the area of chiral switches or sensors. As a class of topological superstructures which are designed at a molecular resolution, pseudo[1]cantenanes have vast potential applications in the area of supramolecular area. Our group [42] also reported a protocol to fabricate mechanically self-locked molecules via a one-step reaction. A pseudorotaxane based on two carboxyl units modified pillar[5]arene threaded by a,o-diaminoalkane was first constructed. Then amidation reaction could take place between one or two pseudorotaxanes and in this way monomeric and dimeric pseudo[1]catenanes could be easily obtained, as shown in Fig. 20. Due to the fixed planar chirality of pillar[5]arene, the chiral dimeric pseudo[1] catenanes were isolated and fully characterized by both experiments (circular dichroism spectroscopy and X-ray crystallography) and DFT calculations. We call this kind of dimeric pseudo[1]catenanes “gemini-catenane.” We believe this convenient protocol for the synthesis of chiral pseudo[1]catenanes and gemini-catenanes could efficiently facilitate the practical applications of such kind of masterly chiral architectures.

4.4

Molecular Figures-of-Eight

Different from the pseudo[1]catenane structure, of which both ends of the axle part connected to the same segment of the macrocycle, a self-threaded molecular 8 architecture connected two portions of the axle to different regions of the macrocycle. Vogtle et al. [43] first constructed a class of self-threaded molecular 8 architectures in 2001, and due to multiple connection sites on the macrocyclic molecule, three

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Fig. 20 Synthetic route of pseudo[1]catenane and gemini-catenanes based on pillar[5]arene. *Only (pS)-enantiomers are shown for clarity purpose [42]

Fig. 21 Construction of molecular figures-of-eight and three different molecular 8 s were obtained with a ratio of 56:37:7 from left to right [43]

different molecular 8 s molecules were obtained with a ratio of 56:37:7, as shown in Fig. 21. Owing to the temperature controlled chemoselective reaction, they successfully separated the chiral molecular 8 molecules from the racemic system of a [2]rotaxane based on sulfonamide. The exact positions of the thread’s two ends were both determined by experimental data (MS and NMR) and molecular dynamics studies. The chirality of molecular 8 depended on both the cycloenantiomerism and helical chirality of the molecular 8 architecture. Hence the pure enantiomers of molecular 8 exhibited obvious Cotton effects. This work not only provided us with a new kind of molecular structure but also explained the chiral optical properties of mechanically interlocked molecular 8 structures in detail.

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Fig. 22 Construction of molecular figures-of-eight based on cyclophane using “click” chemistry [44]

As shown in Fig. 22, Stoddart and Sauvage et al. [44] used a simple [2]rotaxane (cyclophane as macrocycle and naphthyl-based oligomethylene glycol as axle) as substrate and constructed a molecular 8 architecture conveniently in high yield via “click” chemistry in 2011. The electron-deficient tetracationic cyclophane as acceptor and the electron-rich naphthalene-containing polyether chain as donor together formed a donor-acceptor molecular 8. It’s very important to identify both structure and dynamics of a higher-order topological structure, so they separated a pair of trans- and cis-constitutional isomers of molecular 8 later in 2012 [45]. And in this work, with the knowledge of the solid-state structure (the stereochemistry of the major product) of molecular 8 in mind, they realized that they achieved incorrect results from ab initio calculations before.

4.5

Pretzelane

If we further connect the mechanically interlocked molecules [n]cantenane with covalent bonds, the original two or more separated covalent components will be covalently linked, resulting with a more complicated structure. Vogtle et al. [14] had been focused on the construction and investigation of the mechanically interlocked architectures over a long term since the year of 1996, during which for the first time they constructed a mechanically interlocked structure through covalently connected two cyclic amide-based macrocycles in a [2]catenane system, as shown in Fig. 23b. Because of its topological similarity to the pretzel (Fig. 23a) favored by western Europeans, this kind of structure was given the name “pretzelane.” Stoddart et al. [46, 47] also reported some beautiful pretzelane structures. In 2005, they covalently connected the crown ether and the cyclophane in a [2]catenane using

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Fig. 23 (a) Photo of pretzel and (b) schematic illustration of pretzelane constructed from [2] catenane

Fig. 24 (a) Structure of crown ether- and cyclophane-based pretzelane [46]; (b) bistable pretzelane containing a crown ether-containing TTF, 1,5-dihydroxynaphthalene, and a covalently tethered cyclophane ring [47]

stereospecific synthesis and obtained a pretzelane as shown in Fig. 24a. Then they investigated the chiral and electrochemical properties of the pretzelane systematically. Due to the introduction of the stereogenic center and the pretzelane’s helical chirality, one conformational diastereoisomer was much preferred over the other one. In 2009, they reported a bistable pretzelane composing of a crown ether containing TTF and 1,5-dihydroxynaphthalene and a covalently tethered cyclophane ring (Fig. 24b). When this pretzelane was oxidized or reduced, it could exhibit unidirectional motion forwards or backwards. Because of the fascinating topological features and potential functions as components of molecular devices, our group [48] also reported a pretzelane

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Fig. 25 Pretzelane containing Sn-porphyrin and crown ether synthesized by template-directed method [48]

containing Sn-porphyrin, crown ether, and an aromatic dialkylammonium spacer. As shown in Fig. 25, we first synthesized a Sn-porphyrin modified crown ether and a dialkylammonium chain. Then we conveniently synthesized the pretzelane in one step via a template-directed protocol due to the host-guest interaction between the ammonium and crown ether. Finally, we studied its property with NMR and UV-Vis spectroscopy to confirm its pretzelane architecture. We believe this new synthetic strategy for pretzelane could provide fresh ideas for the designation and construction of even more interesting and complicated systems.

4.6

Double-Lasso Macrocycle

In 2012, Coutrot et al. [49] linked the two ends of a nonsymmetrical [C2] daisy chain composed of crown ether and secondary ammonium salt and obtained a class of mechanically self-locked molecule as shown in Fig. 26. They called this kind of architecture double-lasso macrocycle. The straightforward synthesis of this double-lasso macrocycle using “click” chemistry of alkyne and azide on two [C2] daisy provided a new idea for polymerization at high concentration. Also the conformation transformation upon adjusting pH was studied, and they found that the two macrocycles could slide along the alkyl chains thus forming two conformations with great differences. At relatively low pH, the double-lasso macrocycle adopted a loose conformation with a big cavity; while upon deprotonation, the double-lasso presented with a spiral type and tightened conformation with a small cavity. This novel type of self-locked structure provided a new method for the construction of molecular machine.

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Fig. 26 Conformation transformation of the double-lasso macrocycle upon the addition of base and acid [49]

4.7

Conclusion

In conclusion, we discussed the development process of the designation and construction of mechanically self-locked molecules. These complicated structures at molecular level have always been a spotlight because of their potential applications in the field of molecular motion for bionic movement (muscle, etc.). The main driving forces for the formation of such kind of structures are dynamic noncovalent binding (hydrogen bonding, π-π interaction, ionic interactions, host-guest interaction, et al.). While how to exploit different kinds of noncovalent interactions more effectively to realize simpler synthesis of mechanically self-locked molecules is still a key issue that’s worth paying close attention to. Although various of structures (pseudo[1]rotaxane, pseudo[1]catenane, figures-of-eight, pretzelane, and double-lasso molecules, et al.) have been constructed, novel architectures are still needed to be created for more subtle and hierarchical motions. At the same time, along with the discovery of new macrocycles and respective guest molecules, new building units are still waiting to be investigated for mechanically self-locked architectures. With the fast improvement of this basic study on molecular level, it is hopeful that supramolecular mechanically self-locked molecules will play an irreplaceable role in the future.

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5

Photoluminescent Crown Ether Assembly Yan Zhou, Bang-Tun Zhao, and Yu Liu

Contents 5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Luminescent Assemblies Based on Organic Dyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Crown Ether Assembly Based on Lanthanide Metal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.1 A Highly Selective Luminescent Sensor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.2 Luminescent Lanthanide Assemblies Based on Pseudorotaxanes/ Pseudopolyrotaxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4 Luminescent Supramolecular Polymers Based on Crown Ether . . . . . . . . . . . . . . . . . . . . . . . . . 5.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5.1

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Introduction

Crown ether, as cyclic compound composed of several repeating ether units, is discovered by the winner of the Nobel Prize Pedersen in 1967 [1]. Subsequently, the concepts of supramolecular chemistry and host-guest chemistry were put Y. Zhou College of Chemistry and Chemical Engineering, and Henan Key Laboratory of Function-Oriented Porous Materials, Luoyang Normal University, Luoyang, China College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China B.-T. Zhao College of Chemistry and Chemical Engineering, and Henan Key Laboratory of Function-Oriented Porous Materials, Luoyang Normal University, Luoyang, China Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_6

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forward. Traditional crown ether, containing repeating oligo-ethylene oxide units in a cyclic array, has high ability to bind alkali metal ions, alkaline-earth metals ions, ammoniums, and primary alkylammonium salts. Previously, researchers focused their attention on the molecular recognition based on crown ether. Since Stoddart first reported the complexation of bismetaphenylene-32-crown-10 derivative with paraquat and diquat in 1987 [2], the multifunctionalized supramolecular assemblies based on crown ether and organic guests have been fabricated. Nowadays, various synthetic novel crown ethers, which possess multi-cavity structures and multicomplexation modes, have been successively designed and synthesized to enrich their functions and applications through several decades of development, such as supramolecular polymers [3], artificial molecular machines [4], and drug delivery systems [5]. Photoluminescence is among the most fascinating characteristics of functional materials. Luminescent materials are applied for a wide variety of applications, such as chemical sensor [6], bio-imaging [7], drug delivery [8], phototherapy [9], and cell labeling [10]. Therefore, the integration of fluorophores into crown ether moieties is advantageous to construct specific responses or develop multistimuli-responsive photoluminescent crown ether assembly. Crown ether often reversibly binds guest molecules with high selectivity and could be fine-tuned chemically. So, the assemblies, based on crown ether, are sensitive to environmental changes and external stimuli like temperature, pH, light, or competitive guests. These features were successfully utilized to produce more sophisticated functions. In this chapter, we aim to illustrate the general concepts and structure-function-application relationships of photoluminescent crown ether assembly. First, we discuss some general luminescence system based on crown ether and organic dyes. Pseudorotaxanes and pseudopolyrotaxanes based on lanthanide luminescence are presented in the second part. In the last section, we highlight recent developments of supramolecular polymers based on crown ether with photoluminescence behavior. We hope to shed some light on the future work based on crown ether and inspire continuous endeavors in this emerging and exciting research area.

5.2

Luminescent Assemblies Based on Organic Dyes

The idea of introducing fluorophore into crown ether to construct fluorescent supramolecular materials has attracted tremendous attention in the past few decades because of their wide applications in sensors, fluorescence probes, organic lightemitting diodes, and solid-state lighting. In the following section, typical examples are used for briefly discussion and introduction of the construction of the luminescent assemblies based on crown ether and organic dyes. Mechanically interlocked molecules have been investigated extensively due to their switchable ability in response to various external stimuli. In recent years, crown ether has always been used to construct the mechanically interlocked systems due to its easy modification [11, 12]. In 2012, Qu and coworker [13] designed and synthesized a bistable [2]rotaxane with high-contrast fluorescence

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output (Fig. 1a). The molecule shuttle, combining two ferrocene (Fc) groups as electron donors and DB24C8, could move between the dibenzylammonium (DBA) and N-methyltriazolium (MTA) recognition sites. The fluorescence of the 4morpholin-naphthalimide (MA) stopper could be switched off when the shuttle moved to the MTA sites, suggesting a strong photoinduced electron transfer (PET) process from Fc to the excited MA, whereas the fluorescence of MA was switched on through controlling the shuttle to bind with DBA unit. Moreover, the shuttling motion of the molecule shuttle could be chemically dual-mode driven by not only pH stimuli but also addition/removal of the fluoride anion, revealing that the system has a potential application as a novel kind of fluorescent molecular sensing device. In 2013, a continuous work was reported by them [14]. They designed the dual-mode operation of a ferrocene-based bistable [1]rotaxane (Fig. 1b) so that a fluorescent emission “active” mode of the system could be controlled by the acid/

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Fig. 1 Schematic illustration of the shuttling movement. (a) A bistable [2]rotaxane system [13]. (b) A bistable [1]rotaxane system [14]

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base stimuli whereas the “silent” mode of the system could be regulated by the oxidation/reduction reaction of ferrocene unit. This study laid a solid foundation for the fabrication of advanced logic circuits with memories or sequential functions. Most of the molecular machines with switchable fluorescent output were studied in the solution phase, which limited their practical applications. Therefore, Qu et al. [15] introduced the above bistable [2]rotaxane system into SiO2 nanoparticles because of their chemical stability and optically transparent features (Fig. 2b). Intriguingly, the fluorescence intensity could be reversibly modulated by the acid/ base stimuli in the solid state of the SiO2 nanoparticles as well as in the solution state, thus paving a bright avenue for the construction of smart stimuli-responsive surfaces with tunable functions. Subsequently, they grafted the [2]rotaxane system into a polymer chain again and successfully constructed a fluorescent switch based on a polyrotaxane system, further expanding the application fields of solid-state fluorescent sensors (Fig. 2c) [16]. White-light-emitting devices have drawn wide attention in recent years, and these devices are now being considered to be a promising solid-state lighting source [17]. Tian and coworkers [18] reported a bistable [2]rotaxane with orthogonally tunable multicolor fluorescence features including white-light emission via combining a rotaxane-type molecular switch and traditional fluorescent switch (Fig. 3). A blue-light-emitting [2]rotaxane was constructed by N-propyl-1,8naphthalimide (PNA) as the stopper and two Fc electron donor-decorated DB24C8 as the molecule shuttle. With the increase of base, the blue fluorescence intensity of the [2]rotaxane was continuously strengthened due to the weakened PET process between Fc unit and PNA group, accompanied by the decrease of yellow fluorescence intensity of the perylene bisimide derivative (PBI) owing to the aggregation of PBI molecule. Therefore, the emission color, containing whitelight emission, could be reversibly regulated by simply changing pH. These systems provided a reliable method for the construction of multicomponent tunable fluorescence molecular systems. Mechanochemistry, activated by mechanical force instead of conventional stimuli (i.e., pH, light, and heat), has been widely studied in the past few years. However, the conventional mechanophores activated by cleaving covalent bonds required a relatively high activation energy, and the process was usually irreversible [19]. Therefore, a linear polyurethane containing the rotaxane-based supramolecular mechanoluminophore with reversible on/off switching of its photoluminescence properties was reported by Weder and coworkers [20]. As shown in Fig. 4, the [2]rotaxane was fabricated via a 4,7-bis(phenylethynyl)-2,1,3benzothiadiazole (BTH)-decorated 1,5-dinaphtho[38]crown-10 cycle and an electronpoor 1,4,5,8-naphthalenetetracarboxylic diimide (NpI) motif. Tri(p-tert-butylphenyl) phenylmethane stoppers were introduced into the system to lock in the structure. The free crown ether cycle could emit bright fluorescence, while the solution of [2] rotaxane showed no emission because the fluorescence of the BTH unit was quenched by the NpI moiety. Then, the [2]rotaxane was grafted into polymer chains through the reaction of two hydroxyl groups sites modified on the cycle and the

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Fig. 2 Schematic illustration of (a) a bistable [2]rotaxane molecular shuttle, in which the relative shuttling movement could be driven by pH changes. (b) Immobilization of the [2]rotaxane onto SiO2 nanoparticle surfaces [15]. (Adapted with permission [15]. Copyright 2015, Royal Society of Chemistry.) (c) Introduction of the [2]rotaxane into polymer chains [16]. (Adapted with permission [16]. Copyright 2016, Royal Society of Chemistry)

dumbbell with 4,40 -methylenebis-(phenylisocyanate). The polymer chains contained [2]rotaxane were further made into thin films. Intriguingly, the films display the mechanoluminophore functions. The films exhibited the characteristic fluorescence of the BTH with the stress increase, owing to the spatial separation of

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Fig. 3 Schematic illustration of the bistable [2]rotaxane with tunable multicolor fluorescence features [18]. (Adapted with permission [18]. Copyright 2018, Royal Society of Chemistry)

the BTH and NpI. Moreover, the activation process was reversible. As soon as the stress was released, the fluorescence of films was switched off. As a continuous work, they reported another mechanoluminophore system taking advantage of the supramolecular approach, which the optical signal generated could readily be tailored by a simple and rational method (Fig. 5) [21]. Three mechanoresponsive polyurethanes containing blue-, green-, and orange-light-emitting rotaxanes were constructed through varying only the fluorophore (i.e., pyrene, anthracene, or 4(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran) incorporated in the crown ether cycle unit. The photoluminescence of the fluorophores in the systems was suppressed by the NpI group when the systems were in the unactivated state, whereas the fluorescence of each of the fluorophores was switched on and exhibited strong optical signal upon the application of mechanical force, suggesting that each polymer could exhibit instantly reversible, strain-dependent on/off switching of its photoluminescence. In addition, the photoluminescence color containing white-light-emitting of such motifs could be successfully tailored by variation of the fluorophore and also by combining several mechanophores in one system. The results demonstrated that adaptability is a key advantage of supramolecular approaches to construct mechanoresponsive materials.

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Fig. 4 (a) Molecular structure of rotaxane. (b) Synthesis of the mechanophore-containing polyurethane. (c) Schematic illustration of rotaxane-based mechanoluminophores [20]. (Adapted with permission [20]. Copyright 2018, American Chemical Society)

5.3

Crown Ether Assembly Based on Lanthanide Metal

Among the various functional materials, lanthanide-luminescence-based ones have attracted considerable attention in recent years, owing to their unique photo-physical characteristics [22–25]. Their characteristic sharp emission and clearly defined bands have been applied within a number of technologies, such as organic light-emitting diodes [26], sensors [27], novel display devices [28], and biological applications [29]. In addition, they could also be used to the time-gated detection techniques due to their long lifetimes [30]. The obvious features of lanthanide metals make them ideal and highly desirable candidates for integration into luminescent supramolecular assembly, resulting in the emission signals that could be modulated by an external stimulus, including ions, pH, light, temperature, vapors, redox, small molecules, etc.

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Fig. 5 (a) Molecular structures of rotaxanes 1, 2, 3. (b) Molecular structures of the mechanophorecontaining polyurethanes. (c) Schematic illustration of rotaxane-based mechanoluminophores with white-light-emitting characteristic [21]. (Adapted with permission [21]. Copyright 2019, American Chemical Society)

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Therefore, the elaborate designed supramolecular assembly containing lanthanide metals could function as molecular switches, sensing platforms, and molecular machines. In the following part, we will briefly introduce the recent progresses on functions and applications of the lanthanide luminescent crown ether assembly.

5.3.1

A Highly Selective Luminescent Sensor

How to build a platform for the sensitive and selective detection of potassium to achieve the accurate clinical disease diagnosis (such as hypertension, stroke, and seizures) is still a considerable challenge. Pierre [31] reported a luminescent sensor for the time-gated detection of K+ with enhanced selectively based on a diaza-18-crown-6 and Tb3+ ion system (Fig. 6). They chose azaxanthone as the antenna since it was demonstrated to be an efficient sensitizer of Tb3+. Then, the TbDOTA chelate and azaxanthone were separated via a diaza-18-crown-6 coordination site and flexible linker. In the “off” state, the fluorescent intensity of Tb was weak, deriving from large separation between the Tb3+ and its sensitizing azaxanthone. Capturing K+ by the crown ether coordination site favors a cation-π interaction with the aryl ether unit, resulting in the formation of assembly where the antenna is significantly closer to Tb3+ center. Consequently, the luminescence of Tb was increased due to the efficiency of energy transfer from the azaxanthone to the Tb. Moreover, the system showed excellent selectivity for K+, with a 93-, 260-, 105-, and 61-fold selectivity over Na+, Li+, Mg2+, and Ca2+. Furthermore, the luminescence intensity at 545 nm was increased 22-fold by the addition of 10 mM K+ (the clinically useful range of K+ was 0–10 mM), and the signal could be stable for several hours.

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The group of Tang [32] has also focused on developing sensing systems based on crown ether and lanthanide metal, allowing for highly selective detection of Hg2+. They designed and synthesized a benzo crown ether host, 4,5-bis{[(20 -benzylaminoformyl)-phenoxyl]-methyl}benzo-15-crown-5. The zigzag coordination polymeric chains were formed through the synergistic effect of the coordination interaction with Tb3+ and the π-π interaction between the phenyl groups of the two side arms of the neighboring hosts (Fig. 7). The Tb3+ complex exhibited excellent luminescence at 490, 546, 584, and 619 nm, corresponding to 5D4 ! 7Fn (n = 6, 5, 4, 3) transition. Moreover, the complex showed a highly selective and sensitive response to Hg2+. The results showed that the luminescence emission of Tb3+ complex was switched off by the addition of Hg2+, which not just because the crown ether will bind with Hg2+ but also because the fluorescent reporter played a vital role in the binding with Hg2+. Therefore, the energy transfer from the ligand to Tb3+ was prevented. While the alkali, alkaline-earth, and transition metal cations (Li+, Na+, K+, Mg2+, Ca2+, Ag+, Cd2+, Mn2+, Zn2+, and Pb2+) were added into the Tb3+ complex solution, the fluorescence emission intensity of the Tb3+ was slightly influenced by these cations. This Hg2+-recognized system based on lanthanide metal and crown ether provided a novel way to develop a range of chemosensors for the detection of heavy metals. Similar investigations were reported by Gunnlaugsson [33, 34] and Wong [35]. Gunnlaugsson and coworkers [33] constructed novel luminescent switches through

Fig. 7 Molecular structures of crown ether-containing ligand and the structure of the Tb3+ complex [32]. (Adapted with permission [32]. Copyright 2010, Royal Society of Chemistry)

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the combination of cyclen and diaza-aromatic crown ether (Fig. 8a). The aromatic crown ether not only could work as receptors for Na+ and K+ but also could act as antenna for the sensitization of the lanthanide ions. While the pH of the Tb3+ complex solution was 7.4, the system could detect accurately Na+ and K+ upon the change of the fluorescence emission intensity of the Tb3+ complex. In related work by the same group [34], a novel stable dinuclear Eu3+ conjugating through tethering a mono-aza-18-crown-6 moiety to a cyclen macrocyle was designed as a luminescent lanthanide sensor for dicarboxylates (Fig. 8b). The sensor showed its ability to bind small dicarboxylic acids such as aspartic, malonic, succinic, and glutaric acids in pH 6.5 solutions, while just malonic acid gave rise to selective Eu3+ luminescence enhancements, as the emission intensity was reduced for the other acids. This work provides new thought for the development of luminescent sensing of other biologically important structures. Wong and coworkers [35] also

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reported a luminescent Tb3+ complex with pendant quinoline-alkylated diaza-18crown-6 (Fig. 8c). The system showed dual-component recognition of concentrations of H+ and K+ at four independent pH ranges, especially in the physiological pH window. In addition, it exhibited pH- and [K+]-independent long-lived lanthanide luminescent lifetimes in aqueous solution. Recently, Li and coworkers [36] constructed a novel luminescent and self-calibrating sensor for K+ constructed by Ln3+-directed supramolecular self-assembly through the coordination of Eu3+ and Tb3+ with a crown-connected bis-terpyridine (Fig. 9). The 18-crown-6 moiety could efficiently regulate the lanthanide luminescence behavior through the binding of potassium ions via K+-crown cation-π interaction, resulting that the supramolecular assembly could be used as a potential luminescent sensor for selective and quantitative detection of K+. Moreover, the results also showed that the K+ concentration was linearly correlated with the emission intensity ratio of 5D4 ! 7F5 transition (Tb3+) to 5D0 ! 7F2 transition (Eu3+) of the Eu3+/Tb3+ assembly and the detection limit was down to 1 μM. Therefore, this luminescent lanthanide supramolecular assembly could open a window for the construction of novel sensing materials.

5.3.2

Luminescent Lanthanide Assemblies Based on Pseudorotaxanes/Pseudopolyrotaxanes

The fabrication of mechanically interlocked supramolecular architectures as integral components of molecular switches, data storage, and sensor is currently an area of

Fig. 9 Schematic illustration of the construction of lanthanide metal complex and its self-calibrating detection of K+ [36]. (Adapted with permission [36]. Copyright 2018, Royal Society of Chemistry)

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intense research activity. Integrating luminescent lanthanide series into these systems will make the spatial configurational change, chemical binding, or triggered molecular motion to be monitored through the change of fluorescent emission intensity. The Beer group [37] design and synthesize an anion-templated assembly of a d–f heterobimetallic [2]pseudorotaxane (Fig. 10). The host molecule possesses two functional moieties, which consists of a transition metal rhenium(I) bipyridyl metal sensitizer and isophthalamide-based anion recognition site. By chloride anion templation, the [2]pseudorotaxane was constructed through threading into an axle, containing an imidazolium cation and lanthanide luminescent neodymium complex. The [2]pseudorotaxane could exhibit excellent near IR emission through the energy transfer between rhenium(I) and neodymium metal fragments by exciting the rhenium(I) bipyridyl metal antenna. With the rapid development of the lanthanide materials, reversible regulation the luminescence of lanthanide complexes has become one of the researching hotspots in molecular switches currently. Recently, our group constructed a supramolecular assembly of tris[2]pseudorotaxane via the coordination of a host molecule and Tb3+ ion (Fig. 11) [38]. The host molecule possesses a dibenzo-24-crown-8 (DB24C8), suspending a pyridine-2,6-dicarboxylic acid (DPA) ligand. The DPA can form a stable 3:1 luminescent complex with Tb3+ at a high association constant. Therefore, the Tb3+ complex, containing three DB24C8 units, could show the characteristic emission of Tb3+. Then, threading of a guest, modifying a dialkylammonium in the ferrocene (Fc), into the DB24C8, the fluorescence emission of the Tb3+ complex was significantly quenched, due to an intramolecular photoelectron transfer (PET) process from the Fc units to the DPA moieties. Intriguingly, the luminescence of Tb3+ could be reversibly switched on/off by addition of KPF6 and 18-crown-6 (18C6), attributed to the competitive bonding between DB24C8 and 18C6 with K+. This new synthetic strategy of an excellent reversible luminescent lanthanide switch through

Fig. 10 Schematic illustration of an anion-templated [2]pseudorotaxane assembly. [37]

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Fig. 11 Schematic illustration of the fabrication of tris[2]pseudorotaxane assembly [38]. (Adapted with permission [38]. Copyright 2008, American Chemical Society)

electron transfer showed potential application in the fabrication of new moleculebased devices. Then, our group designed a novel kind of [2]pseudorotaxane assembly taking advantage of host-guest binding between DB24C8 derivative, which decorated a terpyridine unit as ligand for lanthanide ions, and fullerene-containing ammonium salt (Fig. 12) [39]. Sensitized by terpyridine, the complex showed strong and unique emission properties of Tb3+ ion in the case of the unthread macrocycle. The phenomenon of fluorescence quenching was observed after the addition of

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Fig. 12 Competitive bonding-driven reversible luminescent lanthanide switch with the PET-ET processes [39]

fullerene-containing ammonium salt, attributed to an intramolecular PET process from the excited singlet state of Tb3+ complex to C60 moiety. Similarly to the above findings, the luminescence of [2]pseudorotaxane could be reversibly switched on/off by the alternating addition of K+ and 18C6. The capability to operate the structure and function of nanodevices via external stimuli is becoming a most attractive candidate for developing multifunctional materials. Light stimulus represents a preferred external physical and chemical tool for manipulating the function of the materials owing to its unique advantages of instant action, high spatial and temporal resolution, and cleanness. Photochromic materials are known to undergo reversible transformations by light between two states with distinct properties [40–45]. Therefore, the integration of photochromism into various devices has endowed the materials with intriguing photoresponsive behaviors and more sophisticated functions. Possessing the ability of excellent thermal stability and prominent fatigue resistance, diarylethene derivatives have been extensively introduced into many systems for constructing optically responsive materials [46]. Our group have successfully developed a [2]pseudorotaxane via combining an unsymmetrical diarylperfluorocyclopentene (DAE) and a Eu3+containing complex of terpyridinyldibenzo-24-crown-8 (Fig. 13) [47]. The guest molecule could exhibit reversible and stable photochromic properties, achieving the interconversion between the ring-opened and ring-closed forms under alternate UVvis light irradiation. Benefiting from the excellent luminescence properties of Eu3+, the assembly displayed satisfactory luminescence, while the guest molecule kept the ring-opened form. Exposing the pseudorotaxane to 365 nm UV light, 80% of the fluorescence intensity of Eu3+ was quenched, revealing an initiated resonance energy

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Fig. 13 Schematic illustration of the light-modulated molecular switch [47]. (Adapted with permission [47]. Copyright 2013, American Chemical Society)

transfer (RET) from the Eu3+ ion to the ring-closed formed diarylperfluorocyclopentene acceptor. The reversible optically modulation of the fluorescence of the pseudorotaxane could be achieved upon alternating UV and visible-light irradiation. Furthermore, by introducing the K+ and 18C6 into the [2] pseudorotaxane, we could also reversibly regulate the fluorescence of the assembly through the competitive bonding. The present results may provide an attractive paradigm for the fabrication of multistimuli-driven molecular switch, logic gates, and molecular machines. As we all know, anthracenes are also photoresponsive units, which can be reversibly transformed into dimerization [48] or trap singlet oxygen to form stable endoperoxides (EPOs) [49] upon UV light irradiation and heating. Yuan et al. [50] reported a Eu3+ complex-based luminescence probe for efficient detection of singlet oxygen via the rapid reaction between anthracene and singlet oxygen, resulting in remarkable luminescence enhancement. Inspired by this finding, we developed a tunable luminescent lanthanide supramolecular assembly based on photoreaction of anthracene (Fig. 14) [51]. The macrocyclic component consists of a 9,10diphenylanthracene (ant) core with photosensitivity, terminal terpyridine (tpy), and two-arm DB24C8. Upon supramolecular assembly formation via the coordination of the macrocyclic host and lanthanide metal ions, irradiation of the systems at 365 nm leads to photoreaction of the ant core and unique lanthanide emission. Intriguingly, the existence of two crown ether rings is to prevent the influence of alkali and alkaline-earth metal ions on luminescence of the Ln3+. Significantly, the

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Fig. 14 Schematic illustration of the lanthanide luminescence driven by the process of reversible photoreaction [51]. (Adapted with permission [51]. Copyright 2017, American Chemical Society)

luminescence of the assembly could be reversibly switched on and off through a regulable photoreaction upon light irradiation or heating. Subsequently, threading a guest, which incorporated a dialkylammonium binding site and a DAE moiety, into the DB24C8, resulted in the formation of the poly[2]pseudorotaxane (Fig. 15) [52]. By switching between closed-form and open-form states of the DAE using UV and visible-light irradiation alternately, the lanthanide luminescence of poly[2]pseudorotaxane can be reversibly modulated.

5.4

Luminescent Supramolecular Polymers Based on Crown Ether

Supramolecular polymers, fabricated via the noncovalent interactions, such as hydrogen bonding, π-π stacking, metal coordination, and host-guest interactions, possess interesting and fascinating physical/chemical properties, including stimuli responsiveness, self-healing, and self-adjusting abilities. Therefore, supramolecular polymers have found a wide range of applications, including light harvesting, drug delivery, and catalysis [53]. By the combination of the fluorophores and dynamic noncovalent connections of supramolecular polymers, supramolecular polymers display the dynamic features attributing to the noncovalent bonds and also exhibit a tunable fluorescent ability through various external stimuli. Self-assembly of molecular units into more complex and multifunctional superstructures is ubiquitous in nature. The number of fascinating superstructures prepared via multilevel self-assembly of artificial nanoscale units is also increasing rapidly. Stang and coworkers [54] designed and constructed a supramolecular oligomer with the concentration-dependent tunable emission properties by threading a fluorescent bis-ammonium salt into the phenanthrene-21-crown-7 (P21C7)containing rhomboidal organoplatinum(II) metallacycle via the host-guest interactions (Fig. 16). Intriguingly, the assemblies, combining the orange-emissive metallacycle and the blue-emissive bis-ammonium linker, could exhibit a controllable emission from orange to blue as the concentration decreases, whereas white-light

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Fig. 15 Schematic illustration of the luminescent lanthanide switch based on a poly[2]pseudorotaxane [52]

emission was obtained at a concentration of 29 μM (Fig. 16c). This study provided an effective strategy for the fabrication supramolecular assemblies with tunable emissive properties. Subsequently, they reported a novel kind of supramolecular polymers taking advantage of host-guest binding between P21C7-containing metallacycles and bis-ammonium salt (Fig. 17) [55]. By modification of the substituents on the metallacycle precursor, the supramolecular polymers showed extraordinary abilities to regulate the fluorescent emission. Then, when coating a yellow-emitting supramolecular polymer thin film onto a blue-light LED, a white-light-emitting LED was obtained (Fig. 17c), indicating the potential of the supramolecular polymers for the construction of photoelectronic materials. Recently, luminescent supramolecular polymer gels, which combine the elasticity of solid, the fluidity of liquid, and the inherent optoelectronic properties, have become an interesting research field. Significant work on luminescent supramolecular polymer gel has been reported by the group of Wong and coworkers [56]. The assembly of three metal ligands, appended to a benzo-21-crown-7 (B21C7) macrocycle, resulted in a Zn2+ complex exhibiting a strong yellow fluorescence (Fig. 18). Threading of a guest, including a bis-ammonium salt binding site, into the B21C7, resulted in the formation of a [3]pseudorotaxane with weak blue fluorescence. The supramolecular polymer gels were constructed successfully by threading of the bisammonium salt into the Zn2+ complex, accompanying with weak yellow fluorescence. Moreover, the supramolecular polymer gels showed an excellent multiresponsive performance. The reversible sol-gel transition could be triggered by temperature, pH, and cation. Therefore, the gel could display diverse fluorescent

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Fig. 16 (a) Molecular structures of crown ether-containing metallacycle and guest molecule. (b) Schematic illustration of the construction of supramolecular oligomers. (c) Emission spectra of supramolecular oligomers at different concentrations [54]. (Adapted with permission [54]. Copyright 2017, National Academy of Sciences (USA))

switching phenomena through controlling the self-assembly process in different ways, suggesting its potential application as advanced intelligent materials. Huang et al. [57] fabricated a novel supramolecular cross-linked network via the host-guest interactions between the pendent DB24C8 units of a conjugated polymer and a bis-ammonium cross-linker (Fig. 19). However, the supramolecular crosslinked network showed a weak fluorescence, compared with conjugated polymer, originating from the aggregation of polymer chains, whereas the fluorescence intensity of this network increased obviously through inputting external stimulus signals, containing potassium cation, chloride anion, pH increase, and heating, attributed to the disassembly process of the supramolecular cross-linked network. In addition, the thin films were prepared by spin-coating the solution of the supramolecular cross-linked network. Interestingly, the fluorescence intensity of the thin films showed an obvious increase when the film was exposed to the vapor of ammonia. This system will pay the way for designing multiple fluorescent sensor materials. The abovementioned supramolecular polymers not only possess the dynamic characteristic but also regulate their fluorescence by various external stimuli. However, all of them undergo an inescapable process of aggregation-caused quenching (ACQ) due to the formation of excimers and exciplexes, which seriously limits their

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Fig. 17 (a) Schematic illustration of the construction of metallacycle. (b) The formation of fluorescent supramolecular polymer from metallacycle and guest molecules. (c) Photos from LED [55]. (Adapted with permission [55]. Copyright 2018, American Chemical Society)

practical applications. In 2001, the concept of aggregation-induced emission (AIE) was first put forward [58]. Luminescent materials with AIE can efficiently solve the self-quenching problem of traditional fluorescent materials. AIE has received considerable attention due to their potential applications for photoelectronic devices, chemo- and biosensors, and bio-imaging. Tetraphenylethene (TPE) is a typical AIEactive molecule. The marriage of TPE and crown ether system provides new smart function materials with unique fluorescent properties. Liu and coworkers [59] reported a highly sensitive and selective K+ probe, constructed via AIE and hostguest molecular recognition. Four benzo-15-crown-5 (B15C5) macrocycles were docked with TPE molecule, endowing the system with the AIE-active motif and supramolecular K+-recognizing functionalities. Supramolecular polymer was obtained by the formation of K+/B15C5 1:2 sandwich complex, accompanied by the turned-on fluorescence via AIE effect, whereas the fluorescence emission changes were negligible in the presence of competitive ions (Li+, Na+, NH4+, Ca2+,

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Fig. 18 Molecular structures of host and guest molecules and schematic illustration of the supramolecular polymer with multiple fluorescent features [56]. (Adapted with permission [56]. Copyright 2016, Royal Society of Chemistry)

Mg2+, and Pb2+), suggesting that the system could be used as an excellent selectivity sensor for K+ ion (Fig. 20a). Tang et al. [60] constructed an AIE-active supramolecular polymer via the interactions of DB24C8-modified TPE derivatives with dibenzylammonium-containing TPE derivatives (Fig. 20b). Upon acidification or basification of the system, the fluorescence of linear supramolecular polymers could be reversibly switched on and off, owing to the self-assembly and disassembly of the system. Yin and coworkers [61] designed a novel fluorescent supramolecular polymer for Pd2+ detection (Fig. 21a). The supramolecular polymer was fabricated via the hostguest interactions with dibenzo[24]crown-8-contained TPE and a bis-ammonium salt, which exhibited much higher fluorescence emission than its monomer due to the restriction of the intramolecular rotation of the TPE unit. Moreover, the 1,2,3triazole moiety could form metal-ligand complex with Pd2+ ion, resulting in significant loss of the fluorescence intensity of supramolecular polymer, attributed to an energy transfer process from the TPE units to Pd2+ ions. Thus, the results suggest that the supramolecular polymer can be used to detect Pd2+ ions. Subsequently, they constructed a hyperbranched fluorescent supramolecular polymer based on metalligand coordinating interactions and host-guest interactions (Fig. 21d) [62]. Two functional monomers were designed and prepared by combining DB24C8 and terpyridine with an alkyl chain and modifying a TPE unit with four dibenzylammonium salts (DBAS). Based on the host-guest interactions of DB24C8 with DBAS and the metal-ligand coordinating interactions of terpyridine with Zn2+, the hyperbranched supramolecular polymer was obtained. Benefiting from AIE effect of TPE, the system displayed strong fluorescent emission. In addition, the supramolecular polymer was able to respond to various stimuli, including temperature, deprotonation/protonation of the ammonium units, the addition/removal of K+ or

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Fig. 19 Schematic illustration of the fabrication of supramolecular cross-linked polymer network [57]. (Adapted with permission [57]. Copyright 2013, American Chemical Society)

Cl, and 1,4,7,10-tetraazacyclododecane (cyclen). The results revealed that this system will have a potential application value in the fabrication of the smart and adaptive luminescent materials. Further research was reported by the same group [63]. A polystyrene backbone with coumarin units and DBAS moieties as functional groups was prepared by polymerization reaction. The TPE-containing host molecule was synthesized by modifying DB24C8 and terpyridine. Then, a cross-linked supramolecular polymer network with two emission bands was constructed via the orthogonal self-assembly of host-guest and metal-ligand coordination interactions of functional polymer chain with TPE-containing host molecule and Zn2+ (Fig. 22a). The system could exhibit different fluorescent emission signals at 390 and 460 nm owing to the emission of coumarin and TPE, and the fluorescence intensities at these two wavelengths could

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Fig. 20 (a) Schematic illustration of the construction of fluorescence probe for K+ based on TPE(B15C5)4, induced by supramolecular recognition between K+ ions and B15C5 moieties [59]. (Adapted with permission [59]. Copyright 2012, Royal Society of Chemistry.) (b) Illustration of the self-assembly via host-guest interaction with pH-responsive properties [60]. (Adapted with permission [60]. Copyright 2015, Royal Society of Chemistry)

be reversibly modulated by the addition and removal of cyclen, Cl, or pH changes, revealing that the supramolecular polymer network could act as a multiple ratiometric fluorescent sensor. In addition, supramolecular gels were formed with the increase in concentration of the supramolecular polymer network, and the gels displayed stimuli-responsive gel-sol transition and good self-healing behaviors. Huang and coworkers [64] also constructed a dual-stimuli-responsive fluorescent supramolecular cross-linked polymer gel combining a polystyrene chain with dialkylammonium salt units and four-arm benzo-21-crown-7 (B21C7)-contained TPE derivative (Fig. 22b). Originating from the host-guest interactions of B21C7/ dialkylammonium salt and the TPE-based AIE effect, the fluorescence intensities of supramolecular polymer gel could be reversibly regulated by thermal stimuli and pH variations, accompanied with the reversible gel-sol transitions. This fluorescence tunable supramolecular gel based on host-guest interactions provided a novel way to construct responsive light-emitting materials. Multiple orthogonal noncovalent interactions were utilized to fabricate new supramolecular polymers with the more sophisticated functions. Recently, Stang et al. [65] reported an efficient strategy to construct fluorescent supramolecular polymer network by the multiple interactions within a single process, including metalligand coordination, hydrogen bonding, and host-guest interactions (Fig. 23a). Firstly, they fabricated a hexagonal metallacycle from a 120 B21C7-containing di-Pt (II) acceptor and 2-ureido-4-pyrimidinone (UPy)-decorated 120 bis-pyridyl donor through the coordination of the pyridyl with organoplatinum. Then, the

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Fig. 21 (a) Construction of supramolecular polymers for Pd2+ detection based on host-guest interactions between DB24C8 and ditopic linkers. (b) 350 nm fluorescence emission-irradiated photo of the electrospun supramolecular polymer nanofibers. (c) Emission spectra of supramolecular polymer with different metal ions in the solid state [61]. (Adapted with permission [61]. Copyright 2015, Royal Society of Chemistry.) (d) Schematic illustration of the construction of hyperbranched fluorescent supramolecular polymer [62]. (Adapted with permission [62]. Copyright 2016, Royal Society of Chemistry)

supramolecular polymer network was achieved via a self-assembly process driven by hydrogen-bonding interactions with the UPy units. The remained B21C7 moieties could offer a platform for further introducing a guest via host-guest interaction. For example, TPE-functionalized dialkylammonium salt and perylene-decorated dialkylammonium salt were incorporated into supramolecular polymer network to obtain two light-emitting supramolecular polymers by taking advantage of B21C7/ dialkylammonium complexation. Moreover, the network could form supramolecular gels at high concentrations or upon solvent swelling. This orthogonal strategy based on noncovalent bond provides a simple yet highly efficient method to achieve

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Fig. 22 (a) Molecular structures of polymer chain and host molecule and schematic illustration of the formation of supramolecular network [63]. (Adapted with permission [63]. Copyright 2018, Royal Society of Chemistry.) (b) Illustration of the fluorescent supramolecular cross-linked polymer gel formed by the self-assembly of B21C7 and polymer chains [64]. (Adapted with permission [64]. Copyright 2015, Springer)

modular functional supramolecular polymer materials. Likewise, Stang et al. [66] recently reported the fabrication of a multifunctional metallacage-core supramolecular gel via orthogonal metal-coordination-driven self-assembly of cis-Pt(PEt3)2(OTf)2, TPE-based sodium benzoate ligands and linear dipyridyl ligands containing 21C7 units (Fig. 23b). Threading a guest, incorporating a dialkylammonium binding site, into the free 21C7 moieties within the metallacage by host-guest interactions, resulted in the formation of a supramolecular polymer network, which further formed a supramolecular gel at relatively high concentrations. Interestingly, the supramolecular polymer gel showed an excellent fluorescence emission, deriving from the AIE properties of TPE derivatives. The employment of noncovalent bond to construct supramolecular polymer gel suggested that the gel network could respond to multiple stimuli and possess outstanding self-healing properties. Moreover, rheological results revealed that the rigidity of the metallacages enhanced the stiffness of the gel. This novel multiple-functional supramolecular polymer network based on orthogonal self-assembly could open an avenue for the fabrication of supramolecular gels with stimuli-responsive and self-healing properties as smart materials.

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Fig. 23 (a) Schematic illustration of the construction of a cross-linked 3D supramolecular polymeric network from hierarchical self-assembly [65]. (Adapted with permission [65]. Copyright 2016, American Chemical Society.) (b) Illustration of the fluorescent supramolecular polymer network formed by the self-assembly of metallacage and bis-ammonium salt [66]. (Adapted with permission [66]. Copyright 2018, American Chemical Society)

5.5

Conclusion

In conclusion, recent developments in the designation and construction of photoluminescent crown ether assembly have been discussed. These complicated structures fabricated via self-assembly at the molecular scale provided many opportunities for the preparation of new smart luminescent supramolecular materials. Various noncovalent interactions, such as metal-ligand coordination, hydrogen bonding, and host-guest interactions, were the essential characteristics of these materials. Ingeniously, the combination of functional units (i.e., DAE, TPE, and anthracene) and the dynamic noncovalent interactions endowed the luminescent materials with multistimuli-responsive and self-healing features. The fluorescence intensity of the systems could be reversibly modulated upon external stimuli, like light, pH, temperature, etc. Moreover, these luminescent materials could be further used in sensors, light harvesting, and bio-imaging.

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Although luminescent crown ether assemblies have played a crucial role in numerous fields in the current research, some uncharted terrains still need chemists to explore. For example, in the field of biological field, how to develop the biocompatible and NIR luminescence systems that can be introduced into cells, even living organisms, is a large unexplored area. In the field of solid-state lighting, how to solve the problems of the low stabilities and low fluorescence quantum yields of these systems also needs to be further investigated. In the field of luminescent supramolecular polymers, how to construct a supramolecular polymer with high mechanical strength, self-healing, and excellent fluorescence characteristics still remains a major difficulty. In a word, this is just the beginning of the journey to prepare ever more sophisticated and complex structures for application in the luminescent materials based on crown ether assembly. Future developments involving crown ether assembly are unconceivable, and we firmly believe that photoluminescent crown ether assembly will play an irreplaceable role in the near future. Acknowledgments We thank NNSFC (21432004, 21672113, 21772099, 21801112, 21861132001), Key Scientific Research Projects of Higher Education of He’nan Province (19A150003), and the Scientific & Technological Project of He’nan Province (172102310476) for financial support.

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Part II Supramolecular Assemblies Based on Macrocyclic Arenes

6

Triptycene-Derived Macrocyclic Arenes From Calixarenes to Helicarenes Ying Han and Chuan-Feng Chen

Contents 6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 Triptycene-Derived Calixarenes and Analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2 Structures in Solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.3 Structures in Solid State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.4 Molecular Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.5 Molecular Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 Helicarenes: New Chiral Macrocyclic Arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.2 Structural Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.3 Applications in Molecular Recognitions and Self-Assemblies . . . . . . . . . . . . . . . . . . 6.4 Conclusion and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.1

139 141 141 150 154 157 162 166 167 169 171 176 178

Introduction

Since Pedersen first reported the synthesis of crown ethers and their cation-complexing properties in 1967, the development of new class of macrocyclic hosts has always been one of the most important topics in host-guest chemistry, and also supramolecular chemistry during the last half century. Consequently, various macrocyclic hosts [1–4] including crown ethers, cryptands, cyclodextrins, cavitands, cyclophanes, Y. Han Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China C.-F. Chen (*) Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_7

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cucurbiturils, calixpyrroles, cyclopeptides, and others have been reported, and these hosts have undoubtedly played a very important role in the emergence and development process of both host-guest chemistry and supramolecular chemistry. In the known synthetic macrocycles, calixarenes have become one of most important macrocyclic hosts and thus found wide applications on supramolecular chemistry. Since calixarenes were first efficiently synthesized and named by Gutsche and coworkers in the late 1970s, they and their analogues including resorcinarenes, cyclotriveratrylenes, pillararenes, and others have attracted much attention during the last decades. So calixarenes were also called as “the third generation of host molecules” after crown ethers and cyclodextrins. Since calixarenes and their analogues are all composed of substituted aromatic rings bridged by methylene or methenyl groups, we can also call them as a type of macrocyclic arenes. Actually, the known macrocyclic hosts are all composed of building blocks with specific structures and reactivity. Undoubtedly, exploration of new building block is important for design and synthesis of novel macrocyclic hosts with specific structure and properties. Iptycenes [5, 6] are a class of aromatic compounds with arene units fused to bicyclo[2.2.2]octatriene bridgehead system. Triptycene, the first and simplest member of this family, has D3h symmetry with a unique Y-shaped rigid structure, in which the three phenyl ring “panels” are connected with the bridgehead carbons (Fig. 1). Because its structure was like the triptych of antiquity, a book with three leaves hinged on a common axis, it was thus named as triptycene. In 1942, Bartlett and his coworkers first reported the synthesis of triptycene by multi-step reactions. Wittig et al. then synthesized the triptycene in one-pot step by addition of benzyne to anthracene in 1956. Stiles et al. further obviously improved the yield of triptycene by the use of a new synthesis of benzyne, which subsequently provided a convenient and efficient method for the synthesis of triptycene. However, triptycene chemistry almost focused on the synthesis of triptycene and its derivatives at the early days of the development. Only after the 1980s of the last century, especially in recent years, triptycene with three-dimensional rigid structure and rich reactive positions has drawn much attention and found more and more applications in molecular machines, supramolecular chemistry, and other research areas. Previously, we [5, 7] have developed a new kind of synthetic hosts by the combination of triptycene building block with unique Y-shaped rigid structure and crown ether chains, including triptycene-derived cylindrical macrotricyclic polyethers [8–11] and tweezer-like triptycene-derived crown ethers [12–14]. The rigid triptycene moiety favors these hosts to generate multi-cavity structures, while the flexible crown ether moiety

Fig. 1 Structure of triptycene

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HO 6 HO

8 HO 1a

1

R 7

* *

2 R

1b R = OH, 1c R = NH2

2 OH 1d

Fig. 2 Structures of substituted triptycenes 1a–1d

facilitates the hosts to adjust their conformation for the encapsulated guests. These specific structural features make the hosts show the diversified complexations with different kinds of guests, especially, multiple stimuli responsive complexation, which will be useful for the design and construction of functionalized supramolecular assemblies. Recently, we also applied the tritopic triptycene-derived tri(crown ethers) into the design and construction of molecular switches and machines [15, 16]. Triptycene derivatives 1a–1d with two hydroxyl groups or amino groups (Fig. 2) are easily available compounds [17]. Based on 1,8-dihydroxyltriptycene 1a as the building block, a new kind of triptycene-derived calixarenes could be obtained, while 1b and 1c could be used into the design and synthesis of the calixarene analogues, heteracalixarenes, and also tetralactam macrocycles. Especially, with the chiral triptycene building block 1d, a new kind of chiral macrocyclic arenes composed of subunit 1d bridged by methylene groups could be achieved. In this chapter, we will summarize our recent research results in synthesis, structures, applications in hostguest chemistry, and molecular assembly of the triptycene-derived macrocyclic arenes including calixarenes, heteracalixarenes and analogues, and helicarenes, a new kind of chiral macrocyclic arenes recently developed by our group.

6.2

Triptycene-Derived Calixarenes and Analogues

6.2.1

Synthesis

6.2.1.1 Triptycene-Derived Calixarenes and Analogues Replacement of the phenol groups in a classic calix[4]arene with one or more 1,8dihydroxyltriptycene 1a moieties, new kinds of calixarenes with large cavities and fixed conformations can be obtained. So we [18, 19] first made use of triptycene moiety 1a with the 3D rigid structure in place of the phenol groups in the calixarene to obtain a pair of diastereomeric triptycene-derived calix[6]arenes or calix[2]triptycene[2]arenes 4a and 5a were synthesized in 19 and 17% yields, respectively (Scheme 1, route a), by one-pot reaction of triptycene derivative 2 with one equivalent of 3a in a catalytic amount of p-toluenesulfonic acid [18]. Under the same reaction conditions, the one-pot reaction of 6 with triptycene derivative 2 gave triptycene-derived calix[6]arenes 4b and 5b in 17 and 11% yields, respectively.

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Y. Han and C.-F. Chen R

R OH HO

OH OMe

OMe

p-TsOH o-dichlorobenzene

OH 3a R = t-Bu 3b R = Ph

OMe 2

route b

route a

+

OMe

R

OMe

OMe

OH 4a R = t-Bu; 4b R = Ph + R

p-TsOH toluene

OMe

R

R

OH route b

OH

OMe

OMe

6a R = t-Bu; 6b R = Ph

OH

OMe

2, p-TsOH o-dichlorobenzene

OH

OMe

OMe R 5a R = t-Bu; 5b R = Ph

Scheme 1 Synthesis of 4 and 5

Although triptycene-derived macrocyclic hosts 4 and 5 could be conveniently obtained by one-pot approach, the relatively low yields limited their practical preparation of the desired macrocycles. Thus, we also obtained 4a (25%), 4b (20%), 5a (19%), and 5b (17%) by the fragment-coupling approach [19]. As shown in Scheme 1, by the reaction of compound 2 with an excess of p-substituted phenol in refluxing toluene in the presence of p-toluenesulfonic acid, the [1 + 2] products 6a and 6b with yields of 89 and 83%, respectively, were obtained. Then, 6 further reacted with 2 in o-dichlorobenzene in the presence of p-toluenesulfonic acid to give the targets 4 and 5. By the treatment of macrocycles 4 and 5 with BBr3 in dry CH2Cl2, the corresponding demethylated 7 and 8 (Fig. 3) were obtained in 71 and 78% yields. When 7a and 8a were treated with AlCl3 in toluene at room temperature, the de-tertbutylated 7c and 8c were obtained in 61 and 54% yields, respectively. Moreover, by treatment of 4a and 5a with AlCl3 in toluene, we also directly got 7c and 8c, respectively, in moderate yields [19]. Treatment of 2 with excess of 2-methyl-1,3-dimethoxybenzene 9a in CH2Cl2 with BF3
Et2O as the catalyst gave 10a in 76% yield, which was then reacted with 2 in the presence of BF3
Et2O to afford 11a and 12a in 29 and 23% yields, respectively. 11a and 12a were demethylated by BBr3 in CH2Cl2 to give 13 and 14 in 86 and 83% yield, respectively. Similarly, 11b–d and 12b–d were also obtained. Further demethylation of 11d and 12d by BBr3 in CH2Cl2 gave 13 and 14 in 90 and 86% yield, respectively (Scheme 2) [20].

6

Triptycene-Derived Macrocyclic Arenes

143

R

R

OH OH OH

R

OH

OH OH

OH OH 7a R = t -Bu; 7b R = Ph; 7c R = H

OH OH

OH

OH R 8a R = t -Bu; 8b R = Ph; 8c R = H

Fig. 3 Structures of 7 and 8

According to the similar synthetic approach as that of calix[6]arenes, a series of novel calix[5]arenes 16a–c containing one 1,8-dimethoxytriptycene moiety could also be obtained by the heat-induced fragment-coupling reactions. When 6a or 6b reacted with 2,6-dihydroxymethylphenols 15a–b in refluxed xylene for 2 days, triptycene-derived calix[5]arenes or calix[1]triptycene[3]arenes 16a–c were obtained in 25, 21, and 23% yield, respectively (Scheme 3). Treatment of 16a–c with BBr3 gave the corresponding demethylated products 17a–c in 86–90% yields. De-tert-butylated products 18a and 18b were obtained by treatment of 17a and 17b with AlCl3 in 82 and 75% yields, respectively. Under the same conditions, 16a and 16b could be simultaneously de-tert-butylated and demethylated to give 18a and 18b in high yields [21]. Dibromo-substituted calix[5]arene 21 was obtained from 19 by the similar synthetic strategy as above (Scheme 4) [22]. Then calix[5]arene 22 with a deeper cavity could be easily synthesized by Suzuki coupling reaction of 21 with phenylboronic acid. Treatment of 22 with dimethyl sulfate in the presence of potassium carbonate gave full methyl etherified calix[5]arene 23a in 85% yield. Due to the lack of the intramolecular hydrogen bonds, 23a adopted a 1,2-alternate conformation, which is different from 22 with cone conformation. By treatment of 16a with excess bromine in CH2Cl2, it was interestingly found pentabromo-substituted calix[5]arene 24 in cone conformation was obtained in 92% yield (Scheme 5). Treatment of 24 with dimethyl sulfate in the presence of potassium carbonate gave 25 in 72% yield, which also adopted 1,2-alternate conformation. Furthermore, by Suzuki coupling reactions of 25 with arylboronic acids in the presence of Pd(PPh3)4 and anhydrous potassium carbonate, calix[5]arene derivatives 23a–b with deep cavities were obtained in good yields [22]. Calixresorcinarenes or resorcinarenes are a class of well-defined macrocyclic compounds related to calixarenes. We [23] recently synthesized a series of calix[6] resorcinarene-like hosts containing two triptycene moieties and two p-substituted phenol moieties. As shown in Scheme 6, starting from 2,7-dimethoxyltriptycene 27,

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Y. Han and C.-F. Chen

R

R R'O

OR'

BF3·Et2O

+

OMe

2

OMe

R'O

R OR'

or TsOH

OH

HO

OR'

R'O

9a R = R' = Me 9b R = OMe; R' = Me 9c R = Br; R' = Me 9d R = Me; R' = H

OMe OMe 10a R = R' = Me (76%) 10b R = OMe; R' = Me (71%) 10c R = Br; R' = Me (68%) 10d R = Me; R' = H (76%) R

R R'O

R'O

OR'

OR' OMe

2

OMe

OMe

+

OMe OMe

BF3·Et2O or TsOH OMe

OMe

OMe

R'O

R'O

OR'

OR' R 12a R = R' = Me (23%) 12b R = OMe; R' = Me (18%) 12c R = Br; R' = Me (15%) 12d R = Me; R' = H (11%)

R 11a R = R' = Me (29%) 11b R = OMe; R' = Me (21%) 11c R = Br; R' = Me (20%) 11d R = Me; R' = H (15%) HO

OH

HO

OH OH

BBr3, CH2Cl2

OH

OH

+

OH OH

R = Me OH HO

OH OH

13 (86%) from 11a 13 (90%) from 11d

OH HO

OH

14 (83%) from 12a 14 (86%) from 12d

Scheme 2 Synthesis of 11–14

we first prepared precursor 29 in two steps, which then reacted with p-substitutedphenols in the presence of p-toluenesulfonic acid to give 30a–c. Treatment of 30a–c with equimolar amount of 29 in o-dichlorobenzene in the presence of p-toluenesulfonic acid produced calixresorcinarenes 31a–c. Similarly, the corresponding demethylated macrocycles 32a–c could be obtained in high yields by BBr3 in CH2Cl2.

6.2.1.2 Triptycene-Derived Heteracalixarene and Analogues 2,7-Dihydroxyltriptycene 1b could also be utilized as the nucleophilic reagent for the design and synthesis of oxacalixarenes by the nucleophilic aromatic substitution reactions. As shown in Scheme 7, by one-pot reaction of 2,7-dihydroxytriptycene 1b and electrophilic reagents 34a–c in DMSO with Cs2CO3 or K2CO3 as the base, oxacalixarenes 35a–c and 36a–c with extended cavities could be conveniently

6

Triptycene-Derived Macrocyclic Arenes

145 R1

R R

OMe

OH

OH R + HO

OH OH 17a R1 = R2 = t-Bu, 90% 17b R1 = t-Bu, R2 = Ph, 86% 17c R1 = R2 = Ph, 90%

OH 6a R = t-Bu 6b R = Ph xylene, reflux

AlCl3 toluene BBr3 CH2Cl2

R1

OMe

R2

OH OH 15a R = t-Bu 15b R = Ph

OMe

OH R1 HO

OH R1 HO

OMe OH 16a R1 = R2 = t-Bu, 25% 16b R1 = t-Bu, R2 = Ph, 23% 16c R1 = R2 = Ph, 21%

AlCl3 R2

R1

OH OH

toluene

R1 HO

R2

OH OH 18a R1 = R2 = H 18b R1 = H, R2 = Ph

Scheme 3 Synthesis of 16–18

synthesized [24]. When compound 1b reacted with 2,3,5,6-tetrachloropyridine 34a in DMSO in the presence of Cs2CO3, the extended oxacalixarenes 35a and 36a could be obtained in 19% and 25% yield, respectively. By the similar nucleophilic aromatic substitution reactions of 1b with 1,5-difluoro-2,4-dinitrobenzene 34b in the presence of K2CO3, the macrocycles 35b and 36b could be obtained in 22 and 15% yield, respectively. However, the extended oxacalixarenes 35c and 36c could not be synthesized under the same coupling conditions as above due to the instabilities of target macrocycles. Under various conditions examined, we found that the target oxacalixarenes 35c and 36c could be obtained by the SN2 reaction of 1b with cyanuric chloride 34c in acetone instead of DMSO in the presence of K2CO3. Moreover, 35c and 36c could be synthesized by the reaction of 1b with cyanuric chloride 34c in acetone with K2CO3 as the base, and they could also be obtained by the two-step fragment-coupling approach. Thus, the reaction of 1b and cyanuric chloride 34c in tetrahydrofuran in the presence of diisopropylethylamine (DIPEA) afforded the [1 + 2] product 37 in 58% yield. Then, the further coupling reaction of compound 37 with 1b in acetone with DIPEA as base at room temperature gave the extended oxacalixarenes 35c and 36c in 12 and 15% yield, respectively.

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Y. Han and C.-F. Chen

Br

Br

HO

OH OMe

Ph

Br

OH

OMe

Br

Ph

OMe

OH

p-hydroxydiphenyl p-TsOH toluene 80%

OMe 19

20 Ph Br B(OH)2

OH

15b

Br OMe

xylene 19%

Ph

HO

Ph

K2CO3, Pd(PPh3)4, DMF 81%

OMe OH 21 Ph Ph

OMe

Ph (CH3)2SO4 K2CO3

OH Ph OMe Ph

HO

Ph

Ph OMe

acetone 85%

Ph Ph

OMe

OMe OMe

OMe OH 22

Ph 23a

Scheme 4 Synthesis and reaction of dibromo-substituted 21

Similarly, oxacalixarene 35d containing two triptycene subunits and two naphthyridine subunits was conveniently synthesized in 37% yield by one-pot reaction of 33 and 34d in refluxed 1,4-dioxane in the presence of Cs2CO3 [25]. When the reaction of 33 and 34d was carried out in DMSO at 105  C with Cs2CO3 as the base, 35d and 36d were isolated in 17 and 9% yield, respectively [26]. By twostep fragment-coupling approach, 38a was synthesized in good yield with paraquat as a template. Reaction of 38a with aniline in acetone in the presence of K2CO3 gave 38b in 78% yield (Scheme 8c) [27]. Compared with oxacalixarenes, homooxacalixarenes are a class of heterocalixarene analogues with the heteroatoms partly or completely replaced by CH2OCH2 groups, which could have bigger cavities and show different recognition properties. With the increased cavity sizes, homoheterocalixarenes can show different recognition properties and a wide field of applications. Recently, we [28] conveniently synthesized triptycene-derived homooxacalixarene analogues 39a–d

6

Triptycene-Derived Macrocyclic Arenes

147

t-Bu

Br Br

OH OMe

t-Bu

OH

Br2 Bu-t CH Cl , r.t. 2 2

HO

Br OMe Br

(CH3)2SO4, K2CO3

Br

HO

acetone 72%

92% OMe

OMe OH 24

OH 16a

OMe R

OMe Br

R

Br Br

Br OMe

B(OH)2 26a R = H 26b R = CH3

OMe

R

R OMe

K2CO3, Pd(PPh3)4, DMF

R

OMe

OMe

OMe OMe OMe R 23a R = Ph, 67% 23b R = p-MePh, 63%

Br 25

Scheme 5 Synthesis and reaction of pentabromo-substituted 24

MeO

OMe

hexamethylenamine CF3CO2H, reflux

MeO

75%

OMe

OHC

NaBH4, MeOH 98%

CHO 28

27

MeO

OMe

HO

OH

p-substituted-phenol 30

R

R MeO

OMe

OH

29

OH

31a R = t-Bu (54%) 31b R = Ph (78%) 31c R = i-Pr (59%)

OH

OH OMe

OH

MeO

R

29, p-TsOH o-dichlorobenzene

p-TsOH, toluene

BBr3, dichloromethane

OMe MeO OH

R 32a R = t-Bu (21%) 32b R = Ph (22%) 32c R = i-Pr (20%)

Scheme 6 Synthesis of macrocycles 32–33

HO

R OH

HO OH

R 33a R = t-Bu (90%) 33b R = Ph (95%) 33c R = i-Pr (92%)

148

Y. Han and C.-F. Chen

Cl

Cl

Cl O

N 34a

Cl

Cl

Cl

O

O

N

Cl O

N

Cl +

Cs2CO3 DMSO, 120 °C N

O Cl

O

O

Cl

Cl

N

35a, 19% O2N O2N

NO2

F

NO2

O

O

Cl 36a, 25%

O2N

NO2

O

O

O

F 34b

+

K2CO3 DMSO, r.t. O

O

OH

O2N

O

O

NO2

O2N

35b, 22%

OH

N

N 34c

Cl N

N

N

N

N O

Cl

36b, 15%

Cl

Cl 1b

NO2

O

O

N

N

O

Cl +

K2CO3 acetone, r.t. N

O N

N

Cl 35c, 12% Cl N Cl

O N

Cl 36c, 18%

Cl N

N

N N

N

O

O N

Cl

O

N

Cl

34c, 2 equiv.

1b

35c (12 %) + 36c (15 %)

DIPEA acetone, r.t.

DIPEA, THF, 0 °C

N

O N

Cl N

Cl 37a, 58%

Scheme 7 Synthesis of oxacalixtriptycenes 35a–c–36a–c

and 40a–d in moderate yields by one-pot reactions of 2,7-dihydroxytriptycene 1b with 1,3-bisbromomethylbenzene derivatives in the presence of Cs2CO3 and further obtained two pairs of “basket-like” triptycene-derived homooxacalixarene analogues 41a–b and 42a–b (Fig. 4). We [29] also designed and synthesized several pairs of novel triptycene-derived N(H)-bridged azacalixarenes 44–47 by two synthetic routes with 2,7-diaminotriptycene 1c and its analogue 43 containing an o-dimethoxybenzene subunit as materials. As shown in Scheme 9, the one-pot reaction of 2,7diaminotriptycenes 1c or 43 with 1,5-difluoro-2,4-dinitrobenzene 34b in dry THF in the presence of DIPEA gave triptycene-derived N(H)-bridged azacalixarenes 44–45 in the yields of 16–27%. By the same reaction conditions, triptycene-derived N(H)-bridged azacalixarenes 46–47 were obtained by the reaction of 1c or 43 with

6

Triptycene-Derived Macrocyclic Arenes

149

(a) OH

N

N

O

N

N

O

Cs2CO3

+ Cl

N

N 34d

Cl

1,4-dioxane, reflux

OH

1b

O

O

35d (37%)

(b) OH

O

Cs2CO3

+ Cl

1b

N

N 34d

Cl

DMSO, 105 °C

N

O

N

35d (17%) +

OH

O

N

N

O

35d (9%)

(c) N

N

O

O

N

N

O O Cs2CO3

34c DIPEA, acetone paraquat

DMSO, 100°C 1b + 34d 82%

35% N

O OH

O

HO N

37b

aniline acetone, K2CO3 reflux, 78%

N R 38a R = Cl 38b R = NHC6H5

Scheme 8 Synthesis of oxacalixtriptycenes 35d and 38a–b

cyanuric chloride 34c in the yields of 8–19%. These target macrocycles 44–47 could also be synthesized in higher total yields by a two-step fragment-coupling method. With 1c or 43 as materials, the [1 + 2] products 48a–b and 49a–b were first synthesized in high yields by the reaction of 2,7-diaminotriptycene with the corresponding electrophilic reagents. Then, the [1 + 2] products further reacted with 2,7-diaminotriptycenes 1c or 43 in CH3CN in the presence of DIPEA to afford the macrocycles 44–47. As shown in Scheme 10, we [30] synthesized a series of triptycene-derived diazadioxacalixarenes 50a–c and 51a–c by a two-step SNAr reaction of 2,7dihydroxytriptycene 1b or 2,7-diaminotriptycene 1c with proper electrophilic reagents, such as cyanuric chloride, 1,5-difluoro-2,4-dinitrobenzene, and 2,6dichloropyridine-3,5-dicarbonitrile. When 2,7-dihydroxytriptycene 1b was reacted with the electrophilic reagents in THF in the presence of DIPEA, the corresponding [1 + 2] products could be obtained in high yields. The further macrocyclization reaction between the [1 + 2] products and the corresponding electrophilic reagents gave the target triptycene-derived diazadioxacalixarenes 50a–c and 51a–c in moderate yields.

150

Y. Han and C.-F. Chen R2

R2

O

O

O

O OR1

OR1

OR1

OR1 O

O

O

O

R2

R2

39a R1 = Me, R2 = t-Bu 39b R1 = n-Bu, R2 = t-Bu 39c R1 = Me, R2 = Ph 39d R1 = n-Bu, R2 = Ph

40a R1 = Me, R2 = t-Bu 40b R1 = n-Bu, R2 = t-Bu 40c R1 = Me, R2 = Ph 40d R1 = n-Bu, R2 = Ph

Ph

Ph

O

O

O

O O

n

n

O O

O

O

O O

O

O

O

Ph

Ph

41a n = 2; 41b n = 3

42a n = 2; 42b n = 3

Fig. 4 Structures of 39–42

6.2.1.3 Triptycene-Derived Tetralactam Macrocycles Due to their capability of binding substrate species strongly and selectively, tetralactam macrocycles have been widely applied to construct a variety of interlocked supramolecular assemblies, develop new molecular machines, and improve the properties of organic dyes by molecular encapsulation. In 2008, we [31] designed and synthesized a pair of novel triptycene-derived tetralactam macrocycles 52a–b. As shown in Scheme 11, by a one-pot [2 + 2] cyclization reaction of pyridine-2,6-dicarbonyl dichloride and 2,7-diaminotriptycene in dry THF in the presence of Et3N, macrocycles 52a–b could be conveniently synthesized in 20–26% yields.

6.2.2

Structures in Solution

Due to the different linking modes of the triptycene moieties, 4a and 5a are a pair of diastereomers. 4a is a syn orientation of the two triptycene moieties, while 5a is an

6

Triptycene-Derived Macrocyclic Arenes

151

Cl

Cl N

Cl N N

Cl

HN

N Cl

DIPEA THF, r.t.

N

N N

HN

NH R

R

R

R N

HN N

NO2 F

R

R

N H

N

HN N

N

N

N H

Cl 44b R = H,16%; 45b R = OMe, 18%

O2 N

NO2

O 2N

NO2

HN

NH

HN

NH

R R

DIPEA THF, reflux

R

+

R F

NH

R

Cl 44a R = H, 27%; 45a R = OMe, 20%

O 2N

N N

R

R

+ R

R

R

NH2

HN

N H

O2N

NO2

HN O 2N

46b R = H, 8%; 47b R = OMe, 9%

46a R = H, 19%; 47a R = OMe, 16% R

N H NO2

Cl

R

N

Cl 1c R = H 43 R = OMe

NH2

N N

Cl

N NH

N

Cl

N Cl

DIPEA THF, r.t. N

Cl N

R

43

R

DIPEA CH3CN, r.t.

44a R = H 45% 45a R = OMe 34%

+

44b R = H 34% 45b R = OMe 27%

N H N

Cl 48a R = H, 87%; 49a R = OMe, 81%

O 2N F

O 2N

NO2

HN

F

NO2 F

R

43

DIPEA THF, reflux

R

DIPEA CH3CN, r.t.

N H O 2N

F

46a R = H 26% + 47a R = OMe 24%

46b R = H 19% 47b R = OMe 11%

NO2

48b R = H, 84%; 49b R = OMe, 79%

Scheme 9 Synthesis of triptycene-derived N(H)-bridged azacalixarenes 44–47

anti orientation isomer [18]. Both of them showed one singlet for the tert-butyl protons, one singlet for the methoxy protons and two singlets for the bridgehead protons of the triptycene moiety in the 1H NMR spectra, while there was only one signal for the methylene carbons in their 13C NMR spectra. Moreover, there were no obvious changes in the methylene proton signals with increasing temperature in their variable-temperature 1H NMR spectra. These observations suggested that both 4a and 5a have highly symmetric structures and fixed conformations. However, their 1H NMR spectra showed a large difference from each other. For the methylene protons, a pair of doublet signals at 3.35 and 4.25 ppm (Δδ = 0.90) were observed in 4a, whereas 5a showed a pair of doublet signals at 3.67 and 3.86 ppm with a Δδ value of about 0.19 ppm. This result implied that macrocycles 4a and 5a are a pair of diastereomers, 4a has a syn orientation of the two triptycene moieties, while 5a is an anti orientation isomer. Similarly, 4b and 5b, 7a–c and 8a–c, 11a–d and 12a–d, 13, and 14 are also diastereomers with symmetric structures and fixed

152

Y. Han and C.-F. Chen Cl N

N

Cl

N

NH

Cl

N

N H

Cl

N

N O

Cl N

N

N

O

NH

N Cl

N

O N

O2N

NO2

F

NH

F

N H

O2N

N H

N

Cl

Cl

50a, 37%

51a, 32%

NO2

O 2N

NO2

O

NH

O

NH

NH

Cl

N

N H

N H

O

NO2

O2 N

O O2N

CN N

50b, 26%

NC

NC

N H

+

1b

Cl

N

O2 N

DIPEA CH3CN, reflux

NC

N

O

N

NO2

OH

NH

+ DIPEA CH3CN, reflux

OH

N N

O

N

N H NO2

51b, 21%

CN

NC

NH

O

CN

CN NH

N

+

DIPEA CH3CN, reflux

O NC

N

N

N H

O

CN

NC

N H CN

51c, 24%

50c, 32%

Scheme 10 Synthesis of triptycene-derived diazadioxacalixarenes 50 and 51

NH2

O

NH2

N

HN

+

THF, 0 °C to r.t. NH

N

HN O

O ClOC

O N

HN

HN

Et3N 43a +

O

O N

NH

NH O

N

HN O

COCl 52a (26%)

52b (20%)

Scheme 11 Synthesis of triptycene-derived tetralactam macrocycles 52

conformations, respectively, in which the formers were syn isomers, while the latter ones were trans isomers [19, 20]. For calix[1]triptycene[3]arenes 16–18, they adopted fixed cone conformation in solution as well although they have bigger cavities than the classic calix[4]arene [21]. For 16a, variable-temperature 1H NMR experiments showed its coalescence

6

Triptycene-Derived Macrocyclic Arenes

153

temperature is more than 100  C, which is much higher than those of the classic ptert-butylcalix[4]arene and p-tert-butylcalix[5]arene. This indicated that the significant contributor in determining the conformational mobility of 16a is not due to the intramolecular hydrogen bonds and the bulky tert-butyl groups but mainly attributed to the introduction of the triptycene moiety with rigid structure. For triptycenederived calix[5]arenes 16b–c, they also showed the similar spectral features to those of 16a. The results showed that all of the triptycene-derived calix[5]arenes 16a–c containing two dimethoxy groups had Cs symmetric structures with a fixed cone conformation in solution. Their demethylated compounds also have the similar 1H NMR spectra features and the same fixed cone conformations as those of their precursors. Moreover, the variable-temperature 1H NMR experiments of 16a–c in DMSO-d6 showed no obvious changes of the methylene proton signals with the increase of the temperatures even up to 373 K. These observations not only confirmed their fixed conformations but also indicated that the conformational inversion barriers of these compounds are very high. Similarly, 21, 22, and 24 with different substituents at the upper rim also kept fixed cone conformation in solution due to the rigid structure of triptycene and the intramolecular hydrogen bonding of the adjacent phenol groups. But after 22 and 24 were all methyl etherified, products 23 and 25 showed 1,2-alternate conformations in the tested temperatures [22]. We also investigated the structures of triptycene-derived calix[6]resorcinarenelike hosts 32–33 [23] in solution by the 1H NMR, 13C NMR, and variable-temperature 1H NMR experiments. The spectra features showed that these calix[6] resorcinarene-like hosts 32–33 are all the cis isomers with fixed cone conformation in solution. Similar to triptycene-derived calixarenes, triptycene-derived oxacalixarenes 35a–d and 36a–d are also a pair of diastereomers with high symmetric structures and fixed conformation in solution, in which 35a–d are cis isomers and 36a–d are trans isomers [24, 26]. For triptycene-derived homooxacalixarene analogues, the 1H NMR spectra of 39a–d [28] showed two singlets for the bridgehead protons with small Δδ value, which implied that they were cis isomer with a high symmetric structure. Meanwhile, the 1H NMR spectra of 40a–d showed the relatively significant different chemical shifts for bridgehead protons, which suggested that they were the trans isomers. It was noteworthy that the two sets of doublet signals of trans isomer 40c for the methylene group were gradually changed to one set of doublet signals above 370 K, which meant that at very high temperature, the rigid conformation of 40c was no longer existed. However, for cis isomer 39c, the methylene proton signals exhibited no obvious changes even up to 380 K. When the two p-phenyl-substituted benzene rings were linked together by crown ether chains, the conformations of macrocycles 41 and 42 could be fixation up to 380 K without free rotation. Triptycene-derived N(H)-bridged azacalixarenes 44a–47a and 44b–47b [29] are also pairs of diastereomers. It was found that the 1H NMR spectra of cis isomers 44a–47a showed the close chemical shifts of the aromatic protons and small different shifts for the benzylic protons with the high symmetry boat conformation, while the trans isomers 44b–46b showed four singlets with significant different chemical shifts for bridgehead protons and two singlets for the protons of N H

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bridged groups. These observations suggested that trans isomers 44b–46b do not adopt the chair conformation but fixed curved-boat conformation without the high symmetry at room temperature, which are different from those of the triptycenederived oxacalixarenes with trans isomers [24]. However, the 1H NMR and 13C NMR spectra of trans isomer 47b showed its high symmetrical structure with a chair conformation in solution. We deduced that the different properties of dynamic conformational interconversion probably resulted in the different conformations between 47b and 44b–46b [24, 29]. Similarly, triptycene-derived diazadioxacalixarenes 50 and 51a–c are also pairs of diastereomers due to the 3D structural characteristic of triptycene unit [30]. By the 1H NMR spectroscopy, their spectra exhibit that the cis isomers 50a–c adopt twisted boat conformation, while the trans isomers 51a–c are in a symmetrical chair conformation. For triptycene-derived tetralactam macrocycles 52a and 52b [31], they are a pair of diastereomers because their 1H NMR spectra are greatly different from each other. Both of cis isomer 52a and trans isomer 52b have highly symmetrical structures, and they exhibit only one signal for the N-H protons and two single signals for the bridgehead protons of the triptycene moieties in their 1H NNR spectra.

6.2.3

Structures in Solid State

As shown in Fig. 5, the crystal structures showed calix[2]triptycene[2]arene 4a is a cis isomer with boat conformation, while 5a is a trans isomer with chair conformation [18]. It was found that all of the macrocyclic compounds have highly symmetrical structures and specific fixed conformations in the solid state, which are consistent with the results in solution. For 7a, a typical cone conformation with high symmetric feature of C2v was shown. Due to the intramolecular hydrogen bonding in 7a, its dihedral angle between the two face-to-face p-tert-butylphenol rings is reduced to 7.44 compared with 138.23 of its precursor 4a. Moreover, the

Fig. 5 Crystal structures of (a) 4a, (b) 5a, (c) 7a, (d) 13d, (e) 16a, (f) 17a, (g) 24, and (h) 25

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cavity cross section of 7a ranged from 9.56  12.09 Å (upper rim) to 7.91  8.84 Å (low rim) [19]. Macrocycle 7c showed similar structural features to those of 7a, and the dihedral angle between the face-to-face phenolic rings is only 6.95 . For 13d containing two 2-methylresorcin subunits, similar structural feature to that of 7a was observed [20]. For triptycene-derived calix[5]arene 16a and its demethylated macrocycle 17a, the crystal structures showed they adopted cone conformations (Fig. 5e, f), in which intramolecular hydrogen bonding between the adjacent phenol hydroxyl groups or between the ether oxygen atoms and their adjacent phenol hydroxyl protons might play an important role in formation of the fixed conformations [21]. We also inferred that these intramolecular hydrogen bonding interactions might play an important role in the formation of their fixed cone conformations. Pentabromo-substituted calix[5] arene 24 also kept cone conformations, but 25 with the phenol hydroxyl groups all substituted by methoxy groups showed 1,2-alternate conformation due to the lack of intramolecular hydrogen bonding (Fig. 5h) [22]. Macrocycles 31a and 32a are all cis isomers with cone conformation (Fig. 6a, b), which are consistent with the results in solution [23]. There existed one pair of intramolecular hydrogen bonding in 31a with the distance of 1.99 Å and two pairs of intramolecular hydrogen bonding with the distances of 1.91–1.99 Å for 32a. As a result, 32a shows a more symmetrical structure than 31a, and the dihedral angle of 9.47 between the face-to-face benzene rings of the triptycene moieties in 32a is much smaller than that of 31a (30.06 ). For oxacalixarenes 35a and 36a, cis isomer 35a has 1,3-alternate conformation with a boat-like structure, while trans isomer 36a

Fig. 6 Crystal structures of (a) 31a, (b) 32a, (c) 35a, and (d) 35d

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shows chair-like conformation [24]. The crystal structure of cis isomer 35d showed that it had 1,3-alternate conformation with a cavity of 13.29  10.99 Å2 (wider rim) and 8.56  8.84 Å2 (narrower rim), in which the nitrogen atoms in the 1,8naphthyridine are all positioned inside the cavity (Fig. 6d) [25]. For trans isomer 36d, it adopted a curved-boat-like conformation in the solid state, which was different from the conformation in solution possibly due to the solvent effect. The X-ray crystal structures confirmed that triptycene-derived N(H)-bridged azacalixarenes 44a, 46a, and 48a were all cis isomers, while 44b was trans isomer [12]. In the solid state, 44a showed a high symmetry with a C2 axis, while 46a and 48a had the similar boat conformations with a little different cavity from that of 44a. These observations indicated that either alternating another aromatic subunits or derivatization on the triptycene moiety, these macrocycles can keep the boat conformations. This unique structure makes triptycene-derived N(H)-bridged azacalixarenes to have the wider rim with the heteroaromatics point to the same direction, which is different from that of reported azacalixarenes. Compound 44b adopted a curved-boat conformation without a high symmetrical structure for the change of the position of one triptycene subunit (Fig. 7), which was different to the normal chair-like conformation of the previously trans isomer of triptycene-based oxacalixarene [24]. For the triptycene-derived diazadioxacalixarenes, the crystal structure of cis isomer 50c [30] showed a high symmetry with boat conformation, in which the two pyridine rings showed the different positions for the different hybrid orbitals and electronic effects of nitrogen atom and oxygen atom. For triptycene-derived tetralactam macrocycles 52a and 52b, the X-ray crystal structures showed that they are a pair of diastereomers as well [31]. Similar to corresponding classical calix[4]arene, 52a is a cis isomer and adopts a cone conformation, four carbonyl groups attach to the wider rim, and the four amide N-H

Fig. 7 Crystal structures. Side views of (a) 44a, (b) 44b, (c) 45a, and (d) 46a. Solvent molecules and hydrogen atoms are omitted for clarity

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protons define the narrower rim, while the trans isomer 52b adopts a chair conformation, in which the two triptycene moieties are trans-connected by the pyridyl amide subunits. Moreover, the pairs of intramolecular hydrogen bonds were observed in both 52a and 52b, which played an important role in the formation of their specific conformation (Fig. 8).

6.2.4

Molecular Recognition

With large enough cavities and specific fixed conformations, triptycene-derived calixarenes and analogues could easily encapsulate small organic molecules in solid states. For example, triptycene-derived calix[6]arene 4a could encapsulate two CH3OH molecules in its cavity. A pair of O H


O hydrogen bonds between the phenolic oxygen atom and the hydroxyl proton of CH3OH were observed in complex 4a@2CH3OH. The cis isomer 2a could also accommodate two CH3OH molecules in its cavity via multiple non-covalent interactions, including O H


O hydrogen bonds, C H


O hydrogen bonds, and C H


π interactions. In the case of the trans isomer 5b, it could encapsulate a CH2Cl2 molecule by multiple noncovalent interactions including C H


Cl and C H


O hydrogen bonding and C H


π interaction between 5b and CH2Cl2. 7c contains one water molecule inside its cavity (Fig. 9a, b) [19]. For calix[1]triptycene[3]arenes, small neutral guest molecules are easily encapsulated in their fixed cone cavities as well (Fig. 9c) [21]. Moreover, calix[6]resorcinarene-like host 32a preferred to form a head-tohead dimeric capsule via two pairs of C H


O hydrogen bonding interactions between the methyl protons of one triptycene moiety and the methoxyl groups of its adjacent macrocycle, while two CH2Cl2 molecules were located in this capsule by C H


Cl interaction between the methyl proton of one macrocycle and each dichloromethane molecule (Fig. 9d) [22]. The cis isomers of triptycene-derived N(H)-bridged azacalixarenes all adopt fixed boat conformations and have large enough cavities, which were similar to those of triptycene-derived calixarenes. They could show the capability of complexation with methanol and acetone molecules inside their cavities [29]. For macrocycle 44a, there existed the O H


N hydrogen bonding between the hydroxyl group of methanol and N atom in the triazine ring and the O H


π hydrogen bonding between the hydroxyl group of methanol and one phenyl ring in triptycene moiety (Fig. 10a).

Fig. 8 Crystal structures. Side views of (a) 52a and (b) 52b. Solvent molecules and hydrogen atoms are omitted for clarity

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Fig. 9 Crystal structures of 2CH3OH@5a (a), H2O@7c (b), CH2Cl2@16a (c), and 2CH2Cl2@32a2 (d)

Fig. 10 Crystal structures. Side views of (a) CH3OH@44a, (b) acetone@46a, and (c) CH2Cl2•acetone@(46a)2. Other solvent molecules and hydrogen atoms are omitted for clarity

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Similarly, the cis isomer 46a could also encapsulate one acetone molecule in its cavity with multiple non-covalent interactions, including C H


O hydrogen bonding and two pairs of C H


π interactions (Fig. 10b). The similar molecular recognition property has not been observed in the reported N(H)-bridged azacalixarenes. Moreover, it was found that two molecules of 46a can form a dimer through the Oδ


Nδ+ and Oδ


Cδ+ interactions with two acetone molecules and two dichloromethane molecules in its cavity (Fig. 10c). Fullerenes and their derivatives have drawn much attention for their wide potential applications. Design and synthesis of new classes of supramolecular containers for fullerenes are of great interest in relation to the development of fullerene-based functional materials. Calix[2]triptycene[2]arenes have enough large and well-defined electron-rich cavity for fullerenes [23]. Consequently, 4b and 5b could form 1:1 stable complexes with C60 and C70 with the association constants (Ka) more than 1  104 M 1 by the fluorescence titrations, which were significantly higher than those ones (9–1300 M 1) of 1:1 complexes between C60 and the classical calixarene derivatives [32]. This probably revealed the introduction of the triptycene moiety not only fixed conformations of the macrocycles but also enhanced the interaction of concave cavities of the macrocycles with the electron-deficient convex surface of the fullerenes. Oxacalixarene 35d with extended cavity could also form 1:1 complexes with C60 and C70, and Ka values for 35d•C60 and 35d•C70 were (7.54  0.29)  104 and (8.96  0.31)  104 M 1, respectively [25]. Similarly, homooxacalixarene analogues 39a–d and 40a–d with fixed conformations and large electron-rich cavities showed efficient complexation abilities toward fullerenes C60 and C70 as well [28], and Ka values for the 1:1 complexes were over 104 M 1. Macrocycle 13 with electron-rich cavities could form 1:1 complexes with paraquat derivatives 53a–d (Fig. 11), and the association constants (Ka) are all over 102 M 1 [20]. It was found that they could show strong complexation capabilities with a series of paraquat derivatives. Oxacalixarenes 35d and 36d with large enough cavities and fixed conformations could also form 1:1 complexes with paraquat derivatives, and the Ka values were about 103 M 1 for 35d and 102 M 1 for 36d [26]. Similarly, 38a showed moderate complexation abilities toward various bipyridinium salts, but affinities of 38b toward the guests were found to be substantially stronger, which might be due to the additional non-covalent interactions between the aniline group and the guests [27]. Formation of the complexes was further evidenced by crystal structures of 35d•53a, 35d•53f, and 38b•53i (Fig. 12). Interestingly, complexation and dissociation of the complex based on 35d containing 1,8-naphthridine subunits could be easily controlled by acid/base stimuli or by the addition and removal of Hg2+ ions [26]. It was further found 35d showed a highly selective fluorescence sensing toward Hg2+ [33]. Moreover, 35d could encapsulate π-extended viologens 54–55 to form pseudo[3]rotaxane-type complexes in solution and solid state, and the complexation between the host and the guests could be reversibly switched by acid and base. Nonsymmetric structure of 35d also resulted in orientationally selective pseudorotaxanes depending to different lengths of the linkers in the guests, which might be ascribed to different complexation modes between the components in the complexes [34].

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Y. Han and C.-F. Chen R N R

n

N 2PF6−

43a R = H, n = 0

43b R = CH2CH3, n = 0

43c R = CH2OH, n = 0

43d R = CH2OCH3, n = 0

43e R = CH=CH2, n = 0

43f R = CH2OCH2CH=CH2, n = 0

43g R = (CH2)4CH2OH, n = 0

43h R = CH2OCH2C CH, n = 0

43i R = CH2C CH, n = 0 44a R = H, n = 1

44b R = CH2OH, n = 1

45a R = H, n = 2

45b R = CH2OH, n = 2

Fig. 11 Structures of guests 53a–i and 54–55

Fig. 12 Crystal structures of 35d•53a (a), 35d•53f (b), 38b•53i (c), and 35d•55a (d)

As a class of near-IR fluorescent dyes with specific photophysical properties, squaraines have shown wide potential applications in such as imaging, nonlinear optics, photovoltaics, ion sensing, and so on. However, in polar solvents, they are susceptible to aggregation, which can limit their applications. Thus, the maintenance of the chemical stability and the photophysical properties of the dyes is the key to the development of squaraine applications. The novel triptycene-based tetralactam macrocycles 52a–b have well-defined conformations, so we first tested their complexation with squaraine 56b [31, 35]. Consequently, we found that the

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macrocycles 52a–b could show highly efficient complexation with the squaraine to form a new kind of stable pseudorotaxane-type complexes in solution and in the solid state. It was noted that the complexation-induced asymmetry of the guest in the complex between 52a and 56b was also observed owing to the cone conformation of 52a. When the free guest 56b and the complexes 52a•56b and 52b•56b were dissolved in THF/water solution (4:1). After 4 days, we found that the guest 56b underwent hydrolytic decomposition to turn colorless, whereas the solution of the complexes retained their blue colors for several weeks. This observation revealed that the formation of complexes could efficiently protect the squaraine dyes from polar solvents. Then we further studied on the complexation of the macrocycles and the squaraine dyes with different terminal groups (Fig. 13) [31, 35], and it was found that squaraine 56a containing smaller terminal groups could thread the wheels 52a–b to form [2]pseudorotaxane complexes. In the case of 56c, it was found that it could penetrate through macrocycle 52b to form a [2]pseudorotaxane-type complex, while there was no similar insertion process between 52a and 56c at room temperature. But [2]rotaxane 52a•56c could be formed through slippage method, when the mixture of 52a and 56c was heated to 333 K for over 6 days. In addition, when host 52a or 52b was mixed with squaraines 56d and 56e and in CDCl3, there were no signals for complexes in 1H NMR spectra even after being heated at 333 K for several days. These results revealed that the bulker N,Nbis-n-butyl and N,N-bisbenzyl groups are large enough as the stopper for the [2] rotaxanes with triptycene-derived macrocycles 52a–b through the slippage method. In the case of the squaraine 56 g with two different bulky stoppers could not form [2]pseudorotaxane complexes with hosts as well. However, when host 52a was mixed with guest 56f, two new sets of resonances could be found in the 1H NMR spectrum, and the intensity of one set was higher than the other one. This result suggested that two isomeric [2]pseudorotaxane complexes based on 52a and 56f were obtained, and the complexation showed a slight selectivity. Thus, we chose 56d–g with bulky stopper groups as the templates to synthesize a new type of isomeric [2]rotaxanes via the clipping reactions. Moreover, a series of squaraine-based [2]rotaxanes could thus be obtained by the condensation reactions between pyridine-2,6-dicarbonyl dichloride and 2,7-diaminotriptycene 1c in the presence of an appropriate squaraine derivative. These rotaxane-type complexes showed higher chemical stabilities than those of free squaraines.

Fig. 13 Chemical structures of squaraine dyes 56a–g

O− R

N+

N R

R' R'

O

56b R = R' = CH3 56a R = R' = H; 56c R = R' = C2H5; 56d R = R' = C3H7 56e R = R' = C6H5; 56f R = C6H5, R' = H 56g R = C6H5, R' = C3H7

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Molecular Self-Assembly

Due to the introduction of rigid triptycene moiety, the novel triptycene-derived macrocyclic hosts showed the fixed conformations, which also makes the macrocycles as the building blocks for the formation of a variety of supramolecular structures via self-assembly. Consequently, it was found that both the cis isomer 4a with cone conformation and the trans isomer 5a with a chair conformation could self-assemble into tubular structures with the aromatic rings as the walls and phenolic oxygen atoms situated in their cavities. Then, these tubular assemblies could further stack into 2D superstructures and 3D microporous architectures with the solvent molecules inside the channels. In these supramolecular structures, the multiple non-covalent interactions based on macrocyclic molecules 4a and 5a between the solvent molecules and the macrocyclic molecules played important roles (Fig. 14) [18]. Similar to macrocycle 4a, cis isomeric calix[6]arenes 7a and 7c could also self-assemble into the tubular structures. In the case of the trans isomer 4b, the self-assembled structure was different from those of the cis isomers with cone conformations. It could self-assemble into a 1D supramolecular structure, and further microporous architecture with a pair of C H


O hydrogen bonding between the aromatic proton of the phenol ring in one macrocycle and the phenolic oxygen of its adjacent macrocycle and the π π interaction between the phenyl rings of the adjacent triptycene moieties [19]. For triptycene-derived calix[6]resorcinarene-like hosts, the cis isomer 32a could form a head-to-head dimeric capsule with two CH2Cl2 molecules inside the dimeric cavity with the C H


O hydrogen bonding interactions and the C H


Cl interactions between the macrocycles and solvent molecules [23]. Then, the dimers could form a tubular structure and further assemble into a 3D microporous architecture, and the CH2Cl2 molecules were situated in the channels. Similarly, its demethylated macrocycle could also self-assemble into the 3D microporous architecture via the previous self-assembled head-to-head dimer by the multiple non-covalent interactions between the macrocycle and its adjacent molecules and solvents (Fig. 15). Expanded oxacalixarenes 35a could assemble into an organic tubular structure by virtue of the multiple chlorine bonding including C Cl


Cl, C Cl


O, and

Fig. 14 Packing structures of (a) 4a and (b) 5a

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Fig. 15 Packing structure of 32a

C Cl


π interactions, in which the aromatic rings acted as the wall and the nitrogen atoms of the pyridine rings all pointed inward the tube (Fig. 16) [24]. Similarly, with multiple intermolecular chlorine bonding interactions, oxacalixarenes 36a and 35c could also assemble into organic tubular structures and further porous architectures. Based on complexation between 13 and the paraquat derivative, a [2]rotaxanetype assembly was synthesized in 28% yield [20]. Similarly, we synthesized a pair of isomeric [2]rotaxanes 56a and 56b based on 35d and 36d, respectively, which is the first example of oxacalixarene to be used as useful wheel for the synthesis of mechanically interlocked molecules. [2]Rotaxane 56a was further evidenced by its crystal structure, in which the axle was bent and one stopper group was positioned close to the 1,8-naphthyridine unit of the wheel with scorpion-like mode (Fig. 17) [26]. Oxacalixarene 35d with an upper semi-cavity encircled by two naphthyridine moieties and a lower semi-cavity by two triptycene moieties encouraged us to further investigate the directional complexation between the macrocycle and a nonsymmetric guest. By 1H NMR spectra and crystal structures, it was unequivocally shown the bipyridinium guests 57a–b preferred to thread from the triptycene rim and subsequently gave [2]rotaxanes 58–59a as major products. With 60 as axle, unidirectional threading was achieved to give [2]rotaxane 61 as the sole product. Thus, the threading direction and the orientation could be finely controlled by adjusting the electrostatic and steric effect of the guests (Scheme 12) [36]. Moreover, macrocyclic 40d could also form a tubular assembly with the aromatic rings as the wall and then 3D microporous architecture (Fig. 18) with a pair of intermolecular complementary C H


π interactions between the aromatic proton of the triptycene moiety of one molecule and the aromatic ring of the triptycene moiety of its adjacent molecule and another C H


π interactions between the proton of the bridging methylene and the aromatic ring of the p-phenyl moiety of its adjacent molecule [28].

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Fig. 16 Packing structure of 35a

O O

N

O

N

O

N+ N+ O O

O

2PF6-

N

N

O

56a from 35d 56b from 36d

Fig. 17 Chemical structures of [2]rotaxanes 56a–b and crystal structure of 56a

Crystals of 62 (Fig. 19a) suitable for X-ray crystallographic analysis were obtained by slow evaporation of a solution of 62 in THF–CH3OH. Its crystal structure showed that the azacalixarene molecule could self-assemble into a novel aromatic single-walled organic nanotube [37]. It was found that the unit cell contains two molecules of 62 (denoted as A and B, Fig. 19b), in the boat-like conformation with similar cavity in one unit cell. The further study showed that two molecules of A were located in opposite positions and generated a rectangular geometry with the four cyano groups and four NH sites in the same direction, while two molecules of B were also located face-to-face and generated a rectangular geometry rotated with respect to the former one by 90 . Owing to the two pyridine rings in one molecule of 62, it can contribute totally four pairs of hydrogen bonds and participate in two zigzag H-bond chains with other molecules for self-assembly. With the proper geometrical constraints of the building blocks and the relatively strong non-covalent interactions, a nanometrescale cubical organic nanotube is formed spontaneously (Fig. 19c). This nanotube is generated totally by four onedimensional H-bond chains, which are parallel or approximately parallel to the axis of tube and lead to the formation of four planes that consist of pyridine rings and

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Triptycene-Derived Macrocyclic Arenes

(a)

165

(b)

t-Bu

Naphthyridine rim

t-Bu PF6-

t-Bu

+

N+

N

+

2PF6-

OH n

35d + t-Bu

N+

Triptycene rim

O

OH

60

35d 3,5-di-tert-butylbenzoic anhydride, 57a (n = 1); 57b (n = 4)

(n-Bu)3P, CHCl3/CH3CN (2:1, v/v), r.t.

3,5-di-tert-butylbenzoic anhydride, (n-Bu)3P, CHCl3/CH3CN (2:1, v/v), r.t.

61

+

major

minor

58a (n = 1) 59a (n = 4)

58b (n = 1) 59b (n = 4)

Scheme 12 (a) [2]Rotaxanes 58–59 formed by directional threading. (b) [2]Rotaxane 61 formed by unidirectional threading. (Reprinted with permission from [36]. Copyright 2018 American Chemical Society)

Fig. 18 Packing structure of 40d

their adjacent atoms. The triptycene motifs in 62 linking these planes are located in the square corner. In addition, the [2]rotaxane based on triptycene-derived tetralactam macrocycle could also self-assemble into a tubular structure in the solid state via the typical hydrogen bonds between the amide protons of the hosts and the carbonyl oxygen

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Y. Han and C.-F. Chen CN

NC

(a)

H N

HN

NH

N

N

NC

62

N H CN

(c)

(b)

A

B

Fig. 19 (a) Molecular structure of 62, (b) crystal structure with the asymmetric unit of 62, and (c) space-filling representation of a 62-based nanotube

atoms of the guests, and the multiple π–π stacking interaction and C H•••π interactions between triptycene subunits and the aromatic rings of the guests, along with the squaraine dyes inside of the channels. However, the similar honeycombed superstructures could not be found in the free macrocycles; it suggested that the non-covalent interactions between the host and the guest as well as the solvent interactions played important roles in the arrangement of extended channels. Moreover, it was further found that the [2]rotaxane with nonsymmetrical macrocycles could self-assemble into an oriented nonsymmetrical channel-like structure (Fig. 20) [35].

6.3

Helicarenes: New Chiral Macrocyclic Arenes

During the past decades, chiral synthetic hosts based on the macrocyclic arenes have attracted much attention for their wide applications in chiral recognition and selfassembly. Generally, chiral macrocyclic arenes could be obtained by introducing chiral auxiliary into the macrocyclic skeleton [38]. Introducing inherent chirality is another strategy to build chiral macrocyclic arenes [39, 40], but their fussy synthesis and the difficulty in utilizing the macrocyclic cavities limit their practical applications to some extent. Recently, Ogoshi and coworkers [41] reported a new type of planar chiral macrocyclic arenes based on pillararenes. Undoubtedly, chiral building

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167

Fig. 20 The oriented channel-like structure of the [2]rotaxane

blocks can provide an efficient and direct way to construct chiral macrocyclic arenes, but no such examples have been reported before. It was known 2,6-dihydroxy substituted triptycene is an easily available chiral compound. Based on this chiral triptycene building block, a new class of chiral macrocyclic arene composed of 2,6-dihydroxyltriptycene subunits bridged by methylene groups could be obtained. Since the macrocycle adopts a hex nut-like structure with a helical chiral cavity, we can name them as helicarenes [42].

6.3.1

Synthesis

Starting from commercially available 2,6-dimethoxyanthracene, we first prepared triptycene derivative ()-65 on a gram scale by Diels–Alder cycloaddition, aldehyde reaction, and reduction reaction. Then, treatment of ()-65 in tetrachloroethane with a catalytic amount of p-toluenesulfonic acid gave macrocycle ()-66 in 15% isolated yield. Finally, the demethylation of ()-66 by BBr3 in dichloromethane produced the target macrocycle ()-65 in 98% yield, which showed good solubility in polar solvents including acetone, acetonitrile, and methanol. Efficient resolution of ()-67 was performed by introducing the chiral auxiliary, separation with common column chromatography, and then hydrolysis to give enantiopure (+)-67 and ( )-67 (Scheme 13), which were evidenced by their CD spectra with mirror images. Recently, we [43] also performed the chiral resolution of ()-65 by HPLC on chiral column, and with (+)-65 and ( )-65 as the precursors, we could conveniently obtain enantiomers (+)-66 and ( )-66, respectively, in gram scales (Scheme 14). Aryl bromides were very useful precursors for organic synthesis, and they could be easily obtained by bromination of aromatic compound. Hence, we tested the bromination of ()-66 with Br2 gave ()-69 in 88% yield, which was demethylated by BBr3 in dichloromethane to give hexabromo-substituted helix[6]arene derivative ()-70 in 95% yield. By Suzuki coupling reactions of ()-70 with aryl boronic acids gave a series of helix[6]arene derivatives ()-71a-f in 55–71% yields. Similarly, starting from (+)-66 and ( )-66, (+)-70 and ( )-70 could be conveniently synthesized and obtained enantiomers (+)-71a-f and ( )-71a-f in good yields through Suzuki coupling reactions (Scheme 15) [44].

HO

OH (+)-P-67

OH

OH OH

MeO

97%

KOH THF/MeOH

65

67%

TsOH

MeO

RO OR

68a

OR

RO

OMe TCE, 100°C 15%

CH2OH

2-carboxylate, 1,2epoxypropane, reflux

benzenediazonium-

Scheme 13 Synthesis and resolution of ()-67

HO

97%

NaBH4, THF/MeOH

MeO

OMe

OR OR

R=

ClO2S

MeO OMe

63

O 2S

O

OMeOMe BBr3 98%

CH2Cl2

81%

RO RO

O

2) Separation

HO HO

(-)-M-67

HO

93%

KOH THF/MeOH

(±)-67

HO OH

OH OH

OH

OR

HO OH

64

OMe CHO

RO 68b

RO

MeO

OR

1) DMAP, Et3N, DCM

(±)-66

MeO OMe

OMe

Cl2CHOMe, AlCl3 DCM, 0°C

HO

OH

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Triptycene-Derived Macrocyclic Arenes

169

MeO

(+)-54

FeCl3 (0.1 equiv.)

OMe

OMeOMe

+ P-Oligomers-1

o-DCB, 100°C, 12h

FeCl3 (0.1 equiv.)

o-DCB, 100°C

MeO OMe (+)-P-66

HPLC on chiral OMe column

MeO (±)-65

(+)-P-66 (10%) + P-Oligomers-2

(41%)

CH2OH

FeCl3 (0.1 equiv.) (-)-54

OMe MeOMeO

MeO

+ M-Oligomers-1

o-DCB, 100°C, 12h

FeCl3 (0.1 equiv.) OMe MeO (-)-M-66 (43%)

o-DCB, 100°C (-)-M-66 (10%) + M-Oligomers-2

Scheme 14 Synthesis of enantiopure (+)-66 and ( )-66

6.3.2

Structural Characterization

For macrocycle ()-67, the six benzene rings belonging to the three triptycene moieties form a large hexagonal prism. The bond vector of the triptycene rim viewed from the top down the C3 axis of the macrocycle, that is to say macrocycle ()-67 has a C3 symmetrical structure. Its variable-temperature 1 H NMR spectra showed no obvious methylene proton signal changes between 40 and 120  C, indicating the macrocycle adopted a fixed conformation in solution over the wide temperature range tested and thus is obviously different from the behavior of the classical calixarenes and pillararenes. The crystal structure of ()-67 (Fig. 21) showed the bond angles between the adjacent triptycene units were 112–114 , which were close to the tetrahedral bond angle of 109 . The distances between the two centers of opposite aromatic faces in ()-67 (Fig. 21) were showed 9.0–9.2 Å of the distances between the two centers of the opposite aromatic rings, which is similar to, or larger than those in pillar[6]arene, β-cyclodextrin, and cucurbit[7]uril. Moreover, the deepened cavity of 5.28 Å in ()-67 was found, and it was also far larger than the longitudinal thickness of triptycene (2.66 Å) [42]. The direction of the triptycene rim was defined by using Cahn–Ingold–Prelog priority rules, which involve moving from the hydroxy-substituted carbon atom with greater priority on the phenylene ring toward the methylene-substituted

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Br MeO

MeO OMe

OMe OMe

Br OMe OMe

OMe Br

Br 2 CH 2Cl 2

MeO

Br MeO

Br

Br

OMe

OMe (±)- 66 (+)- P-66 (-)-M-66

(±)- 69 (88%) (+)- P-69 (91%) (-)-M-69 (90%) BBr 3 CH 2Cl 2

Ar

Br HO

HO Br

OH Br

Br

OH OH

ArB(OH) 2 Cs 2CO 3, Pd(PPh 3)4

HO

Br

OH (±)- 70 (95%) (+)- P-70 (95%) (-)-M-70 (96%)

OH Ar

Ar

OH OH Ar

Br PhCH 3/EtOH/H 2O 55-71% Ar

Ar HO

OH (±)- 60a-f (+)- P-71a-f /(-)-M-71a-f Ar = Ph (a); p-CH 3OC 6H 4 (b); pCH 3C 6H 4 (c);

p-CH 3CH 2C 6H 4

(d); p-FC 6H 4 (e); p-ClC 6H 4 (f)

Scheme 15 Synthesis of hexabromo-substituted helic[6]arene derivatives and their SuzukiMiyaura coupling reactions

carbon atom with lower priority. Correspondingly, we first defined the stereochemistry of enantiomers (+)-67 and ( )-67 as P and M configuration, respectively. Then, from the crystal structure of diastereomer 68a (Fig. 22a), the absolute configuration of its macrocyclic skeleton could be easily determined to be in a P configuration [38]. Moreover, we also obtained the crystal structure of (+)-P-70 (Fig. 22b), which further confirmed the absolute configuration of the enantiomeric helicarenes [43].

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Triptycene-Derived Macrocyclic Arenes

171

Fig. 21 Crystal structure of ()-67

Fig. 22 Crystal structures of 68a (a) and (+)-P-70 (b)

O O −

PF6

N

R-72

+

N

+

N O PF6

−

R-73

PF6 O

O

+

+

O

− −

PF6 N+ R-74

S-72

N

+

N

O

PF6

−

S-73

PF6

−

O S-74

Fig. 23 Structures of chiral guests 72–74

6.3.3

Applications in Molecular Recognitions and Self-Assemblies

Since (+)-67 and ( )-67 contain electron-rich cavities and six hydroxyl groups, we deduced they could efficiently and enantioselectively complex with chiral organic ammonium salts by multiple non-covalent interactions including cation-π interaction. So, we tested the complexation between the chiral hosts and three pairs of chiral guests 72–74 (Fig. 23) and found, even without any modification, the chiral

−

79e

H

O2N

BArF−

N

−

H

H

N

H −

−

F3C

75k

PF6

BArF

N

N

75e

PF6−

− H BArF

79g

N

79c

PF6−

PF6−

N

75d

75j

O2N

−

BArF−

N

BArF

N

75i

79f

75c

PF6−

N PF − 6

79b

O

N

Fig. 24 Chemical structures of guests 75–81

NH

O

H

S

N+ PF6−

75b

PF6−

75h

N

BArF

N

PF6− N+

O

79a

75g

75a

PF6

O2N

N

O

79h

79d

N

N

N H BArF−

BArF−

N H

75m

N

75f

2PF6−

N+ PF6−

76c

6

−

81a

P+ − Br

80a

NH PF

PF6

−

N

PF6−

76a

N

81b

P+ − Br

80b

6

−

OH

76d

N

N

O

P+ − Br

NC

NC

81c

O

2PF6−

2PF6−

76b

NH PF

N

N

− 6

80c

NH PF

78

+

77

BF4−

CN

CN

172 Y. Han and C.-F. Chen

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macrocycles showed obvious enantioselective recognition toward these chiral guests. Especially, for guest 72, methylated derivative of 1-indamine, the enantioselectivity was considerably high [42]. So after, we found ()-66 could form 1:1 complexes with acetyl choline 75a and thiaacetyl choline 75b in solution and solid state. Compared with ()-66, ()-67 with no modification showed stronger binding abilities toward the two guests probably due to the additional multiple non-covalent interactions between the hydroxyl groups of ()-56 with the guests. Therefore, we then tested the complexation between ()-67 and different kinds of quaternary ammonium salts 75c–m (Fig. 24) and found ()-67 showed significant complexation toward these wide tested guests. Moreover, ()-66 and ()-67 could also form 1:1 complexes with different kinds of N-heterocyclic salts 43i, 76a–d, and even TCNQ (77) in solution and solid state (Fig. 25) [44]. ()-66 and ()-67 could form 1:1 complexes with tropylium 78 in solution as well. Color change of the solution and formation of the CT band in UV-vis spectra

Fig. 25 Crystal structures of ()-66•75a (a) and ()-66•76a (b)

RO

RO

OR

OR OR

OR

OR OR

NaBH4

+

NOBF4 RO OR (±)-66.78 (±)-66.78

RO OR (±)-66 (R = Me) (±)-67 (R = H)

Fig. 26 The redox stimulus-responsive switchable complexation

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indicated the charge-transfer interactions in the complexes. Especially, the binding and release of the guest in the complexes could be efficiently controlled by redox stimulus (Fig. 26), and this responsive process could be visually observed by color change of the solution. For the complex based on ()-66, the redox-responsive cycles could be repeated at least 10 times. For the complex from ()-67, similar phenomenon was also found, and the redox-responsive cycles could be repeated at least five times [45]. We [46] proved ()-66 could form 1:1 complexes with protonated tertiary ammonium salts 79a–h and also found the small steric hindrance of the substituent groups on the N atoms or the para-substituted electron-withdrawing group on the aromatic ring of the guests could be beneficial for the complexation. The switchable complexation between the macrocycle and the guests could be efficiently controlled

(a)

MeO

MeO OMe

OMe

OMeOMe

OMeOMe

DBU

+

HBArF MeO

MeO

OMe

OMe

(b) MeO

MeO OMe

OMe

OMeOMe

OMeOMe

TBACl

+

NaBArF NaCl MeO

MeO

OMe

OMe

N H O

O NH

N

N

H

O NH

Cl

NH

Fig. 27 Schematic representation of switchable complexation between ()-66 and the guest controlled by (a) acid/base, and (b) Cl ion

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Triptycene-Derived Macrocyclic Arenes

175

OCN

O OH

N

O

BArF

−

H

+ (±)– 55

DBTDL 51%

82

O

O O

O

O O

H N

O

N H

O O O 83

Scheme 16 Synthesis of [2]rotaxane 83

not only by acid and base stimuli (Fig. 27a) but also by the addition and removal of chloride ion (Fig. 27b). Moreover, based on the host-guest complexation, we further synthesized the first helicarene-based [2]rotaxane 83 (Scheme 16). ()-66 could also form 1:1 complexes with protonated pyridinium salts 80a–c [47], and the binding and release of the guests in the complexes could be efficiently controlled not only by acid and base (Fig. 28a) but also by light stimuli in the presence of photoacid 1-MEM (Fig. 28b). Furthermore, we designed and synthesized three pairs of chiral rotaxanes 84–85 [48] and found the shuttle, oscillation, and palindromic motion of ()-66 between the protonated pyridium site and the alkyl group site could be efficiently controlled by sunlight in the presence of 1-MEM through photo-induced proton transfer (PIPT) strategy (Fig. 29), which also provides the systems with excellent repeatability more than 50 cycles. This represents the first successful example of PIPT strategy in molecular machines based on mechanically interlocked molecules [49]. More recently, we [50] also conveniently synthesized a water-soluble 2,6-helic[6] arene derivative containing six carboxylato groups (87) and found the host could form 1:1 stable complexes with quaternary phosphonium salts 81a–c in water. According to the isothermal titration calorimetric experiments, the association constants for the 1:1 complexes between 87 and guests 81a–c were determined to be over 105 M 1, indicating the host showed strong binding abilities toward the tested quaternary phosphonium salts in aqueous solution. Moreover, the binding and release of the guest in the complexes could be efficiently controlled by acid/base stimulus (Fig. 30).

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(a) MeO OMe

OMeOMe

TfOH

MeO OMe

OMeOMe

+ DBU

N MeO

MeO

OMe

OMe

(b) 1-MEH MeO OMe

OMeOMe

1-SP

420nm +

MeO OMe

OMeOMe

dark

N

1-MEH

MeO

1-SP

MeO

OMe

OMe

NH

N

O3S

N O

HO

1-MEH

O 3S

1-SP

Fig. 28 Schematic representation of switchable processes between ()-66 and the guest controlled by (a) acid/base and (b) photoacid

6.4

Conclusion and Perspectives

In summary, it has been proved that triptycene derivatives with unique threedimensional structure could be utilized as useful building blocks for the design and construction of new kinds of macrocyclic arenes and their analogues. Consequently, a series of triptycene-derived calixarenes, heteracalixarenes, tetralactam macrocycles, and their analogues were conveniently synthesized with satisfactory yields by one-pot method or two-step fragment-coupling reactions. Moreover, these triptycene-derived macrocyclic hosts had large enough cavities and showed fixed conformation in solution. These structural features made them exhibit not only well molecular recognition toward small organic molecules,

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177

(a) O

O

O

O N H

O

N

=

O O O

O O

P- or M-84

O O

O O

O

O O N

H N

O

O O N

O

O

O N

O

O

P- or M-85

O

O

O O

O N H

H N

O

O N H

O

O

O

O O

O

O O

O N

O O

O

P- or M-86

(c)

(b)

84

1-MEH dark

1-MEH sunlight

1-SP 84-H+

1-SP

Fig. 29 (a) Structures of chiral rotaxanes 84–86, (b) light-driven shuttle motion of 84 by PIPT strategy, and (c) sustainability of photo-controlled motion. (Reprinted with permission from [48]. Copyright 2018 American Chemical Society)

fullerenes, and organic dyes but also wide potential applications in molecular recognition and self-assembly. Especially, we developed a new kind of chiral macrocyclic arenes named as helicarenes based on chiral 2,6-dihydroxylsubstituted triptycene subunits bridged by methylene groups. It was found that the helicarenes exhibited convenient synthesis, high stability, good solubility, fixed conformation, easy functionalization, and wide complexation with different kinds of chiral and achiral organic guests. Especially, the switchable

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RO

RO OR

OR OR

H+

OR

OR OR +

OH−

RO OR R = CH2CO2−

RO OR R = CH 2CO 2H

quaternary phosphonium salt

Fig. 30 Acid/base controllable complexation between 87 and quaternary phosphonium salt

complexation based on these macrocycles could be efficiently controlled by multi-stimuli including acid-base, redox, anion, or light stimulus in the presence of photoacid. However, the researches on these triptycene-derived macrocyclic hosts, especially helicarenes, are still in the infancy. Expanding new members of helicarene family and development of their potential applications are an urgent work in supramolecular chemistry. But we believe that the triptycene-derived macrocyclic arenes, especially helicarenes with special structural features and varied complexation behaviors, could become a new kind of synthetic hosts and thus attract more and more attention in macrocyclic and also supramolecular chemistry in the near future.

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Emerging Macrocyclic Arenes Related to Calixarenes and Pillararenes Dihua Dai, Jia-Rui Wu, and Ying-Wei Yang

Contents 7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2 New Macrocyclic Arenes Related to Calixarenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.1 Calix[2]arene[2]triazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.2 Calix[n]imidazoliums . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.3 Tetraphenylethylene (TPE)-Based Oxacalixarenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.4 Hybrid [n]Arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.5 Calix[3]carbazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.6 Cyclo[4]carbazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.7 Calix[n]triazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.8 Calix[n]tetrolarenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.9 Coumarin[4]arene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3 New Macrocyclic Arenes Related to Pillarenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.1 Asararenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.2 Biphenarenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.3 Cyanostar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.4 Campestarenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.5 Oxatub[n]arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.6 [m]Biphenyl-Extended Pillar[n]arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.7 Pillar[4]pyridinium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.8 Leaning Pillar[6]arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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These authors contributed equally to this work.

D. Dai · J.-R. Wu · Y.-W. Yang (*) State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), College of Chemistry, Jilin University, Changchun, China e-mail: [email protected]; [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_8

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7.1

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Introduction

Design and synthesis of macrocyclic compounds are always one of the cutting-edge research topics since the birth of supramolecular chemistry [1–5]. From Pedersen’s groundbreaking discovery of crown ethers in the mid-1960s [6, 7], countless macrocyclic hosts have been impelling the development of host-guest and supramolecular chemistry [8–12]. Among them, macrocyclic arenes comprising of multiaromatic units have made a great contribution owing to their easy accessibility and selective host-guest properties. The most representative case is definitely the calix[n] arene family (calixarenes for short) [13, 14], being considered as the third generation of star supramolecular host. Their structure and conformation properties, postmodification methods, host-guest properties, and supramolecular functions have been intensively studied [15–19]. Besides that, pillar[n]arenes (pillararenes, or pillarenes for short) [20], a relatively new family of synthetic macrocyclic arenes, have also gained wide attention due to their unique and outstanding binding properties and ease of application development during the last decade [21–29], which have also been regarded as the fifth generation of star supramolecular host after cucurbit[n]urils [30]. However, in spite of many significant advances in calixarene and pillarene families, the design and exploration of new synthetic macrocyclic receptors are still an everlasting and challenging topic in supramolecular macrocyclic chemistry. In the last few years, scientists have reported several new families of synthetic macrocyclic arenes, inspired by the rapid development of calixarene and pillarene chemistry. Therefore, we take this good opportunity to give a brief overview of these newly designed macrocyclic receptors, especially with the focus on their syntheses, structures, chemical functionalization, and host-guest properties. We believe that it will be a timely and valuable reference for those who have been engaged in or are interested in the design and development of macrocyclic compounds.

7.2

New Macrocyclic Arenes Related to Calixarenes

7.2.1

Calix[2]arene[2]triazines

Calix[2]arene[2]triazines (1–8) as a new class of heteroatomic calixarene derivatives were first reported by Wang and coworkers in 2004 [31]. These macrocycles can be easily obtained through a high yielding fragment coupling approach with cyanuric chloride and resorcinol as the ring-forming monomers (Fig. 1a, b). The single crystal structures of calix[2]arene[2]triazines (1–8) show a 1,3-alternate conformation with two benzene rings almost perpendicular to the plane of the four bridging heteroatoms. And, the bridging heteroatoms are more inclined to form a conjugation system with the triazine rings rather than the benzene rings as a result of the intramolecular/intermolecular steric and electronic effects. In addition, the cavity features of calix[2]arene[2]triazines, i.e., the distances and inclined angles between

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Fig. 1 (a, b) Synthetic routes and chemical structures of calix[2]arene[2]triazines (1–8) [31]; (c) synthetic route to calix[4]imidazolium (9) and the B3LYP self-consistent reaction field (SCRF) polarizable continuum model (PCM) optimized geometry of the cone conformer of [94ClF]
-t [32]; (d) synthetic route to calix[5]imidazolium (10) and the most stable geometry of the complex composed of neutral C60 fullerene and 105Br [32]

two benzene rings, were strongly influenced by the species of the bridging heteroatoms, which endows the calix[2]arene[2]triazines with great potentials in cavity and electron-controllable molecular recognition process.

7.2.2

Calix[n]imidazoliums

Homo-calix compound, calix[4,5]imidazolium (9, 10), with four or five positively charged imidazolium moieties was first reported by Kim and coworkers in 2013 [32]. 9 and 10 could be easily synthesized through a template-directed synthesis with Cl
and Br
as the template anions during the ring closure process (Fig. 1c, d). The single crystal structure analyses demonstrated a cone-shaped conformation stabilized by multi-noncovalent (C-H)+/π+-anion interactions between the halogen ions and the imidazolium rings. More importantly, 9 exhibits a strong binding affinity toward fluoride (8  104 M
1), which ensures its great potential in fluoride detection and removal. Meanwhile, 10 with more imidazolium moieties and larger size of cavity showed a specially selective recognition toward fullerenes via the well-known noncovalent π+-π interactions (Fig. 1d), which can even make C60 soluble in water.

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Tetraphenylethylene (TPE)-Based Oxacalixarenes

Oxacalixarenes, a class of homocalixarene derivatives with tidy synthetic ease and outstanding host-guest properties, have received much attention [33, 34]. In 2014, taking advantages of both oxacalixarene and TPE, Zhang, Zheng, and coworkers synthesized a novel TPE-based expanded oxacalixarene (11) through the wellknown SNAr reaction by condensation of dihydroxytetraphenylethylene with 2,6dichloropyrazine in DMSO in the presence of Cs2CO3 catalyst [35]. Interestingly, the conformation of 11 in the crystalloid state could be easily altered by the trapped guests, and two kinds of supramolecular grid networks could be clearly realized (Fig. 2a). Afterward, the TPE-based oxacalixarene was first be used to construct a porous tricyclooxacalixarene cage (12) (Fig. 2b), which could further establish a grid-like porous structure in accompany with a remarkable adsorption capacity for carbon dioxide [36]. Very recently, by inducing the TPE-based oxacalixarene cage (TOC) to framework, Zhang, Zheng, Tan, Liu, and coworkers successfully constructed a cage-based emissive polymeric framework (pTOC) (13) [37]. Compared to monomer TOC, the pTOC conquers the problem of window-to-arene packing modes of cages and enlarges their pores (Fig. 2b). Particularly, the pTOC

Fig. 2 (a) The synthetic route to the TPE-based expanded oxacalixarene (11) and its single crystal structures obtained from its solution of benzene (left) or THF (right) [35]; (b) the synthetic route to the cage-based emissive polymeric framework (pTOC) (13) from the tricyclooxacalixarene cage (12) [36, 37]; (c) the synthetic route to the porous organic polymer (15) from the TPE oxacalixarene macrocycle (14) [38]

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rendered a reversible fluorescence enhancement in the presence of CO2 and a recovery with CO2 released. Following this stimuli-responsive property, pTOC could be used for detecting and quantifying trace amount of CO2 among multiple gas mixtures. Similarly, a TPE oxacalixarene macrocycle (14) with high fluorescence quantum yield (70%) was synthesized by a similar method in 2018 [38]. As depicted in Fig. 2c, 14 as the monomer could be utilized to construct a porous organic polymer (15), which presented a decent Brunauer–Emmett–Teller (BET) surface area, specific pore volume, and fluorescence emissive properties. According to the Förster resonance energy transfer (FRET) effect, 15 with blue-greenish emission could be changed to a white-light emission material upon complexation with tris(bipyridine)ruthenium (Ru2+) as its complementary emission color.

7.2.4

Hybrid [n]Arenes

Through a hybrid approach, hybrid [n]arenes were constructed efficiently by Szumna and coworkers in 2015 [39]. This medium-sized macrocyclic compound with different alkoxybenzene units could be directly produced by condensation of two commercially available alkoxybenzene monomers and formaldehyde as catalyzed by trifluoroacetic acid (TFA) (Fig. 3a). Generally speaking, hybrid [4]arenes consisting of four alkoxybenzene units (16–19) are usually in a [2 + 2] or [3 + 1] composite pattern. However, with the condensation of 18 and 19, a novel hybrid macrocycle with [3 + 2] composite pattern could be facilely captured and isolated. For the confirmation of the reversibility of the hybrid-forming reaction, a “scrambling” experiment by reaction of two conventional macrocyclic arenes based on mono-benzene units was adopted. Subsequently, the results demonstrated that the reaction was absolutely reversible and the distribution of the products was thermodynamically controlled. In a word, this acid-catalyzed thermodynamically favored hybrid approach is very efficient and convenient. Following this work, Yu and coworkers designed the first [2 + 1] pattern biphenyl-type hybrid [3]arene (20) in 2016 (Fig. 3b), which is composed of two 1,3,5trimethoxybenzene units and a 4,4-biphenol diethyl ether unit linked with methylene bridges and exhibited a good binding affinity toward 1-dihexylammonium hexafluorophosphate [40]. Then, Szumna and coworkers synthesized a type of anthracene-based hybrid [4]arene (21) by using 1,4,5,8-tetramethoxyanthracene and 1,3dimethoxybenzene as the cyclic-forming monomers in 2017 (Fig. 3c), which could be further used to recognize pyridinium iodide in chloroform due to its extended cavity [41].

7.2.5

Calix[3]carbazole

In 2016, via a convenient one-step approach, a bowl-shaped calixarene derivative named calix[3]carbazole (22) was efficiently obtained by Yang and coworkers (Fig. 3d) [42]. Compared to many conventional carbazolyl-based macrocycles [43,

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Fig. 3 (a) Synthetic route to hybrid [n]arenes and the monomers used in the construction of hybrid [n]arenes [39]; (b) synthetic route to the biphenyl-type hybrid [3]arene (20) [40]; (c) synthetic route to the anthracene-based hybrid [4]arene (21) and the single crystal structure of 21 [41]; (d) the synthetic route to 22 and an energy-minimized model of the complex of calix[3]carbazole (22) with N(C2H5)4+ cation guest [42]

44 ], 22 was obtained in a simpler synthetic method with a higher yield (20%). Not only the desirable product (22) could be facilely obtained, some by-products, i.e., calix[4–6]carbazole, could also be captured and verified simultaneously. Moreover, molecular recognition experiments and energy-minimized models demonstrated that 22 possesses a preferential binding affinity and optical response to tetraethylammonium cation guest via cation
π interactions. Owing to its large π-cavity and chromophoric property, this new class of macrocyclic arenes possesses great potentials in the fields of ion sensing and molecular recognition.

7.2.6

Cyclo[4]carbazole

A new macrocyclic receptor, cyclo[4]carbazole (23), was successfully synthesized by Huang and coworkers in 2016 [45]. Cyclo[4]carbazole 23 could be facilely obtained through a fragment coupling method by the reaction of the carbazole derivative (N-butyl-3,6-dibromocarbazole) in the presence of Ni[COD]2 (Fig. 4a) in a satisfactory yield (18.4%). A series of molecular recognition experiments in conjunction with crystal structure analysis and theoretically simulation suggest that

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Fig. 4 (a) The synthetic route to cyclo[4]carbazole (23) and the host-guest interaction between 23 and iodide anion [45]; (b) the chemical and single crystal structures of calix[4,5]triazoles (24 and 25) as well as the simulated structure of calix[6]triazole 26 [46]; (c) the single crystal structures of calix[4,5]tetrolarene (27 and 28) [47]; (d) the chemical structure and single crystal structure of coumarin[4]arene (29) [48]

23 is a preorganized receptor for iodide ion loading, and a medium association constant of 81.8 M
1 obtained by UV-vis titration method is also reasonable for this kind of electron-rich macrocyclic compounds. Therefore, taking advantage of the high selectivity toward iodide anion, 23 will exert a significant influence on the sensing and removal of iodide anion.

7.2.7

Calix[n]triazoles

Calix[n]triazoles as a new category of calixarene derivatives were developed by Kim and coworkers in 2017 [46]. Calix[4–6]triazole (24, 25, 26) possessing four, five, and six triazole units could be obtained by a series of inter
/intramolecular copper (I)-catalyzed azide
alkyne cycloaddition (CuAAC) reaction (Fig. 4b). Multiple conformations of calix[n]triazoles were demonstrated by a series of conformational analyses, and the 1,3-alternate (for 24), 1,3-alternate (for 25), and 1,3,5-alternate (for 26) conformers are the most stable ones according to the density functional theory

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(DFT) calculations. The multi-conformational feature of calix[n]triazoles endows this group of calixarene derivatives with great potential in anion binding and molecular recognition.

7.2.8

Calix[n]tetrolarenes

Calix[n]tetrolarenes, a new family of macrocyclic arenes, were firstly reported by Cohen and Zafrani in 2017 [47]. Calix[4,5]tetrolarenes (27, 28) were facilely prepared by reaction of the partially methylated 1,2,3,5-benzenetetrol and paraformaldehyde catalyzed by trifluoroacetic acid (TFA) with a total separation yield of 73% (Fig. 4c). Solvents, reaction time, temperatures, and monomeric hydroxyl groups all strongly affect the reaction rate and the distribution of products. It is noteworthy that cyclic pentamers could be facilely produced during the macrocyclization of calix[n]tetrolarenes, which has been proven to be very difficult in the synthesis of traditional calixarenes as a result of its poor thermodynamic favor. Overall, taking both advantages of the synthetic ease and fancy structures of calix[n] tetrolarenes, a wide scope of applications will be unearthed in the near future.

7.2.9

Coumarin[4]arene

In 2018, Venkatakrishnan and coworkers introduced a bicyclic heteroaromatic macrocyclic receptor, namely, coumarin[4]arene (29) [48]. This new macrocyclic arene, closely related to both calix[4]arene and resorcin[4]arene, meanwhile, possesses a specific fluorescence emissive property. 29 could be obtained through a twostep synthetic strategy by using easily available raw materials, giving the desirable compound in a satisfied yield of 84%. Interestingly, compared with an averaged crown conformation of 29 in solution, a stable boat conformation in the solid state was further demonstrated by X-ray single crystal diffraction (Fig. 4d). The flexibility of the structure and connatural fluorescence feature endow 29 with great potentials in molecular recognition and fluorescence sensing. For instance, the idea of constructing fluorescent capsules based on this macrocyclic arene is probable to be realized via complementary multipoint interactions in the near future.

7.3

New Macrocyclic Arenes Related to Pillarenes

7.3.1

Asararenes

In 2013, Stoddart and coworkers reported a new class of macrocyclic arenes with 6–12 aromatic units, namely, asar[n]arenes [49]. Similar to pillarenes, asar[6–15] arenes (30–35) could be obtained through a one-step method by reaction of the monomers (1,2,4,5-tetramethoxybenzenes) with paraformaldehyde, using BF3OEt2 as the catalyst. Besides that, asar[6]arene (30) was demonstrated to be the smallest

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and the thermodynamically favorable cyclic oligomer during the ring closure process. Additionally, according to the single crystal analyses, cavities of asar[6–8] arenes are occupied by its own OMe groups, while asar[9,10]arenes possess larger cavities with extra solvent molecules inside. Moreover, all the structures of asar[n] arenes in some way are analogous to the cycloalkane with the corresponding alkyne units (Fig. 5a, b). Thus, asar[n]arenes with varying sizes and shapes are highly complementary to the toolbox of supramolecular chemistry and will find a wide range of applications in host-guest chemistry and other related fields.

7.3.2

Biphenarenes

Biphen[n]arenes, a new class of macrocyclic arenes closely related to pillarenes, were first introduced by Li and coworkers in 2015 [50]. Per-ethylated biphen[3,4] arenes (36, 37) could be easily synthesized by reaction of 4,4-biphenol diethyl ether building block with paraformaldehyde catalyzed by BF3O(Et)2, giving the target products in a reasonable yield of 22% (for 36) and 8% (for 37) (Fig. 5c). In addition, single crystal structure of 36 exhibits a distorted triangular prism conformation, and 37 shows a “partial chair” topology conformation with the π-electron-rich cavity.

Fig. 5 (a) The backbones of asar[n]arenes 30–35 in the solid states form a variety of different shapes [49]; (b) side views of the crystal packing structures of 30–35 [49]; (c) the synthetic route to biphen[n]arenes (36 and 37) and their crystal structures and the general chemical structure of 38 [50, 52]

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In addition, 36 and 37 could be deprotected by reaction with excess BBr3, indicating the facile functionalization of biphen[n]arene’s family. As for molecular recognition properties of biphen[n]arenes, 37 exhibits preeminent guest-friendly property and is capable of interacting with not only cationic guests but also neutral species. Furthermore, the molecular recognition properties of hydroxylated biphen[4]arene toward 2,7-dibutyldiazapyrenium and some other guests were also investigated in their following work [51]. In 2015, the first water-soluble biphen[3]arene, i.e., carboxylated biphen[3]arene (38), was introduced by Huang and coworkers, and meanwhile, a new supramolecular amphiphilic assembly of 38 and 1-cetylethylammonium chloride was successfully constructed [52]. Similarly, Yu and coworkers synthesized the first cationic water-soluble biphen[3]arene in 2016, which was further used to alter the aggregation behavior of the amphiphilic guest (sodium 1-hexanesulfonate) in water [53]. Very recently, Li and coworkers successfully designed and synthesized a new family of biphen[n]arenes derivatives, namely, 2,2-biphen[n]arenes [54]. Compared to the traditional biphenarenes (4,40 -biphen[n]arenes), 2,20 -biphen[n]arenes possess a higher total synthetic yield. Meanwhile, not only cyclic tetramers, high-order macrocycles including cyclic pentamers, hexamers, heptamers, and octamers were also easily synthesized and separated.

7.3.3

Cyanostar

Cyanostar (40), a C5-symmetric star-shaped macrocycle, was first introduced by Flood and coworkers in 2013 [55, 56]. 40 could be obtained through a one-step Knoevenagel self-condensation by reaction of the meta-substituted difunctional phenylene (39) in a good yield of 81% (Fig. 6a). In the crystalloid state, 40 prefers to stay as π-stacked dimers constituted of chiral P and M enantiomers (Fig. 6c). In the solution, 40 exhibits outstanding binding properties toward PF6
, BF4
, and ClO4
, endowing 40 with great potentials in the detection and separation of electronegative species. Moreover, owning to its anionic preference and shape-persistent features, a phosphate-templated [3]rotaxane could be synthesized in a high yield through click chemistry (Fig. 6b). The efficient synthetic step cooperates with the outstanding ionic recognition property bringing cyanostar all kinds of applications in supramolecular chemistry and other related fields [57–59].

7.3.4

Campestarenes

Campestarenes (41–44), a family of modifiable macrocycles based on Schiff base, were first introduced by MacLachlan and coworkers in 2011 [60]. Hydroxyl groups in this fivefold symmetrical macrocycle guaranteed its flat conformation and stabilized the imine moieties via hydrogen bond interactions (Fig. 7a). Theoretical calculation of 44 demonstrated that an enol-imine tautomeric state is predominant in the gas phase or nonpolar solvents, while a keto-enamine tautomeric state is

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Fig. 6 (a) Synthetic route to cyanostar (40) and its single crystal structure [55]; (b) synthetic scheme for the phosphate-templated [3]rotaxane and its Corey-Pauling-Koltun (CPK) model [55]; (c) sandwiches of two bowl-shaped cyanostars result in a mixture of four possible stereoisomers [55]

dominant in the polar solvents. Then, 45 was successfully synthesized by the same group in 2016 [61]. Similarly, the initial single crystal of 45 also exhibits a flat conformation, and only enol-imine tautomer exists in nonpolar solvents (Fig. 7b). Recently, campestarenes bearing functional moieties were first designed and synthesized by Brothers and coworkers in 2018 and, indeed, extended the application fields of campestarene family [62]. Meanwhile, by introducing the ranyl(VI) as the template, MacLachlan and coworkers discovered two expanded version of campestarenes with six (46) or eight (47) repeating units, definitely, and their electron-rich features guarantee a wide range of supramolecular functions to be exploited in the near future (Fig. 7c) [63].

7.3.5

Oxatub[n]arenes

Oxatub[4]arene (48), a macrocyclic receptor with multiple interconvertible cavities, was first introduced by Jiang and coworkers in 2015 [64]. 48 was synthesized in a reasonable yield of 21% through the well-known Williamson ether condensation by reaction of 2,6-dihydroxynaphthalene and 2,6-dibromonaphthalene under a highdilution condition (Fig. 8a). Meanwhile, the intriguing structure endows 48 with

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Fig. 7 (a) Synthetic route to campestarenes (41–45) [60, 61]; (b) different modes of single crystal structure of 45 [61]; (c) general chemical structures and single crystal structures of 46 and 47 [63]

specific features including lower steric hindrance between neighboring units, straightforward and facile synthesis, and no self-occupied cavity (Fig. 8b). Definitely, the single crystal analyses in conjunction with the 1H NMR, 2D NMR experiments demonstrated four representative conformations that are interconvertible in 48. In other words, the conformation changed predictably due to the structural difference of certain guests being applied (Fig. 8c). Similarly, oxatub[5,6]arenes (49, 50) with larger cavity size and more interconvertible conformations were reported by the same group in 2017 (Fig. 8a) [65]. Due to the larger cavity size, 50 exhibited a nice binding affinity toward both C60 and C70 (216 M
1 for C60 and 548 M
1 for C70). Thus, the diversiform and flexibility of oxatub[n]arenes indicate its wide application in different host-guest systems.

7.3.6

[m]Biphenyl-Extended Pillar[n]arenes

Macrocyclic arenes with large cavity size are always obtained in poor synthetic yields [22, 24]. In order to conquer this challenge, [m]biphenyl-extended pillar [n]arenes ([m]Bp-ExPns) were successfully designed and prepared by our group in 2016 [66]. [m]Bp-ExPns with rigid backbone and large cavity size were facilely synthesized by a two-step strategy. Firstly, pre-connection of the

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Fig. 8 (a) The synthetic route to oxatub[4]arenes (48–50) [64]; (b) chemical structures of four representative conformers of 48, 49, and 50 resulting from naphthalene flipping [64]; (c) summary of guest-selected predominance of one of the four conformers of 48. Butyl groups in the models were abbreviated to methyl groups for viewing clarity [64]; (d) energy-minimized structures of C60@50 and C70@50 [65]

1,4-dimethoxybenzene with diphenyl under Friedel-Crafts alkylation reaction gave the intermediate product (MDM) in a good yield of 50%. Secondly, via the direct condensation of MDM with paraformaldehyde in the presence of BF3O(Et)2, [2] Bp-ExP6 (51), [3]Bp-ExP9 (52), [2]Bp-ExP5 (53), and [2]Bp-ExP7 (54) could be successfully synthesized and separated with yields of 50%, 1.2%, 0.1%, and 0.1%, respectively (Fig. 9a). The main product [2]Bp-ExP6 (51) could be considered as an extended version of traditional pillar[6]arene with the replacement of two opposite 1,4-dimethoxybenzene units by biphenyl units; both the synthetic yield and cavity size are enhanced evidently. Importantly, the single crystal structures of 51 bearing toluene or m-xylene molecule impart 51 with promising potentials in petrochemical field. Very recently, the first water-soluble [2]Bp-ExP6 (55) bearing eight pyridinium moieties was successfully designed and synthesized, which exhibited outstanding binding affinity toward certain sulfonate species in virtue of its distinctive cavity size and positively charged feature [67]. More importantly, 2,6-naphthalene-disulfonate could be easily captured and separated by 55 from its aqueous solution in a form of coprecipitation, which endows 55 with unlimited potentials in the separation and detection of sulfonate species in water (Fig. 9c).

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Fig. 9 (a) Synthetic route to biphenyl-extended pillarenes (51–54) [66]; (b) crystal structures of [2] Bp-ExP6 (51) [66]; (c) the chemical structure of the water-soluble [2]Bp-ExP6 (55) and the selected sulfonate guests related to 55 [67]

7.3.7

Pillar[4]pyridinium

A highly symmetric and quadrupled positively charged macrocycle, namely, pillar [4]pyridinium (56), was introduced by Sashuk, Szumna, and coworkers in 2017 [68]. 56 could be produced by condensation of 4-(bromomethyl) pyridine hydrobromide with equimolar amounts of NaHCO3 and NH4PF6 in acetonitrile (Fig. 10a), giving the target product in a good yield of 50%. Significantly, similar to calix[n]imidazolium as aforementioned, 56 could also serve as an effective fluoride receptor in aqueous solution. In a word, taking advantage of the electronrich feature, pillar[4]pyridinium will find a wide range of applications in the field of ion sensing.

7.3.8

Leaning Pillar[6]arenes

Very recently, a new version of pillar[6]arenes with desirable cavity adaptability and enhanced guest-binding capability, namely, leaning pillar[6]arenes (or leaning towerarenes), was first reported by our group [69–71]. The synthesis of leaning pillar[6]arenes was accomplished by a facile two-step synthetic approach including

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Fig. 10 (a) The synthetic route to pillar[4]pyridinium (56), the ion pairing between 56 and two PF6
anions, and the crystal packing of 56 viewed from the a direction [68]; (b) synthetic route to leaning towerarenes (57–61) [69]; (c) the single crystal structures of pillar[6]arene and leaning pillar [6]arenes (57–60) [69]

a Friedel–Crafts alkylation reaction in conjunction with the Lewis acid catalyzed macrocyclization reaction, giving the MeLP6 and EtLP6 (57, 58) in a reasonable yield of >30%, respectively (Fig. 10b). Significantly, the single crystal analyses in coordination with DFT calculation gave a simple and intuitive explanation for the pillarenes prefer to maintain a pillar-like and rigid structure. Meanwhile, the same synthesis strategy may apply in other pillarenes as well as other macrocyclic arene systems, especially those with mediocre synthetic yields. It is well known that the modification of macrocyclic receptors by introducing various functional groups can provide numerous categories of interesting properties. As in Fig. 10b, by cleavage of the ether groups in 57 or 58, per-hydroxylated leaning pillar[6]arenes (59) could be quantitatively produced. Immediately, a series of functionalized leaning pillar[6]arene derivatives especially a water-soluble version (61) were facilely designed and synthesized. Significantly, the presence of eight positive pyridinium moieties made the 61 an effective anion receptor. In brief, a tilted conformation rather than a traditional pillar structure endows the leaning towerarenes with great performance in macrocyclic and supramolecular chemistry.

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Concluding Remarks

In summary, recent advances in synthetic macrocyclic arenes closely related to calixarenes and pillarenes have been highlighted in this chapter. These macrocycles include calix[2]arene[2]triazines, calix[n]imidazoliums, TPE-based oxacalixarenes, hybrid[n]arenes, calix[3]carbazole, cyclo[4]carbazole, calix[n]triazoles, calix[n] tetrarenes, coumarin[4]arene, asararenes, biphenarenes, cyanostars, campestarenes, oxatub[n]arenes, biphenyl-extended pillarenes, pillar[4]pyridinium, and leaning towerarenes. Although most of the current researches still center on the structural design and synthetic methodology, the research on their variety of functions is still yet to be exploited. But, all of them will certainly enrich the toolbox of supramolecular macrocyclic chemistry and indeed unleash new opportunities in future supramolecular chemistry research. In our lab, we are now in the processes of functionalizing the extended pillarenes for detection of environmentally harmful ions and modifying leaning pillar[6]arenes to obtain stimuli-responsive supramolecular polymers and smart hybrid nanomaterials. In any event, for gaining broad attention by researchers, synthetic macrocycles should at least possess features as follows: (i) easy accessibility and low price, (ii) unique geometries, (iii) special and selective binding properties, and (iv) ease of modification. We strongly believe that all the macrocyclic arenes covered in this chapter possess unlimited potentials and great possibilities in finding more and more applications. Acknowledgments We thank the National Natural Science Foundation of China (21871108, 51673084), Jilin Province-University Cooperative Construction Project – Special Funds for New Materials (SXGJSF2017-3) – Jilin University Talents Cultivation Program, and the JLU Cultivation Fund for the National Science Fund for Distinguished Young Scholars for financial support.

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Supramolecular Medicine of Diverse Calixarene Derivatives Jie Gao and Dong-Sheng Guo

Contents 8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2 Calixarene Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3 Calixarene Decoration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4 Calixarene Biocompatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.5 Calixarenes for Biosensing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.6 Calixarenes for Bioimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.7 Calixarenes for Gene Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.8 Calixarenes as Drug Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.9 Calixarenes as Treatment Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.10 Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.11 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8.1

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Introduction

Supramolecular chemistry is “beyond molecular chemistry,” focusing on the construction of complex structures with specific functions through non-covalent interactions. Compared to covalent bonds in traditional chemistry, supramolecular chemistry emphasizes reversible non-covalent and weak interactions between molecules. These intermolecular interaction forces generally include static J. Gao State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, China e-mail: [email protected] D.-S. Guo (*) College of Chemistry, Key Laboratory of Functional Polymer Materials (Ministry of Education), State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_9

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electricity, π-π stacking, hydrogen bonding, hydrophobic interaction, metal coordination, and van der Waals forces. Supramolecular chemistry is rooted in life and medicine. Molecular recognition, the fundamental concept in supramolecular chemistry, is similar to the interaction between enzymes and substrates or more like a model of “lock and key.” In medicine, the mechanism of drug action is often the supramolecular interaction between drugs and receptors. Supramolecular medicine was arised combining supramolecular chemistry with modern medicine, which emphasis the supramolecular recognition and assembly in medical applications, promoting the level of modern medicine. Broadly speaking, supramolecular medicine can be defined as the supramolecular agents for the prevention, diagnosis, and treatment of diseases [1]. The unique and beneficial properties of supramolecular materials have led to extensive research of their use in the fields of disease diagnosis, imaging, drug delivery, drug discovery, and precision medicine. Medically, the emergence of drug-receptor complexes and nanostructure-based drug delivery systems provides new ways to optimize the pharmacokinetic profile of drugs, achieving more effective treatments with fewer side effects and inactivating toxic substances to achieve detoxification. This provides new momentum for developing groundbreaking strategies on treatment of cancer and other major diseases [2]. In supramolecular medicine, host-guest interactions are attracting increasing attention arising from their distinctive properties due to the introduction of macrocyclic hosts into supramolecular systems. Calixarenes, as third-generation macrocyclic molecules, usually have hydrophobic cavities in which the guests can be embedded. Calixarenes provide ideal platforms for the fabrication of supramolecular medical agents through host-guest molecular recognition. In fact, it can effectively solve some restrictions that hinder the use of traditional medicine for clinical applications by taking advantage of host-guest chemistry. For example, the host-guest complexes can significantly improve the solubility/stability of certain anticancer drugs under physiological conditions. Supramolecular self-assembly can facilitate high accumulation of anticancer drugs in tumors, significantly enhance the therapeutic effect of the anticancer drugs, and reduce their side effects on normal tissues. Furthermore, functional groups (such as targeting ligands, imaging agents, or even therapeutic agents) can be readily integrated into the calixarenechemotherapy system, giving these systems multifunctional therapeutic diagnostic properties. Most importantly, the release of the drug/prodrug loaded in the tumor can be controlled, as it can be based on the different environments (e.g., pH, redox, enzyme) presented between the tumor and normal tissue. The dynamic nature of non-covalent interactions makes supramolecular chemotherapy more versatile than traditional chemotherapy and nanomedicines that lack stimuli responsiveness. The aim of the present chapter is to summarize the latest research results from us and other research groups about calix[n]arenes and their derivatives with respect to their supramolecular medicine applications in biosensing, bioimaging, gene delivery, drug carriers, and treatment agents, as well as advancing some hints on future areas of scientific research related to the above topics. We hope that this review will constitute a useful tool for nonspecialized readers who wish to obtain an overview of current trends related to calixarenes in supramolecular medicine or for experts who want to look for a precise entry in a particular application domain.

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8.2

203

Calixarene Overview

Calixarenes are a class of third-generation supramolecular host molecules, appearing after cyclodextrin and crown ether. These molecules are formed by the orthocondensation of para-substituted phenols with formaldehyde, generally in the presence of inorganic bases, although more rarely, acid-catalyzed cyclization reactions are used (Fig. 1a) [3]. Calixarene was created by C. David Gutsche, who likened three-dimensional structure of the molecule to “calix” (the ancient Greek Holy Grail) and “arene” to the building block of the aromatic structure. Given the complexity of the IUPAC terminology for calixarenes, the name has remained and is now in general usage. The simplified nomenclature of the calixarenes uses [n] to denote the number of phenolic units in the macrocycle. For example, calix[4]arene contains four units. The nature and position of substituents on the aromatic rings are given by sequential numeration, and the appropriate term for the function is placed before the term calix[n]arene. Hydroxyl substitution follows sequential numeration with the substituent name generally placed after calix[n]arene. The calixarene history (Fig. 1b) begins with the pioneering work of Adolf von Baeyer in 1872, who first studied the phenol-formaldehyde reaction and obtained a resinous material.

Fig. 1 (a) General synthetic method for calixarenes. (b) The history of the development of calix[n] arenes

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Despite numerous attempts, Adolf von Baeyer was unable to isolate or characterize the products from this reaction, describing them simply as a substance resembling cement. Subsequently, Leo Baekeland (1905–1909) developed a method for synthesizing phenolic plastic from phenol and formaldehyde in an alkaline medium. Due to the growing interest in this material, Zinke and Ziegler (1942) analyzed that the products of the condensation reaction of alkylphenol and formaldehyde may be the tetramers in the presence of NaOH. In 1955, Sir John Cornforth studied these tetramers and found that there were four different conformational isomers. Finally, Gutsche’s research indicated that these polymers were cyclic homologs, typically tetramers, hexamers, and octamers, while odd species such as pentamers and heptamers were present in small amounts. Thus, Gutsche and colleagues explored the experimental conditions for the synthesis of common calixarene macrocycles and finally determined various reaction conditions for adjusting the synthesis products, such as the type of base, the source of formaldehyde, solvent, and temperature. It should be mentioned that the research of calixarene chemistry in China began in the 1980s, pioneered by Prof. Zhi-Tang Huang (1928–2016) [4].

8.3

Calixarene Decoration

The general structure of calix[n]arene is shown in Fig. 2, wherein the number of phenolic units is 4–20. However, the most studied members are those constituted by 4–8 aromatic units. Calixarenes have good chemical stability, high melting point, adjustable cavity size, and other unique physical and chemical properties, and they can be functionalized on demand [5]. For example, after modification by ionic groups, the resultant calixarene derivatives can reach high water solubility, allowing their potential for applications in supramolecular medicine to be considered. The chemical modification of calix[n]arenes has been thoroughly investigated with the main aim of synthesizing hosts with novel supramolecular properties. The easiest and most common transformations regard: • The para position of the aromatic rings (the upper, wide, or exo rim) by aromatic electrophilic substitution (carboxylates, phosphates, guanidiniums, ammonium groups, sulfonate functionalities, etc.) • Phenolic hydroxyl groups (the lower, narrow, or endo rim) through alkylation and acylation reactions • Methylene bridges • Aromatic walls The chemistry of the modification of the calix[n]arenes has been widely reviewed (Fig. 3) [6, 7]. Two particularly relevant modification types may be important in medical applications: (a) preparation of water-soluble derivatives used as transport molecules for molecules relevant to supramolecular medicine and (b) synthesis of amphiphilic derivatives used to prepare self-assembling systems such as micelles, liposomes, or solid lipid nanoparticles.

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Fig. 2 (Top) The structure of calixarenes. (Bottom) Schematic representation of calix[n]arenes with different numbers of aromatic units

8.4

Calixarene Biocompatibility

For the clinical application of calixarenes in medicine, they must have excellent properties and application prospects. They are not only able to provide chemical/ physical benefits but must also have toxicological or biosafety. If calixarenes are used as carriers, it is desirable that calixarenes not only reduce the toxicity and side effects of the drugs but also allow the drug to have a targeted and stimulating response. Therefore, the biological application of calixarene should be evaluated for the inherent toxicity of calixarenes themselves, including cytotoxicity (the ability to inhibit or kill cells) and in vivo toxicity (short-term toxicity, long-term toxicity, side effects). Biological studies investigating the toxicity of calixarene for clinical use have been reported [8, 9]. Various studies have shown that calixarene, especially water-soluble derivatives, has good compatibility and low cytotoxicity, which are important prerequisites for the applications of calixarenes in supramolecular medicine. Taking sulfonated calixarenes as an example, it was found that parasulfonato-calix[4]arene exhibited extremely low toxicity to mice at doses up to 100 mg/kg [10]. Such property clearly ensures the safety of calixarenes in the clinic to enhance drug dissolution and facilitate delivery. Amino-calix[4]arene-based fluorescent probes were found in cytotoxicity evaluation to be similar in toxicity to phosphate-buffered saline in Chinese hamster ovary cells (CHO) and human

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Fig. 3 Examples of calixarene functionalization

promyelocytic leukemia (HL-60) [11]. Para-Sulfonato-calix[4]arene was proved to be non-cytotoxic, according to the MTT test results of the human ovarian cancer cell line A2780 and the corresponding cisplatin-resistant subline A2780cis [12]. In the study of calixarene hemolysis, para-sulfonato-calix[4]arene and its derivatives did not cause hemolysis even at concentrations up to 200 mM. Para-Sulfonatocalix[6]arene and para-sulfonato-calix[8]arene relative to para-sulfonato-calix[4] arene were enhanced hemolytic effects at the same concentration. But for all sulfonated calixarenes at lower concentrations, this effect was greatly reduced [13]. No hemolytic effects were observed for solid lipid nanoparticles derived from a series of amphiphilic calixarenes [14]. In immunization, three above parasulfonato-calixarenes also did not show activation of neutrophils even at relatively high concentrations, suggesting that these molecules did not induce an immune response [15]. Overall, most of the calixarene derivatives show low or no toxicity in vitro and in vivo, further increasing their attractiveness in the field of supramolecular medicine applications. However, it is important to note that there are still many calixarene derivatives that need to be assessed for their toxicity or immunological responses.

8.5

Calixarenes for Biosensing

Sensing biomolecules are critical for early screening diseases and accurate diagnosis. In general, generalized biomolecules are substances found in blood, urine, stool, or tissues of patients with diseases. These substances are generally metal ions, small molecule compounds, proteins, RNA, etc. Various sensing systems based on calixarene have been applied to the identification of various biomolecules, and

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there are many related reviews [16–20]. Therefore, we only selected the following topics to make some comments: sensing metal ions through coordination and sensing biomolecules through indicator displacement assay (IDA) or tandem assay and the surfaces. Many metal ions and inorganic anions play important roles in human growth and development. Additionally, there are some ions that can harm health and induce diseases. Recently, the sensing and recognition of these ions have been a significant goal in the field of chemical sensors. By simple modification, calixarenes can be used to sense and detect various cations (e.g., alkali and alkaline earth metal cations, lead, transition metal cations, rare-earth metal cations, and organic cations) or anions (e.g., some bio-anions) [19]. Recently, Karakurt et al. designed the “switch-on” fluorescence sensor for the determination of Hg2+ ion based on the perylene bisimide derivative containing calix[4]arene units (PB-CX[4]) (Fig. 4) [21]. In the mixed solvent of DMF and water, the PBCX[4] sensor had a very high selectivity and sensitivity to Hg2+ ions due to the fluorescent switch-on signal generated by the photoinduced electron transfer (PET) effect. According to the results of the JOB experiment, it was found that PB-CX[4] formed a 1:2 complex with Hg2+. The association constant of PB-CX[4] with Hg2+ was determined to be 1.66  109 M 2, and the detection limit was 5.56  10 7 M. Finally, PB-CX[4] was applied to imaging Hg2+ in human colon cancer cell lines by confocal fluorescence microscopy, which has potential bio-application value. M. Yilmaz and co-workers also completed a similar work and synthesized two kinds of water-soluble fluorescent calixarenes for sensing and imaging Hg2+ in living cells [22]. The complexation with Hg2+ would result in fluorescence quenching due to the PET process. The resulting LODs were 1.14  10 5 and 3.42  10 5 M. These nontoxic sensors were then used to sense and image Hg2+ in the SW-620 cell line, and excellent results were observed. A distinctive feature of calixarenes is that they tend to quench fluorescence after complexation with fluorescent dyes. The mechanism is generally considered to be the PET effect [23]. The calixarene skeleton is constructed by base-catalyzed condensation of 4-substituted phenols with formaldehyde. As a rule, the electronrich hydroxyl- or alkoxyl-substituted aryl rings are prone to act as electron donors toward excited states, which lead to fluorescence quenching upon binding of fluorescent dyes. In fluorescence detection technology, the fluorescence signal from “off” to “on” is a more reliable signal conditioning means. A variety of “switchon” fluorescence sensing supramolecular systems have been developed based on the quenching fluorescence property and applied to the detection of tumor markers and other diagnostically significant biological analytes. These fluorescence detection systems are based primarily on the principle of IDA (Fig. 5a): When the calixarenes and dyes act as sensing pairs, the fluorescence of the dyes is in a quenched state; after the analytes are added to the sensing system, the analytes replace dyes by binding to the calixarenes, and the dyes recover their own fluorescence. Whether the sensing system is suitable for detecting analytes depends mainly on the sensitivity and selectivity of the system. To improve sensitivity, the dye should have a high fluorescence quantum yield and maximum quenching fluorescence after being encapsulated by calixarene; to minimize interference from nontarget species, the

Fig. 4 The chemical structure of PB-CX[4] and sensing mechanism of PB-CX[4] with Hg2+ and the PET process [21]. (Reproduced from Ref. [21] with permission from Elsevier)

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Fig. 5 Schematic representation of (a) fluorescence “switch-on” indicator displacement assay (IDA) based on calixarene and (b) supramolecular tandem assay [23]

designed calixarene host should have the ability to selectively bind strongly to the target analyte. In the case of insufficient binding selectivity, an enzyme can be introduced into the supramolecular tandem assay to ultimately achieve specific quantitative detection of the target analyte (Fig. 5b). The detection of biomolecules by sensing systems consisting of calixarene and fluorescent dyes has received considerable attention [23–31]. Li and co-workers reported synthesis and design of SCX8-functionalized reduced graphene oxide (SCX8-RGO) to determine aconitine through the competitive host-guest interaction between p-sulfonato-calix[8]arene (SCX8) and signal probe/target molecules (Fig. 6) [28]. Safranine T (ST), rhodamine B (RhB), and butyl rhodamine B (BRB) were selected as probes, and aconitine was target molecule, respectively. SCX8-RGO can form complexes with three fluorescent molecules and effectively

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Fig. 6 IDA for aconitine (ACO) using SCX8-RGO [28]. (Reproduced from Ref. [28] with permission from Elsevier)

quench their fluorescence. Compared to the probes, aconitine had a stronger affinity with SCX8 and replaced the probes from the SCX8 cavity to achieve fluorescence “turn-on.” The sensor consisting of SCX8-RGO and three probes were able to detect aconitine with linear ranges of 1.0–14.0 μM, 2.0–16.0 μM, and 1.0–16.0 μM, respectively. And detection limits of aconitine were 0.28 μM, 0.60 μM, and 0.37 μM, respectively. Moreover, the sensing system was successfully applied to the detection of aconitine in human serum. The IDA strategy was widely used in sensing systems like those discussed above generally based on lock-and-key model. Unlike IDA strategies but using some of the ideas of IDA, differential sensing was proposed to address those less selective receptors in array sensing [32]. The idea of differential sensing was to mimic the nose of the mammal, using a range of low-selectivity receptors to provide a signal array for each analyte. The signals for each analyte formed a corresponding fingerprint, thereby enabling classification of the analytes. Hof and co-workers developed antibody-free detection histone code using calixarene-based chemical sensor arrays [29]. The posttranslational modification of histones begins with its N-terminal tail, which includes methylation, quaternization, acetylation, and phosphorylation. These affect the function of histones in gene regulation and are associated with various human diseases. Sensing arrays composed of sulfonated calixarenes and dyes were capable of generating signals for cationic amino acids and peptides, making corresponding fingerprints for differentiation (Fig. 7). For example, this sensor kit can identify either methylation and the number of methyl groups on a single histone tail sequence. In addition, the sensor array can also be used to simultaneously detect the concentration of histone modifications. Many of IDA strategies are applied to the detection of biomolecules in water or biological fluids, but the robustness of these methods is inevitably reduced when there is a large amount of component interference, such as inorganic salts. Hof and co-workers reported a self-assembled sensor, DimerDye, that uses a photochemical guest-sensing mechanism and that is intrinsically tolerant of a competitive biological environment (Fig. 8) [30]. Modifying the dye directly on the calixarene, two calixarenes self-assembled into non-emissive dimers through the host-guest interaction in water. When the analyte was detected, the analyte caused the dimer to dissociate while the fluorescence was restored, allowing fluorescence to be turned

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Fig. 8 Sensing mechanism of DimerDye disassembly assay (DDA) and indicator displacement assay (IDA) [30]. (Reproduced from Ref. [30] with permission from the American Chemical Society)

Indicator Displacement Assay (IDA) Dye

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on. In the enzymatic reaction, DimerDye was still able to work effectively in the presence of various salts, metal ions, or coenzymes. As an important supplement to IDA, this strategy is of great significance for detecting biomolecules in complex environments.

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Monitoring enzymatic activity is of the utmost importance for academic and industrial research. Nau’s group first proposed a supramolecular tandem assay strategy based on IDA applied for the determination of enzyme kinetics. Nau and our groups have reported some efforts toward clarifying the working mechanism of enzymes, their inhibitors, and activators [23, 24, 31]. P-Sulfonato-calix[4]arenes have good affinity with acetylcholine (ACh) and choline (Ch), but are not selective. In order to solve the above problems, we cooperated with the Nau group to detect and quantify ACh and Ch using supramolecular enzyme-coupled tandem assay [23, 33]. If acetylcholinesterase was used to convert Ach to Ch, p-sulfonato-calix[4]arenes did not distinguish between substrates and products (Fig. 9, left). The underlying problem was that the calixarene did not have sufficient affinity differences for the two molecules with the same NMe3+ recognition motif. However, choline oxidase can be used to convert choline into detectable betaine for it was zwitterionic and weaker bonding with calixarenes (Fig. 9, right). Lucigenin (LCG) and p-sulfonato-calix[4]arenes were proved to be an excellent “switch-on to switch-off” sensor pair with a fluorescence enhancement factor up to 140. When choline oxidase was present, the fluorescence signal would decrease because the affinity of the product to the p-sulfonato-calix[4] arenes was less than the LCG leading to fluorescence of the LCG being quenched. Through such method, we also investigated enzyme inhibitors, which had important reference value for the screening of drugs. Schader’s group used calixarenes on the surfaces to sense many kinds of basic proteins [34]. The calix[4]arene modified with phosphonate at the upper rim and short alkyl chain at the lower rim (PC4A4C) was introduced in this work. The PC4A4C system showed high affinities with N/C-protected Arg (~104 M 1) and Lys

Fig. 9 Detection and quantification of acetylcholine and choline by supramolecular tandem assays [33]. (Reproduced from Ref. [33] with permission from the American Chemical Society)

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(~103 M 1) in methanol. Not surprisingly, PC4A4C could also bind tightly with Argand/or Lys-rich proteins. Because of the amphiphilic structure, the addition of PC4A4C to the stearic acid monolayer on water resulted in the incorporation of increasing amounts of PC4A4C in the monolayer. The following addition of basic proteins would produce moderate but distinct additional expansions of pressure/area diagrams. After this work, a cationic calixarene containing quaternary ammonium was introduced, and the sensing of acid proteins was realized using the same strategy [35]. On the basis of the above work, Schrader co-assembled phospholipids with polydiacetylene, which showed a blue color and changed to red by various stimuli [36]. The stimulus could be heat, ionic strength, or mechanical pressure. Then, the addition of proteins caused obvious color changes and enabled the detection of proteins by the naked eye. Schrader’s work cleverly took advantage of multivalence and assembly behavior, greatly simplifying the sensing of proteins. Although the work was done more than 10 years ago, it still provides valuable lessons.

8.6

Calixarenes for Bioimaging

When Wilhelm Roentgen filmed the first X-ray of his wife’s hand in 1896, medical diagnosis entered a new era. Since X-rays have been applied to bioimaging, various noninvasive imaging methods have been developed and applied to clinical imaging and research in vivo or in vitro. Calixarene-Gd complexes or their derivatives have been used in magnetic resonance imaging as a tool in medical diagnostics [37–41]. In the field of optical imaging of macrocyclic molecules, Nau et al. detailed and systematically summarized the changes of fluorescence properties when the host-guest complex formed between the fluorescent dyes and the macrocyclic molecules in an aqueous environment [42]. Host-guest complexes between calixarenes and fluorescence dyes or calixarenes directly modified by dyes have been utilized for bioimaging in vitro and in vivo, showing tuneable or targeted florescence response, physiochemical shielding, and enhanced biocompatibility provided by macrocyclic host molecules [43–57]. As mentioned above, one of the advantages of IDA is that it has a broad spectrum of analytes, eliminating the need to design specific receptors for specific analytes. Our group collaborated with Nau’s group to develop a host-guest sensing system using sulfonated calixarene-LCG pairs and applied it to detect enzyme activity, quantify bioactive molecules, and screen drugs [23, 31]. However, the broad spectrum of the IDA method also results in a response to nontarget analytes, which is widespread when testing biological samples. Nau and co-workers used artificial receptors to transfer probes to living cells, and IDA method was used to monitor cellular uptake of biomolecular analytes [43]. The fluorescent dye LCG was quenched by the macrocycle p-sulfonato-calix[4]arene to form a stable host-guest complex. The LCG/calixarene sensing pairs were incubated with V79 and CHO cells. After adding choline, acetylcholine, or protamine to the cell culture medium, they were uptaken into the cells, and formed complexes with calixarenes replaced LCG to achieve fluorescence switch-on response (Fig. 10). This response can be

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Fig. 10 The supramolecular imaging system of p-sulfonato-calix[4]arene•lucigenin using the IDA principle to monitor biomolecule uptake of cells [43]. (Reproduced from Ref. [43] with permission from Wiley-VCH)

traced to the displacement of LCG from calixarene by the analytes. The results establish the principal functionality of IDA with synthetic receptors for the detection of the uptake of bioorganic analytes by live cells [43]. In the field of bioimaging, the key challenge for fluorescent nanoparticles is to prepare particles of size equivalent to single proteins (3–7 nm) and achieve excellent brightness. Klymchenko and co-workers prepared calixarene micelles that are shellcross-linked by fluorescent bifunctional dyes through Cu-catalyzed click chemistry (Fig. 11) [44]. The authors used the conical shape, skeleton, and self-assembly properties of amphiphiles calix[4]arene to regulate the distance between the cyanine dyes and the direction of the dye. Finally, they obtained protein-sized fluorescent nanoparticles and minimized the self-quenching between the fluorescent dyes. They synthesized positively charged amphiphilic calix[4]arenes with acetylene groups on the upper rim to enable a fast and efficient “click” reaction. The calix[4]arenes selfassembled into micelles in water, and cyanine dyes with azide groups undergo the “click” reaction to cross-link the calix[4]arenes to form an organic fluorescent quantum dot with cyanine dyes on the outer surface of the nanoparticles. The hydrodynamic diameter of the nanoparticles was 7 nm, which was equivalent to the size of single proteins (3–7 nm). The fluorescent nanoparticles had the following

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advantages: the size minimal perturbation of biomolecular processes in cell imaging, uniform particle size avoiding wide emission of fluorescence, and cross-linking structure preventing disintegration of nanoparticles after interaction with cell membranes. It is worth noting that the calix[4]arene quantum dots have excellent luminescence properties. The brightness of nanoparticles was twofold brighter than commercial quantum dots (QD-585). Finally, the authors applied calix[4]arene quantum dots to cell imaging and found that the materials can enter HeLa cells and selectively accumulate in endosomes and lysosomes. The results showed that calix[4]arene quantum dots maintain structural integrity in physiological media, organic solvents, and living cells and can be rapidly internalized showing excellent imaging contrast. This type of calixarene organic quantum dot has broad application prospects in cytology, histology, and fluorescent tracers in biochemistry [44].

8.7

Calixarenes for Gene Delivery

The ability to tightly bind and compact DNA and the characteristics of calixarenes to behave as macrocyclic amphiphiles motivated us to test guanidinium-calixarenes as gene delivery vectors. Current studies show that calix[4]arenes are probably the most promising among the described calixarenes for gene delivery applications [17, 58–61]. Their fixed conformation has multiple functional groups at the upper and lower rims, which allow the preparation of cone-shaped macromolecules that can be programmed for fractional assembly in the presence of DNA. The intricate calixarenes designed, especially those with amphiphilic structures, are able to form DNAcalixarene nanoparticles with clear structure, high transfection efficiency and low toxicity. At present, researches in the field are still insufficient, especially for the modification of calixarene, which requires more scientists’ attention. In addition, experiments in vivo are needed to evaluate the effect of calixarene on gene therapy. Recently, Ungaro’s team synthesized positively charged calixarene derivatives with upper rim modified by four arginine residues and lower rim of four hexyl groups or only four arginine residues at the lower rim (Fig. 12a). AFM imaging showed that the calixarenes with the upper rim-modified arginine reacted with DNA to form nanoparticles with a size of 50–60 nm (Fig. 12b), whereas the derivatives of the lower rimmodified arginine formed more larger aggregate. This apparent difference may be partly due to the fact that argininocalix[4]arene 1 had a clear amphiphilic nature relative to ordinary calixarenes. In particular, argininocalix[4]arene 1 showed excellent transfection efficiency even better than Lipofectamine and PEI in various cell lines (Fig. 12c). In contrast, tetralysinocalix[4]arene 3 showed little transfection activity. In addition, the argininocalix[4]arene 2, similar to argininocalix[4]arene 1, which modified the protonated amino groups rather than the guanidine groups, exhibited poor transfection activity, while DOPE can help to increase their activity. This significant difference between

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Fig. 12 (a) Structure of calix[4]arenes 1, 2, and 3. (b) AFM images showing DNA folding by calixarene 1. (c) Transfection efficiency in various cell lines of calixarene 1 (red) compared with calixarene 1 with DOPE (peak), calixarene 2 (blue), calixarene 2 with DOPE (cyan-blue), Lipofectamine (gray), and PEI (light gray) [58]. (Reproduced from Ref. [58] with permission from the Nature Publishing Group)

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Fig. 13 Schematic representation of DNA complex with micelles composed of cationic amphiphilic calixarenes [60]. (Reproduced from Ref. [60] with permission from Wiley-VCH)

argininocalix[4]arenes 1 and 2 suggested that the arginine residues of the amphiphilic calixarene were essential for efficient transfection, which may increase the ability of the DNA-calixarene complexes to cross the cell membrane The most efficient transfection efficiency of argininocalix[4]arene 1 is less cytotoxic and comparable to Lipofectamine. In the current work of gene transfection using calixarene, argininocalix[4]arene 1 may be the best transfection agent. Klimchenko et al. developed a nucleic acid template consisting of a polycationic amphiphilic calixarene, initially a tiny calixarene micelle (about 6 nm in diameter) that forms complexes with DNA by electrostatic interaction. This fractionation process would be advantageous for cationic calixarenes modified by relatively long lipophilic chains (Fig. 13) [60, 61].

8.8

Calixarenes as Drug Carriers

The use of supramolecular concepts to design drug delivery systems has attracted widespread attention from scientists. Significantly, calixarenes and their watersoluble calixarene derivatives have become an important class of supramolecular

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drug carriers in drug delivery systems. There have been many reviews about drug carriers based on calixarenes [62–65]. Depending on the mechanism of delivery implementation, we can generally classify them into the following three categories: inclusion complexes, amphiphilic self-assembly, and supra-amphiphilic selfassembly. Many research groups have reported drug delivery systems based on calixarenedrug complexes [62, 65, 66]. Typically, hydrophilic groups at the rim of calixarenes have been widely utilized to produce water-soluble derivatives, which serve as important containers to encapsulate drugs with poor water solubility in drug delivery [67–70]. Pilar Ljpez-Còrnejo et al. constructed an inclusion complex using p-sulfonatocalix[6]arene and doxorubicin [71]. The complex systems display a preference for locating close to the DNA structure, facilitating the transport of the antibiotic toward the polynucleotide, which means that they can act as an excellent candidate for drug delivery. In addition, calixarenes in the solution partially reduce the side effects of doxorubicin (DOX). The calixarene amphiphiles can provide cavities for drug delivery by suitable arrangement [72]. This highly attractive trait had prompted scientists to develop new materials and devices that may be applied in bio-nanotechnology and nanomedicine [73]. The hydrophilic groups were usually modified at the upper rim of calixarenes, and the lower rim was modified with hydrophobic groups such as linear alkyl group with appropriate length to form stable supramolecular assemblies. Longer alkyl groups usually cause extremely low solubility of amphiphiles and aggregation in solid lipid nanoparticles. Casnati et al. have already extensively reviewed the use of calixarene amphiphiles for nanocarrier applications in drug delivery systems [73]. Zhao et al. synthesized a folic acid-PEG-modified p-phosphonated calix[4]arene. By the calixarene self-assembly to form a nanocarrier, paclitaxel and carboplatin can be simultaneously delivered to tumor cells at an optimal ratio (5:1, mol:mol), with potential synergy effect for ovarian cancer [74]. Tao et al. used the self-assembly of amphiphilic calixarene as a carrier for paclitaxel [74]. The encapsulation of paclitaxel using amphiphilic calixarene was an attempt to improve the water solubility of the drug. The optimized formulation of paclitaxel-loaded amphiphilic calix[4]arene nanocapsules had an encapsulation efficiency of 82.65  2.54%. The paclitaxel-loaded calix[4]arene formulation revealed improved paclitaxel-induced cytotoxicity in human cervical cancer cell culture experiments in contrast to Taxol. Typically, Consoli et al. used a polycationic calix[4]arene-based nanoaggregate entrapping curcumin by a simple and reproducible method for delivering curcumin to anterior ocular tissues (Fig. 14) [75]. The supramolecular assembly of calix[4]arene and curcumin was a clear colloidal solution composed of micellar nanoaggregates in water. The properties of the supramolecular assembly (such as size, polydispersity index, surface potential, and drug loading percentage) all met the requirements for the ocular drug delivery. In vitro and in vivo experiments, curcumin encapsulated by calixarene has significantly enhanced solubility, increased stability, and improved anti-inflammatory effects compared to free curcumin. Nanoassembly did not affect the viability of J774A.1 macrophages and inhibited the expression of

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Fig. 14 Potential eye drop based on an amphiphilic calix[4]arene nanoassembly for curcumin delivery in vivo [75]. (Reproduced from Ref. [75] with permission from the American Chemical Society)

pro-inflammatory markers in J774A.1 macrophages that were subjected to lipopolysaccharide-induced oxidative stress. Histological and immunohistochemical results indicate that the curcumin-calixarene nanoassemblies were capable of reducing lipopolysaccharide-induced inflammation in a rat model of uveitis when administered topically in eyes. In contrast to the above strategy of self-assembly directly through amphiphilic calixarenes, the field of supra-amphiphiles is formed on the basis of non-covalent interactions and dynamic covalent bonds [76]. Our group found that p-sulfonato-calix [4]arenes can promote the self-aggregation of aromatic or amphiphilic molecules by lowering the critical aggregation concentration, enhancing aggregate stability and compactness, and regulating the degree of order in the aggregates. This unique selfassembly strategy was defined as calixarene-induced aggregation (CIA) [18]. Based on the concept of CIA, we constructed the supramolecular vesicle with the enzymestimulated response using biocompatible p-sulfonate calix[4]arene, which had potential application value in the treatment of Alzheimer’s disease [77]. It is well known that enzymes play a very important role in many biochemical processes, and the abnormal expression of enzymes is often associated with certain diseases. Therefore, enzymes are widely used in drug-targeted delivery as an endogenous stimulus response signal. P-Sulfonato-calix[4]arene and myristoylcholine formed the binary vesicles by the host-guest complexation. The vesicles have highly specific response to cholinesterase, which disrupts the hydrophilic-hydrophobic balance, causing the disintegration of the binary vesicles, thereby releasing the loaded drug. The binary vesicle can be constructed by the same principle using other host molecules (Fig. 15). Based on the above work, we subsequently developed supramolecular amphiphilic drug carriers that were responsive to trypsin [78]. Unlike myristoylcholine previously discussed, protamine is a non-amphiphilic natural bio-cationic protein. P-Sulfonato-calix[4]arenes were used to induce protamine aggregation to construct binary supramolecular vesicles. Cell experiments showed that the vesicles have a very sensitive response to trypsin. When the vesicles were encapsulated anticancer drug (DOX), their ability to

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Amphiphilic

No Release BChE

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N

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Fig. 15 Schematic illustration of the cholinesterase-responsive binary supramolecular vesicle system constructed by p-sulfonato-calix[4]arene and myristoylcholine [77]. (Reproduced from Ref. [77] with permission from the American Chemical Society)

inhibit pancreatic cancer cells was superior to that of liver cancer cells. Imaging experiments in vivo found that the supramolecular vesicles can release more dye in tissue with a high concentration of trypsin.

8.9

Calixarenes as Treatment Agents

Calixarenes have structural features suitable for the design and development of new drugs. At present, calixarenes and their derivatives have been found to have antiviral [79], antibacterial, antifungal, antituberculosis, and anticancer activities [80–83]. In 2009, Fátima et al. reviewed the bioactivity of calixarenes and their applications [84]. In 2015, Yousaf et al. summarized the anticancer potential of calixarenes and the potential use of calixarenes in chemoradiotherapy [85]. Additionally, in 2017, Naseer et al. reviewed the functionalized calixarenes as potential therapeutic agents [86]. It is worth noting that clinical trial reports of calixarene-based drugs are still rare. To date, only one calixarene-based, OTX008, is undergoing phase I clinical studies according to the US Clinical Trial Database. OTX008 is a galectin-1 inhibitor that may have antiangiogenic and antitumor activity (Fig. 16) [83]. The drug can downregulate the multifunctional carbohydrate-binding protein, galectin-1, to treatment patients with advanced solid tumors. The clinical trial seems to have been ongoing since 2012, but with no follow-up reports.

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Fig. 16 The chemical structure of calix[4]arene-based galectin-1 inhibitor (OTX008) in clinical phase I [83]. (Reproduced from Ref. [83] with permission from the American Chemical Society)

In addition to the biological activities described above, calixarenes are used in detoxification [87], anti-protein folding [88–90], and protein-protein interaction disruptors [91]. Viologens are widely used as herbicides (e.g., paraquat and diquat) in farmland worldwide due to their fast and efficient herbicidal effects. However, these compounds are extremely toxic to humans and animals without available treatment. Presently, most countries have strictly controlled or banned the use of paraquats. Regardless, there are still many reports of death from paraquat poisoning every year. When paraquat enters the human body, it will accumulate in the alveolar type I cells, type II cells, and kidneys, affecting the process of redox reaction, generating a large number of oxygen-free radicals harmful to tissues, destroying the defense mechanism of cells, and leading to alveolar and interstitial fibrosis (acute or subacute) [92]. According to the biochemical mechanism of viologen in vivo, we developed a supramolecular detoxification strategy based on p-sulfonato-calixarenes. We verified in vivo experiments that p-sulfonato-calix[5]arenes can treat viologen poisoning. When the viologen-poisoned mice were treated with p-sulfonato-calix[5]arenes immediately or after 2 h, the mortality rate was significantly decreased. Moreover, p-sulfonato-calix[5]arenes can also effectively prevent the damage of the lung and liver induced by viologen (Fig. 17). After our above work, Qi et al. studied the detoxification mechanism of p-sulfonato-calix[4]arene with paraquat by pharmacokinetic study in vivo [93]. They measured the concentration of paraquat in rat plasma using high-performance liquid chromatography. The results showed that peak plasma concentration and plasma concentrations under plasma concentration-time curves for animals administration of p-sulfonato-calix[4]arene were significantly lower than the control of p-sulfonato-calix[4]arene complexation on absorption pharmacokinetics, finding that the absorption of paraquat was effectively prevented by the formation of a stable host-guest complex of paraquat with p-sulfonato-calix[4]arene.

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Fig. 17 The toxicity mechanism of viologen and the application of p-sulfonato-calix[5]arene in supramolecular detoxification [87]. (Reproduced from Ref. [18] with permission from the American Chemical Society)

8.10

Conclusions and Outlook

Since C. David Gutsche optimized the calixarene synthesis route and made it possible to synthesize a large amount of calixarenes, more and more chemists have began to pay attention to calixarenes. Various group-modified calixarene hosts were synthesized and applied to different fields depending on the molecular recognition and selfassembly properties. To date, the continued and growing interest toward calixarene macrocycles is evidenced by the study of new supramolecular applications such as calixarene-based supramolecular medicine. The calixarene derivatives are rich and complex, many of which have been reported to have potential applications in medical applications but mostly remain in the laboratory stage. The future goal of calixarene research is to integrate advancements in supramolecular chemistry with clinical trials, taking research from the “bench to bedside.” High-throughput screening methods can be used to screen a wide range of medicinal activities of existing calixarenes and their derivatives to find suitable potential drugs. The pharmacology and toxicology of calixarenes need to be studied in depth and systematically in vitro and in vivo. In the future, the derivatization of calixarene should likely translate “synthesis for synthesis” to “synthesis on demand.” The development of calixarenes in supramolecular medicine has just begun, and more new fields of application need to be explored.

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Cross-References

▶ Responsive Supramolecular Vesicles Based on Host-Guest Recognition for Biomedical Applications ▶ Supermolecules as Medicinal Drugs

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Preparation of Biosensor Based on Supermolecular Recognization Jingjing Jiang, Xinyi Lin, and Guowang Diao

Contents 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2 Biosensing Applications Based on Supermolecular Recognization . . . . . . . . . . . . . . . . . . . . . 9.2.1 Metal Ion Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2.2 Nucleic Acid Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2.3 Immunoassay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2.4 Protein Biosensing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2.5 Small Molecule Determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

Supermolecular chemistry, also known as “chemistry beyond the molecule,” is an emerging interdisciplinary research, which focuses on the study of complex and ordered assemblies formed by noncovalent interactions, such as metal coordination, hydrogen bonding, π-π stacking, van der Waals force, and hydrophobic interaction [1, 2]. As an important research content in supermolecular chemistry, host-guest molecular recognization refers to the process in which a receptor molecule (host) specifically binds with a ligand molecule (guest) through noncovalent interactions and subsequently produces a certain function. The electronic properties and geometry structures of host molecules play an extremely significant role in host-guest recognization. The former enables the interactions between various molecules to obtain effective utilization, and the latter helps to match their geometric configurations with molecular sizes. The unique properties of supermolecular recognization hold

J. Jiang · X. Lin · G. Diao (*) School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_10

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great promise for practical applications in a wide variety of technological fields, such as sensing analysis, molecular imaging, metal extraction, and drug delivery [3–7]. Different kinds of macrocyclic hosts, including crown ether, cyclodextrin, calixarene, cucurbituril, and pillararene, have successively emerged during the booming development of supermolecular chemistry. Macrocyclic hosts with their respective advantages have been widely applied for the construction of sensors. For example, cyclodextrin-functionalized carbon-based materials (especially graphene and carbon nanotubes) not only promote the dispersion and stability of carbon-based materials but also improve the detection sensitivity for some important target molecules through the formation of host-guest inclusions between cyclodextrin and guest molecules [8, 9]. Possessing suitable signal conduction path and appropriate number of target-capturing sites, cyclodextrin-functionalized carbon-based materials have been ideal candidates to construct simple and easy-to-use electrochemical sensors for the accurate monitoring of various trace analytes [10–13]. With the feature of highly symmetrical and rigid architecture, pillararene is capable of achieving the selective binding of specific guest molecules. Since anionic watersoluble pillar[6]arene (WP6) and pillar[5]arene (WP5) displayed distinctly different recognization capability to an aromatic fluorescent dye acridine orange (AO), a novel host-indicator fluorescence system based on WP6 and AO was established and successfully applied for the monitoring of choline compounds and enzymatic reactions [14]. In this chapter, we will give an overview to summarize the recent developments in the preparation of biosensors based on supermolecular recognization with various test techniques and signal amplification strategies, highlighting with significant examples of metal ion detection, nucleic acid analysis, immunoassay, protein biosensing, and small molecule determination. And we believe that this chapter will be favorable for researchers to know latest development directions and develop advanced biosensing methods.

9.2

Biosensing Applications Based on Supermolecular Recognization

9.2.1

Metal Ion Detection

With rising living standards, the harmful influence of heavy metal pollution on survival environment of human being has become a major concern in modern society because of the threaten to human health through the food chain. In view of this serious issue, the monitoring of trace heavy metal ions is of great importance to the environmental protection and human safety [15–17]. For example, Ge et al. constructed the antibacterial and self-healing hybrid coatings using layer-by-layer (LBL) self-assembly technique for the sensitive monitoring of Co2+ [18]. Molybdenum disulfide (MoS2) nanosheets with excellent biocompatibility and photoluminescent characteristics were successfully fabricated on the pre-prepared β-cyclodextrin-modified polyethylenimine/adamantane-modified polyacrylic acid

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(β-CD-PEI/AD-PAA) multilayer coatings, and the fluorescence signal of MoS2 was obviously decreased after the adsorption of Co2+. However, the self-healing capability of MoS2/(β-CD-PEI/AD-PAA)15 coatings was not affected by Co2+ accumulation, which could be attributed to the satisfactory host-guest interaction between β-CD-PEI and AD-PAA. With the help of Hg2+, Wu’s group designed a novel and reversible supermolecular system through the self-assembly of a thymine (T)-substituted copillar[5]arene 1 and tetraphenylethylene (TPE) derivative 2, which were acted as the fluorescent catcher and indicator, respectively [19]. As demonstrated in Fig. 1, the firstly formed pseudorotaxane 2
1 via the host-guest interaction between pillar[5]arene cavity and nitrile moiety in 2 exhibited extremely weak fluorescence signal when the TPE derivative was in a highly dispersed state. Upon gradual addition of Hg2+, pseudorotaxane 2
1 could further coordinate with Hg2+ to produce crisscrossed network structures via the “T–Hg2+ T” pairing and finally wrapped into spherical nanoparticles. Due to the aggregation-induced emission (AIE) feature of indicator [20], a strong fluorescence emission peak was obtained, and the peak intensity increased linearly with the increase of Hg2+ concentration in the range of 0–180 μM. Moreover, the recycle of pseudorotaxane and removal of Hg2+ could be ingeniously achieved by a simple treatment with sodium sulfide. Moreover, the sensing analysis of rare earth elements was also designed via the supermolecular interaction. Inspired by the inclusion complex of β-CD and rare earth metal chelate [21], a novel electrochemiluminescence (ECL) sensing strategy based on molecularly imprinted polymer was proposed for the highly sensitive and

Fig. 1 Proposed strategy of pillararene-based AIE-active supramolecular system for simultaneous detection and removal of Hg2+ [19]

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selective determination of ultra-trace Tb3+ [22]. When Tb3+-ethylenediaminetetraacetic acid (Tb-EDTA) complex incorporated into the hydrophobic cavity of β-CD, a dual-signal amplification mechanism by the combination of ECL resonance energy transfer between β-CD/Tb-EDTA (donor) and Ru(bpy)32+ (acceptor) and the coreactant system of Ru(bpy)32+/Tb-EDTA was realized. As a result, the detection limit of 0.39 pM was dramatically reduced by three orders of magnitudes in comparison with other Tb3+ sensors without the supermolecular recognization.

9.2.2

Nucleic Acid Analysis

Accurate and ultrasensitive detection of trace nucleic acid sequences acts as a significant role in the quantitative analyses of biological markers for various disease diagnoses [23]. Taking advantage of the novel pillararene derivative (trithiocarbonate-substituted pillar[5]arene, P5A-CTA), He and coworkers constructed a recyclable and immobilization-free electrochemical biosensor to detect breast cancer susceptibility gene (BRCA) as a model target based on the homogeneous DNA hybridization technique [24]. As shown in Fig. 2, P5A-CTA was pre-chemisorbed on the surface of Au electrode to construct the sensing platform via the trithiocarbonate group [25, 26]. In the presence of target sequence, sandwichtype nucleic acid architecture was formed via the hybridization reaction of target DNA with methylene blue (MB)-labeled signal probe and dodecylamino-labeled capture probe, which was further captured and introduced on the P5A-CTA-modified Au electrode surface due to the host-guest interaction between P5A-CTA and dodecylamino groups. The response current could be remarkably amplified with the aid of horseradish peroxidase (HRP) and H2O2 resulting from the incorporated

Fig. 2 Schematic illustration for reversible electrochemical biosensing system constructed by Au/P5A-CTA/sandwich-type DNA/HRP for BRCA detection [24]

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MB in signal probe as the efficient electron transfer mediator [27]. Furthermore, this sensing platform showed favorable recyclability after a simple washing treatment with hot acetonitrile to dissociate the inclusion complex. On the basis of the toeholdtriggered strand displacement reaction and host-guest recognization of Fe3O4@SiO2@βCD nanocomposites, Diao’s group realized a facile homogeneous electrochemical analytical method for sensitive target DNA assay, and the fabricated biosensor was successfully used to work in complex biological systems [28]. Some previous researches have verified that epichlorohydrin cross-linked β-cyclodextrin polymer (β-CDP) possessed stronger recognization capability toward guest molecules in comparison with the β-CD monomer [29, 30]. Based on this, a polymerase and λ exonuclease-assisted multiple amplification fluorescence method was reported for sensitive miRNA-21 detection in combination of a significant fluorescence enhancement effect of β-CDP for pyrene, which could be ascribed to the high molecular recognization of β-CDP [31]. Therefore, the proposed biosensor was successfully applied for the quantitative monitoring of miRNA-21 in a dynamic range of 1–5000 pM with a detection limit down to 0.3 pM and displayed high selectivity in discriminating base-mismatched sequences. Analogously, selecting β-CDP as the same host molecule, Diao’s group also developed an enzyme-free electrochemical nucleic acid biosensor by smart integration of β-CDP host-guest recognization and Mg2+-dependent DNAzyme (Fig. 3) [32]. Before addition of target sequence, the closed stem-loop structure of subunit DNA (S-1) hindered the generation of Mg2+-dependent DNAzyme, and subsequently ferrocene dual-labeled

Fig. 3 Schematic illustration of the electrochemical nucleic acid biosensor based on the host-guest interaction and Mg2+-assistant target recycling [32]

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hairpin probe (H-1) could not be accumulated on the surface of nitrogen-doped reduced graphene oxide (NRGO)/β-CDP nanocomposite-modified electrode owing to the principle of dimension matching. After addition of target molecule, the stemloop structure of S-1 was opened, producing the active DNAzyme to catalyze the cyclic cleavage of numerous H-1 in the presence of cofactor Mg2+. The cleaved H-1 allowed ferrocene molecule to enter the cavity of β-CDP and caused an obvious increase of response current. By means of the superior recognization capability of β-CDP and DNAzyme-based enzyme-free amplification technique, the designed biosensor showed prominent performances for DNA and miRNA assays with low detection limits of 3.2 and 18 fM, respectively, which may provide a universal nucleic acid detection approach in the field of bioanalysis.

9.2.3

Immunoassay

As a fascinating recognization technique, supermolecular recognization-based immunoassays have become the attractive sensing method with improved detection characteristics [33–35]. A supermolecular immunosensor based on polypyrrolecyclodextrin-modified electrode surfaces for the immobilization of adamantaneand gliadin-bifunctionalized polysaccharide was constructed for the monitoring of antigliadin antibodies related to celiac diseases [36]. Through the clever design of a supermolecular net material as signal probe, Yuan and coworkers developed an enzyme-free electrochemical immunosensor for procalcitonin (PCT) detection [37]. As demonstrated in Fig. 4a, using a promising template of poly(amidoamine)

Fig. 4 Schematic diagram of fabrication of electrochemical immunosensor: (a) preparation procedure of Fc-Fc/β-CD/PAMAM-Au-labeled Ab2 bioconjugates; (b) comparative DPV signals with and without amplification [37]

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(PAMAM) dendrimers to prevent nanoparticle aggregation [38, 39], PAMAMencapsulated Au nanoparticles (PAMAM-Au) acted as nanocarriers anchored large amounts of amine-terminated β-CD by the chemical absorption interaction. With the unique structure of two ferrocene units, the as-synthesized N,N-bis(ferrocenoyl) diaminoethane (Fc-Fc) as a bridge could bind two β-CD molecules via the hostguest recognization and form the supermolecular net structure of Fc-Fc/β-CD/ PAMAM-Au signal probe. Finally, secondary antibody (Ab2) was attached to the netlike probe for the generation of Fc-Fc/β-CD/PAMAM-Au-labeled Ab2 bioconjugates. The electrochemical immunosensing platform was prepared by the stepwise modification of electrochemically deposited Au nanoflower (DpAu), primary antibody (Ab1), and bovine serum albumin (BSA) on the surface of glassy carbon electrode (GCE). After PCT was introduced to the sensing system, Fc-Fc/β-CD/PAMAM-Au-labeled Ab2 bioconjugates could be captured by the sandwich conformation-dependent immunoreaction, and then a “signal-on” differential pulse voltammetry (DPV) oxidation peak of ascorbic acid (AA) was obtained by the enzyme-free dual amplification strategy, which was composed of the synergetic catalytic activity of PAMAM-Au and Fc-Fc (Fig. 4b). Under the optimal experimental conditions, the electrochemical immunosensor toward the detection of PCT exhibited a wide linear range of 1.8 pg mL–1–500 ng mL1 with a low detection limit of 0.36 pg mL1. Bimetallic alloy nanoparticle often exhibits enhanced selectivity and catalytic activity in comparison to their single-metallic components, and both magnetic and optical characteristics can be fine-regulated via changing the metal ratios in alloy systems [40, 41]. Based on this, Du et al. firstly selected a facile microwave-assisted approach to synthesize N-doped graphene nanoribbons (N-GNRs) from N-doped multi-walled carbon nanotubes (N-MWCNTs), and PdNi alloy nanoparticles with an average size of 10 nm were reduced in situ on the surface of N-GNRs to produce PdNi/N-GNRs nanocomposites in the presence of ethylene glycol and glutamate [42]. The electrochemical immunosensing biosensor was constructed through the sequential assembly of β-CD-functionalized graphene sheets (CD-GS), adamantine-1-carboxylic acid-functionalized Ab1 (ADA-Ab1), and BSA on GCE surface, and subsequent addition of alpha fetoprotein (AFP) resulted in the catch of PdNi/N-GNRs-immobilized Ab2 (PdNi/N-GNRs-Ab2) to generate a distinct amperometric response via the catalysis of the reduction of H2O2. Taking advantages of the high electrocatalytic activity of PdNi/N-GNRs and enhanced recognization capability and electronic conductivity of CD-GS, the proposed sandwich-type immunosensor exhibited an attractive sensing property with a detection limit down to 0.03 pg mL1. Different from the traditional electroanalysis device, lightweight paper-based equipment has drawn tremendous attention in recent years, because of its extraordinary merits, such as low cost, simple operation, convenient surface functionalization, and easy large-scale production [43–45]. In this arrangement, Ge’s group developed an enzyme-free microfluidic paper-based analytical device (μPAD) for the determination of two tumor markers, carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA) (Fig. 5) [46]. In order to improve the defect of poor longitudinal conduction of paper chips, a porous structure of gold nanoparticle (AuNP)-modified paper working electrode (Au-PWE) with all-round

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Fig. 5 Schematic diagram of the immunosensor for the detection of CEA and PSA: (a) Au-PWE; detection mechanism of the CEA (b) and PSA (d); signal responses toward CEA (c) and PSA (e) [46]

conductivity and numerous active sites was selected as the immunosensor substrate to link biological ligand. Then, β-CD-modified Au nanoparticles (CD@AuNPs), with the feature of dual mimicking enzyme activities toward glucose and H2O2 [47], were applied to load Ab2 or peptide through the host-gust recognization of β-CD. In the presence of CEA, the introduced CD@AuNPs initiated cascaded catalysis reactions and boosted the electrochemical signal of o-phenylenediamine (o-PD). However, after the addition of another analyte (PSA), the peptide cleavage reaction was occurred and led to the release of CD@AuNPs from Au-PWE. Therefore, the current intensity displayed a wide linear positive correlation for CEA and negative correlation for PSA, respectively, which indicated that this facile μPAD may provide a promising way for the development of portable devices in disease diagnosis.

9.2.4

Protein Biosensing

Proteins are important active substrates to maintain life and health of organisms, and their quantitative detection also raises concern about the related diseases commonly encountered in biomedical research and clinical diagnosis [48–50]. Li and coworkers

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firstly design a general electrochemical signal readout strategy to assay protein by coupling protein-binding peptide with signal reporter via the supermolecule formation [51]. As illustrated in Fig. 6a, the noncovalent coupling between electrochemical reporter (methylviologen, MV) and peptide could be realized through a two-step reaction process. MV was pre-captured by cucurbit[8]uril (CB[8]) for the generation of MV@CB[8] complex, and formed MV@CB[8] further bound with aromatic side chain-confined peptide by the supermolecule formation. In order to detect the target protein, the sensing platform was constructed by the self-assembly of proteinbinding peptides on the Au electrode surface (Fig. 6b). After the interaction with target, a portion of peptides become protein-bound, and the rest of protein-free peptides were subsequently coupled with MV@CB[8]. Thus, the more target protein was captured, the less reporter was introduced to the electrode surface. This general sensing method was successfully used to quantitatively monitor two kinds of disease-marker proteins, tumor necrosis factor-α and amyloid β 1–42 soluble oligomer, respectively. Aptamers, the single-stranded nucleic acid molecules, display high affinity to proteins or other macromolecular compounds, which are comparable to the antigen-antibody special immune systems. Aptamer-based sensors (also called aptasensors) with the feature of easy labeling and flexible modification have been widely used in biological analyses and disease diagnostics [52–54]. For example, He et al. presented a “signal-on” electrochemical aptasensor for thrombin detection by the utilization of β-CD-modified CdS nanoparticles as both the signal reporter and host recognizer [55]. Nevertheless, since the electrochemical signal of an “on-off” or

Fig. 6 (a) Schematic diagram of coupling peptide with reporter via supermolecule formation and (b) assay for protein detection [51]

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“off-on” system usually originates from one kind of redox probe, the environmental variations, such as solution pH and concentration, may give rise to the positive or negative false signal. Ratiometric electrochemical assays have attracted more and more research interests recently due to the removal of most errors via the normalization of environmental variations [56, 57]. Considering the advantages of ratiometric electrochemical method, Chen et al. designed a smart protein bio-gate as a mediator to regulate the competitive host-guest interaction between β-CD and two guests (redox probes) for sensitive assay of prion (Fig. 7) [58]. Making use of the supermolecular recognization of β-CD toward methylene blue (MB), MB-labeled prion-aptamer (MB-Apt) could be attached to the multi-walled carbon nanotubes-β-CD (MWCNTs-β-CD) composite-modified GCE surface. The introduced MWCNTs not only provided a high surface-to-volume ratio but also accelerated the electron transfer. After the gradual addition of prion, the specific interaction between MB-Apt and target prion stimulated the production of a protein bio-gate to seal the cavity of β-CD. As a result, the guest displacement of MB by ferrocenecarboxylic acid (FCA) originating from the competitive host-guest interaction was blocked, which led to the increase of MB peak current (IMB), concomitant with a decrease in the FCA peak current (IFCA). However, in the presence of other proteins, the specific prion-aptamer interaction was inhibited. MB-Apt could be replaced by FCA due to its higher binding affinity to β-CD. It is clear that the ratio of IMB to IFCA (IMB/IFCA) was dependent on the concentration of prion, which provided a ratiometric electrochemical sensing strategy for sensitive prion analysis. As a new-type test technique, photoelectrochemistry (PEC) evolved from electrochemistry has already become a popular research hotspot because of its low background and high

Fig. 7 Schematic illustration of the ratiometric electrochemical aptamer-based biosensors for prion detection [58]

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sensitivity [59, 60]. Photoelectrochemical process usually involves in the photon-toelectron conversion caused by electron excitation and consequent charge transfer of photoactive substances (such as inorganic or organic semiconductors) produced under the light irradiation [61, 62]. In view of the favorable biocompatibility, high electronic mobility, and desirable chemical stability of titanium dioxide (TiO2), a simple prion PEC aptasensor with a low detection limit of 50.9 fM was constructed by the integration of the enhanced photoelectric property of Au-TiO2 composites and good host-guest interaction between thiol-β-CD (SH-β-CD) and rhodamine B (RhB) [63]. The precise monitoring of enzyme activity is of great practical significance for further understanding their functions, developing early diagnoses, and discovering potential new drugs [64, 65]. Herein, a reliable real-time luminescent assay of acid phosphatase (ACP) activity was proposed on the basis of a reversible nanoswitch controlled by the competitive hydrophobic interaction (Fig. 8) [66]. Stable copper nanoclusters (CuNCs) were firstly prepared via a green one-pot method using D-penicillamine and copper nitrate in aqueous solution. Owing to the AIE property, severely aggregated CuNCs as the nanoswitch displayed brightly red luminescence under acidic conditions. The catalytic hydrolysis of ACP toward p-nitrophenyl phosphate disodium brought about the production of p-nitrophenol. The hydrophobic interaction between CuNCs aggregate and p-nitrophenol motivated the adsorption of p-nitrophenol on the surface of CuNCs aggregate, and this closed contact quenched the luminescence of CuNCs aggregate. Therefore, such an ACP sensing strategy could be established in terms of the negative correlation between luminescence intensity and ACP level. Moreover, the recovery of luminescence could be achieved by the introduction of α-cyclodextrin (α-CD), which originated from the release of p-nitrophenol from CuNCs surface triggered by the stronger hydrophobic

Fig. 8 Schematic illustration of detection strategy for ACP activity based on the luminescent CuNCs nanoswitch controlled by hydrophobic interaction [66]

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interaction between α-CD and p-nitrophenol. Feng’s group reported a universal fluorescence biosensor for glycosidase assay and inhibitor screening using β-CD-functionalized carbon quantum dots (β-CD-CQDs) as the nanoprobes [67]. As shown in Fig. 9, taking β-galactosidase as the target example, its introduction initiated the rapid hydrolysis of 4-nitrophenyl-β-D-galactopyranoside into p-nitrophenol, and the generated p-nitrophenol was driven by the host-guest recognization to enter the β-CD cavity of nanoprobes. A sharp decrease in the fluorescence emission of β-CD-CQDs was obtained by a static quenching mechanism. As a consequence, a good linear relationship between the fluorescence intensity and β-galactosidase level was established with a low detection limit of 0.6 U L1. The inhibitor screening function of this strategy was also investigated by choosing D-galactal as an effective inhibitor of β-galactosidase, and obvious fluorescence recovery results confirmed the feasibility to screen potential inhibitors. In addition, the developed biosensor was successfully applied to monitor the β-galactosidase expression level in ovarian cancer cells. On account of the increased recognization sites from α-CD-encapsulated gold/silica core-shell nanoparticles (Au/SiO2/α-CD), Zhao et al. established a sensitive ECL biosensor to test the activity of human 8-oxoguanine DNA glycosylase (hOGG 1) [68]. Guest-labeled ECL probe was firstly attached to the Au/SiO2/α-CD nanocomposite-modified electrode surface for the preparation of ECL sensing platform. In the presence of hOGG 1, targetinduced terminal protection happened and inhibited the digestion of exonuclease I (Exo I) and exonuclease III (Exo III) toward the guest-labeled ECL probe. The

Fig. 9 Schematic illustration of the universal detection strategy for glycosidase activity based on a combined host-guest recognition and specific static quenching-induced signal transduction mechanism by taking β-galactosidase as the example [67]

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amount of undigested probes on the electrode surface was obviously dependent on the concentration of active hOGG 1, which allowed the quantitative assay of target DNA glycosylase.

9.2.5

Small Molecule Determination

With the advancement of supermolecular chemistry, indicator displacement assay (IDA) via the competitive recognization between a test substance and an indicator with the same binding site on the host has aroused considerable research interest for optical (mostly fluorescent and colorimetric) sensing applications [69–71]. For instance, a novel pillararene-indicator system between WP6 and AO was proposed [14]. As shown in Fig. 10a, the complexation between WP6 and AO (WP6  AO) gave rise to a significant decrease in the fluorescence emission of AO due to the hostguest charge-transfer interactions. Upon subsequent introduction of choline (Ch), the yellow-green fluorescence of AO recovered. With the similar binding affinity for WP6, the analogical phenomenon also could be observed after the addition of acetylcholine (ACh). When the host molecule was replaced by WP5, AO exhibited a size-selective complexation and could not enter into the electron-rich cavity of WP5. Moreover, the constructed pillararene-indicator system was further employed in the monitoring of enzymatic reactions catalyzed by choline oxidase (Fig. 10b). It is clear that WP6 showed distinctly different binding affinities with a substrate (Ch) and a product (betaine, Bt) in the catalytic process of choline oxidase. Thus, the different displacement efficiencies of Bt and Ch from WP6  AO complex motivated the IDA-induced fluorescence variation mechanism. By adopting the IDA system, van der Wall et al. also designed a supermolecular colorimetric sensing strategy for drug detection in urine of a model therapeutic peptide drug octreotide based on the cucurbit[7]uril/neutral red (CB[7]/NR) host-indicator complexes [72]. Wang’s group constructed a stable and sensitive supermolecular fluorescent nanoparticles system via the multiple noncovalent interactions for the detection of intracellular H2O2 (Fig. 11) [73]. Rhodamine B-modified ferrocene derivative (Fc-RB) in aqueous solution was able to form an inclusion complex with fluorescein isothiocyanate-modified β-CD (FITC-β-CD) by the host-guest interaction between β-CD host and Fc guest. Due to the collaborative stabilization of hydrophobic interaction, FITC-β-CD/Fc-RB complex with inherent amphiphilicity could selfassemble into stable supermolecular nanoparticles under physiological conditions and exhibit strong fluorescence resonance energy transfer (FRET) effect, accompanied with the strong emission from RB (acceptor) and low emission from FITC (donor). When the supermolecular nanoparticles were internalized by cancer cells, the endogenous H2O2 could disrupt FITC-β-CD/Fc-RB amphiphilicity and inhibit FRET effect, which finally led to the decrease in acceptor emission and increase in donor emission. In terms of the remarkable fluorescence changes, the formed supermolecular nanoparticles realized the sensitive monitoring of H2O2 in cancer cells and might have potentials in cell imaging. Li and coworkers established a tunable fluorescent supermolecular system in aqueous solution via the host-guest

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Fig. 10 (A) Chemicals used here and illustration of the turn-on fluorescence detection of choline through indicator displacement process. (B) Reactions catalyzed by choline oxidase and the corresponding supramolecular enzyme tandem assays employed for monitoring the reaction process [14]

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Fig. 11 FITC-β-CD/Fc-RB amphiphile and its H2O2-activated behavior [73]

interactions between a fluorene derivative carrying two bispyridinium units (FPy) and cucurbit[8]uril (CB[8]) [74]. On account of the hydrophobicity of polycyclic aromatic hydrocarbon and near planarity of biphenyl, FPy in aqueous solution produced weak fluorescence emission. When the molar ratio of FPy to CB[8] was 1:1, the obtained FPy/CB[8] (1:1) complex displayed an obviously enhanced fluorescence emission. After the further increase of stoichiometry to 1:2, a 30 nm redshift was obtained, indicating a tunable fluorescence emission property. Considering the aggregation-induced quenching effect, the strong electrostatic attraction between FPy/CB[8] (1:1) and adenosine-50 -triphosphate (ATP) resulted in a remarkable decay of fluorescence signal, which exhibited a sensitive ATP sensing with a low detection limit at the nM level. By selecting catalyzed hairpin assembly (CHA) as the enzyme-free nucleic acid-based signal amplification method, a novel fluorescence biosensor was developed for the small molecule adenosine detection [75]. In the absence of adenosine, the specific binding between aptamer-trigger strand and inhibitor strand hindered the activation of two hairpin probes (H1 and H2) (Fig. 12a). Pyrene labeled at the single-stranded stem of H1 probe could be easily captured by the hydrophobic cavity of β-CDP and then generated a significantly enhanced fluorescence signal. Upon the addition of adenosine, CHA reaction was

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Fig. 12 Schematic illustration of the proposed enzyme-free nucleic acid amplified detection method based on catalyzed dynamic assembly and host-guest interactions between β-cyclodextrin polymer and pyrene. Numbers marked with * are complementary to the corresponding unmarked numbers [75]

activated by the adenosine-aptamer binding event (Fig. 12b). The inherently unstable aptamer-trigger:H1 intermediate catalyzed the dynamic assembly of H1 and H2 to produce H1:H2 duplex, accompanying with the release of aptamer-trigger. The dissociated aptamer-trigger could further motivate the next CHA reaction and finally result in the formation of numerous H1:H2 duplex. Due to the steric hindrance effect, pyrene labeled at the H1:H2 duplex was difficult to enter the cavity of β-CDP, which led to a decreased fluorescence emission. Under the optimized conditions, a low detection limit of 42 nM was obtained by the combination of the superior recognization capability of β-CDP and CHA-induced signal amplification. The proposed biosensor may extend the aptamer-based sensing application, not just nucleic acid and protein.

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Conclusion

In this chapter, we have described the recent advances of supermolecular recognization-based biosensors and briefly summarized their applications for the monitoring of metal ions, nucleic acids, antigens, proteins, and small molecules, by means of several inspiring examples. These sensing strategies involving supermolecular recognization can offer some new approaches for the design of advanced biosensors. Moreover, the newly emerging host molecules (e.g., pillararene) present a huge potential in the development of easy-to-use biosensors. Thus, with the rapid development of supermolecular chemistry, we believe that more biosensors will be developed, which will play a greater role in clinical diagnosis, food safety, and environmental monitoring. Acknowledgments This work was financially supported by the National Natural Science Foundation of China (No. 21703199 and 21773203) and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Application of Anion-π Interaction on Supramolecular Self-Assembly

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Contents 10.1 10.2 10.3 10.4 10.5

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Theoretical Study of Anion-π Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Representative Experimental Evidences of Anion-π Interactions . . . . . . . . . . . . . . . . . . . . . . Anion-Templated Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Self-Assembly with Anion as Primary Building Blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.5.1 Self-Assembly with Electron-Deficient Arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.5.2 Self-Assembly with Macrocyclic Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.6 Self-Assembly with Anions as Secondary Building Blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10.1

253 254 256 260 262 262 264 271 272 273

Introduction

The study of anion-π interactions should be dated to 1993, when Schneider and coworkers described the attractive interaction between negative species and polarizable aryl parts [1]. There are no successive reports after that. Almost 10 years later in 2002, Mascal [2], Deyà [3], and Alkorta [4] at the same time published their independent theoretical studies on energetical favorable interaction between anions and typical electron-deficient aromatics such as triazine, hexafluorobenzene, and perfluoroaromatic compounds. Deyà also termed this interaction as anion-π interaction, reassembling its electrostatic antipode cation-π interaction. A rapid development of anion-π interactions has been witnessed ever since. Various computational studies have been conducted to confirm existence and probe the nature of anion-π interactions. Subsequent experimental efforts, either through incorporating simple D.-X. Wang (*) Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_11

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Fig. 1 Interaction geometries of anion-π interactions

electron-deficient arenes into macrocyclic and supramolecular skeletons [5–9] or employing extended π units such as naphthalenediimides (NDI) [10, 11] and hexaazatriphenylene-hexacarbonitrile (HAT(CN)6) [12, 13], have exemplified and demonstrated not only the existence but also the marvelous applications of anion-π interactions. Now anion-π interaction has been realized as one of the important driving forces in anion recognition, sensing, ion channel, and catalysis. It is worth addressing that utilizing anion-π interactions as a driving force to direct self-assembly, however, remains largely unexplored. This hindrance is mainly caused by the various interaction modes in anion-π interactions. In sharp contrast to cation-π interaction where cations are exclusively located over the center of an aromatic ring, in anion-π, three types of interaction geometries, i.e., the typical non-covalent anion-π complex (Fig. 1a) and weak and strong σ-type motifs complexes B and C, were suggested being energetically favorable (Fig. 1b, c) [6]. The versatile binding geometries result in reduced directionality and increased difficulty on rational design. Despite the significant challenge in anion-π-directed self-assembly, remarkable achievements though still very few have been witnessed during the past decade. Through cooperating anion-π with other non-covalent interactions and/or rationally designing the organic and anionic building units to maximize the strength and to confine the directionality of anion-π interactions, intriguing self-assembly structures have been obtained. This review will give a summary of anion-π-controlled self-assembly, with efforts mainly focusing on selfassembly structures that anions serve as template, as primary building units, and as secondary building units. The extensive reports on cation coordination systems where anion-π is usually auxiliary and barely affects the assembly entity are beyond the scope of this review.

10.2

Theoretical Study of Anion-p Interactions

It is well known that benzene possesses negative electrostatic potential on the aromatic ring, the interaction between electron-rich aromatics and positively charged species, i.e., cation-π interaction has been widely recognized in supramolecular chemistry and biosystems [14]. Interaction of benzene ring with electronrich species has ever been regarded to be disfavored thermodynamically. This “old” knowledge was argued by Alkorta’s calculations in 1997 [15], when in their report they suggested the favorable interaction of hexafluorobenzene, an electron-deficient aromatic ring, with several electron-donating small molecules

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such as HF, LiH, and HCN. Two years later, Dougherty [16] and Besnard [17] independently reported theoretical studies on interaction of water and hexafluorobenzene, the so-called lone-pair electron-π interaction. The binding energy was predicted as being in the range of 1.5–4 kcal/mol, depending on the calculation methods utilized. Inspired by the results of lone-pair electron-π interaction, in 2002 Deyà and coworkers [3] conducted theoretical calculations at HF/6-31++G** and MP2/6-31++G** levels to demonstrate the energetically favored anion-π interaction based on hexafluorobenzene as the π receptors. By using Molecular Interaction Potential with Polarization (MIPp), they pointed out that the main contributions to anion-π interaction are electrostatic and polarization components. The minima for the complexes between anions and the π-cloud of the perfluoroaromatic derivatives were obtained with stabilization energy ranging from 8 to 27 kcal/mol depending on the charge-negative species applied. In this report, Deyà and coworkers termed the interaction between anion and π receptor as “anion-π interaction.” Almost at the same time, Mascal [2] and Alkorta [4] independently published their theoretical studies describing anion-π interactions. In Mascal’s work, they reported a MP2/6-31+G* method for the interaction of 1,3,5-triazine and trifluoro-1,3,5-triazine with anions including fluoride, chloride, and azide. Besides the non-covalent anion-π binding mode in which anion interacts with the centroid of an electron-deficient aromatic ring, minima for both C-H


X hydrogen bonding and formation of reactive complexes derived from nucleophilic attack on the triazine ring were also predicted. On the other hand, Alkorta developed DFT (B3LYP/6-31++G**) and MP2 (MP2/6-31++G** and MP2/6-311++G**) ab initio methods to evaluate the interaction of anions with perfluorobenzene compounds. It is very interesting to note that although anion-π interaction predicted by most of the calculations is attributed to the electrostatic and polarization effects, different opinions have also appeared in literature. Kim and coworkers [18], for example, have carried out high-level ab initio calculations and used symmetry-adapted perturbation theory (SAPT) method to investigate the nature of anion-π interactions. Except for electrostatic and induction energies, they suggest that the contribution from dispersion energy is substantial for anion-π interaction. Being different from most of the theoretical studies focusing the typical non-covalent anion-π interaction mode, viz., the interaction of anion with the centroid of electron-deficient aromatics, Hay and his coworkers [19] emphasized varied anion-π interaction motifs. On the basis of MP2/aug-cc-pVDZ calculations of the interactions of F , Cl , and Br with 1,2,4,5-tetracyanobenzene (TCB), 1,3,5-tricyanobenzene, triazine, and hexafluorobenzene, they proposed three distinct energetically favored complexes as depicted in Fig. 1. Recently, Xu [20] set up a highly accurate extended ONIOM (XO) method based on double-hybrid density functional XYG3/6-311++(d,p) level to understand the anion-π nature in depth. They applied specific systems involving tetraoxacalix[2] arene[2]triazine and four anions including SCN , NO3 , BF4 , and PF6 . With the optimized structures, contribution and strength of anion-π and other non-covalent interactions were systematically analyzed. This novel theoretical method provides new angle on the study of anion-π interactions.

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Representative Experimental Evidences of Anion-p Interactions

At the early stage after the theoretical predictions on anion-π interactions, many endeavors have been made to exemplify such non-covalent interaction from experiment. Here we gave some representative examples that have single crystal structures to definitely support anion-π interaction. In 2004, Meyer and coworkers prepared copper (II) chloride complexes with hexakis(pyridine-2-yl)-[1,3,5]-triazine-2,4,6triamine as ligand (Fig. 2a) [21]. In the single crystal structure, the complex contains chloride (Cl ) and [CuCl4]2 as counteranions. The most interesting feature of the complex is chloride (Cl8) resides above one of the triazine rings. The distance between the centroid of the ring and chloride is 3.17 Å, and the angle of Cl


centroid axis to the plane of ring is 87 . The two structural features are highly in line with the theoretical prediction of typical anion-π interaction. In the same year, Reedijk et al. [22] provided a Cu (II) complex structure describing the interaction between pyridine and chloride using a pyridine- and triazine-containing ligand. In this report the encapsulation of one chloride anion by four pyridine rings was demonstrated as a result of possible anion-π interaction between them (Fig. 2b). Despite the fact that anion-π could be found in many metal coordination complexes, the main argument lies in that it is difficult to distinguish the contribution between anion-π interaction and intrinsic Coulombic interaction. In this context, electron-deficient charge-neutral organic molecules could provide ideal platform to elucidate and probe the contribution of anion-π interactions. However, this is a rather challenging task. Only limited examples demonstrating unambiguously anion-π interactions can be found in literature till now. In 2004, Kochi and coworkers [23] reported their study of the interaction between anions and a series of neutral organic π receptors including tetracyanobenzene (TCB), 1,3,5-trinitrobenzene (TNB), 2,3,5,6-tetracyanopyrazine (TCP), 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (p-CA),

Fig. 2 Crystal structure of anion-π interactions in coordination systems by (a) Meyer and coworkers and (b) Reedijk and coworkers

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3,4,5,6-tetrachlorocyclohexa-3,5-diene-1,2-dione (o-CA), and 1,1,2,2-tetracyanoethene (TCNE). From the crystal structure of the complexes formed with halides and TCP (Fig. 3), for example, halides are found to shortly contact with carbon atom of the π receptors, giving X


C distances in the range of 2.93–3.49 Å. These structures indicated the formation of weak σ-type rather than typical anion-π interaction. Spectral and thermodynamic study revealed the charge-transfer origin between the donor and acceptor in the complex. Similar binding modes of TCB and Br , I , respectively, were also demonstrated by Hay and coworkers in 2007 [19]. In the complexes that four TCB molecules contacted each anion, three distinct orientations, i.e., above the arene plane nearest to a carbon bearing a CN group, above the arene plane nearest to a carbon bearing a hydrogen atom, and nearly within the plane of the arene contacting a C-H hydrogen atom, were observed. Typical non-covalent anion-π interaction was firstly reported by us in 2008 [24]. The study was based on a tetraoxacalix[2]arene[2]triazine molecule 1, a unique molecule bearing a V-shaped cleft formed with two electron-deficient triazine rings and halides. As unveiled by the X-ray crystallography (Fig. 4), 1 formed ternary complex with one halide anion and a water molecule. The included chloride or bromide located almost over the center of one of the triazine rings, with a vertical distance to triazine plane being 3.218–3.247 Å (dCl-plane) or 3.273–3.348 Å (dBr-plane), respectively. The short distance of halide to the triazine centroid indicated convincingly a typical non-covalent anion-π interaction. Concurrently, the water molecule, which was hydrogen bonded to halide, forms H2O


π (lone-pair electron-π interaction). Later in 2013, we [25] demonstrated the generality of anion-π Fig. 3 Weak σ-type interaction between TCP and chloride demonstrated by Kochi and coworkers

Fig. 4 Complexation of tetraoxacalix[2]arene[2]triazine 1 with Cl and Br through typical anionπ interactions

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interactions with the same host and anions of varied geometry including linear thiocyanate (SCN ), triangular nitrate (NO3 ), tetrahedral tetrafluoroborate (BF4 ), and octahedral hexafluorophosphate (PF6 ). The complexations as revealed by X-ray crystallography showed clearly that anions despite their various geometries form 1:1 complexes with 1. Typical anion-π interaction was ubiquitously observed in all complexes; besides, concurrent σ-type interaction was also found depending on the specific geometry of the anion (e.g., in [1
NO3] complex) (Fig. 5). We have also applied a conformationally rigid cage molecule bis(tetraoxacalix [2]arene[2]triazine) 2 containing three identical electron-deficient V-shaped clefts to demonstrate various halide-π geometry [26]. In the complex of 2 with chloride (Fig. 6), chloride (Cl2) was situated above the carbon atom of triazine ring with chloride-carbon distance (dCl(2)–C(2)) being 3.342 Å, indicating a weak σ-type interaction (C


Cl ). To complex bromide, however, host 2 self-regulated its structure yielding three V-shaped clefts of different sizes; each cavity provided different bromide-π interactions. In the smallest cleft, bromide (Br2) anion formed close contact with one of the triazine rings forming typical anion-π interaction (dBr2-triazine = 3.429 Å). In the largest cleft, however, a bromide and water were included within the cavity through concurrent anion-π (dBr1-triazine = 3.516 Å) and lpe-π (dO4-triazine = 2.892 Å) interactions. In 2013, Stoddart and coworkers [27] reported the anion-π interaction between a NDI-containing triangular cage molecule 3 and linear I3 anion. The solid-state complex structure revealed I3 anion almost completely fills up the tube-shaped cavity of the triangular molecular prism (Fig. 7).

Fig. 5 Anion-π complexes formed with tetraoxacalix[2]arene[2]triazine 1 and (a) SCN , (b) NO3 , (c) BF4 , and (d) PF6

Fig. 6 Different types of anion-π interaction formed with 2 and chloride and bromide

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Fig. 7 Anion-π interaction between a NDI-containing triangular cage and I3 anion by Stoddart and coworkers

Fig. 8 Anion-π interactions between corona[3]arene[3]tetrazine 4 and chlorides by Wang and coworkers

Tetrazine as an amusing π-receptor has been incorporated into a novel type of macrocyclic host molecules named coronarenes by Wang and coworkers [28]. The existence of tetrazine component in the macrocyclic backbone rendered the molecules electron-deficient property. As a representative example, O6-corona[3]arene[3] tetrazine formed a 1:3 complex with Et4NCl in solid state. Each of the three chlorides in the complex located above each tetrazine centroid at a distance of 3.06–3.20 Å, forming typical anion-π interactions (Fig. 8). It is also worth noting that anion-π interactions were detected as modulations of stronger non-covalent interactions such as hydrogen bonding [29, 30] and ion-dipole interaction [31]. Albrecht and coworkers reported the binding of pentafluorobenzamide toward bromide through cooperative H-bonding and anion-π interaction [29]. Single crystal structure demonstrated that bromide located above the plane of pentafluorobenzene ring and concurrently formed hydrogen bonding

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I1 I2 H9A

H9B

O1

O9 C22 O5

N7 Ca1 O6

O8 O7

Fig. 9 Crystal structure of the solvent-separated ion-pair complex between 5 and CaI2

with amide. On the other hand, Ballester and coworkers [30] used “two-wall” aryl-extended calix[4]pyrrole as model system and studied the thermodynamic characterization of halide-π interaction in solution. The solid-state structures of the inclusion complexes revealed that chloride was not located directly perpendicular to the centroid of the phenyl rings but somewhat offset. Very recently, with a rational designed tritopic ion-pair receptor 5 [31], we demonstrated an unusual solvent-separated ion-pair complex with CaI2. Single crystal structure revealed that the two iodides, respectively, were stabilized by each triazine ring through anion-π interactions (dI1-plane = 3.621 Å, dI2-plane = 3.649 Å), while the calcium ion (Ca1) was bound by four oxygen sites of the pentaethylene glycol chain, two axial water molecules, and one acetonitrile molecule. The two iodides and calcium ion resided in a triangular array, with the water molecule (O9) nearly occupying the center position and separating the iodidecalcium ion pairs through two H-bonds. Such array is distinctively different from the regular octahedral lattice of CaI2, demonstrating the stabilization contribution from both the cation and anion binding sites within the receptor (Fig. 9). In another work, we reported a significant conformational control of oxacalix[3]arene[3]triazine macrocycle with anion-π interactions [32]. In solid state, the macrocycle showed relatively flexible conformation, giving a tighten-waist 1,3,5-alternate conformation. After complexation with halides through anion-π interactions, the macrocyclic backbone underwent dramatical conformation changes. For complexation with chloride, a pyramidal conformation was resulted, whereas a C3-symmetric 1,3,5alternate conformation was observed for complex with bromide.

10.4

Anion-Templated Self-Assembly

In most anion-π-related coordination complexations, anions act mainly as counterions to compensate the positive charge; anion-π therefore slightly affects the assembly structure. Remarkably, Dunbar and coworkers reported comprehensive investigation of anion-templated self-assemblies, where anion-π plays important

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roles in controlling the assembly structures [33–36]. In 2005 they performed a reaction of first-row transition metal ions with bis-bipyridine ligand (bptz) in the presence of specific anions [33]. Cyclic structures were obtained with Ni(II), Zn(II), and Fe (II) as revealed by X-ray crystallography. The decisive roles of anions in the formation of a particular cyclic structure were carefully discussed. Interestingly, among the different anions encapsulated inside the metallacages, small anions such as BF4 and ClO4 led to molecular squares, whereas the larger anion SbF6 favored pentagon structure (Fig. 10). Alternatively, the reaction of [Ni(CH3CN)6] [NO3]2 with bptz in a 1:1 ratio produced probably a triangular structure as supported by MS and IR. It was found that treating the pentagon sample with an excess of BF4 or ClO4 anion led to the complete conversion of pentagon to square. The reverse transformation, however, needs forcing conditions such as a large excess of SbF6 , reflux, and long reaction time, and then a partial transformation of the square to the pentagon took place. Careful examination of the relevant structural parameters suggested by the authors that cyclic structures may be stabilized by anion-π interactions as judged from the short distances between centroids of tetrazine rings with the O/F atoms of the encapsulated anions. A more comprehensive investigation of anion-π interactions was later performed by the same group [34]. They combined crystallographic and computational methods that systematically studied the roles of anion-π interactions in Ag(I) complexes with tetrazine-containing bptz or pyridazine-containing bppn ligands, respectively. The theoretical optimizations revealed the central ring of bptz (tetrazine) shows higher electropositive character than that of bppn (pyridazine). They found the higher π-acidity of tetrazine renders bptz amenable to anion-π rather than π-π interactions. In all the Ag(I)-bptz complexes, anion-π interactions were generally observed. The different anion-π details corresponding to

Fig. 10 Structure of anion-templated complexes and their scheme of interconversion by Dunbar and coworkers

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different anions determined the resulting assemblies as polymer, planar dinuclear, or propeller-type dinuclear structures. Whereas the Ag(I)-bppn complexes gave rise to grid-type structures regardless of the anion, which is attributed to the electron-rich πligand favors the maximized π-π stacking at the expense of anion-π interactions. Taking the Fe(II) metallacycles as examples, Dunbar and coworkers [35, 36] applied 19 F NMR spectroscopy to provide evidence that anion-π interactions are the main driving force in the templating process leading to particular structures in solution. Whereas random Fe(II)/bytz oligomers were formed in the presence of nontemplating anions such as CF3SO3 , closed polygons were favored in the presence of templating anions including BF4 , AsF6 , and SbF6 . At elevated temperature, the considerable broadening 19F NMR resonance indicated rapid exchange of the encapsulated anions with free species, while lowering the temperature led to broadening of 19F NMR resonance of polygons, and a second distinct 19F NMR resonance corroborating the presence of encapsulated anions occurred. From the low activation energy determined, the authors concluded that anions acted as templates rather than merely diffusing into preformed cages. In another report by Choi et al. [37], they set up mechanochemical reactions of 3,6-dimethoxy-s-tetrazine (dmotz) with AgCF3SO3 and AgClO4. Different structures such as 1D linear polymer ([Ag(dmotz)(CF3SO3)]n) or 2D grid polymer ([Ag (dmotz)2(ClO4)]n) were obtained depending on the specific anions applied. Intermolecular anion-π interactions between tetrazine ring and CF3SO3 , for example, led to the tightening of 1D linear chains, whereas ClO4 was surrounded with four tetrazine rings which provided the 2D structure.

10.5

Self-Assembly with Anion as Primary Building Blocks

As the main challenge in anion-templated self-assemblies (vide supra) is that it is difficult to distinguish the contribution of anion-π and coordination interactions, using charge-neutral π receptor as one building component to probe anion-π-directed assembly is therefore particularly intriguing. However, due to the flexible directionality of anion-π non-covalent bond, this task is very challenging, and the early examples that appeared in literature were mainly observed in crystal structures. The rational design of anion-π-controlled self-assembly based on charge-neutral building blocks emerged until very recently.

10.5.1 Self-Assembly with Electron-Deficient Arenes In 2008, Kochi et al. [38] examined the behavior of a series of planar π-acids toward various types of polyatomic anions by means of crystallography. They demonstrated from about 20 crystal structures that similar repeating anion/π-acid arrangement consisting of a vertical one-dimensional (1D) stack of π-acid alternatively interspersed with the π-bonded anions (Fig. 11). Anions interacted with the carbon atom of π-acid molecule forming the so-called σ-type interaction. The location of anions

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Fig. 11 Linear 1D molecule “wire” formed with TCP and tetrabutylammonium thiocyanate by Kochi and coworkers, (a) anion/π-acid chain without TBA+, and (b) with the protecting sheath of TBA+

over the π-acid showed subtly different details depending on the specific geometry of anions. Consequently, the atom-to-atom distances for the σ-type interactions were in the range of 2.79–3.45 for different anionic species. Every π-acid molecule is precisely arrayed with specific dihedral angles (plane to plane). A 3:2 (anion to π-acid) ratio was regarded as the repeated unit to lead to indefinite 1D molecular “wire” (


D A D A D A


). Another character of the self-assembly is π-acid/ anion wire is surrounded by the sheath of countercations (e.g., TBA+) and then was isolated from its neighboring 1D wire. By means of UV-vis spectroscopy, the authors investigated the charge transfer (CT) between π-acid molecules and anions, and they believed CT plays critical roles on the linear 1D molecular arrays. In 2010, Dunbar and coworkers [12] reported 1D vertical chain self-assembly with a strong π-acidic arene hexaazatriphenylene-hexacarbonitrile (HAT(CN)6) and anionic halides as building units. The cocrystallization of HAT(CN)6 with [n-Bu4N]+X (X = I , Br ) afforded isostructural analogs {([n-Bu4N][X])3[HAT (CN)6]2}
3 C6H6. From these structures, infinite chains {[HAT (CN)6]2X3}3


X


{[HAT(CN)6]2X3}3


X


{[HAT(CN)6]2X3}3 consisting of layers ABCD as the repeated units were formed. Two types of anionHAT(CN)6 interactions were revealed from the ABCD entity. One X (X = I , Br ) showed short contact with the centroid of HAT(CN)6 (layer C and D), giving anioncentroid distances shorter than the sum of van der Waals radius, which is in line with

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Fig. 12 1D vertical chain self-assembly between HAT(CN)6 and halide by Dunbar and coworkers

typical anion-π interaction. Furthermore, each of the three equivalent X is located over the periphery of HAT(CN)6 (layer A–C), forming σ-type interactions in an η2,η3 fashion (Fig. 12).

10.5.2 Self-Assembly with Macrocyclic Molecules To address the challenge on rationally designing self-assembly motifs directed by anion-π interaction, we envisioned that tetraoxacalix[2]arene[2]triazine backbone could serve as an ideal building unit. The 1,3-alternate macrocyclic backbone bears a V-shaped cavity formed with two convergent electron-deficient triazines. We have shown that the V-shaped cavity is able to include a variety of anions through anion-π interactions [24, 25]. The bridging oxygen atoms endow the cavity with fine-tunable properties and allow the best fit of a given anion, thus leading to a good control on the interaction directionality. In 2010 [26], we reported the two-dimensional self-assembly with bis(tetraoxacalix[2]arene[2]triazine) 2 and halide anions X (X = Cl , Br ) interacting entities. Slow evaporation of the solvent from mixture of 2 and tetraethylammonium halides at room temperature afforded complexes of [2-(Et4NCl)3-(H2O)3] and [2-(Et4NBr)2-H2O], respectively. Different self-assembly structures were observed depending on the type of halides involved. In the case of [2-(Et4NCl)3-(H2O)3] complex, the organic building block remained as D3h symmetry and therefore gives three identical V-shaped cavities. Each V-shaped cleft accommodated one chloride anion through weak σ-type interaction (vide supra) and one H2O molecule through lone-pair electron-π interaction, and the two included species were hydrogen bonded to each other. Then the hydrogen-bonded chloride-water pair in each V-shaped cleft interacted with other pair of chloride-water that belongs to other complex entity, forming a hydrogen bonding network. Six cage-anion-water entities cyclized into a repeat unit, affording to a two-dimensional honeycomb-like self-assembly (Fig. 13a). In the case of complex [2-(Et4NBr)2-H2O], the demand

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for versatile bromide-π interactions led to a significant conformation change of the cage molecule, producing three V-shaped clefts of different sizes (vide supra). Multiple non-covalent interactions including bromide-π, lpe-π, and hydrogen bond led to capsule-like structure as repeat units, affording infinite two-dimensional selfassembly (Fig. 13b). To further take advantage of the chloride-π interaction to induce self-assembly, we designed phenoxy-substituted tetraoxacalix[2]arene[2]triazine building block 6 and investigated the self-assembly with chloride [39]. In the absence of chloride, the building block itself showed unique self-assembly. For example, one triazine nitrogen of one molecule 6 formed lone-pair electron-π interaction with the triazine of another molecule. In addition, weak intermolecular hydrogen bonds between hydrogen bond acceptor such as triazine nitrogen, bridging oxygen, and aryl hydrogens were also observed. Directed by the multiple weak non-covalent interactions, 6 formed a cyclic hexamer structure in solid state. In the presence of chloride, the cyclic hexamer self-assembly of building block 6 was disrupted and transformed into a rectangular cage structure. The driving forces for this transformation were revealed. Chloride-π interaction (dchloride-plane = 3.238 Å), water-π (lone-pair electron-π), and chloride-water hydrogen bond facilitated the formation of ternary complex. Two ternary complexes provided a rectangular cage structure with the help of hydrogen bond network between chloride and water and π-π stacking between two face-to-face arrayed benzene rings (Fig. 14). In our another work, we designed organic building block by introducing hydroxyl substituents on the larger rim of tetraoxacalix[2]arene[2]triazine 7 and studied its self-assembly with anions [40]. The hydroxyl group served as lone-pair electrons and hydrogen bond donor instead of the aforementioned water molecule to form host-halide-hydroxyl ternary complex. As hydroxyl is covalently attached on the building block, such ternary complex led to an infinite linear self-assembly (Fig. 15).

Fig. 13 (a) Honeycomb-like self-assembly formed with cage molecule 2 and chloride and (b) twodimensional self-assembly formed with cage molecule 2 and bromide

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Fig. 14 Chloride-induced self-assembly transformation from cyclic hexamer to rectangular cage structure through anion-π non-covalent interactions

Fig. 15 Infinite self-assembly formed with hydroxyl-substituted tetraoxacalix[2]arene[2]triazine 7 and anions, (a) chloride, (b) nitrate

In 2017, we designed [41] a series of tetraoxacalix[2]arene[2]triazines 8 bearing different anionic heads such as carboxylate, sulfonate, sulfate, and phosphate. These molecules served as dual building units with the V-shaped electron-deficient cavity as anion binding site, whereas the anionic head as the “guest.” With this rational design, anion-π self-assembly was firstly investigated in solution. It is worth noting that when anion-π interaction between anion and triazine rings occurs, the low-rim hydrogen atom (e.g., H1, H2, toward the cavity) can be forced to participate the anion binding via weak hydrogen bonding, which enables the monitoring of self-assembly behavior with NMR technique.

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From the recorded 1H NMR spectra of 8 at variable concentrations, H1 and H2 did downfield shift gradually upon concentration increase, while other proton signals almost remained intact. This suggested intermolecular interaction would occur with the anionic head being included within the V-shaped cavity of another molecule through weak hydrogen bonding along with the dominant anion-π interaction. The assembly behavior was further confirmed by variable temperature (VT) 1H NMR where upfield shift of H1 and H2 was observed from 25  C to 75  C, in line with disfavored assembly (disassembly) at elevated temperature (Fig. 16). The supramolecular aggregation was further investigated by diffusion-ordered NMR spectroscopy (DOSY) and dynamic light scattering (DLS). As expected, in all the cases for the dual building blocks, diffusion coefficient gradually decreased upon concentration increase. On the other hand, the hydrodynamic radius of aggregates as determined by DLS gradually increased upon increasing sample concentration. Both techniques indicated larger and larger assembly formation during the self-assembling course. The aggregation was further evidenced by electrospray ionization mass spectrometry (ESI-MS), from which monomeric, dimeric, and trimeric peaks were observed. In solid state, single crystal structures gave detailed insight of the intermolecular self-assemblies. For the three compounds bearing carboxylate, sulfonate, and sulfate, the anionic head was included within the V-shaped cavity of another adjacent molecule through anion-π interaction along with weak hydrogen bonding. As such, 1D chain-like assembly was formed with the shape of the chain

Fig. 16 Dual building blocks 8 (a), self-assembly of 8b in solution studied by 1H NMR spectra of variable concentration (b), variable temperature (VT) (c), and DLS results (d)

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being affected by the specific anionic head involved (Fig. 17). When flexible linkers were introduced in between the benzene ring of the macrocycle and carboxylate head (9), the ability to form self-assembly was diminished due to the increased flexibility of anionic head and was dependent on the linkers applied. The existence of oxygen leads to linker being more flexible, which is unfavorable to the intermolecular complexation [42]. Very recently, self-assembly between bisoxacalix[2]arene[2]triazines 10–13 (Fig. 18), in which two macrocyclic motifs are linked at their larger rim, and naphthalene-1,5-disulfonate dianion was investigated. The anion-π-driven selfassembling processes were systematically studied by means of 1H NMR spectra and DLS in solution, combination of SEM, TEM, and AFM on surface [43]. While both concentration-variable 1H NMR and VT 1H NMR of an equimolar host-guest mixture supported progressive formation and disassembly of the oligomeric species, DLS measurements gave evidence of larger species formation. In DLS, peaks corresponding to the oligomeric species at small size and very large aggregates (average size of 735 nm) were observed. Remarkably, after extensive supersonic of the concentrated solutions at different host-guest ratios ([host] = 20 mM), significant Tyndall effect was observed under the irradiation of laser beam, supporting the formation of colloidal aggregates as observed by DLS. The morphology of the host-guest self-assembly was revealed by SEM, TEM, and AFM techniques.

Fig. 17 1D chain-like structures of dual building blocks (a) 8a, (b) 8b, and (c) 8c in solid state

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Fig. 18 Bisoxacalix[2]arene[2]triazines as dual building units of anion-π self-assembly

Fig. 19 Self-assembly of 11 in the absence (a) and presence (b) of naphthalene-1,5-disulfonate

Surprisingly, coherent particles were formed in the presence of an excess of 11–13, as confirmed by SEM, TEM, and AFM images (Fig. 19). To probe the contribution of anion-π interaction, energy dispersion spectroscopy (SEM-EDS) analysis was carried out, and peak for element S from naphthalene-1,5-disulfonate was also clearly observed. Particularly, the intensity analysis suggested that the S component was mainly concentrated in the joint parts of the coherent particles. On the other hand, experiments with naphthalene-1,5-disulfonic acid and naphthalene-1sulfonate as control compounds did not give the as-mentioned coherent particles, demonstrating the essential role of anion-π interaction in self-assembly formation. Diverse self-assembling structures afforded with interaction between corona[4] arene[2]tetrazine 14 and anions of different geometries were demonstrated by Wang and coworkers [44]. In solid state, 14 formed complexes with various anions

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including spherical Cl , Br and I , linear SCN , planar triangular NO3 , tetrahedral BF4 and ClO4 , and organic anion naphthalene-1,5-disulfonate. All complexes involved typical anion-π interactions between anion and tetrazine moiety with only the exception of complexation with nitrate in which anion interacted with tetrazine through σ-type interactions. Most anions were sandwiched by two tetrazine rings from two macrocycles. Depending on the nature of anions, and due to the effect of different non-covalent bonds between anions and coronarenes, varied self-assemblies were generated. For example, Cl , Br , I , SCN , and ClO4 induced the host-guest to one-dimensional chain-like structure, while the presence of BF4 afforded an interesting ladderlike self-assembly. Different to the organic anions, the organic anion naphthalene-1,5-disulfonate appeared to be encapsulated by two coronarene molecules, each complexed capsule assembled into a linear structure through DMSO solvent which associated with other tetrazine ring of coronarene via a lone-pair electron-π interaction (Fig. 20).

Fig. 20 Self-assembly of 14 with bromide (left) and tetrafluoroborate (right) by Wang and coworkers

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10.6

271

Self-Assembly with Anions as Secondary Building Blocks

Taking tetraoxacalix[2]arene[2]triazine as a functionalization platform, we designed a series of amphiphilic molecules by introducing long alkyl chains on the larger rims [45]. These amphiphilic molecules self-assembled into stable vesicles in a mixture of THF and water, with the surface of the vesicles engineered by electron-deficient cavities. When anions including NO3 , F , Cl , Br , BF4 , SCN , and ClO4 were allowed to interact with the vesicles and monitored with DLS, the size of selfassembled vesicles were selectively influenced, giving a selectivity of F < ClO4 < SCN < BF4 < Br < Cl < NO3 . As the effect of anions on vesicles is almost in agreement with the order of binding constants at molecular level, it indicates that anion-π interaction most probably competed over other possible weak interactions and accounts for this interesting selectivity. Upon the affinity of vesicular surface to anions, the change of the surface zeta (ζ) potential of the vesicles might contribute to the enlargement of vesicles. Later we designed macrocyclic amphiphiles bearing different hydrophilic substituent groups on the larger rim of the triazine rings, in order to explore the self-assemblies of amphiphilic molecules and to probe the responses of vesicles toward anions in water [46]. The nature of substituents showed significant effect on the self-assembly, only substituents with proper hydrophilicity and length could form vesicles. Vesicular surfaceanion study confirmed the function of anion-π interaction and enhanced regulation as a result of cooperative anion-π and hydrogen bonding. Very recently, we further modified the macrocyclic amphiphiles by introducing L-prolinol on triazines [47]. The resulting vesicles formed with this amphiphiles are decorated by chiral cavities on the surface and show selective response to chiral anions including (2S, 3S)-2,3dihydroxysuccinate (D-tartrate), S-mandelate, and S-(+)-camphorsulfonate against their respective enantiomers. DFT calculations revealed that the enantioselectivity stemmed from cooperative anion-π interactions and hydrogen bonding between the chiral electron-deficient cavity and the organic anions. In 2015, we reported an example of anion-π-controlled self-assembly and disassembly [48]. The idea was established on the interaction between tetraoxacalix[2] arene[2]triazine as host molecule and anionic surfactants including sodium dodecyl sulfate (SDS), sodium laurate (SLA), and sodium methyl dodecylphosphonate (SDP) as the guest species. 1:1 mixture of the host-guest solution was quickly injected in water to afford an aqueous solution with final concentration being 6  10 4 M. After vortexing for 1 min, the solution produced an opalescent colloidal solution, indicating the formation of self-assembled aggregates. Very low critical aggregation concentrations (CAC) in the range of 5.0–7.5  10 6 M were obtained. The vesicular morphology of the aggregates was revealed with SEM, TEM, and XRD techniques. To get more insights on the formation of vesicles, SEM-EDS analysis was set up to reveal the building units of the vesicles. Element peaks corresponding to host and guest were observed, indicating both components contributed to the formation of the vesicles. The anion-π interaction between host and guest was supported by means of HRMS, single crystal structure, and DFT calculation. In other words, host and anionic surfactant formed supramolecular amphiphilic

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Fig. 21 Anion-π-controlled self-assembly and disassembly

complexes through anion-π interactions. Such complex as secondary building blocks self-assembled into vesicles with the help of cooperative hydrophobic effect of the long alkyl chains. The controlled disassembly of the vesicles under different conditions was revealed. For example, the presence of other competing anions showing stronger interaction with host molecule such as NO3 , Br , or Cl would disrupt the anion-π binding and lead to disassembly of the vesicles to irregular morphologies. Alternatively, the controllable disassembly of the vesicles under decreased pH values was realized by a drug release experiment. A drug doxorubicin was encapsulated into the vesicles, then the vesicles were allowed to various extravesicular pH values, and the fluorescent intensity of the encapsulated DOX was monitored. The increased fluorescent intensity with the decrease of pH values indicated the release of DOX, as the protonation of the anionic head of surfactant could weaken the anion-π interaction between host and guest and thus led to the concomitant disassembly of the vesicles (Fig. 21). In 2017, Tang et al. reported an anion-π+-assisted aggregation-induced emission (AIE) system [49]. They constructed AIE-active building blocks of 1,2,3,4-tetraphenyloxazolium (TPO-P) and 2,3,5-triphenyloxazolium (TriPO-PN) with inherent positive charge. Strong emission of TPO-P and TriPO-PN in the solid state was observed, which was attributed to anion-π+ interactions that prevent the formation of π-π stacking between two building blocks. In contrast, their charge-neutral analogue did not show AIE effect as a result of aggregation-caused quenching (ACQ).

10.7

Conclusions

As a new type of recognized non-covalent interactions, anion-π interactions as driving force in self-assembly is still in its infancy in comparison with the energetically compatible non-covalent interactions such as hydrogen and halogen bond. The flexible directionality in anion-π interaction is probably the main obstacle. However, the representative findings in this field highlighted herein the fact that anion-π interaction can be important driving force in self-assembly. On one hand, in metal coordination systems, anion-π as additive interaction was responsible for template

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effect to afford specific metallacycles. More significantly, anion-π interactions showed ability to drive charge-neutral building blocks and anions into various self-assemblies. With rational designed organic building blocks, the strength and directionality of anion-π interactions could be enhanced; this and along with the intriguing reversibility and easy regulation endow it a promising driving force in rational designed and functional self-assembly.

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Functional Rotaxanes From Synthetic Methodology to Functional Molecular Materials

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Cai-Xin Zhao, Qi Zhang, Gábor London, and Da-Hui Qu

Contents 11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 Synthetic Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2.1 [2]rotaxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2.2 [1]rotaxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2.3 Daisy Chains and Poly[n]daisy Chain-Based Rotaxane Muscles . . . . . . . . . . . . . 11.2.4 Hetero[n]rotaxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3 Functionalization of Rotaxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3.1 Rotaxane-Based Fluorescent Molecular Switches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3.2 Artificial Rotaxane-Type Switchable Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3.3 Artificial Molecular Production Line . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3.4 Artificial Molecular Pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.4 Rotaxane-Based Functional Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.4.1 Rotaxane Molecular Switches on Surfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.4.2 Controlled Drug Release System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.4.3 Self-Healing Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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C.-X. Zhao · Q. Zhang · D.-H. Qu (*) Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai, China e-mail: [email protected]; [email protected]; [email protected] G. London Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok kürútja 2., Budapest 1117, Hungary e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_12

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Introduction

Artificial molecular machines have attracted considerable attention from synthetic chemists due to their unique ability to mimic many aspects of biological phenomena [1]. Rotaxanes, consisting of one or more macrocycles and an encircled dumbbelllike thread component, have been extensively studied and developed and thus became one of the major classes of artificial molecular machines [2]. Since the first [2]rotaxane was reported in the 1990s [2a], the structural complexity of rotaxanes has increased rapidly along with the development of synthetic methodology and host-guest chemistry [3]. Various rotaxanes have been designed and constructed based on versatile macrocycles, such as cyclodextrins [2b, 4], cucurbit [n]uril [5], crown ethers [2c, 6], pillarenes [7], cyclophanes [8], and benzylic amide macrocycles [9]. Recently, some novel types of rotaxanes, such as [1]rotaxane [10], daisy chain [11], and hetero[n]rotaxane [12], are rising and being developed extensively due to their peculiar structure and unique molecular motion. Consequently, the development of novel synthetic methodology is crucial for the further advancement of these new classes of rotaxanes. Their stimuli-responsive nature is one of the most attractive features of rotaxanes, which makes them capable of producing molecular-scale motion upon external stimuli [2f] including pH [2c, 11b, c], redox [8, 11h], light [3d, 4a–c, 11a], and microenvironmental changes [7, 11i]. The motion is mostly driven by the relative difference in binding constants between the recognition stations and the macrocycles: the macrocycles tend to be close to the stations with higher binding constants; and dynamic shuttling motion would occur when two or more stations are recognized by the macrocycles with comparable binding strength [13]. Rotaxanes can be developed into effective and versatile molecular switches only if reversibility can be combined with their stimuli-responsive behavior [14]. Considering the nature of the output signal, functional molecular switches based on the typical [2]rotaxane framework have been designed and fabricated to modulate physical properties [15], such as fluorescence change [15c] or wettability [15b], and chemical properties, such as catalytic activity [15d]. Hence, we can call rotaxanes as “versatile” species within the family of artificial molecular machines. Although functional switches have been constructed based on [n]rotaxane systems, most of the reported examples operate in solution. This facilitates their characterization, however, limiting potential applications of rotaxanes due to the difficulty of controlling dissolved material in many practical aspects [2f]. Inspired by the transition of life on earth from sea to land, with the transition of rotaxanes from solution (sea) to solid surfaces/interfaces (land), the emergence of new properties is expected to form the basis of new functional materials [16]. However, new and challenging problems are in the way of this “evolution”: the development of reliable covalent/noncovalent interactions to bind the organic rotaxane component to the inorganic platform, the unexpected changes in the working manner of immobilized rotaxanes [17], and the difficulties in detecting single-molecular motion in a solid sample.

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Nevertheless, some groups have successfully constructed functional systems of rotaxanes immobilized on surfaces [18], interfaces [19], and even in a porous organic framework [20]. These elegant hybrid systems were able to perform useful tasks, such as controlled drug release [21], fluorescent sensing [22], and represented novel examples of smart surfaces [23] and self-healing materials [24], pointing toward promising and exciting perspectives for the materials applications of immobilized rotaxanes. In this chapter, we are focusing on the three major transition steps of the evolution of rotaxanes from their components into functional hybrid materials (Scheme 1): (i) synthetic methodology of rotaxanes, including the typical [2]rotaxane, and the newly emerged [1]rotaxane, [c2]daisy chain and hetero[n]rotaxane structures; (ii) following the effective and facile synthesis of a “bare” rotaxane A, functional rotaxane B is obtained by appropriate modification of the structure. The introduction of functional groups provides rotaxane B with functions such as distance-dependent electron/energy transfer on the single-molecular level; and (iii) functional rotaxane B can be immobilized onto a solid surface/interface to obtain hybrid material C via effective covalent/noncovalent interactions. We might call C as a functional material when the immobilized functional rotaxane B works effectively on the solid surface/interface. Both the structural design and functionalization are within the scope of this chapter, and strategies to achieve diversity in the functionalization of rotaxanes are highlighted as well. This summary is expected to serve as a guideline for the design and construction of functional rotaxanes and further advance the “evolution” of rotaxanes.

11.2

Synthetic Methodology

In this section, synthetic methodologies to assemble different types of rotaxanes are summarized. Typical synthesis approaches to [2]rotaxane are demonstrated first, which have been well studied and developed the most intensively. Furthermore,

Scheme 1 The three transition steps in the evolution of a rotaxane from its components to a functional hybrid material: (i) synthetic methodology to synthesize rotaxane effectively, (ii) functionalization with functional group to obtain functional rotaxanes in solutions, and (iii) immobilization on a surface to obtain functional materials

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the synthesis of some newly rising rotaxanes, such as [1]rotaxane, [c2]daisy chain, poly[n]daisy chain molecular muscle, and hetero[n]rotaxane, will be discussed. Since the late 1980s, the development of supramolecular chemistry, especially macrocycle-based host-guest chemistry, provided a deep understanding of various noncovalent intermolecular interactions and thus accelerated the development of the so-called “template-directed” strategy as a general synthetic methodology of rotaxanes [25]. Some templates, such as metal-ligand templates, hydrogen-bonding templates, donor-acceptor templates, active metal templates, and radical templates [8a, 25c], have been proved to be very effective in the facile fabrication of rotaxanes.

11.2.1 [2]rotaxanes [2]rotaxane, consisting of a macrocycle component and a thread with two stoppers at both ends, is commonly considered as the most typical and representative example of rotaxanes. Generally, the typical synthetic methodologies of [2]rotaxanes include capping, snapping, clipping, and slipping as shown in Fig. 1 [2f, h–i]. The capping method (Fig. 1 (i)) involves the noncovalent pre-self-assembly of a macrocycle and a thread to form a pseudorotaxane intermediate, and the subsequent covalent bonding with the two stoppers. Obviously, the pre-assembly process requires reliable templates for effective formation of the pseudorotaxane [25]. Meanwhile, the following covalent bonding process needs a reliable and efficient reaction that occurs selectively in the complex reaction mixture. Fortunately, click chemistry provides a general solution for this issue due to the unique selectivity of click reactions. Click type reactions have proved to be advantageous in the construction of rotaxanes [26]. Similarly to the capping method, snapping involves the pre-assembly of semi[2] rotaxane and covalent bonding with a stopper (Fig. 1 (ii)). As the macrocycle component is pre-synthesized in both methods, capping and snapping are especially suitable for the synthesis of [2]rotaxanes based on cyclodextrins, cucurbit[n]urils, and other macrocycles whose syntheses and modifications are not straightforward. Furthermore, capping is more favored for the construction of symmetrical [2] rotaxanes, while snapping is suitable to fabricate unsymmetrical [2]rotaxanes. Clipping (Fig. 1 (iii)) and slipping (Fig. 1 (iv)) methods are both involve the Fig. 1 Typical synthetic methodologies of [2] rotaxanes: (i) capping, (ii) snapping, (iii) clipping, (iv) slipping

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dumbbell-like thread component. The former uses the dumbbell-like thread as the template for the synthesis of the macrocycle, meaning that the macrocycle is formed around the recognition station on the dumbbell-like thread. In the slipping route, the macrocycle can overcome the blocking barrier and thread into the middle of two stoppers at elevated temperatures [27]. In addition to these typical synthetic approaches, some novel strategies have been developed and employed recently in the construction of [2]rotaxanes, such as threadingfollowed-by-shrinking [28] and threading-followed-by-swelling [29]. These involve the controlled change of the differences in space between the macrocycle component and the stoppers. Such strategies are expected to play a key role in the efficient construction of more diverse rotaxanes and stimulating the development of additional synthetic approaches to advance the evolution of rotaxanes.

11.2.2 [1]rotaxanes In the family of rotaxanes, [1]rotaxane is unique as the macrocycle and thread components are covalently bound in its structure. Compared to [2]rotaxane, [1] rotaxane produces an coupled motion upon an external stimulus, meaning that the motion of the macrocycle would also lead to the motion of the thread part, rather than the independent motion of the macrocycle in a [2]rotaxane. Although achieving stimuli-controlled motion on a single-molecular level seems crucial to operate complex nano-machinery, only a little progress has been made toward the precise control of molecular motion in a [1]rotaxane [30, 31]. [1]rotaxane 1-H containing a ferrocene unit has been reported by our group recently [30b]. As shown in Fig. 2, the synthesis was initiated by the intramolecular pre-assembly of a semi[1]rotaxane via the strong hydrogen-bonding interaction between dibenzo-24-crown-8 (DB24C8) macrocycle and the dibenzylammonium Fig. 2 The synthesis approach to a series of [1](n) rotaxanes developed by our group [30b, 31]. The red macrocycles, blue sites, and purple sites represent DB24C8, DBA sites, and MTA sites, respectively. The yellow rotor moiety represents the ferrocene unit. The gray sites represent the deprotonated DBA sites

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(DBA) station. The stopper unit was attached by a CuAAC click reaction [26] via a triazole linkage resulting in the interlocked [1]rotaxane 1-H. By the N-methylation of the triazole moiety, a secondary recognition station, N-methyltriazolium (MTA), was introduced. Owing to the presence of the MTA station, upon addition of 1 equivalent of diazabicyclo[5.4.0]undec-7-ene (DBU) to deprotonate the DBA station, DB24C8 macrocycle would move toward the MTA station, leading to a contracted [1]rotaxane 1 due to the integrated structure. On the other hand, the addition of excess trifluoroacetic acid (TFA) could initiate the re-protonation process and drive [1]rotaxane 1 back to [1]rotaxane 1-H. For further amplification of the contraction and stretching motion, tri- and tetrabranched [1](n)rotaxanes (n = 3: compound 2-H; n = 4: compound 3-H) were also synthesized via a similar template-directed click reaction [31]. [1]rotaxanes 2-H and 3-H were able to undergo similar acid/base responses as well, and significantly the molecular size upon contraction from 2-H to 2 in acetone solution was calculated to change from 30.7 to 21.9 Å, respectively, while that for the contraction from 3-H to 3 was calculated to change from 30.9 to 22.5 Å, respectively. These percentage changes in size for 2-H and 3-H are 28.7% and 26.9%, respectively, which are both close to the value (27%) observed in the contraction of human muscle [31].

11.2.3 Daisy Chains and Poly[n]daisy Chain-Based Rotaxane Muscles Recently, significant synthetic effort has been focused on the preparation and study of biomimetic systems. Creating and understanding of such systems is crucial, as they could serve as models for biological phenomena and could also lead to the emergence of new properties [32]. Rotaxane-based molecular muscles have the unique capability of mimicking the muscle-like contraction and stretching motion on a single-molecular level [11, 26d]. In this field, [c2]daisy chain type rotaxanes are key structures that are fabricated from the dimerization of AB-type linear monomers containing two self-complementary moieties, A (host) and B (guest). Pioneering work on such systems was reported by the group of Sauvage in 2000, in which the contraction and stretching motion of the individual molecular muscle could be switched reversibly via addition of metal ions [33]. Since then, rotaxane muscles based on versatile macrocycles have been designed and constructed successfully [11]. The available synthetic methods are limited mostly to the template-directed pre-assembly and then stopping route. Importantly, in these systems the distance between the macrocycle and the recognition site should be small enough to prevent the formation of [an]daisy chain polymers as unwanted byproducts [34]. A typical representation of bistable [c2]daisy chain rotaxanes is shown in Fig. 3a. Muscle-like contraction and stretching motion can be achieved upon applying external stimuli (Fig. 3a, A and B) such as light, pH, or redox changes, solvent effect, and metal ion coordination [11g]. The stimuli input can be seen as the energy input for driving the muscles to produce mechanical work. Although the rotaxanebased molecular muscles can perform single-molecular muscle-like motion, obviously, the single-molecular scale is too small to be used to control macroscopic

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Fig. 3 Schematic representation of the stimuli-responsive muscle-like behavior of (a) [c2]daisy chain rotaxane and (b) poly[n]daisy chain; (c) the reported examples of [c2]daisy chain-based polymers using covalent [35a, b] and noncovalent [35c, e, f] strategies for polymerization

distances. Hence, linear polymerization of daisy chain-containing monomers has emerged recently to obtain poly[n]daisy chains [11g, 35]. The linear polymerization is expected to extend the length change of the daisy chain from a single-molecular muscle to macroscopic muscle fibers. As shown in Fig. 3b, in a polymer of daisy chain (the “n” value represents the degree of the polymerization), the length change of the whole linear polymer would be the summation of that of “n” daisy chain

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repetitive units. However, the challenge lies on the suitable polymerization method due to the high structural complexity of daisy chain monomers. Stoddart and co-workers [35a] employed the highly selective click reaction to covalently connect daisy chain monomers (Fig. 3c), realizing the polymerization of rotaxane muscles for the first time. However, the degree of polymerization was not large enough (n = 11 for polymer 4 [35a]; n = 22 for polymer 5 [35b]), which may be due to the formation of cyclic oligomers and low solubility of the formed polymers [11g]. Supramolecular polymerization seems to be a more promising strategy for the amplification of rotaxane muscles. Giuseppone and co-workers were the first who realized supramolecular polymers consisting of thousands of rotaxane muscles (n = 3000 for polymer 6) [35c]. In their system, noncovalent metal ion coordination simultaneously provided good solubility and high affinity for supramolecular polymerization; meanwhile, the improved rigid structure of the daisy chain monomer inhibited the formation of cyclic oligomers. Another example, reported by the same group, is the hierarchical self-assembly of daisy chain monomers via multiple hydrogen-bonding interactions (polymer 7) [35e]. In this case, the hydrogenbonding connected daisy chain linear polymers could be further assembled into fiber-like structures in a larger scale via the self-assembly of alkyl side chains. The obtained muscle-like fibers could be actuated by external acid/base stimuli. Importantly, the contraction and stretching motion of bistable poly[n]daisy chain could be observed under an electron microscope. This work is a significant step toward the construction of artificial muscle fibers by bottom-up approaches, advancing further the amplification of single-molecular motion into the macroscopic world. Recently, our group has reported a self-assembled poly[n]daisy chain system based on the well-known 2-ureido-4-pyrimidinone (Upy) quadruple hydrogenbonding unit (Polymer 8) [35f]. In this work, the photo-initiated formation of poly [n]daisy chain was demonstrated for the first time, involving photo-labile coumarin moieties as protecting groups of the Upy terminals. When protected by the coumarins, Upy-terminated daisy chain monomers could not form polymers even at high concentrations. After removal of the coumarin moieties using UV light irradiation, the exposed Upy units were efficiently assembled the daisy chain monomers into poly[n]daisy chains via their strong hydrogen-bonding interactions. The importance of this work is in the introduction of photo-initiated polymerization, which allows for the remote-controlled assembly of poly[n]daisy chains that could have potential use in biological applications.

11.2.4 Hetero[n]rotaxanes As a platform for the construction of functional molecules, rotaxanes need increasingly complex structure in order to perform multiple and diverse tasks within a single molecule [3]. Construction of hetero[n]rotaxane, a rotaxane with two or more kinds of macrocycles, is a significant route toward advanced rotaxanes with high structural complexity [12, 26c]. The simultaneous introduction of two different types of macrocycles would bring much possibility for multiple steady states in a

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single-molecular system. A recent work reported the unique performance of hetero [4]rotaxane in a novel tuneable solid-state fluorescent material [36], even as a pigment for artwork painting, showing the promise of hetero[n]rotaxanes in diverse applications. Herein, we focus on the synthetic methodology for the formation of hetero[n]rotaxanes, especially the crown ether-based species due to the multiple types of this macrocycle and its wide employment in the construction of rotaxanes. Template-directed pre-self-assembly and then stopping is a reliable route for the construction of rotaxanes [25]. However, in the case of hetero[n]rotaxanes, the presence of two or more different macrocycles increase the number of possible assembly routes, which ultimately results in a nonselective formation of a mixture of products. Hence, a “programmed” advanced self-assembly route should be developed and employed for the selective template-directed pre-self-assembly process. The programmed self-assembly should bear the capability of selective dimerization in a multiple component mixture, just like in DNA base pairing (A for T, and G for C). Self-sorting can be a reliable strategy for the selective pre-self-assembly in a complex mixture [26c, d, 37]. As shown in Fig. 4a, Schalley and co-workers [38] demonstrated for the first time that integrative self-sorting of two kinds of crown ether macrocycles, D24C8 and B21C7, can be used for the effective construction of a hetero[3]rotaxane. The key feature is the introduction of a phenyl group between two ammonium sites, which brings a steric barrier for the smaller macrocycle B21C7 rather than for D24C8. Hence, in the apolar solution, stoichiometric mixture of thread 9 and D24C8 and B21C7 macrocycles could self-assemble into one single species, semi[3]rotaxane, and the following stopping by phenyl units afforded the target compound, hetero[3]rotaxane 10 in high yield. The same group utilized this self-sorting system to fabricate many elegant hetero(pseudo)[n]rotaxane with high structural complexity, showing that this strategy can be a general approach for the construction of hetero[n]rotaxanes. Liu and co-workers [12a] assembled twin-axial hetero[7]rotaxane 15 via self-sorting strategy, as shown in Fig. 4b, which involved a self-sorting system of four components, thread 11, thread 12, macrocycle bis(p-phenylene-34-crown-10) (BPP34C10), and macrocycle B21C7. The key design element also lies on the steric barrier formed by a phenyl moiety for the smaller macrocycle B21C7. Through the efficient click reaction between the two intermediates, pseudo[3]rotaxane 13 and semi[2]rotaxane 14, hetero[7] rotaxane 15 could be afforded with a high yield (42%). This work demonstrated the synthesis of a more complex hetero[7]rotaxane in a one-pot fashion, significantly advancing the application of self-sorting in the synthesis of rotaxanes. As an attempt to integrate daisy chain rotaxanes and hetero[n]rotaxanes to further increase structural complexity, our group has reported a novel daisy chain-containing hetero[4]rotaxane 20, synthesized via an improved self-sorting strategy [39a]. In our system, shown in Fig. 4c, self-sorting was initiated in the mixture of a daisy chain monomer 16, thread 17, and B21C7. Although the previously reported work [38] has accomplished self-sorting process involving D24C8 and B21C7 on a thread with two ammonium sites, however, the daisy chain monomer 16 underwent an interpenetration motion in its self-assembly accompanied by the formation of the semi[2]rotaxane 19. As a result, only two intermediate species could be detected in the apolar solution: daisy

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Fig. 4 Synthetic methodology for the construction of a series of hetero[n]rotaxanes: (a) hetero[3] rotaxane 10 [38], (b) hetero[7]rotaxane 15 [12a], (c) hetero[4]rotaxane 20 [39] by the self-sorting synthetic strategy

chain 18 and semi[2]rotaxane 19, and the subsequent one-pot CuAAC click reaction could afford the target product 20 efficiently. This improved system gave further insight into self-sorting processes and expanded the toolbox for the construction of more complicated rotaxanes with daisy chain structure. As a continuation of research, in a very recent work, our group further employed a facile and efficient one-pot “click” stoppering strategy to construct a novel hetero[6] rotaxane bearing three different kinds of crown ether macrocycle [39b]. In this selfsorting system, six components include three kinds of crown ether, namely, BPP34C10, DB24C8, and B21C7, and their corresponding cation guest molecules, namely, a 4,40 -bipyridine dication (BPY2+) and DBA and benzylalkylammonium

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(BAA) ions, respectively. Such work is considered to be a significant advance in the construction of mechanically interlocked molecules with high structural complexity, as well as a good supplement in the areas of multicomponent self-sorting and noncovalent self-assembly.

11.3

Functionalization of Rotaxanes

The introduction of appropriate functional groups into rotaxanes is essential for the synthesis of diverse structures capable of performing different tasks. Although there are well-developed synthetic methodologies available for the construction of such systems, new methods have to be introduced constantly according to the intended application of the rotaxane. The unique shuttling motion on a single-molecular scale of a rotaxane brings remarkable possibilities toward the development of functional structures. Significant efforts have been concentrated into the functionalization of rotaxanes, fabricating series of versatile systems bearing multiple functions, such as fluorescent molecular switches, switchable rotaxane catalysts, molecular production line, and molecular pumps [1i, 2f]. These functions can be considered as the fundamental basis of potential applications of rotaxanes advancing their evolution into molecular materials and devices.

11.3.1 Rotaxane-Based Fluorescent Molecular Switches Molecular switches, a class of molecules that are able to alter their physical and/or chemical properties between two or multiple states, have been considered as key elements in many optical and electronic devices [40]. Although molecular switches have been widely applied in the construction of smart materials, such as fluorescent probes [41a], surfaces with controlled wettability [41b], stimuli-responsive polymers [41c], or smart nanoparticles [41d], the expanding set of potential new applications demands new molecular switches. Recently, some novel molecular switches based on molecular machines, including molecular motors [42], rotaxanes, and catenanes [43], have emerged and performed many unique switching-based tasks. In the case of rotaxane molecular switches, one of the advantages lies in the precise control of the relative position of the macrocycle moiety, including the precise control of the corresponding distance between the macrocycle and the two stoppers. Hence, the integration of two appropriate functional moieties, such as a fluorophore and an electron donor into the stoppers and the macrocycle, respectively, would borrow the distance-dependent photoinduced electron transfer (PET) effect to the rotaxane system [44]. In such a system the PET effect could be precisely controlled through the control of macrocycle motion. Furthermore, this molecular motion could be also visual owing to the change in fluorescence. Hence, a fluorescent molecular switch could be constructed accordingly. Pioneering work in the field of rotaxane-type fluorescent switches came from the group of Sauvage [45], in which the PET effect could be switched through the addition and removal of transitional metal ions. Later, our group developed a series

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of fluorescent molecular switches with remarkable changes in fluorescence and their functional applications as molecular logic gates and fluorescent sensors [4a–c, 30a–c, 46]. Recent work by our group focused on the ferrocene-containing [2]rotaxane [46b] and [1]rotaxane systems [30c, 46g] as shown in Fig. 5. These bistable systems could be switched in response to acid and base stimulus, mainly based on the typical acid-/ base-controlled hydrogen-bonding interaction between D24C8 macrocycles and dibenzylammonium (DBA) sites. Remarkably, ferrocene, an electron donor, was connected covalently to D24C8 macrocycles in these systems, which integrated the stimuli-responsive macrocycle motion with an electron donor. In the initial state, the D24C8 and ferrocene moieties were distant from the fluorophore, and hence, the inhibited PET effect allowed for a high-intensity fluorescence, which we can call as “on” state of the fluorescence. After deprotonation of DBA sites by addition of base (DBU), the macrocycle moiety lost its strong hydrogen-bonding interaction with the DBA sites and moved toward the N-methyltriazole sites, positioning the ferrocene moiety near the fluorophore unit, resulting in the “off” state of fluorescence due to active PET effect. Furthermore, the inverse process could be driven by reprotonation of DBA sites by addition of acid (TFA). As the whole process was proved fully reversible, this fluorescence switching system could be integrated into more complex molecular devices for optical and electronic applications in the future. Employing the above described strategy involving distance-dependent PET effect controlled by macrocycle motion in a bistable [n]rotaxane, various efficient fluorescent molecular switches could be designed and constructed. Nevertheless, multistate fluorescent switches are also vital for practical applications such as logic gates, pH sensors, or biological probes, especially those switches that are capable of responding to multiple types of external stimuli [4a–c]. Recently, our group reported examples of multi-stimuli-responsive rotaxane fluorescent switches with multiple states [46h]. Similarly, employing bistable [2]rotaxane as the platform, dithienylethene, a well-known photoswitch, was introduced on the macrocycle moiety as the electron donor unit. Besides the pH-responsive capability originated from [2]rotaxane, the photo-responsive ring opening and closing capability of dithienylethene evolved this system into a tetra-state fluorescent switch that can be controlled by acid/base stimuli and light irradiation synergistically. Furthermore, in the ferrocene-containing system, shown in Fig. 5, redox chemistry as an additional control element was introduced, as the ferrocene moiety could be oxidized by addition of Fe(ClO4)3. In this way, the PET effect between the ferrocene moiety and a fluorophore could be inhibited [30c]. Hence, a pH- and light-controlled NOT logic gate could be designed based on the fluorescence intensity. The work discussed above can be expected to advance the evolution of rotaxanes into functional fluorescent molecular switches.

11.3.2 Artificial Rotaxane-Type Switchable Catalysts In biological systems, chemical reactions are catalyzed by bio-catalysts, enzymes, that are well-known from their efficiency and specificity. Although many efforts

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Fig. 5 Schematic representation of a series of rotaxane-type fluorescent molecular switches developed by our group [30c, 46]

have been focused on the development of artificial catalysts with high efficiency, which significantly advanced chemical industry, however, these industrial catalysts are mostly used for the corresponding given reactions instead of a multi-type of substrates, meaning the nonselective nature. Recently, inspired from natural catalysts, artificial switchable catalysts have attracted much attention due to their unique capability of mimicking the selective catalytic behavior of enzymes [47]. The selectivity involves the stimuli-responsive on/off mode in catalytic activity, meaning that these catalysts can be active in a transformation in one state and inactive in the other state. As demonstrated, rotaxanes provide a reliable platform for the construction of stimuli-responsive catalytic systems [48] (Fig. 6).

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Fig. 6 The artificial switchable rotaxane-type catalysis reported by the group of Leigh [47a]

Pioneering work in the field of rotaxane-type switchable catalysts performed in the group of Leigh [47a]. In their first example, a typical acid-/base-controlled bistable [2]rotaxane 21 containing dibenzylammonium sites was employed as the catalyst for a well-known Michael addition reaction. The free secondary amine could catalyze the Michael addition reaction; hence, the [2]rotaxane 21 could accelerate the reaction kinetics remarkably, meaning a catalytic “on” state. However, upon protonation of dibenzylammonium (DBA) sites by addition of acid, the DB24C8 macrocycle moved toward the DBA site due to the higher affinity and shielded it, affording the [2]rotaxane 22 with unexposed DBA sites. Due to the shielded catalytic site, no reaction occurred in the presence of [2]rotaxane 22, meaning a catalytic “off” state. The “on” and “off” state could be switched reversibly by the precise control of acid/base addition. This switchable rotaxane system was used to catalyze other reactions through different activation mechanisms, including iminium catalysis,

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enamine catalysis, tandem iminium-enamine catalysis, and trienamine catalysis [48a]. Furthermore, the introduction of chirality into the rotaxane catalyst could be exploited in conjugate addition reactions giving improved enantioselectivities compared to non-interlocked catalysts [48d]. All these elegant rotaxane-type catalysts provide a significant strategy for the construction of artificial switchable catalysts, advancing rotaxanes toward functional smart catalysis.

11.3.3 Artificial Molecular Production Line The performance of biological machines in crucial biological tasks within a complex living organism inspired chemists to mimic this evolved biological machinery by synthetic small molecules [32, 49]. Walking protein machines, called myosin, kinesin, and dynein, are capable of “walking motion” powered by chemical energy (the hydrolysis of adenosine triphosphate), performing like someone stepping forward with two feet. There have been reports on successful examples of DNA-based molecular walkers that can move gold NPs or mediate multistep synthesis [50]. However, to build purely synthetic molecular walkers based on small molecules remained a challenge until recently, when the group of Leigh designed and constructed the first synthetic small-molecule walker using the Schiff base and disulfide dynamic covalent chemistry [32a]. Employing the versatile strategy of dynamic covalent bonding, Leigh and co-workers also reported a synthetic small-molecule walker that accompanied with decreasing fluorescence change [32c]. More recently, the same group reported a more advanced, completely synthetic small-molecule machine, involving a robotic arm that could pick up, transport, and release molecular cargo [32f]. Rotaxanes can also perform as small-molecule walkers, and even as artificial molecular production lines when the macrocycle moiety is walking along the thread, which has been realized by Leigh and co-workers [51]. As shown in Fig. 7, [2] rotaxane 23 consists of a sterically bulk stopper at one of the ends, a macrocycle moiety, and a thread bearing three amino acid units in a specific order. In its initial state, rotaxane 23 is stable due to the protecting groups present in the amino acids and thiol group. The molecular production line does not work until the acidcatalyzed cleavage of the Boc and trityl protecting groups, in the presence of CF3COOH. Upon exposure of the free primary amines and the thiol group, the molecular walker was activated. Firstly, the thiolate catalyst was activated upon deprotonation of the thiol by N, N-diisopropylethylamine, and then the first transacylation reaction (O-S acyl transfer) occurred between the thiolate group and the first amino acid phenolate ester building block. The formed phenylalanine thioester could further react and transfer the amino acid to the end of the growing peptide chain and regenerate the catalytic thiol group through a 1,11-S, N acyl transfer process. The first step of the molecular walker was finished, and then through sequential transacylation reactions, amino acid transfers, and thiolate regenerations, the macrocycle walker unit was able to pick up the amino acids from the track by moving along the thread. Ultimately, the system was yielding a non-interlocked thread and a macrocycle containing a peptide chain with four amino acids. Finally,

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Fig. 7 The operation mode of the first artificial molecular production line for peptide synthesis [51]

the macrocycle detached from the molecular track after the last amino acid stopper was cleaved, and then the synthesized sequence-specific tetrapeptide was obtained by acid hydrolysis. The synthesis of polypeptides is an essential process in living organisms. In this work, Leigh and co-workers used tandem mass spectrometry (MS/MS) to confirm the product of the rotaxane-based molecular walker. The results indicated that the amino acid sequence obtained from this novel synthesis strategy was identical with an authentic sample synthesized by conventional methods. Furthermore, the authors also demonstrated that there was no other by-product peptide detected, indicating that the reactions are highly specific. Simultaneously, a control reaction was carried out under the same conditions by using the non-threaded track and macrocycle that showed no evidence for the formation of the same product under these conditions. Thus, it can be concluded that the interlocked architecture of the molecular walker is

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essential for the sequence-specific peptide synthesis through the working mechanism presented in Fig. 7. Despite there are some limitations, such as slow kinetics compared to a ribosome and loss of the sequence information on the track during its working, this rotaxane-based molecular walker is an excellent simulation of sequence-specific peptide synthesis in biological systems and represents an important step toward complex artificial molecular machinery.

11.3.4 Artificial Molecular Pumps A machine that works like a pump is capable of the directional transport of cargo even from a lower energy state to a higher one, which occurs not only in the macroscopic world (such as a water pump or a crane) but also in biological systems (such as the membrane-spanning carrier protein that is capable of driving cargoes across cell membranes against concentration gradients) [52]. However, to mimic this function using synthetic molecules is challenging because the directional motion needs the precise control of two “driving forces”: one has to drive the cargoes to enter into the pump from one side, and the other has to drive the cargoes out of the pump from the other side. Hence, the driving force must be directional [53]. Furthermore, for an artificial system, the two processes should be sequential and controllable by external stimuli, also the input energy to power the pump [54]. Some development on pumping protons and metal ions across a membrane has been realized by artificial systems [55]. Besides, pumps made of small molecules are emerging toward the directional transport of more general cargoes [56, 57]. Very recently, Credi and co-workers [56]reported a light-powered directional molecular pump based on an azobenzene-containing rotaxane system (Fig. 8a). In this system, the macrocycle, 2,3-dinaphtho[24]crown-8 ether 24, was used as the cargo to be transported. The pump involved a DBA-containing asymmetric thread 25 including two different pseudo-stoppers, a photoswitchable trans-azobenzene moiety at one terminal and a passive methylcyclopentyl unit at the other terminal. Upon mixing these two components, the macrocyclic cargo 24 would enter into the thread pump

Fig. 8 The directional pumping operation of an artificial molecular pump powered by light [56] (a) and by chemical redox reaction [57] (b, c)

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autonomously due to the presence of DBA sites which can form metastable host-guest structure with macrocycle 24. Interestingly, macrocycle 24 always shuttled into thread 25 from the side of trans-azobenzene because of the lower steric barrier of transazobenzene compared to that of the methylcyclopentyl moiety, which in fact has realized the first “driving force” of the pump as discussed above. The other driving force involved the photo-induced isomerization of azobenzene from the trans- to the cis- form, resulting in a large steric barrier as a stopper for macrocycle 24, and then macrocycle 24 would be released off the thread autonomously due to the dynamic and metastable nature of the host-guest system formed by 24 and DBA sites. Significantly, macrocycle 24 would shuttle out of the thread selectively from the methylcyclopentyl side due to the presence of the cis-azobenzene stopper. Hence, in this process, the cargo, macrocycle 24, is transported directionally by a light-powered molecular pump. This work provides significant new strategy for the construction of (pseudo)rotaxanetype molecular pumps, advancing the evolution of machine-like motion of rotaxanes. Stoddart and co-workers [57] have reported an artificial molecular pump based on the radical cation template. As shown in Fig. 8b, macrocycle 26 cyclobis(paraquat-pphenylene) (CBPQT4+), also well-known as blue box, was employed as the cargo, and a thread 27 was designed as the molecular pump containing a pseudo-stopper with multiple positive charges at one end and a sterically bulk stopper at the other end. The molecular pump was operated by mixing thread 27 and macrocycle 26. In the initial state, positive charge repulsion was dominated, generating a charge-based energy barrier to inhibit the penetration of macrocycle 26. Upon addition of excess chemical-reducing agent to reduce the viologen dication moieties on both of macrocycle 26 and thread 27 into viologen radical cation moieties, the strong radical cation dimerization interaction drove the reduced macrocycle to shuttle into the viologen radical cation sites on the thread. Meanwhile, the decreased charges of reduced macrocycle (from tetracation to dication) also decreased the charge repulsion between the macrocycle and the terminal pyridinium salt sites, making the entrance of the pump more accessible for the macrocycle. The release of macrocycle 26 involved the subsequent chemical oxidation, converting the viologen radical cations back into the viologen dication state, resulting in the removal of radical cation dimerization interaction and the recovery of the strong positive charge repulsive force. In this state, due to the higher positive charge repulsion between the tetracationic macrocycle 26 and the pyridinium salt compared to the steric barrier generated by the isopropylphenyl units, the macrocycle spontaneously and autonomously crossed the isopropylphenyl moiety and resided at the stopper-containing end of the thread on a PEG chain. The whole process shown in Fig. 8b represents the motion of the first macrocycle cargo. The pumping of the second cargo (Fig. 8c) could be performed in a similar fashion because the isopropylphenyl units acted as a steric ratchet for macrocycle 26, meaning that the macrocycle could only pass the ratchet directionally, from the viologen sites toward PEG chain. Hence, in theory, the amount of the macrocycle (cargo) that can be pumped should be unlimited if the PEG moiety is long enough to accommodate the pumped cargoes. This work simulates the biological membrane transport phenomenon by carrier proteins and thus introducing novel functions that a rotaxane can bear on a single-molecule level.

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Rotaxane-Based Functional Materials

Although the functional rotaxanes discussed above have performed well as novel molecular switches and biomimetic molecules, most of these rotaxanes are used in solution, which is a limitation in several practical aspects in the construction of functional materials [16]. Hence, functional rotaxanes should be evolved further toward immobilization on solid surfaces and interfaces. Macroscopic surfaces could act as a platform on which molecular-scale rotaxane motions and functions could be amplified into macroscopic changes in properties, such as optics, sizes, morphology, dispersion, or catalytic activity [16h]. However, considering the differences between solution phase and solid phase, several challenges has to be considered when a rotaxane is immobilized on a surface or inside a solid material, but also new opportunities are emerging given the unexpected performance of an immobilized rotaxane and the mutual communication (such as PET effect, FRET effect, SPR effect) between the rotaxane moieties and the inorganic surfaces. Herein, we focus on the general and reliable strategies of rotaxane immobilization on solid surfaces. Synergistic effects between rotaxanes and surfaces are also highlighted in the recent examples of novel functional materials, including solid-state molecular switches, controlled drug release systems, or self-healing materials.

11.4.1 Rotaxane Molecular Switches on Surfaces As demonstrated in Fig. 5, rotaxanes could be developed into a series of molecular switches with tuneable fluorescence, responding to external stimuli [46]. However, the practicability of a fluorescent switch in solution is limited in portable functional materials applications. To operate rotaxane switches on a solid surface is essential for the development of novel switchable fluorescent materials. Surfaces [16h], porous metal organic frameworks [20], and polymers [35] have been proved reliable platforms for the effective functioning of molecular switches or molecular machines. Effective operation of rotaxanes on these platforms needs enough free space for the stimuli-responsive motion of the macrocycle, which is not an issue in a dilute solution. However, confinement effects dominate on a surface, interface, or solidstate polymer, meaning that crowding of rotaxanes would affect the operation of rotaxanes by steric hindrance. Hence, it is necessary to decrease to some extent the concentration of rotaxanes on the solid platform [58]. Another challenge is finding general and reliable strategies to attach rotaxanes to different surfaces. Although there are many approaches developed for the effective functionalization of surfaces, the structural complexity of rotaxanes requires specific and effective methods for the immobilization. Click reactions provide unique specificity and efficiency compared to other organic coupling reactions, and we also demonstrated their advantages in the construction of rotaxanes with high structural complexity [26]. Employing the CuAAC click reaction, the effective immobilization of the [2] rotaxane fluorescent switches have been realized by our group using the a linear polymer platform [59] (Fig. 9a) and inorganic silica NPs [60] (Fig. 9b). The common

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Fig. 9 The acid-/basecontrolled fluorescence “on/ off” switching of [2]rotaxanebased fluorescent molecular switches immobilized on polymer [59] (a) and silica NPs [60] (b)

advantages of the two solid materials lie on their excellent optical transparency, facile preparation and modification, and wide applications in optoelectronic devices, sensors, and biomaterials. The general strategy for the construction of the presented hybrid materials involves the one-step click reaction between the alkynyl-terminated [2]rotaxane fluorescent switch and the azide-modified polymers or silica NPs. Significantly, the proportion of the azide groups on the surfaces is vital for the functioning of rotaxanes. Due to the high yield of the click reaction, it could be considered that all azide groups are reacted with rotaxanes, which means the azide group concentration on the surfaces can be approximatively equal to the amount of immobilized rotaxanes. Hence, it is facile to adjust the immobilization concentration of rotaxanes by controlling the amount of azide on the solid substrates. Following the construction of the surface- or polymer-bound rotaxane fluorescent switches, solidstate fluorescent molecular switches can be driven by treatment with acid (TFA) and base (DBU). Importantly, due to the separable nature of the solid-state materials, the

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polymer- and silica-bound rotaxanes can be driven reversibly by acid/base stimulus cleanly, as the excess reagents can be washed away, while the switches remain attached due to the strong covalent bonding with the surfaces. These works demonstrated a general strategy to fabricate novel solid-state molecular switches based on stimuli-responsive rotaxanes and significantly advanced the evolution of rotaxanes from solution- to solid-phase applications. Besides the above strategy to transfer rotaxane switching into solid state, other approaches have been reported for the construction of rotaxane-functionalized solid materials. The precise control of surface properties by stimuli-responsive molecular motion can also lead to fascinating switchable surfaces, including bending a gold sheet through the molecular shuttling motion of thousands of immobilized rotaxanes [61], transporting a liquid drop by the irradiation of light [18a], or altering the surface plasmonic resonance of the gold nanodisks [62]. Zhang and co-workers reported a surface with switchable, light-controlled wettability by employing the α-CD-based rotaxane self-assembled monolayer on a gold substrate [63]. As shown in Fig. 10, thread 28 included a trifluoromethyl-terminated photo-responsive trans-azobenzene moiety, whose host-guest recognition by α-CD macrocycle could be switched by light, and a thiol end used for bonding with the gold surface. After immobilizing the rotaxane (trans-28@α-CD) onto the gold surface diluted with alkyl thiols 29, the surface exhibited hydrophilicity with a relatively small water contact angle (about 70 ). This could be explained by the shielding of the hydrophobic trifluoromethyl groups by the hydrophilic macrocycle, α-CD. Upon irradiation with UV light, the isomerization of azobenzene drove the hydrophilic macrocycle away from the cis-azobenzene sites, and the subsequent exposure of hydrophobic trifluoromethyl units led to the increased water contact angle (about 120 ) and the hydrophobic nature of the surface. The whole process

Fig. 10 Smart surface with light-controlled switchable wettability based on a rotaxane immobilized on a gold surface [63]

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was proved reversible by light irradiation. This work is a significant step for the design of smart surfaces with switchable wettability in a light-controlled fashion. Our group reported the successful construction of a muscle-like molecular actuator based on [c2] daisy chain rotaxane to reversibly modulate the gap distance between two linked gold (Au) NPs [64]. As shown in Fig. 11, this molecular muscle actuator enables the equipped Au NPs with stimuli-responsive capability through the acid-/base-powered molecular transformation. Although many efforts have been successfully put into transforming artificial molecular muscles from microscopic molecular scale to macroscopic polymer scale [35], this groundbreaking work realized nanostructure manipulation by muscle-like molecular actuator – a couple of Au NPs linked by the molecular actuators can be reversibly switched with addressable gap distance that is correlated with the length of molecular actuator. This research represents a brighter functionalization and application of artificial

Fig. 11 Schematic operation mode of the [c2]daisy chain-based muscle-like molecular actuator for the Au NPs [64] (d represents the distance between the two Au NPs in different states)

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molecular machines in nanotechnology and molecular devices, especially those working at single- to few-molecule level.

11.4.2 Controlled Drug Release System The goal of realizing precisely controlled drug release in biological systems has been pursued in the last decades, when many designs have been developed and realized in some degree [65]. However, there is still much room for improvement in design strategies toward stimuli-responsive loading and release of drugs. Rotaxanes, considering their excellent stimuli-responsive capability, are of great potential in this field [66]. As shown in Fig. 12, Stoddart and co-workers immobilized bistable [2] rotaxane 30 onto the surface of MCM-41 [66a], a representative species of mesoporous silica with ordered nanopores, by the covalent connection though silanebased coupling. Loading and releasing of cargo (Dye Rhodamine B) could be achieved with this system through the following states. In state (a) the tetracationic macrocycle moiety rests at the electron-rich tetrathiafulvalene (TTF) site due to its stronger affinity to TTF compared to that to DNP sites. In this state the pores of MCM-41 are open, allowing the dye cargo to enter the pores driven by concentration gradient. This process can be defined as the loading step. Subsequently, in state (b) the oxidation of TTF units to TTF2+ dications takes place repelling the CBPQT4+ macrocycle toward the DNP sites, which accordingly closing the pores of MCM-41. With this step the cargo loading is completed. State (c) is the last, controlled release step. It involves the reduction of TTF2+ dications back to neutral TTF units, leading to the open state of the nanovalves and the subsequent release of cargoes. This work marked the first step toward artificial rotaxane-based nanovalves for controlled cargo release and provided a general model based on a stimuli-responsive mesoporous silica hybrid system.

Fig. 12 Artificial nanovalve based on rotaxane-modified MCM-41 NPs and its stimuliresponsive operation mode for controlled loading and release of cargoes [66a]. (The yellow ball represents the dye cargo, Rh. B molecules)

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Considering the role of the macrocycle as a plug of the pores, in theory, this reversible rotaxane-based nanovalve can be applied for loading and releasing many other cargoes of similar sizes. Stimuli-responsive nanovalves could be fabricated using other types of (pseudo)rotaxane systems responding to different signals, including light, pH, enzyme, heat, or magnetic field [21]. These modes of valve activations are designed for the automatic release of cargo in different environments, such as cancer cells in living systems, known to be more acidic than other healthy tissues. Hence, a pH-controlled drug release system can be designed in terms of a loading-in-neutral and release-in-acid mode, which would be able to recognize cancer cells and then release the drug to affect the target cancer cell selectively. Stoddart, Zink, and co-workers reported a pH clock-operated nanovalve system involving a cucurbituril CB[6]-containing rotaxane (Fig. 13) [67]. Its ability to respond to pH change was based on the host-guest system between a secondary amine and CB[6] macrocycle. After loading the dye cargo in neutral or acidic solution, the loaded silica NPs can precisely release the cargo gradually when the pH value of the surrounding environment decreases below 5.4 (Fig. 13b). This work further evolved rotaxane-based nanovalve systems toward a pH-programmed selfrecognizing-and-releasing mode, which has more potential in advanced biological applications.

11.4.3 Self-Healing Materials Self-healing materials have attracted much attention [68] due to their remarkable capability of self-recovery after external mechanical damage. Their development

Fig. 13 The pH-controlled MCM-41 nanovalve system based on CB[6] rotaxane (a–c) and the release rate to time curve of the acid-induced cargo release [67]

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would prolong the lifetime of many materials considerably and would contribute to the development of new classes of smart materials. In the last decades, much progress has been made in the field of self-healing systems, which in many cases involve the introduction of dynamic covalent/noncovalent bonding as key interaction [68c, d]. This strategy led to sticky interfaces that could undergo self-adhesion after mechanical damage, providing polymeric materials with self-healing functions. However, the introduction of dynamic interactions also increases the difficulty of synthesis and decreases mechanical strength of the polymeric material. Therefore, it is necessary to develop novel strategies for the construction of self-healing systems. In case of conventional polymer coatings, scratching force would irreversibly break the covalent bonds in some degree to meet the deformation brought by stress, which causes the so-called scratch damage as shown in Fig. 14a, b. Ito and co-workers were the first who introduced poly[n]rotaxanes based on α-CD macrocycle into the fabrication of self-healing polymeric coatings [69]. In their system polyethylene glycol (PEG) chains forming inclusion complexes with a number of α-CD macrocycles were employed as the backbones. In the initiate state, the α-CD

Fig. 14 The schematic representation of scratching a conventional coating (a, b) and a selfrecovery material (SRM) coating (c, d) [69]

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macrocycles shuttle dynamically and freely along the PEG chains. Upon mixing the rotaxane chains in high concentration, the noncovalent intermolecular dimerization between two α-CD macrocycles would work as a crosslink in the system, resulting in a transparent polymeric gel network with high mechanical strength and chemical stability. Upon addition of external stress by a spiky tip, the surface would produce microscopic deformation and subsequent visual scratch. However, in contrast to conventional polymer coatings (Fig. 14b), the directional shuttling movement of α-CD macrocycles would occur away from the deformation instead of the irreversible breaking of covalent backbone: the macrocycles at the stressed area move to the sides for decreasing the space volume of the stressed area (Fig. 14c). After removal of the stress, the dynamic shuttling movement of α-CD macrocycles would become unidirectional and uniform again smoothing the surface, resulting in self-recovery of the scratched state (Fig. 14d). Obviously, this system has limitation regarding the degree of damage because too large deformation generated by too high stress would not be met with the directional movement of α-CD macrocycles, leading to irreversible breaking of covalent backbone. In any case, this work ingeniously combined self-healing behavior of polymeric materials with the dynamic shuttling movement of macrocycles on a molecular scale, providing a significant method for the amplification of rotaxane molecular motion and the application of rotaxanes toward functional self-healing materials.

11.5

Conclusions

In the past 20 years, rotaxane, as a luminous member in the family of artificial molecular molecules, has evolved remarkably in terms of synthetic methodology, functionalization, and materials applications. In a recent work, our group reported [2]rotaxane composed of an amphiphilic molecular thread with three binding stations would be inserted into lipid bilayers as a unimolecular vehicle to perform passive ion transport through its stochastic shuttling motion [70]. Nowadays rotaxanes are considered as a core part of chemistry and materials design [71]. In structural design and construction of rotaxanes, several novel and reliable synthetic strategies, such as self-sorting, have been highlighted in this chapter. Novel strategies have also been combined with conventional methods toward efficient syntheses of rotaxanes with high structural complexity. The functionalization of rotaxanes to increase structural complexity is the most developed for the class of bistable [2] rotaxanes, due to their widely applied unique stimuli-responsive capability in the construction of functional molecular switches and devices. Meanwhile, rotaxanes also have the potential of mimicking the functions of biological machines like enzyme catalysis, pumping, or peptide synthesis. Inspired by the evolution of living systems in nature from sea to land, the working platform of rotaxanes has also evolved from solution to surfaces and interfaces, resulting in a forthcoming period full of challenges but also opportunities. The challenging issues lie on the unexpected operation modes when numbers of rotaxanes are immobilized on a surface, because the steric and orientation effects could alter the operation mode on a surface

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compared to that in solution. On the other hand, the differences provide many opportunities for construction of novel functional materials, such as smart surfaces with switchable properties, controlled drug release systems, and self-healing materials. Herein, we foresee a challenging but bright prospect for rotaxanes. The synergy between new synthetic methodology, functionalization, and materials applications would bring about further developments and extensive applications of rotaxanes in the coming years. As the ultimate purpose, advanced functional materials and devices based on rotaxanes would bring a novel industrial generation toward the smart period.

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Biphen[n]arenes: Synthesis and Host–Guest Properties

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Contents 12.1 12.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis of Biphen[n]arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.2.1 4,40 -Biphen[n]arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.2.2 2,20 -Biphen[n]arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.2.3 Terphen[n]arenes and Quaterphen[n]arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3 Functionalized Biphen[n]arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3.1 Anionic Water-Soluble 44BPns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3.2 Cationic Water-Soluble 44CBP3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3.3 Anionic Water-Soluble 22BP4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.4 Structures of Biphen[n]arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.5 Host–Guest Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.6 Ammonium Guests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.7 Pyridinium-Based Dicationic Guests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.8 Neutral π-Electron Deficient Guests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.9 Biological and Pharmaceutical Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.10 Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.11 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Bin Li and Yiliang Wang contributed equally with all other contributors. B. Li · C. Li (*) Key Laboratory of Inorganic-Organic Hybrid Functional Material Chemistry, Ministry of Education, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, College of Chemistry, Tianjin Normal University, Tianjin, China Center for Supramolecular Chemistry and Catalysis, Department of Chemistry, Shanghai University, Shanghai, China e-mail: [email protected]; [email protected] Y. Wang Center for Supramolecular Chemistry and Catalysis, Department of Chemistry, Shanghai University, Shanghai, China © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_13

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Introduction

The design and synthesis of new types of synthetic macrocyclic receptors with novel and intriguing structures is always a popular topic in macrocyclic and supramolecular chemistry. The most well-known supramolecular hosts, including cyclodextrins (CDs), crown ethers, calix[n]arenes, and cucurbit[n]urils (CBs), are widely investigated as building blocks for molecular recognition [1], self-assembly [2], smart materials [3–6], drug delivery [7, 8], and molecular machines [9, 10]. In recent years, some new synthetic macrocycles have been reported and have gained much attention, such as Sessler’s “Texas-sized” box [11], Stoddart’s “Ex-box” [12], Wang’s corona[n]arenes [13], Chen’s helic[n]arenes [14], Jiang’s oxatub[4]arene [15], Flood’s cyanostar [16], and others [17, 18]. Macrocyclic arenes, including calixarenes [19], resorcinarenes [20], cyclotriveratrylenes [21], pillararenes [18, 22], etc. [23, 24] (Scheme 1), have been significantly important supramolecular macrocycles over the past decades. They are all composed of mono-benzene and mono-heterocycle units bridged by methylene. Meanwhile, they possess π-electron rich cavities, which can capture cationic guests driven by cation  π interactions. Furthermore, one important feature of macrocyclic arenes is that they can be readily modified with certain functional groups to improve the solubility, host–guest binding ability, and self-assembly characteristics. In 2015, we reported a new class of macrocyclic host compounds, namely “4,40 -biphen[n]arenes,” which are based on the 4,40 -dialkoxy or hydroxy biphenyl monomer [25]. In 2017, we introduced another type of biphenarenes, 2,20 -biphen[n] arenes, to the supramolecular world [26]. Very recently, extended biphen[n]arenes (e.g., terphen-[n]arenes and quaterphen[n]arenes) were designed and synthesized by our group [27] (Scheme 2). Biphen[n]arenes have similar advantages as other typical macrocyclic arenes such as one-pot synthesis, versatile functionality, and superior

Scheme 1 Structures of some typical macrocyclic arenes

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Scheme 2 General structures of biphen[n]arenes, terphen[n]arenes, and quaterphen[n]arenes [25–27]

host–guest properties. Above all, their topological structures are remarkably unique. For example, 4,40 -biphen[3]arene displays distorted triangular-prism structure; 4,40 -biphen[4]arene shows cuboid-like box; and terphen[n]arenes and quaterphen [n]arenes exhibit giant cavity sizes and nice self-assembly properties due to long and rigid terphenyl and quaterphenyl monomers. Particularly, the cavity diameter of the largest macrocyclic molecule, quaterphen[6]arene, is more than 3.0 nm, which far exceeds the cavity sizes of traditional macrocycles. Due to the above interesting properties, biphen[n]arene chemistry has been attracted tremendous attentions in the past 4 years. In this chapter, the latest progress in the synthesis, structural features, their application in molecular recognition, and self-assembly properties of biphen[n] arenes and extended biphen-[n]arenes will be reviewed.

12.2

Synthesis of Biphen[n]arenes

The development of synthetic macrocycles with distinctive structures is great significance in the field of supramolecular chemistry. Even though some new macrocyclic receptors have been constructed, far more are needed to advance macrocyclic chemistry. In the following section, the syntheses of novel biphen[n]arenes, terphen [n]arenes, and quaterphen[n]arenes are discussed and introduced. All of these macrocycles can be obtained through simple one-step reactions from commercially available or easy-to-made monomers.

12.2.1 4,40 -Biphen[n]arenes In 2015, our group successfully synthesized 4,40 -biphen[n]arenes (44BPns) [25]. The 44BPns are prepared through a one-pot condensation of 4,40 -biphenol diethyl ether and paraformaldehyde in CH2Cl2 in the presence of a Lewis acid catalyst such

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as FeCl3, BF3O(Et)2, or trifluoromethanesulfonic acid (TfOH). One acyclic dimer and two cyclic oligomers (44BP3 and 44BP4) were successfully obtained in 9%, 22%, and 8% yields, respectively (Scheme 3). The monomer units are connected by methylene bridges at the 3,30 -position.

12.2.2 2,20 -Biphen[n]arenes The repeating units of calix[n]arenes, cyclotriveratrylenes, resorcin[n]arenes, and pillar[n]arenes, are phenol, and ortho-, meta-, and para-dihydroxybenzenes, respectively. Although their monomers look like similar, the resulting macrocycles exhibit dramatically different topological structures and recognition properties. For example, cyclotriveratrylenes, resorcin[n]arenes, and pillar[n]arenes, composed of ortho-, meta-, and para-dihydroxybenzene monomers, show bowl-, basket-, and pillar-shaped cavities. In calix[n]arenes, the para-substituted phenols are linked by methylene bridges at the 2- and 6-positions as a result of the higher electron density at these positions than that at the 3- and 5-positions, and the 4-position of the electron-rich site is occupied by the substituent (Scheme 4a). When using 1,2-dialkoxybenzenes as

Scheme 3 Synthesis of 4,40 -biphen[n]arenes [25]

Scheme 4 Macrocyclic arenes based on phenolic monomers

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the monomers to prepare cyclotriveratrylene with a rigid bowl-shape, the reaction sites were the 4- and 5-positions of 1,2-dialkoxybenzenes because the reactions at the 3- and 6-positions are unfavorable due to steric hindrance (Scheme 4b). When 1,3-dialkoxybenzenes are used as monomers to obtain calix[4]resorcinarenes, four resorcinarene molecules are connected at their 4- and 6- positions (Scheme 4c). Pillar [n]arenes, with highly symmetrical cyclic structures, were first reported by Ogoshi et al. in 2008 [18]; they are connected by a methylene bridge at the 2- and 5-positions as a result of highly reactive reaction sites and a low steric hindrance (Scheme 4d). Therefore, considering a change in the relative positions of the two hydroxyl groups of the dihydroxybenzene building blocks, we wondered whether it is possible to use 2,20 -dialkoxy biphenyls as the monomer to obtain new biphenarenes because the reaction sites of the 3,30 -positions (para position of dialkoxy) have a high electron density and a low steric hindrance. As expected, the other type of 2,20 -dialkoxy disubstituted biphen[n]arenes (22BPns, n = 4–8) were successfully synthesized in 2017 by our group [26] (Scheme 5a). In addition, we tried to obtain the pillar-shaped hosts 3,30 -biphen[n]arenes (33BPns) based on the 3,30 -diethoxy biphenyl linked by a methylene bridge at the 4,40 -positions. However, no cyclic oligomers were detected after many attempts. One possible reason is that both the ortho- and the para-positions (marked as red arrows in Scheme 5b) to the ethoxy groups are efficient reaction sites, making the reaction quite complex. The synthetic method of 22BPns is similar to that of 44BPns. 22BPns can be directly prepared from 2,20 -dialkoxy biphenyl and paraformaldehyde in 1,2-dichloroethane at 25  C, with BF3O(Et)2 as the catalyst. Changing the relative position of the disubstituted dialkoxy substituents resulted in the formation of macrocycles containing 4–8

Scheme 5 (a) Synthesis of 22BPns (n = 4–8). (b) Attempted synthesis of 33BPns [26]

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monomers, with total yields of up to 51%, which is much larger than that for 44BPns (about 30%).

12.2.3 Terphen[n]arenes and Quaterphen[n]arenes The classic macrocycles such as cyclodextrins, calixarenes, cucurbiturils, and pillar[n]arenes have relatively small cavity sizes of less than 10 Å. Therefore, some biomacromolecules (e.g., peptides and proteins) cannot be encapsulated by these macrocycles due to their limited cavity sizes. What’s more, it is difficult to enlarge the cavity sizes by increasing the number of monomers. For instance, pillar [8-10]arenes and cucurbit[13-15]urils exhibit very small pseudo-cavities [28] and a twisted configuration [29], respectively. Despite the fact that larger macrocycles have been constructed via coordination [30, 31] or dynamic covalent bonds [32, 33], their structural stabilities are relatively poor compared with covalent macrocycles. Inspired by biphen[n]arenes, we wondered whether oligo(para-phenylene)s could be used to prepare extended macrocycles. As envisaged, recently, two new classes of macrocycles, terphen[n]arenes (TPns) (n = 3–6) and quaterphen[n]arenes (QPns) (n = 3–6), were synthesized by our group through 2,200 -dimethoxy terphenyl and 2,2000 -dimethoxy quarterphenyl monomers linked by methylene bridges, respectively [27] (Scheme 6). Due to the longer and more rigid terphenyl or quarterphenyl monomers, these macrocycles displayed much larger cavities compared with classic synthetic receptors. For example, the cavity size of the largest macrocycle QP6 is more than 3.0 nm, which is far greater than traditional cyclodextrins, calixarenes, cucurbiturils, and pillar[n]arenes. The syntheses of terphen[n]arenes and quaterphen[n]arenes were carried out through a one-step procedure by cyclocondensation of 2,200 -dimethoxy terphenyl or 2,2000 -dimethoxy quaterphenyl monomers and paraformaldehyde in chloroform at

Scheme 6 Synthesis of terphen[n]arenes and quaterphen[n]arenes [27]

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room temperature, with BF3O(Et)2 as the catalyst. The macrocycles TPns and QPns were prepared in relatively high yields of 41% and 35%, respectively. In addition, the monomers are easily prepared using commercial reagents by highly efficient Suzuki coupling reaction.

12.3

Functionalized Biphen[n]arenes

Functionalization of macrocyclic receptors is very important in molecular recognition and self-assembly because it can change the solubility and physical/chemical properties of the macrocycles. Especially, water-soluble macrocycles are significantly important for biological, environmental, and analytical applications [34–37]. Per-alkoxy and per-hydroxy substituted biphen[n]arenes are not water soluble. Therefore, the host–guest recognition of biphen[n]arenes is almost always studied in organic solvents. However, one of the important advantages of biphen[n]arenes is their versatile functionality because they have reactive hydroxyl groups on both cavity portals. In this section, the syntheses of watersoluble biphen[n]arenes containing anionic or cationic groups on both rims are introduced.

12.3.1 Anionic Water-Soluble 44BPns Biphen[n]arenes are essentially conveniently modified. The per-hydroxy biphen-[n]arenes (44BPns-OH) could be quantitatively prepared by cleavage of the ether groups through the reaction with excess BBr3. Due to their reactive hydroxyl groups, functionalized biphenarene derivatives can be facilely prepared through nucleophilic substitution reactions of 44BPns-OH and alkylating agents. 44BPns-OH have different molecular recognition properties in comparison with alkoxy-substituted hosts; they are insoluble in low-polarity solvents such as CHCl3, CH2Cl2, and toluene, but they have good solubility in acetone, acetonitrile, DMF, and DMSO [38]. Water-soluble 4,40 -biphen[3]arenes (44CBP3) containing six carboxylate anions were synthesized by Huang and our group simultaneously [39, 40]. Subsequently, our group reported another water-soluble 4,40 -biphen[4]arene (44CBP4) bearing eight carboxylato moieties [41]. As shown in Scheme 7, ethoxycarbonylmethoxysubstituted biphen[3]arene (44BP3-COOEt) was synthesized by the nucleophilic substitution reaction of 44BP3-OH and ethyl bromoacetate in the presence of base. Subsequent hydrolysis of the ethoxy moieties under basic conditions and then acidification with HCl afforded the carboxylic acid-substituted biphen[3]arene (44BP3-COOH) in very high yield (89%). The water-soluble 44CBP3 was further obtained by reacting 44BP3-COOH with aqueous ammonia solution. The presence of six negative charges makes it possible for this biphen[3]arene to act as a cation receptor in water. The host–guest recognition and self-assembly of 44CBP3 are introduced in the section “Cationic Water-Soluble 44CBP3.”

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Scheme 7 Synthesis of the anionic water-soluble 4,40 -biphen[3,4]arene [39–41]

12.3.2 Cationic Water-Soluble 44CBP3 Yu et al. demonstrated cationic water-soluble 4,40 -biphen[3]arene (44CBP3TM) with six quaternary ammonium groups (Scheme 8) [42]. The precursor 44BP3-Br, containing six alkyl bromide terminal groups, was prepared through the cyclization of monomer with para-formaldehyde in 1,2-dichloroethane in the presence of BF3O(Et)2 catalyst. It was easily functionalized to generate water-soluble 44CBP3-TM by treating 44BP3-Br with excess trimethylamine in methanol. Meanwhile, the self-assembly behavior of 44CBP3-TM was investigated.

12.3.3 Anionic Water-Soluble 22BP4 Besides the above-mentioned water-soluble 4,40 -biphen[n]arene, a water-soluble 2,20 -biphen[n]arene (22CBP4) containing eight carboxylato moieties was synthesized by our group (Scheme 9) using a similar synthetic procedure of 44CBP3 and 44CBP4 [43]. 22CBP4 has a very good solubility (10 mM) in water. In addition, the first example of complexation of biological and pharmaceutical molecules by 22CBP4 in water was investigated (Table 1).

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Scheme 8 Synthesis of cationic water-soluble 4,40 -biphen[3]arene [42]

Scheme 9 Synthesis of anionic water-soluble 2,20 -biphen[4]arene [43]

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Table 1 Association constants (Ka) for the complexation of guests with biphen[n]arenes and their derivatives Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Guest G1BArF G1BarF G1PF6 G2BarF G2BarF G3BarF G3BarF G4BarF G4BarF G5PF6 G6BarF G6BarF G72BarF G72BarF G8Cl G10Cl G11BarF G11BarF G11BarF G11BarF G11BarF G12BarF G12BarF G12BarF G12BarF G12BarF G132I G132I G142BarF G142BarF G142BarF G142BarF G142BarF G142BarF G142BarF G142PF6 G142PF6 G142Br G152Br G162Br

Host 44BP3 44BP4 44BP4-OH 44BP3 44BP4 44BP3 44BP4 44BP3 44BP4 44BP4-OH 44BP3 44BP4 44BP3 44BP4 44CBP3 44CBP4 22BP4 22BP5 22BP6 22BP7 22BP8 22BP4 22BP5 22BP6 22BP7 22BP8 44CBP3 44CBP4 44BP3 44BP4 22BP4 22BP5 22BP6 22BP7 22BP8 44BP4-OH 44BP4-OH 44CBP3 44CBP3 44CBP3

Solvent CDCl3 CDCl3 Acetone-d6 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 Acetone-d6 CDCl3 CDCl3 CD2Cl2 CD2Cl2 H2O H2O CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 D2O H2O CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 Acetone-d6 Acetonitrile-d3 D2O D2O D2O

Ka (M1) 28  2 (1.3  0.1)  103 32  4 29  1 570  40 28  2 (2.2  0.3)  103 26  3 (2.2  0.2)  103 160  20 b

(1.5  0.3)  104 b

(3.1  0.4)  104 (2.57  0.80)  104 (2.46  0.21)  104 (3.6  0.6)  103 (2.3  0.4)  104 (1.5  0.3)  104 (1.0  0.1)  104 (1.1  0.1)  104 (4.2  0.4)  103 (8.1  0.6)  103 (1.3  0.2)  104 (7.0  0.4)  103 (7.5  0.7)  103 (1.1  0.2)  104 (2.52  0.23)  104 b

92  5 92  14 63  13 110  17 170  17 250  26 58  5 170  20 (2.4  0.1)  104 (5.1  0.3)  104 (4.7  0.4)  103

Method NMRa NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR ITC ITC NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR ITCc NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR

References [25] [25] [38] [25] [25] [25] [25] [25] [25] [38] [25] [25] [25] [25] [39] [41] [26] [26] [26] [26] [26] [26] [26] [26] [26] [26] [40] [41] [25] [25] [26] [26] [26] [26] [26] [38] [38] [40] [40] [40] (continued)

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Table 1 (continued) Entry 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63

Guest G172Br G172PF6 G182Cl G182PF6 G192BarF G192BarF G202BarF G202BarF G202BarF G202BarF G202BarF G202BarF G202BarF G202Br G212BarF G212BarF G222PF6 G222PF6 G222PF6 G23PF6 G23PF6 G23PF6 G23PF6

64

G23PF6

65

G24

66

G26

67

G27

68 69 70 71 72 73 74

G28 G28 G29 G29 G30–G35 G30–G35 G36Cl

Host 44CBP3 44BP4-OH 44CBP3 44BP4-OH 44BP3 44BP4 44BP3 44BP4 22BP4 22BP5 22BP6 22BP7 22BP8 44CBP4 44BP3 44BP4 44BP4-OH 44BP4-OH 44BP3 44BP4-OH 44BP4-OH 44BP4-OH 44BP4-OH

Solvent D2O Acetone-d6 D2O Acetone-d6 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 CD2Cl2 H2O CD2Cl2 CD2Cl2 Acetone-d6 Acetonitrile-d3 Acetone-d6 Acetone-d6 DMSO-d6 DMF-d7 Acetone-d6/ CDCl3 (1:1, v/v) 44BP4-OH Acetone-d6/ CD2Cl2 (1:1, v/v) 44CBP3D2O TM 44CBP3D2O TM 44CBP3D2O TM 44BP3 CDCl3 44BP4 CDCl3 44BP3 CDCl3 44BP4 CDCl3 44BP3 CDCl3 44BP4 CDCl3 44CBP4 H2O

Ka (M1) (9.6  1.7)  103

(2.1  0.3)  103

Method NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR ITC NMR NMR NMR NMR NMR NMR NMR NMR NMR

References [40] [38] [40] [38] [25] [25] [25] [25] [26] [26] [26] [26] [26] [41] [25] [25] [38] [38] [38] [38] [38] [38] [38]

(3.1  0.3)  103

NMR

[38]

(1.56  0.07)  103 NMR

[42]

592  1

NMR

[42]

622  2

NMR

[42]

b

NMR NMR NMR NMR NMR NMR ITC

[25] [25] [25] [25] [25] [25] [41]

b

(1.5  0.2)  103 b b

41  6 34  4 320  30 640  30 (2.2  0.2)  103 (1.3  0.3)  103 (1.4  0.1)  103 (1.0  0.1)  103 (2.60  0.16)  104 39  2 390  10 230  30 240  30 b

250  20 b b

61  12 b

100  20 b b

(1.16  0.10)  104

(continued)

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Table 1 (continued) Entry 75 76 77 78

Guest G37Cl G38Cl G39Cl G40Cl

Host 44CBP4 44CBP4 22CBP4 22CBP4

Solvent H2O H2O H2O (pH 7.4) H2O (pH 7.4)

Ka (M1) Method (3.51  0.42)  103 ITC b ITC (5.87  0.24)  105 Fd (2.29  0.27)  106 F

References [41] [41] [43] [43]

a

Determined by the NMR titration method No interactions were found or the association constants were too small (0 λ20 λ2>0 +0.05

–0.05 Strong attraction Vander Waals interaction

Strongrepulsion

Fig. 9 (a) The lowest energy conformers of 44BP3 and 44BP4. (b) The lowest energy conformer of the 44BP4 and G28 complex. (c) Color-filled RDG isosurfaces depicting NCI regions in the G28  44BP4 complex. Green regions refer to π–π stacking as well as C–H  N and C–H  H–C interactions. The steric interactions are shown in red. Reproduced from Ref. [45] with permission from WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

cavity of 44BP4 according to the calculation. The orientation of the encapsulated guest parallel to the trans-biphenyl units is the lowest in energy (Fig. 9a, b). The complexation mechanism can be explained by the fact that G28 accepts electrons to form the anion radical G28. The confinement of G28 within the host cavity (cation radical 44BP4+) occurs due to a donor–acceptor interaction. Meanwhile, host–guest binding in such complexes is facilitated through hydrogen bonding and π–π stacking as well as C–H  π interactions (Fig. 9c).

12.9

Biological and Pharmaceutical Molecules

In 2016, we demonstrated the first host–guest complex of water-soluble biphenarenes towards biological and pharmaceutical molecules was demonstrated by our group [41]. 44CBP4 exhibited sequential binding for acetylcholine (G36Cl) ! choline (G37Cl) ! betaine (G38Cl), with the same sequence as the enzymatic reaction. The Ka value for G36Cl ((1.16  0.10)  104 M1, Entry 74) is 3.3 times larger than that for G37Cl ((3.51  0.42)  103 M1, Entry 75), while no obvious complexation was found for G38Cl (Entry 76). The selective binding of the neuromodulator G36+ is interesting as it plays important roles in cognitive and cerebral functions. 44CBP4 also strongly interacts with the pharmaceutical molecule 1-adamantanamine hydrochloride (G10Cl), with a Ka value of (2.46  0.21)  104 M1 (Entry 16).

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To date, only one water-soluble 2,20 -biphen[n]arene (22CBP4) has been reported. The binding behavior towards two pharmaceutical molecules, palmatine (G39+) and berberine (G40+), was also investigated [43]. Fluorescence titration experiments showed that G39+ and G40+ exhibited dramatic fluorescence enhancement of more than 600 times upon binding with 22CBP4. Particularly, the fluorescence intensity was strong enough to be readily distinguished by the naked eye (Fig. 10). Although the two guests have similar structures, the association constant of G40+ with

Fig. 10 (a) Fluorescence spectra of G39+ in the absence and presence of 22CBP4 in aqueous phosphate-buffered solution at pH 7.4. (b) Visible emission of G39+ and G40+ samples in the absence and presence of 22CBP4 under 365 nm. Reproduced from Ref. [43] with permission from Beilstein J. Org. Chem.

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22CBP4 (Ka = (2.29  0.27)  106 M1) is 3.9 times greater than that of G39+ (Ka = (5.87  0.24)  105 M1) (Entries 77 and 78). The easy accessibility, good water solubility, and favorable binding properties of these water-soluble biphen[n]arenes make them suitable for many applications in the biomedical field, such as chemical sensors, drug delivery, supramolecular amphiphiles, etc.

12.10 Self-Assembly Macrocycle-based self-assembly blocks have been widely investigated in supramolecular chemistry. Developing biphenarene-based self-assembly blocks is an efficient approach to translate biphenarenes into functional systems and materials for practical applications. The amphiphilic guest G9+, with a secondary ammonium-bearing hydrophilic head and an alkyl chain-bearing hydrophobic tail, was employed for complexation with 44CBP3 to construct a supra-amphiphile in water by electrostatic and hydrophobic interactions [39]. Due to the relatively poor solubility of G9+ in aqueous solution, another guest, G8+, was used as a model molecule for studying the inclusion properties with 44CBP3. It was found that 44CBP3 binds to G8+ in a 1:1 inclusion complex with a high association constant of (2.57  0.80)  104 M1 (Entry 15), indicating that G9+, with the same secondary ammonium recognition motif, could also have strong host–guest interactions with 44CBP3 in water. The optimal molar ratio for the amphiphilic assembly between 44BP3 and G9+ is 1:20,

Fig. 11 (a) DLS data of the G9+  44CBP3 aggregates. TEM images of (b) G9+  44CBP3 aggregates and (c) G9+  44CBP3 aggregates under pH = 4.0. (d) illustration of aggregate formation and the process of pH-responsive. Reproduced from Ref. [39] with permission from the Royal Society of Chemistry

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which provides a much lower critical aggregation concentration of 5.20  106 M as compared to that of G9+ alone 5.65  105 M, suggesting the formation of a stable host–guest complex with 44BP3. They can self-assemble into vesicular structures in water, as confirmed by transmission electron microscopy (TEM). In addition, dynamic laser scattering (DLS) experiments showed that the average diameter of aggregates was about 130 nm, with a clear Tyndall effect (Fig. 11). Of note, the self-assembling system was pH-responsive. When the pH was decreased to 4.0, the model guest pyrene contained in the hydrophobic layer of the vesicles could be released with the collapse of the vesicles. This study provides a potential possibility for delivery systems based on biphen[n]arene. Another cationic biphenarene derivative, the water-soluble biphen[3]arene (44CBP3-TM) bearing three trimethylammonium moieties on both sides, can encapsulate the amphiphile G25 to form a supra-amphiphile with a hydrophilic biphenarene head and a hydrophobic alkyl tail [42]. Sodium 1-hexanesulfonate (G24), as a model guest, was utilized to investigate the inclusion complex. The model guest could be encapsulated by 44CBP3-TM in a 1:1 stoichiometry with a Ka value of (1.56  0.07)  103 M1 (Entry 65) due to the main driving forces of hydrophobic and electrostatic interactions in water. In addition, 44CBP3-TM could bind to other anions such as sodium benzenesulfonate (G26) and sodium benzoate (G27) in a 1:1 stoichiometry, with Ka values of 592  1 M1 (Entry 66) and

Fig. 12 TEM images of (a) G25 and (b) G25  44CBP3-TM. (c) Enlarged image of G25  44CBP3-TM. (d) Illustration of aggregate formation. Reproduced from Ref. [42] with permission from the Royal Society of Chemistry

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622  2 M1 (Entry 67), mainly driven by electrostatic interactions. In particular, the critical aggregation concentration of the inclusion complex between 44CBP3-TM and G25 was evaluated to be 1.24  105 M, which is lower than that of G25 alone. It is believed that the supra-amphiphile forms through the host–guest recognition motif. TEM and DLS experiments assisted in the visualization of the self-assembly sizes and morphologies of the supra-amphiphiles. As shown in Fig. 12, TEM confirmed that 44CBP3-TM and G25 could self-assemble into regular nanoparticles with a diameter of ~18 nm in water, drastically different from the smaller micelles formed by G25 alone. The DLS results showed that the average diameter of the aggregates was ~19 nm, in agreement with the corresponding value obtained from the TEM images. Self-assembly has become a powerful method for the construction of functional nanoarchitecture, especially the formation of supramolecular organic gels by selfassembly of low-molecular-weight building blocks. Recently, our group reported the synthesis of terphen[n]arenes and quaterphen[n]arenes. Meanwhile, the macrocyclic pentamers and hexamers exhibit interesting self-assembly behavior, which leads to the formation of gels (G-TP5, G-TP6, G-QP5, and G-QP6) in organic solvent through intermolecular π  π interactions [27]. Powder X-ray diffraction experiments confirmed that organogel formation was governed by multiple π  π stacking interactions. As shown in Fig. 13, scanning electron microscopy (SEM) and TEM

Fig. 13 SEM and TEM images of (a) G-TP5, (b) G-TP6, (c) G-QP5, and (d) G-QP6. Reproduced from Ref. [27] with permission from WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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of the gels displayed that they had diverse morphologies with interwoven fibers, nanosheets, or entangled macropore networks. Radioactive iodine, with very long half-life of 1.57  107 years, is produced in the process of fossil fuel combustion from the nuclear power industry and spread rapidly in air and water. Thus, it is significant to capture and store radioactive iodine from nuclear fuel processing by appropriate adsorbents. Interestingly, these xerogels displayed a good ability to capture iodine not only in aqueous solution but also in the gaseous phase. The xerogels exhibited a good iodine adsorption capacity in the iodine vapor, with amounts of 0.67, 0.58, 0.35, and 0.49 g g1 for G-TP5, G-TP6, G-QP5, and G-QP6, respectively (Fig. 14b). In addition, the aqueous iodine solution changed from yellow to completely colorless at 30 min after the addition of G-TP5 (Fig. 14c). Furthermore, the time-dependent UV/vis curve of iodine in water dramatically decreased in the presence of G-TP5, with the iodine concentration reduced from 254 ppm to 10 ppm in 60 min. The absorbed iodine could be effectively released in methanol or by heating.

Fig. 14 (a) Time-dependent UV/vis absorption spectra of aqueous I2 solution upon G-TP5 addition. (b) Time-dependent I2 vapor uptake by the xerogels at 75  C. (c) Color change of the aqueous I2 solution upon G-TP5 addition. (d) Color change after adsorption of iodine by G-TP5. Reproduced from Ref. [27] with permission from WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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12.11 Conclusion In summary, as new classes of macrocyclic arenes in supramolecular chemistry, biphen[n]arenes, terphen[n]arenes, and quaterphen[n]arenes have been successfully designed and constructed. Due to their easy accessibility (one-step synthesis), π-electron rich cavities, and unique conformation, studies on their functionalization, molecular recognition, and self-assembly have been explored. For example, the macrocycles of biphen[n]arenes and their derivatives show good host–guest complexation abilities toward organic cationic guests and electron-deficient neutral molecules. The excellent self-assembly properties of long and rigid oligo (para-phenylenes) monomers of terphen[n]arenes and quaterphen[n]arenes render them amenable to gelation by self-assembly in organic solvent through intermolecular ππ interactions. The investigations of biphen[n]arene, terphen[n]arene, and quaterphen[n]arene chemistry are just in their infancy. Further studies of these macrocycles are urgently needed, including various functionalizations of biphen[n]arenes, the molecular recognition between biomacromolecules (i.e., peptides or proteins) and larger cavities of terphen[n]arenes and quaterphen[n]arenes, and the further derivatization of terphen[n]arenes and quaterphen[n]arenes. On the other hand, exploration of new members of extended biphen[n]arene families such as quinquephen[n]arenes and sexiphen[n]arenes can also be anticipated in the future. Last but not least, we believe that these macrocyclic arenes will receive increasing attention and that further research will be performed in the future. Acknowledgments We thank the National Natural Science Foundation of China (21772118 and 21472121), the Shanghai “Pujiang Program” (16PJD024), and the “Shuguang Program” for the financial support.

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Xuan Wu, Yong Chen, and Yu Liu

Contents 13.1 13.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Construction of Pillar[N]Arene-Based Supramolecular Polymer . . . . . . . . . . . . . . . . . . . . . . . 13.2.1 Supramolecular Polymer Formed by Host-Guest Interaction . . . . . . . . . . . . . . . . . 13.2.2 Supramolecular Polymer Formed by Hydrogen Bonding and Halogen Bond . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.2.3 Supramolecular Polymer Formed by Metal-Ligand Binding . . . . . . . . . . . . . . . . . . 13.2.4 Supramolecular Polymer Constructed by Covalent Polymer . . . . . . . . . . . . . . . . . . 13.3 Function of Pillar[N]Arene-Based Supramolecular Polymer . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.3.1 Chemical Sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.3.2 Stimuli-Responsive Soft Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.3.3 Application for the Nano-carrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.3.4 Application for Optical Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.3.5 Other Functional Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

As a new generation of macrocyclic host molecule, pillararene has attracted tremendous attention since its firstly being synthesized in 2008 [1] and advanced rapidly. Different with calixarene [2], which was meta-bridged phenolic macrocycles and X. Wu College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Y. Chen · Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_14

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exhibited the vase-shape architecture, the pillararene was para-bridged hydroquinone units or their derivatives, which was pillar-shaped novel hosts (Fig. 1). According to the number of repeating units, this type of hosts was named as pillar[n]arene (PnA). To enable this type of host molecules easy accessibility, three major strategies have thus been employed (Scheme 1) [3]. The first one is the Lewis acid-catalyzed condensation of 1,4-dialkoxybenzene and paraformaldehyde. The second one is the p-toluenesulfonic acid-catalyzed condensation of 1,4-dialkoxy-2,5-bis(alkoxymethyl) benzene. The last one is cyclooligomerization of 2,5-dialkoxybenzyl alcohols or 2,5dialkoxybenzyl bromides catalyzed by an appropriate Lewis acid. Due to the relatively low yields of high-order pillar[n]arene (n
7) [4], most researches have been focused on the P5A, P6A, and their derivatives. Based on these methods, a few modified strategies have been developed to synthesize functional unit modified pillar[n]arene to improve their binding affinity, thus resulting in the extensive application in both organic solution and aqueous solution [5]. Comparing to other macrocyclic host molecules, the pillar[n]arene presented some unique properties, such as totally symmetrical and relatively rigid structure, and versatile functionality, thus making them the promising candidates for applications in nanomaterials, molecular recognition, chemosensors, ion transport, supramolecular polymers, and so on [6]. Different from covalent polymers, supramolecular polymer was defined as polymers based on monomeric units held together by directional and reversible secondary interactions, resulting in polymeric properties in dilute and concentrated solutions, as well as in the bulk [7]. When the interaction between the monomers is generated by moderately strong, reversible noncovalent, but highly directional, forces that result in high-molecular-weight linear polymers under dilute conditions, the self-assembly is classified as a supramolecular polymerization. In supramolecular polymers, which are formed by the reversible association of bifunctional monomers, the average degree of polymerization (DP) is determined by the strength of the end group interaction [7b]. The degree of polymerization is obviously dependent on the concentration of the solution and the association constant, and a theoretical

Fig. 1 Crystal structure of DMP5A from the side (a) and upper view (b). (Reprinted with permission from Ref. [1a]. Copyright © 2008 American Chemical Society)

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relationship is given in Fig. 2. To obtain polymers with a high molecular weight, a high association constant between the repeating units is a prerequisite. Therefore, various types of supramolecular polymers have been successfully constructed incorporation with noncovalent interaction, such as hydrogen bond, π-π interaction, hydrophobic interaction, metal-ligand binding, etc. Among these noncovalent interactions, host-guest interactions have also attracted great interest OR Paraformaldehyde

Strategy 1:

Lewis Acid RO

R = alkyl

OR

OR OR1

Strategy 2:

CH2

p-Toluenesulfonic Acid

R1O RO

n RO

R1 = alkyl, benzyl

OR OR2

Strategy 3:

Lewis Acid RO

R2 = OH, Br

Scheme 1 Three synthetic routes for pillar[n]arenes

Fig. 2 Theoretical relationship between the association constant Ka and DP, using a simple isodesmic association function or “multistage open association” model. (Reprinted with permission from Ref. [7b]. Copyright 2001 © American Chemical Society)

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because there are multiple and cooperative noncovalent interactions in the inclusion complexes of hosts and guests. In this chapter, the supramolecular polymer constructed by pillar[n]arene was summarized, as well as their potential application, which is mainly focused on the pillar[5]arene and pillar[6]arene. And we hope it can provide inspiration for the constructions of smart materials based on pillar[n]arenes.

13.2

Construction of Pillar[N]Arene-Based Supramolecular Polymer

13.2.1 Supramolecular Polymer Formed by Host-Guest Interaction As a new generation of macrocyclic molecules, pillar[n]arene exhibited excellent host-guest properties due to their rigid structures, electron-rich cavities, and easy modification. Traditionally, the main driving forces to form the host-guest complexation were C-H•••π, C-H•••O, and cation•••π interaction. Based on these fundamental researches to explore the suitable guest molecules for this type host molecules, tremendous supramolecular polymers have also been successfully constructed. Huang and coworkers reported the first example of pillar[5]arene-based supramolecular polymer (Fig. 3) [8]. Based on the discovery that the n-hexane was included in the cavity of the copillararene in the crystal structure, a long alkyl chain as the guest molecule was modified onto the pillar[5]arene through the typical [4 + 1] cycloaddidtion, thus affording the A-B-type monomers. It was discovered that this molecule could self-assemble into the linear supramolecular polymer through the host-guest interaction both in solid-state and solution phases. In the crystal structure, the octyl group of a copillararene deeply inserted into the electronrich cavity of the adjacent copillararene and the monomers were arranged along an axis to form a head-to-tail linear supramolecular polymer. The cationic molecules could also be encapsulated into the cavity of pillar[n] arenes for their electron-rich cavity [9]. Due to the different sizes of pillar[5]arene

Fig. 3 (a) Schematic illustration of formation of supramolecular polymer reported by Huang and coworkers, (b) crystal structure of formed linear polymer. (Reprinted with permission from Ref. [8]. Copyright © 2011, John Wiley and Sons)

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and pillar[6]arene, they exhibited different binding affinities with different guest molecules. Traditionally, the pillar[5]arene had a better binding ability with the secondary ammonium salt, while the bulky guest molecules, such as paraquat and positively charged DABCO derivatives, preferred to binding with pillar[6]arene (Fig. 4) [10]. Therefore, the same strategy with the previous research, the secondary ammonium salt was modified to the pillar[5]arene to form the A-B-type monomer, whose binding constant was determined to be (2.40  0.20)  103 M1 in the chloroform. Driven by the strong host-guest interaction between these two motifs, the linear supramolecular polymer was formed. In addition, the obtained supramolecular polymer had anion responsiveness due to the ion-pair effect. As well known, the decrease in the ion-pair interaction would increase the binding ability, and the inverse proposition was also correct [5c, 11]. Therefore, the addition of Cl into the polymer solution, the formed supramolecular polymer would disassemble for the formation of tight ion pairs between the secondary ammonium cation and halide anion. If the imidazole unit was incorporated into the pillar[5]arene, a pHresponsive supramolecular polymer could be successfully constructed, in which the difference in the binding constants between pillar[5]arene/imidazolium motif and pillar[5]arene/imidazole motif played the vital role, whose values were (1.0  0.3)  104 M1 and (2.3  0.2)  102 M1, respectively, in chloroform [12]. These results indicated the pH would affect the degree of polymerization of these molecules, which meant in the acidic solution the higher-molecular-weight supramolecular polymer would be formed than in the neutral solution, concluded by the theoretical relationship between the association constant and degree of polymerization. Besides the single constituent to form the A-B-type supramolecular polymer, the hybrid polymers could be formed by adding another host molecule. Along with this line, Wang and coworkers synthesize a novel host molecules, in which the cryptand was fused into the pillar[5]arene, thus affording a host molecule with two cavities with different binding abilities (Fig. 5) [13]. From the fundamental research in the hostguest property, it was delighted to find that the cryptand cavity could selectively bind pyridinium cation and the pillar[5]arene cavity selectively bound the neutral guest with the cyano group at the end in an orthogonal manner. Therefore, the orthogonal supramolecular polymer could be successfully constructed by addition of two homoditopic guests with pyridinium cation and cyano group into the host solution.

13.2.2 Supramolecular Polymer Formed by Hydrogen Bonding and Halogen Bond Hydrogen bond, as an extensively exited noncovalent interaction, has been one of the research hotspots and widely applied into molecular recognition, construction of foldamers and helix structures, crystal engineering, as well as the supramolecular polymer. Among all types of hydrogen bond structures, ureidopyrimidinone (UPy) has attracted tremendous attention due to the high binding constant (107 M1 in chloroform), self-complementary structures, and easy access [7c]. Wang and coworkers firstly introduced this motif into the pillar[5]arene-based supramolecular

Fig. 4 Chemical structures of A-B-type supramolecular polymer reported by Ogoshi and coworkers. (Reprinted with permission from Ref. [10]. Copyright © 2012, Royal Society of Chemistry)

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Fig. 5 Hybrid polymer constructed by Wang and coworkers. (Reprinted with permission from Ref. [13]. Copyright © 2015, Royal Society of Chemistry)

polymer systems (Fig. 6) [14]. Due to the self-complementary nature of UPy motif, a series of UPy interlocked rotaxanes has been successfully synthesized using the strategy of “diamine threading followed by endcapping with UPy units,” in which the pseudorotaxane was firstly formed between the diamines and pillar[5]arenes followed by the endcapping reaction to form the UPy motif. In such novel dynamic polyrotaxanes, the UPy motifs particularly played quite important roles in the reversible formation of main-chain backbones of supramolecular polymers. The stepwise and one-pot strategies would provide a novel and efficient methodology for the smart design and construction of new types of higher-ordered architectures and sophisticated molecular devices. Wang and coworkers also reported other types of supramolecular polymer by modifying the UPy motif on the side ring of pillar[5]arene to form the bifunctional UPy pillar[5]arene, which could self-assemble into the linear supramolecular polymer by hydrogen bonding [15]. In this self-assembly manner, the cavity of pillar[5] arene was not occupied by other guest molecules. Therefore, the addition of the corresponding guest molecules would produce different topological self-assembly manners. The polypseudorotaxane could be constructed by adding diamine into the pillar[5]arene polymer [15b], and the polymer network could be formed by the

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Fig. 6 Graphical representation of the construction of dynamic polyrotaxanes reported by Wang and coworkers. (Reprinted with permission from Ref. [14]. Copyright © 2012 American Chemical Society)

addition of homoditopic guest with pyridinium cation molecule [15a]. Besides the abovementioned self-complementary UPy-based supramolecular polymer, the supramolecular polymer could also be constructed between the monofunctional UPy pillar[5]arene by introducing another noncovalent interaction [15c]. Herein, an orthogonal supramolecular polymer was reported by Wang and coworkers by introducing the homoditopic guest with pyridinium cation molecule into the monofunctional pillar[5]arene. As well known, the host molecule could form a dimer in the solution due to the strong binding affinity of UPy motif, and the pyridinium unit could be encapsulated into the cavity of pillar[5]arene. Based on these results, the orthogonal supramolecular polymer was formed. Halogen bond [16], similar to other noncovalent interaction, occurs when “there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity.” Although it is the least exploited noncovalent interaction, it has been

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widely applied in liquid crystals, nonlinear optics, separation of isomers, catalysis, and anion binding. Researches also have been conducted on the fabrication of pillar[5] arene-based supramolecular polymers [17]. Huang and coworkers firstly introduced halogen bond into pillar[5]arene-based supramolecular polymer [17a]. A pillar[5] arene derivative bearing two pyridyl groups as the halogen bond acceptor was synthesized, which could form a linear supramolecular polymer backbone with 1,4diiodotetrafluorobenzene (DITFB) in chloroform as well as in solid state (Fig. 7). With the supramolecular polymer backbone in hand, a linear side-chain supramolecular

Fig. 7 Schematic representation of the formation of the supramolecular polymer backbone and the side-chain polypseudorotaxane. (Reprinted with permission from Ref. [17a]. Copyright © 2018, John Wiley and Sons)

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polypseudorotaxane could be constructed by adding n-hexane. Moreover, the formation of polypseudorotaxane was certificated by X-ray crystal analysis. Połoński and coworkers reported two crystalline supramolecular polypseudorotaxanes constructed by combining permethylated pillar[5]arene as a macrocyclic wheel with 1,4-bis(1imidazolyl)butane and 1,4-bis(iodoethynyl)benzene or 1,4-diiodo-1,3-butadiyne linked by C–IN halogen bonds and creating a polyrotaxane axis [17b].

13.2.3 Supramolecular Polymer Formed by Metal-Ligand Binding Mental-ligand binding is also another widely existed binding module in the nature, which gradually evolved to be a controllable and highly efficient methodology for the construction of supramolecular architectures with well-defined shapes and sizes. The moderate bond energy (15–50 kcal/mol) of metal-ligand bonds, as well as their directional and predictable features, endowed these supramolecular coordination complexes considerable stability yet reversibility [18]. Along with this line, a new 120 monofunctionalized pillar[5]arene dipyridyl donor and 180 linear di-Pt(II) acceptors with different lengths were selected and synthesized to construct the hexakis-pillar[5]arene metallacycles by Yang and coworkers (Fig. 8) [19]. Due to the well-defined structures of the hexamers, they

Fig. 8 Schematic representation of the formation of supramolecular polymer gels reported by Yang and coworkers. (Reprinted with permission from Ref. [19]. Copyright © 2014 American Chemical Society)

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could act as the cores for the further construction of supramolecular polymer network after the addition of homoditopic guest molecules to form the host-guest complexation with pillar[5]arene. More importantly, by taking the advantages of the dynamic nature of metal-ligand bonds and host-guest interactions, reversible multiple stimuli-responsive gel-sol phase transition of such polymer gels was successfully realized, which could be destroyed by addition of TBABr and competitive guests and recovered by adding AgOTf to remove Br- and pillar[5]arene to remove competitive guests. Wang and coworkers adopted “threading followed by coordination” method to synthesize coordination polymer [20]. Firstly, the guest molecule with the pyridine unit as the ending group was synthesized, which could form a stable 1:1 complexation with pillar[5]arene. Due to the introduction of pyridine motif, the complex could further coordinate with metal cation to form the supramolecular polymer. Therefore, the Pd(OAc)2 was added to form the linear polymer for the 1:1 binding ratio between the pyridine guest and Pd(OAc)2. Interestingly, due to the partial encapsulation of guest molecules by pillar[5]arene, the intramolecular hydrogen bonding would exist between the formed polyrotaxane backbones, leading to the further cross-linking to form the supramolecular gel. Moreover, Shi and coworkers reported an orthogonal supramolecular polymer, in which the host-guest interaction, ππ stacking, and metal-ligand binding were introduced into this system (Fig. 9) [21]. Firstly, the terpyridine derivative with a long bromoalkyl chain was synthesized, which could form the 1:1 inclusion complex with pillar[5]arene by the recognition motif of bromoalkyl chain, as well as the 2:1 coordination compound with the Eu(III) ion by the terpyridine motif.

Fig. 9 The cartoon representation of the formation of a linear supramolecular polymer reported by Shi and coworkers. (Reprinted with permission from Ref. [21]. Copyright © 2017, Royal Society of Chemistry)

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Then, the electron-poor molecule, N,N0 -bis(n-butyl)pyromellitic diimide, was added to form an “exo-wall” complex with electron-rich pillar[5]arene due to the π•••π stacking, thus affording the linear Eu(III)-coordination fluorescent supramolecular polymer.

13.2.4 Supramolecular Polymer Constructed by Covalent Polymer The researches on covalent polymer-based supramolecular polymer was firstly conducted by Harada and coworkers, in which the cyclodextrins were used as the host molecules to encapsulate the linear polymer, such as PPG, PEG, and PVA, to form the polypseudorotaxane [22]. This combination of macrocyclic molecules and covalent polymers could expand the application of traditional polymer and construct functional materials, such as self-healing materials, slipping materials, isolated molecular wires, etc. Pillar[n]arene, as a new generation of host molecules with excellent properties, could also be applied to construct this type of supramolecular polymers, and the researches were mainly focused on two parts, one is to form the main chain encapsulated polymers, and the other is the side-chain supramolecular polymers. Similar with cyclodextrin-based main chain encapsulated polymers, Ogoshi and coworkers firstly reported the main chain polypseudorotaxane, by incorporating pillar[5]arene and viologen polymer (VP-8)) (Fig. 10) [23]. In this work, the inclusion complex was formed both in DMSO and the mixed solution of CH3CN and acetone and results in the charge transfer complex while exhibiting different dynamic behaviors. In the CH3CN and acetone system, the pillar[5]arene shuttling along the polymer axis was faster than the NMR time scale, concluded from NMR spectra. While in the DMSO solution, this shuttling movement was much slower than the NMR time scale. This dynamic behavior depended on the external temperature, at temperature above 60  C, the shuttling movement of pillar[5]arene was faster than the NMR time scale, and pillar[5]arene molecules dethreaded from the viologen polymer chain at temperature above 110  C. Moreover, the alkyl linker length between viologen motifs also affected the formation of supramolecular polymer; the shorter chain would decrease the potential to form inclusion complex. The adamantyl group was applied for the conversion of polypseudorotaxane to polyrotaxane as the stopping group, which exhibited excellent to stabilize the radical cation species due to the electron donors of pillar[5]arene molecules. Besides the viologen polymer, the polyaniline could also be concluded by pillar[5]arene for the strong reducing ability of the EB form in polyaniline. And tri(ethylene oxide) modified pillar[5]arene encapsulated polytetrahydrofuran to form the similar polyrotaxane. Some researches are also conducted to synthesize conjugated polymer incorporated pillar[5]arene. The pioneering work was firstly conducted by Müllen and coworkers by using the Sonogashira polycondensation between the diyne modified pillar[5]arene and dihalo-aromatic compound to obtain the conjugated polymer with the number-average molecular weight at 16 kDa [24]. However,

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Fig. 10 (a) Chemical structures of pillar[5]arene and viologen polymers, (b) dynamic behavior of polypseudorotaxane reported by Ogoshi and coworkers. (Reprinted with permission from Ref. [23]. Copyright © 2010 American Chemical Society)

the further construction of polypseudorotaxane was not conducted. The Sonogashira polycondensation was also applied by Cao and coworkers to synthesize another pillar[5]arene incorporated conjugated polymer (P1) with the number-average molecular weight (Mn) about 13 kDa. After binding the homoditopic guest, the polypseudorotaxane was successfully constructed (Fig. 11) [25]. Besides the mentioned polymer, the side-chain supramolecular polymers have also been fabricated. Wang and coworkers successfully synthesized the side-chain functionalized polyphenylethynylene, whose linker was flexible alkyl chain. After

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the binding with pyridinium cation, the polypseudorotaxane could be formed with the decrease in fluorescence intensity, which could be recovered by addition of halide ion to destroy the polypseudorotaxane [26]. Moreover, the pillar[6]arene and ferrocene were also be modified to the side chain of different polymers, respectively. Due to the high binding affinity between pillar[6]arene and ferrocenium

Fig. 11 (continued)

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Fig. 11 (A) Synthesis of pillar[5]arene-based conjugated polymer, (B) formation of polypseudorotaxane. (Reprinted with permission from Ref. [25]. Copyright © 2017, John Wiley and Sons)

cation (K = (2.0  0.1)  104 M1), the supramolecular cross-linked network could be formed after the addition of external redox reagent [27].

13.3

Function of Pillar[N]Arene-Based Supramolecular Polymer

As well known, supramolecular polymer was defined as polymers based on monomeric units held together by directional and reversible noncovalent interactions, which exhibited the dynamic nature upon the external stimuli, such as the temperature, pH, light, or competitive molecules. Therefore, with the careful design of pillar [n]arene-based supramolecular polymer, we could obtain the functional systems,

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which showed potential application in the chemical sensors, drug delivery systems, or other smart materials.

13.3.1 Chemical Sensors Fluorescent sensors have attracted attention for both analytical sensing and optical imaging because of their high sensitivity, fast response time, and technical simplicity [28]. Once the analyte is recognized by the receptor, the fluorescence signal can be observed in the form of quenching, enhancement, or shift in the fluorescence maxima due to either electron transfer, charge transfer, or energy transfer processes. This allows on-site and real-time detection in an uncomplicated and inexpensive manner, providing qualitative and quantitative information. Wang and coworkers reported a pillar[5]arene-modified conjugated host polymer (M1), using the polyphenylacetylene as the backbone (Fig. 12) [26]. Therefore, this polymer could form the side-chain supramolecular polymer with noctylpyrazinium cation guest. Due to the strong charge transfer between the guest molecules and conjugated polymer, the fluorescence was quenched. After the addition of the halide anion (tetrabutylammonium salts), the fluorescence recovery could be observed due to the strong ion-pair interaction between n-octylpyrazinium cation and halide anion. The fluorescence enhancement of this system increased in the order of I < Br < Cl, and the differences in fluorescence intensity could be easily distinguished by naked eyes under UV light illumination, acting as the halide anion probe. Wu and coworkers reported a thymine-substituted copillar[5]arene, which could coordinate with Hg2+ tightly through a THg2+T pairing to produce linear supramolecular polymer (Fig. 13) [29]. Moreover, a tetraphenylethylene (TPE) derivative was synthesized with a nitrile motif at the end of alkyl chain, which exhibited strong binding affinity with the pillar[5]arene. The copillar[5]arene and TPE derivative could only form the host-guest complex, which could not restrict the rotation of TPE motif, resulting in no fluorescence in the mixture solution. However, the addition of Hg2+ would lead to the formation of supramolecular network resulting from both the coordination interaction and the host-guest interaction, in which fluorescence of TPE would be on for restriction of TPE motif. Moreover, this system could selectively bind with Hg2+, due to the unique coordination capacity of Hg2+ toward the thymine moieties, and shield the interference of other metal ions. Finally, the bonded Hg2+ could be removed by the addition of S2, resulting in the generation of HgS precipitate, to regenerate the sensor systems. Lin and coworkers synthesized a bis-naphthalimide functionalized pillar[5] arene (MP5), in which the naphthalimide group could act as a ππ stacking site for the formation of linear supramolecular polymer as well as a fluorophore (Fig. 14) [30]. After the formation of the supramolecular polymer, it could further self-assemble into the stable π-gel, with strong aggregation-induced fluorescence in the cyclohexanol. Moreover, this supramolecular π-gel could successively sense Fe3+ as well as efficiently remove Fe3+ in water. The addition of Fe3+ into the gel would destroy the ππ stacking between the naphthalimide group and form the cationπ interaction, which could also maintain the structure of gels, while induce the quench in the fluorescence emission.

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Fig. 12 Cartoon representation of the formation of pillar[5]arene-modified pseudorotaxane and polypseudorotaxanes system and their responsiveness to Cl, Br, and I. (Reprinted with permission from Ref. [26]. Copyright © 2013 Xiao-Yu Hu and Le-Yong Wang. Published by Elsevier B.V)

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Fig. 13 Proposed strategy for the sensing and removal of Hg2+ based on the formation of supramolecular polymers. (Reprinted with permission from Ref. [29]. Copyright © 2017 American Chemical Society)

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Fig. 14 (a) Synthesis of bis-naphthalimide functionalized pillar[5]arene (MP5), (b) external stimuli of pillar[5]arene-based gels. (Reprinted with permission from Ref. [30]. Copyright © 2018. Royal Society of Chemistry)

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Compared with other reported fluorescent sensors for Fe3+, this work showed a lower detection limit, which was 6.06  108 M. Meantime, the quenched fluorescence could be recovered by L-Cys, which acted as the competition of ππ stacking and cationπ interactions in the gel state. Wei and coworkers reported a pillar[5]arene-based supramolecular organic framework for the detection of both metal ions and anionic molecules, in which two kinds of pillar[5]arene were incorporated (Fig. 15) [31]. Firstly, the bisthioacetylhydrazine functionalized pillar[5]arene (DPSH) could self-assemble into linear supramolecular polymer through the hydrogen bond. Then this linear assembly could further bind the bis-bromohexane functionalized pillar[5] arene (DPHB) through the host-guest interaction, which result in the successful construction of supramolecular organic framework. This framework showed a fluorescent response for Fe3+, Cr3+, Hg2+, and Cu2+ ions; the fluorescence emission of the framework was quenched. The lowest fluorescent response concentration of Fe3+, Cr3+, Cu2+, and Hg2+ for the framework was determined in the range of 1.0  106 M to 1.0  107 M by fluorescent titrations. Moreover, the framework containing the metal cations could also be used as the fluorescence probe for the anionic molecules for the competitive binding with the metal ions. For example, to the framework solution containing Fe3+, only the F and L-Cys could induce the emission of bright blue fluorescence at 456 nm. Other tested frameworks exhibited similar phenomena, the framework containing Hg2+ could selectively sense Br, and Cu-framework could selectively bind L-Cys. And the lowest fluorescent response concentrations were all determined to be in the range from 1.0  107 M to 1.0  108 M. This work showed a novel and efficient way for the development of multifunctional framework materials for multi-guests detection and recyclable separation.

13.3.2 Stimuli-Responsive Soft Materials Gels are soft solids or solid-like materials that immobilize a large amount of solvent in a three-dimensional network held together by covalent bonds and noncovalent or topological interactions [32]. These materials are appealing to various applications owing to their compositional and structural versatility that allows introducing responsiveness to external stimuli. Yang and coworkers prepared multiple stimuli-responsive supramolecular gels using metal-ligand bonds and host-guest interactions, in which discrete hexakispillar[5]arene metallacycles with different diameters were prepared by metal-ligand bonds between the di-pyridine modified pillar[5]arene and different linear di-Pt(II) acceptors [19]. Then the addition of ditopic guest containing nitrile motif, acting as the cross-linker, would result in the formation of cross-linked polymer, which further convert into the gels. These obtained supramolecular gels not only exhibited the thermal responsiveness but also exhibited responsibility to halide ions as well as the competitive guest molecules. As well known, the metal-ligand bonds possessed relatively moderate bond energies, which could be destroyed by the competitive ligand. In this system, the gel to sol transition behavior was observed when bromide

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Fig. 15 (a) The chemical structures of DPSH and DPHB; (b) cartoon representation for the formation of the SOF-THBP; (c) multi-guest-response properties of SOF-THBP and metal-ions coordinated SOFs; (d) recyclable separation properties of SOF-THBP. (Reprinted with permission from Ref. [31]. Copyright © 2017, John Wiley and Sons)

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anions were added, because the metal-ligand bonds were dissociated by the formation of Pt-Br complexes. The addition of AgOTf could remove the Br anion by formation of AgBr precipitate, thus resulting in the reformation of the discrete hexakis-pillar[5]arene metallacycles. Moreover, the competitive guest, 1,4-dicyanobutane, could also induce the gel-sol transition by destroying the hostguest interaction between the ditopic guest and the metallacycles. And the addition of the native pillar[5]arene to include the competitive guest would lead to the recovery of supramolecular gels. Wang and coworkers reported rotaxane-based stimuli-responsive supramolecular gels, in which the pseudorotaxane could be formed by the ditopic guest containing the pyridine as the ending motifs and pillar[5]arene (Fig. 16) [20]. After the addition of Pd(OAc)2, the metalla-supramolecular polymer could be formed with the rotaxane as the main backbone. Thanks to the intermolecular hydrogen between the guest molecules, the supramolecular gels could be obtained in a high concentration. Due to the dynamic nature of hydrogen bond, this gel exhibited responsiveness to the external temperature as well as the concentration of the gelators. Moreover, the gel to sol transition could also be achieved by the addition of PPh3 to destroy the previous metal-ligand bonds. However, due to the occurrence of precipitate, the reverse sol to gel transition could not be achieved. Yang and coworkers reported a stimuli-responsive blue fluorescent supramolecular gel based on the pillar[5]arene-modified TPE derivatives and corresponding guest molecules [33]. Firstly, they successfully synthesized the pillar[5]arene-modified TPE derivatives (H1) and the ditopic guest molecules (G2) containing the nitrile motifs (Fig. 17a) [33a]. Similar to the above gel formation process, the 2D supramolecular polymer could be generated by mixing the host and guest molecules, which could further aggregate into gels. The formation of large-scaled supramolecular polymer could restrict the rotation of TPE motif, affording the strong blue fluorescence emission. This fluorescent supramolecular gel exhibited responsiveness to the temperature and solvent. The increase in the temperature destroys not only the host-guest interaction but also the aggregation manners, leading to the destruction of supramolecular gels and the decrease in the fluorescence intensity. Moreover, they also explored the influence of alkyl chain length on the formation of stimuliresponsive supramolecular gels (Fig. 17b) [33b]. Two sets of pillar[5]arene-modified TPE derivatives (SH and LH) and neutral guests (SG and LG) with three binding sites were synthesized; the only difference in these molecules was the alkyl chain length, which could both form the supramolecular polymer by simply mixing corresponding host and guest molecules. However, only the set with long alkyl chain could form the supramolecular gels, resulting from the flexible structure induced looser supramolecular networks to include solvent molecules. And this supramolecular gel also exhibited external stimuli to the change in temperature. Zhang and coworkers synthesized a copillar[5]arene derivative containing one 1,4-bis(hexadecyl)benzene unit, which could form the supramolecular gels in the CH3CN solution, driven by the C-Hπ interaction and the van der Waals forces [34]. This gel showed the aggregation-induced enhanced emission at 450 nm. The addition of the electron poor competitive guest molecule, hexadecylpyridinium chloride,

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Fig. 16 Schematic of the formation of polyrotaxanes and sol-gel transformation reported by Wang and coworkers. (Reprinted with permission from Ref. [20]. Copyright © 2016. Royal Society of Chemistry)

would result in the destruction of the linear supramolecular polymer by the formation of host-guest complexation. Moreover, due to the strong charge transfer from the electron-rich pillar[5]arene and electron-poor guest molecule, the fluorescence could be quenched. The external temperature could also induce the reversible sol-gel transition, as well as the reversible change in the fluorescence emission.

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Fig. 17 (a) Schematic illustration of the construction of fluorescent supramolecular polymers. (Reprinted with permission from Ref. [33a.] Copyright © 2014. Royal Society of Chemistry). (b) Schematic illustration of the chemical structures of SH, SG, LH, and LG and fabrication of supramolecular assemblies of SGSH and supramolecular gel of LGLH. (Reprinted with permission from Ref. [33b]. Copyright © 2018, John Wiley and Sons)

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Researches also have been conducted on the polymer-based supramolecular gels, in which the cross-linked network was constructed by the host-guest interaction between the pillar[n]arene and corresponding guests. Wang and coworkers constructed a redox-responsive gel based on copolymers containing pillar[6]arene moieties and ferrocene derivatives (Fig. 18) [27]. Herein, the copolymers containing pillar[6]arene moieties and ferrocene derivatives were prepared. No supramolecular gels were formed by mixing these two polymers in an organic solvent because no complexes were formed between the ferrocenes and pillar[6]arenes moieties. However, the addition of an oxidant to the mixture triggered the formation of a supramolecular gel because the ferrocenes were converted to ferrocenium cations, which could be included by pillar[6]arene, resulting in the formation of cross-linked network. Moreover, this gel to sol transition could be achieved by the addition of competitive host (native pillar[6]arene) and competitive guest (cobaltocenium hexafluorophosphate), which could destroy the formed stable inclusion complex, leading to the destruction of supramolecular gels. Liao and coworkers constructed another type of polymer-based supramolecular gels (Fig. 19) [35]. Firstly, they synthesized a copolymer with pendant pillar[5]arene via free radical polymerization. Herein, a ditopic guest molecule with the pyridinium cation was synthesized for the cross-linker, which was different with the previous research by using the copolymer containing the guest molecules. The supramolecular polymeric gel based on the pyridinium-pillar[5]arene motif was fabricated readily by mixing the bifunctionalized guest with the copolymer. On the basis of the competition of host-guest interactions, such a gel could be transformed to sol by addition of competitive host (native pillar[5]arene) or guest molecules (butanedinitrile). Besides host-guest interactions, ordered stacking of pillararenes played an important role in construction of this supramolecular gel, which could realize the gel-sol transition by increasing temperature and the reverse process by decreasing temperature.

13.3.3 Application for the Nano-carrier With the development of supramolecular chemistry, supramolecular delivery systems are providing incredible opportunities for biomedicine, especially for the diagnosis and treatment of diseases, due to the dynamic nature of noncovalent interaction leading to the diversification of delivery systems [36]. The combination of macrocyclic molecules and the covalent polymers could provide more external stimuli responsiveness than the traditional polymeric drug delivery systems. Inspired by biodegradable and biocompatible polyglutamic acid, Wang and coworkers synthesized a butyl-ammonium group functionalized polymer (polymer 3) with the biotin moiety as the targeted unit (Fig. 20) [37]. Due to the host-guest interaction between butyl-ammonium group and the anionic pillar[5]arene (WP5), the side-chain supramolecular polymer could be obtained, which could further selfassemble into vesicles thanks to the electrostatic interaction and hydrophobic effect. Furthermore, this hollow assembly could encapsulate the hydrophilic anticancer drug mitoxantrone (MTZ). And the release of the encapsulated MTZ could be

Fig. 18 Schematic illustration of pillar[6]arene-based redox-responsive gels reported by Wang and coworkers. (Reprinted with permission from Ref. [27]. Copyright © 2015, American Chemical Society)

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Fig. 19 Schematic illustration of dynamic gels reported by Liao and coworkers. (Reprinted with permission from Ref. [35]. Copyright © 2016, American Chemical Society)

achieved in the cancer cell environment, resulting in the death of cancer cells. Moreover, the MTZ-loaded vesicles with targeting biotin ligands could not only improve the anticancer efficiency of MTZ but also effectively reduce the undesirable cytotoxicity toward normal cells. This method to construct polymetric nano-carriers based on host-guest complexation with covalent polymer showed great advantages in comparison to traditional polymers; tedious synthesis is often required. Huang and coworkers reported a dual-responsive nano-carrier based on azobenzene-containing random copolymer (3) and tri(ethylene oxide) modified pillar[7]arene (WP7) (Fig. 21) [38]. In this system, the azobenzene unit could be included into the cavity of pillar[7]arene, leading to the formation of polypseudorotaxane. Due to the introduction of pillar[7]arene, the amphipathy of the copolymer was changed, thus resulting in the formation of vesicles, which could encapsulate the model drug (calcein). Because of the thermoresponsiveness of tri (ethylene oxide) modified pillar[7]arene and photoresponsiveness of the azobenzene unit, the reversible transformations between solid nanospheres based on the selfassembly of the polymer backbone and vesicles based on the self-assembly of the supra-amphiphilic polypseudorotaxane are achieved by adjusting the solution temperature or UV-visible light irradiation. Therefore, the controlled release of the encapsulated cargoes could be achieved by both light and temperature. The same research group also conducted research on the pillararene-based amphiphilic supramolecular diblock polymer-based on the host-guest recognition between a watersoluble pillar[5]arene and a viologen salt. The efficient encapsulation and release of anticancer drug (doxorubicin hydrochloride) could be realized for the efficient cancer therapy. Liu and coworkers synthesized a novel lateral-modified pillar[5]arene derivative through bromination reaction at methylene bridge of the dimethoxypillar[5]arene, which could form the covalent polymer with cystamine dihydrochloride, exhibiting highly stable nanostructures, and possess very thin shells composed of lateral covalent cross-linked pillar[5]arenes (Fig. 22) [39]. By taking advantages of the structural features of the nanocapsule shell that composed of host macromolecules,

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Fig. 20 Schematic illustration of (a) the strategy for the construction of supramolecular polymersomes and (b) the fabrication of supramolecular polymersomes and their applications in targeted drug delivery. (Reprinted with permission from Ref. [37]. Copyright © 2014. Royal Society of Chemistry)

the tumor-penetrating peptide with the binding site with pillar[5]arene was introduced to construct the supramolecular polymer-based nano-carriers by host-guest manner, thus successfully developing it as a new target smart vehicle for efficient drug delivery. Huang and coworker synthesized a TPE and bipyridinium derivative modified brush copolymer (PTPE), which could form the side-chain supramolecular polymer with biotin-modified pillar[5]arene (P5-PEG-Biotin) due to the inclusion bipyridinium unit into the cavity of pillar[5]arene (Fig. 23) [40]. Furthermore, this supramolecular polymer could self-assemble into nanoparticles resulting in the

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Fig. 21 Illustration of the dual-responsive controlled assembly and disassembly of supramolecular vesicles and the process of dual-responsive release of calcein molecules. (Reprinted with permission from Ref. [38]. Copyright © 2015, American Chemical Society)

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Fig. 22 Designing of reductive-responsive pillar[5]arene-based single molecular layer polymer nanocapsules for targeting anticancer drug delivery. (Reprinted with permission from Ref. [39]. Copyright © 2018, American Chemical Society)

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Fig. 23 (a) Chemical structures and cartoon representations of M, P5, P5-PEG-Biotin, and PTPE. (b) Schematic illustration of the formation of SNPs self-assembled from the amphiphilic supramolecular brush copolymer P5-PEG-Biotin. PTPE and their use as drug delivery vehicles. (Reprinted with permission from Ref. [40]. Copyright © 2014. Royal Society of Chemistry)

enhanced fluorescence emission of TPE moiety at 471 nm, and due to the well overlap between the emission spectrum of TPE and the absorption spectrum of DOX, indicating that TPE could act as a fluorescent donor for DOX, the DOX was successfully loaded into the formed nanoparticles to form a self-imaging drug delivery system. This dynamic FRET system exhibited some advantage in the potential clinical therapy. When the DOX was released in the cancer cells, the energy

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transfer process would be broken, resulting in a variation in the fluorescence signal, which could be used to track the process of translocation, drug release, and excretion of the nanomedicine.

13.3.4 Application for Optical Materials Fluorescent material is an important kind of smart material, which can be applied in fluorescent sensors, optoelectronics, probes, biomedicine imaging, and light-emitting diodes [41]. Among the various fluorescent materials, fluorescent supramolecular polymers are very interesting as the fluorescent nature of the chromophores can be controllably regulated by polymerization process of supramolecular polymers. Yang and coworkers reported the switchable optical waveguide microfibers based on fluorescent supramolecular polymer for the first time (Fig. 24) [42]. Firstly, the pillar[5]arene-based supramolecular polymer was constructed by mixing the bispillar[5]arene host and diphenylanthracene-derived guest with ditopic binding sites. And the supramolecular polymeric microfibers were prepared easily from the viscous solution. This obtained microfibers could act as an active optical waveguide material with long propagation distance (400 μm) and low optical propagation loss (0.01 dB/μm), which was much longer than the most reported organic micro/nanocrystalline waveguide materials, providing a chance to investigate the long-distance light propagation. Moreover, the ternary supramolecular microfibers could be obtained by the addition of dithienylethene-based guest molecular. Due to the overlap between the emission band of diphenylanthracene and the absorption band of dithienylethene in the closed form, the switchable optical waveguide system could be successfully constructed, in which the clear blue emission was detected at the other tip, indicating the light propagation of this microfiber, while after the irradiation, the light propagation of the microfiber was inhibited, ascribing to the energy transfer from the diphenylanthracene units to the dithienylethene units.

Fig. 24 Switchable optical waveguide microfibers reported by Yang and coworkers. (Reprinted with permission from Ref. [42]. Copyright © 2018, American Chemical Society)

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Wang and coworkers reported a FRET-capable supramolecular polymers based on a boron-dipyrromethene (BODIPY)-bridged pillar[5]arene dimer with BODIPY guests for mimicking the light-harvesting system of natural photosynthesis [43]. Herein, two guest molecules were synthesized with bis-binding sites and tri-binding sites for pillar[5]arene, thus constructing the AA/BB-type and A2/B3-type supramolecular polymers. Due to the overlap between the emission band of host molecules and the absorption band of guest molecules, the fluorescence (or Förster) resonance energy transfer (FRET) could be occurred, and the transfer efficiency was calculated to be 51% and 63%, respectively. This was the first example of pillar[5]arene-based supramolecular polymers for mimicking the light-harvesting system. Tian and coworkers reported an emission-tunable supramolecular polymer by changing metal ion types or using mixed metal ions (Fig. 25) [44]. Firstly, the Fig. 25 Schematic depiction of the fluorescent supramolecular hyperbranched polymer prepared from monomer B3, AC, and metal ion by orthogonal self-assembly. (Reprinted with permission from Ref. [44]. Copyright © 2018, John Wiley and Sons)

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homotritopic pillar[5]arene monomer (B3) was synthesized, which comprised of three symmetrical pillar[5]arene groups linked by rigid alkynyl chains, as well as the heteroditopic building block (AC), which contained a terpyridyl ligand group and a triazole binding site. After the addition of metal ions, the hyperbranched polymer could be constructed by orthogonal self-assembly: pillararene-based host-guest interaction and metal-ligand bond. By simply altering the metal ions or the percentage of mixed metal ions, different emission colors could be observed. Moreover, the addition of competitive ligand could result in the quench in the fluorescence emission. This method would provide a convenient approach toward the construction of structure-tunable fluorescent supramolecular materials with different colors. Moreover, Cao and coworkers also pioneeringly conducted researches on the OLED devices based on the AA/BB-type supramolecular polymers constructed by pillar[5]arene (Fig. 26) [45]. The monomers H3 and G3 were designed based on fluorene derivatives that lead to a blue emission. Another guest molecule G4 was synthesized based on fluorene-co-benzothiadiazole derivatives with a green-emitting character as the dopant unit in the formed linear AA/BB-type supramolecular polymers. As a result of the efficient energy transfer caused by the exciton trapping on narrow band gap guest G4, by applying a doping strategy, the light-emitting color of the resulting polymers could be easily turned from blue to green. Meanwhile, photoluminescent efficiencies up to 81.6% were obtained. All the supramolecular polymers prepared in this work were utilized as the emissive layers (EMLs) in light-emitting devices, and a maximum luminance efficiency (LE) of nearly 5 cd A1 was achieved.

13.3.5 Other Functional Materials Thermal responsive materials have been widely researched due to their potential application in controlled drug release, molecular separation, and tissue culture substrates [46]. As well known, their lower critical solution temperature (LCST) was depended on their external environment. Along with line, Yu and coworkers constructed a side-chain supramolecular polymer by using the paraquat modified copolymer and water-soluble pillar[10]arene (WP10) [47]. After the formation of supramolecular polymer, the TCP was improved by the gradual addition of WP10, caused by the increased electrostatic repulsion and steric hindrance arising from the introduction of WP10, which inhibited intra/interpolymer aggregations in solution more effectively. Moreover, the addition of competitive guest molecule, 1,10-phenanthrolinium, would destroy the supramolecular polymer, resulting in the recovery of TCP to the original value, reflected by the transparency of the solution. This method to tune the transparency of solution would be applied as the smart window [48]. Wang and coworkers synthesized a supramolecular cross-linker polymer network by the host-guest interaction between the glycol-modified pillar[6] arene (EGP6) and the ferrocene groups [48b]. Due to the thermal responsiveness of EGP6, the transparency of the hydrogel could be reversibly tuned by the temperature. In the relatively high temperature, the hydrogel became turbid, thus regulating the input of solar energy for a more comfortable indoor environment. Moreover, by

Fig. 26 The construction of supramolecular polymers with different emitting colors and model device structure reported by Cao and coworkers. (Reprinted with permission from Ref. [45]. Copyright © 2017, American Chemical Society)

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addition of ATO nanoparticles, which could result in plasmonic heating induced by NIR absorption, the photoresponsive smart window was successfully constructed (Fig. 27) [48a]. The swelling-shrinking materials have been utilized as shape-memory polymers, artificial muscles, and actuators [49]. However, the swelling-shrinking transition of hydrogels was either in small degree or did not efficiently exhibit responsiveness to external multistimuli in these systems. Wang and coworkers report a smart hydrogel whose swelling ratio could be dramatically promoted by host-guest interaction based on water-soluble pillar[6]arene (WP6), and the well-swollen hydrogel showed good

Fig. 27 Chemical structures and schematic illustration of sunlight-induced photo-thermochromic supramolecular nanocomposite hydrogel film for smart window reported by Wang and coworkers. (Reprinted with permission from Ref. [48a]. Copyright © 2018, John Wiley and Sons)

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Fig. 28 Illustration of the dramatically promoted swelling by WP6-ferrocene host-guest interactions and subsequently pH-responsive swelling-shrinking transition and application in controlled drug (DOXHCl) release. (Reprinted with permission from Ref. [50]. Copyright © 2016, American Chemical Society)

multistimuli responsive behaviors (Fig. 28) [50]. Firstly, the ferrocene group modified cross-linked polymer was synthesized, which exhibited little swollen ratio. After binding with WP6, formation of side-chain supramolecular cross-linked polymer, the swollen ratio was dramatically improved to more than 25 times. Moreover, in an acidic environment, the swelled hydrogel could shrink, and this process exhibited excellent reversibility. Taking advantage of this swelling-shrinking transition, the controlled uptake and release of DOX could be achieved, which might have potential application as controlled drug delivery systems.

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Conclusion

In summary, the pillar[n]arene-based supramolecular polymer has attracted tremendous attention in the past decade. We could easily construct various pillararenebased supramolecular polymeric assemblies with various topologies and properties

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by employing the host-guest properties of pillararenes for their facile modification and intrinsically intriguing inclusion properties. Moreover, due to the dynamic nature of the noncovalent interaction between pillar[n]arene and corresponding guest molecules, these assemblies exhibited excellent responsiveness to external stimuli, such as pH, concentration, solvent polarity, temperature, photochemistry, and competitive components. Therefore, they might have potential application into the chemical sensors, stimuli-responsive materials, and optical materials. However, compared to crown ethers, cyclodextrins, calixarenes, and cucurbiturils, it is still an immature project to build pillararene-based supramolecular polymers. There are a lot of challenges and opportunities in this emerging research field. Firstly, although various pillar[n]arene-based supramolecular polymer was successfully constructed, little efforts had been engaged in the research their properties and applications, especially in the energy and environment fields. Secondly, to date most researches were conducted in the organic solvent and mainly focused on the pillar[5]arene and pillar[6]arene, which would limit their potential application in the biological fields as well as the real life. Finally, how to combine the lab research with the industrial production was still the barrier to overcome.

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Part III Supramolecular Assemblies Based on Cyclodextrins

Functionalized Cyclodextrins and Their Applications in Biodelivery

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Jiang Liu, Peng Yu, Matthieu Sollogoub, and Yongmin Zhang

Contents 14.1 14.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Selectively Functionalized Cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.2.1 Functionalization of Cyclodextrins on the Primary Rim . . . . . . . . . . . . . . . . . . . . . . 14.2.2 Functionalization of Cyclodextrins on the Secondary Rim . . . . . . . . . . . . . . . . . . . 14.3 Applications of Cyclodextrins as Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3.1 Cyclodextrins as Gene Delivery Efficiency Enhancers . . . . . . . . . . . . . . . . . . . . . . . . 14.3.2 Cyclodextrin-Based Multivalency Drug Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3.3 Cyclodextrin Assembled Nanocarriers Based on Enhanced Permeability and Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3.4 Sensitive Molecules Transported by Cyclodextrin Nanocarriers . . . . . . . . . . . . . . 14.3.5 Stimuli-Responsive Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3.6 Delivery of the Extremely Hydrophobic Molecule C60 . . . . . . . . . . . . . . . . . . . . . . . 14.4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.5 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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J. Liu · M. Sollogoub Centre National de la Recherche Scientifique (CNRS), Institut Parisien de Chimie Moléculaire (IPCM), Unité Mixte de Recherche (UMR) 8232, Sorbonne Université, Paris, France P. Yu China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China Y. Zhang (*) Centre National de la Recherche Scientifique (CNRS), Institut Parisien de Chimie Moléculaire (IPCM), Unité Mixte de Recherche (UMR) 8232, Sorbonne Université, Paris, France China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China e-mail: [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_15

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Introduction

The history of cyclodextrins (CDs) began in France in the late nineteenth century, with the work of a pharmacist and chemist, Antoine Villiers, on the action of enzymes on various carbohydrates, which he particularly studied using the butyric ferment Bacillus amylobacter (Clostridium butyricum) on potato starch. After the starch was treated with the butyric ferment method, a lot of chemicals were obtained, of course, and some of the by-products attracted Villiers’s attention. By manipulating the experimental conditions, Villiers obtained two distinct crystallized “cellulosines” (as named by Villiers)—most probably, α-dextrin (α-cyclodextrin) and β-dextrin (β-cyclodextrin). It was only in 1972 that Manor and Saenger demonstrated that the formula of one of these cyclodextrins was ((C6H10O5)6-H2O) [1]. Once the structures of CDs were confirmed, chemists started to modify the hydroxyl groups of CDs to yield plentiful applications. The hydroxyl groups of each sugar unit at the 2-, 3-, and 6-positions compete for nucleophilic reagents in most conditions, making selective modification extremely difficult. In fact, there are minor differences among them—for example, the hydroxyl groups at position 2 (OH-2) are the most acidic (acid dissociation constant (pKa) 12.2) [2], those at position 6 (OH-6) are the most nucleophilic, and those at position 3 (OH-3) have the lowest reactivity. These features give CDs considerable potential for functionalization via modification of specific hydroxyl groups. On the basis of this, pioneering chemists have developed various different selective functionalization strategies, including site-selective functionalization [3], which has been a boon to those who need special functionalized molecules to fulfill new purposes they have devised. According to the chemical and physical properties of CDs, the water solubility of enhanced hydrophobic molecules is one of the special properties of CDs. In one remarkable example, Zhang and coworkers used conjugation of functionalized CDs with C60 to improve the water solubility of C60 by 1010 times [4]. Also, there has been some interesting work on cytotoxic anticancer drugs, most of which have very low solubility in aqueous media and low apparent permeability as well [5]. To overcome these problems, scientists have designed and prepared various delivery systems based on CDs, which have demonstrated good results. Some scientists have even synthesized stimuli-responsive delivery systems that release drugs in an acidic environment (pH 6.8), such as the tumor microenvironment [6, 74]. Functionalized CDs can also be employed as platform molecules—for example, their hydrophobic cavities interact with some hydrophobic molecules, such as some drugs, to improve their water solubility and optimize their bioavailability. Hydroxyl groups modified for such purposes can be used in specific preferred applications such as multivalent carriers and targeted drug delivery systems. In this review we first discuss CD functionalization methods and then discuss their delivery applications.

14.2

Selectively Functionalized Cyclodextrins

Selectivity is an essential meaning in chemistry, which attracts all chemists’ attention, and the same situation also occurs in cyclodextrin chemistry. Although use of regioselectivity as an effective method to access a specific hydroxyl group at a

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preferred position has made some significant progress, there are still some central chemical challenges in cyclodextrin chemistry. Some examples are described in the following sections.

14.2.1 Functionalization of Cyclodextrins on the Primary Rim 14.2.1.1 Cyclodextrin Capping Strategy In cyclodextrin chemistry, capping strategies are very useful and historical techniques for functionalization of cyclodextrins. They can be traced back to 1976, when the first rigid cap (a diphenylmethane cap) was reported by Tabushi et al. [7]. They then developed a series of rigid aromatic disulfonyl chloride capping systems, which enriched regioselective functionalization in cyclodextrin chemistry [8] (Fig. 1). The method for introducing two different groups on the primary rim of β-CD was first reported by Tabushi [9]. They used oxidized N-benzyl-N-methylaniline-p, p0 -disulfonate as a cap on the primary rim of β-CD moieties to produce four inseparable isomers, 1–4, which were treated with NaN3 and then thiophenol— two different kinds of nucleophilic reagents—to afford “combination selectivity” in the preparation of unsymmetrically substituted cyclodextrins (CDXYs) 9–12 (Scheme 1). Breslow also employed a similar strategy to introduce a selective cap at positions A and B of β-CD via phenylsulfonyl chloride substituted then treated with KI to obtain CD 13. The iodine-substituted CD 13 was treated with dithiol reagent 14 to afford asymmetric A,B and B,A capping of β-CD isomers 15 and 16. This was another early-stage example of regioselective functionalization of CDs to produce A, B and B,A isomers, which were not controllable [10] (Scheme 2). 14.2.1.2 Site-Oriented Selectively Functionalized Cyclodextrins As mentioned above, several significant sulfonylation techniques have been demonstrated that are applicable to preparation of di-sulfonylations on the primary rim of CDs, the use of sulfonylation techniques is required to design and synthesize special regioselective sulfonyl reagents, which are not a general solution for regioselective functionalization of CDs. Scientists never stop trying to devise more general, more efficient, higher-yielding, and more selective methods for functionalization of CDs. To selectively deprotect the per-protected CDs was another way of achieving regioselective functionalization of CDs. When Sinaÿ and coworkers [11, 12, 13a] studied benzyl deprotection of sugars with aluminum reagents, they found that a structure of two oxygen atoms was necessary for these reactions (Table 1). They proposed a mechanism for diisobutylaluminum hydride (DIBAL-H)–mediated deprotection: the first aluminum reagent was chelated by the two oxygen atoms to form 18, and the second aluminum reagent would attach the less-hindered oxygen atom by coordination to form 19. During this process, the aluminum plays a Lewis acid role in activating the C–O bond and also delivers its hydride to form a PhMe at the same time, giving 20. After being quenched by H2O, complex 20 will give alcohol 21. On the basis of this mechanism, they found that some aluminum reagents such as DIBAL-H could be used to remove the benzyl group from the perbenzylated

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Fig. 1 First reference to a capped cyclodextrin [7]

sugars and CDs. This discovery could also be applicable for functionalization on the primary rim of CDs, resulting in the introduction of two or more different functions on the primary-rim regioselectively [11, 12] (Scheme 3). Furthermore, they found that the double debenzylation reaction occurred by a stepwise process, which meant it was possible to stop the reaction at the monohydroxy cyclodextrin (23) stage if the reaction time was controlled well. After being treated with DIBAL-H, 23 would give cyclodextrin diol 25 with an excellent yield,

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Scheme 1 Selective capped β-cyclodextrin (β-CD) strategy to prepare differentiated β-CD derivatives [9]

which was similar to the treating of the perbenzylated CD with DIBAL-H directly. According to this, they found that the first deprotection directed the second one, which was very interesting and useful. This process had this directed manner because in the first deprotection reaction, the DIBAL-H coordinated with the monohydroxy cyclodextrin, 23, to form an alumina oxide derivative, 24, which could contribute steric hindrance to force the second aluminum reagent to reach the O-benzyl group from the farthest sugar unit in 24 to give diol 25 (Scheme 4) [13, 14].

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Scheme 2 Breslow’s selective capped β-cyclodextrin (β-CD) strategy [10]

Table 1 Different substrates treated with aluminum reagents [13a] Entry

Reagent (equiv.) DIBAL-H (5)

Time [h] 96

DIBAL-H (5)

4

TIBAL (5)

18

DIBAL-H (10)

5

Result No reaction

Yield [%] 0 89

No reaction

0 80

DIBAL-H diisobutylaluminum hydride, equiv. equivalent, TIBAL triisobutylaluminum

Scheme 3 Mechanism of diisobutylaluminum hydride (DIBAL-H)–induced debenzylation [13a]

Because of steric hindrance, the deprotection manner directs the second deprotection reaction occurring at the opposed sugar unit. This manner can be used to approach some new patterns, so Guieu and Sollogoub [14] introduced a vinyl group at the A unit of CD 26. After treatment with DIBAL-H in a small equivalent (2.0) for 2 h, 26 would give 27, a clockwise guidance product. In a larger equivalent (30.0) of DIBAL-H for 1 h, 26 would give 28, with clockwise guidance and a

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Scheme 4 Double debenzylation of perbenzylated cyclodextrins occurs by a stepwise mechanism, with the first debenzylation orienting the second [101]

hindrance-directed diol. Two conclusions were drawn: (1) when the sugar unit coordinates with the Al reagent, it provides huge steric hindrance, which orients the deprotection reaction to the opposed sugar unit; and (2) the steric decompression guides the deprotection reaction clockwise to the neighbor sugar (Scheme 5) [15] (Fig. 2). Sollogoub and coworkers [15] also reported a capping strategy for disarming the protection of benzyl groups on the primary rim of CDs. They outlined how capping of a CD could be dissymmetric in the cap formation or, more rarely, in its opening. Unlike the disulfonyl chloride capping strategy, the researchers chose perbenzylated CDs as a starting material after a DIBAL-H-induced deprotection reaction to give diol 29. Then 29 was followed by allylation to give an uncapped product, 30. Via a masterly metathesis reaction, the two alkyls built a bridge to give a capped CD, 31, with a good yield. The bridge would provide some steric hindrance, which could selectively introduce a DIBAL-H-mediated deprotection reaction at the neighbor glucose units of both cap sites. A striking example of this strategy is shown in Scheme 6. The capped CD 31 was treated by DIBAL-H to give the only diol compound, 32, in an 85% yield. Interestingly, the uncapped CD 30 under the same DIBAL-H deprotection reaction conditions afforded three diols: 29, 34, and 35. These results could strongly prove the “critical importance” of the cap for regioselective debenzylation [13b]. There was also another very smart thing in the olefin cap strategy: the olefin cap could be reopened by a metathesis reaction that stored the allyl easily, and the allyl had high potential to be further modified. The same olefin cap strategy also worked on β-CD, but the most different part was that for β-CD it would afford regioisomeric diols 39 and 40 with 60% and 14% yields, respectively, which was very impressive (Schemes 6 and 7). A similar strategy was reported by Bols and coworkers [16], who introduced a propene bridge to the diol CD as a cap. On the basis of this strategy, Sollogoub and

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Scheme 5 Clockwise and opposed sugar–directed deprotection reactions [101]

Fig. 2 Clockwise and opposed sugar–directed deprotection reaction [101]

coworkers treated the capped CD 41 with DIBAL-H. In different concentrations of DIBAL-H and at different temperatures, it displayed different selectivity. For example, treated 41 with 1 M of DIBAL-H, heated to 50  C, produced 42-A in a 90% yield. With 0.1 M of DIBAL-H at room temperature, it produced 42-B in a 52% yield. Compound 42-A was treated with tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and then Pd to form tridifferentiated compound 43, and compound 42-B was also further modified to give 44-A and 44-B [14, 17]. In comparison with the olefin cap strategy, this new strategy was a great improvement in terms of both yield and selectivity, and even provided a new selectivity by which Sollogoub and coworkers could make a primary-rim-differentiated CD, especially to achieve hexadifferentiated α-CD [3] (Scheme 8). In the work on hexadifferentiated α-CD, the propene cap played a very important role in offering precise selectivity for deprotecting the benzyl at the C sugar unit. Sollogoub and coworkers [3] introduced hexadifferentiated groups into the primary rim of α-CD via five DIBAL-H deprotection reactions. First, perbenzylated α-CD 45 was treated with DIBAL-H to afford monol-CD 46, then the only hydroxyl group was substituted by olefin after oxidizing and Wittig reactions; second, olefin-CD 47 was treated with DIBAL-H to generate a clockwise deprotection reaction derivative, 48, then the hydroxyl group was substituted by an azide group; third, azide CD 49 was treated with DIBAL-H to give an opposed deprotected amino alcohol CD, 50, then the amino and alcohol positions were bridged by

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Scheme 6 Bridging and open bridge strategy for synthesis of tridifferentiated α-cyclodextrin (α-CD) [15a, 15c]

Scheme 7 Bridging strategy for synthesis of tridifferentiated β-cyclodextrin (β-CD) [15b]

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Scheme 8 Tridifferentiation of α-cyclodextrin (α-CD) [17]

propane to give a bridged CD, 51; fourth, CD 51 was treated with DIBAL-H to generate another clockwise deprotected CD derivative, 52, then after a few steps the amino was protected by a benzyl group and the alcohol was substituted by an azide group to afford another azide CD, 53; and fifth, azide 53 was treated with DIBAL-H to give the final compound, 54 (Scheme 9). On the basis of the above description, obviously these were a series of very exciting discoveries, which also could prove that DIBAL-H-mediated deprotection of benzyl groups from perbenzylated CDs was quite successful. Why is the benzyl group deprotected method so useful? It is because this method supplies excellent regioselectivity and a high yield. There are also other reasons; for example, perbenzylated CDs are easily soluble in ordinary solvents, which can provide researchers with at least two evident benefits: (1) they are easy to purify in organic solvents; and (2) they react easily with many more reagents in solvents. This is why, a few years later, some researchers could synthesize more complicated CD derivatives, such as by using hexadifferentation for α-CD and heptadifferentiation for β-CD [manuscript in preparation], which promoted the development of CD chemistry and other related areas. Functionalization of the secondary rim normally is more difficult than modification of the primary rim, because the hydroxyls under the secondary rim show significant properties that differ from those of the hydroxyls on the primary rim. The pKa value of the C-2 hydroxyl is 12, and it can be selectively activated by a strong base, such as NaH, but one needs to use a certain amount of the base to avoid activating the primary hydroxyls by mistake. The C-3 hydroxyl—the least reactive one—always reacts after C-6 and C-2, which also can easily be selectively functionalized [18].

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Scheme 9 Hexadifferentiated α-cyclodextrin (α-CD) procedure [3]

14.2.2 Functionalization of Cyclodextrins on the Secondary Rim 14.2.2.1 Supramolecular Inclusion Complex Strategy To functionalize the secondary rim, sometimes a supramolecular strategy also works. Ueno and Breslow [19] designed a guest molecule conjugated with a promodified part, meta-nitrophenyl tosylate, which would be caught by the cyclodextrin via host–guest interaction to make a better chance for the tosyl(Ts) group close to the hydroxyls on the secondary rim not these on the primary rim.

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Mono-tosyl-β-cyclodextrin 56 was prepared by use of a group transfer strategy. Meta-nitrophenyl tosylate reacts with β-cyclodextrin 55 in a dimethylformamide (DMF)/water buffer. Though this method gave only a 10% yield of 56, it could avoid a random modified product. For this reason, the supramolecular concept strategy is still very smart and inspired (Scheme 10). After decades of work, Ho Law and Jacques Defaye [20] optimized this reaction by using a more active tosyl group donor, 1-( p-tolylsulfonyl)-(1H )-1,2,4-triazole, 58, instead of 3-nitrophenyl p-toluenesulfonate, to give a 42% yield with mild conditions. They added 58 into the NaH-deprotonated DMF solution at room temperature. After concentration, the residue was quenched by water, followed by acetone precipitation from the aqueous solution, and the unreacted starting material and crude were separated. The solution was filtered over the column to give 59 in a 42% yield (Schemes 11, 12, 13). Sollogoub and coworkers [24] also developed another functionalized method on the secondary rim. They treated perbenzylated CD 60 with Et3SiH and I2 (6.6 equiv.) for 30 min, from 60 to 35  C, to get compound 61, with a deprotection reaction occurring at the 3-O position of α-CD, in a good yield of 58%. Electrospray ionization mass spectrometry (ESIMS), 1H nuclear magnetic resonance (NMR) spectroscopy, and correlation spectroscopy (COSY) NMR showed that compound 70 was produced with high selectively (Scheme 12).

Scheme 10 Functionalization under the secondary rim via host–guest interaction [19]

Scheme 11 Sulfonyl reagent 1-( p-tolylsulfonyl)-(1H )-1,2,4-triazole introducing the Ts group [20]

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Scheme 12 Selective deprotection on the secondary rim of perbenzylated cyclodextrin [24]

Scheme 13 Rigid benzophenone-3,30 -disulfonate bridging strategy for secondary-rim functionalization [21]

14.2.2.2 Bridging Cyclodextrin Strategy Yamada and coworkers [21] designed and synthesized benzophenone-3,30 -disulfonyl imidazole, 62, as a rigid sulfonylated reagent to modify the hydroxyls under the secondary rim by treating benzophenone-3,30 -disulfonyl chloride with triethylamine and imidazole. Twenty grams of dried γ-cyclodextrin in DMF (400 mL) was added, 62 (6.8 g), and then a 4-Å molecular sieve activated powder (20 g), stirred at 30  C for 20 h (Scheme 13). After filtration of the reaction mixture, followed by concentration of the filtrate to give a residue, the residue was washed in warm 20% aqueous MeOH (400 mL), which could isolate excessively sulfonated γ-cyclodextrins (an insoluble solid) and the target compound, 2A,2B-disulfonated γ-cyclodextrin, 63. The liquid was applied on reversed-phase column chromatography to give pure 63 in a 30% yield. The most notable thing was that there were no other disulfonate isomers, such as 2A,2C-, 2A,2D-, 2A,2E-, 3-, and 6-sulfonates. With use of this method, the most remarkable

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Scheme 14 Rigid 1,4-dibenzoyl benzene-30 ,300 -disulfonate bridging strategy for secondary-rim functionalization [22]

benefit was that they developed a mild nonalkaline reaction condition that could avoid decomposition of the sulfonates because of the existing bases (Scheme 13). To find an A, C-glucose-unit regioselectively modified method for α-, β-, and γ-CDs, they designed and synthesized a larger rigid sulfonylated reagent, 1,4-dibenzoyl benzene-30 ,300 -disulfonyl imidazole, 64, which was prepared from 1,4-dibenzoyl benzene-30 ,300 -disulfonyl chloride, imidazole, and triethylamine in a 99% yield. The procedures for α-, β-, and γ-CDs were similar; they treated the CDs in DMF by adding a 4-Å molecular sieve activated powder and the disulfonyl imidazole. After purification, the best yield of 2A-, 2C-hydroxyls modified for α-, β-, and γ-CDs were 51%, 58%, and 40%, respectively. They also studied the effect of the concentrations of the reagents on the yield, and the results showed that the reaction had the best yield (55%) when the concentrations of disulfonyl imidazole and β-CD were 3.7 mM and 11 mM, respectively [22]. After treating α- and β-CDs with p-toluenesulfonyl imidazole to successfully produce regioisomeric 2A,2B- and 2A,2C-disulfonates, they started to design a longer “bridge” disulfonyl imidazole system which could produce 2A,2D-disulfonates. For preparing 2A,2D-disulfonates of CDs, the procedure was the same. First, a fresh 4-Å molecular sieve activated powdered was added to a solution of CD in DMF, then the longer disulfonyl imidazole was added and the mixture was stirred at 30  C for 5 days. The reaction was analyzed by high-performance liquid chromatography (HPLC). The results for the CDs were that β-CD demonstrated the best

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selectivity. The yields of 2A,2D-disulfonates, 68, and 2A,2C-disulfonates, 67, were 53% and 3.5%, respectively. For γ-CD, the yields of 2A,2D-disulfonates, 70, and 2A,2C-disulfonates, 69, were 37% and 4.0%, respectively. For α-CD, the yields of 2A,2D-disulfonates, 66, and 2A,2C-disulfonates, 65, were 16% and 3.8%, respectively. These results indicated that the authors had developed a disulfonyl imidazole bridge strategy that not only could provide satisfactory regioselectivity and excellent yields, especially for β-CD, but also two potential further modified positions. Thus, the disulfonyl imidazole strategy was quite successful [23] (Scheme 14).

14.3

Applications of Cyclodextrins as Delivery Systems

Drugs and biosensors are not easy for our bodies to take up, because of their chemical and physical properties that largely limit their utility for cure or detection in our bodies. Even if we can inject them into our vessels, a lot of drugs and biosensors do not work when injected into the blood directly; therefore, they need delivery carriers to transport them to specific positions and release them. Though use of cyclodextrins as pharmaceutical excipients has been studied extensively for the past few decades, there are still some new applications to be explored, such as molecular inclusion complex systems, nanocarrier systems, stimuli-responsive delivery systems, and targeted delivery systems, which can improve the physicochemical stability, solubility, dissolution rate, and bioavailability of drugs.

14.3.1 Cyclodextrins as Gene Delivery Efficiency Enhancers A liposome-mediated DNA delivery system is an efficient delivery method for gene therapy. These nonviral carrier systems are absorbed by the membrane fluidity of cells, which is known as endocytosis. The cell membrane fluidity is largely regulated by cholesterol, which can be manipulated by methyl-β-cyclodextrin [25]. On the basis of this concept, Sakurai and coworkers used schizophyllan, a polysaccharide consisting of a repeating unit that includes three glucoses conjugated with a β(1–3)-D-glucan bone grafted to a glucose at the OH-6 position of the second glucosyl residue, as the backbone to connect cholesterols. These derivatives can form stable complexes with oligonucleotides (ONs) [26, 27], but at some densities of cholesterol the formation kinetics are unfavorable, which may prevent the schizophyllan derivatives and the ONs from forming complexes (Fig. 3). Therefore, the authors added β-CD into the schizophyllan–cholesterol derivatives to control the densities of cholesterol, and they then added the ONs to form a new species of the complex, which improved the complexation ability, resulting in sufficient desired complexes to achieve great cellular permeation ability [28, 29]. Small interfering RNAs (siRNAs) have proved to be efficient in cancer therapy, but a major challenge for the use of siRNAs in humans is delivery of the siRNAs to the target tissues and organs. Therefore, Ribas and coworkers designed and prepared a nanoparticle transport system, including (1) a linear cyclodextrin-based polymer

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Fig. 3 β-Cyclodextrin (β-CD)–mediated cholesterol-appended schizophyllan–antisense oligonucleotide (ON) complex formation [29]

(CDP); (2) a human transferrin protein (TF)–targeting ligand, which has specific affinity for TF receptors (TFRs) expressed on the tumor cell surface; (3) a hydrophilic polymer (polyethylene glycol (PEG)), which can stabilize nanoparticles in biological fluids; and (4) a siRNA designed to reduce the expression of ribonucleoside-diphosphate reductase subunit M2 (RRM2), an anticancer target. This was the first powerful demonstration of a cyclodextrin-based nanoparticle for targeted delivery of siRNA in humans [30, 31] (Fig. 4).

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Fig. 4 Nanocarriers assembled using cyclodextrin (CD) polymers, small interfering RNA (siRNA), adamantine–polyethylene glycol (AD-PEG), and AD–PEG–transferrin protein (AD-PEG-TF) [31]

14.3.2 Cyclodextrin-Based Multivalency Drug Carriers Attachment of biorecognizable sugar ligands in several copies to a cyclomaltooligosaccharide (such as cyclodextrin) at precise positions via covalent bonds to form multivalent conjugates has been demonstrated in some specific delivery systems. Moreover, the commercial availability of the native CDs, their very good biocompatibility, and the convenience of position- and face-selective functionalization allow strict control of the valency of the sugar ligand attachment to CDs [32]. Carbohydrate ligands play a very important role in biological recognition, and the recognition processes are strongly related to their density in the specific region. Therefore, multivalent oligosaccharides display a significant improvement in biorecognizable ability. The cyclodextrin family can be employed as platforms after functionalization to conjugate saccharides, forming multivalency derivatives [33–36]. These multivalency derivatives are very good carriers for site-specific drug delivery. The hydroxyls on both the primary rim and the secondary rim can be substituted by other functional groups through selectively functionalized reactions to obtain mono-CD glycoconjugates, bis-selective CD glycoconjugates, faceselective CD glycoconjugates, dual-face CD glycoconjugates, and hyperbranched glycoconjugates (Fig. 5).

14.3.2.1 Cyclodextrin-Monobranched Glycocluster The concept of a CD–glycodendritic architecture, based on a single primary position of CDs connected to a branched saccharide through a spacer, seems to be well adapted for molecule encapsulation for site-specific drug delivery. The CD system shuttles the drug to the lectin (receptor) under the recognition of the glycocluster to improve the density of the drug at the specific position in order to enhance treatment and avoid side effects (Fig. 6). In view of the above description, Zhao and Astruc [37] designed a molecular system consisting of a dual β-CD cavity conjugated with hexavalent α-mannose (α-Man) saccharides to complex the antimitotic drug docetaxel (Taxotere). The distance between two CDs was appropriate for two phenyl rings, which were easy to complex with Taxotere (Fig. 7). After a macrophage mannose receptor (MMR)

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Fig. 5 Concepts of mono-, dual, primary-rim, and primary-and-secondary-rim conjugation to saccharide ligands [32]

affinity experiment, the sandwich structure CD system was shown to specifically bind at the membrane of mouse alveolar macrophages [38a].

14.3.2.2 Regioselectively Substituted Cyclodextrin Bisglycoconjugates Hattori, Yamanoi, and coworkers designed and synthesized a series of bisglycoconjugates based on perbenzylated β-CD platforms, selectively deprotecting two benzyl groups at the primary positions A and D to give a diol. Then the two hydroxyls were substituted by amines connected with saccharide units (β-galactose) by linkers or spacers to synthesize a series of divalent conjugates. The authors used doxorubicin as a guest model to evaluate the properties of the bisglycoconjugate

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Fig. 6 Cyclodextrin (CD)based monovalency drug carrier

system, which displayed great potential in enhancing lectin binding and an encapsulation ability that could be used in site-specific drug delivery [39–42] (Fig. 8).

14.3.2.3 Primary-Rim-Conjugated Heptavalency Glycol Ligands The hydroxyls on the primary rim of CDs were selectively substituted by nucleophilic atoms, then the saccharide ligands were connected with spacers to form CD–saccharide conjugates. This strategy to synthesize primary-rim glycoclusters is one of the most efficient methods, with a satisfactory yield that can provide a reliable chemical resource for testing the suitability of different spacers and saccharide ligands [43–45] (Fig. 9). A well-designed synthetic multivalent mannotriose would be a promising tool for investigation of the allergenicity and antigenicity of yeast mannans. Crohn’s disease (inflammatory bowel disease) is caused by a disturbed immune response to antigens of yeast mannans [46, 47]. However, achievement of polysaccharide synthesis is still a real challenge. On the basis of the above concept, Carpenter and Nepogodiev employed per-6-thio cyclodextrins, 71, as a platform coupled with halogen-armed carbohydrates (α-Man-(1–3), α-Man-(1–2), α-Man mannotriose, 72) through multiple SN2 reactions to afford CD 73 in a 57% yield, which was a great help for similar research [48] (Scheme 15).

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Fig. 7 Taxotere delivered by a cyclodextrin-based targeted shuttle [38b]

Parrot-Lopez and coworkers reported a strategy of using per-(C-6)-amino β-CD 74 as a core, after a peptide formation reaction with 75 to afford a hepta-β-Gal β-CD derivative, 76, which could be recognized by the galactosespecific lectin from Kluyveromyces bulgaricus yeast cells (KbCWL) [49, 50] (Scheme 16).

14.3.2.4 Dual-Face-Substituted “Bouquet-Type” Glycoclusters Ortiz Mellet and coworkers employed β-CD as a platform to introduce two alkynes at the OH-6 and OH-3 positions, followed by Sonogashira crosscoupling or a “click” reaction to afford a tetradecavalent α-Man conjugate. The iminosugar with the C9 spacer (79, n = 8) exhibited the greatest multivalent effect against Jack bean α-mannosidase activity of 0.022 mM, as compared with 188–204 mM for monovalent 1-deoxynojirimycin, a nitrogen-containing glycomimetic, indicating affinity enhancement by four orders of magnitude [51] (Scheme 17).

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Fig. 8 Bisglycoconjugates supported by β-cyclodextrin (β-CD) [32]

Fig. 9 Concept of cyclodextrin (CD) heptavalency

14.3.3 Cyclodextrin Assembled Nanocarriers Based on Enhanced Permeability and Retention For some specific purposes (for example, prodrugs), cyclodextrins are sometimes assembled as nanoparticles for drug delivery utility. One of the most obvious advantages is that nanoparticles can be designed to take advantage of the enhanced

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Scheme 15 Hepta-thiol cyclodextrin glycoconjugate [48]

permeability and retention (EPR) effect, which can target the drug to the site of the tumor tissue to improve the bioactivity and decrease the side effects of the drug. How does the EPR effect work? The general explanation for this phenomenon is that for tumor cells to grow quickly, sufficient nutrients and oxygen must be supplied via the vessels around the tumor tissues. Normal blood vessels do not have the capacity to adequately cater for the rapid growth of tumor tissues; therefore, they must stimulate the production of blood vessels. These neovasculatures are usually abnormal in terms of both form and architecture, resulting in newly formed vessels with wide fenestrations between endothelial cells and a wider lumen. This leads to abnormal molecule transport dynamics, allowing macromolecules to stay longer in the abnormal vessel system. This is a big advantage of the EPR effect for use of high molecular weight molecules (such as nanodrugs) [52–54] (Fig. 10). Cho and coworkers [58] designed and prepared a methyl β-CD–hyaluronic acid–ceramide (HACE) nanoassembly system for implementing targeted treatment of CD44 receptor–expressed cancer. Methyl β-CD (MbCD) can uptake cholesterol from the cell membrane, which can induce downstream signal pathways of apoptosis [56]. HACE conjugates are amphiphilic molecules that can self-assemble into nanoparticles, and HACE is the target ligand for the CD44 receptor [57]; thus, HACE and MbCD–formed nanoparticles can be targeted by the EPR effect. Furthermore, HACE ligands can largely decrease the off-target effect that the dual-effect is larger than either EPR effect or the decrease of off target effect alone. The dual-target

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Scheme 16 Hepta-amide cyclodextrin glycocluster [50]

effect was verified by mice experiments, which suggested that HACE–MbCD nanoparticles provided more suppression of cancer growth and more apoptotic events in tumor tissues than MbCD or HACE nanoparticles alone [58] (Fig. 11). Camptothecin (CPT) is a well-known and highly cytotoxic chemical, which can kill tumor cells, as well as normal cells, with weak selectivity. In addition, CPT is a hydrophobic molecule that is difficult to transport through the cell membrane. Therefore, attempting to avoid its side effects and improving its transportability into cells have been attractive and challenging tasks for scientists. Using CRLX101, a nanoparticle self-assembled from a linear cyclodextrin polymer conjugate with CPT, Ribas and coworkers [31] tried to deliver the CPT to a specific site. With sufficient host–guest interaction, the individual polymer strands cross-linked and self-assembled into nanoparticles around 20 to 40 nm in diameter and 10% CPT by

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Scheme 17 Preparation of tetradecavalent α-Man conjugate via Sonogashira cross-coupling and a “click” reaction [32]

weight. These nanoparticles were evaluated in mice and clinically in patients. The results supported the hypothesis that nanoparticle therapeutics can localize within human solid tumors, and this may occur via the EPR effect [59–62] (Fig. 12). Cyclodextrins and hyaluronic acid (HA) are very widely used in drug delivery because they are water soluble, biocompatible, and biodegradable polysaccharides. Notably, HA can also be recognized by various cancer cells that overexpress HA receptors on their cytomembranes (CD44 and hyaluronan-mediated motility receptor (RHAMM)); thus, it is often used in targeted drug delivery systems [63–68]. Liu and coworkers designed and prepared a β-CD grafted onto HA to form a complex with adamplatin by host–guest interaction (Fig. 13). On the basis of the

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Fig. 10 Effect of enhanced permeability and retention (EPR) on tumor targeting [55]

above description, this delivery system would improve the water solubility of adamplatin and decrease its toxicity. In an antitumor activity evaluation with mice, this result was illustrated by comparison with cisplatin. The authors observed that the HA platform provided targeted drug delivery action and transported the adamplatin into cancer cells while exhibiting minimal uptake into normal tissues [69].

14.3.4 Sensitive Molecules Transported by Cyclodextrin Nanocarriers Low levels of vitamin E (VE) have very adverse consequences, but VE is also very sensitive to oxygen and light irradiation. To overcome this problem, Chen and coworkers constructed a series of primary-rim-capped crowning β-CDs derivatives, which could form host–guest complexes with VE and self-assembled particles. These particles improved the stability of VE significantly and also showed obvious temperature-responsive release [70] (Fig. 14). Like VE, lutein is a very important nutrient. It is also a very unstable compound, with low solubility in water. Ouyang and coworkers constructed a kind of lutein, cyclodextrin, poloxamer 188, and Tween 80 complex, which improved the water solubility tremendously (79.94  2.21 μg/mL, 406-fold). Interestingly, its dissolution rate and bioavailability were also improved remarkably, as demonstrated by combined modeling and experimental methods [71] (Fig. 15).

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Fig. 11 Tumor cell targeting and therapeutic strategy using hyaluronic acid–ceramide (HACE)–methyl β-CD (MbCD) nanoparticles [58]

CD

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Strands are held together via guest-host complexes between CPT and cyclodextrin

CPT

CPT

Polymer-Drug Assembly

ca. 20-40nm

n Potent Topo-1 inhibitor camptothecin (CPT)

Prolonged release of CPT inside tumor cells by linkerhydrolysis,resulting in sustained inhibition of Topo-1 and HIF-1α

Cryo-Electron Microscopy image of CRLX101

Fig. 12 Cyclodextrin (CD), polyethylene glycol (PEG), and camptothecin (CPT) conjugate assembled nanoparticles [62]

14.3.5 Stimuli-Responsive Delivery Systems Stimuli responsiveness is a very common phenomenon in nature, as are pH responsiveness, light responsiveness, electricity responsiveness, and so on. These responsiveness actions can also be employed in drug delivery and release. The most

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Fig. 13 Hyaluronic acid–cyclodextrin (HACD) and adamplatin assembled nanoparticles [69]

prominent advantage of stimuli-responsive delivery systems is precise controlled release as a result of specific stimuli. Jia and coworkers [74] developed cyclodextrin vesicles (CDVs) for capture and release of myoglobin (Myo), which is a very useful cardiac biomarker for early detection of acute myocardial infarction [72, 73]. These authors prepared a captureand-release system, including so-called SH-CDVs, which were grafted onto a mesoporous poly(glycidyl methacrylate–pentaerythritol triacrylate) (poly (GMA-PETA)) monolith, and SH-CDVs was the key factor in this pH-reversible system. The SH-CDVs (diameter ~90 nm) presents as vesicle shapes when the environmental pH is 7.4, but when the pH is decreased to 5.0, the vesicle shapes transform into fiber tubes (diameter ~8 nm) (Fig. 16a). On the basis of this fact, the authors loaded the myoglobin into the sample when the SH-CD was in the form of tubes, and then they increased the buffer pH to 7.4, causing the SH-CD to transform into vesicle shapes and uptake the myoglobin at the same time. The mixture was then washed to remove other molecules from the vesicles. Finally, the buffer was acidified to 5.0 in order to release the myoglobin, which could be detected by mass spectrometry and other forms of detection [74] (Fig. 16b).

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Fig. 14 Crowning β-cyclodextrin (β-CD) and vitamin E (VE) assembled nanoparticles, which release VE under thermal control [60]

Lee and coworkers reported a pH-sensitive gold nanoparticle (AuNP) release system. They used two kinds of γ-cyclodextrin (γ-CD). One was functionalized with amine and dopamine (DOPA) on both rims (CD-NH2). The dopamine side was anchored to the AuNPs, and the amine side, providing a positively charged environment, was faced to another CD modified with 2,3-dimethyl maleic acid (DMA) and chlorin e6 (Ce6) (CD-DMA), which was used as a negatively charged surface molecule. DOPA-PEG, which also provided a positively charged environment, was a component of this system, coupled to the surface of the AuNPs through DOPA [75–77]. In most tumor microenvironments (pH 6.8) [78] the CD-DMA part would be stimulated, leaving the CD-NH2 part with the positive charge of the AuNPs, causing tumor cells to extensively uptake the charged AuNPs (through interaction with the negatively charged tumor cell membrane) [76]. This process would improve the efficiency of light-driven tumor-specific photothermal therapy (PTT) and photodynamic therapy (PDT) because of the release of Ce6 from the AuNPs [79, 80], resulting in induction of cell apoptosis or necrosis pathways. This process was demonstrated in subsequent experiments by the authors [81] (Fig. 17). Nitric oxide (NO) is a gaseous signaling molecule and a very important biological messenger, controlling various biological processes in most organisms. Three scientists shared the 1998 Nobel Prize in Physiology or Medicine for discovering the role of nitric oxide as a cardiovascular signaling molecule. NO also displays anticancer and antibacterial activities in certain concentrations (these are dosage related); however, at high concentrations it can be toxic to mammalian cells and tissues [82]. Hence, a lot of scientists are interested in design and synthesis of NO donors. Sortino and coworkers developed a photoactivatable probe system containing

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Fig. 15 Before assembly (a) and after assembly (b), lutein molecules are indicated in a spherical structure, with poloxamer 188 in yellow, Tween 80 in red, and γ-cyclodextrin (γ-CD) in green [71]

fluorophore/photochrome dyads, which can be imaged. Nitric oxide photodonors and cyclodextrin nanoparticles can load both the dyads (Fig. 18, 1a) and the donors (Fig. 18, 2). The nanoparticles can not only introduce the dyads and donors into the cancer cytomembrane but also protect their photochemical and photophysical properties against water damage. The nanoparticles are probes and carriers at the same time, and can release NO to activate fluorescence under optical control [83]. It is well know that the S–NO bond could be stimulated by heat, ultraviolet light, certain metal ions, superoxide, and seleno compounds. Homolytic cleavage of the S–NO bond would liberate the NO [84]. On the basis of this knowledge, Yannakopoulou and coworkers reported multifunctional S-nitrosothiols on β-CDs (SNO-βCDs) as potential prodrugs that were capable of storing NO from the S–NO bond, simultaneously releasing NO under controlled thermal or photochemical stimuli [85] (Scheme 18).

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a

Fiber tube

pH 5.0 pH 7.4

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b Loading buffer pH 5.0

Washing pH 7.4

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MS Glycopeptides

pH 5.0 Nonglycopeptides

Fig. 16 Myoglobin (Myo) detection based on pH-controlled cyclodextrin (CD) nanoshape transformation, when the pH of the environment is 7.4 the SH-CD systems present vesicle shape, but when the pH reduce to 5.0, the shape of the SH-CD systems will transfrom into fiber shape. (Fig. 16a). The SH-CD systems (fiber tubes) could be added into the sample (including Myo) in the buffer (pH = 5.0) then the pH value was adjusted to 7.4 for the SH-CD systems (SH-CDV, vesicles) to catch Myo, followed by washing other molecules which were survival under the uptake of the SHCDV. After that the SH-CDV systems were acidified (pH = 5.0) to release Myo for detection [71].

Ce6 cCD-DMA dCD-NH2

Cyclodextrin PEG Ce6

pH AuNP

DOPA

AuNP dCD-NH2 cCD-NH2

pH 7.4

pH 6.8

Fig. 17 pH-sensitive cyclodextrin (CD)-release system [81]

Schoenfisch and coworkers reported a series of N-diazeniumdiolatefunctionalized β-CD derivatives as NO carriers to release NO under acidic conditions. The authors introduced amine on the primary rim of β-CD via a hydroxyl substitution reaction (Fig. 19a), then the amine-CD derivatives (mono- and heptasubstituted) were treated with NO gas under high pressure (10 bars) and strong alkaline conditions to prepare N-diazeniumdiolate-modified CD derivatives. Each molecule of diazeniumdiolate will release two molecules of NO, triggered by proton cations in lower-pH conditions (the authors tried to stimulate the diazeniumdiolate by proton cations under a pH of 7.4 at 37  C, but no NO release reaction occurred) (Fig. 19b). The authors also evaluated antibacterial activity against Gram-negative

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Fig. 18 Photoactivatable probe and nitric oxide release system, when the nanoparticales under a illumination, λ = 400 nm (1a transformed to 1b, both 1b and 2 revealed significant absorption spectra) the 2 would release NO by a radical chemistry process, and at the same time the 1b could be imaged [83].

Scheme 18 Process of NO storage and release, the primary rim hydroxyl(s) of native β-CD was (were) substituted by thiol(s) to generate 80 and 82, then treated by NaNO2 to form S-nitrosothiol(s) 81 and 83, respectively, both 81 and 83 would release NO under heat or UV radiation [85].

Pseudomonas aeruginosa, a model pathogen associated with a number of serious medical infections (for example, in patients with traumatic burns or cystic fibrosis) [86, 87]. The results displayed significant antibacterial action and showed the potential for codelivery of other drugs by CD cavity encapsulation [88]. On the basis of the host–guest interaction between Azo and CD, Chen and coworkers designed and prepared a photoresponsive multivalent supramolecular system immobilized on a gold platform. The gold platform supported the whole system, which included a thiol–Azo part linking the Azo to the gold platform via thiol–gold interaction and the β-CD conjugate 7-mannose, which can specifically recognize and bind to the type 1 fimbriae protein (such as FimH) expressed on the surface of many Gram-negative bacteria (like Escherichia coli) [89]. When the CD with mannose attaches to the bacteria, they can be immobilized on the gold via

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Fig. 19 NO storage and release process, the NO molecules storaged in N-diazeniumdiolate and released under acidic condition [88]

Fig. 20 Light-driven bacterial release and capture device, the trans Azo on the platform could stablize the CDs-bacterial through the host-guest interaction (bacterial captured); after an irraditation(λ = 365 nm), the trans Azo became cis Azo, allowing the CDs-bacterial systems to escape from the platform (bacterial released) [90]

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host–guest inclusion between the CD–mannose and the Azo. After ultraviolet irradiation (365 nm) for 30 min, the trans-Azo changed to its cis form to escape the CD cavity, resulting in release of the bacteria. The form of Azo can be transformed by irradiation with different wavelengths of light. Therefore, this system can capture and release bacteria by repeated irradiation with different types of light, showing great potential for applications in biosensors and diagnostic devices [90] (Fig. 20). Another similar but more complicated switchable system was also developed by Chen and coworkers [94], which contained a gold surface as anchor positions, with poly 2-hydroxyethyl methacrylate (HEMA)–grafted phenylboronic acid (PBA) as

Fig. 21 Sugar and pH switchable release and capture system [94]

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branched covalent bonding sites for functionalized β-CD derivatives and different CD derivatives. The authors prepared three kinds of CD derivatives (CD-X): a CD–fluorescein isothiocyanate conjugate (CD-FITC), a CD–lysine conjugate (CD conjugated with seven lysine ligands), and a CD–quaternary ammonium salt (CD-QAS) conjugate (CD conjugated with seven QAS; the QAS structure is shown in Fig. 21). The CD-X derivatives were effectively bound to PBA via double B–O bonds between the second rim of the CD and the PBA in alkaline conditions, and also the B–O bond is easy to break up by addition of fructose (cis-diol molecules) and hydrion, leading to capture or release of the CD derivatives. The QAS residues can attract bacteria by electrostatic and/or hydrophobic interactions, and the lysine can bind some specific proteins such as Plg; thus, these systems can be used to capture and release some bacteria and proteins, which can be applied in medical diagnostics, protein purification, and antibacterials [91–94].

14.3.6 Delivery of the Extremely Hydrophobic Molecule C60 Since its discovery, C60 has attracted a lot of attention in many areas of science and technology, including the area of biology. Some kinds of C60 derivatives have been found to display certain bioactivities, such as antibacterial, antiviral, and even

Fig. 22 Cyclodextrin (CD-C60) conjugates and bis-αCD-C60 bioactivities against hepatitis C virus (HCV) [98, 99]

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anticancer activities [95–97]. However, bioapplication of C60 is largely limited by its poor water solubility. To overcome this disadvantage, Zhang and coworkers designed and synthesized a bis-αCD-C60 conjugate (Fig. 22a) using αCDs as carriers, after a selective deprotection reaction on the second rim to give monolCD, followed by a coupling reaction to produce a CD dimer, which, via Bingel–Hirsch cyclopropanation, provided the bis-αCD-C60 conjugate. This functionalized strategy tremendously enhanced the water solubility of C60 from 1.3  1011 to 0.5 mg/mL. On the basis of a similar concept, they also synthesized two other species of bis-γCD-C60 conjugates (Fig. 22b, c) with water solubility of 27.5 mg/mL and 3.5 mg/mL, respectively. Interestingly, the authors evaluated the ability of a bis-αCD-C60 conjugate to inhibit hepatitis C virus (HCV) in Huh7 cell lines. This revealed significant anti-HCV activity (half-maximal inhibitory concentration (IC50) 0.17 μM) (Fig. 22d), which was strongly dose dependent [98]. They also evaluated the anti-influenza A/WSN/33 (H1N1) virus activity of bis-γCD-C60 conjugates in MDCK cell lines and found that they displayed distinct activity. The IC50 values of conjugates B and C were 87.73  6.9 μM and 75.06  5.1 μM, respectively, while that of oseltamivir (Tamiflu), which was used as a control, was 33.6  2.2 μM [99].

14.4

Conclusions

The special geometric structure of cyclodextrins (CDs) and their three different kinds of hydroxyl groups express different chemical properties, which provide excellent potential reactive sites for further modification to fulfill numerous applications. Since scientists first demonstrated the structure of CDs, they have never stopped exploring their applications and methods of functionalization. Sometimes, because they want to achieve specific goals, they look for and discover appropriate functionalization method(s); sometimes they research particular methodologies based on new functionalization methods and discover new applications. At the early stages, functionalization of CDs was random; then, as scientists discovered more chemical properties of CDs (for example, the three different kinds of hydroxyl groups express different chemical properties; the hydroxyl groups on the primary rim possess less steric hindrance than those on the secondary rim), chemists started to develop selective functionalization strategies. Tert-butyldimethylsilyl chloride (TBDMSCl) is the most common reagent chosen to synthesize primary-rim-modified cyclodextrins because under optimal conditions it can give a 90% yield of the desired products [100]. Site-specific selective functionalization of CDs is a more challenging aim to accomplish. Since certain methods such as aluminum–alkane reagent–mediated deprotection of per-protected CDs were discovered [13a], the process of site-selective functionalization of CDs has been accelerated. With their hydrophilic surface and hydrophobic inner cavity, CDs are perceived as ideal molecules for developing delivery systems, such as nanoparticle and multivalence delivery systems, that can be used in delivering molecules for medical diagnosis, biosensing, gene therapy, or chemotherapy. Ideas from scientists have

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been developed into concepts, and those concepts have then been demonstrated in their laboratories. CD cavities and CD assembled nanoparticles or vesicles, which encapsulate hydrophobic chemotherapy agents or probes for transportation into cells, have been realized. However, most of these studies are still at the laboratory stage, and scientists continue to seek solutions to improve their results in order to enhance their potential utilities. The prospects for translating their concepts from the laboratory into practical utilities for clinical applications are very promising.

14.5

Cross-References

▶ Cyclodextrin Hybrid Inorganic Nanocomposites for Molecular Recognition, Selective Adsorption, and Drug Delivery ▶ Drug/Gene Delivery Platform Based on Supramolecular Interactions: Hyaluronic Acid and Folic Acid as Targeting Units ▶ Nanoscaled Cyclodextrin Supermolecular System for Drug and Gene Delivery Acknowledgments The authors acknowledge the financial support received from the China Scholarship Council for Jiang Liu’s PhD fellowship.

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Contents 15.1 15.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cyclodextrin-Functionalized Carbon Nanomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.2.1 Molecular Recognition by Electrochemical and Luminescent Sensors . . . . . . . 15.2.2 Carbon Materials Functionalized with Cyclodextrins as Adsorbents . . . . . . . . . 15.2.3 Cyclodextrin-Functionalized Carbon Materials for Drug Delivery . . . . . . . . . . . 15.3 Cyclodextrin-Functionalized Magnetic Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.3.1 Molecular Identification-Detection by Electrochemical and Luminescent Sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.3.2 Cyclodextrin-Functionalized Magnetic Materials for Adsorption and Separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.3.3 Cyclodextrin-Functionalized Magnetic Materials for Drug Delivery . . . . . . . . . 15.4 Cyclodextrin-Functionalized Semiconductor Quantum Dots . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.4.1 CD-Functionalized QDs as an Achiral Recognition Sensing Platforms . . . . . . 15.4.2 CD-Functionalized QDs as a Chiral Recognition Sensing Platform . . . . . . . . . . 15.5 Cyclodextrin-Functionalized Noble Metal Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.6 Conclusions and Outlooks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15.1

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Introduction

Supramolecular hybrid inorganic nanocomposites, as a burgeoning type of hybrid nanomaterials, have been prepared by anchoring macrocyclic organic molecules and supramolecules onto inorganic nanoscaffolds. Macrocyclic organic molecules, such as crown ethers, cryptands, calixarenes, cucurbiturils, pillararenes, and cyclodextrins, have frequently been used as building blocks for supramolecular hybrid inorganic materials. These macrocyclic molecules anchoring onto the surface of inorganic nanomaterials particularly act as the valid host molecules that one or more “guest” W. Liang · S. Shuang (*) Shanxi University, Taiyuan, China e-mail: [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_17

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molecules can bind to a “host” cavity reversibly. Among the various macrocyclic molecules, native and modified cyclodextrins (CDs) have long been recognized as the host molecules with inherent hydrophobic internal cavity and hydrophilic external surface in host-guest chemistry [1, 2]; therefore, much attention of CDs has attracted in the construction of supramolecular hybrid inorganic nanomaterials. Cyclodextrins (CDs), readily available α-, β-, and γ-CDs, are cyclic oligosaccharides comprising six, seven, or eight D-(+)-glucopyranosyl units linked by α-1, 4-glycosidic bonds. α-, β-, and γ-CD molecules are shaped like cones with the primary hydroxyl groups from the narrow edge and secondary groups extending from the wider edge, which gives CD molecules a relatively hydrophobic central cavity and a hydrophilic outer surface. Moreover, CDs can be easily chemically modified to selectively introduce functionality on the primary and secondary faces [3]. Due to readily available, harmless, and capable to form sophisticated molecular and supramolecular structures, the CDs have been attracting immense attention from the scientific community for decades. This interest toward CDs is additionally strongly motivated by their numerous potential applications. Cyclodextrin hybrid inorganic nanocomposites have made the combination of inorganic nanomaterials as solid supports and CDs used as the surface functional groups, leading the development of hybrid materials with improved functionalities and evolving many applications in chemical, environmental, and biological fields [4–6]. In this chapter, we shortly present the developments carried out in the preparation of cyclodextrin-contained carbon nanomaterials, magnetic nanomaterials, semiconductor quantum dots, and noble metal nanoparticles as well as their applications as molecular recognition sensor, adsorbent, and drug nanocarriers (Fig. 1).

15.2

Cyclodextrin-Functionalized Carbon Nanomaterials

Carbon nanomaterials (CNMs), with graphite being the parent structure, are found in different dimensionality including zero-dimensional fullerenes, one-dimensional carbon nanotubes (CNTs), two-dimensional graphene-family materials (GFMs) (i.e., graphene sheet, graphene oxide (GO), reduced graphene oxide (rGO), and graphene quantum dots (GQDs)), and three-dimensional graphene materials. Due to their unique electronic, optical, thermal, mechanical, and chemical properties, CNMs have attracted particular attention in many research fields. The properties of CNMs are strongly dependent on their atomic structures and interactions with other materials in the nanometer-scale dimensions. Therefore, the development of the CNMs’ chemical modification has led to the discovery of new applied materials. A wide variety of different chemical modification of CNMs, such as graphene, CNTs, and GQDs, were achieved via covalent and non-covalent approaches [7]. Through the optimization of chemical modifications with small molecules and biomolecules and the coupling with other nanomaterials (i.e., luminescent and magnetic), carbon nanomaterials have emerged as a platform for the preparation of

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carbon nanomaterials

magnetic nanomaterials

noble metal nanoparticles

quantum dots

molecular recognition

adsorptionseparation

drug delivery

Fig. 1 Scheme of the representation of selected cyclodextrin hybrid inorganic nanocomposites and their applications

sophisticated multifunctional smart materials capable of molecular recognition, adsorbents, and drug delivery, including cancer treatments. Cyclodextrins (CDs), as the supramolecules with good water solubility and high biocompatibility, have been found to be ideal candidates to be conjugated to CNMs, toward combining their most promising features. Linking CDs to CNMs is considered to enable the introduction of some desired activity, and new features to the resultant nanostructures, as well as the improvement of the physicochemical or biological properties of pristine CNMs. The number of articles within this area of research is still growing, and new interesting materials are obtained. This part focuses on recent advances in the synthesis and application of the conjugates of CNMs and CDs in sensors, adsorption, and drug delivery.

15.2.1 Molecular Recognition by Electrochemical and Luminescent Sensors CNMs can be considered as promising materials to be used for molecular recognition by electrochemical and luminescent sensors. A significant number of

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unsaturated π-bonds in their structure lead to a high electrical conductivity of CNMs. Enabling and enhancing the electron transfer process between an electrode and a given molecule is the principle of such applications of CNMs. It is considered that the enhancement in properties of CNMs toward electrochemical detection of the molecules can be achieved via incorporation of cyclodextrin units into the material. The CDs promote the supramolecular recognition of various molecules. Hence, the considered reason of improved performance of the CD-bearing CNM sensors is the synergistic effect between the adsorption of the detected molecules on the surface of the CNMs and the formation of the inclusion complexes with CDs. Electrochemical sensing that uses conjugates of CNMs with CDs constitutes an emerging and widely explored area of molecular recognition research. Graphene oxide is a material characterized by a single graphene sheet, or “monolayer,” that displays unique electronic and mechanical properties that are advantageous for sensing applications. Fabrications of the sensors based on CD-modified two-dimensional GO or rGO covered both covalent and non-covalent approaches. From the synthetic point of view, the presence of oxygen groups on the surface of GO or rGO opens avenues for an enhanced hydrogen-bonding-dependent self-assembly phenomenon with the inclusion of CD units, as well as for covalent functionalization via, e.g., amide or ester bond formation. More works referred to the experimental procedure reported by Guo et al. (Fig. 2) [8] suggested the formation of the noncovalent β-CD/rGO material via the hydrogen-bonding-dependent adsorption of CDs on the surface of rGOs. Application of non-covalent CD/GO and CD/rGO materials as versatile electrochemical sensors can be clearly claimed, because these constructs were used for the detection of various molecules. Bioactive species [8, 9], drugs [8, 9], and organic pollutants [10, 11] were detected with excellent LOD values. Also the three-dimensional rGO as the bearing material has been used to conjugate with CD for fabricating an electrochemical sensor [9, 12]. Meanwhile, carbon nanotubes, with unique tubular shape, possess encouraging electronic properties, such as good electrical conductivity and broad electrochemical potential window, and MWCNTs perform more excellent electronic properties in comparison to SWCNTs. CD/MWCNT sensors were successfully applied for the electrochemical determination of organic pollutants [13] and various biomolecules [14, 15]. Recently, construction of the hybrid carbon platforms composed of more than one graphene nanostructure, as cyclodextrin-bearing materials for electrochemical sensing, was also studied. Second carbon material [16], metallic nanoparticles [17] and metal oxide nanoparticles [18] have been introduced to the carbon platform for electrochemical sensing. Introduction of the second carbon material to a carbon platform was found to increase the number of CD units in the nanostructure, because of enhancing hydrogen-bonding interactions. And the hybrid with metallic nanoparticles and metal oxide nanoparticles improved the electrical conductivity and catalytic performance of CD-conjugated CNMs electrochemical sensor. Due to the CD cavity’s unique hydrophobic character and inherent chirality, electrochemical sensing of CD-conjugated carbon nanomaterials for chiral recognition has been widely investigated [12, 19–23]. The cyclodextrin-conjugated graphene quantum dots β-CD/GQDs have been applied for the electrochemical detection of

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Fig. 2 The procedure for preparing CD-graphene organic-inorganic hybrid nanosheets and GNs, and sensing the guest molecules by an electrochemical strategy [8]. (Copyright 2010 American Chemical Society)

amino enantiomers [19, 20]. In another case, the graphene-β-cyclodextrin-nanocomposite-modified carbon paste electrode (GNS-β-CD-CPE) was developed to detect moxifloxacin hydrochloride (MOX) enantiomers by adsorptive stripping differential pulse voltammetric (AdSDPV) technique [23]. In very recent works, self-assemblies of Cu2+-modified β-cyclodextrin on poly-L-arginine/multi-walled carbon nanotubes (Cu-β-CD/PLA/MWCNTs) [21] and three-dimensional graphene with hydroxypropyl- β-cyclodextrin (3D-G/HP-β-CD) [12] have been constructed as the effective sensors for chiral recognition of tryptophan (Trp) enantiomers (Fig. 3). Both two developed sensors demonstrate excellent selectivity and applicability for the quantification of Trp in real blood samples. Luminescence spectrometry is another valid method to explore the molecular recognition by CD-conjugated GNMs. Graphene has a higher quenching efficiency compared to other quenching agents, due to its enhanced electrical conductivity and two-dimensional planar structure, and therefore is a great energy transfer acceptor for FRET-based luminescent sensors [24, 25]. In one example, graphene oxide was used as a sensing platform for the detection of amantadine as demonstrated by Li et al. [24]. This probe was based on the host-guest interaction of mono-[6-(2-aminoethylamino)6-deoxy]-β-cyclodextrin (EDA-CD)-functionalized graphene oxide with amantadine and rhodamine. In the absence of analyte, the emission of Rhodamine 6G was

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quenched by addition to the cyclodextrin-modified graphene oxide layer; however, introduction of amantadine, a pharmaceutical agent, displaced Rhodamine 6G from the surface and led to significant fluorescence increases. Furthermore, Mondal et al. also used a graphene-bound β-cyclodextrin as a cholesterol sensor based on the competitive host-guest interaction between Rhodamine 6G and cholesterol [26]. The emission of Rhodamine 6G was quenched by encapsulation in the cavity of the graphene-bound β-cyclodextrin. Cholesterol selectively displaced the Rhodamine 6G, freeing it from the quenching agent and turning the fluorescence back on. Carbon dots (CDots) or graphene quantum dots (GQDs), which are quasi one-dimensional graphene particles, have also been widely used for molecular recognition by luminescent sensors [27–29]. For example, the α-CD-modified CDots have been used in molecular recognition of derivatives of methyl viologen (MV2+), due to the MV2+induced assembly of CDots via the host-guest approach [28]. The electron transfer processes between CDots and MV2+ have been explored carefully by time resolved fluorescence decay and transient absorption spectroscopy.

15.2.2 Carbon Materials Functionalized with Cyclodextrins as Adsorbents The high surface area of the carbon nanomaterials as well as their ability to bind various organics via π-π stacking not only can be utilized toward the abovediscussed electrochemical and luminescent detection but also can be played in adsorption. The main examples of such application of CNMs, primarily for graphene-family nanomaterials and carbon nanotubes, are in water treatment, which is associated with removing organic pollutants from aqueous solutions. Moreover, it has been well established that because of the unique properties of CDs toward the formation of inclusion complexes, these molecules can be employed to further enhance the sorption capacity of the resultant CNMs adsorbent. Therefore, a new trend to fabricate CD-decorated CNMs adsorbents can be regarded as the promising way in the development of applied materials for water treatment. In general, the chemical energy of the covalent bond is higher in comparison to non-covalent interactions, and the stabilization of material structure could be ensured by covalent bonds during the adsorption process. Therefore, in contrast to electrochemical sensors of the conjugates of CDs and CNMs, covalent approaches were mainly employed for preparing CD-CNMs as the adsorbents. β-Cyclodextrin grafted on the surface of multi-walled carbon nanotubes exhibits a high adsorption in the removal of polychlorinated biphenyls (PCBs) from aqueous solution [30]. A crosslinked nanoporous polymer containing CD and carbon nanotube (CNT) has shown excellent adsorption capacity for p-nitrophenol which can be removed as much as 99% from a 10 mg/L spiked water sample; in contrast, activated carbon removed only 47% [31].

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Recently, construction of the magnetic hybrid carbon platforms as cyclodextrinbearing materials for adsorption was studied widely. Because of the superparamagnetism of magnetic nanoparticles, the magnetic adsorbents (containing Fe3O4 [32, 33] or Fe NPs [34] in the structure) were found to increase recycling ability with facilitating separation by external magnetic field. The presence of CD units in the resultant adsorbent can be considered as a crucial key point to enhance the stability of the material and to reduce the rate of the aggregation/agglomeration process, together with triggering some desired effects toward binding the adsorbate, such as inclusion complex formation.

15.2.3 Cyclodextrin-Functionalized Carbon Materials for Drug Delivery Carbon nanomaterials have also been studied as drug delivery systems (DDS). The properties of CNMs, such as low toxicity, high surface area, and unique mechanical and electrical properties, make CNMs promising drug or gene delivery vectors. Incorporation of CD units into a CNMs nanoplatform is considered to enhance the nanomaterial’s biological features, increase the number of drug molecules in the structure, and improve the stability and hydrophilicity of the material. All these features lay the basis for the design of effective DDS based on CD-conjugated CNMs. In recent years, CNM-based targeted DDS with the inclusion of CDs has been explored primarily for GO [35] and MWCNTs [36] via covalent or non-covalent approaches. Their biocompatibility, dispersion stability, drug loading, and releasing properties were mainly studied. It is noteworthy that several drugs as the model drugs, like doxorubicin, [35] camptothecin [35], and guanine-based drugs [36], have been investigated to explore the possibility of drug loading and releasing. This means that the CD units incorporated into the CNMs retain their unique properties toward the formation of inclusion complexes with therapeutics. Also, the release profile of the drug was also studied, and controlled drug release at different pH values was presented. These studies can be considered as the initial research works on such systems toward their further bio-applications. An emerging and still developing area of research in the field of nanomedicine is the creation of targeted and control released DDS. This so-called active targeting is achieved via incorporation of targeting ligands (TLs), such as antibodies or appropriate vitamins, into the structure of the nanomaterial [37]. The principle of targeted delivery involves the selective binding of the therapeutic system to a specific molecular target, such as tumor receptors. Active targeting was achieved via linking the nanoplatform with folic acid (FA) [38, 39], hyaluronic acid (HA) [40, 41], biotin [42], monoclonal antibodies (MoAb) [43], or nucleic acids [44]. In most cases, doxorubicin (DOX) [38, 41, 45] was used as a model drug; however, the systems for the delivery of camptothecin (CPT) [40], epirubicin (EPI) [45], or 5-fluorouracil (5-FU) [46] were also studied. In general, for CD-conjugated carbon nanomaterials DDS, the drug release behavior could be controlled by pH-dependent and photothermal stimulation. The host-guest interaction and hydrogen bonding between

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cyclodextrin and drug molecules dominate the pH-responsive drug release from the DDS. Because of the environment of cancer cells is more acidic than that for healthy cells, the pH-responsive drug release phenomenon together with the active targeting process enables an increase in the therapeutic’s pharmaceutical availability and the reduction of its toxicity. For example, the release ability of doxorubicin (DOX) from a β-CD-modified rGO nanosheet does not exceed 20% under physiological conditions (pH 7.4, 37  C), but over 60% of DOX is released in an acidic environment (pH 5.3, 37  C) [45]. In addition, it is noteworthy that the photothermal-stimulated drug releases that utilize the wonderful photothermal conversion performance of carbon nanomaterial have been provided a valid approach to improve the effect of photothermal therapy [39, 41]. Liu and co-workers constructed a tumor-targeted delivery system for CPT based on the inclusion complexation of hyaluronated adamantane (HA-ADA) with β-CDfunctionalized graphene oxide (GO-CD) (Fig. 4) [40]. The ternary supramolecular nanomedicine (CPT@GO-CD–HA-ADA) exhibited a higher curative effect and a

Fig. 4 Construction of CPT@GO-CD-HA-ADA supramolecular assembly [40]. (Copyright 2014 Royal Society of Chemistry)

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lower cytotoxicity than free CPT. The β-CD/ADA inclusion complex prevented the GO skeletons from intermolecular aggregation, and the resultant uniform and smallsized GO nanosheets promoted the targeted receptor-mediated internalization of the biocompatible supramolecular complex by cells. Another multifunctional-targeted drug delivery platform formed from CDHA-MGO (Fe3O4-reduced graphene oxide covalently modified with β-cyclodextrin-hyaluronic acid polymers) was contributed by Shuang and co-workers [41]. The obtained CDHA-MGO nanocomposite has good water dispersibility, easy magnetic separation, high near-infrared (NIR) photothermal heating, and excellent biocompatibility. The β-cyclodextrin-hyaluronic acid polymers efficaciously enhance the doxorubicin (DOX) loading amount up to 485.43 mg/g. Meanwhile, the Fe3O4-graphene oxide provides a facile photothermal response mechanism to handle the NIR-triggered release of DOX in weak acidic solvent environments. All the mentioned results clearly demonstrate the applicable potential of the developed nanoplatforms and lay the basis to further exploit these nanoconstructs as novel systems dedicated to targeted anticancer therapies in humans.

15.3

Cyclodextrin-Functionalized Magnetic Nanoparticles

In the last decades, many types of magnetic nanoparticles (MNPs) can be synthesized, including iron oxides and iron sulfide (Fe2O3, Fe3O4, and Fe3S4), as well as cobalt, manganese, nickel, and magnesium ferrites. Among them, Fe3O4, which is a ferromagnetic black color iron oxide of both Fe(II) and Fe(III), has been the most extensively studied. Many applications of magnetic nanoparticles rely on the use of magnetic fields to manipulate their properties, which depends on the effectiveness of the particle magnetic moment and the field gradient. However, most of these nanomaterials easily oxidize in the air atmosphere and show low stability in acidic media, which may lead to changes in their magnetic properties. Therefore, the synthesized MNPs are typically coated to improve their stability and dispersibility in water and to provide chemical functionality for the addition of bioactive molecules. Using proper coating can also minimize precipitation and the formation of agglomerates and prolong the circulation time in further applications. Cyclodextrins (CDs) and their derivatives are well-known to form complexes with a large variety of organic molecules in aqueous solution by host-guest interaction, and thereby increasing both the water solubility and the stability of such molecules. The attachment to MNPs of CDs, able to form inclusion complexations with guest molecules, gives rise to MNPs with host-guest abilities without altering their original properties. Furthermore, the modification of CDs and their derivatives has dramatically enhanced the solubility, stability, and biocompatibility of the MNPs. Among the most used CD coating methods are in situ coating, post-synthesis adsorption, or post-synthesis grafting. Covalent anchoring was found to enhance the stability of CD-MNPs compared with adsorption coating [47, 48]. Vast cases in modification of CD in the surface of MNPs followed the layer-by-layer (LBL) technique [49–55]. For example, the surface of magnetic particles was modified with 3-aminpropyltriethoxysilane (APTES) firstly. The next step was the covalent

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bonding of mono-tosyl-CD onto the surface of modified iron NPs by means of layerby-layer process [49–52]. Also, the one-pot route has been exploited to the preparation of CD-stabilized MNPs [56, 57]. Functionalized MNPs hold great potential in environmental, biomedical, and clinical applications owing to their many unique properties, such as larger surface area, and high permeability. In this part, we focus on the recent advances in the construction of CD-functionalized MNPs and their applications in identification-detection, adsorption-separation, and drug delivery.

15.3.1 Molecular Identification-Detection by Electrochemical and Luminescent Sensors MNPs have captured many interests in chemosensors for identification and detection in terms of their high surface area, strong magnetic responsivity, electrical properties, and high adsorption ability [58]. Cyclodextrins (CDs), as a group of naturally cyclic oligosaccharides with a hydrophobic inner cavity and a hydrophilic exterior, may bind selectively various organic, inorganic, and biological molecules to form complexes. Therefore, CD-coated MNPs have been investigated as promising method for ion and molecular recognition by electrochemical sensing and spectral analysis [59–62]. Electrochemical sensing that uses conjugates of MNPs with CDs constitutes an emerging and widely explored area of molecular recognition research [52, 59–61]. Some bioactive species, like uric acid [49], dopamine [59], DNA [60], and amino acids [52, 61], have been detected with excellent LOD values. Furthermore, due to the CD cavity’s inherent chirality, electrochemical sensing of CD-MNPs for chiral recognition has been also investigated. For instance, Muñoz et al. synthesized a novel and specific material based on thiolated β-cyclodextrin-coated gold nanoparticle functionalized with cobalt ferrite magnetic nanoparticles (β-CDSH/Au/ CoFe2O4-NPs) for modifying on graphene-paste electrode (Fig. 5) [61]. The β-CD-SH/Au/CoFe2O4-NP-modified graphene-paste electrode as a chiral sensor has been validated by chirally recognizing tryptophan (TRP) enantiomers, showing a good selectivity and sensitivity. Spectrometry is another valid method to investigate the ion recognition by CDfunctionalized MNPs [53, 62]. Through the combination of the host-guest interaction and sol-gel grafting approach, a fluorescent TSRh6G-β-cyclodextrin fluorophore/adamantane-functionalized magnetic nanoparticles (TFIC MNPs) has been constructed as a fluorescence sensing platform for Hg2+ recognition (Fig. 6) [62]. The addition of Hg2+ induced a remarkable emission enhancement of TFIC MNPs as a “turn-on” type fluorescence sensor and resulted in an obvious color change of the sample solution from light brown to pink. Due to the larger surface area and high permeability, the CD hybrid nanomaterial TFIC MNPs displayed significant selectivity and sensitivity for Hg2+ over other metal ions tested in aqueous solution. Otherwise, the TFIC MNPs could be separated and collected Hg2+ via external magnetic field, which can be used as an efficient adsorbent for the removal of trace Hg2+ from the aqueous environments.

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15.3.2 Cyclodextrin-Functionalized Magnetic Materials for Adsorption and Separation CD-MNP-based nano-adsorbents have played an important role in the adsorption and separation of bioactive species, drugs, and inorganic or organic pollutants from several solution media. There are several advantages of CD-MNP adsorbents, such as (I) easy preparation and eco-friendliness, (II) low-cost and low-reagent consumption, (III) high selectivity and easy manipulation with an external magnetic field, (IV) being reusable adsorbents, and (V) high pre-concentration factors and combination with other modern detection techniques in online or offline mode. Therefore, a new trend to fabricate CD-decorated MNPs adsorbents can be regarded as the promising way in the development of applied materials for water treatment and biomedicine. For CD-functionalized MNPs, the use of these materials for the abatement of environmental toxicants has been increasing continuously. The heavy metal ions [56, 63–65], radionuclides [54, 66], and organic molecules [51, 67–69] have been

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Fig. 6 The illustration of the synthesis of TFIC MNP fluorescent sensors for Hg2+ [62]. (Copyright 2013, Royal Society of Chemistry)

adsorbed and separated from the aqueous solutions. For example, the carboxymethylβ-cyclodextrin (CM-β-CD)-modified Fe3O4 nanoparticles (CMCD-MNPs) for removal of copper ions from aqueous solution have been constructed by grafting CM-β-CD onto the magnetite surface using the carbodiimide method [63]. The results showed that the

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grafted CM-β-CD on the Fe3O4 nanoparticles enhanced the particle adsorption capacity owing to the strong ability of the multiple hydroxyl and carboxyl groups in CM-β-CD to adsorb metal ions. Another work revealed that β-CD-Fe3S4 NPs exhibited an enhanced and selective removal capacity toward Pb(II) in comparison with bare Fe3S4 NPs [56]. This research demonstrated that β-CD-stabilized Fe3S4 NPs can be a potential material for Pb(II) removal from wastewater. In another two works, the Fe3O4@CD MCs [66] and succinyl-β-cyclodextrin-APTES@Fe2O3 [54] were synthesized for the removal of Eu(III) and U(VI) from aqueous phase, respectively. In comparison to naked MNPs, the CD-modified MNPs demonstrated a higher adsorption capacity toward Eu(III) and U (VI), and these two adsorbents exhibit the pH dependence to radionuclides adsorption. In our recent work, the β-CD-modified Fe3O4 nanoparticles have been synthesized by layer-by-layer approach and used to adsorb methylene blue in aqueous solution [51]. In addition, carboxymethyl-β-cyclodextrin polymer-coated Fe3O4 nanoparticles (CDPMNPs) have been used to remove the phenolic pollutants from water [68]. These researches demonstrated that the CDs and CD polymer-coated Fe3O4 nanoparticles could be used as the promising adsorbents for the elimination of organic pollutants from wastewater by magnetic separation technology. The high surface area of the CD-coated magnetic nanomaterials (CD-MNMs) as well as their ability to separate with an external magnetic field not only can be utilized toward the above-discussed water treatment, but also CD-MNMs can act as the adsorbents for drugs [55] and bioactive species [70, 71] separation. Due to the CD cavity’s unique hydrophobic character and inherent chirality, chiral separation of CD-conjugated MNPs for drugs and bioactive species has been widely investigated [33, 57, 72, 73]. For instance, the β-CD-functionalized Fe3O4 nanospheres have been provided the ability to chirally discriminate amino acids enantiomers while serving as magnetic separators for effectively separating the isomers of different amino acids, especially for the tryptophan (Fig. 7) [57].

15.3.3 Cyclodextrin-Functionalized Magnetic Materials for Drug Delivery Magnetic nanoparticles are promising supramolecular chemotherapeutic drug carriers because they can deliver anticancer drugs more selectively to the target site under the guidance of an external magnetic field and hence abate the lesions in tissues precisely. The CD-modified iron oxide nanoparticles are attractive drug carriers by virtue of their biocompatibility, biodegradability, aqueous dispersibility, and magnetizability. The ability of CD-coated MNPs to function as nanocarriers has been demonstrated in several cases [50, 74–76]. A size-controllable supramolecular magnetic nanoparticles (SMNPs) have been prepared by utilizing a supramolecular system based on the host-guest interaction between β-CD and Ad with magnetic nanoparticles [75]. The DOX encapsulated on the DOX@SMNPs can be controlled release by quickly generating thermal energy when applying an external alternative magnetic field (AMF). The approximately 50% of DOX was released by applying an AMF only 2 min and effectively inhibited

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Fig. 7 The illustration of preparation procedures and separation mechanism of β-CD-modified Fe3O4 nanoparticles for amino acids isomers [57]. (Copyright 2011, Royal Society of Chemistry)

the tumor cell, which significantly decreasing the side effects compared to normal protocols. This result indicated that the drug dosage for cancer treatment can be significantly reduced by a magnetic field-controlled accurate. Level of drug concentration delivery to a tumor. Shuang and co-workers constructed a pH-responsive controlled release system based on β-cyclodextrin-assembled magnetic Fe3O4 nanoparticles (β-CD-MNPs) for stereoisomeric doxorubicin (DOX) and epirubicin (EPI) delivery [50]. The loading behaviors of β-CD-MNPs for both DOX and EPI followed multilayer Freundlich isotherm adsorption, and the loading amounts are 70.27 mg/g (DOX) and 39.46 mg/g (EPI), respectively, owing to the different conformation of inclusion complexes. The β-CD-MNPs/DOX reveals higher and faster release in vitro and stronger resolution in cell than that of β-CD-MNPs/EPI. These findings could be extended to the design of the delivery of other stereoisomeric drugs, which may afford further guidance for their loading and release in biomedical applications.

15.4

Cyclodextrin-Functionalized Semiconductor Quantum Dots

Semiconductor quantum dots (QDs) exhibit unique optical and photophysical properties and represent one of the major advances in materials science in the last two decades. Because of QDs offer some advantages compared with conventional chromophores, such as broad absorption, narrow emission lines, low

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photobleaching, long lifetimes, and high quantum yields, QDs have been widely used as fluorescence probes in analytical chemistry, biology, and medicine. For application of QDs in sensor or in biological imaging, the QDs must be dispersible in aqueous solution and luminous with higher fluorescence efficiency. Thus, the synthesis and application of water-soluble QDs with controlled size and surface functionality should be explored and developed [77]. Cyclodextrins (CDs), as a representative supermolecule host, can form a size-modulated host-guest inclusion complex in the cavity and provide an external selectivity tuned by the functionalities on the rim. The CDs can be used as an ideal functional molecule to improve the solubility, stability, and biocompatibility of QDs. The combination of the luminescence properties of QDs and the molecular recognition ability of CDs has provided highly sensitive and selective sensing platforms for various targets. In this part, we focus on the recent advances in the construction of CD-functionalized QDs and their applications in molecular recognition [78, 79].

15.4.1 CD-Functionalized QDs as an Achiral Recognition Sensing Platforms Luminescence sensing that uses conjugates of QDs with CDs constitutes an emerging and widely explored area of general ion or molecular recognition research [80–84]. Li et al. reported a kind of CD-modified CdSe/ZnS QDs, which have been prepared by using ultrasonic irradiation of a mixture of TOPO-coated CdSe/ ZnS QDs and α-, β-, or γ-CD in anhydrous ethanol [80]. A host-guest interaction between TOPO ligand and CD resulted in the CD coating on the surface of QDs. Furthermore, the CD-modified CdSe/ZnS QDs have been explored to detect the phenol isomers by quenching fluorescence intensity. The quenching luminescence of the CD-coated QDs was attributed to the fact that the phenol molecules entered the cavity of the coating CD and competed with the TOPO to form an inclusion complex. Specifically, it was found that the luminescence of α-CD or β-CD-modified QDs can be quenched by all of the phenols, but only a little effect on γ-CD-modified QDs. Li et al. prepared a kind of CD-CdSe QDs by directly replacing the oleic acid (Ole) on the CdSe QDs surface with β-CD in an alkaline aqueous solution [81]. CDs are modified on QDs’ surface via covalent binding, and the resulted β-CD-CdSe QDs exhibited high photoluminescence efficiency and stability in the water environment. Moreover, the several transition-metal ions (Ag+, Hg2+, Co2+, Zn2+) have efficiently quenched the restored fluorescence of β-CD-CdSe QDs. The results demonstrated the potential utility of β-CD-CdSe QDs for the detection of these ions with wide linear range. Another sensing system based on β-CD and CdSe/ZnS QDs was developed for determination of ascorbic acid [82]. In this case, the fluorescence of the QDs was quenched by the oxidized ascorbic acid. Moreover, the β-CD-CuInS2 QDs have attracted attention as a new class of sensor for detection of adenosine-5-triphosphate (ATP) [83]. A slight enhancement of fluorescence emission from β-CD-CuInS2 QDs

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was observed upon addition of ATP-binding aptamer due to the host-guest interaction between aptamer and β-CD. The addition of ATP to β-CD-CuInS2 QDs/aptamer system further enhanced the fluorescence emission, which due to the aptamer-ATP complexes formed and included into the cavity of β-CD.

15.4.2 CD-Functionalized QDs as a Chiral Recognition Sensing Platform Due to the CD cavity’s inherent chirality, luminescence sensing of CD-conjugated QDs for chiral recognition has been widely investigated [85–89]. In one example, Willner et al. have designed β-CD-modified CdSe/ZnS QDs for optical sensing and chiroselective sensing of different organic substrates based on a fluorescence resonance energy transfer (FRET) or an electron transfer (ET) mechanism [85]. The β-CD coated on the surface of CdSe/ZnS QDs was used to accommodate rhodamine B dye that acted as an optical label. Such systems were utilized for direct sensing of organic substrates exhibiting electron-acceptor or electron-donor properties via electron transfer quenching of the luminescence of the QDs. Moreover, the β-CDfunctionalized QD/dye system was used for the chiroselective optical discrimination between D, L-phenylalanine and D, L-tyrosine enantiomers. The specific selection of aromatic chiral amino acid was explained by favored interactions of the phenylring with the β-CD receptor. The same β-CD-functionalized QDs were also used as direct luminescence sensors for the optical detection of p-nitrophenol using an ET quenching route. In a similar manner, water-soluble CD-modified CdSe/ZnS QDs were utilized as selective fluorescent assays for the recognition of amino acid enantiomers [86, 87]. The selective enantiorecognition of L-penicillamine and D-penicillamine was accomplished by host-guest interaction between the penicillamines and the β-CD pockets on the QDs. Wei et al. reported a photoluminescence chiral assay for tryptophan enantiomers based on mono-6-SH-β-cyclodextrin capped Mn-doped ZnS quantum dots (β-CDMn-ZnS QDs) (Fig. 8) [88]. The β-CD-Mn-ZnS QDs have been prepared by hydrothermal process and exhibited dual photoluminescence (PL) at 430 nm and 598 nm. The PL intensity of β-CD-Mn-ZnS QDs responded to tryptophan enantiomers differently: L-Tryptophan enhances the PL intensity of β-CD-Mn-ZnS QDs drastically, whereas the D-isomer barely affects it. In addition, L-tryptophan can be detected in the presence of its stereoisomer with a detection limit of 5.4 nM in a linear range of 0–6.0 mM.

15.5

Cyclodextrin-Functionalized Noble Metal Nanoparticles

Noble metal nanoparticles (NPs), such as Au NPs, Ag NPs, and Pd NPs, have attracted a growing interest of researchers due to their wide spectrum of potential applications in fields such as sensing, catalysis, or nanomedicine. The utility of metal NPs for any particular application strongly depends upon their physicochemical

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Fig. 8 Detection of L/D tryptophan enantiomers by mono-6-SH-β-cyclodextrin capped Mn-doped ZnS quantum dots via photoluminescence intensity enhancing [88]. (Copyright 2015 Royal Society of Chemistry)

properties. Thus, a variety of synthetic strategies have been adopted to synthesize metal NPs with size, shape, and composition control. For application in biological sensing or in cell imaging, the corresponding nanoparticles must be soluble in water, and much attention has been paid to the development of green synthetic approaches leading to aqueous suspensions of nanoparticles. Therefore, CDs have appeared to be very eco-friendly capping agents for the metal nanoparticles synthesis. The role of CDs is diverse, ranging from stabilization of the NPs by providing a protective layer that prevents aggregation to increasing solubility in aqueous media. α-, β-, and γ-CDs, and their derivatives, have been widely employed to modify metal nanoparticles by interacting with proper guest molecules [90, 91]. In this part, we focus on the recent advances in the construction of CD-functionalized noble metal nanoparticles and their applications in identification-detection sensing platforms. CD-coated Au and Ag NPs provide a kind of hybrid nanomaterials which can pave the way toward novel biological tracers as well as optoelectronic nanosensor. Generally, a distance-dependent surface plasmon resonance (SPR) band of AuNPs and AgNPs has been extensively employed for designing assembly-/disassemblymodulated colorimetric sensors. In this case, the high extinction coefficient of AuNPs and AgNPs permits that they can act as the ideal energy acceptors in constructing fluorescence resonance energy transfer (FRET) system for sensing and biosensing [92–97]. For example, a (RB-β-CD@Au NP) composite can be employed as an energy acceptor for turn-on fluorescent sensing of cholesterol based on the guest replacement reaction as shown in Fig. 9 [92]. In addition, β-CD-stabilized Au NPs revealed a unique ability to detect micromolar quantities of Pb2+ in the presence of other interfering metal cations, resulting in a visual color change from red to blue [93]. On the other hand, many systems were demonstrated as very effective substrates for the detection of various organic compounds using

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Fig. 9 Schematic illustration of fluorescent turn-on detection of cholesterol using the (RB-βCD@Au NP) composite [92]. (Copyright 2016 American Chemical Society)

surface-enhanced Raman spectroscopy (SERS). The SERS technique is a very effective tool to analyze molecules by highly increasing the Raman signal intensity coming from molecules, which have been adsorbed on nanosized metallic surfaces [98]. Several organic moleculars, such as 1,10-phenanthroline, dopamine, aminopyrene, crystal violet, rhodamine B (RB), 4-aminothiophenol, have been demonstrated that CD-capped Au and Ag NPs exhibit a significant SERS effect to these molecular probes [99–101].

15.6

Conclusions and Outlooks

The correlative research and developments in the area of functionalized inorganic nanomaterials, such as carbon, magnetic, semiconductor, and metal nanoparticles, have emerged into a cutting edge multidisciplinary nanotechnology. Notably, CDs have been widely used as ideal functional molecules to improve the stability, solubility, and bioavailability of these inorganic nanoparticles, based on their unique properties as supermolecular hosts. The remarkable optical, electronic, and magnetic properties of these inorganic nanoparticles can be combined with the recognition and inclusion ability of cyclodextrins for the development of multifunctional nanodevices. Such all-in-one nanodevices can bring together all the assets of materials involved in constructing nanohybrids, in a comprehensive manner, which may lead to a synergistic effect for sensing, removal or purification, and drug delivery. Thus, the CD hybrid inorganic nanocomposites offer fast, sensitive, and selective molecular recognition sensors; inexpensive, eco-friendly, high efficient, and recyclable adsorption-separation system; as well as new nanocomposites designed specifically to carry anticancer drugs and to treat cancer in virtue of high targeting and multiple stimuli-responsive brought by synergetic effect of all materials. Although the construction and application of CD hybrid inorganic nanomaterials have been widely developed in recent years and achieved some charming advances, there are still many challenges for scientists. Firstly, the intelligent molecular recognition platform with more sensitivity and selectivity should be developed, of which the binding affinities can be adjusted according to response microenvironments for real-time monitoring in vivo. Secondly, the degradation function should be integrated into the CD hybrid inorganic nano-adsorbents. For the environment pollution treatment, perfect nano-adsorbents are extremely stable during the

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adsorption process, while they validly decompose the adsorbed substance by a specific catalyst, resulting in the pollutant getting rid of the environment effectively. Undoubtedly, the steadiness and reproducibility of the fabrication of chemical sensors and adsorbents should be further explored. And the employment of CD hybrid inorganic nanomaterials as both chiral sensors for enantiomeric recognition and chiral receptors for enantioselective separation of small chiral molecular guests still awaits exploration in the near future. Furthermore, multifunctional CD hybrid inorganic nanomaterials should be advocated in nanomedicine, which integrated with diagnostic, imaging, and therapy into one nanosystem. The diagnostic and imaging played the important role in reporting the presence and location of the tumor, its status and its response to a specific treatment. And the synergistic combinations of multiple therapeutic modalities with controlled therapeutic process reduced the side effects and enhanced the effectiveness of cancer treatment. All of these provide the possibility of precision therapy. In particular, as we all know, the application of CD hybrid inorganic nanomaterials in nanomedicine should focus on an in-depth insight into the safety issues in the further, if starting the clinical trials. The development and commercial applications in the further should be sufficiently considered the abovementioned correlative fields.

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Photoresponsive Supramolecular Polymers Based on Host-Guest Interactions

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Contents 16.1 16.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photoresponsive Supramolecular Polymers Based on Cyclodextrin (CDs) . . . . . . . . . . . . 16.2.1 CD-Based Polymer Networks and Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.2.2 CD-Based Polymer Self-Assemblies and Vesicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.3 Photoresponsive Supramolecular Polymers Based on Cucurbituril (CBs) . . . . . . . . . . . . . 16.3.1 Adjustable Dynamic Photophysical Properties Based on CB . . . . . . . . . . . . . . . . . 16.3.2 Supramolecular Polymer with Photoisomerism Based on CB . . . . . . . . . . . . . . . . 16.3.3 Controllable Supramolecular Polymerization Based on CB . . . . . . . . . . . . . . . . . . 16.4 Photoresponsive Supramolecular Polymers Based on Crown Ether . . . . . . . . . . . . . . . . . . . . 16.4.1 Networks and Hydrogels of Supramolecular Polymer Based on Crown Ether . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.4.2 Conjugated Polymer Network and Its Disassembly Induced by Different Signals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.5 Photoresponsive Supramolecular Polymers Based on Calixarene . . . . . . . . . . . . . . . . . . . . . . 16.5.1 Supramolecular Polymer with Photoisomerism Based on Calixarene . . . . . . . . 16.5.2 Networks and Self-Assemblies of Supramolecular Polymer Based on Calixarene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.6 Photoresponsive Supramolecular Polymers Based on Pillararene . . . . . . . . . . . . . . . . . . . . . . 16.6.1 Cross-Linked Polymer Networks Based on Pillararene . . . . . . . . . . . . . . . . . . . . . . . 16.6.2 Supramolecular Polymer with Photoisomerism Based on Pillararene . . . . . . . . 16.6.3 Supramolecular Polymer with Two Guest Monomers Based on Pillararene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.8 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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F. Gu · X. Ma (*) Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, China e-mail: [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_18

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16.1

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Introduction

Owing to their potential applications in the fields of optics, biology, and medicine, supramolecular materials are drawing more and more attention from researchers. Supramolecular polymers are constructed from monomer components, small supramolecular systems, or polymers that are repeatedly linked by such reversible noncovalent interactions as hydrogen bonds, π-π stacking, hydrophobic effects, host–guest interaction, and electrostatic interactions [1]. Since the noncovalent interactions are reversible, supramolecular polymers tend to make differences to external factors, such as pH changes, chemical and electrochemical redox, light stimulation, temperature/concentration changes, enzyme stimuli, etc. and accompanied by assembly conformation or property changes. The host–guest interaction is the driving force of the host–guest complex, which involves the synergy of a variety of noncovalent bonds, such as hydrophobic interactions, hydrogen bonds, ionic bonds, van der Waals forces, and electrostatic interactions. Since the discovery of cryptands and crown ethers by Lehn, Cram, and Pedersen, the host–guest system has greatly contributed to the development of supramolecular chemistry. As the name suggests, the host–guest system consists mainly of two components: the host and the guest, which form the supramolecular inclusion. The host molecule usually contains a cavity that specifically recognizes the guest molecule. The host–guest function has characteristic selectivity, because the subject has various restrictions on the object, such as size, shape, charge, and polarity. In the development of supramolecular chemistry, the control and regulation of molecular recognition based on host–guest interaction in supramolecular polymers has attracted a lot of attention [2]. The mechanism of polymerization and the nature of the polymer are determined by the strength and nature of the host–guest units. The host molecules involved in the preparation of supramolecular polymers based on host–guest systems are typically crown ethers, cyclodextrins, cucurbiturils, calixarenes, and column aromatics. And the guest molecules are generally organic compounds that can enter the bulky cavity. In the following, we will outline the development of photoresponsive supramolecular polymers in this field according to the classification of the host molecules. Organic materials have many advantages such as good regulation, rich color, smart molecular design, low cost, and toxicity compared with inorganic materials. The combination of supramolecular chemistry to construct highly efficient luminescent materials not only simplifies the preparation process but also imparts good stimuli responsiveness and reversibility to these materials through noncovalent attachment. The noncovalently guided assembly–disassembly process can affect the aggregation and energy transfer between the fluorophores [3], thus regulate the luminescence behavior of the materials. Therefore, luminescent systems constructed concerning supramolecular systems are generally capable of responding to external stimuli such as pH, temperature, solvent polarity, light radiation, redox, etc. accompanied by reversible conformation and structural transformation. In recent years, materials with tunable luminescence properties have been demonstrated their

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potential applications in many fields, such as optoelectronic devices, fluorescence sensing, and imaging agents [4]. Due to the introduction of many functional units [5], reports on supramolecular polymers will be further explored because of its luminescent properties. Herein, we discussed an overview of the photoresponsive supramolecular systems induced by the host–guest interaction. The host–guest recognition is an important noncovalent bonding using hosts such as CD, CB, crown ether, calixarene, and pillararene to encapsulate the guests in the constructed supramolecular system. Furthermore, the guest unit undergoes a reversible structure or conformation difference under specific light stimulation, resulting in the corresponding changes of the supramolecular polymer. In this chapter, we introduce the photoresponsive supramolecular systems according to the different types of hosts and make summaries and outlooks on its functions and applications.

16.2

Photoresponsive Supramolecular Polymers Based on Cyclodextrin (CDs)

CDs are a class of widely used supramolecular macrocyclic host molecules, which are cyclic oligomers composed of α-(1-4)-glycosidically linked glucopyranose units. In the structure of the CD, there is a hydrophilic surface and a hydrophobic cavity, and its hydrophobic cavity can form an inclusion in water with a series of organic molecules. Because of this unique advantage of CD, scientists have linked it to the phosphorescent emission of organic molecules. Reports on CD-induced room temperature phosphorescence (CD-RTP) were first published in the early 1980s [6]. In 2011, we also reported a RTP addressing pseudorotaxane induced by the inclusion of β-CD and α-BrNp. After that, we constructed a supramolecular hydrogel system capable of rapidly self-healing and room temperature phosphorescence based on the action of β-CD and α-BrNp [7]. For a supramolecular system based on the action of the host and guest, the host molecule can be selected based on the size of the cavity of the macrocyclic molecule. The cavity size of the γ-CD molecule is 0.75 nm, which is much larger than that of α-CD and β-CD. The structures and related properties of CDs are shown in Fig. 1.

16.2.1 CD-Based Polymer Networks and Hydrogels Many photoresponsive supramolecular polymer systems in side-chain are based on cyclodextrin because of its high solubility and protective effect on the optical signal. Herein, we introduce the cyclodextrins interacted with the corresponding object to achieve light response control. In 2015, Wu et al. [8] reported a novel supramolecular complex which is formed by tetra-ortho-methoxy-substituted azobenzene (mAzo) and β-cyclodextrin (β-CD), shown in Fig. 2. They synthesized a mAzo-functionalized polymer and a β-CD-functionalized polymer and obtained the supramolecular hydrogels by mixing the two polymers. The supramolecular

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Fig. 1 Chemical structures, approximate geometric dimensions, and physical properties of cyclodextrins. (Reprinted with permission from Ref. [6]. Copyright (2014) American Chemical Society)

Fig. 2 Schematic model (a) and photographs (b) of the reversible sol–gel transition of the PAAmAzo/PAA-β-CD mixture. (Reprinted with permission from Ref. [8]. Copyright (2015) Royal Society of Chemistry)

hydrogel was used as a protein carrier which could precisely control the release of the protein by red light. More interestingly, the author also demonstrated that the redlight-responsive supramolecules showed more advantages compared with the conventional UV-responsive supramolecules in controllable aspects.

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Fig. 3 Construction of the supramolecular polymeric hydrogel by host–guest interaction between host–guest polymers and its rapidly self-healing property. (Reprinted with permission from Ref. [9]. Copyright (2014) John Wiley and Sons)

Ma et al. (2014) [9] synthesized two water-soluble side-chain polymers with polymer monomers containing β-cyclodextrin and α-bromonaphthalene, seen in Fig. 3. Based on the host–guest interaction, the hydrogel material can be simply prepared by the mechanical mixing of the β-cyclodextrin host polymer and the α-bromonaphthalene guest polymer. Meanwhile, the hydrogel material is available of rapidly self-healing within 1 min in the natural environment, and owing to the inclusion interaction in this supramolecular system, the supramolecular polymer has strong phosphorescence emission at room temperature. Later, Ma et al. (2016) [10] developed another poly-BrNpA/γ-CD system based on the host–guest recognition between γ-CD and the BrNpA moiety, which could emit a RTP signal in aqueous solution, as shown in Fig. 4. As a new CD-RTP system, its emission could be controlled by the photoisomerization of the Azo unit of poly-Azo in aqueous solution. Moreover, a pure organic RTP hydrogel based on the poly-BrNpA/γCD system was also constructed. This study may help to enrich the strategies to construct CD-RTP systems and pave the way for chemists in designing new RTP materials.

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Fig. 4 Schematic representation of the CD-RTP system via host–guest interaction between polyBrNpA and γ-CD. (Reprinted with permission from Ref. [10]. Copyright (2016) Royal Society of Chemistry)

Xu et al. (2015) [11] reported a new kind of drug carrier constructed by supramolecular polymers. Due that the prolonged ultraviolet (UV) exposure is harmful to cells and UV light has limited tissue penetration ability, this system offers a solution using a magnetic field to aggregate microcapsules to an accurate area and then release the drug upon UV light. The grafted β-CD of CD-g-DexO and AD-PASP will be broken down in an acidic tumor environment, leading to the release of drugs to the certain location. This research of the drug carrier is expectedly designed as multimodal functional imaging probe for treatment of cancer. Zhao et al. (2017) [12] incorporated gold nanorods (GNRs) into the hydrogel networks formed by the copolymerization of N-isopropylacrylamide (NIPAm) and methacrylated poly-β-cyclodextrin (MPCD)-based macromere to fabricate an injectable and near-infrared (NIR)/pH responsive poly(NIPAm-co-MPCD)/GNRs nanocomposite hydrogel, which could serve as a long-acting implant for chemophotothermal synergistic cancer therapy, shown in Fig. 5. The nanocomposite hydrogel showed superior mechanical and swelling properties, gelation characteristics, and excellent NIR-responsive property. A hydrophobic acid-labile adamantane-modified doxorubicin (AD-DOX) prodrug was loaded into the hydrogel efficiently by host–guest interaction. The nanocomposite hydrogel exhibited a manner of sustained

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EPI GMA H N

NIPAm

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Acid-labile hydrazone bond H N

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>LCST

Fig. 5 Schematic illustration of the formation of injectable, NIR/pH-responsive nanocomposite hydrogel, and chemophotothermal synergistic cancer therapy as a long-acting implant. (Reprinted with permission from Ref. [12]. Copyright (2017) American Chemical Society)

drug release and could sustain the slow and steady release of DOX for more than 1 month. The pH-responsive release of DOX from the nanocomposite hydrogel was observed owing to the cleavage of acid-labile hydrazone bond between DOX and the adamantly group in acidic environment. NIR irradiation could accelerate the release of DOX from the networks, which was controlled by the collapse of the hydrogel networks induced by photothermal effect of GNRs. The in vitro cytotoxicity test demonstrated the excellent biocompatibility and photothermal effect of the nanocomposite hydrogel. Moreover, the in situ-forming hydrogel showed promising tissue biocompatibility in the mouse model study. The in vivo antitumor test demonstrated the capacity of the nanocomposite hydrogel for chemophotothermal synergistic therapy with reduced adverse effects owing to the prolonged drug retention in the tumor region and efficient photothermal effect. Therefore, this injectable and NIR/pH-responsive nanocomposite hydrogel exhibited great potential as a long-term drug delivery platform for chemophotothermal synergistic cancer therapy.

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16.2.2 CD-Based Polymer Self-Assemblies and Vesicles Due to the excellent chemical stability and remarkable biocompatibility, nanodiamonds (NDs) have received widespread research attention by the biomedical field. The excellent water dispersibility of NDs has significant importance for biomedical applications. Therefore, surface modification of NDs with hydrophilic polymers has been extensively investigated over the past few decades. Zhang et al. (2018) [13] synthesized β-CD containing hyperbranched polymer functionalized ND (ND-β-CD-HPG) composites with high water dispersibility via supramolecular chemistry based on the host–guest interaction between β-CD and adamantine (Ad). The hydroxyl groups of NDs first reacted with 1, 1-adamantanecarbonyl chloride to obtain ND-Ad, which was further functionalized with β-CD containing hyperbranched polymers to form the final ND-β-CD-HPG composites. The successful preparation of ND-β-CD-HPG composites was confirmed by several characterization techniques. Furthermore, the loading and release of the anticancer agent doxorubicin hydrochloride (DOX) on ND-β-CD-HPG composites was also examined to explore its potential in drug delivery. When compared with traditional methods of surface modification of NDs, this method was convenient, fast, and efficient. We demonstrated that ND-β-CD-HPG composites have great water dispersibility, low toxicity, high drug-loading capacity, and controlled drug-release behavior. Based on these characteristics, ND-β-CD-HPG composites are expected to have high potential for biomedical applications. Jiang et al. (2018) [14] prepared an oligo(ethylene glycol)-based amphiphilic star polymer containing fluorescent coumarin as end groups and dual tertiary amine as center. This polymer could self-assemble into vesicles in the aqueous solution. The crosslinking pattern in the hydrophobic membrane of the vesicles could form noncovalent crosslinking by adding γ-CD into the solution, and the formed 2/1 host–guest inclusion between γ-CD and coumarin groups led to a higher sensitivity and faster disassembly speed of the vesicles by injecting CO2; while after 365 nm light irradiation, the formed coumarin dimers acting as crosslinking point gave a more stable hydrophobic membrane and less sensitive to CO2. The work reported here gives a notable polymer system that the CO2-responsive behaviors can be easily tuned by controlling the crosslinking pattern, bearing a great promise in the areas including latexes, surfaces, sensors, carriers, and so on. Zhang et al. (2014) [15] reported a fabrication of photoresponsive block-controllable supramolecular polymer which was constructed through host–guest interactions. This supramolecular polymer based on the assembly of two homopolymers according to the host–guest recognition between CDs and Ad/Azo moieties in aqueous solution is a kind of triblock polymer. Upon alternating irradiation of UV/ visible light, this triblock polymer can reversibly transform into supramolecular diblock polymers with the change in morphology between the self-assembly and disassembly. In addition, this supramolecular polymer showed potential applications in stimuli-responsive drug delivery systems. Yuan et al. (2017) [16] prepared a kind of functional (PCL-CD)16/ Azo-PDMAEMA supramolecular aggregates with tunable morphologies based

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on the IC between the dendritic host polymer and the linear guest polymer. The morphologies of the aggregates could be adjusted by changing the molar ratio of (PCL-CD)16: Azo-PDMAEMA in the supramolecules. The supramolecular aggregates changed from nanorods to nanowires, and then to spherical micelles when the (PCL-CD)16:Azo-PDMAEMA molar ratio was changed from 1:1 to 1:8 and 1:16, respectively. Benefitting from the UV-response of β-CD/Azo IC, the supramolecular aggregates demonstrated UV responsive properties. Upon UV light irradiation, the morphologies of the aggregates became irregular and agglomeration occurred. Meanwhile, because of the thermoresponsive PDMAEMA, the supramolecular aggregates showed thermoresponsive properties. When the temperature was increased, the aggregates changed into smaller aggregates and then aggregated with each other upon further heating. Therefore, the supramolecular aggregates with tunable morphologies were UV- and thermoresponsive. These functional nanomaterials have potential applications in nanotechnology and biomedicine.

16.3

Photoresponsive Supramolecular Polymers Based on Cucurbituril (CBs)

CBs represent another class of cyclic host molecules. As shown in Fig. 6, they are macrocyclic oligomers of methylene-bridged glycolurils, which are named after the shape of the zucchini of the genus Cucurbita. They are called cucurbit[n]

Fig. 6 (Top) Synthesis of CB[n] homologues and (bottom) different representations of CB[7] structure. (Reprinted with permission from Ref. [17]. Copyright (2015) Royal Society of Chemistry)

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uril (CB[n]) depending on the number of units of glycoluril. They contain a hydrophobic cavity lining the urea carbonyl and can enclose a series of neutral or positively charged guests with very high binding constants, providing an opportunity for the development of new supramolecular polymers. The first member of this circular family is hexamer CB[6], and since then CB[n] has evolved to include smaller or larger homologs (CB[5]-CB[10]). In this family, CB[6] and CB[8] have poor water solubility, while CB[5] and CB[7] have moderate solubility. In this regard, Mock, J. Fraser Stoddart, Kimoon Kim, Lyle Isaacs, etc. have done a lot of exploratory work [17]. However, due to the difficulty in the modification of CBs, supramolecular polymers based on CB[5], CB[6], and CB[7] are rarely reported. The particularity of CB[8] is that its larger cavity can entrap two specific guest molecules. Therefore, in the CB family, CB[8] is the most promising host molecule for the construction of supramolecular polymers. However, limited by the poor water solubility ( PC2), the network structure tended to be heterogeneous because the confinement effect suppressed the movement of the cross-linked α-CDs. When the fluid flowed through the supramolecular gel film, if P < PC1, the fluid needed to flow through the dense homogeneous structure, thus causing a large hydraulic distortion, resulting in a larger f value; however, if P > PC2, the fluid flowed through the low cross-linked area of the heterogeneous structure, so the resulting hydraulic distortion is small resulting in a small friction coefficient. This particular physical feature allows chemists to regulate the liquid permeability of the sliding ring gel film material by simply adjusting the applied pressure.

17.3.4.3 Electrical Stimuli Response As shown in Fig. 20, Harada et al. [70] constructed electrochromic hydrogel materials by copolymerization of acrylamide, acrylamide β-CD, and acrylamide phenolphthalein. Phenolphthalein, as a color-changing material, is pink in alkaline aqueous solution, but it will become colorless when it is encapsulated with β-CD under alkaline condition. When the alternating current was applied to the hydrogel and the voltage was 0 V, the gel tended to be colorless. However, when the voltage

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Fig. 20 Schematic illustration of electrochromic hydrogel based on copolymerization of acrylamide, acrylamide β-CD, and acrylamide phenolphthalein and its electrochromic behavior [70]

was 60 V, the gel changed to pink, which could be attributed to the joule heat generated at certain voltage inducing dissociation of β-CD and phenolphthalein complex. When the voltage reduced to 0 V, β-CD and phenolphthalein unites and bonded again. This system provided the possibility for macroscopic observation of bonding state in polymer materials.

17.3.4.4 Chemical Stimuli-Responsive Materials It is very difficult to agglutinate hard materials without glue due to the poor mobility of molecules on the adhesive interfaces and the rough surfaces of the hard materials. Harada et al. [71] exploited supramolecular complexation between β-CD and adamantane to bond host-guest-derivatized polyacrylamide (pAAm) xerogels with only trace amount of water (Fig. 21). Firstly, they synthesized a series of pAAm polymer derivatives with different substitution degrees of β-CD and adamantane separately. Then the adhesive strengths between polymers with different ratios of hosts and guests were characterized by hoisting experiments. Experimental results showed that the adhesive strength between the two classes of xerogels increased along with the increase of β-CD units and adamantane units grafted on aerogels, respectively, suggesting that the binding strength between the host and the guest aerogels is based on the effective bonding between β-CD and adamantyl units. This conclusion was further evidenced by the use of small molecules for competitive bonding. At the same time, the perfect pulling together of the aerogels’ interfaces could be clearly observed under optical microscope. Finally, authors constructed an aerogel containing both β-CD (0.3 mol %) and adamantine (0.4 mol %), which exhibited a high self-healing ratio (88% of its original state). All the results jointly indicated that host-guest interaction could act as a binder during the adhesion of the supramolecular aerogels. Conventional adhesives can bond a wide variety of materials, and in order to prevent such indiscriminate bonding, Harada et al. [72] reported an intelligent adhesive hydrogel material which could adhere to a specific target surface under

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Fig. 21 Schematic illustration of the water-responsive host and guest xerogels and their adhesive property [71]

specific conditions and response to chemical stimuli (host-guest interaction and metal ions) due to competitive binding (Fig. 22). Firstly, acrylamide, β-CD modified acrylamide and 2,20 -bipyridyl modified acrylamide as monomers and methylene acrylamide as cross-linking agents were copolymerized to gain a functional adhesive host hydrogel (Bpy-β-CD gel). Similarly, a guest hydrogel was obtained by copolymerization of acrylamide and t-butyl acrylamide together. Then the adhesive property between host and guest hydrogels was investigated, and the driving force was proved to be the dynamic binding of β-CD and 2,20 -bipyridine as imagined. As shown in Fig. 20, when metal ions (Co2+, Ni2+, Cu2+, and Zn2+) were bonded to 2,20 -bipyridine, binding strength between β-CD and t-butyl surpassed that of metal ions 2,20 -bipyridine, and β-CD on the host hydrogel tended to selectively bind tbutyl group on the guest hydrogel resulting in the adhesion of two gels. More importantly, this adhesive property is selective for different metal ions which could be explained by the different complexation ratios of metals and 2,20 -bipyridine ligand and their contributions for cross-linking. In such a supramolecular system, the free switching of two independent chemical signals (metal ion complexation, hostguest interaction) provided a new idea for efficient orthogonal bonding of macroscopic object.

17.3.4.5 Multi-stimuli-Responsive Materials Wu et al. [73] constructed a supramolecular hydrogel using PEG- and β-CD-modified oligomeric silsesquioxane and disulfide-bridged azobenzene dimers (Fig. 23). Taking advantage of the photo-responsive property of azobenzene guest, the hydrogel turned into sol upon UV light irradiation and recovered to gel state under dark condition. Due to the redox-responsive property of disulfide linkage, the hydrogel could become a clarified solution when reducing agent (dithiothreitol) was added and can revert to gel when oxidizer (H2O2) existed. Meanwhile, as a result of the reversible binding between β-CD and azobenzene, sol-gel transition could also take place when temperature changed or competing guest molecules were added. More importantly, the abovementioned intelligent hydrogel has a good mechanical property and is biocompatible demonstrated by both NIH3T3 and MCF-7 cell lines. In summary, authors constructed a smart hydrogel which could respond to various

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Fig. 22 Schematic illustration of the metal ion-responsive host and guest gels and their adhesive property [72]

Fig. 23 Schematic illustration of the fabrication process of a multi-stimuli-responsive hydrogel [73]

external stimuli and broadened the mind of chemists for developing smart materials with certain functions.

17.4

Conclusion

In summary, the construction of supramolecular CD hydrogels is a hot research field under fast development. The main driving forces for the construction of CD hydrogels are dynamic non-covalent interactions such as hydrogen bonding, hostguest bonding, ionic interactions, etc. Sometimes covalent bonds were introduced to CD gels to enhance the gels’ mechanical properties at the expense of the dynamic self-healing properties. How to rationally use various covalent and non-covalent functions to build CD hydrogel materials with excellent performance is still an important issue that people need to pay close attention to.

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CD hydrogels combine the advantages of both gels’ micro-fluidity and elasticity, and CDs’ good water solubility, biocompatibility, and specific bonding ability have been applied as biosensors, detection sensors, adsorption removal sponges, and smart materials. Although CD gels play a pivotal role in numerous fields, they are also facing enormous challenges. For example, in the field of drug delivery, how to increase the loading rate of drugs on CD gels, prevent the drug leakage during the delivery process, and achieve more effective killing of diseased cells and zero damage to normal cells still remain a major difficulty. In the field of chemical detection, how to further reduce detection limit of small molecules such as sugars, herbicides, insecticides, etc. and achieve rapid visual inspection also need to be further investigated. In the field of environmental protection, how to achieve more rapid and effective removal of pollutants and provide effective means for the control of water, air, and soil pollution are still urgent. In the field of new materials, how to fabricate smart CD hydrogel material is also a great challenge. With the fast improvement of basic research, it is hopeful that supramolecular CD gels will play an invaluable role in the future. Acknowledgments We thank NNSFC (21432004, 21672113, 21772099, 21861132001) for the financial support.

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Jiabin Yao, Yoshihisa Inoue, and Cheng Yang

Contents 18.1 18.2 18.3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CD-Mediated Unimolecular Photochirogenic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CD-Mediated Bimolecular Chiral Photochemical Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.3.1 Enantiodifferentiating Photodimerization of Benzaldehyde Mediated by Native β-CD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.3.2 Photocyclodimerization of 2-Anthracenecarboxylic Acid Mediated by Native and Modified γ-CD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.3.3 Photocyclodimerization of 2-Anthracenecarboxylic Acid Mediated by β-CD via 2:2 Complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.3.4 Wavelength Control of Supramolecular Photochirogenesis Mediated by CDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.3.5 Dual Supramolecular Photocyclodimerization of 2-Anthracenecarboxylate Anchored to α-CD Scaffold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.3.6 Miscellaneous Bimolecular Chiral Photoreactions Mediated by CD . . . . . . . . . 18.4 Catalytic Supramolecular Photochirogenesis with Sensitizing CD Hosts . . . . . . . . . . . . . . 18.5 Conclusion and Future Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.6 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18.1

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Introduction

Despite the recent success, asymmetric synthesis still remains some major challenges. In particular, chiral polycyclic and highly strained compounds are generally difficult to obtain or tedious to prepare through conventional catalytic or enzymatic J. Yao · C. Yang (*) Sichuan University, Chengdu, China e-mail: [email protected] Y. Inoue (*) Osaka University, Suita, Japan e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_20

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reactions, but immediately and efficiently accessible via photochemical reactions. Asymmetric photochemistry has thus attracted much attention as an alternative or complementary synthetic route to such compounds [1]. However, electronically excited organic molecules generated by photoirradiation are short-lived and highly reactive compared with the corresponding ground-state molecules, and hence difficult to maintain long-lasting stable chiral intra- and intermolecular interactions, rendering the stereochemical control in the excited state highly challenging. Indeed, the early photochirogenic endeavors in isotopic media encountered rather disappointing results, affording only low-modest enantioselectivities that are obviously insufficient for practical applications [1]. Later studies have however revealed that the enantioselectivity of some chiral compounds, such as (E)-cyclooctene, can be greatly improved by optimizing the structure of chiral sensitizer and the environmental factors [2]. A more versatile and promising approach is the use of chiral supramolecular host as a tool for manipulating the stereochemical outcomes of asymmetric photoreactions [2–6]. Chiral host basically accommodates one, but sometimes more, guest substrates in its cavity through noncovalent interactions, providing the perpetual chiral environment for preorganizing the substrate(s) and also for transferring the supramolecular chirality to the included substrate(s) in the excited state. Indeed, a vast variety of chiral supramolecular systems have hitherto been exploited as the environment for photochirogenesis, which include chirally modified zeolites [7], cyclodextrins (CDs) [8], chiral hydrogen-bonding templates [9, 10], chiral liquid crystals [11], and chiral supramolecular gels [12]. Possessing good water-solubilities and hydrophobic cavities suitable for accommodating small to medium-sized organic molecules [13], commercially available α-, β-, and γ-CDs (Fig. 1) are the first and most frequently employed chiral hosts in supramolecular photochirogenesis. The major advantages of exploiting CDs as hosts for mediating photochirogenic reactions include: (1) the optical transparency over the wide wavelength range down to deep UV, which allows not only the direct photoexcitation of accommodated guest substrate(s) but also the unrestricted choice of chromophores attached to the CD portal for sensitized photoexcitation; (2) the

Fig. 1 Chemical structures of α-, β-, and γ-cyclodextrins (CDs)

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inherently chiral cavity, which serves as a built-in source of chirality without incorporating additional chiral auxiliary; (3) the ready and wide-ranging modifiability, which enables us to significantly alter the size, shape, hydrophobicity, and chiral properties of the cavity; and (4) the environmentally benign approach, which employs the biodegradable glucose-based macrocyclic hosts, aqueous media, and photon as a traceless reagent. By virtue of these features, CDs have widely been exploited as chiral supramolecular hosts for mediating various photochirogenic reactions for three decades. In this chapter, we will review the studies on chiral photochemical reactions mediated by CD hosts, mainly focusing on those reported in the last decade; for earlier studies, see the previous reviews [13]. The main goal of supramolecular photochirogenesis is to transfer the host chirality to a guest substrate residing in the cavity through supramolecular interactions. In this regard, the use of chiral hosts is theoretically triply beneficial, allowing the thermodynamic chiral recognition upon complexation of prochiral substrate(s) in the ground state, the spectroscopic differentiation of the resulting diastereomeric hostguest complex pair upon photoexcitation, and the kinetic stereocontrol of the subsequent reaction in the excited state. To optimize the photochirogenic performance and gain upmost stereochemical outcomes, the amount of free substrate remaining in the bulk solution should be minimized, as the photoreaction occurred outside the host cavity inevitably affords a racemic product. However, the complexation of organic guests with CD hosts, relying mostly on the hydrophobic interaction, is generally rather modest with the association constants ranging from 10 to 105 M
1 [13]. In order to supplement the modest binding affinity and to optimize the stereochemical outcome, an excess amount of host is often employed in the CD-mediated supramolecular photochirogenesis. This may however hinder the catalytic use of CD host at least in the direct excitation strategy if no invention is exploited to discourage the photoreaction outside the cavity. Chiral photochemical reactions mediated by CDs can be driven by direct excitation and also by photosensitization. The direct excitation of a UV/vis-absorbing substrate accommodated in CD cavity is more straightforward and frequently employed, whereas the photosensitization strategy necessitates chromophoremodified CD as a sensitizing host but is intrinsically catalytic, as only the guest substrate accommodated in the host cavity undergoes the highly efficient intracomplex energy or electron transfer leading to chiral product. We will discuss the former type of unimolecular photochirogenic reactions in section “CD-Mediated Unimolecular Photochirogenic Reactions” and bimolecular ones in section “CDMediated Bimolecular Chiral Photochemical Reactions,” while the latter type of unimolecular reactions will be discussed in section “Catalytic Supramolecular Photochirogenesis with Sensitizing CD Hosts.”

18.2

CD-Mediated Unimolecular Photochirogenic Reactions

Figure 2 summarizes the CD-mediated unimolecular chiral photoreactions reported in recent years [14–26].

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Fig. 2 Chiral unimolecular photochemical reactions mediated by CD

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Ramamurthy and coworkers investigated the β-CD-mediated chiral photoisomerizations of prochiral cis-1,2-diphenylcyclopropanes (1), pyridones (3), and tropolones (5) to the trans-isomer (2) and the valence isomers (4 and 6) (Fig. 2, Eqs. 1–3) [14–16]. They demonstrated that β-CD forms a stable host-guest complex with 1 both in solution and in the solid state, which photoisomerizes to optically active 2 in the CD cavity upon direct irradiation [14]. Thus, the photolyses of β-CD complexes of 3 and 5 in the solid state afford the corresponding cyclization products 4 and 6 in enantiomeric excesses (ee’s) of up to 60% for 4b and 33% for 6b. In sharp contrast, the solution-phase photolyses of 3 and 5 in the presence of excessive β-CD lead to the formation of 4 and 6 in very low ee’s. Interestingly, the ee of 4b obtained in the solid-state photolysis of the β-CD complex of 3b is sensitive to moisture, being reduced from 60% to 26% with decreasing water content of the host-guest complex in the solid state from 9% to 2% [15]. However, the presence of other solvents (such as n-hexane) does not appreciably influence the product’s ee. The higher ee obtained for the more moist complex was ascribed to the hydrogenbonding interactions of water molecules with CD and/or substrate in the host-guest complex, which may constrain the orientational and conformational freedoms of the substrate in the complex [15]. The solid-state photocyclization of the complex of 5a with α-, β-, and γ-CD yields 6a in 5%, 28%, 0% ee, respectively, indicating that only the host size-matched to the guest, i.e., β-CD in this particular case, can afford significant ee [16]. Eycken and coworkers found that para-substituted 4-phenoxybutenes 7a,b (Fig. 2, Eq. 4) form the corresponding 1:1 complexes with β-CD, which precipitate from hot aqueous solution [17]. Photoirradiation of the complexes in the solid state affords polycyclic product 8a,b. On the other hand, meta-isomers 9a,b (Fig. 2, Eq. 5) form the corresponding 1:2 host-guest complexes with β-CD, and photocyclize to give a mixture of regioisomeric 10a,b and 11a,b upon irradiation in the solid state. The highest ee reported for 10a is 17%, while the other products are produced in lower ee’s. The enantioselectivity observed is ascribed to the selective blockage of one of the enantiotopic faces of the aromatic ring upon complexation with β-CD, which facilitates the preferential attack of the vinyl from the open face. Mori et al. investigated the effects of complexation of aromatic ester 12 with β-CD on the subsequent photochemical decarboxylation. They found that the photodecarboxylation of (S)-12 in solution proceeds concertedly in a cheletropic manner through the spiro-lactonic transition state (Fig. 2, Eq. 6) to afford 13 with complete memory of the original chirality [22–26]. When racemic 12 is photolyzed in the presence of β-CD, (R)-13 is obtained in 14% ee, suggesting that (R)-12 undergoes faster photodecarboxylation in the cavity of β-CD.

18.3

CD-Mediated Bimolecular Chiral Photochemical Reactions

α-, β-, and γ-CD possess hydrophobic cavities of different sizes. α-CD binds only a small linear molecule or moiety, such as alkyl chain, in its narrow cavity (5–6 Å in diameter) [13b], while β-CD usually includes one medium-sized molecule, such as

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benzene derivative, in its cavity (6–8 Å in diameter) [13b]. In rather exceptional cases [21, 27], β-CD forms a higher-order 2:2 complex with certain guest molecules to facilitate the subsequent bimolecular photoreaction. Possessing the largest cavity (8–10 Å in diameter) [13b] among the three commercially available CDs, γ-CD can accommodate two medium-sized flat molecules, such as fused aromatics, to function as a chiral molecular container for bimolecular reaction. Since the affinities of organic guests toward native CDs are modest in general and the hydrophobic interaction operative between the host and guest is nondirectional in nature, introducing functional group(s) is an often employed and indeed effectual strategy for enhancing the binding affinity and also for enforcing specific orientation and conformation to the substrate(s) in the cavity.

18.3.1 Enantiodifferentiating Photodimerization of Benzaldehyde Mediated by Native b-CD Photolysis of benzaldehyde 14 gives a mixture of dimeric products 15–17 (Fig. 3) through intermolecular hydrogen abstraction [18–20]. Rao and Turro investigated the effects of β-CD on the product distribution as well as the enantioselectivity of chiral product 15 obtained in the photodimerization of 14 [21]. Upon irradiation of 14 in an aqueous solution containing β-CD, 17 is obtained as a major product in 60–70% yield, while 15 and 16 are obtained in mere 3% and 80% upon addition of high concentration CsCl (6 M). The greatly enhanced formation of the nonclassical slipped cyclodimers is rationalized

Table 2 Thermodynamic parameters for the 1:1 and 2:2 complexation of 2-anthracenecarboxylate with β-CD in phosphate buffer at pH 9.0 with and without added cesium chloride 


1

Stoichiometry T/ C CsCl/M K/M 1:1 50 0 1900  30 25 0 3800  50 0.5 4400  30 6.0 5500  90 0.5 0 8500  100 2:2 50 0 90  10 25 0 150  30 0.5 230  10 6.0 300  30 0.5 0 270  30 a

T = 298 K

ΔG /kJ mol

ΔH /kJ mol

TΔS a/ kJ mol
1


20.4  0.1


22.6  0.1


2.2  0.1


12.4  0.5


16.5  0.1


4.1  0.1




1




1

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Fig. 6 (a) Fluorescence spectra of AC (2 μM) in the presence (blue) and absence (red) of β-CD (5 mM) in phosphate buffer (pH 9.0) at 25  C (λex = 327 nm). (b) Normalized (in the shortwavelength region below 393 nm) fluorescence spectra of AC at 2 μM (blue) and 200 μM (red) in the presence of β-CD (5 mM) in phosphate buffer (pH 9.0) at 25  C (λex = 327 nm) and the fluorescence spectrum of the excimer, which was obtained by subtracting the former spectrum from the latter. Adapted with permission from Ref [27]. Copyright (2018) American Chemical Society

by the ion-pairing interaction of Cs+ with anionic ACs residing in a β-CD capsule to facilitate the sled conformation of the AC pair in the 2:2 complex and the subsequent formation of the slipped cyclodimers upon irradiation. Encouraged by this result, they designed and synthesized a series of mono- and dicationic β-CD derivatives 38–43 to achieve the exclusive formation of irregular dimers 36 and 37 in 71% and
45% ee, respectively, by optimizing the environmental parameters. As a representative supramolecular photochirogenic reaction, the complexation and photocyclodimerization mechanisms that enable the exceptional stereochemical and photochemical outcomes have been elucidated in considerable details [27]. As illustrated in Fig. 8 (left), when two prochiral ACs are accommodated in a capsule composed of inherently chiral β-CDs in a HT manner (essentially no HH cyclodimers obtained experimentally), there exist three configurational possibilities with respect to the re- and si-enantiotopic faces of AC that confront in the resulting 2:2 complex, which lead to the formation of diastereomeric re-re, re-si/sire, and si-si complexes precursor to the HT cyclodimers 18, 19, 36, and 37. The resi and si-re complexes are equivalent to each other in the ground state, but photoexcitation of the re- or si-AC in a si-re (or re-si) complex breaks the centrosymmetric nature of the two facing ACs to render the re-si and re-si complexes a pair of diastereomers, while the re-re and si-si complexes are inherently diastereomeric to each other in the ground and excited states. Since the AC pair in a 2:2 complex is unable to exchange the position or orientation within the short lifetime of excited-state AC, the stereochemical outcomes (regio- and enantioselectivity) are determined basically by the ground-state thermodynamics and the excited-state kinetics but are still manipulable by various internal and external factors, such as host modification, excitation wavelength (vide infra), temperature, pressure, solvent, and added salt.

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Fig. 7 Photocyclodimerization of AC to classical 9,10:90 ,100 -cyclodimers 18–21 and nonclassical 5,8:90 ,100 -cyclodimers 36 and 37 mediated by native and cationic β-CDs 38–43

18.3.4 Wavelength Control of Supramolecular Photochirogenesis Mediated by CDs Excitation wavelength is a photochemistry-specific external variable, which is totally independent of the ground-state thermodynamics and the excited-state kinetics, but is a unique tool for controlling the photochirogenic consequences through the spectral difference among the relevant diastereomeric precursor complexes. The wavelength effects on the regio- and enantioselectivities of AC photocyclodimerization have recently been examined, using native and modified γ-CDs 28, 33a, 33b, 44, and 45 (Fig. 9) as chiral hosts [42, 43]. Thus, the photocyclodimerization of AC with native

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Fig. 8 Photocyclodimerization of AC via diastereomeric re-re, re-si/si-re, and si-si 2:2 complexes with β-CD to regular 9,10:90 ,100 -cyclodimers 18 and 19 and slipped 5,8:90 ,100 -cyclodimers 36 and 37 in a capsule composed of two β-CDs

γ-CD affords HT cyclodimers 18 and 19 in 55% and 33% yield upon irradiation at 300 nm but in 31% and 61% at 440 nm with accompanying inversion of the anti/syn ratio. Also, the ee’s of 19 and 20 obtained with native and modified γ-CDs are significantly affected by the irradiation wavelength to reach the highest values of 54% and
37%, respectively, for native γ-CD by adjusting the irradiation wavelength, solvent, added salt, and temperature [43]. In summary, the representative supramolecular photochirogenesis of AC mediated by γ-CD involves the three key steps illustrated in Fig. 10, where the overall

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Fig. 9 Chemical structures of N-alkylated diamino- and diammonio-γ-CDs

Fig. 10 The chiral discrimination steps operative in supramolecular photochirogenesis, exemplified for the photocyclodimerization of AC mediated by γ-CD

chirality control is achieved upon: (1) host-guest interaction to form diastereomeric complexes by the difference in thermodynamic stability (K), (2) photoexcitation of the resulting diastereomeric complexes by the difference in absorbance (e), and (3) the subsequent chemical transformation in the excited state by the difference in reaction rate (k), all of which rely on, and hence are manipulated by, the chiral supramolecular environment [43]. Conceptually the same three-step scheme and chiral discrimination mechanism should operate in most of the supramolecular photochirogenic reactions reported so far and to be reported.

18.3.5 Dual Supramolecular Photocyclodimerization of 2-Anthracenecarboxylate Anchored to a-CD Scaffold In the foregoing and subsequent subsections, the enantiodifferentiating supramolecular photochirogeneses of prochiral substrates are discussed, while this section deals with the diastereodifferentiating photochirogenesis of chirally modified AC mediated by supramolecular hosts.

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Substrates 46 and 47–49 (Fig. 11), in which one or two ACs are anchored to an α-CD scaffold employed as a bulky, water-soluble, chiral auxiliary, have been synthesized to investigate how and to what extent the α-CD attached and the anchoring position affect the stereoselectivities of AC photocyclodimerization [44, 45]. γ-CD and cucurbit[8]uril (CB[8]) smoothly bind two AC moieties to form a 1:2 complex with mono-AC substrate 46 and the corresponding 1:1 complexes with 6A,6X-di-AC-substituted 47–49 (X = B-D). Photolyses of these substrates in the absence and in the presence of γ-CD or CB[8], followed by the saponification of photoproducts, afford the AC dimers 18–21 in varying ratios and ee’s. The product distribution obtained for mono-AC substrate 46 in the absence of host is very similar to that of unsubstituted AC, and the ee’s of chiral cyclodimers 19 and 20 are low (5% and
16%, respectively), implying that the α-CD introduced to AC through an ester linkage is not effective enough to alter the stereochemical consequence of the photocyclodimerization occurring inside the γ-CD cavity. However, the addition of γ-CD as a chiral host greatly enhances the regio- and enantioselectivities of AC photocyclodimerization to give the HT dimers 18 and 19 in 98% combined yield and syn-HH 19 in 91% ee under the optimized condition, i.e., in water at
20  C under a pressure of 210 MPa [44]. Intriguingly, the use of achiral CB[8] host of a comparable cavity size does not appreciably improve the ee’s but leads to an exclusive formation of the sterically more demanding HH dimers 20 and 21 (in 99% combined yield), for which the long rigid host skeleton that hinders the photocyclodimerization of two HT-oriented ACs in a precursor complex is likely to be responsible [44]. The photolyses of 6A,6X-di-AC-substituted 47–49 afford the product distributions strongly dependent on the anchoring position (or the inter-AC distance on the CD rim) and good to high ee’s for the major chiral product even in the absence of host. In particular, 6A,6C-di-AC-substituted 48 gives anti-HH 20 in 64% yield and

Fig. 11 AC substrates anchored to α-CD scaffold

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69% ee in water and in 81% yield and 90% ee in methanol both at 0  C. By adding γ-CD or CB[8] to the aqueous solution, the chemical and optical yields of 20 derived from 48 are further augmented to 97–98% yield and 98–99% ee in 14% aqueous LiCl solution at
18  C, achieving an ultimate stereocontrol for the first time in a supramolecular photochirogenesis [45].

18.3.6 Miscellaneous Bimolecular Chiral Photoreactions Mediated by CD Although AC is certainly the most frequently employed guest substrate in the majority of CD-mediated bimolecular chiral photoreactions, a couple of other prochiral substrates have also been subjected to the supramolecular photochirogenesis studies. Thus, the enantiodifferentiating photocyclodimerization of methyl 3-methoxyl-2-naphthoate (50) and 2-hydroxyanthracene (HA) has been mediated by γ-CD and some other chiral hosts (Fig. 12) [46–49]. The photolysis of 50 affords cubane-like cyclodimer 52, which is not a direct one-step process but proceeds stepwise through the initial intermolecular [4+4] photocyclodimerization at the 1,4-position to 51 and the subsequent intramolecular [2+2] photocycloaddition at the 2,3-position [46]. Although 50 does not smoothly photocyclodimerize in aqueous solution, the addition of γ-CD significantly improves the photocyclodimerization efficiency through the 1:2 complexation with 50 to give chiral cyclodimers 51 and 52 in 39% and 48% ee, respectively [47]. A subsequent study using modified γ-CDs 22a–22d (Fig. 5) has provided a lesson that the secondary-rim modification lowers the enantioselectivity of photocyclodimerization

Fig. 12 Photocyclodimerization of methyl 3-methoxyl-2-naphthalenecarboxylate (50) and 2-hydroxyanthracene (HA) mediated by γ-CD and other chiral hosts

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of 50 probably due to the interrupted hydrogen-bonding network that leads to a flexible CD skeleton [47]. The γ-CD-mediated photocyclodimerization of 2-hydroxyanthracene (HA) to cyclodimers 53–56 has been performed in aqueous solutions and in the solid state [49]. In contrast to AC (vide supra), anionic HA forms a fairly stable 1:1 complex with γ-CD (K1 = 4100 M
1) but essentially no 1:2 complex in a basic solution at pH 10.5. This contrasting behavior of HA against AC has been ascribed to the negative charge delocalized over the entire HA molecule, which leads to the electrostatic repulsion when two anionic HAs are accommodated in a CD cavity [49]. On the other hand, neutral HA forms a stable 1:2 complex with γ-CD. Photolysis of HA in aqueous solution (pH 7) containing γ-CD yields syn-HT 54 in 12–14% ee and anti-HH 55 in 5–6% ee. Photoirradiation of a solid-state complex prepared by grinding HA with 0.5 equivalent of γ-CD affords 54 of
17% ee in 11% yield and racemic 55 in 48% yield [49].

18.4

Catalytic Supramolecular Photochirogenesis with Sensitizing CD Hosts

Native CDs have been used for mediating the asymmetric geometrical photoisomerization of (Z )-cyclooctene 57Z (Fig. 13). β-CD forms a 1:1 complex with 57Z to form precipitates from the aqueous solution, the direct irradiation (185 nm) of which affords the (E)-isomer 57E in mere 0.24% ee, demonstrating the poor chiral induction ability of native β-CD cavity at least for 57Z. This is probably due to the smooth interior surface of CD cavity and the nondirectional hydrophobic interaction that jointly allow great rotational and conformational freedoms to the included guest inside the cavity [50]. Inoue and coworkers have explored the possibility of supramolecular enantiodifferentiating photosensitization (which is catalytic in nature) for the first time using

Fig. 13 Asymmetric geometrical photoisomerization of prochiral (Z )-cyclooctene (57Z) and (Z,Z)-1,3-cyclooctadiene (58ZZ) to their chiral (E)- and (E,Z)-isomers (57E and 58EZ)

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57Z and 58ZZ as prochiral substrates and a series of benzoate- and naphthalenemodified CDs 59 and 60 and CD-incorporating rotaxane 61 as chiral sensitizing hosts (Fig. 14) [51–58]. In this supramolecular photosensitization system using arene-modified CDs, the hydrophobic arene moiety is self-included in the own CD cavity in the absence of guest substrate (Fig. 14, left). Under the condition, the arene

Fig. 14 Enantiodifferentiating photoisomerization of (Z )-cyclooctene and (Z,Z)-1,3cyclooctadiene included and sensitized by chromophore-modified CDs (59 and 60) and rotaxane with a sensitizing axle (61)

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moiety encapsulated in the cavity, if excited, cannot transfer the excitation energy to the substrate existing in the bulk solution. However, once a substrate (e.g., 57Z) is included in the cavity, the arene moiety will be relocated to make a space for the incoming guest but still stay near the CD portal to keep the van der Waals contacts and the π-π interaction with the included guest (Fig. 14, middle), which should greatly reduce the rotational and conformational freedoms and facilitate the energy transfer inside the chiral cavity. It is to be emphasized that the build-in sensitizer is temporarily masked or inactivated in the absence of the guest to prevent the energy-transfer to free substrates in the bulk solution, but becomes active to promote the asymmetric photoisomerization once the substrate is introduced to the chiral cavity. This intelligent device, if perfectly functions, achieves an ideal on/off switching of the chiral supramolecular photosensitization, and the fundamental concept should be useful in constructing a variety of catalytic supramolecular photochirogenic systems. The supramolecular photosensitization of 57Z with 6-O-benzoyl-β-CD 59b affords 57E in modest ee’s of up to 11%, while the size-mismatched α- and γ-CD analogues 59a and 59j give much lower ee’s [51]. The enantioselectivity of 57E is significantly improved to 46% ee by introducing a methoxy group at the metaposition of the benzoyl moiety, i.e., 59d. In contrast, the regioisomeric ortho- and para-methoxy-substituted 59c and 59e and meta-methoxycarbonyl-substituted 59 g give 57E in much lower 4%,
11%, and
2% ee, respectively [54]. This result reveals the critical roles of the substituent introduced to the sensitizer moiety in the supramolecular photosensitization, and also indicates the possibility of further enhancing the enantioselectivity by more sophisticated chemical modifications as well as the necessity for elucidating a clearer picture of the supramolecular complexation and photosensitization mechanisms. The asymmetric photoisomerization of 57Z with chiral sensitizer performed in isotropic media is often critically affected by the entropy-related environmental variants, such as temperature, solvent, and pressure [59–63]. On the contrary, the enantioselectivity observed for the supramolecular photoisomerization of 57 included and sensitized by the above β-CD derivatives is much less sensitive to temperature, which has been attributed to the restricted motions of the substrate and the sensitizer moiety in the CD cavity. In contrast, the enantioselectivity for the supramolecular photoisomerization of 57Z with permethylated β-CD derivative 59i turned out to be a critical function of temperature, which has been rationalized by the flexible skeleton of permethylated β-CD due to the loss of the hydrogen-bonding network on the secondary rim of CD. The photoisomerization of (Z,Z)-1,3-cyclooctadiene 58ZZ sensitized by chiral alkyl benzene(poly)carboxylates, such as phthalates, pyromellitate, and mellitate, has been investigated in isotropic media to afford 58EZ in low ee’s of up to 17% even at
40  C [64]. Naphthalene-modified α-, β-, and γ-CDs 60a–60c employed as chiral sensitizing hosts do not improve the enantioselectivity of the photochirogenic reaction, affording 58EZ in only 2–5% ee [65]. Recently, Yang and coworkers have demonstrated that [4]rotaxane 61, composed of a γ-CD wheel and a chromophoric biphenyl axle end-capped with cucurbit[6]urils (Fig. 14), can co-include one 58ZZ

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molecule in the γ-CD cavity together with the biphenyl axle, which in turn promotes the sensitized photoisomerization of 58ZZ inside the cavity to afford 58EZ in 15% ee [66]. This study provides a new strategy for creating a conformationally flexible, yet structurally robust, chiral photosensitizing binding site by implanting an end-capped achiral chromophore into a chiral large cavity. A crucial difference from the chromophore-modified CDs is the unremovable or non-flipping-out nature of the implanted chromophore. CD-based polymeric hosts 62a-c (Fig. 15), which are prepared by crosslinking β- or γ-CD with pyromellitic dianhydride and named nanosponges (CDNSs) due to the strong adsorption ability, have also been employed as chiral photosensitizing hosts or anisotropic media for the enantiodifferentiating photoisomerization of 57Z and 58ZZ [67, 68]. Interestingly, upon gradual increase of the concentration from 0.2 to 2000 mg/mL, CDNS experiences a series of phase transitions from homogeneous solution to suspension containing nanoparticles, then to flowing gel, and eventually to rigid gel. In nice agreement with this phase behavior, the enantioselectivity of 58EZ obtained in the photoisomerization of 58ZZ sensitized by CDNS exhibits a series of abrupt changes near the phase transition

Fig. 15 CD-based polymeric hosts called nanosponges 62a-c, prepared by crosslinking β- or γ-CD with pyromellitic dianhydride (PDA) in different ratios

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concentrations of CDNS. For example, in the photoisomerization of 58ZZ sensitized by β-CDNS 62a, the ee of 58EZ obtained decreases from 4.7% to 0% as the phase changes from solution to suspension, but then increases to 6.1% in rigid gel. Although γ-CDNS 62c affords racemic 58EZ in both solution and flowing gel, its ee increases to 13.3% in rigid gel. Similar phase-dependent enantioselectivity has been observed for the photoisomerization of 57Z mediated by CDNSs, for which the chiral microenvironment varied with the phase transition of CDNS is likely to be responsible. More recently, Yang and coworkers have reported the visible-light-driven enantiodifferentiating photocyclodimerization of AC sensitized by Schiff base-Pt (II) complex-grafted γ-CDs 63 and 64 via the triplet-triplet annihilation (TTA) mechanism (Fig. 16) [69]. They have proposed the following mechanism. Upon laser excitation (LE) at 532 nm, the Schiff base-Pt(II) complex is promoted to the triplet excited state via rapid intersystem crossing (ISC), which is followed by the efficient triplet-energy transfer (ET) to the AC included in the CD cavity via the Dexter mechanism. This LE-ISC-ET sequence is repeated twice in a short period of time to produce a pair of triplet-excited ACs. This triplet AC pair spontaneously undergoes the TTA to give a singlet-excited and ground-state AC pair in the cavity, which promptly reacts with each other to give regioisomeric cyclodimers 18–21. When a catalytic amount of 63 is employed as a TTA-sensitizing host, syn-HT 19 is obtained as a major product in 61% yield and 31% ee, while sensitizing host 64 affords 19 in lower yield (50%) and ee (26%), due to the dispersive triplet-energy transfer.

Fig. 16 Schiff base-Pt(II) complex-grafted γ-CDs employed as TTA-sensitizing hosts for the photocyclodimerization of AC

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Conclusion and Future Perspective

We have reviewed and discussed the recent developments and achievements in the supramolecular photochirogenesis employing native and modified cyclodextrins as chiral hosts, which certainly provide us with valuable mechanistic insights and practical tools for precisely controlling the diastereomeric complex formation and the subsequent enantiodifferentiating photochemical transformation. Indeed, a near perfect stereocontrol is achieved to yield a single enantiomeric photoproduct in some specific cases, which is highly encouraging in further advancing the study but is not always the case in reality. A difficulty in using CDs as chiral hosts lays in the axisymmetric cavity of native CD with fairly smooth interior wall surface, where the chirality transfer from CD to prochiral substrate guided by the nondirectional hydrophobic interaction is not very stereoselective in general, often resulting in modest results. However, the recent studies have revealed that the chemical modification of CD is highly effective in breaking or distorting the axisymmetric cavity of native CD and thus improving the stereoselectivity of supramolecular photochemical reaction. Experimentally, the fairly sophisticated tuning of the size, shape, flexibility, and chiral environment of CD cavity is feasible to optimize the chemo-, regio-, and stereoselectivities of chiral photoreactions, as discussed above. Supramolecular photochirogenesis in the solid state, e.g., crystal and zeolite supercage, may appear more straightforward to achieve a higher level of chiral induction than that in solution (though accompanies low conversion and no host turnover). This is true as far as a given pair of chiral host and prochiral guest substrate forms a single diastereomeric complex that is photoreactive in the solid state, which is however not always the case. In solution, the photoreaction of free unbound substrate to racemic product as well as the conformational freedoms remaining in the complexed substrate often deteriorates the stereochemical outcomes. Nevertheless, the undesirable photoreaction of free substrate in the bulk solution can be suppressed by adding salts carrying heavy metal or spin (e.g., Cs+ and Cu2+) [27, 37], which quench the excited state by accelerating the intersystem crossing through the spin-orbit coupling interaction. The conformational flexibility of the substrate accommodated in chiral host is not necessarily a difficulty or disadvantage but rather provides us with an indispensable handle to critically manipulate and optimize the stereochemical outcomes by modifying the host structure and also by changing the external entropy-related factors (e.g., temperature, solvent, and pressure), as discussed above [40, 53, 55, 61, 62]. In some extreme cases, the antipodal products are obtained by manipulating the entropy-related variant, while using the identical host [33, 40]. The supramolecular photochirogenesis through higher-order 2:2 complex, which has been found for the photocyclodimerization of AC mediated not only by β-CD [27] but also by chiral hydrogen-bonding template (2-prolinol) [70], provides a new opportunity to precisely regio- and enantio-control the ground-state complexation and the subsequent photoreaction. However, more striking is the fact that the higherorder complexation enforces the encapsulated ACs to exhibit a novel reactivity to afford the otherwise-inaccessible photoproducts, which has never been realized in

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the foregoing studies [42]. Achieving catalytic supramolecular photochirogenesis without incorporating sensitizer moiety has been only partially successful [37, 71] and is still a great challenge to chemists.

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Cross-References

▶ Cyclodextrin-Based Supramolecular Hydrogel ▶ Functionalized Cyclodextrins and Their Applications in Biodelivery ▶ Supramolecular Assembly Constructed from Multi-charged CyclodextrinInduced Aggregation Acknowledgments We acknowledge the support of this work by the National Natural Science Foundation of China (No. 21871194, 21572142, 21372165, 21402129 and 21402110), the National Key Research and Development Program of China (No. 2017YFA0505903), and the Science & Technology Department of Sichuan Province (2019YJ0160, 2019YJ0090, 2017SZ0021).

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30. Wakai A, Fukasawa H, Yang C, Mori T, Inoue Y (2012) Theoretical and experimental investigations of circular dichroism and absolute configuration determination of chiral anthracene photodimers. J Am Chem Soc 134(10):4990–4997 31. Nakamura A, Inoue Y (2003) Supramolecular catalysis of the enantiodifferentiating [4 + 4] photocyclodimerization of 2-anthracenecarboxylate by γ-cyclodextrin. J Am Chem Soc 125(4):966–972 32. Ikeda H, Nihei T, Ueno A (2005) Template-assisted stereoselective photocyclodimerization of 2-anthracenecarboxylic acid by bispyridinio-appended γ-cyclodextrin. J Org Chem 70(4):1237–1242 33. Yang C, Fukuhara G, Nakamura A, Origane Y, Fujita K, Yuan DQ, Mori T, Wada T, Inoue Y (2005) Enantiodifferentiating [4 + 4] photocyclodimerization of 2-anthracenecarboxylate catalyzed by 6A,6X-diamino-6A,6X-dideoxy-γ-cyclodextrins: manipulation of product chirality by electrostatic interaction, temperature and solvent in supramolecular photochirogenesis. J Photochem Photobiol A Chem 173(3):375–383 34. Yang C, Nakamura A, Fukuhara G, Origane Y, Mori T, Wada T, Inoue Y (2006) Pressure and temperature-controlled enantiodifferentiating [4+4] photocyclodimerization of 2-anthracenecarboxylate mediated by secondary face- and skeleton-modified γ-cyclodextrins. J Org Chem 71(8):3126–3136 35. (a) Yang C, Nakamura A, Wada T, Inoue Y (2006) Enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylic acid mediated by γ-cyclodextrins with flexible and rigid cap. Org Lett 8(14):3005–3008; (b) Yang C, Mori T, Inoue Y (2008) Supramolecular enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylate mediated by capped γ-cyclodextrins: critical control of enantioselectivity by cap rigidity. J Org Chem 73(15):5786–5794 36. Yang C, Ke C, Fujita K, Yuan DQ, Mori T, Inoue Y (2008) pH-Controlled supramolecular enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylate with capped γ-cyclodextrins. Aust J Chem 61(8):565–568 37. Ke C, Yang C, Mori T, Wada T, Liu Y, Inoue Y (2009) Catalytic enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylic acid mediated by a non-sensitizing chiral metallosupramolecular host. Angew Chem Int Ed 48(36):6675–6677 38. Ke C, Yang C, Liang W, Mori T, Liu Y, Inoue Y (2010) Critical stereocontrol by inter-amino distance of supramolecular photocyclodimerization of 2-anthracenecarboxylate mediated by 6-(ω-aminoalkylamino)-γ-cyclodextrins. New J Chem 34(7):1323–1329 39. Wang Q, Yang C, Fukuhara G, Mori T, Liu Y, Inoue Y (2011) Supramolecular FRET photocyclodimerization of anthracenecarboxylate with naphthalene-capped γ-cyclodextrin. Beilstein J Org Chem 7:290–297 40. Yao J, Yan Z, Ji J, Wu W, Yang C, Nishijima M, Fukuhara G, Mori T, Inoue Y (2014) Ammoniadriven chirality inversion and enhancement in enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylate mediated by diguanidino-γ-cyclodextrin. J Am Chem Soc 136(19):6916–6919 41. Yi J, Liang W, Wei X, Yao J, Yan Z, Su D, Zhong Z, Gao G, Wu W, Yang C (2018) Switched enantioselectivity by solvent components and temperature in photocyclodimerization of 2-anthracenecarboxylate with 6a,6x-diguanidio-γ-cyclodextrins. Chin Chem Lett 29(1): 87–90 42. Wang Q, Yang C, Ke C, Fukuhara G, Mori T, Liu Y, Inoue Y (2011) Wavelength-controlled supramolecular photocyclodimerization of anthracenecarboxylate mediated by γ-cyclodextrins. Chem Commun 47(24):6849–6851 43. Yang C, Wang Q, Yamauchi M, Yao J, Zhou D, Nishijima M, Fukuhara G, Mori T, Liu Y, Inoue Y (2014) Manipulating γ-cyclodextrin-mediated photocyclodimerization of anthracenecarboxylate by wavelength, temperature, solvent and host. Photochem Photobiol Sci 13(2):190–198 44. Yang C, Mori T, Origane Y, Ko YH, Selvapalam N, Kim K, Inoue Y (2008) Highly stereoselective photocyclodimerization of α-cyclodextrin-appended anthracene mediated by

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γ-cyclodextrin and cucurbit[8]uril: a dramatic steric effect operating outside the binding site. J Am Chem Soc 130(27):8574–8575 45. Yang C, Ke C, Liang W, Fukuhara G, Mori T, Liu Y, Inoue Y (2011) Dual supramolecular photochirogenesis: ultimate stereocontrol of photocyclodimerization by a chiral scaffold and confining host. J Am Chem Soc 133(35):13786–13789 46. Luo L, Cheng SF, Chen B, Tung CH, Wu LZ (2010) Stepwise photochemical chiral delivery in γ-cyclodextrin-directed enantioselective photocyclodimerization of methyl 3-methoxyl-2naphthoate in aqueous solution. Langmuir 26(2):782–785 47. Liang W, Zhang HH, Wang JJ, Peng Y, Chen B, Yang C, Tung CH, Wu LZ, Fukuhara G, Mori T, Inoue Y (2011) Supramolecular complexation and photocyclodimerization of methyl 3-methoxy-2-naphthoate with modified cyclodextrins. Pure Appl Chem 83(4):769–778 48. Luo L, Liao G, Wu X, Lei L, Tung C, Wu L (2009) γ-Cyclodextrin-directed enantioselective photocyclodimerization of methyl 3-methoxyl-2-naphthoate. J Org Chem 74(9):3506–3515 49. Fukuhara G, Umehara H, Higashino S, Nishijima M, Yang C, Mori T, Wada T, Inoue Y (2014) Supramolecular photocyclodimerization of 2-hydroxyanthracene with a chiral hydrogenbonding template, cyclodextrin and serum albumin. Photochem Photobiol Sci 13(2):162–171 50. Inoue Y, Kosaka S, Matsumoto K, Tsuneishi H, Hakushi T, Tai A, Nakagawa K, Tong L (1993) Vacuum UV photochemistry in cyclodextrin cavities. Solid-state Z-E photoisomerization of a cyclooctene-β-cyclodextrin inclusion complex. J Photochem Photobiol A Chem 71(1):61–64 51. Inoue Y, Dong F, Yamamoto Y, Tong L-H, Tsuneishi H, Hakushi T, Tai A (1995) Inclusionenhanced optical yield and E/Z ratio in enantiodifferentiating photoisomerization of cyclooctene included and sensitized by β-cyclodextrin monobenzoate. J Am Chem Soc 117(44):11033–11034 52. Inoue Y, Wada T, Sugahara N, Yamamoto K, Kimura K, Tong LH, Gao XM, Hou ZJ, Liu Y (2000) Supramolecular photochirogenesis. 2. Enantiodifferentiating photoisomerization of cyclooctene included and sensitized by 6-O-modified cyclodextrins. J Org Chem 65(23):8041–8050 53. Fukuhara G, Mori T, Wada T, Inoue Y (2006) Entropy-controlled supramolecular photochirogenesis: enantiodifferentiating Z-E photoisomerization of cyclooctene included and sensitized by permethylated 6-O-modified β-cyclodextrins. J Org Chem 71(21):8233–8243 54. Lu R, Yang C, Cao Y, Wang Z, Wada T, Jiao W, Mori T, Inoue Y (2008) Supramolecular enantiodifferentiating photoisomerization of cyclooctene with modified β-cyclodextrins: critical control by a host structure. Chem Commun (3):374–376 55. Fukuhara G, Mori T, Wada T, Inoue Y (2005) Entropy-controlled supramolecular photochirogenesis: enantiodifferentiating Z-E photoisomerization of cyclooctene included and sensitized by permethylated 6-O-benzoyl-β-cyclodextrin. Chem Commun (33):4199–4201 56. Lu R, Yang C, Cao Y, Wang Z, Wada T, Jiao W, Mori T, Inoue Y (2008) Enantiodifferentiating photoisomerization of cyclooctene included and sensitized by aroyl-β-cyclodextrins: a critical enantioselectivity control by substituents. J Org Chem 73(19):7695–7701 57. Gao Y, Wada T, Yang K, Kim K, Inoue Y (2005) Supramolecular photochirogenesis in sensitizing chiral nanopore: enantiodifferentiating photoisomerization of (Z )-cyclooctene included and sensitized by POST-1. Chirality 17(S1):S19–S23 58. Gao Y, Inoue M, Wada T, Inoue Y (2004) Supramolecular photochirogenesis. 3. Enantiodifferentiating photoisomerization of cyclooctene included and sensitized by 6-O-mono(omethoxybenzoyl)cyclodextrin. J Incl Phenom Macrocycl Chem 50(1):111–114 59. Inoue Y, Yokoyama T, Yamasaki N, Tai A (1989) Temperature switching of product chirality upon photosensitized enantiodifferentiating cis-trans isomerization of cyclooctene. J Am Chem Soc 111(16):6480–6482 60. Inoue Y, Yamasaki N, Yokoyama T, Tai A (1993) Highly enantiodifferentiating photoisomerization of cyclooctene by congested and/or triplex-forming chiral sensitizers. J Org Chem 58(5):1011–1018

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Yao-Hua Liu, Heng-Yi Zhang, and Yu Liu

Contents 19.1 19.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Linear CD Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.2.1 CD Covalently Linked to the Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.2.2 Sliding-Ring Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.3 Network CD Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.4 Hyperbranched CD Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

Cyclodextrins (CDs), one of the most important hosts in supramolecular chemistry, is a class of oligosaccharide macrocyclic compounds obtained by the tail-to-end linkage of D-glucopyranose, found by Villiers in 1891 [1]. Since the glucose units of CDs are in an untwisted chair conformation, that is, the 4C1 conformation, CD exhibits a truncated cone structure. The primary hydroxyl groups (C-6-OH) of CD are on one side of the molecule, forming the small mouth end of CD (main surface). On the other hand, all of the secondary hydroxyl groups (C-2, 3-OH) of CD are at

Y.-H. Liu College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China H.-Y. Zhang · Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_21

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the other end of the molecule, forming the large mouth end of CD (secondary surface) (Fig. 1a) [2]. According to the number of glucose units, CDs can be divided into α-, β-, γ-CD, which are the most common members, and so on. Owing to the different sizes of the hydrophobic cavities, which have chiral microenvironment, in different CDs, CDs can bind a variety of organic, inorganic molecules [3], ions [4], and biomolecules [5, 6], respectively, forming stable inclusion complexes. CDs, as seminatural products produced by microbial fermentation, have topping merits, such as cheap, nontoxic, water-soluble, excellent biocompatibility, easily modified, and so on [2], compared with other supramolecular hosts. Therefore, CD chemistry has been extensively studied. Besides, supramolecular chemistry is the intersection of many disciplines, which effectively integrates various fields and knowledge, thus developing and expanding into a multi-domain discipline. In recent years, many researchers have combined polymers with CD chemistry. This kind of intersection allows researchers to take advantage of both the cavity of CD and the characteristics of polymers so that they constructed a variety of CD polymers to make interesting and valuable research in various fields [7–13], especially in biology including drug delivery [10, 11], gene therapy [12], and medical imaging [13]. The construction of CD polymer is based on the reactivity of OH groups or on their property to form complexes with host-guest non-covalent interactions. Depending on the type of polymer, CD polymers can be roughly classified into several types, such as linear CD polymers, network CD polymers, and hyperbranched CD polymers (Fig. 1b). Those polymers not only retain the ability of inclusion, sustained release, catalysis, and recognition from CDs but also have good

Fig. 1 (a) Structural formula and schematic diagram of CDs. Schematic illustration of (b) linear CD polymers, (c) network CD polymers, and (d) hyperbranched CD polymers

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mechanical strength, stability, and chemical adjustability based on polymers. On account of these outstanding advantages, CD polymers have already attracted more and more attention. In this chapter, the latest progresses in the construction of CD polymers and their applications in medical biology will be reviewed. And we hope it can provide inspiration for the constructions and functions of new supramolecular polymers based on CDs.

19.2

Linear CD Polymers

Linear CD polymers are the most widely used and most researched type of CD polymers all over the world. Researchers generally constructed CD polymers using covalent linkages, copolymerization, host-guest interactions, and so on. Therefore, linear CD polymers, which have characteristics of easy modification, good biocompatibility, multifunction, and water-solubility, have a good application in the field of medical biology.

19.2.1 CD Covalently Linked to the Polymers CD is a kind of macrocyclic host that is easy to be modified, especially the hydroxyl groups of CDs located on C6. Therefore, numerous CD derivatives have been synthesized since their discovery [14]. Among these compounds, some CD derivatives have functional groups that can be polymerized. On the other hand, a portion of CD derivatives can react with the side chains of the polymers. Therefore, researchers have built a variety of polymers in which CD was covalently grafted onto the polymer chains by using those CD derivatives. Typically, CDs are on the side chain of the polymer. Only in a small portion of the polymers, CDs are on the backbone of the polymers. The CD polymers obtained by the method described above not only have the characteristics of linear polymers but also can utilize the cavities of CDs to encapsulate a plurality of compounds. The combination of linear polymers and CD chemistry makes the linear CD polymers be useful in drug delivery, cancer therapy, photodynamic therapy, biomaterials, and so on. One type of linear CD polymers is that CDs are on the side chain of the polymer. Previously, our group reported CD-modified hyaluronic acid (HA-CD) which is obtained by amide condensation reaction between the amino groups of CD derivatives and the carboxyl group of the hyaluronic acid located on side chains (Fig. 2a) [15]. Hyaluronic acid (HA), a water-soluble, biocompatible, and biodegradable polysaccharide, has been used as a targeting agent and delivery vehicle in many drug-delivery systems [16, 17], which can realize targeted recognition of cancer cells that overexpress HA receptors on the cancer cell surface [18–20]. Such CD polymer (HA-CD), which combined the advantages of CD and HA, not only maintains the targeting of cancer cells from HA but also can utilize the cavity of CD to encapsulate adamantane or other groups. Additionally, HA-CD has been used as building blocks for constructing multifunctional biomaterials. In this work, we constructed a series of

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Fig. 2 (a) The synthetic route of HA-CD. (b) Schematic illustration of the construction of HAP based on linear CD polymers [15]

conjugated hyaluronic acid particles (HAP), composed of a hydrophobic anticancer drug core and hydrophilic CD/HA shell (Fig. 2b). HAP was comprehensively tested as a drug-delivery system for an adamplatin prodrug in vitro and in vivo. This drugdelivery system based on HA-CD maintains the activity of cisplatin but reduces the toxicity of cisplatin, as well as achieves targeted drug delivery. Thereafter, our group designed and constructed a series of biological systems by using HA-CD [21–26]. Recently, our group reported a new type of supramolecular nanofiber based on β-CD-modified hyaluronic acid (HA-CD) and targeting peptide (MitP) (Fig. 3) [21]. The nanofibers markedly suppressed invasion by and metastasis of cancer cells both in vitro and in vivo. In addition, tumor-burdened mice treated with the nanofibers showed a higher survival rate of mortality compared with control mice from the metastatic spread of cancer cells. These nanofibers, as a convenient tool for deepening our understanding of dynamic biological events, facilitate the development of designed smart biomaterials for cancer therapy. Based on previous work, novel geomagnetism-responsive photothermal supramolecular nanofibers based on HACD and mitochondrion-targeting-peptide-tethered inorganic gold nanorods (AuNRLA) were constructed for treatment of cancer cells via photothermal activation [22]. Because of the photothermal properties from the AuNRs in the nanofibers, NIR irradiation induced severe cancer cell damage and suppressed cancer cell invasion and metastasis in vivo, even making cancer cell death in vitro. Grafting of CDs to preformed polymers and polymerization of vinyl CDs derivatives are commonly used methods for constructing CD polymers used in pharmaceutical applications. In addition to HA-CD, lots of CD polymers have been explored since the 1980s. For example, Li et al. reported a thermoresponsive

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Fig. 3 Schematic illustration of the fabrication of the supramolecular nanofibers containing HACD [21]

hydrogel based on poly(acrylic acid)-graft-β-CD (PAAc-g-β-CD) and polyacrylamide (PAAm) using the interpenetrating polymer network (IPN) method which can improve its loading and release of drugs (Fig. 4a) [27]. The phase-transition temperature or upper critical solution temperature (UCST) of the hydrogel in this work was about 35  C. Therefore, the IPN hydrogel showed a positive release at body temperature (37  C). Compared with the normal hydrogels, the IPN hydrogels based on CD polymers presented improved drug loading and controlled release. Kim et al. have synthesized β-CD polymers and paclitaxel (PTX) polymers by connecting β-CD and PTX with poly[IB-alt-MAnh] and poly[MVE-alt-MAnh], respectively, giving the supramolecular nanoparticles (Fig. 4b) [28]. The supramolecular nanoparticles showed high stability and efficiently loaded paclitaxel and released into the targeted cancer cells via both passive and active targeting mechanisms by the broken of ester linkages between PTX and the polymer backbone within the targeted cancer cells. These novel supramolecular nanoparticles show outstanding antitumor activity in a mouse tumor model. The work provides new thought for the development of targeted antitumor drug delivery. Another type of linear CD polymers is those of CDs as part of the backbone. In this case, Davis et al. have done a lot of work based on linear CD polymers in assembly of biomaterials [29–31], in vivo biodistribution [32–34], pharmacodynamics [35–37], and clinical studies [38–42]. The synthesis of 6A,6D-dideoxy-6A,6Ddiiodo-β-CD is the key to successfully prepare this type of linear CD polymers. Typically, Davis et al. reported a synthetic delivery nanoparticle (approximately 70 nm diameter) [42], which is designed to circulate and then to accumulate and permeate in tumors by intravenous injection (Fig. 5). The nanoparticles contain four parts: (1) linear CD polymers [43], (2) siRNA designed to reduce the expression of the RRM2, (3) the polyethylene glycol (PEG) molecules terminated with adamantane, and (4) the polyethylene glycol (PEG) molecules terminated with a human transferrin protein (TF), which can engage TF receptors (TFR) on the surface of the tumors cells. They conducted the first in-human phase I clinical trial involving

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Fig. 4 Schematic illustration of (a) the IPN hydrogels based on linear CD polymers [27] and (b) the supramolecular nanoparticles constructed by CD polymers and PTX polymers [28]

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Fig. 5 Schematic illustration of synthetic delivery nanoparticles [42]

Fig. 6 (a) The synthesis of a class of linear CD polymers [44]. (b) Schematic illustration of the two-photon absorption (TPA) nano-micelle and its imaging in live cells and tissues [46]. (Reprinted (adapted) with permission from Ref. [46]. Copyright (2014) American Chemical Society)

the systemic administration of siRNA to patients with solid cancers using the synthetic delivery nanoparticles. This work provided evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. In a word, this work demonstrated that RNAi can occur in humans from delivered siRNA by the synthetic delivery nanoparticles, so that siRNA can be used as a gene-specific therapeutic by delivery systems. Besides, compared with Davis’s work, an irregular linear CD polymer was easily accessible via a reaction of CDs and epichlorohydrin in a sodium hydroxide solution with toluene in one step (Fig. 6a) [44]. Based on those polymers, Yang et al. constructed a novel two-photon absorption (TPA) nano-micelle used in tumor tissue imaging [45]. Afterward, they also constructed a supramolecular nano-micelle based on TPA fluorescent nanoconjugate of linear CD polymer and two-photon dye with

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the two-photon excitation (TPE) technique (Fig. 6b) [46]. This supramolecular nanoassembly can be used as nanoprobe for caspase-3 activation imaging in biological fluids, live cells, and tissues for specific, high-contrast imaging. This work provided a novel methodology model for development of two-photon fluorescent probes based on nano-micelles of CD polymers for in vitro or in vivo determination of enzyme or other biological molecule.

19.2.2 Sliding-Ring Materials Sliding-ring materials are usually constructed by polyrotaxane or polypseudorotaxane architecture where macrocyclic host can move on the central axis. In particular, the polyrotaxanes and polypseudorotaxanes containing CDs have been extensively studied by researchers. Since Harada et al. reported the preparation of polypseudorotaxanes where many α-CDs are entrapped on a polyethylene glycol (PEG) by blocking both ends of the polymer chain [47], various polyrotaxane and polypseudorotaxanes based on CDs were designed and reported [48]. α-CD can form complexes with oligoethylene [49] and poly(e-caprolactone) [50], β-CD with poly(propylene glycol) (PPG) [51] and polypropylene [52], and γ-CD gave complexes with poly(methyl vinyl ether) [53], polyisobutylene [54], even poly (dimethylsiloxane) [55], and poly(dimethylsilanes) [56] (due to limited space, only a few representative work are listed here). In these studies mentioned, researchers demonstrated the existence of a “tunnel”-type structure using X-ray powder diffraction (XRD) or crystal structure while used nuclear magnetic resonance (1H NMR) to characterize the stoichiometry of polymer and CDs. Some similar polyrotaxanes or polypseudorotaxanes based on CDs are still being discovered. By way of the modification of the host CDs and the introduction of different types of guest macromolecules, the sliding-ring materials based on CDs have shown great application prospects in biological system simulation, molecular recognition, microsensors, drug release, tissue engineering, genetic engineering, and so on. The Yui research team contributed greatly to the further application of CDs polyrotaxane in the field of biology. Their research spans a wide range of topics, including biodegradable materials [57–60], drug delivery and release [61–63], biocompatible materials [64, 65], and the interaction of polyrotaxane with organisms [66–68]. Typically, Yui et al. designed and synthesized the biocleavable polyrotaxane (DMAE-SSPRX), where cationic-modified α-CDs (DMAE-α-CDs) was threaded onto a PEG chain capped with benzyloxycarbonyl tyrosine using the disulfide linkages (Fig. 7) [69]. Compared with a linear polyethyleneimine (LPEI22k), DMAE-SS-PRX has a better effect on plasmid DNA (pDNA) condensation. In addition, the motion of αCDs in the axle of polyrotaxane [70] of the DMAE-SS-PRX might prevent spatial mismatching between the amino groups in DMAE-α-CDs and phosphate groups in pDNA, showing very effective in condensation of pDNA. What’s more, the disulfide linkages in DMAE-SS-PRX polyplex can be broken in the presence of dithiothreitol (DTT) which led to unstable polyplex so that pDNA was released in vitro. This work provides new strategies and methods for designing novel gene delivery and may be a

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Fig. 7 Schematic illustration of the biocleavable polyrotaxane (DMAE-SS-PRX) [69]

matter of considerable for biomaterials design based on CD polymers used for gene therapy. On the other hand, polypseudorotaxanes generally also have some novel chemical and physical properties in medical biology. Therefore, the interaction between cell or DNA and CD-based polypseudorotaxanes has been widely investigated. Stoddart et al. reported the polypseudorotaxanes by the self-assembly of lactosidemodified α-CDs and polyviologen (Fig. 8a) and proved that there were strong interactions between the polypseudorotaxanes and galectin-1 by T-cell agglutination experiments, which provides new ideas for targeted therapy [71]. Since Schneider et al. reported that the anthryl-modified β-CDs could be chemically interacted with DNA [72], our group successfully prepared two new fluorescent polypseudorotaxanes by threading the anthryl-modified β-CDs onto the poly(propylene glycol) bis(2-aminopropylether) (PPG-NH2) chains (Fig. 8b) [73]. With the continuous addition of DNA, the anthryl group can be embedded in the hydrophobic DNA grooves without energy transfer, resulting in a gradual increase in the fluorescence intensity at 413 nm of the polypseudorotaxanes. At the same time, the binding constant of the polypseudorotaxanes and DNA is about four times higher than that of the anthryl-modified β-CDs monomers. This interesting work provides a new strategy for the polypseudorotaxanes as a sensitive analytical tool in DNA chemistry or for regulating gene expression or delivery. Subsequently, our group firstly introduced cucurbit[6]uril (CB [6]) into the side chain of the polypseudorotaxanes based on hexamethylene diamine hydrochloridemodified β-CDs and PPG-NH2, obtaining a new type of two-dimensional

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Fig. 8 Schematic illustration of (a) polypseudorotaxanes by the self-assembly of lactoside-modified α-CDs and polyviologen [71]. (Reprinted (adapted) with permission from Ref. [71]. Copyright (2004) American Chemical Society.) And (b) fluorescent polypseudorotaxanes based on the anthryl-modified β-CDs and PPG-NH2 [73]

Fig. 9 Schematic illustration of the new type of two-dimensional polypseudorotaxane (2D PPRs) [74]

polypseudorotaxane (2D PPRs) (Fig. 9) [74]. 2D PPRs with different contents of CB [6] presented different condensation abilities with pEGFP-C2 plasmid DNA in the agarose gel electrophoresis assay. Correspondingly, hexamethylene diamine hydrochloride-modified β-CD monomers have almost no condensation effect on plasmid DNA. Therefore, the regulation of plasmid DNA condensation ability can be achieved by adjustment of the CB [6] content, so that an efficient gene vector can be achieved. Besides, our group reported polypseudorotaxane constructed by tryptophan-modified β-CD and PPG-NH2. The polypseudorotaxane not only can be

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capable of attaching gold nanoparticles, but tryptophan units can also capture C60 [75]. Even more amazing is that the polypseudorotaxanes showed an ability to cleave DNA under light irradiation. At the same time, we also found that the selfassembly of the polypseudorotaxane containing thiol-modified β-CD and gold nanoparticles are effective DNA cleavage agents [76].

19.3

Network CD Polymers

Network CD polymers (we can also call them crosslinked CD polymers) were the first type of CD polymers crosslinked with epichlorohydrin by Solms and Egli in 1965 [77]. Compared with linear CD polymers, the network CD polymers may have more stable structure, good thermal stability, easier preparation, porous structure, and a higher CD content. Since there is a plurality of hydroxyl groups in the CDs, there may be multiple branching points in the polymerization process to form network structures. When the degree of polymerization is not high, network CD polymers are water-soluble. As the degree of crosslinking and the molecular weight increases, the network CD polymers which only can swell and not dissolve will be formed. In addition to epichlorohydrin, diacids, dicarboxylic acid dihalides, diesters, diisocyanates, dihalohydrocarbon, and diepoxides were also used to crosslink CDs to obtain network CD polymers. Different CDs, crosslinkers, and reaction conditions result in network CD polymers obtained having different properties (molecular weight, thermal stability, specific surface area, biocompatibility, solubility, and so on), so that they can be used as biomaterials in medical biology. So far, epichlorohydrin-crosslinked network CD polymers are most studied. Dating back to about 40 years ago, some researchers have these materials which were crosslinked by epichlorohydrin for drug delivery [78, 79]. Komiyama et al. have constructed molecularly imprinted network CD polymers crosslinked by toluene 2,4diisocyanate in the presence of various steroids, which are removed after completion of the polymerization reaction, in DMSO (Fig. 10) [80]. These CD polymers can specifically bind the steroid in the mixtures of H2O and THF. This type of imprinted molecule based on network CD polymers is used for chromatography, which can greatly improve the separation ability of the chromatogram and increase the number of theoretical plates. The method in this work may be useful for the preparation of natural products and biomedical molecules. Nanosponges, as insoluble materials, which are constructed by either inorganic or organic compounds have nanometric porosity, so these materials may have outstanding absorption or complexation properties. Among these nanosponges, a wellknown example is CD-based nanosponges (CD-NSs) based on network CD polymers. Although the development history of network CD polymers is more than 60 years, CD-NSs only develop for nearly two decades. However, since Li and Ma constructed first CD-NSs by reacting β-CD with toluene-2,4-diisocyanate and hexamethylene diisocyanate used for purification of sewage [81, 82], the nanosponges based on network CD polymers have achieved rapid development [83]. Nowadays,

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Fig. 10 (a) Schematic illustration of molecular imprinting of CD. (b) Chemical structures of steroids and other guests used in Komiyama’s work [80]. (Reprinted (adapted) with permission from Ref. [80]. Copyright (1999) American Chemical Society)

CD-NSs can easily be prepared by reacting the CDs with a specific crosslinker, and more and more applications of the CD-NSs have been found, including biology. Thanks to the good biocompatibility and inclusion ability of CDs, CD-NSs may have many applications in biology. Among them, the most studied application of CD-NSs is drug delivery. For example, Zhang et al. constructed pH-responsive nanoparticles based on CD-NSs prepared by crosslinked α-CDs using 2-methoxypropene for delivery of paclitaxel (PTX) (Fig. 11a) [84]. The hydrolysis time of CD-NSs can be precisely controlled by using different acetal, reaction times of acetalation, and pH. Considering cell culture in vitro and acute toxicity experiments in vivo, the CD-NSs convincingly were proved to have good biocompatibility. Importantly, compared with other pH-responsive materials, the CD-NSs presented more drug loading, lower side effects, and more effective antitumor activity. The novel CD-NSs in this work provide researchers new method into design of stimuliresponsive materials for drug delivery and tumor therapy. Besides, Pizzimentia et al. constructed the GSH-targeted CD-NS-loaded doxorubicin (DOX) with high antioxidant defenses (Fig. 11b) [85]. Compared with free DOX, not only the drug carried by CD-NSs was internalized faster in all types of cells examined in confocal microscopy analysis, but also the CD-NS-loaded DOX can more effectively reduce cell viability and induce G2/M cell accumulation and cell death in DU145 and HCT116 cells. Furthermore, the CD-NS-loaded DOX that can specifically extravasate in tumor tissue showed a longer plasma circulation time from the pharmacokinetic experiment, so that the CD-NSs may enhance drug accumulation in tumor tissue. Therefore, the CD-NS-loaded DOX can more effectively reduce tumor growth and weight than free DOX. In a word, the CD-NSs prepared in this work as a drug-delivery carrier has outstanding potential applications in cancer therapy.

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Fig. 11 Schematic illustration of (a) pH-responsive nanoparticles based on CD-NSs [84]. (Reprinted from Ref. [84]. Copyright (2013), with permission from Elsevier) and (b) the GSHtargeted CD-NSs [85]

19.4

Hyperbranched CD Polymers

Another common and intensively studied type of CD polymers is hyperbranched CD polymers. Hyperbranched polymers with low viscosity, good solubility, and noncrystalline have a large number of reactive groups, which can introduce various functional groups, such as CDs [86, 87]. The combination of hyperbranched polymers and CDs has quickly become a research hotspot, attracting more and more researchers’ attention. In recent years, hyperbranched CD polymers have been successfully prepared by researchers using various methods, and their applications have been explored in sundry fields. The preparation of hyperbranched CD polymers can be roughly divided into two categories: (1) CDs are located in the outer layer of the hyperbranched polymer and (2) CDs as supramolecular linker by host-guest interaction or covalent linker are located in the inner layer of the hyperbranched polymer. For the former type, Lee et al. successfully attached β-CDs to the peripheral end group of two dendrimer poly(ethylenimine)s (PEIs) [88]. After that, Mamba et al. constructed hyperbranched CD polymers by β-CD carbonyl imidazole and

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Fig. 12 Chemical structures of a series of hyperbranched CD polymers using polyaminomethylene and CDs constructed by Uekama [90–92]. (Reprinted (adapted) with permission from Ref. [90]. Copyright (2001) American Chemical Society.) (Reprinted (adapted) with permission from Ref. [91]. Copyright (2002) American Chemical Society.) (Reprinted (adapted) with permission from Ref. [92]. Copyright (2003) American Chemical Society)

hyperbranched PEI [89]. Uekama et al. constructed a series of hyperbranched CD polymers using polyaminomethylene and CDs with gene delivery capabilities (Fig. 12) [90–95]. They firstly synthesized hyperbranched polyamidoamine dendrimer with α-, β-, and γ-CDs, respectively [90]. These hyperbranched CD polymers can condense pDNA and protect pDNA from being degraded by DNase I. Compared with those hyperbranched polyamidoamine dendrimers without CDs or the mixture of hyperbranched polyamidoamine dendrimers and CDs, these hyperbranched CD polymers showed an effectively luciferase gene expression, especially in the hyperbranched α-CD polymers which presented the highest transfection activity. Furthermore, the hyperbranched α-CD polymers have the superior gene transfer activity than Lipofectin reagent (commercial cell transfection reagent). Then they prepared

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Fig. 13 Schematic illustration of the multimolecular micelles based on hyperbranched polyglycerol (HPG) modified by β-CD [96]

hyperbranched α-CD polymers with different hyperbranched polyamidoamine dendrimers to research the effect of different dendrimers in hyperbranched α-CD polymers on gene transfection [91]. To investigate the effect of the content of α-CDs in hyperbranched α-CD polymers on gene transfection efficiency, they prepared the hyperbranched α-CD polymers with different average degrees of substitution of αCDs [92]. Besides, they not only evaluated the potential application of the hyperbranched α-CD polymers as a small interfering RNA (siRNA) carrier [93] but also researched the transfer activity of hyperbranched α-CD polymers as short hairpin RNA (shRNA) carrier which expresses pDNA [95]. Li et al. reported the hyperbranched polyglycerol (HPG) modified by β-CD used as drug-delivery carrier (Fig. 13) [96]. They constructed hyperbranched CD polymers by reacting amino-hyperbranched polyglycerol (HPG-NH2) and mono-6deoxy-6-OTs-β-CD, which can self-assemble into multimolecular micelles with different sizes depending on the content of β-CD. These hyperbranched CD polymers which present good biocompatibility can effectively load and control release of PTX. In general, this work indicated that the multimolecular micelles based on hyperbranched CD polymers could be used as a promising drug-delivery carrier. In addition to the covalent bond between CDs and the groups of hyperbranched polymer, it is common for researchers to modify some groups, which can form inclusion complexes with CDs, on the end of hyperbranched polymers, such as adamantane, azobenzene, and ferrocene. As a result, hyperbranched CD polymers can also be constructed by host-guest interaction. Our group reported a hyperbranched CD polymer constructed by bridged tris (permethyl-β-CD) and MnIII-porphyrin bearing poly(ethylene glycol) (PEG) side chains (MnIII-TPP) which had a great potential application in bioimaging (Fig. 14a) [97]. The introduction of CDs can stabilize the low-cost (MnII-TPP). These hyperbranched CD polymers are almost nontoxic and have a higher longitudinal relaxivity (r1) than the linear supramolecular polymer reported by us previously [98]. Liu et al. reported thermoresponsive hyperbranched CD polymers based on poly(N-isopropylacrylamide) oligomer (Ada-PNIPAM-(β-CD)2) modified by one adamantane and two β-CD moieties at the chain terminals (Fig. 14b) [99]. Because of the stable inclusion complexation between adamantane and β-CD, the oligomers can selfassembly into hyperbranched CD polymers in aqueous solution. As the

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Fig. 14 Schematic illustration of (a) hyperbranched CD polymer constructed by MnIII-TPP and bridged tris(permethyl-β-CD) [97] and (b) thermoresponsive hyperbranched CD polymers based on poly(N-isopropylacrylamide) oligomer (Ada-PNIPAM-(β-CD)2) [98]

concentration of Ada-PNIPAM-(β-CD)2 increases, the molecular weight of hyperbranched CD polymers also increases. Interestingly, these hyperbranched CD polymers have a certain temperature sensitivity, which may have potential application in biomaterials. Tian et al. designed and constructed the hyperbranched CD polymers with coreshell structure (Fig. 15) [100]. They firstly synthesized the hyperbranched poly(βCD)s and then incorporated poly(N,N-dimethylaminoethyl methacrylate) (PDMA) segments onto the outer layer of the hyperbranched poly(β-CD)s to construct the amphiphilic hyperbranched CD polymers. The amphiphilic hyperbranched CD polymers can simultaneously and effectively encapsulate double-guest molecules, which are levofloxacin lactate (LL) and phenolphthalein (PP). Notably, PP was almost only encapsulated in the cavity of β-CD, but LL was almost only gone into hyperbranched cavity from the calculation results of Gaussian 03 software, UV–vis spectrum, fluorescence spectroscopy, and previous work [101–103]. Due to the different microenvironments of the different cavities, the releases of double-guest molecules showed the different completely phenomenon. Therefore, the release behaviors of drugs from samples can be controlled effectively by regulating the DB values of the core layer or the PDMA chain lengths of the shell layer. Researchers can achieve effective control of the release behavior of the drug from the amphiphilic

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Fig. 15 Schematic illustration of the hyperbranched CD polymers with core-shell structure and their controlled release behaviors [100]

hyperbranched CD polymers by adjusting the length of the chain in the core layer and degrees of branching (DB).

19.5

Conclusion

In conclusion, CD polymers developing as a hot research field have important applications in biology. CD polymers are constructed by covalently attaching CDs to polymers or using supramolecular non-covalent interactions (host-guest interactions between CDs and guest molecules). As more and more groups are modified onto CDs through different methods and reaction sites, plentiful CD polymers will be prepared in the future. Thus, more application value of CD polymers will be discovered and utilized in biology field including biodegradable materials, drug delivery and release, biocompatible materials, and clinical studies. Although CD polymers have shown great value in the field of biology in current research, some problems still need to be resolved, for example, how to achieve the accurately stimuli-responsive release at the target site in drug carrier and release, how to achieve the nontoxic and thorough degradation and metabolism in biomaterials and so on. In-depth and comprehensive clinical research of CD polymers is relatively less. In a word, there is still a broad space for development in the research field of CD polymers. The preparation of CD polymers with novel structures and special functions remains a challenge that chemists need to solve in future research work. It is believed that a large number of new research results based on CD polymers will continue to emerge and play an invaluable role in biology in the future. Acknowledgments We thank NNSFC (21432004, 21672113, 21772099, 21861132001) for financial support.

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Construction and Biomedical Application of Magnetic Supramolecular Assemblies

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Qilin Yu, Yong Chen, Bing Zhang, Ying-Ming Zhang, and Yu Liu

Contents 20.1 20.2 20.3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Magnetic Building Blocks for Magnetic Supramolecular Assemblies . . . . . . . . . . . . . . . . . Construction of Magnetic Supramolecular Assemblies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.3.1 Zero-Dimensional Supramolecular Nanocomposites . . . . . . . . . . . . . . . . . . . . . . . . . . 20.3.2 One-Dimensional Magnetic Supramolecular Nanofibers . . . . . . . . . . . . . . . . . . . . . . 20.3.3 Two-Dimensional Magnetic Supramolecular Nanoassemblies . . . . . . . . . . . . . . . . 20.4 Biomedical Application of Magnetic Supramolecular Assemblies . . . . . . . . . . . . . . . . . . . . . 20.4.1 Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.4.2 Magnetic Hyperthermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.4.3 Suppression of Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.4.4 MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.4.5 Magnetofection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Q. Yu Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, China e-mail: [email protected] Y. Chen · Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected]; [email protected] B. Zhang · Y.-M. Zhang College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China e-mail: [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_22

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Introduction

Supramolecular chemistry, especially host-guest supramolecular chemistry, is strongly prompted by the development of multi-stimuli and multifunctional supramolecular assemblies, which could dynamically respond to various physical/chemical/biological factors [1, 2]. Among these various assemblies, magnetic supramolecular assemblies are emerging systems that are constructed by magnetic building blocks and based on supramolecular interactions and could be sensitively respond to external magnetic field [3, 4]. Owing to the noninvasive, wireless, and high-flexible properties, magnetic fields may regulate formation and dynamic change of magnetic supramolecular assemblies in a biocompatible way, endowing the assemblies to have potential application in most living systems, especially for drug delivery and imaging [5, 6, 7, 8].

20.2

Magnetic Building Blocks for Magnetic Supramolecular Assemblies

The magnetic building blocks are the core components of magnetic supramolecular assemblies. Typical magnetic building blocks are composed of organic moleculemodified inorganic magnetic cores (e.g., magnetic nanoparticles, magnetic nanorods, and magnetic nanosheets) or magnetic heterometallic complexes (e.g., single molecular magnets (SMMs)). In the building blocks, the inorganic/organic magnetic cores endow the blocks with magnetism-responsive properties, and the organic ligands are grafted on the surface of the cores, mediating the supramolecular assembly by providing the interaction groups between the blocks, together with stabilizing the inorganic/organic magnetic cores (Fig. 1) [9, 10, 11]. Supraparamagnetic nanoparticles are the main magnetic building blocks, i.e., the nanoparticles of Fe, Co, Ni, their oxides (e.g., Fe3O4, γ-Fe2O3, CoFe2O4,

Fig. 1 Building blocks used for constructing magnetic supramolecular assemblies. MNP, magnetic nanoparticle; MNR, magnetic nanorod; MNS, magnetic nanosheet; SMM, single molecular magnet. The SMM cluster indicates [Dy30Co8Ge12W108O408(OH)42(OH2)30]56 [11]

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MnFe2O4, etc.), and metal alloys based on them (e.g., CoFe, FePt, CoPt, etc.). Among them, Fe3O4 nanoparticles are commonly used since they have wonderful magnetism-responsive properties and are easy for synthesis and modification. Traditional Fe3O4 nanoparticles could be synthesized by four methods, including coprecipitation, thermal decomposition, microemulsion, and hydrothermal synthesis [12]. In the coprecipitation method, for example, FeCl2 and FeCl3 were mixed in H2O, and then NaOH was added to the mixture, followed by heating treatment to form the Fe3O4 nanocrystals [13]. The obtained nanoparticles were further used for surface modification by aminopropyltriethoxysilane (APTES) or other silanization agents for further covalent grafting [14]. Moreover, Fe3O4 nanoparticle-grafted one-dimensional or two-dimensional nanomaterials (e.g., graphene oxide nanosheets) could also be used for construction of the magnetic supramolecular assemblies after equipped with molecular recognition units for endowing the ability of supramolecular interaction [15]. Another type of magnetic building blocks is heterometallic complexes, which are mainly based on coordination chemistry. The coordination interaction between metal ions and organic ligands through the Lewis acid/base interactions may lead to spontaneous formation of heterometallic complexes with ordered and dynamic structures [16, 17]. Among them, the magnetic heterometallic complexes, also named single molecular magnets (SMMs), are formed by coordination between the common transition metals (e.g., Mn, Fe, Co, Ni, V) or rare-earth metals (e.g., La, Dy, Er) in oxidation states and their corresponding organic ligands [18–20]. For example, Kou et al. synthesized H2pyaox-based mixed-valent {Mn14} cluster SMMs, named [MnIV2MnIII10MnII2O8(Hpyaox)14(pyaox)2-(N3)2](ClO4)4(OH)2
2MeOH
23H2O, which displays an S = 6 spin ground state and slow magnetic relaxation [21]. Ibrahim et al. prepared a kind of tetrahedral heterometallic polyoxometalate (POM) [Dy30Co8Ge12W108O408(OH)42(OH2)30]56 (Fig. 1), which shows remarkable SMM behavior [11]. These magnetic complexes could be developed as the core for construction of high-ordered supramolecular assemblies.

20.3

Construction of Magnetic Supramolecular Assemblies

By depending on the supramolecular interactions, such as host-guest interaction, hydrophobic interaction, and coordination, the magnetic building blocks could be dynamically self-assembled into zero-, one-, or two-dimensional nanostructures. These assembling processes could be induced and regulated by specific stimuli, especially the magnetic field and light.

20.3.1 Zero-Dimensional Supramolecular Nanocomposites As the frequently produced magnetic supramolecular nanoassemblies, zero-dimensional magnetic supramolecular nanocomposites, e.g., vesicles, micelles, and particles, were abundantly constructed and used for biomedical applications (especially for drug delivery and imaging) [22, 23]. In these nanocomposites, chemotherapeutic

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drugs or fluorescence dyes were often integrated into the assemblies, generating multifunctional and multi-stimuli-responsive systems for drug delivery, magnetic resonance imaging (MRI), and magnetofection.

20.3.2 One-Dimensional Magnetic Supramolecular Nanofibers In the nature, one-dimensional magnetic supramolecular assembly is a well-known phenomenon; in the magnetotactic bacteria, the magnetosomes could self-assemble to form one-dimensional nanofibers [24, 25]. In the biomimetic area, it is very interesting to mimic the formation of magnetosome-composed nanofibers by controlling the supramolecular interaction between the magnetic nanoparticles. Recently, we constructed a novel geomagnetism and light dual-responsive one-dimensional supramolecular assemblies, i.e., magnetic supramolecular nanofibers. The nanofibers were composed of peptide-modified Fe3O4 magnetic nanoparticles (MNPs) and β-cyclodextrin-modified hyaluronic acid (HACD) (Fig. 2) [26]. Firstly, the MNPs were synthesized using the classical coprecipitation method, obtaining the cube-like nanoparticles with the diameter of 10–20 nm. The obtained MNPs were further silanized by APTES to provide chemically modifiable –NH2 groups on the surface of the MNPs (MNP-NH2). MNP-NH2 was further modified with a mitochondrion-targeting peptide (MitP) (FITC-ACP-Fx-r-Fx-K-Fx-r-Fx-K,

Fig. 2 Synthetic route of the magnetic supramolecular nanofibers. MitP, mitochondrion-targeting peptide; MNP, magnetic nanoparticles. (Copyright 2018 American Association for the Advancement of Science)

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MitP) by the glutaraldehyde-mediated cross-linking reaction, obtaining MitP-MNPs that possess mitochondrion-targeting ability. Owing to numerous cyclohexylalanine pendants located around the core of MitP-MNPs, and abundant β-CD on the HACD polymer, large-sized supramolecular assembly may be further achieved through the hierarchically intermolecular organization. When HACD was added, a strong multivalent binding between the hydrophobic cyclohexyl group of MitP and β-CD’s cavity induced the formation of the supramolecular nanofibers with 100–500 nm in diameter and several micrometers in length. Interestingly, the constructed one-dimensional supramolecular magnetic nanofibers could sensitively respond to various magnetic fields. This assembling process has two critical properties: (1) the assembling direction of the nanofibers is strictly along with the magnetic field. When the components were under the geomagnetic field, the nanofibers could be gradually induced along with the direction of this field, just like a campus; when treated by the artificial strong field, the nanofibers could be formed along with the direction of this field. (2) The assembling rate of the nanofibers is in proportion with the strength of magnetic field. Moreover, the formation of nanofibers could also be regulated by light irradiation in the presence of the photo-responsive molecule arylazopyrazoles carboxylate (AAP) as the competitive guest. Under the green light irradiation, AAP was transformed into transAAP, disrupting the assembling process of this nanofibers; under the UV irradiation, trans-AAP is transformed into cis-AAP, and the nanofibers could be formed.

20.3.3 Two-Dimensional Magnetic Supramolecular Nanoassemblies By using modified magnetic nanoparticles, two-dimensional magnetic supramolecular nanostructures could be achieved on proper substrates or interfaces. In an early study, Sun et al. realized polymer-mediated self-assembly of magnetic FePt nanoparticles to form two-dimensional nanofilms. The magnetic FePt nanoparticles were firstly modified by the functional polymers poly(vinylpyrrolidone) (PVP) or poly(ethylenimine) (PEI), followed by self-assembling on PEI-modified silicon oxide surface, generating wide-range and uniform two-dimensional nanofilms [27]. Recently, we further designed a tumor-targeting two-dimensional nanostructure, named MNP@GOMitPHACD, based on MitP-modified and MNP-grafted graphene oxide (GO) and HACD. Similarly, the magnetic assembling process could be induced under geomagnetic field (Fig. 3), forming nanofilms for coating the tumor cells.

20.4

Biomedical Application of Magnetic Supramolecular Assemblies

20.4.1 Drug Delivery Traditional chemotherapeutic drugs with small molecular weights are widely used in clinic. However, their efficiency is frequently compromised by poor water solubility, weak targeting specificity, and emergency of drug-resistant cancers. It is a feasible

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Fig. 3 Schematic illustration of assembly of the MNP@GO-MitPHACD two-dimensional supramolecular nanostructures

strategy to load these small molecules into the supramolecular magnetic nanocomposites to form zero-dimensional magnetic drug-delivering nanocomposites, which could specifically target the tumor sites and release the drugs by elaborately controlling the magnetic field. For example, Lee et al. constructed one kind of magnetic supramolecular nanoparticles composed of adamantane-modified magnetic nanoparticles (Ad-MNP), adamantane-modified polyamidoamine dendrimers (Ad-PAMAM), β-cyclodextrin-grafted polyethylenimine (CD-PEI), and doxorubicin (Dox) (Fig. 4). In the DOX-containing magnetic supramolecular assemblies, the components could self-assemble into nanoparticles by host-guest interaction, magnetic attraction, and hydrophobic force. By the enhanced permeability and retention (EPR) effect, the nanoparticles could accumulate at the tumor sites and release DOX with the aid of alternative magnetic field (AMF), which could cause remarkable heat production of the MNPs. These magnetothermally responsive supramolecular nanoparticles could severely damage the tumor cells and exhibit splendid antitumor efficiency in vivo [28].

20.4.2 Magnetic Hyperthermia Hyperthermia is a useful method with long history for treating abundant diseases and dysfunctions, such as infections, immune disorders, and cancers [29, 30]. For

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Fig. 4 AMF-responsive magnetic supramolecular assemblies for controlled drug release for cancer therapy [28]

example, during cancer therapy, hyperthermia has been developed to stimulate nonspecific immunotherapy of cancers (41–46  C) or induce tumor cell necrosis and apoptosis for tumor destruction (>46  C) [31]. Two strategies, i.e., magnetic hyperthermia and photo-hyperthermia, are hot topics in anticancer fields, since they have almost no side effect as compared to the traditional chemotherapy, radiotherapy, and surgery. Among them, magnetic hyperthermia is a therapeutic method that the magnetic nanomaterials could adsorb the electromagnetic energy and convert it into heat when exposed to an external electrical and magnetic field, especially alternative magnetic field (AMF) [32]. Therefore, it is highly applicable in treatment of deeply tumors, with no obvious damage to normal tissues. Recently, we found that both the two-dimensional MNP@GO-MitPHACD supramolecular assemblies and the one-dimensional tumor actin-targeting MNP-ABP-AdaHACD have splendid anticancer ability under AMF. Espinosa et al. reported that the constructed magnetic assemblies based on cubic MNPs could realize high heating efficiency in combination with magnetic hyperthermia and photothermal treatment [33].

20.4.3 Suppression of Metastasis Besides the most prevalent application in drug delivery and magnetothermal therapy, supramolecular assemblies themselves could also be used to fight against cancer diseases by its confining effect on tumor invasion and metastasis. For example, as

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demonstrated above, we designed the one-dimensional MNP-MitPHACD supramolecular nanoassemblies and found that they could not only recruit the mitochondria owing to the presence of MitP but also bind the HA receptor-expressing tumor cells that could interact with HACD, confining the tumor cells at the primary sites and inhibiting tumor invasion and metastasis [26] (Fig. 5). When the nanoassemblies were mixed with the mitochondria isolated from tumor cells in physiological solutions, the assemblies could strongly bind the dispersed mitochondria, resulting in directional assembling of this organelle along with the nanofibers. In the tumor cells, the MitP-MNPHACD nanoassemblies could target the mitochondria, leading to severe mitochondrial fragmentation, reduction of mitochondrial membrane potential, release of mitochondrial cytochrome C to the cytoplasm, and activation of caspase-3-mediated apoptosis and cell cycle arrest. More strikingly, the nanoassemblies could strongly bind the tumor cells, confining the cells on the surface of Matrigel and suppressing tumor cell invasion and metastasis both in vitro and in vivo. For example, after injection of the MitPMNPHACD nanoassemblies into the lung tumor cell-infected mice, all of the

Fig. 5 Suppression of tumor invasion and metastasis by the MitP-MNPHACD nanoassemblies. (Copyright 2018 American Chemical Society)

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mice survived, whereas the control and MitP-MNP-treated mice died after 6 days of tumor cell infection. Furthermore, the histopathological observation revealed that the supramolecular assemblies had no obvious toxicity to the reticuloendothelial system (RES) organs, including the liver, spleen, and kidney, implying good biocompatibility of the assemblies. Together, the biocompatible MitP-MNPHACD could efficiently suppress tumor invasion and metastasis, preventing death of the mice from malignant tumors. The constructed two-dimensional supramolecular assemblies, MNP@GOMitPHACD (Fig. 4), also have a great impact on tumor metastasis. Besides the strong efficiency of the assemblies to target and damage the tumor mitochondria, MNP@GO-MitPHACD caused severe attenuation of tumor cell (A549-Luc2-tdT-2) invasion into the Matrigel. Interestingly, no nanostructures were found inside the invading cells after treatment with MNP@GO-MitPHACD, indicating that the Matrigel as confined environment may have hindered internalization of MNP@GOMitPHACD and that the extracellular 2D nanostructures may have served as a barrier to cell migration. In vivo metastasis experiments further showed that MNP@GO-MitPHACD were distributed at the tumor cell sites and strongly inhibited migration of the A549-Luc2-tdT-2 tumor cells, restricting the cells to locations near the site at which they had been injected. In contrast, MNP@GO-MitP were distributed throughout the body and failed to inhibit tumor metastasis; tumor cells migrated all the way from the injection site to the whole body. This inhibitory effect of MNP@GO-MitPHACD on tumor metastasis was further confirmed by the 4T1 lung metastasis model, in which MNP@GO-MitPHACD could almost thoroughly prevent lung metastasis of 4T1. These results suggest that the biocompatible MNP@GOMitPHACD nanostructures could efficiently inhibit tumor invasion and metastasis. When combined with gold nanorods or chemotherapeutic drugs, this nano-system could realize both tumor metastasis inhibition and tumor damage simultaneously. For example, in one of our other study, a strategy of metastasis prevention-photothermal removal cooperation was developed for enhancement of the anticancer efficiency (Fig. 6) [34]. The growth of the AuNR-MitP-MNPHACD nanofibers, which are composed by HACD and MitP-modified gold nanorods (AuNR-MitPMNPs), was precisely regulated by the weak geomagnetic field. In the biological systems, the nanofibers could suppress tumor cell metastasis by restricting the cells to a confined environment. When the tumor site was irradiated by a near-infrared (NIR) laser, the tumor tissues were severely damaged and removed. Therefore, the developed magnetic supramolecular assemblies have a bright application prospect in tumor therapy and related treatment.

20.4.4 MRI MRI is an emerging and powerful imaging strategy, since that it exhibits excellent spatial resolution of soft tissues, low toxicity to normal cells, and deep tissue penetration. Although MRI had relatively low sensitivity as compared to optical imaging and positron emission tomography, its sensitivity could be enhanced with

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Fig. 6 Schematic illustration of the AuNR-MitP-MNPHACD against tumor metastasis and growth with the aid of NIR [34]. (Copyright 2018 American Association for the Advancement of Science)

the aid of MRI contrast materials, e.g., superparamagnetic Fe3O4 nanoparticles that could strongly shorten the spin-spin relaxation (T2) time [35, 36]. To further improve the MRI contrast effect, Wan et al. prepared one kind of magnetic supramolecular assemblies based on the stearic low molecular weight polyethylenimine (PEI)-supermagnetic Fe3O4 nanoparticles and minicycle DNA and found that the assemblies showed highly sensitive MRI effect [36]. In the future, novel magnetic supramolecular assemblies may be developed for further improvement of MRI sensitivity and be endowed with more functions.

20.4.5 Magnetofection Owing to the significance of gene transfer in fundamental biology and biomedicine, a series of transfer strategies have been developed, such as chemical agent-mediated transfection (e.g., calcium phosphate, PEI, etc.), lipofection, electrotransformation, virus-mediated transfection, and so on [37]. Magnetofection is a strong transfection

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strategy, since it has several advantages, including high transfer efficiency, improvement of the kinetics of the delivery process, and regulation of accurate localization of nucleic acid by magnetic field. Especially, for the cell types that are hard to be transferred using the traditional transfection methods, such as microglia, primary cells, and stem cells, magnetofection is a good choice [38]. Standard magnetofection reagents are various magnetic supramolecular assemblies composed of ligand-modified MNPs, carried nucleic acids, and enhancers (polyplex or nonviral lipoplex) or viral vectors [39, 40]. The increased transfection was supposed to be associated with enhanced sedimentation on the cell surface and improved cell incorporation and response to changed magnetic field (e.g., AMF) [34].

20.5

Conclusion

Overall, magnetic supramolecular assemblies, whose formation depends on the driving force by magnetic field in combination with supramolecular interactions, are becoming the hot topic of supramolecular chemistry, bionics, material science, and biomedicine. A series of these assemblies, including various zero-dimensional clusters, one-dimensional fibers, and two-dimensional sheets/films, have been developed with wonderful morphology and multi-stimuli responsiveness and multifunction. Especially, in the biomedicine field, magnetic supramolecular assemblies could be widely applied in controlled drug release, magnetic hyperthermia, inhibition of metastasis, MRI, magnetofection, etc. Further researches will focus on development of novel magnetic supramolecular assemblies and new magnetic building blocks, together with improvement of their biomedical properties and discovery of the novel biological application. It is very exciting that biomimetically magnetic supramolecular assembling is becoming a magnificent bridge that promotes the interaction between chemistry and biology.

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Supramolecular Assembly Constructed from Multi-charged Cyclodextrin-Induced Aggregation

21

Pei-Yu Li, Yong Chen, and Yu Liu

Contents 21.1 21.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Supramolecular Assembly Constructed from Polyanionic Cyclodextrin-Induced Aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.3 Supramolecular Assembly Constructed from Polycationic Cyclodextrin-Induced Aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.4 Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21.1

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Introduction

Cyclodextrins are a family of cyclic oligosaccharides containing 6-8 D-glucose units linked by α-1,4-glucose bonds, referred to as α-, β-, and γ-cyclodextrin, respectively. As generated from the enzymatic degradation, cyclodextrins are water-soluble, nontoxic, and commercially available at a low cost. More importantly, as the second generation of supramolecular macrocycles, cyclodextrins could bind various neutral or negatively charged shape-compatible guest molecules by the hydrophobic cavity. This fascinating property made cyclodextrin a good candidate in molecular recognition, sensing, drug carriers, biomimetic catalysts, and so on [1–3].

P.-Y. Li · Y. Chen · Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected]; [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_23

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Recently, supramolecular amphiphilic assembly constructed from molecularinduced aggregation gained a lot of attention due to their functional versatility, biocompatibility, and being tunably responsive to various external stimuli [4, 5 ]. Randaccio, Purrello, and Sciotto came up with the early prototype of “molecularinduced aggregation”. They found that the complexation between a tetrakis-acetatesmodified sulfonatocalixarenes and a cationic porphyrin led to the formation of aggregates with pH-tunable host/guest stoichiometries [6]. After that, other watersoluble macrocyclic molecules, including cucurbiturils [7, 8], pillararenes [9–12], and cyclodextrins [13, 14], were also employed to construct supramolecular amphiphiles through the “molecular-induced aggregation” strategy. In a molecular-induced aggregation process, the host molecules were able to promote the self-aggregation of aromatic or amphiphilic guest molecules by lowering the critical aggregation concentration (CAC), increasing the stability and compactness, and regulating the degree of order in the aggregates. Three key factors are required for the “molecular-induced aggregation”: (1) strong binding affinities between hosts and the polar head groups of guests, (2) charge compensation between hosts and guests, and (3) the pre-organized cyclic scaffold of hosts. For the amphiphilic guest molecules, the electrostatic repulsion between the polar head groups prevents the formation of large three-dimensional assemblies. Upon complexation with hosts, the electrostatic repulsion between the polar head groups is replaced by the electrostatic attraction between host and guest which facilitates the formation of large assemblies. The “molecular-induced aggregation” process can be summarized as two steps. First, the host and guest molecules rapidly form a complex driven by the host-guest interactions. Then, the additional guest molecules readily integrate into the complex, which further transform into a 2:n complexes and large three-dimensional aggregates. Compared with other macrocyclic host compounds, multi-charged cyclodextrins are a series of novel “molecular-induced aggregation” candidates. The cavities of cyclodextrin can include various inorganic/organic/biological molecules and ions with high size/shape selectivity [15, 16]. The negative charge density of sulfatocyclodextrin (SCD) is much higher which is also the most important “molecular-induced aggregation” factor. This chapter mainly summarizes the recent researches on the supramolecular assembly constructed from multi-charged cyclodextrin-induced aggregation and their applications in biological and medical fields.

21.2

Supramolecular Assembly Constructed from Polyanionic Cyclodextrin-Induced Aggregation

A typical example of polyanionic cyclodextrin-induced aggregation was a trypsinresponsive supramolecular assembly constructed of SCD and protamine (Fig. 1) [17]. Protamine, a natural protein, was used as an excipient in insulin formulations with potential biological applications including binding DNA and providing a highly compact conjuration of chromatin in the nucleus of the sperm [18]. As a natural cationic protein, protamine has no amphiphilic self-assembly property for its high

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Fig. 1 Schematic illustration of trypsin-responsive supramolecular assembly

hydrophilicity. Interestingly, when added with SCD, the aqueous solution of protamine showed obvious Tyndall effect due to the large aggregates formed by polyanionic cyclodextrin-induced aggregation. The critical aggregation concentration (CAC) of SCD in the presence of protamine was 0.016 mM measured by optical transmittance experiment, while the preferable mixing ratio between SCD and protamine was also determined as 20 mg mL 1 protamine/0.027 mM SCD. The structural and morphological information of the protamine/SCD assembly was obtained from transmission electron microscopy (TEM) and dynamic light scattering (DLS). The spherical particles formed by polyanionic cyclodextrin-induced aggregation had an average diameter of 190 nm. Trypsin, an enzyme which can cleave protamine to amino acids and peptides with unparalleled specificity, was added, which led to the enzyme-responsive disassembly of protamine/SCD nanoparticles. The trypsin-responsive disassembly could also trigger a release of substrates loaded by the protamine/ SCD nanoparticles. Trisodium salt of 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) was chosen as a model molecule which can be loaded by the protamine/SCD nanoparticles through an electrostatic interaction. After the treatment of trypsin, more than 80% of HPTS was released in 5 h along with the disassembly process of protamine/SCD nanoparticles, while only a very low release of HPTS was observed in the same amount of time with no trypsin added. Aniline, a fluorescence dye which can be included in SCD cavity, was also loaded in the protamine/SCD nanoparticles. The result of the fluorescence experiment proved that the SCD cavities in the protamine/ SCD nanoparticles still remained the binding affinities toward guest molecules. It is believed that this protamine/SCD nanoparticle was a potential enzyme-triggered controllable release model with site-specific response ability and with high drug delivery efficiency and low undesired side effects. Fig. 2 showed another example of polyanionic cyclodextrin-induced aggregation which was constructed from chitosan and sulfonate-β-cyclodextrin (SCD) [19]. Chitosan, a natural cationic saccharide, can provide cationic polyelectrolyte from

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Fig. 2 Schematic illustration of the pH-responsive supramolecular assembly

the protonated amino groups produced by the deacetylation of chitin. In this work, two kinds of chitosans in different degrees of deacetylation were applied to construct assemblies with SCD: chitosan-0.95 represents chitosan with 95% deacetylation degree, and chitosan-0.6 represents chitosan with 60% deacetylation degree. The critical aggregation concentrations (CAC) of SCD/chitosan supramolecular nanoparticles were determined as 0.020 mM for SCD in the presence of chitosan-0.6 and 0.024 mM for SCD in the presence of chitosan-0.95. The hydrodynamic diameters of SCD/chitosan-0.6 and SCD/chitosan-0.95 nanoparticles were 122 and 173 nm measured by DLS experiment along with a spherical morphology observed in TEM images. Both of the SCD/chitosan-0.6 and SCD/chitosan-0.95 nanoparticles were stable at the temperature from 10  C to 70  C. After that, berberine (BE), a commonly used bacteriostasis drug for treating digestive tract, was used as the model substrate for loading experiment. Interestingly the BE-loaded SCD/ chitosan-0.95 nanoparticles were found stable at pH 2 and disassembled at pH 8. These BE-loaded SCD/chitosan-0.95 nanoparticles were applied for releasing BE from the stomach to the intestine in BALB/C mice. The respective release efficiency was 12.83  1.51 % in the stomach and 50.26  8.21 % in the intestine, which indicated an efficient release from the stomach to the intestine. As the difference of pH to release berberine in accord with the pH between the stomach and the intestine, these supramolecular nanoparticles might have promising application in precise drug release.

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SCD Amphiphilic BChE

Assembly

Nanoparticles

Cbl Anticancer Drug Release

QA-Cbl

Cl Cl

RO O

=

RO

=

O 7

OR

R = SO3Na or H

O N + Cl–

O

N

Cl

=

O

N

Cl

HO

Fig. 3 Schematic illustration of the enzyme-responsive supramolecular assembly

The polyanionic cyclodextrin-induced aggregation principle was also used to construct prodrug and macrocyclic supramolecular assembly (Fig. 3) [20]. Prodrug is a compound which has no biological activity or low activity while becoming an active drug after being metabolized in the body. The combination of prodrugs with macrocyclic molecules is a new therapeutic idea that can overcome problems existing in the traditional chemotherapy [21–23]. In this work, choline-modified chlorambucil (QA-Cbl), a positively charged water-soluble prodrug, was chosen as guest molecules. Through the enzymatical degradation process, the QA-Cbl can be converted to the anticancer drug chlorambucil (Cbl) and choline by butyrylcholinesterase (BChE). Compared with traditional drug encapsulation, this polyanionic cyclodextrin-induced aggregation method with prodrug QA-Cbl directly used as building blocks presents high drug-loading efficiency. This SCD/QA-Cbl nanoparticle has both enhanced permeability through retention (EPR) effect and reverse cancer multidrug resistance (MDR). The best mixing ratio was measured as 0.04/ 0.70 mM for SCD and QA-Cbl, and the drug-loading efficiency was 77.14%. The TEM images of the SCD/QA-Cbl nanoparticles showed a spherical morphology with diameters around 200 nm which was further confirmed by DLS results. The assembly was formed through electrostatic interactions between the polyanions of SCD and the quaternary ammonium cation head of QA-Cbl. The probable mechanism of the forming multilayer structure is as follows. The QA-Cbl itself did not aggregate into large nanoparticles. After being mixed with SCD, one single SCD could form a complex with several QA-Cbls, and these complexes could further arranged into large multilayer planes. After the multilayers grew large

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enough, it curved into multilayered sphere with an alternating shell structure. The SCD/QA-Cbl nanoparticles were synergistically stabilized by electrostatic, ππ, and hydrophobic interactions. Finally, the BChE-responsive substantiate release process of Cbl from the SCD/QA-Cbl nanoparticles was characterized by highperformance liquid chromatography (HPLC) and mass spectrometry. In the presence of BChE (0.2 U/mL), Cbl was released, while no drug release was observed in the absence of BChE. This supramolecular assembly formed by prodrug and macrocyclic molecules provides an applicable strategy for cancer therapy with great efficiency and specificity. Fig. 4 presented a typical example of ionizable cyclodextrins which was the hepta-carboxyl-β-cyclodextrin (H3) [24]. In this work, the amphiphilic molecule G was chosen as the guest, which had a hydrophilic quaternary ammonium head and two hydrophobic alkyl chain tails. The CAC value of G was measured as 0.1 mM. From the TEM images of G, rodlike micelles could be observed with a length of hundreds of nanometers and a width of 9 nm. Three carboxyl-modified cyclodextrins H1, H2, and H3 were added to the G solution separately, and only the mixing solution of H3 and G had Tyndall effect, which indicated the formation of large aggregates. Only H3 could induce the aggregation of guest molecules, indicating that the multi-charged cyclodextrin played a key role in the assembly process. With the addition of H3, the CAC of G reduced to 10 μM. The preferable mixing ratio between H3 and G was determined to be 1:7 by transmittance experiment, which is consistent with the ratio of anion/cation as 1:1. The H3@G assembly formed by ionizable cyclodextrin-induced aggregation possessed a spherical morphology with a diameter of 90 nm which is different from the aggregates formed by

HO

O +

N –

G

Br

O HPTS

– O O SO

O O S S – O O O O + 3 Na

HOOC N NN O HO

O

OH H3

7

(Per-COOH-β-CD) Self-assembly

G

Fig. 4 Schematic illustration of the supramolecular assembly formed by ionizable cyclodextrininduced aggregation

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self-aggregation of the guest molecule. 2D ROESY spectrum further confirmed the assembly mechanism that G was gathered around H3 instead of being captured by the H3 cavity. This also proved the importance of electrostatic interactions in the molecular-induced aggregation. The H3@G assembly was also found to be stable in the temperature between 25  C and 70  C. After that, a ternary assembly H3@Ama@G was constructed in which a pharmacological drug for anti-Parkinson and antiviral amantadine (Ama) was selected as model drug. The complexation stoichiometry binding radio of 1:1 between H3 and Ama was confirmed through the job analysis, and the apparent binding constant was 2.34  104 M 1. Then, the release behavior of the H3@Ama@G was investigated with trisodium salt of 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) chosen as the cargo. The release rate of HPTS-loaded assemblies was much faster than that of the free HPTS solution. Another example was a BChE-responsive supramolecular nanoparticle with hepa-carboxyl-modified cyclodextrins (carboxyl-CD) as the macrocyclic host induced the molecular aggregation of myristoylcholine (Fig. 5) [25]. Myristoylcholine was an enzyme-responsive antimicrobial agent which could not form enzyme-responsive self-assembly due to the similar CAC value of the substrate and product [26, 27 ]. With the addition of carboxyl-CD, an obvious Tyndall effect could be observed from the solution of myristoylcholine which indicated the formation of large aggregates. The CAC value of the carboxyl-CD-induced myristoylcholine was measured as 0.074 mM through a transmittance experiment,

Self-assembly

BChE

COCH N N

HO

SO3Na

NaO3S

SO3Na

N

HO OH

O 1

HPTS

Carboxyl-CD

Myristoylcholine

BChE Myristic acid

+ Choline

Fig. 5 Schematic illustration of the enzyme-responsive supramolecular assembly

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and the preferable mixing ratio was 1:7. The mechanism of the “carboxyl-CDinduced aggregation” may be summarized as follows: The myristoylcholine molecules did not form a large self-aggregate. With carboxyl-CD added, a complex between one carboxyl-CD and several myristoylcholines was formed. Then, through the hydrophobic interactions between the aliphatic tails of myristoylcholine, several complexes integrated together to form a large aggregate and curved to a spherical nanoparticles. The transmission electron microscopy (TEM) images showed a spherical morphology with an average diameter around 200 nm which is consistent with the hydrodynamic diameter of 288 nm measured by dynamic light scattering (DLS). After treated with BChE, the optical transmittance of carboxyl-CD/ myristoylcholine increased to >95% in 2 h resulting from hydrolysis of the guests. Per-6-thiolated β-cyclodextrin sodium salt (SACD) is a polyanionic macrocycle with seven negative changes on the upper rim (Fig. 6). The multiple carboxylate groups were introduced through a thioether linkage increasing the molecularinduced aggregation behavior of β-cyclodextrin. Ferrocene-modified quaternary ammonium salt (FC12+Br–) was chosen as the guest molecule [28]. The critical aggregation concentration (CAC) of FC12+Br– decreased to 0.068 mM with the addition of SACD as over seven times lower than the CAC itself. The optimal molar ratio of the SACD/FC nanoparticles was determined at 1:20 for SACD:

Fig. 6 Schematic illustration of the pH-responsive supramolecular assembly

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FC12+Br– through an optical transmittance experiment. At the beginning, simple inclusion complexes of SCAD and FC12+Br– formed driven by the hydrophobic and electrostatic interactions. The additional FC12+Br– molecules readily co-assembled with these complexes through electrostatic interactions and grew into binary nanoparticles. From the TEM images, a spherical morphology with an average diameter of 180 nm was observed, which is consistent with the DLS results. The SACD/FC nanoparticles also possessed a zeta potential as –77.67 mV, indicating that the electrostatic interaction played an important role to keep the stability of the non-covalent aggregates. Interestingly, the SACD/FC nanoparticles disassembled at pH 4.0 due to the protonation of carboxylic group of SACD. Meanwhile, the SACD/ FC nanoparticles reassembled at pH 7.5. Finally, doxorubicin hydrochloride (DOX) was chosen as model drug to investigate the drug-loading efficiency and acidresponsive release of the SACD/FC nanoparticles. The release rate greatly increased under acid conditions at pH 4.0 and 6.5. More than 90% of DOX were released at pH 4.0 within 150 min. The efficient cargo release property of the SACD/FC nanoparticles under acidic condition accords with the intrinsic acidic environment of tumor cells, which made this supramolecular assembly formed by multi-charged cyclodextrin-induced aggregation a specific site release drug delivery candidate.

21.3

Supramolecular Assembly Constructed from Polycationic Cyclodextrin-Induced Aggregation

The molecular-induced aggregation behaviors of polycationic β-cyclodextrin toward three anionic surfactants with different hydrophobic tails in length were investigated (Fig. 7) [29]. The critical aggregation concentrations (CACs) of the three surfactants were 39.9 mmol
L 1 for sodium decyl sulfonate (SDES), 20 mmol
L 1 for sodium undecyl sulfonate (SUS), and 9.7 mmol
L 1 for sodium dodecyl sulfate (SDS). With the addition of polycationic β-cyclodextrin, the CAC values of the three surfactants sharply decreased by a factor of 14–467. The preferable mixing ratio between the polycationic β-cyclodextrin and the surfactants was 1:7 measured by the optical transmittance experiments. All of the aggregates possessed a spherical morphology with a diameter of 200–400 nm in the TEM images, which was further confirmed by the DLS experiment. Furthermore, the aggregates formed by β-cyclodextrin with SLS and SDBS possessed a moderate positive zeta potential and were selected to study the guest encapsulation ability. Another polycationic β-cyclodextrin-induced aggregation supramolecular assemblies were constructed with seven ethyl imidazolium-acetyl pendants (EICD) and hyaluronans (Fig. 8) [30]. Hyaluronidase (HAase)-hyaluronan (HA) pair attracted great attention because hyaluronan acceptors are overexpressed on the surface of cancer cells and hyaluronidase plays an important role in the movement of cancer cells to degrade hyaluronan [31, 32]. The critical aggregation concentration (CAC) of HA was 15 μM, while the EICD-induced CAC value was 11 μM. The diameter value of the EICD-induced assembly was 630 nm from dynamic light scattering (DLS) experiment, and this value was further confirmed by images of confocal laser

N

I–

O

7

+

O

O

O

O

S

S

S

O

– Na+ O

O

– Na+ O

O

O S

O

– Na+ O

O

Na+ –O

S

Fig. 7 Schematic illustration of the supramolecular assembly formed by polycationic β-cyclodextrin-induced aggregation

O

OH

Host 1

N+

HO

O

Na+ –O

SLS

C12

SDBS

SDS

C12

SUS

C11

SDES

C10

C12

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Fig. 8 Schematic illustration of the enzyme-responsive supramolecular assembly

scanning microscopy (CLSM). The transmission electron microscopy (TEM) and atomic force microscopy (AFM) images of the EICD-induced assembly showed a consistent spherical morphology. The EICD-induced assembly was also found stable over at least 4 h and could withstand the temperature from 25  C to 75  C. The enzyme responses of EICD-induced assembly were investigated in a 37  C water bath for 6 h. With the addition of HAase, the large aggregates of EICDinduced assembly disappeared. In addition, negatively charged dye 2,6-TNS and positively charged dye thioflavin T were chosen as model substrates to investigate the loading ability of EICD-induced assembly. Thioflavin T was found able to be loaded in the EICD-induced assembly by the EICD cavity, while 2,6-TNS was loaded by the means of the cooperation of HA through charge interaction. More interestingly, with HAase, the surface of the EICD-induced assembly could be changed from ionic to cationic, which made it a potential sequential multiple drug carrier. Besides the enzyme response, another photo-responsive supramolecular assembly based on polycationic β-cyclodextrin-induced aggregation was also reported (Fig. 9) [33]. In this work, the corresponding guest molecule was a anionic azobenzene-containing surfactant (G). The critical aggregation concentration

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Fig. 9 Schematic illustration of the light-responsive supramolecular assembly

(CAC) of G itself was measured as 0.128 mmol
L 1, which greatly decreased to 6.1  103 mmol
L 1 due to the polycationic β-cyclodextrin-induced aggregation effect. The preferable mixing ratio between polycationic β-cyclodextrin and the anionic azobenzene guest was 1:7, which was consistent with the host-guest charge-to-charge ratio. Interestingly, a reversible and recyclable growth/shrinkage movement of the assembly could be observed due to the photoisomerization of the anionic azobenzene guest molecule. After irradiated at 365 nm for 30 min, the large nanoparticles of H&trans-G with a diameter of 300 nm disappear, while small nanoparticles with an average diameter of 90 nm appear assigned to the corresponding H&cis-G assemblies. A cycle experiment with 365 and 450 nm light irradiation proved the good reversibility of the growth/shrinkage process. After that, RhB (a typical model fluorescent dye) and doxorubicin (an anticancer drug) which can be encapsulated by cyclodextrin cavity were selected as a model substrate to investigate the encapsulation efficiency and the photo-induced release ability of the H&trans-G assembly. As expected, the assembly formed by polycationic β-cyclodextrin-induced aggregation possessed high encapsulation efficiency of 22% and 31.6%, and the corresponding release ratio of doxorubicin within 5 h was 77%. Therefore, this supramolecular assembly would be a potential light-triggered controllable release carrier.

21.4

Conclusions and Outlook

With the good properties as water-soluble, nontoxic, commercially available, various binding affinities, and high charge density, multi-charged cyclodextrin was a promising candidate for construction of supramolecular assemblies through “molecular-

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induced aggregation.” These assemblies gave widely applications in the fields of biological and medical science. However, with the aim of better understanding of “multi-charged cyclodextrin aggregation,” there still remain several tasks including (1) modifying other groups on the rim of cyclodextrin to gain more recognition ability, (2) finding the differences among α-, β-, and γ-cyclodextrin in “molecularinduced aggregation” and taking advantage of it, and (3) extending the scope of stimuli-responsive method. It could be expected that these endeavors will bring the supramolecular assemblies based on multi-charged cyclodextrin aggregation more prospect. Acknowledgments We thank NNSFC (21432004, 21672113, 21772099, 21861132001) for financial support.

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Cyclodextrins-Based Shape Memory Polymers and Self-Healing Polymers

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Sheng Zhang, Shi-Lin Zeng, and Bang-Jing Li

Contents 22.1 22.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SMPs Based on CDs-Guest Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.2.1 General Aspect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.2.2 SMPs Based on CDs-Polymer Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.2.3 SMPs Based on CDs-Guest Group Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.3 SHPs Based on CDs-Guest Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.3.1 General Aspect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.3.2 Self-Healing Hydrogels Based on CD-Guest Interactions . . . . . . . . . . . . . . . . . . . . 22.3.3 Self-Healing Composites Based on CD-Guest Interactions . . . . . . . . . . . . . . . . . . . 22.4 SMPs and SHPs Based on CD-Guest Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.5 Prospect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Natural materials exhibit the ordered structures assembled biomolecules by supramolecular interactions, and perform various biological functions. Inspired by nature, smart and functional materials based on supramolecular chemistry have attracted considerable attention [1–3]. Shape memory polymers (SMPs) and self-healing polymers (SHPs) are two representative examples of biomimetic smart materials. The former can change from one or more temporary shapes to a predetermined shape in response to an external stimulus [4]; the latter are able to repair cracks or fracture by themselves spontaneously or in response to external stimuli, such as humidity, S. Zhang (*) · S.-L. Zeng Sichuan University, Chengdu, China e-mail: [email protected]; [email protected] B.-J. Li Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_24

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heat, or light. In the past decade, the SMPs and SHPs fields have undergone explosive development. Many innovative SMPs and SHPs, such as multishape, multiresponsive, and multifunctional SMPs and SHPs, have emerged [5–7]. In the case of many types of SMPs and SHPs, cyclodextrins (CDs)-based supramolecular forces has been increasingly utilized as driving forces to achieve shape memory or self-healing functions on account of its distinct features as compared to other supramolecular interactions. The most important advantages of using CDs-based interactions as driving forces are that (1) CDs are cyclic oligosaccharides made from starch, which show extremely low toxicity and are widely available. Therefore, CDs-based materials show great potential in biomedical applications; (2) CDs are capable of including a variety of compounds ranging from small molecules and ions to polymers in their cavities with high selectivity to form inclusion complexes (ICs). Thus, a number of SMPs and SHPs could be developed; (3) the inclusion complexation between CDs and many guests is sensitive to diversified stimuli. Therefore, CDs-based interactions are good candidates for developing novel stimulus-sensitive or stimulus-multisensitive SMPs and SHPs. This chapter outlines recent progress in SMPs and SHPs based on CDs-guest interactions, provides insights into the materials design, and points out future opportunities.

22.2

SMPs Based on CDs-Guest Interactions

22.2.1 General Aspect In principle, SMPs should possess at least two different kinds of segments: netpoints for stabilizing the whole material and determining the permanent shape and reversible segments for switching on/off the molecular mobility so as to freeze/release the temporary shape. The netpoints can be chemical cross-links, physical cross-links (e.g., molecular entanglement), or crystallites with a high melting point. The switching segments are generally segments that show reversible melting transitions or glass transitions at low temperature [8–10]. From an energy perspective, the shape memory effect of polymeric materials is an entropic phenomenon. In a typical one-way dual-shape memory process, the initial SMPs sample is rigid and hard to deform. The molecular chains in this initial shape are at a higher entropy (lower energy) state. Upon applying stimuli, the sample becomes soft because the mobility of some molecular chains is activated; as a result, the sample is easy to deform to a temporary shape when an external force is applied. This deformation leads to an entropic change (energy state raises). When depressing the mobility of chains by stimuli, the deformation imposed to the sample can be maintained even after removal of the external force. At the same time, the entropic energy in the system is stored. Once the mobility of chains is again activated, the entropic energy is released, driving the system back to its higher entropy (lower energy) state. Thus, the sample recovers to its original shape [11].

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The shape memory capacity is always described by two parameters: Rf and Rr. The shape fixity rate (Rf) describes the ability of the reversible segments to fix the mechanical deformation, and the shape recovery rate (Rr) quantifies the ability of the material to recover its original shape [12]. Cyclic mechanical investigation and bending test are two typical way to quantify the shape memory effect.

22.2.2 SMPs Based on CDs-Polymer Interactions A lot of polymers such as polyether, polyester, polyalkene, polyaniline, and polysiloxane have been found to be able to form ICs with different types of CDs [13]. The CDs-polymer ICs have a crystalline structure due to the strong hydrogen bonding formation between adjacent CDs. These crystalline ICs are thermally stable, which have no melting behavior but only decompose above 300 [14]. Utilizing this feature, our group developed a physical way to introduce netpoints into SMPs. For instance, partial α-CD-poly(ethylene glycol) ICs was prepared by controlling the molecular weight of poly(ethylene glycol) (PEG) and the ration of PEG/α-CD through casting method. In general, PEG has only a melting transition with melting point of 50–70 and does not meet the SMPs requirement. However, partial α-CD-PEG ICs contained not only thermal-sensitive PEG crystallites but also thermal stable α-CD-PEG ICs. As a result, partial α-CD-PEG ICs showed good shape memory properties. The recovery ratio of these materials could reach 97%. The PEG crystallites and α-CD-PEG ICs acted as the reversible phase and fixing phase, respectively (Fig. 1a) [15]. This strategy introduced the permanent segment through physical self-assembly, which was in contrast to the conventional chemical approaches. Furthermore, this approach was also expected to provide shape memory function to several other classical polymers since a lot of polymers could form ICs with CD molecules. In the later study, we prepared biodegradable shape memory materials based on partial inclusion between α-CD with degradable and hydrophobic polycaprolactone (PCL) [16, 17] and a supramolecular network composed of γ-CD

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Fig. 1 Molecular mechanism of the shape memory effect of a partial α-CD-PEG inclusion complex. (Reprinted in part with permission from Ref. [15]. Copyright 2008, Elsevier)

PEG crystallite

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and PEG [18]. The partial α-CD-PCL not only showed good shape memory properties with the recovery ratio exceeding 90% but also good degradability in the presence of lipase. It was demonstrated that the formation of inclusion segments significantly accelerated the degradation of materials. In the case of γ-CD-PEG network, the PEG chains were cross-linked by interlocking γ-CDs rather than covalent bond or traditional physical attractive interaction. In this material, the PEG/γ-CD inclusion cross-links, and the PEG crystallites accounted for the fixing and reversible cross-links, respectively. By adjusting the mass content of inclusion segments, the shape fixed at 100% and the shape recovery at >95% were observed. In addition, Zhang and co-workers designed a thermally responsive SMP utilizing H-bonding between α-CDs [19]. This responsive SMP was prepared by block copolymerization of acrylamide-(AM) and dimethyhexadecyl [2-(dimethylamino) ethyl-methacrylate] ammonium bromide (C16DMAEMA) in the presence of α-CD. The crystalline domains, induced by the H-bonding between α-CDs threaded on the hydrophobic side of the polymer chains, could reversibly melt and crystallize in response to temperature. As a result, the material showed excellent shape memory properties. Manufacturing SMPs using CDs-polymer interactions is a very simple way to endow shape memory function to classical polymers. However, to date, this kind of shape memory material has only been triggered by temperature.

22.2.3 SMPs Based on CDs-Guest Group Interactions It has been demonstrated that the ICs between CDs and various small molecular guests can be modulated by diversified stimuli. In the past decade, introducing CDs and guest moieties into polymer chains has become a very effective method for building intelligent responsive materials [20, 21]. Our group first used the CDs-guest interactions to design athermal-responsive shape memory materials [22]. As shown in Fig. 2, a pH-sensitive shape memory material was prepared by cross-linking the β-CD-modified alginate (Alg) and diethylenetriamine (DETA)-modified Alg. In a basic medium (pH 11.5), the DETA groups showed a hydrophobic feature and formed IC with β-CD. In a neutral medium, the DETA became hydrophilic due to the ionization of the amine and resulted in dissociation of the β-CD-DETA IC. This pH-dependent reversible formation/dissociation of β-CD-DETA IC switched off/on the molecular mobility so as to freeze/release the temporary shape, and the crosslinked Alg chains served as fixing netpoints for stabilizing the permanent shape. It was shown that this material can be processed into a temporary shape as needed at pH 11.5 and recover to its initial shape at pH 7.0. Both the recovery and fixity ratios were around 95%. Furthermore, this material showed good degradability and biocompatibility; thus, it had a high potential for medical applications. The interactions between CD and guests may also be sensitive to other stimuli, such as light and redox. Therefore, using host-guest interactions as molecular switches, we can design a variety of new SMPs with novel triggers other than thermal stimulus. For example, in our later study, a redox-induced SMP was

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Fig. 2 Molecular mechanism of the pH-induced shape memory effect of β-CD-Alg/DETA-Alg. (Reprinted in part with permission from Ref. [22]. Copyright 2012, John Wiley and Sons)

developed by cross-linking β-CD-modified chitosan (β-CD-CS) and ferrocene (Fc)-modified branched ethylene imine polymer (Fc-PEI) [23]. Because β-CDs are able to include in Fc groups to form ICs, but dissociate with oxidized Fc, the β-CD-CS/Fc-PEI material was able to recover to its original shape after immersion in an oxidant solution. Intriguingly, if glucose oxidase (GOD) was immobilized within the β-CD-CS/Fc-PEI network, the resultant material could show shape memory behavior in response to glucose. This phenomenon was due to the fact that GOD oxidized glucose to produce hydrogen peroxide and then oxidized Fc. Multiresponsive SMPs are also easy to realize using this strategy. For instance, a temperature-, light-, and chemical-sensitive SMP can be prepared by introducing α-CD and azobenzene (Azo) into a poly(acrylate acid)/alginate (PAA/ Alg) network [24]. The host-guest interactions between α-CD and Azo acted as molecular switches in the material. Because the formation/dissociation of α-CD Azo ICs can be modulated by temperature, light, or chemicals, this material can be processed into a temporary shape as needed and recover its initial shape under tri-stimuli. Ritter and co-workers [25] prepared another SMPs based on CD inclusion by incorporating 2-(N-(adamantan-1-yl)ureido)ethyl-methacrylate (AdMA, as hydrophobic monomer) and N,N-diethylacrylamide (DAM, as thermosensitive monomer) into the cross-linked polymer networks. The resulted hydrogel can be programmed to form a temporary shape due to the thermosensitive DAM-based segments and recover to its original shape after the addition of β-CD. This shape memory effect is due to the fact that the hydrophobic Ad domains would switch to hydrophilic ICs by the addition of a sufficient amount of free β-CD. Yan and co-workers reported a poly

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(ionic liquid) gel (PIL), which showed shape memory behavior because of a similar mechanism [26]. In summary, the diversified stimuli of CD-guest interactions provide a good opportunity to develop SMPs with novel stimulus sensitivities other than thermal induction. However, it should be noted that most SMPs based on CD ICs are hydrogels because the inclusion between CDs and guest groups always requires the help of water [27].

22.3

SHPs Based on CDs-Guest Interactions

22.3.1 General Aspect According to the self-healing mechanism, self-healing can be divided into two types, extrinsic and intrinsic. Extrinsic self-healing systems require external healing agents. The healing agents and catalyst are typically embedded in the polymer matrix in the form of microcapsules or capillary networks. When a mechanical damage was exerted to the capsules or capillary networks, they were ruptured, and the healing agents were released to the damaged region and repaired damage. This extrinsic healing method is fast and efficient, and the self-healing process is autonomous. But the healing is not repeatable at a given place. Intrinsic self-healing materials are usually based on dynamic covalent bond chemistry or non-covalent bond chemistry. Commonly using dynamic chemical reactions requires external stimulus intervention. While non-covalent bond may induce autonomous self-healing behavior since they are easily broken and regenerated at ambient conditions. CD-guest interactions are one of typical supramolecular interactions. Due to high selectivity and dynamic equilibrium of host-guest interactions, CD-guest-based SHPs have three advantages: (1) repeatable healing process requiring no external energy, (2) high healing rate, and (3) long storage time, which means the broken parts still show healing property after long time. In general, the extent of “healing” can be expressed as stress recovery efficiency. Healing efficiency = mechanical value/mechanical value (pristine). In some studies, the area of crack recovery was also used to evaluate the healing effect of materials.

22.3.2 Self-Healing Hydrogels Based on CD-Guest Interactions In 2011, Harada et al. firstly explored CD-guest interactions as self-healing mechanism [28]. This supramolecular hydrogel is formed by mixing poly(acrylic acid) (PAA) possessing β-CD as a host polymer and PAA with possessing Fc as a guest polymer. Two cut (PAA-6-β-CD /PAA-Fc) hydrogel pieces were able to rejoin and the crack sufficiently healed to form one gel due to the reformation of host-guest interaction between the side chains of both polymers (Fig. 3). Later, various polymeric hydrogels with CD-guest groups have been explored [29–31]. For example, β-CD functionalized poly(acrylamide) compolymerized with

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Fig. 3 After standing for 24 h, two cut (PAA-6-β-CD /PAA-Fc) hydrogel pieces were able to rejoin, and the crack sufficiently healed to form one gel and the schematic illustration of selfhealing. (Reprinted in part with permission from Ref. [28]. Copyright 2011, Springer Nature)

the guest modified monomer (N-adamantane-1-acrylamide) formed hydrogels, which showed immediate and autonomous self-healing with complete restoration of the initial adhesion strength at ambient conditions [30]. When polymers are composed of biodegradable matrices and biocompatible guest moieties, the resulting supramolecular hydrogels showing biodegradable or biocompatible [32, 33]. For instance, Yin et al. reported a kind of self-healing hydrogels based on self-assembly between cholesterol (Chol)-modified triblock-poly(L-glutamic acid)-block-poly(ethylene glycol)-block-poly(L-glutamic acid) ((PLGA-PEG-PLGA)-Chol) and β-CD-modified ply(L-glutamic acid) (PLGA-β-CD). The macroscopic self-healing tests and rheological measurements demonstrated that the hydrogels have outstanding self-healing capability. Furthermore, these hydrogels can degrade in vitro. The degradation time lied on the molecular weight of PLGA. These degradable and biocompatible self-healing hydrogels provide a fascinating glimpse for the applications in tissue engineering, drug delivery, and other related biomedical fields. Host-guest interactions between CDs and various guests are sensitive to external stimulus. Therefore, we can not only control the self-healing behavior by stimulus but also endow other functions through the association and dissociation of ICs with CDs and guest molecules to CDs-based hydrogels. For example, Harada group developed a kind of multifunctional stimuli-responsive supramolecular hydrogels with coloring and self-healing properties [34]. As shown in Fig. 4, these hydrogels are prepared using polyacrylamide (PAAm) as the main chain and β-CD and phenolphthalein (PP) as the side chains. These β-CD-PP AAm hydrogels exhibited a color change when heat, electric stimuli, or a competing molecular is applied at a pH less than 8, which were cause by the dissociation of β-CD-PP. In addition, the β-CD-PP AAm hydrogels showed self-healing properties due to the mobile and reversible host-guest reformation.

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Fig. 4 (a) Chemical structure of β-CD-PP AAm hydrogels. (b) Color change of β-CD-PP AAm hydrogels by heating and applying an alternating electric voltage (60 V). (c) After standing for 24 h, two cut β-CD-PP AAm hydrogels pieces were rejoined. (Reprinted in part with permission from Ref. [34]. Copyright 2017, American Chemical Society)

22.3.3 Self-Healing Composites Based on CD-Guest Interactions Up to now, most SHPs focus on restoring their mechanical properties by mending the mechanical damage [35–39]. Only few attempts have been made to materials which are able to restore other functional properties. Our groups develop a strategy for selfhealing functional materials by connecting functional inorganic particles, such as nanotubes, magnetic particles, TiO2 particles, and polymer network through CD-guest interactions [40–42]. The resulting materials combine the good mechanical properties and the functions of inorganic particles and, furthermore, show healing ability owing to the host-guest interactions. For example, a kind of conductive elastomers with autonomic self-healing properties has been prepared by using poly(2-hydroxyethyl-methacrylate) (PHEMA) as polymer matrix and connecting β-CD-modified single-walled carbon nanotubes (β-CD-SWCNTs) with polymer matrix through host-guest interactions [41]. The preparation process was shown in Fig. 5a. These composites combined the elasticity of polymer network and the conductivity of the SWCNTs had autonomic healing ability owing to the host-guest interactions. The mechanical healing efficiency reached around 90% and electrical healing efficiency reached

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around 95%. In addition, these materials also showed interesting proximity and humidity sensitivity. Many functional particles could also be modified easily by CDs; therefore, we prepared a series of functional self-healing composites using this strategy. For example, electromagnetic wave-absorbing coating is a kind of important modern materials for military and civil applications. However, coatings show a high risk of being damaged because of their specific application on the surface. The scratches on the coatings not only lead to the reduction of their lifetime but also to the deterioration of wave-absorbing properties. In order to enhance the coating lifetime, a kind of self-healing electromagnetic wave-absorbing coating was developed by introducing β-CD-Fc interactions between absorbing fillers (Fe3O4) and poly (hydroxyethyl-methacrylate-butyl acrylate) (PHEMA-BA) matrix. These p(HEMABA)-Fe3O4 coating exhibited good absorption performances over a broadband range of radar band since the wave-absorbing capacity of Fe3O4 [42]. More importantly, after being damaged, the cracks on this coating can be healed completely with the aid of small amounts of water. Simultaneously, the electromagnetic absorbing ability of the coating is restored along with the self-healing process. Using TiO2 instead of Fe3O4, a UV-blocking coating with self-healing ability was developed. TiO2 particles endowed excellent blocking properties to the coating, and host-guest interaction between particles and polymer matrix served as healing motif [43]. Using similar mechanism, we also prepared a kind of reusable xerogel containing quantum dots with high fluorescence retention [44]. It was found that sufficient polymer chains mobility, a small amount of water, and high inclusion constant of host-guest interactions were essential to the self-healing process for this kind of composites [45].

22.4

SMPs and SHPs Based on CD-Guest Interactions

Over the past decade, SHPs have attracted increasing attention because they offer enormous possibilities to improve the reliability of man-made materials. Encouraging progress in the field of SHPs has been achieved. However, damage with high degree of deformation is hard to be healed since fracture surfaces cannot autonomously come together into need closure for healing. Addressing this problem, a new concept that uses shape memory effect to assist the self-healing process has been explored [46–51]. It is a challenge to prepare materials that have both shape memory and selfhealing properties since the structural requirements of the two types of polymers are in conflict. SHPs require high chain mobility, while SMPs need a permanent network restricting chain motion. It is good way to solve this problem through introduction of two kinds of supramolecular interactions into materials. For example, Harada et al. explored two different kind of host-guest ICs of β-CD with adamantane (Ad) and Fc to bind polymers together to form a supramolecular hydrogel (β-CD-Ad-Fc gel). Both host-guest interactions contributed to the selfhealing, whereas the redox-responsive β-CD-Fc complexes acted as switches to retain and release the deformation in the shape memory test [52].

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Our groups further designed a kind of moisture and water-responsive shape memory and self-healing materials [51]. This material had semi-interpenetrating polymer networks, which contained two kinds of supramolecules, hydrogen bonds and β-CD-Ad complexes (Fig. 6a). The hydrogen bonds served as water-sensitive switches, making the material showed moisture-induced shape memory effect. The host-guest interactions acted both as permanent phases and self-healing motifs, enabling further increased chain mobility at the cracks and self-healing function. As shown in Fig. 6b, the sample was damaged and deformed as V-shape. The wound was too wide to be self-healed. As the sample was put into 100% RH environment

Fig. 6 (a) Synthetic route of the PVP/P(HEMA-CO-Ba) semi-IPNs. (b) The progress of moisturesensitive shape memory-assisted self-assisted self-healing. (Reprinted in part with permission from Ref. [51].Copyright 2017, John Wiley and Sons)

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for 3 h, the film recovered to its original shape, and the wound on both sides touched each other, and then the crack was healed due to the reformation of β-CD-Ad. Moisture or water has the advantages of being green, inexpensive, and moderate. This athermal triggered shape memory-assisted self-healing ability shows great values for biomedical and biotechnology applications.

22.5

Prospect

In this chapter, we have highlighted a burgeoning trend in SMPs and SHPs design than exploits CDs-based interactions to endow shape memory or self-healing function to the materials. The nature of host-guest interactions not only always determines the triggering method of SMPs and SHPs but also provides some other functions to the materials. The development of new trigger methods and new functionalities is desirable for broadening SMPs and SHPs applications to new territories. But several challenges still exist. For example, SMPs and SHPs based on CD-guest interactions always have relatively poor mechanical strength compared with the conventional SMPs and SHPs, since the strength of CD-guest interactions is weaker than that of chemical bonds. It is a big challenge to increase the mechanical properties of SMPs and SHPs based on CD-guest interactions to meet the requirements of applications. In addition, simplify their fabrication for realistic applications is also a challenge that requires attention.

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Part IV Supramolecular Assemblies Based on Cucurbiturils

Stimuli-Responsive Self-Assembly Based on Macrocyclic Hosts and Biomedical Applications

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Contents 23.1 23.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Macrocyclic Host Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.2.1 Cyclodextrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.2.2 Cucurbituril . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.2.3 Calixarene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.2.4 Pillar[n]arenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.3 Stimuli Types for Biomedical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.3.1 pH Responsiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.3.2 Reducing Agent Responsiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.3.3 Reactive Oxygen Species Responsiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.3.4 Photosensitive or Temperature Sensitive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.3.5 Guest Responsiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.4 Drug Delivery Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.4.1 Organic/Polymeric Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.4.2 Inorganic/Composite Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.4.3 Hydrogel Biomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.4.4 Bioimaging Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.5 Conclusion and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.6 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23.1

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Introduction

Self-assembly systems, including nanoparticles, microparticles, and hydrogels, have important biomedical applications [1–6]. Among these biomedical applications, the most widely studied are drug delivery and bioimaging. Drug delivery is generally used to solubilize, stabilize, or targeted deliver small-molecule or macromolecule W. Mao · D. Ma (*) Department of Chemistry, Fudan University, Shanghai, China e-mail: [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_27

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therapeutic drugs. Some therapeutic drugs (nucleic acid, etc.) are unstable under physiological condition and could not be internalized by cell membrane. It is necessary to deliver these drugs to achieve therapeutic efficacy. Bioimaging is another important biomedical application to visualize structure of cells, tissues, or organs. Self-assembly could be used as facile strategy to construct biomaterials with multiple components and functions to achieve desired applications. To render biomedical applications possible, it is often necessary to introduce stimuli responsiveness to self-assembly design. Stimuli are generally divided into two categories: (1) physiological stimuli, such as pH, reducing environment, and reactive oxygen species (ROSs), and (2) external stimuli, including photo-irradiation and temperature [7]. Physiological stimuli are existing in physiological or pathological tissues. External stimuli are locally applied to target tissues. Either stimuli types are used to trigger responsiveness of self-assembly systems. For bioimaging applications, self-assembly systems are designed as probes to detect physiological or pathological environment with certain stimuli. For drug delivery purposes, physiological or external stimuli are used to trigger the release of encapsulated cargo. Macrocyclic hosts are important building blocks for the construction of stimuliresponsive self-assembly systems. By using host-guest interaction as supramolecular “cross-linker,” it is possible to construct complex self-assembly systems with variable morphology, which is crucial to achieve biomedical applications. Stimuli may trigger the morphology conversion of self-assembly systems and release of encapsulated cargo. Importantly, host-guest interaction is dynamic and reversible. Macrocyclic host-based self-assembly systems may respond to biomarkers and demonstrate stimuli responsiveness based on guest displacement. Different types of macrocyclic hosts are used to construct stimuli-responsive selfassembly systems, including cyclodextrin (CD), cucurbituril (CB), calixarene (CA), pillararene (PA), and crown ether. CD is generally considered to be biocompatible compound for biomedical purpose. CD is also low cost and commercially available. As a consequence, CD is a useful macrocyclic host for drug delivery and bioimaging purposes, which may even be used for translational medicine. CB is known to be a high-affinity and selective host for suitable guests in water [8]. CB is a powerful tool to construct self-assembly systems in water. In recent years, PA has emerged as a new type of macrocyclic host to construct functional materials [9]. The above types of macrocyclic hosts are used to assemble nanoparticles, microparticles, and hydrogels. The resulting biomaterials are used for drug delivery and bioimaging applications. With the combination of stimuli responsiveness and host-guest interaction, sophisticated biomedical applications could be achieved.

23.2

Macrocyclic Host Molecules

Among various types of macrocyclic host molecules, CDs, CBs, CAs, and PAs are the most widely used in biomedical applications. As shown in Fig. 1, macrocyclic hosts are composed of different building blocks, which render them variable architectures. All the four types of macrocyclic hosts are composed of homologues with

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Fig. 1 Chemical structures and schematic diagrams of cyclodextrin, cucurbituril, calixarene, and pillararene

different numbers of building blocks and cavity sizes. Macrocyclic hosts have a wide variation in size. For example, cavity volume of CB[10] is about 10.6 times larger than that of CB[5] (870 Å vs. 82 Å) [10]. Taking advantage of different host architectures and sizes, self-assembly morphology and stimuli responsiveness could be fine-tuned to achieve desired applications.

23.2.1 Cyclodextrin CDs are a type of macrocyclic hosts composed of oligosaccharides linked by α-1,4glycosidic. Due to the oligosaccharide nature and industrial scale production of enzyme triggered starch degradation, CDs have excellent biocompatibility and low cost. CDs contain hydrophobic cavity and hydrophilic external surface, which render them to be good hosts for suitable guests. As a consequence of these major advantages, CDs are arguably the most popular macrocyclic hosts for biomedical applications. There are three common types of CDs, α-CD, β-CD, and γ-CD, which are composed of 6, 7, and 8 glucose units. These CDs share the same truncated coneresembled shape with a hollow cavity. The depth of the hollow cavity is 7.8 Å for all the three types of CDs. CDs share two interesting structural characteristics: (1) hydroxyl groups of the glucose units are pointing toward the outside at the orifice of the two ends; (2) methinic protons are located inside the cavity. CDs are soluble in water. By modifying hydroxyl groups, various CD derivatives have been developed with useful recognition and solubility characteristics. One of the most important applications for CDs is to solubilize hydrophobic pharmaceutical drugs. CD is composed of a hydrophobic cavity, which could encapsulate hydrophobic drugs by host-guest interaction. Phase solubility diagram is plotted to show the correlation between concentration of solubilized pharmaceuticals and that of host molecule. As shown in Fig. 2, there are multiple types of phase

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Fig. 2 Type of phase solubility diagram. (Adapted with permission from Ref. [3]. Copyright 1998 American Chemical Society)

solubility diagrams [3]. Type A indicates the formation of soluble complexes and type B indicates the formation of compounds with definite solubility. Type A could be further divided into subtypes AL, AP, and AN, where the pharmaceutical solubility increases linearly and deviates positively or negatively from the straight line with CD concentration, respectively. While a 1:1 stoichiometry complex leads to the AL-type diagram, higher-order complex formation results in the AP-type. The formation mechanism for the AN-type is complicated with a significant contribution of solute-solvent interaction of the complexation. B-type could be divided into subtypes BS and BI. The BS-type diagram is composed of an initial ascending portion, followed by a plateau region and then a decrease in the solubility. By comparison, the BI-type diagram is lack of the initial ascending region. The solubility phase diagram is a powerful tool to investigate the efficiency of solubility enhancement by CD. Subtypes could give us insights into complexation mechanism. To fully explore the potential of CD as pharmaceutical excipient for solubility enhancement, multiple types of CD derivatives have been developed. Hydroxylsubstituted CDs are used for solubility enhancement for pharmaceutical drugs. Among these CD derivatives, hydroxypropyl β-CD is one of the most successful clinical applications. Another clinically successful cyclodextrin derivative is sulfonated β-CD, which is Captisol® by its trade name. These CD derivatives have been developed into successful pharmaceutical excipients for oral or intravenous delivery.

23.2.2 Cucurbituril CBs are macrocyclic hosts with glycoluril as building unit. CBs have two constrictive carbonyl portals and hydrophobic cavity. Several members of CB family have decent solubility in water, including CB[5] and CB[7]. The poorly soluble CB homologues, CB[6], CB[8], and CB[10], could be solubilized with the use of acid, salt, or watersoluble guests. CBs are known to be high-affinity hosts for suitable guests in water

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(up to 1017 M
1) [11]. As a consequence of their variable sizes, CBs have selective binding toward guests with different sizes and functional groups. Therefore, CBs are excellent macrocyclic hosts to construct self-assembly for biomedical applications. CBs are prepared by one-pot reaction to yield a mixture of CB homologues, which are separated based on different solubilities in various solvents. Functionalization of CBs is relatively difficult. The general protocol is to oxidize CBs with potassium persulfate or hydrogen peroxide. The preparation is typically low yield and tedious to isolate. To tackle this challenge, CB derivatives have been developed, which are prepared by multistep organic synthesis. CB[8] could form 1:2 ternary complex with suitable guests with high binding affinity. CB[8] is capable of encapsulating methyl viologen and 2,6-dihydroxynaphthlene simultaneously. The formation of ternary complex is due to intramolecular charge transfer from electron-rich 2,6-dihydroxynaphthlene to electron-deficient methyl viologen. By choosing property guests and suitable chemical modification to guests, supramolecular cross-linking based on this ternary complex could be developed and used for selfassembly construction. The excellent recognition property of CBs renders them the ability to encapsulate drugs and dyes by host-guest interaction. Isaacs and co-workers prepared a biotinmodified CB[7] derivative by multistep organic synthesis. This CB[7] derivative retains the good binding affinity of macrocyclic CBs and could encapsulate common antitumor drug oxaliplatin [12]. Supramolecular interaction between host and oxaliplatin is discovered to be high-affinity and kinetically stable, which render this complex possible to be used for drug delivery purpose. Cell study indicates that targeting effect of biotin could significantly enhance cell uptake of oxaliplatin, when encapsulated by CB[7] derivative.

23.2.3 Calixarene CAs are considered to be the third-generation macrocyclic host after crown ether and CDs. The preparation of CAs involves the base-catalyzed condensation reaction of phenol and formaldehyde with phenolic units linked by methylene bridges at the meta-positions. CAs have variable cavity dimensions according to the number of phenolic units. CAs with even numbers (n = 4, 6, 8) are easier to synthesize and purify and have been widely investigated. By comparison, CAs with odd numbers (n = 5, 7, 9) are relatively more difficult to synthesize and less frequently used. CAs have unique unsymmetrical cone shape with an upper rim and a lower rim. Both rims could be chemically modified to achieve desired functions. The lower rim is featured with phenolic oxygen and a hydrophilic property. The upper rim is hydrophobic due to the methyl groups. Therefore, guests can be encapsulated by the cavity at both rims of CAs, which include small organic molecules, ions, macromolecules, and so on. Various forces, including hydrophobic effect, ion-dipole interaction, and hydrogen-bonding interaction, drive the complexation. CAs are relatively less frequently used macrocyclic host molecules for molecular recognition and self-assembly construction in water compared to CDs. There are

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some interesting biomedical applications of CAs based on their intriguing host-guest characteristics. Hennig et al. developed a label-free continuous enzyme assay by using macrocyclic hosts CB[7] and CX4 [13]. As shown in Fig. 3, when encapsulated inside the host cavity, fluorescent intensity of dye may increase (“switch on”) or

Fig. 3 Assay principle, chemical structures of the macrocycles, and complexation equilibria with fluorescent dyes. (a) Assay principle illustrating a switch-off and switch-on fluorescence response of macrocycle-dye reporter pairs in the course of an enzymatic transformation. (b) Complexation equilibrium of CB7 with the fluorescent dye Dapoxyl and associated fluorescence response. (c) Complexation equilibrium of CX4 with the fluorescent dye DBO and associated fluorescence response. (Adapted with permission from Ref. [13]. Copyright 2007 Springer Nature)

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decrease (“switch off”). By adding guest, dye could be displaced out of the host cavity, which reverses fluorescent “switch on” or “switch off.” Based on this indicator displacement principle, fluorescent analytical method based on host-guest chemistry was developed. Two host-dye complexes were used for the assay: CB[7]-Dapoxyl complex as a “switch-on” indicator and p-sulfonatocalix[4]arene-DBO complex as a “switch off” indicator. These two supramolecular complexes were used to monitor the enzymatic process of amino acid decarboxylation catalyzed by decarboxylase. Catalytic product is a stronger guest for macrocyclic host and could displace encapsulated dye, which results in change in fluorescence intensity. This method was successfully applied to continuously track decarboxylase enzymatic activity. Robustness of the assay was tested based on CX4 sensor system in the presence of different buffers and common additives as well as its dependence on the dye/host ratio by varying the dye concentration. It was discovered that in all cases, three- to eightfold increase in fluorescence was observed, indicating that the enzyme was catalytically active. This new assay concept is complementary to other assays involving membrane channels and calorimetric microarrays and offers a promising alternative to the broad use of individually raised and subsequently labeled antibodies. Considering the vast amount of water-soluble as well as organic-soluble synthetic receptors with different affinities, this assay principle could also be applied to other systems and sensing purposes. Fluorescent dye-based indicator displacement assay was pushed forward to cell study. As shown in Fig. 4, Norouzy et al. used p-sulfonatocalix[4]arene and N, N0 -dimethyl-9,90 -biacridinium dinitrate (lucigenin, LCG) as a “switch off” reporter pair [14]. Biological and pharmaceutical molecules acetylcholine, choline, and protamine were used as analytes. Reporter pair and analyte were sequentially uptaken by live cells. By imaging cells with fluorescence microscopy, it was discovered that fluorescence intensity enhanced significantly when analyte was uptaken. It was proposed that encapsulated dye was displaced by analyte. This work demonstrated that indicator displacement assay could be a powerful tool to detect suitable analyte in live cells. To monitor concentration and distribution of biological or medicinal molecules is important and yet challenging. The supramolecular method reported in this work indicated guest displacement might offer new route to achieve this goal in a noninvasive and continuous manner.

23.2.4 Pillar[n]arenes PAs are a new type of macrocyclic host molecules with pillar-shaped architecture [9]. PAs are generally prepared by one-pot condensation reaction of pmethoxybenzene and paraformaldehyde with methylene bridges on para-positions. PAs of variable sizes have been developed with PA[5]-PA[7] as the most frequently used homologues. PAs are hydrophobic macrocyclic host molecules. By introducing carboxylic acid groups or amino groups to PAs, water-soluble PAs or WPs have been developed with high solubility in water. WPs could encapsulate small-molecule guests by multiple

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Fig. 4 The uptake of analytes into cells preloaded with the macrocycle-dye complex results in displacement of the dye from the macrocycle and an associated fluorescence increase. (Adapted with permission from Ref. [14]. Copyright 2014 John Wiley and Sons)

forces, including hydrophobic effect of the hollow cavity and ion-dipole interaction of the carboxylic acid or amino groups. The interplay of multiple driving forces renders WPs to be high-affinity host molecules for suitable guests. For example, the value of Ka for complex formed between WP7 and methyl viologen is up to (2.96  0.31)  109 M
1 in water [15]. One interesting aspect of WP is its intrinsic pH responsiveness. As shown in Fig. 5, Li et al. used WP6 with carboxylic acid groups to targeted deliver antitumor drug oxaliplatin to acidic microenvironment of tumor [16]. Carboxylic acid groups are deprotonated under neutral condition and protonated at acidic pH. Therefore, oxaliplatin could be encapsulated by WP6 and controlled released when reached tumor tissues. This WP6-based nano-container was used to deliver oxaliplatin in vivo and was discovered to enhance the efficacy of oxaliplatin. Targeted delivery of chemotherapeutic agents is generally achieved by nanomedicine, which could encapsulate and controlled release cargo in target tissues. By comparison, this targeted delivery by nano-container

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Fig. 5 Schematic illustration of the DDS effect expected to be operative in the case of a 1:1 mixture of OX and CP6A. (Adapted with permission from Ref. [16]. Copyright 2017 Royal Society of Chemistry)

is a simple and effective design, which ensures complete cargo release in tumor tissues.

23.3

Stimuli Types for Biomedical Applications

The purpose of introducing stimuli responsiveness to self-assembly systems for biomedical applications depends on the specific motive. Generally speaking, for drug delivery applications, the purpose is to overcome biological barriers [17]. The existence of multiple biological barriers makes drug delivery by systemic administration challenging. Among these barriers, stable encapsulation during circulation and efficient cell internalization are two of the most challenging tasks. On the other side, stimuli responsiveness is often used to trigger spectroscopic change for bioimaging applications.

23.3.1 pH Responsiveness Acidic pH is a common pathological indication in tumor and inflammatory tissues [18]. Endosomal compartment is also known to be acidic. Selective pathological and

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physiological conditions are mildly acidic, usually in the range of pH 6.5–5.5. pH responsiveness is used to trigger the controlled release in pathological tissue or after internalized by endocytosis. Therefore, it is often used for targeted delivery of pharmaceutical drugs to pathological tissues. pH responsiveness is generally based on two mechanisms: (1) protonation of carboxylic acid or amino groups at acidic pH, which triggers the release of cargo, and (2) acid-degradable linkers, which release drug under acidic environment. Compared to carboxylic acid group, there are primary, secondary, and tertiary amino groups with variable pKa value, which could be fine-tuned for desired controlled release characteristics. As for acid-degradable linkers, there are multiple choices, including acetal, hydrazine, silyl ether, and so on. By introducing different substitutes to acid-degradable linkers, the degradation and release rate could be adjusted accordingly.

23.3.2 Reducing Agent Responsiveness Reducing agents are widely existing in physiological or pathological environment [19]. For instance, there is reducing agent glutathione (GSH, 5–10 mM) inside animal cells. By comparison, extracellular environment has negligent level of GSH. This significant difference in GSH level could be used to trigger controlled release. Disulfide bond is the most widely used reducing agent-responsive linker, which may rapidly degrade in the presence of GSH and other reducing agents. Another important reducing agent-responsive linker is thioester. Stimuli-responsive DDSs could respond to GSH and release cargo by carrier degradation or prodrug conversion.

23.3.3 Reactive Oxygen Species Responsiveness During vital biological processes, a number of species are produced by the body derived from molecular oxygen. One class of these species is referred to as “reactive oxygen species (ROS),” including the superoxide, hydroxyl and peroxyl radical, hydrogen peroxide, singlet oxygen, and hypochlorous acid/hypochlorite. The major ROS production route is the mitochondrial respiration process. ROS are involved in a wide range of physiological and pathological processes, including signal transduction, inflammation, carcinogenesis, and neurodegenerative injury [20]. It is an interesting topic to design probes for the detection of ROS. Preferably, category of ROS is to be determined. Drug delivery systems (DDSs) targeting pathological ROS is of great importance. Tumor and inflammatory tissues are often overexpressed with ROS. Therefore, ROS-responsive probes or DDSs are important for bioimaging or targeted drug delivery to tumor or inflammatory tissues. A variety of chemical linkers responsive to ROS are used in biosensor or DDS design.

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23.3.4 Photosensitive or Temperature Sensitive Photo-irradiation is a type of responsiveness that could be triggered externally. Photo-irradiation could also be used to heat up target tissues with the assistance of photosensitizer. Compared to physiological stimuli, physical stimuli are capable of being applied in a local region and turned on/turned off by remote control on demand. Azobenzene is one of the most frequently used photo-switches. By applying photo-irradiation in UV or visible wavelength, azobenzene could be switched between cis- and trans-configurations. The transition in configuration may lead to cargo release. Small-molecule photosensitizers, such as porphyrin, or some nanoparticles, such as gold nanorods, could be used to heat up target tissues.

23.3.5 Guest Responsiveness For self-assembly systems based on host-guest interaction, in addition to the common stimuli types as mentioned above, guests could also be used to trigger responsiveness. Guest displacement has been used to monitor biological process with fluorescent indicator. The same design principle has been applied to drug delivery, in which encapsulated drug is displaced by guest introduced into the system. While externally introduced guest displacement only works for in vitro study, DDSs have been successfully designed to release cargo in vivo by responding to biomarker, such as ATP.

23.4

Drug Delivery Applications

To achieve efficacy of therapeutic agents, it is often necessary to develop DDSs to solubilize, stabilize, or targeted deliver pharmaceutical drugs. Small-molecule drugs, including antitumor drugs, antimicrobial drugs, and regenerative drugs, are involved in drug delivery. In recent years, nucleic acid, proteins, and other biomacromolecule drugs have emerged as another type of highly important pharmaceutics for drug delivery. Depending on types of target tissues, drug delivery routes are composed of subcutaneous administration, intravenous injection, transdermal delivery, and so on. Multiple biological barriers need to be overcome. Take intravenous administration as an example, first, DDSs have to withstand blood circulation and avoid quick clearance. Next, enhanced accumulation of pharmaceutical drugs in target tissues is desired. Subsequently, DDSs are designed to be efficiently internalized by cells and quickly release drug to achieve required efficacy. As for some types of drug delivery, there are additional biological barriers to overcome. For example, to deliver pharmaceutical drugs into brain, blood-brain barrier (BBB) has to be penetrated. DDSs are divided into several categories, including organic/polymeric nanoparticles, inorganic nanoparticles, and hydrogel biomaterials. Organic and polymeric nanoparticles are either self-assembled or cross-linked, which could encapsulate

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drugs by noncovalent interaction or conjugate drug by prodrug strategy. Inorganic nanoparticles could easily prepare with versatile sizes and shapes, which could combine with organic or polymeric materials to form composite nanomaterials. Hydrogel biomaterials are able to be implanted into target tissues and programed to release encapsulated drugs in a sustained manner. Macrocyclic hosts are generally used as building blocks in the construction of DDSs. The use of host-guest chemistry could help design complex DDSs. Stimuliresponsive groups are incorporated into DDS to realize required drug delivery efficacy. By taking advantage of dynamic nature of host-guest chemistry, we may introduce complex stimuli responsiveness to DDS design.

23.4.1 Organic/Polymeric Nanoparticles Organic or polymeric nanoparticles are self-assembled or cross-linked to maintain nanoscale size. Several organic or polymeric materials are approved for medical use by the Food and Drug Administration (FDA). Therefore, organic/polymeric nanoparticles are the most widely used type of nanoscale DDSs for clinical use. Some of the best examples include liposome nanoformulation for doxorubicin and paclitaxel. pH-responsive CD-based nanoparticles were reported by He et al. [21]. As shown in Fig. 6, α-CD was functionalized with acetal to yield acetalated α-CD by hydroxyl groups. Acetalated α-CD was hydrophobic compound, which could be conveniently processed and fabricated into nanoparticles by microemulsion. Hydrophobic antitumor drug paclitaxel was loaded into nanoparticles during microemulsion process. Acetalated α-CD was a pH-responsive biomaterial, which could degrade under mildly acidic condition to release encapsulated pharmaceutical drugs. The resulting nanoparticles were designed to release cargo in endosome and lysosome when internalized via endocytosis. Biocompatibility of blank acetalated α-CD nanoparticles were evaluated by body weight and organ index. Both experiments

Fig. 6 Schematic illustration of the construction of pH-sensitive PTX nanoformulation based on acetalated a-CD (Ac-aCD). (Adapted with permission from Ref. [21]. Copyright 2013 Elsevier Ltd.)

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confirmed that these nanoparticles had no acute toxicity and were safe to be used for drug delivery. Next, paclitaxel-loaded nanoparticles were used against multiple tumor-cell lines to determine their bioactivity. Results confirmed that nanoparticles were efficient drug delivery platform to deliver drug to B16F10, HeLa, HepG2, MCF-7, and MDA-MB-231 cells. Moreover, paclitaxel-loaded nanoparticles show increased in vitro efficacy to PTX-resistant cancer cells. Lastly, paclitaxel-loaded nanoparticles were used on tumor-bearing mice model and discovered to suppress tumor growth. As a consequence, acetalated α-CD was a pH-responsive nanomaterial for the delivery of antitumor drugs in vitro and in vivo. Polyvalency is a useful strategy to assemble stable nanoparticles. Namgung et al. reported nano-assembly based on poly-CD and poly-paclitaxel for antitumor therapy [22]. Authors used poly-CD as a biocompatible biomaterial. Polyvalency supramolecular interaction between CD and paclitaxel assisted the formation of nanoparticles, which were further stabilized by hydrogen-bond between CDs. These nanoparticles could disassemble due to dilution, salt, or free CD competition. Paclitaxel was conjugated to polymer backbone by ester bond, which could degrade to release free paclitaxel triggered by esterase. These nano-assemblies were evaluated against several tumor-cell lines in vitro and demonstrated potent bioactivity. For MCF-7 cells, nano-assemblies had an IC50 of 120-fold lower compared to that of free paclitaxel. Before nano-assembly was used for in vivo study, hemolysis assay was carried out to confirm the biocompatibility of these nano-assemblies. Then, nanoassemblies were used against two tumor models: human colon cancer HCT-8 cells and human breast cancer MDA-MB-231 cells. For both tumor models, nanoassemblies had good efficacy with high suppression effect toward tumor volume growth. Biodistribution study was carried out with MCF-7 or MDA-MB-231 tumorbearing mice. It was discovered that for both tumor models, nano-assemblies were accumulated and cleared by the liver, kidney, and gastrointestinal tract. There were decent accumulations of paclitaxel in tumor with a relatively higher tumor accumulation for MDA-MB-231 tumor model. This work demonstrated the interplay of host-guest interaction and multivalency for drug delivery applications, and supramolecular interaction is a powerful tool to conveniently construct nanoscale DDSs. Zhang et al. took advantage of paclitaxel-conjugated CD to assemble photocontrolled reversible microtubule [23]. As shown in Fig. 7, microtubule (MT) assembly was obtained by mixing CD derivative (PTX-CD) and paclitaxel-modified photochromic arylazopyrazole (PTX-AAP) as a result of host-guest interaction between CD and AAP. MTs were photo-switched by UV-irradiation due to configuration transition of azobenzene. Self-assembly of PTX-CD and PTX-AAP could form different types of nanoscale architectures, which were carefully characterized by transmission electron microscopy (TEM). Fluorescence-dye-staining assays were exploited to study the complexation-induced intertubular aggregation at the cellular level. Normal MTs were uniformly distributed in the whole cell. By contrast, nanoparticulate aggregates of approximately 4–8 μm were formed around cell nuclei in the trans-MT group, which could trigger the cell death. Therefore, photocontrolled microtubule morphology change could be used to switch on or switch off cell cytotoxicity, which is a new strategy for disease diagnosis and treatment.

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Fig. 7 Schematic and molecular structures of (PTX-AAPPTX-CD)@MT ternary supramolecular assembly. (Adapted with permission from Ref. [23]. Copyright 2018 John Wiley and Sons)

Overproduction of ROS is associated with pathogenesis, development, and progression of aging and various diseases (cancer, diabetes, inflammatory, cardiovascular, degenerative illness). Nanocarriers responsive to overexpressed ROS could be useful drug delivery vectors. Zhang et al. developed biocompatible ROS-responsive nanoparticles as superior drug delivery vehicles [24]. As shown in Fig. 8, ROS-responsive β-CD was synthesized by conjugating 4-phenylboronic acid pinacol ester onto hydroxyl groups. The obtained material was processed into

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Fig. 8 Material synthesis and nanoplatform engineering. ROS-responsive β-cyclodextrin (β-CD) is synthesized by conjugating 4-phenylboronic acid pinacol ester (PBAP) onto hydroxyl groups. The obtained material (Ox-bCD) can be processed into core-shell nanoparticles by either selfassembly or self-assembly/nanoprecipitation approaches. Thus engineered nanocarriers may be hydrolyzed into parent β-CD molecules upon exposure to ROS. (Adapted with permission from Ref. [24]. Copyright 2014 John Wiley and Sons)

core-shell nanoparticles by either self-assembly or self-assembly/nanoprecipitation approaches. The resulting nanoparticles were evaluated for their responsiveness to ROS. It was discovered that low concentration H2O2 would result in the degradation of nanoparticles. Subsequently, biocompatibility of nanoparticles was evaluated in vitro and in vivo. It was confirmed that nanoparticles were nontoxic to multiple cell lines and on mice model. Also, no inflammatory reaction was observed. Because CD is commercially available and inexpensive compound, these ROS-responsive DDSs may be useful targeted delivery vectors. Self-assembled nanoparticles were also important drug delivery vectors for nucleic acid macromolecular drugs. Davis et al. reported the use of CD-based selfassembly DDS for the delivery of small-interfering RNA (siRNA) in vivo [25]. As shown in Fig. 9, nanoparticulate DDS was composed of (1) a linear, CD-based polymer (CDP), (2) a human transferrin protein (TF)-targeting ligand displayed on the exterior of the nanoparticle to engage TF receptors (TFR) on the surface of the cancer cells, (3) a hydrophilic polymer (PEG used to promote nanoparticle stability in biological fluids), and (4) a siRNA designed to reduce the expression of the RRMs (M2 subunit of ribonucleotide reductase). Self-assembly of nanoparticles was based on host-guest interaction between CD and adamantane (AD). These siRNA-loaded nanoparticles were used for systemically administration in humans. Patient tumor samples confirmed the accumulation of nanoparticles in tumor cells. Gene expression assay showed a successful siRNA delivery to tumor tissues. mRNA expression reached up to 76% silencing ratio, and RRM2 protein expression was silenced up to 77%. Silencing of RRM2 and TFR protein expression was confirmed by IHC and

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Fig. 9 Schematic representation of the targeted nanoparticles. The polyethylene glycol (PEG) molecules are terminated with adamantane (AD) that form inclusion complexes with surface cyclodextrins to decorate the surface of the nanoparticle with PEG for steric stabilization and PEG-TF for targeting. (Adapted with permission from Ref. [25]. Copyright 2010 Springer Nature)

Western blotting assays. Finally, siRNA gene silencing mechanistic study was carried out. siRNA-induced mRNA cleavage fragment was detected by 50 -RLM-RACE assay with PCR amplification. This was the first example of successful gene silencing based on siRNA by systemic administration in humans, which demonstrated the powerful drug delivery tool of self-assembly systems based on host-guest interaction. The use of nucleic acid as therapeutic drug is of great importance for gene therapy, which is the key for personalized treatment for cancer, diabetes, and other major diseases. Macrocyclic host molecule played a major role in the delivery of nucleic acid, which showed that host-guest chemistry might be a key player in gene therapy and other novel disease treatment methods. Other types of macrocyclic host molecules have been used to construct stimuliresponsive organic/polymeric DDSs. Gao et al. used biomarker displacement activation as a general host-guest strategy for targeted phototheranostics [26]. Amphiphilic CA was used to construct nanoscale self-assembly system. Photosensitizer was loaded into CA cavity with high-affinity host-guest interaction (Fig. 10). As a result of photo-quenching effect of CA, photosensitizer was on the “OFF” state when encapsulated by CA. Tumor tissues were reported to overexpress ATP, which could reach a level of 100 μM, more than 104-fold higher than that of normal tissues ( Cel and Gly8 > Gly5, which was also

Fig. 8 Molecular structures of amphiphilic glyco-resorcinarenes Mal8, Cel8, Lac8, Mal5, Cel5, and Lac5, schematic illustration of phosphate-induced agglutination of GNSs formed by Mal8, Cel8, and Lac8, and the hierarchical increasing of GNSs to glycoviruses and their aggregates in the presence of DNA. (Reprinted with permission from Ref [13]. Copyright 2015 Royal Society of Chemisty)

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confirmed by TEM observation. Moreover, via evaluating the cell transfection experiments of all the prepared glycovirus, they observed that the Lac8 and Lac5 viruses were remarkably HepG2-selective and their activities were two orders of magnitude higher than expected on the size basis. This was mainly because that the receptor-mediated specific path involving the asialoglycoprotein receptors on the surfaces of hepatic cell. Soon afterwards, they also utilized the amphiphilic glycoresorcinarenes to modify the surface of lipophilic TOPOQDs, thus forming the QDconjugated sugar particles (diameter~15 nm) [41]. It was demonstrated that the efficiency of these sugar particles marking endosomes was much more and much less than the pure GNSs (~5 nm) and the virus-like DNA-GNP conjugate (~50 nm) respectively, meaning that the size control of virus is of paramount importance for designing artificial molecular delivery. Casnati and coworkers have developed a series of various approaches to achieving sugar-targeted drug delivery on the basis of multivalent carbohydrates built on the calixarene scaffolds. For example, as a proof-of-concept, they prepared the calixarene-supported glucosylated bolaamphiphile (BA) which inserted in the bilayer of 1,2-dioleoyl-snglycero-3-phosphocholine (DOPC) liposomes, forming multivalent glucoside-covered liposomes [42] (Fig. 9). These liposomes were capable of incorporating calcein in the internal aqueous compartment of liposomes. As recorded by fluorescence spectra, it was found that the presence of glucosylated BA reduced the rate of calcein release, to ~50%, compared with the liposomes formed by DOPC alone, due to the proposed rigidifying effect of glucolated BA on the lipid bilayer. This raised the promising potential for developing a sustained release formulation. Moreover, the enhanced and stronger lectin-sugar binding affinities of liposomes incorporating glucolated BA were observed, compared to that of single molecules. Fluorescence experiments revealed glucoside-incorporated liposomes efficiently induced the fluorescence quench of FITC-labeled ConA via CPRs at low concentrations, without restoring the fluorescence after the addition of free glucose. Turbidity experiment also confirmed this higher affinity of the observed interactions. It will be very worthy of seeing whether this system can be explored further and assessed in cell or even living experiments. After that, they synthesized a new kind of mannoside-functionalized amphiphilic glycocalixarene (Calix-Man) which beared four mannoside groups on the top rim and the same numbers of alkyl chains on the other side [43] (Fig. 10a). And this amphiphilic Calix-Man could be modified on gold nanoparticles (AuNPs) capped by dodecanethiol, via the noncovalent modification strategy. By using the method of chloroform-to-water phase transfer, the hydrophobic backbone and alkyl chains of amphiphilic Calix-Man intercalated the hydrophobic dodecanthios surfactant layer driven by the effective and stable hydrophobic interactions, imparting water solubility to the glyco-nanocomplex (Au–Calix-Man) by taking advantage of their hydrophilic mannoside units (Fig. 10b). This innovative approach for constructing glycocalixarene-functionalized AuNPs avoided the tedious synthesis of glycocalixarene calixarenes with thiol groups, thus resulting in a one-step sugar modification of nanoparticle with excellent stabilization in aqueous solution. Considering the overexpression of mannose receptor on some tumor cells, such as

Fig. 9 Chemical structures of glucosylated bolaamphiphilies (BA) and the schematic illustrations of glucosylated BA and the interaction of glucoside incorporated liposomes and ConA. (Reprinted with permission from Ref [42]. Copyright 2013 Royal Society of Chemisty)

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Fig. 10 (a) Chemical structures of amphiphilic Calix-Man and Mono-Man. (b) Schematic illustration of Au–Calix-Man construction through chloroform-to-water phase transfer. (c) Quantified nanoparticle statistic up taken by HeLa cells without (red bars) and with dextrans (blue bars). (d) Schematic representation of enhanced targeting efficiency of the mannose receptor by simple multivalent interaction between Au–Mon-Man NPs and a target cell (left panel) versus clustered multivalent interaction between Au–Calix-Man NPs and a target cell (right panel). (Reprinted with permission from Ref [43]. Copyright 2014 Royal Society of Chemisty)

HeLa, the uptake of Au–Calix-Man by Hela cells was investigated. As a control experiment, the AuNPs were functionalized by amphiphilic Mon-Man (a single phenol group bearing one mannoside unit) and amphiphilic polymer, respectively. After incubating with HeLa cells for 2 h, separately, they found that, on the one hand, the mannose-free Au–PMA were internalized by the cells through a less efficient passive endocytosis with poor influence after the addition of dextran, and on the other hand, the cellular uptake for Au–Calix-Man was much higher than that for Au–Mon-Man, with remarkable influence after the addition of dextran (Fig. 10c). This result not only indicated the significant enhancement of bind ability between receptors overexpressed on cell surface and the clustered multivalent glyconanoparticles but also revealed the macrocyclic calixarene structure plays an important role in improving the multivalent interactions with sugar receptors (Fig. 10d).

35.5

GNSs Fabricated via the Self-Assembly of Saccharide-Containing Pillar[n]arenes-Based Amphiphiles

Pillar[n]arenes reported in 2008 are a very young member of macrocyclic hosts with a unique rigid pillar architecture due to the linkage of methylene ( CH2 ) bridges at para-positions of 2,5-dialkoxybenzene rings [44]. Thanks to their easy and

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Fig. 11 (a) Synthetic route and molecular structure of sugar-functionalized macrocyclic amphiphile. (b) Schematic illustration of the self-assembly process of sugar-functionalized macrocyclic

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selective chemical modification and their guest binding via host-guest in both of water and organic solvents, pillar[n]arenes are becoming promising and preferred candidates for the formation of multifunctional, smart, and complex supramolecular nanostructures used in different areas [45]. For example, the group of Huang has systematically studied the molecular recognition, supramolecular self-assembly, and supramolecular polymers based on the pillar[n]arenes [46]. However, to date, the pillar[n]arene-based glycomaterials have been rarely reported. In 2013, the research team of Nierengarten firstly reported a multivalent glycoclusters via functionalizing pillar[5]arene with ten mannosides at the two sides via click reactions [47]. And they found that the pillar[5]arene-based glycoclusters has exhibited a promising candidate as an inhibitor of the adhesion of an uropathogenic Escherichia coli strain to red blood cells. Later, just several related works were reported. Almost at the same time, Huang and coworkers designed and prepared a new sugar-functionalized amphiphilic pillar[5]arene bearing five galactosides units at one side as hydrophiphilic portion and five alkyl chains at the other side as hydrophilic part [48] in Figure 11a. After dispersing this sugar-functionalized amphiphilic pillar [5]arenes in water, as observed by TEM experiments, it was observed that they first self-assembled into bilayer glyco-vesicles with average diameter 150 nm. It was noteworthy that the vesicles covered by galactoside gradually transformed into multilayered glyco-nanotubes with several micrometers length in aqueous solution via standing them one week (Fig. 11b-d), driven by the CCIs of inter-vesicles and the van der Waals interactions confirmed by Fourier transform infrared spectroscopy (FT-IR). Then, they utilized the glyco-nanotubes to study cell-cell interactions via biomimicking glycalyx structures. As expected, the glyco-nanotubes like cell glues could effectively agglutinate E. coli through strong multivalent interaction between carbohydrate on nanotube surface and proteins on bacteria surface (Fig. 11e, f).

35.6

GNSs Fabricated via the Self-Assembly of Saccharide-Containing Metallacycles-Based Amphiphiles

Over the past decade, discrete organoplatinum(II) metallacycles have received tremendous attention for the fabrication of diversiform and functional hierarchical assemblies via a combination of coordination-driven self-assembly and other noncovalent interactions, due to their precise and rich architectures [49, 50]. For example, diamond, triangular, or hexagonal architectures with different size have been easily prepared through selecting different building blocks to form the metalligand coordinated bonds. Comparing with the traditional covalent bond of synthetic ä Fig. 11 (continued) amphiphile. Representative TEM images of sugar-functionalized macrocyclic amphiphile in water after standing five min (c) and one week (d). Representative microscopic photograph (e) and TEM image (f) of E. coli agglutination incubated with glyco-nanotubes. (Reprinted with permission from Ref [48]. Copyright 2013 American Chemical Society)

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macrocycles, the dynamic and directed supramolecular metal-ligand bond of metallacycles not only offers considerable synthetic advantages such as few steps, high efficiency, and fast and facile production of the defect-free designed structures but also provides precise control over the numbers, locations, and relative orientations of the functional moities in the hierarchical constructs. The structures of supramolecular metallacycles have been solidly proven by NMR, MS, and even single crystal. To date, many efforts have been made to construct the well-defined hierarchical assemblies through hierarchical self-assembly. However, saccharide-functionalized amphiphilic metallacycles with a metallacyclic core as hydrophobic part and the modified saccharide as hydrophilic unit have been rarely studied. The first case of saccharide-functionalized amphiphilic metallacycles was finished by Stang and coworkers in 2014 [51]. They utilized the strategy of coordination-driven selfassembly toward the construction of different saccharide-functionalized metallacycles with different architectures (rhomboid and hexagons), sugar kinds (glucoside, mannoside, galactoside, and lactoside), and numbers (2 and 3), via selecting different saccharide-containing donors and acceptors. It was a pity that they did not further study the self-assembly behaviors of these novel metallacyles in water. Subsequently, using the similar method, the same group constructed a hexagonal metallacycles with three pendant methyl viologen (MV) units. It is known that a cavity of CB[8] is capable of binding one MV unit and one naphthalene group via host-guest interactions, forming 1:1:1 supramolecular heteroternary complexes. Then, they obtained the amphiphilic saccharide-functionalized metallacycles via mixing MV-containing metallacycles, cucurbit[8]uril, and galactosidefunctionalized naphthalene with molar ratio 1: 3: 3 (Fig. 12a). As proved by TEM, these galactoside-functionalized metallacycles further self-assemble into welldefined glyco-nanospheres and tapes, depending on the concentration, driven by the hydrophobic and π π interactions of metallacycles in water [52] (Fig. 12b, c).

35.7

Conclusion

In summary, the important roles of carbohydrate multivalent effect in nature and the remaining questions about the mechanisms involved in multivalent interactions, and the request of various functional glycomaterials will continuously keep the carbohydrate-related fields as hot topic of sustained fundamental research in future. It has been widely demonstrated that the well-defined supramolecular GNSs have become the most promising candidates for amplifying and modulating the biological information encoded by multivalent carbohydrates. And the selective, flexible and precise chemical modifications of the macrocycles enabled precise control of the saccharidecontaining macrocyclic amphiphiles. Based on these, tremendous progresses of the fabrication of GNSs from amphiphilic saccharide-containing macrocycles have been made during the past decades. Various well-defined GNSs, such as micelles,

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Fig. 12 (a) Preparation of discrete hexagonal metallacycles with three pendant MV units and schematic illustration of formation and further self-assembly of sugar-containing metallacycles in water. Representative image of sugar-containing metallacycles assemblies in water after standing for 1 week with different concentrations: (b) 1.7 μM and (c) 3.4 μM. (Reprinted with permission from Ref [52]. Copyright 2018American Chemical Society)

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vesicles, cylinders, and tubules formed by macrocyclic amphiphiles, have been produced to serve as different applications via multivalent enhanced CPRs, including biomimicry of glycocalyx, biomembranes, anticancer target, antibacterial and immunotherapy, and so on. Besides, the assembly and disassembly behaviors can be controlled by some physical stimulus such as pH, CO2, and light through taking advantage of the dynamic nature of noncovalent interactions of host-guest interactions between macrocycles and guest molecules, and coordination interactions. As for self-assembly of saccharide-containing macrocyclic amphiphiles, it is still remaining big challenges to construct diversiform and even precise supramolecular assemblies compared with that formed by some biomacromolecules such as DNA and proteins. As mentioned above, there are two great superiorities of saccharide-containing macrocyclic amphiphiles compared to carbohydrate amphiphiles. Firstly, they possess the tunable, well-defined and even precise architectures. Secondly, they can be easily modified or functionalized via host-guest recognitions. The former means that it is totally possible to achieve diversiform and controllable morphologies like that from DNA and proteins through precisely controlling the architectures of saccharide-containing macrocyclic amphiphiles. The later provides a unique strategy to further decorate and functionalize the assemblies for various applications in different areas without tedious synthesis, via host-guest interactions. Thus, we believe there is still plenty of room for the macrocyclic amphiphiles-containing carbohydrates to be utilized in the construction of sophisticated glyco-assemblies with rich architectures, multifunctional properties, and wide applications.

35.8

Cross-References

▶ Functionalized Cyclodextrins and Their Applications in Biodelivery ▶ Nanoscaled Cyclodextrin Supermolecular System for Drug and Gene Delivery ▶ Stimuli-Responsive Self-Assembly Based on Macrocyclic Hosts and Biomedical Applications Acknowledgments We thank financial support of CPSF (No. 2017M621354 and 2018T110335) for generous financial support.

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In Vivo Self-Assembly of Polypeptide-Based Nanomaterials

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Man-Di Wang, Yan-Qing Huang, and Hao Wang

Contents 36.1 36.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Functional Peptides and Driving Forces of Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36.2.1 Category of Functional Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36.2.2 Driving Forces of Peptide Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36.3 In Vivo Self-Assembled Peptide-Based Nanomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36.3.1 The Properties of “In Vivo Self-Assembled Peptide-Based Nanomaterial” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36.3.2 In Situ Peptide Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36.3.3 Polymer-Peptide Conjugates (PPCs) Self-Assembly In Vivo . . . . . . . . . . . . . . . . 36.4 Challenge and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36.1

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Introduction

Polypeptide is a chain consisting of no more than 50 amino acid monomers linked by peptide bonds. Compared with proteins, peptides lack complex stereochemical structures but perform functions vital to biological systems. With non-covalent interactions, peptides can self-assemble into two-dimensional or three-dimensional structures. M.-D. Wang · H. Wang (*) CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, China University of Chinese Academy of Sciences (UCAS), Beijing, China e-mail: [email protected] Y.-Q. Huang Beijing Academy, Beijing, China © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_42

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The wide existence of peptides in human bodies makes them have intrinsically biological functions, such as bioactive, biodegradable, and biocompatible. Those features have been deemed to be the building blocks of biological materials [1]. During the half-century of research and development, thousands of peptide sequences have been applied in the field of biopharmaceutics. They can increase the targeting of drug delivery, promote the half time of small molecules in circle system, express as a therapeutic drug, etc. Different functional short peptides can combine into a long peptide chain and express a tandem function [2, 3] (Fig. 1).

Fig. 1 The principle of designing in situ selfassembled peptide-based nanomaterials and their applications

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Another highlight research about peptides is their superstructure. From now on, several kinds of peptide-based structures, such as nanotube, nanofibril, nanoparticle, nanowire, etc., are designed and applied to perform special functions [4, 5]. The driving forces, mainly non-covalent interaction, include hydrogen bonding [6], π π stacking interactions [7], hydrophobic-hydrophilic interactions [5], and ionic bonding [8]. These highly ordered peptide nanostructures can be used in bioimaging, cancer therapy, tissue engineering, antibacterial, and regenerative medicine field [1]. For example, Wang and his co-workers utilized nanofibrils to enhance bioactive molecule retention at disease sites [9]. Joel H. Collier and his co-workers used Q11 self-assembling peptides to co-assemble into a “β tail” structure to deliver multiple proteins [10]. Samuel I. Stupp and his co-workers designed a peptideamphiphile self-assembly induced by pH to make a nanofibril scaffold reminiscent of extracellular matrix [11]. Recently, a concept “in vivo self-assembly” has been proposed. Compared to the in vitro self-assembly, in vivo peptide self-assembly has a structural transformation induced by other in vivo microenvironment factors. This strategy can help small molecules to in situ form nanostructures and at the same time escape biological barrier. Yang and his co-workers utilized phosphatase and glutathione (GSH) to realize tandem self-assembling in liver cancer cells [12]. Wang and his co-workers designed a three-module peptide to realize the morphological transformation from nanoparticles to nanofibrils [2]. The detailed principle and mechanism will be analyzed in section “In Vivo Self-Assembled Peptide-Based Nanomaterials.” In this chapter, we will focus on in vivo self-assembled peptide-based nanomaterials and explain their design principles and applications.

36.2

Functional Peptides and Driving Forces of Self-Assembly

36.2.1 Category of Functional Peptides As building a tower needs brick, concrete, and rebar, an applied peptide chain should always be made up of different functional peptides. The scientists need to select various functional peptides so that they can realize different aims. In this section, we focus on the “in vivo self-assembly” relative functional peptides and separate them into targeting and responsive peptide self-assemblies (section “Driving Forces of Peptide Self-Assembly” followed by the driving forces of self-assembly) and give a detailed introduction.

36.2.1.1 Targeting Peptides To some extent, targeting peptides, instead of monoclonal antibodies, can target cell surface ligand receptors. However, antibodies, which essentially belong to a family of proteins, have a large molecular weight. And the cost of production limited its clinical application scale. The binding abilities of peptides give targeting capability to different tissues and lesions. In strategy of “in vivo self-assembly” system, cell

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Table 1 Targeting peptide. N.A.: not available Targeting position Tumor vasculature

Extracellular matrix (ECM)

Peptide sequence RGD NGD IFLLWQR CGLIIQKNEC CREAK CRRHWGFEFC CTTHWGFTLC CPIEDRPMC

Length 3 3 7 10 5 10 10 9

Receptors Integrin αVβ3αVβ5 Aminopeptidase N Annexin1 Clotted plasma protein Clotted plasma protein MMP-2/9 MMP-2/9 α5β1

Refs. [16] [17] [44] [45] [46] [19] [19] [47]

surface targeting [2], tumor microenvironment targeting [13], and bacteria-infected location targeting [14] peptides were widely used. RGD and NGR are the first two targeting peptides shown in the peptide libraries [15]. RGD, a typical peptide to target tumor microenvironment, can bind to integrins αVβ3 and αVβ5 which specifically exist in tumor blood vessels [16]. Similar to RGD, NGD is also a vital tripeptide to target tumor vasculature, corresponding to another different receptor-aminopeptidase N [17]. In tumor microenvironment, matrix metalloproteinase (MMP) is another overexpressed substance; thus, it can degrade extracellular matrix (ECM) to enable tumor cell metastasis [18]. The peptides CRRHWGFEFC and CRRHWGFEFC have exhibited high affinity for MMP-2 and MMP-9 and can inhibit their enzymatic activities [19]. The peptide TGRAKRRMQYNRR can utilize electrostatic interactions to bind to bacteria membrane, targeting the bacteria-infected region for imaging and treatment [18, 20]. As a fragment of amyloid β (Aβ), the peptide KLVFF and its derivative can combine with Aβ and inhibit Aβ to form β-sheet structure aggregation [21]. Wang and his coworkers used KLVFF to target Aβ entering the cells, and promoting the degradation of Aβ upregulates autophagy [22]. Some other targeting peptides are summarized in Table 1.

36.2.1.2 Responsive Peptides In nature, some peptides, which have a significant conformational change when simulated by the microenvironment factors, are called responsive peptides. These switch-peptides play an important role in morphology transformation, which is one of the most significant keys of “in vivo self-assembly” strategy. The stimuli factors are pH, temperature, light, enzyme, metal ions, etc. (Table 2). Zhang and co-workers have reported a peptide chain EAK12-d (AEAEAEAEAKAK) that could transform from a β-sheet to an α-helix structure in response to pH or temperature changes [23]. Elastin-like polypeptides (ELPs) are biopolymers which have a transition temperature (Tt). When below the Tt, they have good solvability in aqueous solution but aggregate beyond the Tt. ELPs are combined by pentapeptide repeat VPGXG where X is another amide acid except for proline. Wang and his co-workers utilized ELP monomers to design topology-

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Table 2 Responsive peptides Stimulations pH

Enzyme MMP-2

Furin MMP-1

Caspase-3/7 MMP-7 MMP-13 MMP-9

Peptide sequence AEAEAEAEAKAK ADADADADARARARAR H7K(R2)2 KIAQLKYKISQLKQ EIAQLEYEISQLEQ VKVKVKVKVPPTKVKVKVKV VKVKVKTKVDPPTKVKVKVKV PLGVRG GPVGLIGK GPLGIAGQ PVGLIG RVRRCK GPQGIAGQ GPQGIWGQ APGL DEVD VPLSLTM RPLALWRS PQGLA FFFFCGLDD PVGLIG

Length 12 16 12 14 14 20 20 6 8 8 6 6 8 8 4 4 7 8 5 9 6

Refs. [23] [48] [33] [49] [49] [50] [50] [38] [51] [52] [53] [51] [54] [54] [54] [26] [55] [56] [57] [58] [53]

controlled nanostructures and in situ self-assembly by both intracellular TGasecatalyzed and temperature response [24]. Enzymes can often trigger responses for responsive peptides. As an important overexpressed enzyme in tumor microenvironments, MMPs are often considered when designing nanostructures. The peptide GPLGIAGQ can be cleaved into GPLG and IAGQ by MMP-2 and PVGLIG into PVG and LIG by MMP-2/MMP-9. Caspase, a kind of protease that is closely related to apoptosis, can recognize and cleave specific peptide chains [25]. For example, DEVD is a short peptide that can be cleaved by caspase-3/caspase-7 [26]. Other responsive peptides are shown in Table 2.

36.2.2 Driving Forces of Peptide Self-Assembly The application of polypeptides is restricted by poor stability in vivo and short halflife, which is easy to be digested by protease and quickly eliminated in vivo. Selfassembly is considered to be one of the most promising methods to promote the stability of peptide-based nanomaterials through hydrogen bonds, ionic bonds, and π-π interactions.

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As precursors of proteins, peptides have well-defined secondary structures, with the most prominent being the α-helix and β-pleated sheet structure. α-Helix structures, with a periodicity of 3.6, are formed through hydrogen bonds between amide backbones [27]. Smith and co-workers designed two complementary leucine-zipper peptides (SAF-p1 and SAF-p2) that can assemble into two-stranded coiled-coil rods [28]. This system can co-assemble to form long and thickened protein fibers about 4.2 nm along the fiber axis. Hydrogen bonding between amino acid backbones can form β-sheets that form parallel or antiparallel structures. The aggregation of which will always resemble nanofibers. The first report of β-sheets identified in proteins was in the early 1950s by Pauling, Corey, and others [29]. The major mechanism of self-assembly is hydrogen bond. KLVFF is a segment of Aβ sequence which is a significant reason of the formation of Alzheimer’s disease (AD). The pentapeptide can form nanofibers by hydrogen bonds [21]. Besides, most β-sheet peptide monomers have hydrophobic and hydrophilic sides. For example, multidomain peptides (MDPs) can first form a dimer with hydrophobic interaction in solution and then form nanofibers with a hydrophobic core by the peptide dimer [30]. This kind of peptides can extend their length by adjusting the pH and salt composition of solvent. Stupp’s groups have designed a kind of amphipathic peptide which can self-assemble into β-sheet nanostructure [31]. In addition, enough ionic bonds interact with periodic repetition of the hydrophilic surface, and π-π interactions, such as diphenylalanine (FF), are able to further stabilize the β-sheet structure. Inspired by FF, some aromatic compounds were developed to conjugate with peptides and selfassemble by π-π interactions, such as carbobenzyloxy, naphthalene, Fmoc, bispyrene (BP), and purpurin 18 (P18) [7]. Some typical self-assembled peptides were summarized in Table 3.

36.3

In Vivo Self-Assembled Peptide-Based Nanomaterials

36.3.1 The Properties of “In Vivo Self-Assembled Peptide-Based Nanomaterial” The “in vivo self-assembly strategy” indicated that the internal environment factors, such as pH, enzyme, ligand-receptor interaction, etc., stimulate the structure or morphology transformation of peptide-based nanomaterials. The two vital aims to design such nanomaterial are (i) the ability to self-assemble in a target area and remain stable without being degraded by enzymes and (ii) the ability to transform into multiple structures that have more functions than a single structure. Wang and his co-workers have presented an assembly-induced retention (AIR) effect [9] that the fibrous nanostructures exhibit longer blood circulation than the small molecules or their spherical counterparts. Thus, Wang’s group designed a system where small molecules (or nanoparticles) transform to nanofibrils to achieve in situ self-assembly in vivo [2, 3, 9]. Yang’s group designed a tandem molecular self-assembly to enhance the bioimaging in tumor area [12]. Xu’s group have reported a hydrogel precursor which can be recognized by enzyme and then self-assemble into hydrogel

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Table 3 Peptide self-assembly motifs Interaction Hydrogen bond

Peptide category Amyloid

Amphipathic

Peptide name Aβ(1622) Aβ(3040) β-turn(711) β-turn (23-27) EAK16II KFE8 RADA16 Q11 MAX1

π π interaction

Low molecular weight peptide

– –

Hydrophilichydrophobic interaction

Organopeptide hybrids

TGFBPA Filler PA β-sheet PA

Peptide sequence NH2-KLVFFAE-OH

Refs. [21]

NH2-AIIGLMVGGVV-OH

[59]

NH2-DSGYE-OH

[59]

NH2-DVGSN-OH

[59]

Ac-AEAEAKAK-NH2

[6]

Ac-FKFEFKFE-NH2 Ac-RADARADA-NH2 Ac-QQKFQFQFEQQ-NH2 VKVKVKVKVDPPTKVKVKVKVNH2 FF-OH FF-NH2 Boc-FF Fmoc-FF HSNGLPLGGGSEEEAAAVVV (K)-CO(CH2)10CH3 H3C(CH2)14CO-VVVAAAEEE CH3(CH2)14CONHVVVAAAKKK-OH

[60] [61] [10] [62] [5] [63] [63] [63] [64] [64] [31]

in situ inside live cell [32]. The detailed mechanism will be accurately analyzed in the following sections.

36.3.2 In Situ Peptide Self-Assembly Based on the functions of the nanomaterial, researchers often combine several different functional peptide motifs into one coherent system, shown in Fig. 1. In this section, we will introduce this strategy according to the different stimulating factors for peptide self-assembly.

36.3.2.1 pH Response In order to meet fast metabolism and proliferation, the tumor cells require higher glycolysis than normal tissue. Accordingly, lactic acid has been overproduced which results into the low pH in tumor microenvironment. As displayed in Fig. 2, many peptide motifs have the characteristic of pH response. Michael Altman et al. have reported that EAK12-d (AEAEAEAEAKAK) and DAR16-IV (n-ADADADADARARARAR) have both stable α-helix and β-sheet conformations

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Fig. 2 (a) Schematic illustration of nanoparticle (NP) transformation at acidic pH. (b) The structures of designing molecules. (c) CD spectral characterization of transformation process with the β-sheet structure formation. (d) Time-dependent ex vivo fluorescence images of tumor tissues and major organs, such as the heart, liver, spleen, lung, and kidney, collected at 4, 24, 48, 72, and 96 h postadministration by PBS and NPs-1. (Reproduced with permission [3]. Copyright 2017, Wiley-VCH)

in different pH [23]. PloyHis has the different hydrophilic and hydrophobic ability in different pH. This feature has been used to design pH-responsive polymeric micelles by Zhang group to release paclitaxel in vivo [33]. Wang and his co-workers designed a pH-responsive peptide that led to the formation from nanoparticles (NPs) to nanofibers (NFs), from pH 7.4 to pH 6.5 (Fig. 2a) [3]. The peptide BP-FFVLK-PEG-His6 consists four motifs (Fig. 2b): (i) a bis-pyrene (BP) motif that is a hydrophobic unit and with green fluorescence emission by AIE effect [34], (ii) peptide sequence KLVFF which can aggregate to form β-sheet structure by hydrogen bond, (iii) a pH-responsive unit (His6), and (iv) a hydrophilic chain (PEG1000). The His6 is hydrophobic in pH 7.4 but is hydrophilic in pH 6.5. Therefore, this specific peptide sequence can form nanoparticles (NPs) through hydrophobic-hydrophilic interactions. The change of pH in the microenvironment can trigger changes of hydrophobichydrophilic balance, which can lead to the transition from nanoparticles to nanofibers. The five peptides designed by the authors, shown in Fig. 2b, exhibit such morphology transformation. The NPs were injected into tumor-bearing mice by intravenous injection, and due to passive targeting mechanisms, the NPs transform

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into NFs and construct nest-like hosts that covered the tumor region. These structures have β-sheet secondary structures (Fig. 2c). And the “nest” can restrain the tumor for more than 96 h (Fig. 2d). Moreover, small molecular drugs such as doxorubicin (DOX) can be loaded into the hydrophobic region of the β-sheet, thereby allowing the accumulation of small molecular drugs in the tumor region. However, due to the complex environment in vivo, the pH is not stable and homogeneous. So the pH response strategy is not the most extensive, sensitive, and accurate method to design the peptide nanomaterials in vivo.

36.3.2.2 Enzyme Response Due to the diversity of enzymes in the body and their predetermined expressions, a versatile strategy of stimulating peptide self-assembly is through enzymes. Take tumor, for example. Matrix metalloproteinases (MMPs), furin, and caspase family are overexpressed in many kinds of tumor area. Correspondingly, the peptide sequence shown in Table 2 can be cleaved by those enzymes. Recently, a concept, enzyme-instructed self-assembly (EISA), has been reported by Xu’s group [35]. Then, this concept has been widely recognized by researchers and applied to design nanomaterials [36, 37]. Wang and his co-workers have reported a building block (Ppa-PLGVRG-Van 1), which can enhance the sensitive imaging of bacterial infection, to specifically target the bacteria-infected location in mice [38]. As the shown in Fig. 3b, the building block is composed of three moieties: (i) a signaling molecule pyropheophorbide-α, (ii) a peptide sequence Pro-Leu-Gly-Val-Arg-Gly (PLGVRG) which is a linker that can be cut by gelatinase, and (iii) the vancomycin (Van) as a targeting ligand. After intravenous injection in mice, the peptide compound targets and accumulates in the bacteria-infected location. The overexpression of gelatinase at the targeting location cleaves the peptide segment PLGVRG, then the signal molecule can aggregate into supramolecular structures through enhancement of hydrophobic and decrease in steric hindrance. These supramolecular aggregates can enhance photoacoustic signal at the infected location. This new discovery can provide new possibilities for biomedical applications. Besides being directly responsive to enzymes, some peptides self-assemble after being stimulated by enzyme-responsive small molecules. Xu and his co-workers utilized ALP-triggered dephosphorylation to adjust the molecular hydrophobicity [32]. As shown in Fig. 4b, molecule 1 (NapFFKYp) is an amphipathic peptide with two moieties: the hydrophobic NapFF moiety and the hydrophilic KYp moiety (p is the abbreviation for phosphorous ester). Alkaline phosphatase (ALP) can recognize tyrosine phosphate residues and remove phosphorous ester by dephosphorylation. Molecule 2 NapFFK(NBD)Yp is a precursor. NBD is a fluorophore that can give more intense fluorescence in hydrophobic environment than in water. The precursor 2 can freely diffuse in solution and cannot self-assemble in the low concentration as shown in Fig. 4a. Then precursor 2 accumulates into cell, and dephosphorylation affords the corresponding hydrogelator 3. Hydrogelator 3 is more hydrophobic than the precursor, which endows hydrogelator 3 self-assembly to form nanofibers in the

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Fig. 3 (a) Illustration of bacterial infection imaging based on an in vivo aggregation strategy. First, the targeting molecule (Van) causes Ppa-PLGVRG-Van to accumulate at the site of responsive bacterial myositis; then, the gelatinase produced by gelatinase-positive bacteria in the infectious microenvironment cleaves the peptide linker, triggering self-aggregation in situ; finally, the supramolecular aggregates significantly enhance the photo-acoustic signal so that the bacterial infection can be detected by imaging. (b) Molecular structure of the designed peptide. (c) 3D reconstruction of an infected site (104cfu bacteria) 24 h after intravenous injection of 1 (200 μL, 2.0  10 4 M). (Reproduced with permission [38]. Copyright 2015, Wiley-VCH)

certain concentration. The fluorescent confocal microscope has shown the hydrogel in cells (Fig. 4). Recently, cellular organelle self-assembled triggered cellular dysfunction has been proposed by Ryu and his co-workers [37]. The researchers took advantage of amphiphile peptide (Mito-FF) where pyrene is a fluorescent probe and Mito is a mitochondria-targeting hydrophilic moiety and positive charge carrier (Fig. 5b). As shown in the schematic illustration of Fig. 5a, after cellular diffusion in cytoplasm, the peptide does not self-assemble because the concentration is below the critical aggregation concentration (CAC). Then targeting and accumulating in mitochondria and self-assemble as a β-sheet structure because the peptide concentration in mitochondria is above CAC. The self-assembled nanofibers induced cellular dysfunction and triggered cell apoptosis. Compared with intracellular enzyme-instructed selfassembly (EISA), organelle localization-induced supramolecular self-assembly (OLISA) can increase local concentration and reduce the total dose of the materials to further reduce cytotoxicity. In order to further study the fibril formation inside the mitochondria, the researchers designed another peptide: Mito-FF-NBD, where

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Fig. 4 (a) Principle of imaging enzyme-triggered supramolecular self-assembly inside cells. ER, endoplasmic reticulum; G, Golgi apparatus; L, lysosome; m, mitochondria; n, nucleus. (b) The synthesis route of the precursor 2 and the generation of the fluorescent hydrogelator 3 via an enzyme-catalyzed dephosphorylation. (i) Na2CO3, methanol, water, 50  C, 2 h; (ii) ALP. (c) Enzyme-trigged self-assembly inside live cells. Fluorescent confocal microscope images show the time course of fluorescence emission inside the HeLa cells incubated with 500 or 50 μM of 2 in PBS buffer, which shows the different distribution of fluorophores inside living cells. Scale bar, 50 μm for time course panels and 10 μm for the enlarged panels. (Reproduced with permission [32]. Copyright 2012, Macmillan Publishers Limited)

4-nitro-2, 1, 3-benzoxadiazole (NBD) can release stronger fluorescence in hydrophobic conditions (Fig. 5d). The co-assembly of Mito-FF and Mito-FF-NBD can help to detect concentration-relative self-assembly (Fig. 5f is schematic illustration; Fig. 5 is confocal microscope of co-assembled system). Compared with pH response strategy, EISA is more specific, accurate, and flexible. Enzyme response is the most important strategy to realize in vivo selfassembly.

36.3.2.3 Ligand-Receptor Interactions Another in vivo self-assembled strategy is utilizing the ligand-receptor interaction. Some overexpressed ion or receptor in tissue microenvironment can influence the external supermolecule’s spatial arrangement. For example, via the ligand-receptor interaction, the peptide Fmoc-GGDADA can propagate by binding to vancomycin (Van) via hydrogen and further dissociation [39]. The Vans are released to solution, and binding peptide again and the polypeptide can autocatalyze themselves into aggregates (Fig. 6a, b). The resulting aggregates of Fmoc-GGDADA can inhibit the

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Fig. 5 (a) Intramitochondrial assembly of Mito-FF. The self-assembly process is driven by the increased mitochondrial membrane potential of cancer cells, leading to high mitochondrial accumulation of Mito-FF followed by self-assembly into fibrils. The intramitochondrial fibrils further disrupt the membrane, resulting in leakage of mitochondrial contents to the cytosol, which eventually induces cellular apoptosis. (b) Structural design of the mitochondria-targeting peptide amphiphile, Mito-FF, which is equipped with a pyrene group for fluorescence detection inside cells and TPP for targeting of mitochondria. (c) Mitochondrial co-localization of Mito-FF measured with MitoTracker Red FM shows high localization inside mitochondria (scale bar, 5 μm). (d) Molecular structure of Mito-FF-NBD. (e) Co-assembly inside mitochondria indicated by the bright green fluorescence of Mito-FF-NBD in the presence of Mito-FF (lower panel); however, such emission was not observed with Mito-FF-NBD alone (upper panel) (scale bar, 2 μm). (f) Schematic diagram showing co-assembly of Mito-FF-NBD with Mito-FF. (Reproduced with permission [37]. Copyright 2017, Macmillan Publishers)

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Fig. 6 (a) Structures of the ligand (Van), the receptor (a D-Ala-D-Ala derivative), and the relevant controls. (b) The ligand-receptor interaction-catalyzed molecular aggregation. (c) Schematic representation of metal ion binding-induced reconstruction of BKR nanoassemblies from nanoparticles to nanofibers in solution and on the cell surface. (d) Molecular structure and schematic illustration of peptide of AECM. (e) Schematic illustration of the biomimic construction of AECM based on transformable 1-NPs for highly efficient inhibition of tumor invasion and metastasis. (Reproduced with permission [2, 39, 40]. Copyright 2015,2017, American Chemical Society. Copyright 2016, Royal Society of Chemistry)

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proliferation of HeLa cells with half maximal inhibitory concentration (IC50) value of 184  10 6 m. Recently, Wang and his co-workers utilized metal-ligand interaction to design a peptide BP-KLVFF-RGD (BKR) which can achieve a morphology transformation [40] (Fig. 6c). Due to the hydrophilic-hydrophobic interaction, the peptide BPKLVFF-RGD (BKR) has a nanoparticle supermolecule arrangement. It is widely known that RGD can especially recognize integrin αvβ3, which is driven by the interactions between RGD and the metal ions (Ca2+, Mg2+). Because of the change of microenvironment, the BKR has a spatial arrangement transformation – from nanoparticles to nanofibers and then maintaining long retention on the cell surface. To use this strategy, an artificial extracellular matrix (AECM) has been constructed to avoid tumor metastasis [2] (Fig. 6d, e). The authors designed a Y-type dual targeting motif (peptide sequence: RGD-YIGSR). Besides, the other two motifs are (i) signal molecule bis-pyrene (BP) and (ii) self-assembled KLVFF. BP and KLVFF are hydrophobic and RGD-YIGSR is hydrophilic. The amphipathic molecule has formed nanoparticle first. When the targeting unit binds the cancer cell surfaces, the ligand-receptor interactions triggered the molecular transformation from nanoparticles to nanofibers. The nanofibers have formed a net structure outside the cells which is similar to the ECM, so the authors call it the AECM (artificial ECM). The AECM cannot be degraded by enzymes, so it can inhibit the tumor invasion and metastasis. Moreover, the ligand and receptor can also be a same object. Wang and his coworkers have intelligently designed a nanosweeper to degrade Aβ by upregulating autophagy. In this system, the ligand is the artificial synthetic KLVFF peptide, and the receptor is the KLVFF sequence of cerebral Aβ [22]. However, from now on, the mechanism of ligand-receptor interaction-induced transformation is not clear, which is the biggest barrier of the development in this field. Besides, the universality of this strategy needs further researches and discussions.

36.3.2.4 Redox Reaction Besides pH, enzyme, and ligand-receptor interaction, other simulation can be used to contribute to the transformation of peptide in vivo. For example, Yang and his coworkers utilized redox reaction to achieve tandem molecular self-assembly [12]. The first self-assembly utilized alkaline phosphatase (ALP) to regulate molecule’s hydrophilic-hydrophobic property, and the second self-assembly utilized GSH to cleave the disulfide bond (Fig. 7). This diphenylalanine (FF) system is reported frequently by Xu’s group. In order to adjust the hydrophilic property of the molecule which concludes diphenylalanine (FF), they combined phosphorylated amino acids into the peptide chain to increase the hydrophilic property. The -H2PO3 can be cleaved by extracellular ALP. The change of hydrophilic will lead to the change of conformation. The second self-assembly of this work is a redox reaction. GSH is a widely known molecule existing in the tumor microenvironment. It can cut off the disulfide bond. RGD is a length of hydrophilic peptide. After cutting off sERGD, the selfassembled GFFY will self-assemble into nanofibers. This work could lead to the

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Fig. 7 (a) Chemical structures and schematic illustration of the conversion of 1 into 2 by phosphatase (ALP) and then of 2 into 3 by glutathione (GSH). (b) Proposed mode of the tandem molecular self-assembly in the extra- and intracellular environment of liver cancer cells. (Reproduced with permission [12]. Copyright 2017, Wiley-VCH)

development of supramolecular nanomaterials with improving performance in cancer diagnostics and therapy. Redox reaction is a common method in small molecule drug chemistry field. Rao’s group has reported a biorthogonal reaction to realize in situ self-assembly in vivo [41]. But it always utilizes small molecule motifs, not peptide. So we don’t discuss it particularly in this chapter.

36.3.3 Polymer-Peptide Conjugates (PPCs) Self-Assembly In Vivo Compared with polypeptide materials, polymer-peptide conjugate materials have more modified sites, better biocompatibility, and longer blood circulation time.

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36.3.3.1 Thermosensitive PPCs Thermosensitive polymers are widely used in biomedical material field. The thermosensitive polymers have lower critical solution temperatures (LCST). This material will be in a solid state if its environment temperature is below the LCST and a gel state when above. The LCST is also dependent on hydrophilic motifs; therefore, the more hydrophilic motifs attached to the polymer, the higher the polymer’s LCST is. Based on this information, Wang et al. designed thermosensitive PPCs which can achieve intracellular sol-to-gel transition [42]. Their polymer-peptide conjugate is composed of three sections: a thermoresponsive polymer backbone (PNIPAAm), a hydrophilic peptide sequence whose goal is to modulate LCST, and a signal molecule side chain (Fig. 8). As shown in Fig. 8a, the LCST of the material is higher than  37 C. So during blood circulation, the material does not aggregate into gels. When it penetrates into cells, the enzyme or other object will recognize the peptide response and cleave the hydrophilic motif, which can decrease the LCST. Then, the material  aggregated into gels at 37 C. This material can be used for in situ sensing and monitoring cellular physiological processes.

Fig. 8 (a) Schematic representation of stimuli-instructed construction of controllable nanoaggregates for monitoring tumor therapy response and (b) illustration of PPC structure and chemical structures of the thermoresponsive polymer backbone, peptide side chain, and signal molecule. (Reproduced with permission [42]. Copyright 2017, American Chemical Society)

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ELPs, also a kind of thermoresponsive material, have been designed to combine with polymerization peptide and signal molecules by Wang group [24]. The end amino acid of the peptide is lysine, so monomer molecules have dissociative amide and amino. After entering the cytoplasm, the monomer can be catalyzed by TGase to conduct a polymerization process via the reaction between amide and amino. The newly formed amide makes the formation of peptide monomer to ELP topologycontrolled nanostructures, including ELP random coil, ELP nanoparticle, and ELP gel, which can exhibit AIR effect and inspire scientist to explore new nanomaterials applied in living subject.

36.3.3.2 pH Response PPCs The pH response PPC means a kind of nanomaterial that can delivery drugs as a vehicle and change structure when simulated by changing pH. The nanovehicles always have acid-sensitive bonds, for example, hydrazine, acetal, orthoester, and amide. Due to the better biocompatibility, scientists always used a polymer as a response motif. Wang and his co-workers have designed a pH-responsive polymerpeptide conjugate for monitoring the process of nanovehicles’ intracellular acidinduced structural change [43]. The polymer-peptide conjugate was combined by (i) dextran (DEX) polymer, (ii) targeting peptide CGGRGD, and (iii) phenylboronic acid-modified P18 (NPBA-P18). The DEX is linked to the P18 by a phenylboronic linkage, a pH response bond that helps the nanovehicle transition at different pH levels. Either thermosensitive or pH response PPCs, the main components are polymers. The peptide only plays one function role. Different types of materials can be linked together to form new nanomaterials, which can effectively enhance the versatility of materials.

36.4

Challenge and Outlook

In this chapter, we have introduced the principle of “in vivo self-assembly strategy,” utilizing microenvironment response linker to control the deformation of materials and the release of drugs. Here, we focus on pH, enzyme, temperature, ligandreceptor interaction, and redox reaction response and introduce the details with specific articles as example. During the modulation of different peptide motifs, the peptide-based nanomaterials can (i) achieve different functions and (ii) self-assemble in different areas. Compared to peptide molecules, peptide self-assembled nanomaterials have high stability and long retention effect. These advantages afford the material’s various applications: first, to be as a biosensor to monitor some intracellular activities; second, to be as a carrier to carry drugs into the desired location; and third, to be as a simulation agent to activate autophagy. However, with the development of in situ construction peptide materials in vivo, some emerging challenges have appeared. (i) The mechanism of the self-assembled process in vivo is not clear, which is a barrier to achieve the precise control in vivo. And, the fuzzy mechanism will lead to difficulty in designing precursors. (ii) The

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reason of disassembly and excretion of supramolecules in vivo is not available, which will increase the difficulty of toxicity evaluation. (iii) The interaction of peptide self-assembly with small molecules in vivo needs to be reported more so that the self-assembly can be applied in many theranostic fields. In a word, “in vivo self-assembly” strategy will lead to benefits of designing nanomaterials which can be applied in theranostic regions and clinical medicine. To completely explore the treasures, a lot of efforts will be required by scientists. Acknowledgments This work was supported by the National Science Fund for Distinguished Young Scholars (51725302).

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53. Gao W, Xiang B, Meng T-T, Liu F, Qi X-R (2013) Chemotherapeutic drug delivery to cancer cells using a combination of folate targeting and tumor microenvironment-sensitive polypeptides. Biomaterials 34(16):4137–4149. https://doi.org/10.1016/j.biomaterials.2013.02.014 54. Lutolf MP, Lauer-Fields JL, Schmoekel HG, Metters AT, Weber FE, Fields GB, Hubbell JA (2003) Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: engineering cell-invasion characteristics. Proc Natl Acad Sci U S A 100(9):5413–5418. https://doi.org/10.1073/pnas.0737381100 55. von Maltzahn G, Harris TJ, Park J-H, Min D-H, Schmidt AJ, Sailor MJ, Bhatia SN (2007) Nanoparticle self-assembly gated by logical proteolytic triggers. J Am Chem Soc 129(19):6064–6065. https://doi.org/10.1021/ja070461l 56. Sewell SL, Giorgio TD (2009) Synthesis and enzymatic cleavage of dual-ligand quantum dots. Mater Sci Eng C-Biomimetic Supramol Syst 29(4):1428–1432. https://doi.org/10.1016/j. msec.2008.11.015 57. Yang J, Jacobsen MT, Pan H, Kopecek J (2010) Synthesis and characterization of enzymatically degradable PEG-based peptide-containing hydrogels. Macromol Biosci 10(4):445–454. https:// doi.org/10.1002/mabi.200900295 58. Yang Z, Ma M, Xu B (2009) Using matrix metalloprotease-9 (MMP-9) to trigger supramolecular hydrogelation. Soft Matter 5(13):2546–2548. https://doi.org/10.1039/b908206a 59. Raymond DM, Nilsson BL (2018) Multicomponent peptide assemblies. Chem Soc Rev 47(10):3659–3720. https://doi.org/10.1039/c8cs00115d 60. Marini DM, Hwang W, Lauffenburger DA, Zhang SG, Kamm RD (2002) Left-handed helical ribbon intermediates in the self-assembly of a beta-sheet peptide. Nano Lett 2(4):295–299. https://doi.org/10.1021/nl015697g 61. Sun Y, Zhang Y, Tian L, Zhao Y, Wu D, Xue W, Ramakrishna S, Wu W, He L (2017) Selfassembly behaviors of molecular designer functional RADA16-I peptides: influence of motifs, pH, and assembly time. Biomed Mater 12(1). https://doi.org/10.1088/1748-605x/12/1/015007 62. Sathaye S, Zhang H, Sonmez C, Schneider JP, MacDermaid CM, Von Bargen CD, Saven JG, Pochan DJ (2014) Engineering complementary hydrophobic interactions to control beta-hairpin peptide self-assembly, network branching, and hydrogel properties. Biomacromolecules 15(11):3891–3900. https://doi.org/10.1021/bm500874t 63. Ma H, Fei J, Li Q, Li J (2015) Photo-induced reversible structural transition of cationic diphenylalanine peptide self-assembly. Small 11(15):1787–1791. https://doi.org/10.1002/ smll.201402140 64. Shah RN, Shah NA, Lim MMD, Hsieh C, Nuber G, Stupp SI (2010) Supramolecular design of self-assembling nanofibers for cartilage regeneration. Proc Natl Acad Sci U S A 107(8):3293–3298. https://doi.org/10.1073/pnas.0906501107

Construction of Well-Defined Discrete Metallacycles and Their Biological Applications

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Xu-Qing Wang, Xi Liu, Wei Wang, and Hai-Bo Yang

Contents 37.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37.2 Biological Applications of Pt- and Pd-Based Metallacycles . . . . . . . . . . . . . . . . . . . . . . . . . . . 37.3 Biological Applications of Ru-Based Metallacycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37.4 Biological Applications of Rh- and Ir-Based Metallacycles . . . . . . . . . . . . . . . . . . . . . . . . . . . 37.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37.1

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Introduction

Metal ions and metal complexes, i.e., both bulk metal ions such as Na+, K+, Mg2+, and Ca2+ and the remaining trace ions, most commonly of Fe2+, Ni2+, Cu2+, Mn2+, Zn2+, Co2+, Mo2+, and V2+, are of great importance in biological systems [1]. They can interact with the diverse binding sites in biomolecules, such as the hydroxyl groups of sugars in proteins, the N-heterocyclic rings of nucleotides, and nucleic acids in DNA or RNA, and take part in various biological processes [2]. Taking advantage of such novel biological interactions between metal ions (or metal complexes) and biomolecules, the employment of metal complexes for biomedical and biochemical applications has attracted more and more attentions during the past few decades, thus resulting in the blooming of medical inorganic chemistry [3]. The well-known anticancer drug is cisplatin, a platinum complex whose biological property was discovered by accident about 50 years ago [4]. It shows high efficiency as an anticancer drug in the form of cis-Pt(NH3)2Cl2. Because of this inspiring discovery, a number of analogous Pt(II) complexes such as carboplatin, oxaliplatin, X.-Q. Wang · X. Liu · W. Wang · H.-B. Yang (*) School of Chemistry and Molecular Engineering, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University, Shanghai, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_43

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nedaplatin, etc. were developed and used as therapeutic agents for a wide range of cancers [5]. Although great developments have been achieved in this area, these agents also suffered some limitations such as their toxicity and the tendency to induce drug resistance, thus the development of new metallodrugs is still in great demand. During past decades, coordination-driven self-assembly has evolved as a facile and efficient approach for the construction of novel metallosupramolecular structures such as two-dimensional (2D) metallacycles and three-dimensional (3D) metallacages [6]. Starting from various building blocks, coordination-driven selfassembly could lead to the successful construction of well-defined discrete metallacycles with both structural and functional diversity [7]. Moreover, through either pre- or post-self-assembly functionalizations, diverse functional groups could be introduced into the resultant metallacycles, thus allowing for the construction of functionalized metallacycles with tunable structures and properties [8]. Based on coordination-driven self-assembly strategy, the resultant diverse metallacycles, especially those derived from biologically active Pt, Ru, and Ir-based building blocks, have been employed as promising candidates for potential biological applications [9]. In this chapter, an overview of the biological applications of 2D metallacycles is provided divided by the metallic building blocks. In each section, the emphasis will be focused on the design strategy of building blocks and the biological applications of the final metallacycles.

37.2

Biological Applications of Pt- and Pd-Based Metallacycles

Considering the extensive applications of Pt-based drugs as cancer therapeutic agents [10], platinum-based (as well as analogues palladium–based) metallosupramolecular assemblies have received a great deal of attention during the past three decades [11]. Since the pioneering reports on the constructions of discrete palladium and platinum metallacycles in the early 1990s by Fujita [12] and Stang [13], a great number of metallacycles have been synthesized through facile and efficient coordination-driven self-assembly, laying the foundation for the exploration of their biological applications. As early as in 2008, Autexier, Moitessier, and Sleiman et al. [14] demonstrated the synthesis of a Pt(II)-based metallo-square 1, which was easily prepared in a single step from two simple building blocks via the coordination-driven self-assembly approach (Fig. 1). The metallacycle 1 could act as an efficient G-quadruplex binder and telomerase inhibitor. By using a fluorescence resonance energy transfer (FRET) melting assay, a significant increase of 34.5
C in the thermal denaturation temperature was observed, indicating the good stability of the G-quadruplex. Moreover, due to such strong binding affinity between metallo-square and the G-quadruplex, it showed significant telomerase inhibition. In 2011, two new tetracationic heterobimetallacycles were prepared by Chi and coworkers [15], which could bind and unwind supercoiled DNA. As shown in Fig. 2, starting from a bis-pyridine amide ligand 2 and metal acceptors 3 or 4, the targeted

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Fig. 1 Chemical structures of the metallacycle 1

1

2

3 M = Pd 4 M = Pt

5 M = Pd 6 M = Pt

Fig. 2 Schematic representation of the synthesis of heterometallacycles 5 and 6

heterobimetallacycles 5 and 6 were readily prepared through self-assembly. The structures were confirmed by the single-crystal X-ray analysis. Moreover, by employing photophysical and gel electrophoresis methods, the interaction between the resultant heterobimetallacycles with supercoiled DNA was examined. The results indicated that both metallacycles could efficiently bind with duplex DNA, and metallacycle 5 displayed a greater binding affinity toward DNA. In 2014, Stang, Olenyuk, and coworkers [16] reported the synthesis of two rhomboidal Pt(II)-based metallacycles and further evaluated the in vivo anticancer activity. As shown in Fig. 3, mixing bipyridyl donors 7 or 8 with organoplatinum acceptor 9 in methanol at 50
C gave rise to the metallacycles 10 or 11. Both metallacycles 10 and 11 were water soluble in the physiological range of concentrations and nontoxic to the normal cells. Moreover, on the basis of their emissive feature, the uptake and localization of these metallacycles within A549 and HeLa cells were determined using laser-scanning confocal microscopy. According to the in vivo anticancer activity study, metallacycle 10 could efficiently reduce the rate of tumor growth in subcutaneous mouse tumor xenografts as evidenced by the tumor

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7 X=H 8 X = CH 3

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10 X = H 11 X = CH 3 Fig. 3 The synthesis of rhomboidal metallacycles 10 and 11 via coordination-driven self-assembly

growth inhibition (T/C%) value of 36% (Fig. 4), thus revealing its potential as therapeutic agent. In 2016, Stang et al. [17] further demonstrated the construction of novel fluorescent metallacycle-cored polymers and explored their applications as the contrast agents for cell imaging. As shown in Fig. 5, a tetraphenylethene (TPE) derivative 12 bearing two pyridyl groups for metal coordination and two amino groups for polymerization was prepared as the building block. The rhomboidal Pt(II) metallacycle 14 was then generated through the assembly of 120
dipyridyl donor 12 with 60
platinum acceptor 13. Starting from the rhomboidal Pt(II) metallacycle, the mild and efficient amidation reaction between alkylamine and N-hydroxysuccinimideactivated carboxylic acid resulted in the formation of two novel metallacycle-cored polymers 17 and 18. Due to the existence of TPE units, the resultant polymers revealed the enhanced fluorescence emission property, which was then explored for the applications as bioimaging agents. As shown in Fig. 6, in vivo experiments revealed that, even after injection of 18 for 24 h, a remarkable fluorescent emission of the MDA-MB-231 (a human breast adenocarcinoma cell line) tumor was still observed, therefore indicating both the high chemostability and photostability of 18 in vivo. Moreover, by using the same Pt(II)-based metallacycle as the core, Stang et al. [18] further synthesized a four-armed amphiphilic copolymer that served as a novel drug delivery system (Fig. 7). Similar with the previous report, in this platform, TPE units in the metallacyclic core acted as the fluorescent probe for live cell imaging upon aggregation, and the metallic building block, the 3,6-bis[trans-Pt(PEt3)2]phenanthrene (PhenPt), was an anticancer drug. In addition, four copolymeric arms displayed GSH responsiveness that could be used for drug delivery. By controlling the experimental condition, the resultant polymer was further self-assembled into different nano-structures including nanoparticles and vesicles that exhibited varied cytotoxicities toward HeLa cells. Moreover, DOX or DOXHCl could be encapsulated into the nanostructures that resulted in a synergistic anticancer effect. Through

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Fig. 4 (a) Representative pictures of tumors, excised from control and 10-treated mice. (b) Localization of the near-infrared contrast agent IR-783 in the tumors of the control and treated mice. The signal was processed with Living Image software with one representative sample for each group presented above. Mice from the 10-treated group show lower intensity of the signal originating from the tumor-accumulated contrast agent compared with the control group

a GSH responsive elimination reaction, the amphiphilicity changes led to the controlled release of the encapsulated drug. Recently, taking advantage of the formation of a novel heteroternary complex of methyl viologen (MV), cucurbit[8]uril (CB[8]), and the naturally occurring anticancer drug Curcumin (Cur), Louie, Pan, Stang, and coworkers [19] demonstrated an effective Cur delivery system toward the cancer cells. As shown in Fig. 8, the employment of coordination-driven self-assembly resulted in the successful synthesis of a water-soluble discrete metallacycle 24 with three MV units. Starting from the metallacycle 24, the complexation with CB[8] and Cur led to the formation of watersoluble host–guest complex. Notably, ca. 100-fold improved IC50 value of the resultant host-guest complex relative to free Cur against diverse cancer cell was revealed by in vitro studies, highlighting the great potential of the combination of coordination-driven self-assembly and host–guest interactions for hydrophobic drug delivery. Considering the attractive two-photon absorption (TPA) properties of Ru(II) polypyridyl complex, a heterometallic Ru–Pt metallacycle was prepared by Chao, Stang, and coworkers [20], which could serve as a two-photon photodynamic therapy (PDT) agent (Fig. 9). Due to the introduction of Ru(II) polypyridyl complex, the resultant metallacycle displayed excellent photostability, two-photon absorption characteristics and even the higher singlet oxygen (1O2) quantum yield (ΦΔ).

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12

13 14

17

15

16 18

Fig. 5 Synthetic routes and cartoon representations of metallacycle-cored polymers 17 and 18

Fig. 6 (a) Optical and fluorescence image of a mouse after intratumoral injection of 200 μg 18. The image was taken 24 h post injection. (b) Biodistribution of 18 24 h after intratumoral injection

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19 14

20 Fig. 7 Chemical structures and synthetic routes of amphiphilic copolymer 20

Cellular studies indicated that the formation of highly charged, large metallacyclic structure was beneficial for the internalization process, thus leading to the selective accumulation of the metallacycle in mitochondria and nuclei. More importantly, the photoexcitation of the metallacycle could efficiently trigger the intracellular 1O2 generation to cause the cell death. And in vivo studies further confirmed that it could remarkably inhibit the tumor growth under a low light dose as revealed by the gradually shrinking of the A549 tumor in mice after 14d PDT treatment with metallacycle (Fig. 10). This study provide another promising candidate as PDT agent.

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21

22

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23

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CB[8]

25

27

Fig. 8 Schematic representations of the synthesis of MV-functionalized metallacycle 24 via coordination-driven self-assembly and the formation of host–guest complex 27 from the complexation of 24, CB[8], and Cur

28

29 30

Fig. 9 Synthesis of heterometallic Ru–Pt metallacycle 30

By introducing boron dipyrromethene (BODIPY) units into the building block, two highly emissive self-assembled metallo-triangles were prepared by Yu, Huang, and Cook et al., which could serve as a potential photodynamic therapy (PDT) system [21]. Notably, in this study, the platinum building blocks 31 and 32 were toxic chemotherapeutics and the BODIPY building block 33 was excellent photosensitizer for PDT. According to the in vitro studies, the synergistic anticancer effect upon the formation of the metallacycles, which combined both chemotherapy and photodynamic therapy, was confirmed (Fig. 11). Recently, Zheng and coworkers [22] demonstrated a new strategy toward platinum drug delivery. As shown in Fig. 12, Pt(IV) prodrug was introduced into the

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Fig. 10 Two-photon PDT in vivo. The mice were randomly allocated into four different treatments: (i) physiological saline (control), (ii) physiological saline and two-photon laser irradiation (light), (iii) 30-injected only (30), and (iv) 30-injected and subjected to two-photon laser irradiation (30+light). Representative photographs of A549 tumors in mice with four different treatments

dipyridyl building block. The sequential coordination-driven self-assembly of the resultant conjugated dipyridyl ligand 36 with organoplatinum acceptor 38 resulted in the successful synthesis of the corresponding hexagon 39 with three equivalents of Pt(IV) prodrugs. As a control complex, hexagon 40 without Pt(IV) prodrugs was also prepared through the self-assembly of 37 and 38. According to the cell-based experiments through the MTT assay and live/dead cell assay, the superior therapeutic property of metallacycle was confirmed, which was mainly attributed to the high cellular uptake of 39. Starting from a new pyrazine-based organometallic clip, Das and coworkers [23, 24] prepared a series of metallacycles and further evaluated their biological applications (Fig. 13). For instance, for the irregular hexagons 45 and 46 synthesized through a [2+2] coordination-driven self-assembly, the smaller metallacycle displayed the superior cytotoxic effect than the larger one against all tested cancer cells, making it a novel potential anticancer drug. In addition, the two-component self-assembled hexagon 47 prepared by an [1+1] coordination-driven self-assembly also showed the cancer cell growth inhibition behavior. Notably, compared with the corresponding organometallic clip, a positive effect of the metallacycle formation on cytotoxicity was observed.

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31

31 - 32

32

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33 34 = ( 31 + 33 ) 35 = ( 32 + 33 )

Fig. 11 Chemical structures of building blocks 31-33 and cartoon representation of the preparation of triangular metallacycles 34 and 35

In 2017, Lee and coworkers [25] reported a suite of Pd-based metallacycles, of which the synthetic route was depicted in Fig. 14. The mixture of Pd (dppp) triflate complex 48 [dppp = 1, 3-bis-(diphenylphosphino)propane] and bidendate ligands 49-52 in dichloromethane gave rise to the formation of metallacycles 53-56 via coordination-driven self-assembly. The obtained metallacycles were solvent-dependent, which displayed an equilibrium between triangular and square architectures. Moreover, these metallacycles displayed highly cytotoxic against the brain cancer cells, and could strongly interact with biomolecules such as protein and DNA. In addition, the existence of boron dipyrromethane (BODIPY) moieties made it easy to visualize the complex inside the cancer cells under a confocal microscope.

37.3

Biological Applications of Ru-Based Metallacycles

Among transition metal complexes, Ruthenium (Ru) complexes are well known for their potential biological activities, and some of them, such as NAMI-A and KP1019, are already in clinical trials as potential anticancer agents, thus indicating a promising future in the field of anticancer medicine [26]. In recent years, Ru-based metallo-assemblies have also found to display excellent biological properties [27].

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37 36

36 – 37

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38 39 = ( 36 + 38 ) 40 = ( 37 + 38 )

Fig. 12 Schematic representations of the synthesis of Pt(IV) prodrug-conjugated hexagon 39 and control hexagon 40

As early as in 1992, Tocher and coworkers [28] firstly reported a metal-arene complex acting as an anticancer agent. The small drug molecule 57 contained metronidazole antibiotic and a Ru center. Interestingly, the selective cytotoxicity of complex 57 exceeded that of free metronidazole. This result indicated that the introduction of metal centers can enhance the anticancer activity (Fig. 15). In 2009, Therrien et al. [29] investigated the anticancer activity of the Ru-based tetranuclear metalla-rectangles. As shown in Fig. 16, dinuclear arene ruthenium complexes 58-61 were selected as acceptor building blocks. In the presence of silver triflate as a halide scavenger, the mixture of 58-61 reacted with different donors (pyrazine, 4,40 -bipyridine, 1,2-bis(4-pyridyl)ethylene) in methanol solution at room temperature generated a series of tetranuclear metalla-rectangles 62-73. Interestingly, the authors found that the large rectangle incorporating 1,2-bis(4-pyridyl)ethylene linkers displayed approximately five times more cytotoxic (IC50  6 μM) than the bipyridine-containing rectangles (IC50  30 μM), which suggested the correlation between the structural properties (size, flexibilities, and packing arrangements) with the cytotoxicities. Almost at the same time, Navarro, Barea, and coworkers [30] also investigated the biological activities of Ru-based tetranuclear metallomacrocycles. As depicted in Fig. 17, the dinuclear half-sandwich Ru(II) complex 74 was firstly treated with AgCF3SO3, and the sequential reaction with 4,7-phenantroline or 4,40 -bipyridine ligand in methanol solution resulted in the formation of the metallacycles 75 and 76, respectively. The resultant cyclic assemblies 75 and 76 were found to be able to

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45

46 41

47

42

43 44

Fig. 13 Chemical structures of building blocks 41-44, and the synthesis of metallacycles 45-47

interact noncovalently with DNA, inducing the significant conformational changes of DNA. Moreover, these metallacycles also exhibited antitumor activity, especially toward the human ovarian cancer cell line A2780cisR, showing the acquired resistance to cisplatin with the respective 4.6 and 8.3 μM IC50 values. Based on the arene ruthenium complexes, Stang, Chi, and coworkers [31–34] reported several arene ruthenium metallomacrocycles and studied their antiproliferative activity and ability to interact with biomolecules. As shown in Fig. 18, a series of metalla-rectangles 93–130 were obtained through the [2+2] self-assembly of Ru(II) molecular clips 77–80 bridged by different O,O-chelating moieties and the linear pyridyl-based donors 81-92. The in vitro anticancer activities of these assemblies were determined against various human cancer cell lines, and some complexes displayed significant activity with IC50 values comparable to the reference drug cisplatin and doxorubicin. Moreover, they revealed that the larger metallacycles displayed the higher activity than small ones. Along these lines, in 2014, Chi and coworkers [35] further reported the synthesis of two new large molecular metalla-rectangles by coordination-driven self-assembly, which was derived from a dipyridyl donor 131 and arene-ruthenium acceptors 58, 132–134 (Fig. 19). The structure of metalla-rectangle 135 was determined by singlecrystal X-ray diffraction analysis. The antitumor efficacy of metalla-rectangle 137

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49 50 51 52

48

53 54 55 56

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R = Me R = Ph R = CF 3Ph R = NO2Ph

R = Me R = Ph R = CF3Ph R = NO2Ph

Fig. 14 The synthesis of Pd-based metallacycles 53-56 Fig. 15 The first metal-arene compound evaluated for anticancer activity. The ligand in red is the antibiotic agent metronidazole

57 was found to be considerably stronger against several human cancer cell lines, even much more effective than cisplatin and doxorubicin. Similarly, starting from dicarboxylate-bridged arene-ruthenium acceptors 139–141 and dipyridyl donors 142–143, a series of metallacycles were prepared by Chi et al. [36] through coordination-driven self-assembly (Fig. 20). The anticancer activities were then evaluated both in in vitro and in vivo methods. The resultant results revealed that metallacycles 146 and 149 could inhibit the growth of HCT-15 human colon and AGS human gastric cancer cells. Moreover, metallacycles 146 and 149 could induce autophagy in HCT-15 cells, which could mediate the anticancer activity in human colorectal cancer cells. Moreover, starting from a new cobalt sandwich donor, Chi, Kang, Kim, and coworkers [37] also prepared a class of heterometallic rectangles through the

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58

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60

61

Fig. 16 The chemical structures of dinuclear arene ruthenium complexes 58–61 (top) and the synthesis of the metalla-rectangles 62–73 (bottom)

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Fig. 17 The formation of metallomacrocycles 75 and 76

coordination-driven self-assembly strategy in 2016. Figure 21 outlined the synthetic route, the self-assembly of a ditopic cobalt-based sandwich donor 150 with the ruthenium(II)-based acceptors 132–134 gave rise to the formation of heterometallic rectangles 151–153 in good yields. These bimetallic rectangles were found to be cytotoxic to AGS cells (the human gastric carcinoma cell line) because they could promote the conversion of LC3-I into LC3-II and increased caspase-3/7 activity, which further induced the autophagy and apoptosis. Upon being treated with metallacycles 151–153, the autophagic activities and apoptotic cell death ratios were found to increase in AGS cells. These results demonstrated that heterometallic rectangles 151–153 could induce the gastric cancer cell death by modulating autophagy and apoptosis, which thereby have potential applications for the treatment of human gastric cancer. Recently, Chi et al. [38] reported the successful synthesis of metallomacrocycles 155–158 via the coordination-driven self-assembly of a thiophene-based dipyridyl donor 154 and Ru(II) molecular clips 58, 132–134 (Fig. 22). The anticancer activities of 155–158 were further evaluated, and the combined results indicated that metallacycle 157 could inhibit the hepatic cancer because it could induce apoptotic cell death by activating intrinsic and extrinsic apoptosis pathways. By using the Ru(II)–qtpy (2,20 :4,400 :40 ,400 ’-quaterpyridyl) complexes with different ancillary ligands as building blocks, Thomas and coworkers [39] demonstrated the synthesis of a series of tetranuclear metallacycles as well as the further evaluation of their binding affinities toward duplex DNA. For metallacycle 159 with 2, 20 bipyridine (bpy) as the ancillary ligand, upon the progressive addition of CT-DNA, a decrease of the luminescence intensity of 159 was observed. This finding was different with its mononuclear constituent building block, in which little or no change in luminescence on DNA binding was revealed. Furthermore, according to the viscosity studies, non-intercalative interaction between 159 and duplex DNA was suggested. However, in contrast to 159, both metallacycles 160 and 161 displayed luminescence increase response upon the DNA binding. All collective data indicated that the selection of ancillary ligands could remarkably modulate the photophysical and biophysical properties of these tetranuclear metallacycles (Fig. 23).

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77

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93 = ( 79 + 81 ) 94 = ( 80 + 81 ) 95 = ( 77 + 82 ) 96 = ( 78 + 82 ) 97 = ( 79 + 82 ) 98 = ( 77 + 83)

104 = ( 77 + 85 ) 105 = ( 78 + 85 ) 106 = ( 79 + 85 ) 107 = ( 80 + 85 ) 108 = ( 77 + 86 ) 109 = ( 78 + 86 ) 110 = ( 79 + 86 ) 111 = ( 80 + 86 )

99 = ( 78 + 83 ) 100 = ( 79 + 83 ) 101 = ( 77 + 84 ) 102 = ( 78 + 84 ) 103 = ( 79 + 84 )

87

89

88

90 112 = ( 77 + 87 ) 113 = ( 77 + 88 ) 114 = ( 79 + 87 ) 115 = ( 77 + 89 ) 116 = ( 77 + 90 ) 117 = ( 77 + 91 ) 118 = ( 77 + 92 ) 119 = ( 78 + 89 ) 120 = ( 78 + 90 ) 121 = ( 78 + 91 ) 122 = ( 78 + 92 )

91

92 123 = ( 79 + 89 ) 124 = ( 79 + 90 ) 125 = ( 79 + 91 ) 126 = ( 79 + 92) 127 = ( 80 + 89 ) 128 = ( 80 + 90 ) 129 = ( 80 + 91 ) 130 = ( 80 + 92 )

Fig. 18 Chemical structures of molecular clips 77–80 and linear donors 81–92, cartoon representations of metallacycles 93–130

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131 135 = ( 131 + 136 = ( 131 + 137 = ( 131 + 138 = ( 131 +

58 , 132 - 134

132 ) 58 ) 133 ) 134 )

131

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Fig. 19 The synthesis of metalla-rectangles 135–138

142

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139 - 141

144 = ( 142 + 139 ) 145 = ( 142 + 140 ) 146 = ( 142 + 141 )

147 = (143 + 139 ) 148 = (143 + 140 ) 149 = (143 + 141 )

X = solvent or CF3 SO3

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141

Fig. 20 The synthesis of metallacycles 144–149 through coordination-driven self-assembly

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132 - 134

151 = ( 150 + 132 ) 152 = ( 150 + 133 ) 153 = ( 150 + 134 )

150

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134

Fig. 21 Schematic representations of the coordination-driven self-assembly of heterometallic rectangles 151–153

Moreover, due to the coexistence of Ru(II)– and Re(I)–polypyridyl units in the skeleton, Thomas et al. [40] further explored the employment of metallacycle 159 as singlet oxygen sensitizer for photodynamic therapy. Photocytotoxicity studies confirmed that, through the singlet oxygen generation, metallacycle 159 could cause biomolecules damage, which was phototoxic to MCF7 cells. Furthermore, by using another cell line A2780cis ovarian cancer cells, metallacycle 159 revealed the more potent cytotoxicity than cisplatin. Compared with its dark value with the IC50 of 61.7 mm, the IC50 decreased to 0.3 mm at the light dose of 48 Jcm2, making it a novel PDT sensitizer. On the basis of arene ruthenium complexes, in 2015, Therrien et al. [41] also prepared a suite of Ru(II)-based metalla-rectangles. Fig. 24 outlined the synthetic route. The dinuclear Ru(II) ligand 162 was firstly treated with two equivalents of AgCF3SO3. The sequential reaction with various ditopic N-ligands, such as pyrazine (prz), 4,40 -bipyridine (bpy), 1,2-bis(4-pyridyl)ethylene (bpe), 4,40 azopyridine (azp), and di(pyridin-4-yl)oxalamide (bpo), resulted in the formation of the corresponding metalla-rectangles 163–167 in good yields. The antiproliferative activity was evaluated in vitro on the human ovarian cancer cells A2780 and A2780cisR, as well as the noncancerous cell line HEK-293. The

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154 58, 132 - 134 155 -158

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58

133

134

Fig. 22 Synthesis of metallomacrocycles 155–158 via coordination-driven self-assembly

159

160

161

Fig. 23 The chemical structures of metallomacrocycles 159–161

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163 164 165 166 167

162

prz bpy bpe azp bpo

Fig. 24 Synthesis of metalla-rectangles 163–167 from 162 and the ditopic N-ligands

170 (168) 171 (169)

172 (168) 173 (169)

168

169

Fig. 25 Chemical structures of metalla-rectangles 170–173

obtained results suggested that metalla-rectangles 164 and 167 displayed excellent activity and selectivity for cancer cells, which might be attributed to the larger molecular weight and lipophilicity. Boron-dipyrromethene (BODIPY) is a kind of fluorescent dye, which displayed wide applications in light harvesting, photodynamic therapy, imaging, and in solar

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Fig. 26 Intracellular compound localization. Nuclei stained with DAPI in the presence or absence of compound treatment were observed under a confocal microscope (excited at 488 nm). (a) MCF-7 cells treated with 3 mM 170 and 1 mM 172; (b) HeLa cells treated with 3 mM 170; (c) U87 cells treated with 3 mM 170 and 171 and 0.75 mM 173. White arrows indicate fluorescent compound aggregates in the cytoplasm. (Reproduced with permission from Ref. [42], Royal Society of Chemistry)

58, 132-134

174 175-178

132

58

133

134

Fig. 27 The synthesis of metalla-rectangles 175–178

cells. In 2016, Lee et al. [42] designed a new pyridine-functionalized BODIPY ligand, and utilized it for the synthesis of Ru(II) and Ir(III) metalla-rectangles (Fig. 25). Initial biological screening revealed the anticancer activities of these rectangles in killing cancer cells. For instance, 170 and 172 were found to be against breast (MCF-7). Moreover, 171 and 173 were against brain (U87) cancer cells. Notably, they all displayed the better IC50 than that of cisplatin. In addition, it was found that some

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rectangles interacted strongly with DNA as well as protein. In particular, the introduction of BODIPY moiety into the metallomacrocycles made it exceedingly simple to visualize the complex inside the cancer cells under a confocal microscope (Fig. 26). Furthermore, in 2017, Lee and coworkers [43] prepared a new thiophenefunctionalized BODIPY ligand 174 and employed this ligand to produce four Ru (II) metalla-rectangles by coordination-driven self-assembly with ruthenium(II)based acceptors 58, 132–134 (Fig. 27). Notably, the introduction of thiophene group significantly improved the selectivity for cancer cells. All these complexes exhibited dose-dependent antiproliferative activities against cancer cells, in which some compounds could selectively kill cancer cells. Confocal laser scanning microscopy (CLSM) studies suggested that the complexes adopted a cytoplasmic mechanism of action in causing cell death. Moreover, the binding studies revealed that metalla-rectangles 175–178 could substantially interacted with DNA and protein.

37.4

Biological Applications of Rh- and Ir-Based Metallacycles

Similar with Ru-based complexes, iridium (Ir) complexes also showed excellent biological properties. In general, such cationic metal complexes could form crosslinks with DNA, causing hydrolysis and redox or photoreactions in living cells, thus revealing biological functions [44, 45]. In 2013, starting from the neutral dinuclear complexes 179 and 180, as well as the linear ditopic ligands, pyrazine, 4, 40 -bipyridine, and 1, 2-bis(4-pyridyl)ethylene, a series of metalla-rectangles 181–186 were successfully synthesized by Therrien and coworkers [46], some of which were confirmed by single-crystal X-ray structure

181 M = Rh 182 M = Ir

183 M = Rh 184 M = Ir 179 M = Rh 180 M = Ir 185 M = Rh 186 M = Ir

Fig. 28 Synthesis of metalla-rectangles 181–186 from 179 and 180

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Construction of Well-Defined Discrete Metallacycles and Their Biological. . .

187 M = Rh 188 M = Ir

1067

189 M = Rh 190 M = Ir

191 M = Rh 192 M = Ir

193 M = Rh 194 M = Ir

Fig. 29 Synthesis of the metalla-rectangles 189–194

analysis. In addition, according to the antiproliferative activity evaluation of the resultant metallacycles against the selective cancer cell lines, all cationic tetranuclear metalla-rectangles revealed high cytotoxicity with IC50 values in the low micromolar range (Fig. 28). Moreover, by using the same linear ditopic ligands, Therrien et al. [47] further reported the synthesis of Rh(III)- and Ir(III)-based metalla-rectangles 189–194 from the embelin-derived metalla-clips 187 and 188 in 2014 (Fig. 29). The antiproliferative activity evaluation of the resultant tetranuclear complexes in vitro on cancerous (DU-145, A-549, HeLa) and noncancerous (HEK-293) cell lines indicated that the corresponding Rh-based metallacycles showed a better activity compared with the Ir-based metallacycles. More importantly, all metallacycles displayed a very good selectivity for cancerous over noncancerous cells. Recently, Lee, Gupta, and coworkers [48] developed a new BODIPY-based ligand 195, which was used to prepare novel Ir(III)-based metalla-rectangles driven by coordination interactions. Rectangle 199 was found to be highly active against two cancer cells (HeLa and U87 cells) with IC50 values almost threefold superior to cisplatin. Moreover, rectangle 199 did not seem to break the nuclear membrane after 48 h of incubation, which indicated a cytoplasmic mechanism of action for the bioactivity in cancer cells. Additionally, both complexes 198 and 199 displayed dose-dependent abilities to bind with DNA and protein. Similarly, Lee, Gupta et al. synthesized Ir (III) metalla-rectangles containing benzimidazole moieties through coordination-driven self-assembly. These two complexes could selectively kill cancer cells and interact with biomolecules like DNA and proteins as well (Fig. 30).

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195 196 - 197

196

198 = ( 195 + 196 ) 199 = ( 195 + 197 )

197

Fig. 30 Schematic representations of the formation of metalla-rectangles 198 and 199

37.5

Conclusion

Taking advantage of the efficient and facile coordination-driven self-assembly, a series of Pd-, Pt-, Ru-, Rh-, Ir-based metallacycles were successfully constructed. Due to the existence of the biologically active metal complexes in the resultant metallacycles, further explorations of their biological applications such as DNA and proteins binding, bioimaging, drug delivery, anticancer activity, etc. have been performed. Attributed to the diverse structures of the resultant metallacycles and the special arrangements of the metal complexes within the skeletons, most metallacycles displayed the impressive biological activities especially anticancer activity, thus making them promising candidates as novel antitumor agents for anticancer therapy. However, although plenty of metallacycles have been evaluated, none has reached the clinical trial stage. In order to reach the ultimate goal, there is still a long way to go. The constructions of new and novel metallacycles and the investigations on their biological applications will remain a hot research topic in the future.

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Fabrication and Application of Cyclodextrin-Porphyrin Supramolecular System

38

Feng-Qing Li, Yong Chen, and Yu Liu

Contents 38.1 38.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fabrication of CD-Porphyrin Supramolecular Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.2.1 Inclusion Complexes of CDs with Porphyrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.2.2 Cyclodextrin-Porphyrin Conjugates through Covalent Bonding . . . . . . . . . . . . . 38.3 Applications of CD-Porphyrin Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.3.1 Biomimetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.3.2 Light-Harvesting Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.3.3 Medicinal Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.3.4 Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.3.5 Supramolecular Smart Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38.1

1073 1074 1074 1079 1084 1085 1091 1091 1095 1096 1098 1099

Introduction

Cyclodextrins (CDs) are a family of naturally occurring oligosaccharides bearing a basket-shaped macrocycle. CDs have attracted extensive research interest due to their good biocompatibility, high water solubility, low toxicity, and commercial availability [1]. Native CDs are comprised of six, seven, and eight α-Dglucopyranose units and referred as α-, β-, and γ-CDs, respectively. The cavity interior of CDs is lined up with the glycosidic O-4 atoms, the H-3 hydrogen atoms at the secondary face, as well as the H-5 hydrogen atoms near the primary face. It endows CDs peculiar amphiphilic character with a hydrophobic interior cavity and a hydrophilic periphery. Taking advantages of the cavity interior and the good water F.-Q. Li · Y. Chen · Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_44

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solubility of CDs, CDs can form stable assembly with diverse organic guest molecules (including adamantanyl and azobenzenyl groups) in aqueous system [2]. Furthermore, the abundance of hydroxyl groups enables natural CDs to be decorated with varieties of functional molecules (such as targeting and transport group and photosensitizer) [3]. It is conducive to expand their application in drug transfer, molecular imaging, and photosensitizer [4]. On the other hand, porphyrins are heterocyclic macrocycles formed from four pyrrole rings linked by four methylene groups. Coordinated with different metal ions (such as chlorophylls, cobalamines, heme in hemoglobin, etc.), porphyrin derivatives play a pivotal role in living systems [4]. Therefore porphyrin derivatives have been widely used as functional building blocks in supramolecular chemistry depending on their extensive and good biocompatibility, excellent geometric and morphological properties, and electrical and photochemical properties [5–8]. The great intrinsic properties of CDs and porphyrins have attracted great research interest to fabricate CD-porphyrin supramolecular systems and to explore their potentiality for novel functional materials. It is well-known that CDs can serve as proteinoid appendage in biological system and provide a hydrophobic environment for porphyrins to trigger their functionality [9, 10]. Furthermore, CDs can prevent self-aggregation of porphyrin molecules and improve their water solubility and ability to yield singlet oxygen [11, 12]. Supramolecular complexes composed of native/modified CDs and porphyrins have been reported to possess great potentiality in mimicking biological system [13]. Study on CD-porphyrin supramolecular system is still at the beginning stage and shows a bright future. In this chapter, the basic building blocks to construct supramolecular complexes of CDs and porphyrins are mainly classified as non-covalent inclusion complexes (binding through cooperation of hydrophobic, van der Waals, and hydrogen-bonding interactions), and covalently linked CD-porphyrin conjugates. Subsequently, the application of CD-porphyrin complexes for bio-mimicking, light-harvesting systems, and medicinal chemistry in recent years and their relationship with the building blocks are discussed. Meanwhile, supramolecular smart materials composed of CDs and porphyrins reported recently are emphasized. We hope this chapter will provide new theoretical basis for researchers in supramolecular chemistry and stimulate creative inspiration in this area.

38.2

Fabrication of CD-Porphyrin Supramolecular Systems

38.2.1 Inclusion Complexes of CDs with Porphyrins Varieties of inclusion complexes composed of CDs with different guest molecules have been designed through accurate analysis on the molecular binding behaviors, which is closely influenced by the individual molecular structures [14]. For guest molecules, it is critical to have a suitable size and shape to be recognized by the CD host. The average radii of α-, β-, and γ-CDs are 4.3, 5.0, and 5.9 Å, respectively. The diameter of porphyrin is larger than the cavity of single native CDs. Fortunately, the formation of a head-to-head dimeric structure of β-CDs provides a dimer cavity which is twice more than the volume of the monomer cavity. In the β-CD dimer, the secondary

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hydroxyl sides face to each other and are linked by many hydrogen bonds to form a barrel-like structure. The dimer cavity is large enough to accommodate bulky guest molecules such as porphyrins [15, 16]. Hydrogen-bonding interaction together with spatial fitting plays an important role in the formation of inclusion complex. The binding constant for the inclusion complexes of native CDs and naturally occurring porphyrin such as deuteroporphyrin IX, hematoporphyrin IX, and coproporphyrin III is relatively weak. This is ascribed to absence of appropriate CD-binding sites [17]. To alter or even improve their inclusion properties, great efforts have been made for modification on both CDs and porphyrins. The hydroxyl groups available in CD molecules show distinct differences in the reactivity [18]. Methylation is the simplest modification on CDs. Either partial- or per-O-methylated β-CD (PM-β-CD) can increase the depth of the cavity to improve the inclusion properties for bulky molecules. On the basis of the pKa values of the complexed tetrakis(4-sulfonatophenyl)porphyrin (TSPP) free base, the stability of the 1:2 complex of TSPP and PM-β-CD is expected to be much larger than that of the TSPP-2,6-DiMethylatated-β-CD complex. In aqueous solution, a stoichiometric solution of TSPP (1
106 M) and TMe-β-CD (2
106 M) yields the 1:2 complex quantitatively. The results indicate that the K11 value is >106 M1. Even in 1:3 H2Oethylene glycol solution, the K11 and K12 values are 2.0
104 and 5.8
104 M1, respectively [19, 20]. Depending on the differences in reactivity between O-2H, O-3H, and O-6H hydroxyl groups, two popular types of PM-β-CD which are substituted from different face and with quite different conformation have been prepared [21, 22], as shown in Fig. 1. Both of them exhibit strong binding ability with synthetic porphyrins which have ionic aryl substituents at the meso positions [9, 13]. The main binding mode is the partial inclusion of porphyrin into the dimer cavity of cyclodextrin via the secondary face, as shown in Fig. 2. Compared to cationic porphyrin guests, anionic porphyrins such as tetrakis(4-sulfonatophenyl)porphyrin (TSPP) are more favorable to be accommodated into the dimeric cavity of PM-β-CDs [23]. It is well demonstrated that by the change of apparent pKa values of their deprotonated forms in the presence of PM-β-CDs, the pKa value of anionic TSPP in water shows substantial decrease (from 5.4 to 0.4) through complexation with PM-β-CD, while cationic porphyrins do not show any pKa value change. 1H NMR spectroscopy demonstrates the formation of the trans-type 2:1 complex of PM-β-CD and TSPP in which the two PM-β-CD molecules face to each other. Solvation can strongly affect the inclusion behaviors of PM-β-CD and porphyrins. None of the porphyrins can form complexes with PM-β-CD in DMSO because no hydrogen bonds are formed between DMSO and PM-β-CD that the anionic guest may be repelled by the negatively polarized rims of the CD cavity. On the contrary, polar protic solvents such as H2O, ethylene glycol, and methanol can reduce the electrostatic repulsion between negatively charged guests and CDs. Supramolecular complexes of CDs with porphyrins have broad application in fabrication of multi-chromophoric arrays with tunable photophysical properties, magnetic resonance imaging, even to mimic and understand the biological model [24–26]. In living systems, porphyrins coordinated with different metal ions show different and significant functions [27]. It is expected that CD provides a

β-CD

β-CD

2-OTs-β-CD

6-OTs-β-CD

Fig. 1 Two popular types of PM-β-CD which are substituted from different rim

b

a

2,3-monoepoxy-β-CD

6-N3-β-CD

2,3-monoepoxy-PM-β-CD

6-N3-PM-β-CD

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a

1077

b

TSPP ZnTSPP CoTSPP MoTSPP MnTSPP FeIITSPP FeIIITSPP

M = 2H. M = Zn. M = Co. M = Mo. M = Mn. M = FeII. M = FeIII.

= PM-β-CD.

Fig. 2 Structure of synthetic TSPP derivatives and their 2:1 inclusion complex with PM-β-CD

microscopically apolar environment like proteins around the center of a porphyrin ring and prevents self-aggregation of the porphyrin through accommodating the substituents at the meso positions of the porphyrin into CD cavity [28, 29]. For example, Mn porphyrins are good candidates as an magnetic resonance imaging agent due to higher transmembrane permeability than that of common MnIIchelates and less toxicity than that of MnO nanoparticles at a higher dose [30]. Based on strong inclusion interaction between PM-β-CD and 5,10,15,20-tetrakis(phenyl)-porphyrin inserted with Mn (MnTPP), a supramolecular polymer was reported to increase the magnetic resonance (MR) imaging capability within the blood, kidney, and urinary bladder of the mice. The poly(ethylene glycol) on TPP increased the stability and biocompatibility and prolonged blood circulation. The cavity of PM-β-CD stabilized the low valent MnIITPP and prevented the oxidization so as to get a higher electronic spin [31]. Cyclodextrin dimer linked on the secondary face can enhance the binding stability of the dimers with guest molecules. A systematic study reported that β-CD dimers with two good binding groups can form inclusion complex with relatively rigid substrates with binding constants exceeding 109 M1 [32]. Koji Kano group designed a series of PM-β-CD dimers linked on the secondary face through bridging of pyridine or other heterocyclic group [22, 33–41]. The nitrogen atom in the linker is facilitated to bring coordination interaction with the metal atom in the porphyrin core. Not only the binding constants of these PM-β-CD dimers with FeII/FeIIITSPP reach up to 108 M1 [42], the inclusion complexes composed also exhibit prosperous future in biomimetics which will be discussed in detail at 3.1.

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Multivalent binding strategy has become an attractive method to construct functional supramolecular assembly [3]. Decorated porphyrins with moieties that possess strong binding ability with CDs become an effective and feasible way to fabricate supramolecular complexes with new function. Taking advantage of the high binding affinity between β-CD and adamantane moieties through strong hydrophobic interaction, an integrated multifunctional system was constructed by a supramolecular surface modification of graphene oxide (GO) with folic acid (FA) through a synthetic bifunctional molecule that contains a planar porphyrin moiety as a binding group and an adamantane moiety decorated on porphyrin molecule that is encapsulated in the cavity of cyclodextrin. The resultant supramolecular assemblies could specifically carry doxorubicin into folate receptor-positive malignant cells without imparting an enhanced toxicity (Fig. 3) [43]. Zinc porphyrins are very important units for preparation of heteroporphyrin arrays in the study of energy transfer and/or electron transfer in artificial photosynthetic systems [44, 45]. Zinc porphyrin linked with a 1-adamantanamine tail achieved an efficient and dominant pathway of static quenching in the presence of mono-6-nitrobenzoyl-β-CD with remarkably large electron-transfer rate (kSET, ca. 1.0
109 s1) [46]. As shown in Fig. 4, through host-guest interaction between a MnIII porphyrin core with four adamantyl moieties and the β-CD termini of temperature-sensitive

Fig. 3 Synthesis of FA-CD-PorAda/DOX/Go assembly through multivalent binding strategy. (Reproduced with permission [43]. Copyright 2012, Wiley-VCH)

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Fig. 4 Schematic representation of the preparation of the enzyme model composed of MnIII porphyrin with four adamantyl moieties and the copolymer with β-CD termini. (Reproduced with permission [47]. Copyright 2010, The Royal Society of Chemistry)

copolymer, an artificial smart bifunctional enzyme was formed in aqueous solution. The MnIII porphyrin was utilized as a “supramolecular linker” and an efficient active site of superoxide dismutase (SOD) and the tellurium moiety in the block copolymer as glutathione peroxidase (GPx) active sites. The resulting complex exhibited stable SOD-like activity of 0.137 mM (IC50) at 37  C and high GPx catalytic efficiency [47].

38.2.2 Cyclodextrin-Porphyrin Conjugates through Covalent Bonding Porphyrins are the common active site of a great deal of natural enzymes which perform high specificity and excellent catalytic activity. Self-aggregation of porphyrins in aqueous solution is usually a hindrance owing to the formation of catalytically inactive dimmers in the reaction process [48–50]. It remains a great challenge for biomimetic chemistry to synthesize artificial enzyme with good chemo-, regio-, and stereoselectivity. In the attempt to unravel the mechanisms behind the biological processes, biomimetic systems made of a porphyrin moiety covalently attached to a recognition element that mimics the hydrophobic pocket of natural enzymes have been investigated [51–53]. CDs have been extensively employed for this purpose, as they possess a well-defined, hydrophobic, chiral cavity and since well-determined methods for their selective chemical modification are now available. To mimic the light-induced electron transfer process in the reaction center protein of photosynthesis which is the reduction potential of the acceptor relative to the oxidation potential of the donor, CD-Por 1 (Fig. 5a) was designed as an electron donor to take advantage of the ability of cyclodextrins to complex hydrophobic species (electron acceptor) into their central cavity. The ESR spectroscopy of benzoquinone showed the signal intensity initially increased rapidly and then more slowly. It is attributed to complexation of benzoquinone by CD-Por 1 which adopt a conformation on freezing in which intramolecular electron transfer can occur, while the lower rate of increase may correspond to intermolecular quenching of the excited state of complexes of CD-Por 1 with benzoquinone in which the molecule exists in unfavorable conformations such that intramolecular transfer cannot occur. In support

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a

β-CD

β-CD

CD-Por 1

b

β-CD

β-CD

CD-Por 2

c

PM-β-CD

PM-β-CD

CD-Por 3

Fig. 5 Synthesis of and chemical structures of CD-Por 1–3

of this hypothesis, acceptors such as naphthoquinone and fluoroquinolone, which are larger than the others examined and may not fit into the cyclodextrin cavity as efficiently, do not give rise to an ESR signal significantly larger than that of the control. The results innovated to govern the efficiency of electron transfer through host-guest interaction of CD-porphyrin conjugates [54, 55]. In nature the relevant enzymatic reactions involve oxidation by metalloporphyrins, with reversible enzyme binding of the substrate in such geometry that specific substrate positions are within reach of the oxygen atom on the metal. The development in synthetic chemistry makes access to flexibly integrate CDs with porphyrins to prepare artificial enzyme with the use of geometric control in terms of selectivity [13, 48]. Utilizing reductive amination of 6-deoxy-6-formyl-β-CD with 5-( p-aminophenyl)-10,15,20-tris( p-sulfonatophenyl)porphyrin in the presence of an excess of sodium cyanoborohydride affords cyclodextrin-porphyrin conjugate (CD-Por 2, Fig. 5b) in 23% yield [56, 57]. Although the cyclodextrin is hydrophilic, CD-Por 2 showed a marked tendency to dimerize in aqueous conditions which can only be avoided by the formation of a 1:1 inclusion complex with heptakis(2,3,6-triO-methyl)-β-cyclodextrin. Synthesized from 5-(phydroxy phenyl)-10,15,20-tris (3,5-dicarboxyphenyl)porphyrin and monotosylated PM-β-CD, CD-Por 3 (the structure shown in Fig. 5c) forms a very stable 1:1 complex with zinc [5-phenyl-

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CD-Por 4 X = S, R1 =β-CD, M=2H. CD-Por 5 X = S, R1 =β-CD, M=Zn. CD-Por 6 X = S, R1 =β-CD, M=Fe. CD-Por 7 X = S, R1 =β-CD, M=MnIII. CD-Por 8 X = O, R1 =PM-β-CD, M=2H. CD-Por 9 X = S, R2=β-CD, M=2H. CD-Por 10 X = S, R2=β-CD, M= MnIII. CD-Por 11 X = S, R3=β-CD, M=2H. CD-Por 12 X = S, R3=β-CD, M= MnIII.

Fig. 6 The chemical structure of CD-Por 4–12

10,15,20-tris(3,5-dicarboxyphenyl)] porphyrin (K = (7.0  0.3)
105 dm3 mol1) with an energy transfer efficiency (93%) larger than that obtained in the case of CD-Por 4 (Fig. 6) [48, 58]. Attachment of two or four CD substrate-binding sites at the meso positions of the porphyrin from [p-(methylsulfonyl) phenyl] porphyrin and 6-iodo-β-cyclodextrin (CD-Por 4–12, as shown in Fig. 6) was utilized to selectively catalyze the oxidation of different specific substrates. As shown in Fig. 7, the MnIII complex could selectively catalyze the oxidation of olefinic substrates with binding site anchored into two β-CD rings to stretch the substrate across the porphyrin ring, while the substrate double bond directly above the MnIII atom in porphyrin. There is an interesting effect of added adamantanecarboxylate, which up to a certain concentration raises the selectivity for the well-bound substrate. When the substrate binds to CD-Por 7 or CD-Por 12 on one face of the porphyrin, there is a possibility that the oxo group goes to the other face and performs nonselective oxidation of substrates. The adamantanecarboxylate coordinates to that face and prevents such nonselective

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O Mn O O

Fig. 7 Schematic diagram of a substrate binding into two cyclodextrins of a MnIII porphyrin. The Mn carries oxygen that will add to the substrate double bond, and the opposite face is shielded by adamantanecarboxylate

oxidation [48, 58]. To enhance the stability of the metalloporphyrin catalyst with β-CD rings, tetrafluorophenyl rings were used to replace the phenyl group in CD-Por 7; both high conversion and high turnover in the selective hydroxylation of androstanediol derivatives can be achieved [59]. Apart from etherification, esterification, and nucleophilic substitution reaction, another one of the most highly dependable and popular tools for facile construction of CD-porphyrin conjugates is click reaction. The unique advantages of mild reaction condition and efficient performance with a wide range of solvents enable click reaction very popular in synthesis of various CD derivatives [60]. Utilizing Cu-catalyzed click chemistry, a series of natural or methylated β-CDs connected to the meso position of tetraphenylporphyrin, was synthesized and widely used in mimicking bioenzyme, light-harvesting system, and photodynamic therapy. Porphyrin-bridged octaPM-β-CD module (CD-Por 13, Fig. 8a) synthesized via click reaction was reported not only to enhance aqueous solubility and preclude porphyrin-based stacking interactions but also facilitate directional host-guest inclusion complexation with pristine C60 in water [45, 61]. Scanning tunnel microscope (STM) images suggested that the nanorod structure was composed of sequential repeats of four 2: 1 PM-β-CD-C60 interactions (Fig. 8b). The resulting porphyrin-C60 nanorod is particularly attractive for the fabrication of functional nanomaterials, given the potential light-harvesting and photo-induced electron transfer properties of their constituents. Multivalent binding strategy is still applicable for complexes composed of CD-porphyrin conjugates. Harnessing the robust host-guest interaction between β-CD and adamantane derivatives, the unidirectional and heteromeric assemblies of CD-Por 14 and Ada-Por into a striking high-aspect ratio (single-molecule wide)

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a

CD-Por 13 R = PM-β-CD, M = Zn. CD-Por 14 R = β-CD, M = Zn. Ada-Por R = Ada, M = 2H.

b

c +

CD-Por 13 Porphyrin 4

+

= Fullerene C60 1) Toluene/DMF

CD-Por 14

Ada-Por Water

2) Purification

Porphyrin-C60 Nanowire

Porphyrin Nanowire

Fig. 8 (a) Chemical structure of CD-Por 13–14 and Ada-Por. (b) Preparation of porphyrin-C60 nanowire via inclusion complexation of pristine C60 by CD-Por 13. (Reproduced with permission [45, 61]. Copyright 2009, The Royal Society of Chemistry). (c) Porphyrin nanowire composed of CD-Por 14 and Ada-Por. (Reproduced with permission [62]. Copyright 2010, American Chemical Society)

nanowire (Fig. 8c) were formed in water. Given the modularity, water solubility, and resistance to disassembly of the homomeric porphyrin nanowires, it is expected that alternate arrays with interesting electronic, catalytic, or photodynamic properties could be achieved [62]. One challenge in self-assembly is to design molecular building blocks in which the parameters that determine the behaviors and interactions of each component in the system could be changed easily for organizing themselves into desired patterns and functions [63]. An amphiphilic compound is inclined to assemble into vesicles which represent an important class of materials with special roles in the fields of drug delivery, microreactors, filters, and artificial biomembranes. 5-(40 -dodecyloxyphenyl)-10,

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Fig. 9 Schematic representation of the guest-induced morphological transition from vesicle to network composed of amphiphilic PM-β-CD-porphyrin derivatives. (Reproduced with permission [64]. Copyright 2015, Wiley-VCH)

15, 20-tri (permethyl-β-CD)-modified zinc porphyrin was synthesized by means of the click reaction of an alkylated ZnII-porphyrin derivative with 6-deoxy-6-azidopermethyl-β-CD in a good yield. This amphiphilic compound can, respectively, selfassemble into nanoscaled vesicles and fibers in aqueous solution through changing the host-guest stoichiometry ratio (Fig. 9) [64]. The time-dependent transmission electron microscope (TEM) experiments demonstrated the process of the morphological transition from vesicles to networks. The NMR spectroscopic results suggested that the origin of the morphological transition is ascribable to the 360 rotation of the opposing pairs of PM-β-CD units induced by tetrasodium tetraphenyl porphyrin tetrasulfonate guest. Both vesicles and networks can be applied as potential drug carriers. The release rate of doxorubicin hydrochloride (DOX) is distinctly different in these drug-encapsulated supramolecular assemblies so that the release rate of loaded agents can be satisfactorily controlled by changing the host/guest molar ratio. The results not only provide a novel approach to easily construct supramolecular nanoarchitectures with desired nanostructures but also pave a feasible way to rationally design the drug delivery systems with different controlled-release abilities.

38.3

Applications of CD-Porphyrin Complexes

Nature inspires scientists to devise smart nanoarchitectures and innovative approaches to simplify, mimic, or even regulate biological and physiological mode systems [65]. Cyclodextrin can be served as an ideal substitution of proteinoids to provide a hydrophilic rim and a hydrophobic cavity for porphyrin derivatives to mimic the microenvironment and versatile functions. Accordingly, various supramolecular complexes based on CDs and porphyrins either covalent binding or inclusion complexes have been elaborately and sophisticatedly synthesized. The applications on CD-porphyrin supramalecular complexes published before 2015 have been reviewed in detail by Michał Kryjewski et al. [13]. In this section, we will highlight representative works related to CD-porphyrin supramalecular complexes in biomimetics, light harvesting, catalysis, and pharmacy published recently and significantly.

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38.3.1 Biomimetics The diversity of dioxygen chemistry spans all subcategories of chemistry and is the cornerstone of aerobic life. The reduction reaction from dioxygen to water is not only extremely important in biology for cellular respiration and oxidative phosphorylation but also the cathodic reaction in sustainable fuel cells and, therefore, of great interest for industrial application [66]. In the muscle/bloodstream of living organism, myoglobin/hemoglobin can reversibly bind molecular oxygen (O2) on its heme ion to carry O2. In this process, iron porphyrins are fixed in the globular proteins and convert from a six-coordinated low-spin state to a five-coordinated high-spin state to reversibly bind dioxygen and reduce it to water. The globins not only encapsulate the heme to prevent m-oxo dimer formation but also provide a hydrophobic microenvironment to inhibit the nucleophilic attack on the FeII–O2 bond by H2O molecules, which leads to oxidation of the FeII to the FeIII state [67, 68]. The Fe-Cu heterobinuclear active site also plays a key role in the reduction process of dioxygen to water. FeIII/FeII TSPP have been widely used as the active site in model systems of myoglobin (Mb) and hemoglobin (Hb). The presence of PM-β-CD can inhibit μ-oxo dimerization of FeIIITSPP by forming an inclusion complex with the sulfonatophenyl groups of the porphyrin. Koji Kano group synthesized a series of PM-β-CD dimers with pyridine/imidazole linker to form inclusion complexes with FeIITSPP which have an extremely high stability constant (up to 108 M2) [22, 33–41]. As shown in Fig. 10, pyridine and imidazole linkers, which coordinated with the metal atom in the porphyrin centre by the nitrogen atom, anchored porphyrins into the dimeric cavity of PM-β-CD and originated the oxygen molecule(carbon monoxide, and cyanide anion) goes to the other face [33]. Taking advantage of the high binding constants and good water solubility of the complexes, synthetic Mb and/or Hb model complexes that reversibly bind molecular oxygen have been successfully obtained in aqueous solution at room temperature. FeII-hemoCD1 complex can efficiently detect and capture endogenous carbon monoxide in cells. When the linker was replaced by imidazole moieties, the FeIIITSPP/Im3CD complex can successfully capture cyanide anion and served as an antidote for cyanide poisoning for in vivo use [35]. The spectroscopic and kinetic study of the cyanide binding to FeIIITSPP/Im3CD complex revealed the formation of mono- and dicyano adducts with Kass values of 5.5
105 and 3.8
105 M1, respectively, at pH 8.0 and 20. But the Kass values for FeIIITSPP by itself and the 2:1 TMe-β-CD-FeIIITSPP complex are too small for practical application as antidotes for cyanide poisoning. FeIIITSPP/Im3CD complex with a wider interspace between the two cyclodextrin units causes easy penetration of H2O into the capsule, leading to H2O-promoted autoxidation of O2-FeIIPIm3CD to FeIIIPIm3CD and a superoxide ion. In addition, the carbon monoxide affinity of FeIIPIm3CD (P1/2CO = 1.6
103 Torr at pH 7.0 and 25  C) is much lower than that of hemoCD1 (1.5
10–5 Torr). The authors confirmed that FeIIIPIm3CD injected into the femoral vein of a rat was rapidly excreted in the urine without reduction to its ferrous form. An inevitable problem in porphyrin derivatives utilized in biology as photosensitizers is delivery of the synthetic compounds into the cell. The use of cell-

Fe II-hemoCD1

II

Fig. 10 Chemical structure of PM-β-CD dimer and their assemblies with FeIII/FeII TSPP

Fe III-hemoCD1

III

II

Fe II-hemoCD1-O2

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penetrating peptides (CPP) can effectively deliver lots of photosensitizer molecules into cells. Kano et al. covalently attached artificial host molecule (PM-β-CD) to the arginine octamer (R8) with a terminal alkyne by a copperI-catalyzed azide-alkyne cycloaddition reaction to non-covalently deliver TSPP into cells [36]. The UV-vis and NMR spectroscopy demonstrated the formation of 2:1 inclusion complex. The cellular uptake experiments of the TSPP-R8-CD complex using HeLa cells suggest that R8-CD (Fig. 11a) can be used as a powerful molecular tool for intracellular delivery of tetraarylporphyrins in vivo. Recently, they quantified carbon monoxide (CO) produced in control and heminstimulated cells using a simple photometric method that utilized FeIIhemoCD1. Then, they covalently attached the octaarginine peptide to a maleimide-appended FeIIImet-hemoCD1 to synthesize R8-hemoCD1, a cell-permeable CO scavenger [37, 38]. The 1H NMR spectroscopy suggested that the supramolecular Mal-methemoCD1 complex exists as an approximate 1:1 mixture of the 5,15- and 10,20-

Fig. 11 (a) The chemical structure of R8-CD. (b) Preparation of R8-hemoCD1. (c) Schematic representation of R8-hemoCD1 as a scavenger of intracellular CO. (Reproduced with permission [37]. Copyright 2017, American Chemical Society)

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complexes shown in Fig. 11b. After conjugation with R8, the FeIII complex was reduced by Na2S2O4 to ferrous complex of R8-hemoCD1. The R8-hemoCD1 complex not only can remove intracellular CO resulted in increased ROS generation in macrophages but also can inhibit the anti-inflammatory effects mediated by a CO-releasing agent. In mitochondria, cytochrome c oxidase (CcO) catalyzes the reduction of oxygen molecular to water by using a heme/copper heterobinuclear active site. The mechanism for the reduction of oxygen molecular catalyzed by cytochrome c oxidase (CcO) in mitochondria can be simplified as shown in Fig. 12a [39, 66]. Kano et al. designed an inclusion complex of bis(PM-β-CD) connected with a copper (II) terpyridyl complex linker, FeIII-O2/CuICD2 complex, to mimic the distal trishistidine-ligated heterobinuclear active center of CcO in water. It is the first watersoluble biomimetic model with high efficiency to date. The UV-vis titration experiments demonstrated the formation process of (CuIICD2) complex and CuIICD2/ FeIITSPP complex and their O2-binding ability. The heterobinuclear Fe/Cu active site is successfully accommodated in the hydrophobic pocket of PM-β-CD dimer, as shown in Fig. 12b. ESI-MS and optical absorption spectroscopy revealed the formation of a μ-oxo (FeIII-O-CuII) structure [(TSPP)FeIII]+/[(TerpyCD2)-CuII]2+ with pKa value of 8.8. Reduction of [(TSPP)FeIII]+/[(TerpyCD2)CuII]2+ with sodium dithionite yielded the reduced analogue [(TSPP)FeII]0/[(TerpyCD2)CuI]+, which reacted with O2 to yield a ferric superoxide species formulated as a (P)FeIII-(O2•-)CuI(L3) complex. The superoxide complex was metastable, and it gradually converted to the oxidized analogue [(TSPP)FeIII]+/[(TerpyCD2)CuII]2+ with a pH-dependent rate constant. At lower pH values, in the range of ca. 7–10, the superoxide decayed more rapidly, suggesting that some proton-coupled process is involved in the conversion of the superoxide complex to [(TSPP)FeIII]+/[(TerpyCD2) CuII]2+. Electrochemical technique analyses of O2-reduction by [(TSPP)- FeIII]+/ [(TerpyCD2)CuII]2+ and its reference samples, [(TSPP)FeIII]+ and [(TSPP)FeIII]+/ [(TerpyCD2)CuII]2+, showed that under the conditions employed, diffusion-limited catalytic O2 reduction was enhanced for the heme-Cu complex (n ~ 3.0 electrons per O2) compared to that for the “reference” compounds (n ~1.63). This simplified synthetic heme/copper models facilitate us to deeply understand the reaction mechanism of cytochrome c oxidase chemistry. The inclusion complex with a small size was easily cleared out of body through the urinary system, leading to short circulation times. To increase the molecular size and retain them in the blood for a long time, CDs and porphyrins fixed to a large platform, including metal/inorganic nanoparticles and polymers, have been designed [40]. Through poly-ethylene glycol with thiolated arms, FeIIITSPP could be anchored on the surface of Au nanoparticles and maintained itsμ-oxo dimer. By formation of inclusion complex with Py3CD, the FeIIITSPP/AuNPs could carry diatomic molecules such as dioxygen and CO in vivo. However, the drawback of the FeIIITSPP/AuNPs to the accumulation in the spleen and liver limits their application. Instead, polymers modified with porphyrins or CDs as functional moiety gradually become popular candidates for Mb/Hb mimicking, due to their high molecular

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Fabrication and Application of Cyclodextrin-Porphyrin Supramolecular System

I

a)

II

II

III

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I

III

II

IV

b)

Fig. 12 (a) The simplified mechanism for the O2 reduction reaction catalyzed by CcO. (b) Oxygenation of the FeIITSPP/CuITerpyCD2 complex to form a superoxo PFeIII–O2/CuICD2 complex. (Reproduced with permission [39]. Copyright 2018, The Royal Society of Chemistry)

weight, predictable conformations in solution, and multiple-level hierarchies derived from their chemical and spatial structures [69]. The polymeric assembly provides a hydrophobic microenvironment and a hydrophilic periphery for the porphyrin and further enhances its stability in a biological environment. Taking advantage of the high binding constant and stability of FeIIITSPP/Py3CD complex, FeIIITSPP attached to poly(acrylic acid) was successfully retained FeIIITSPP/hemoCD oxygen carriers for a long residence time in the blood. The FeIIITSPP/hemoCD polymer with small amount of FeIIITSPP/hemoCD active site per polymer is more stable than the larger one ascribed to the self-catalyzed autoxidation owing to hydrogen peroxide transition state [41].

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Fig. 13 Schematic illustration of the formation of the artificial oxygen carriers through supramolecular assembly and the subsequent oxygen binding. (Reproduced with permission [72]. Copyright 2016, The Royal Society of Chemistry)

Block copolymers with controlled architectures and narrow molecular weight distributions can also serve as a carrier and confined reactors for metalporphyrins [70]. A core-shell complex micelle constructed through coassembly of diblock copolymer with 4-vinylypridine moiety, FeIIITSPP, and β-CD inclusion complex was reported to mimic dioxygen carrier. Fe/Zn porphyrins were encapsulated into the cavities of β-CD to prevent aggregation of porphyrins and the irreversible formation of a μ-oxo-dimer. The pyridine groups of block copolymers or imidazole groups of the heptapeptide coordinated to the centric FeIII and constituted the fivecoordinated porphyrin for oxygen binding [71]. In order to improve the stability and biocompatibility of the complex micelle, they designed a core-shell complex micelle through multivalent binding strategy of poly(ethylene glycol)-block-poly (L-lysine)(PEG-b-PLys), a heptapeptide, CoIITSPP, and PM-β-CD (Fig. 13). The complex micelle provided double hydrophobic barriers, the cavity of the cyclodextrin and the core of the complex micelle, for CoIITSPP to resist nucleophilic molecules.

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38.3.2 Light-Harvesting Systems In photosynthesis system, chlorophyll anchored in light-harvesting protein to absorb light and achieve prompt ultrafast photo-induced electron transfer. Great efforts have been dedicated to mimic this efficient multilevel electron/energy transfer process [5]. Compared to covalently linked electron donor and acceptor dyads, supramolecular complexes of donor and acceptor built in aqueous solution by means of hydrophobic interactions exhibit great priority in controlling the distance and orientation. The most common drawback of chromophores is their poor water solubility which resulted in substantial π-π stacking interaction and fluorescence quenching. Engineering aromatic chromophores with CDs is conducive to improve their water solubility. Furthermore, utilizing the strong binding ability of CDs with guest molecules that possess complementary spectra characteristics, highly ordered nanoarchitectures with well-defined topology, and desired physicochemical properties can be achieved. Significantly, the spectrum of CDs in ultraviolet and visible regions is optically transparent. It facilitates to fabricate heteroporphyrin arrays in aqueous solution without any influence on the absorption and electron transfer process by CDs. Hexabenzocoronene is a novel class of carbon-rich supramolecular architectures consisting of 13-fused-6-menbered rings. Strong electron/energy transfer from hexabenzocoronene donor to porphyrin acceptor has been reported through conjugating them covalently [73]. Yu Liu group modified hexa-cata-hexabenzocoronene (CHBC) with three PM-β-CDs to enhance the physicochemical properties of porphyrin derivative with CHBC in water. The PM-β-CDs improved water solubility of CHBC and formed inclusion complex with TSPP. Significantly, the inclusion complex not only exhibited an efficient energy transfer process from CHBC to TSPP in aqueous solution but also exhibited excellent activity of cleaving DNA under visible light irradiation (Fig. 14) [74].

38.3.3 Medicinal Chemistry In recent decades, photodynamic therapy (PDT) utilizing reactive oxygen species (ROSs) generated from molecular oxygen in the presence of photosensitizers upon irradiation by appropriate wavelength of light has shown to be an effective and fascinating method to treat cancer and local infection caused by different microorganisms, such as Gram-positive and Gram-negative bacteria, viruses, fungi, and protozoa [75]. Porphyrin derivatives such as Photofrin have been widely used in clinical cancer treatment contributed to their relatively high efficient singlet oxygen generation quantum yield and selectivity for cancer cells. The hydrophobic porphyrins are likely to aggregate together in blood vessels, which therefore hinder their singlet oxygen production. Through covalent or non-covalent bond interaction, the amphiphilic property of CDs can assist porphyrin derivatives to overcome this shortcoming and enhance their antitumor activity through promoting

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a N N N O

O O

O

O

O

O

O

O O

O

Click reaction

O

O

N3

O

O

O O

O

O

O

O

N

N N

O O

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N N N

4

CHBC-1

SO3Na

NaO3S

N

N H H N

NaO3S

N3

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O O

O

O

O

O

O

O

6

SO3Na TSPP

b

EET

Fig. 14 Synthesis of PM-β-CD modified CHBC and its assembly with TSPP. (Reproduced with permission [74]. Copyright 2017, The Royal Society of Chemistry)

singlet oxygen generation quantum yields and/or photogeneration of nitric oxide [76–78]. For example, CDs conjugated with porphyrins bearing pentafluorophenyl moiety have been reported to not only increase solubility of the resulting conjugates in aqueous media and enhance membrane permeability but also achieve multifunctional drug delivery and therapy based on the binding ability of CDs with anticancer agents

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(referred as PDT-drug delivery therapy) [13]. CDs can serve as scaffolds for the systemic administration of porphyrin sensitizers and other antitumor photodynamic agents. The hydrophobic interior cavity of CDs plays a key role in entrapping and sustaining release of antitumor photodynamic agents to the sickly tissues. The inclusion complex of PM-β-CDs with porphyrin derivatives which has different aromatic substituents at the meso-positions showed different photodynamic activities toward cancer cells under illumination at wavelengths over 600 nm, the most suitable wavelengths for photodynamic therapy. Porphyrin derivatives containing aniline and phenol substituents showed high photodynamic activities than Photofrin, which is attributed to the efficient intracellular uptake of the complexes by tumor cells [79]. Antimicrobial photodynamic therapy has become an emerging well-known antibacterial therapeutic approach to fight against multidrug-resistant bacteria infection [12, 80]. TSPP, NiIITSPP, and ZnIITSPP derivatives have been proposed for photoinactivation of Gram-negative bacteria. Immobilized CDs on polypropylene fibers (PolyCTR-CD) have been reported to entrap TSPP in the cavities of CDs to be utilized as photosensitizer-eluting scaffold (PolyCTR-CD/TPPS) for antimicrobial photo dynamic therapy (Fig. 15). Grafted CDs on polymers can increase the CD amount grafted. The PolyCTR-CD/TPPS complex can achieve sustained and controlled delivery in release medium and simultaneous photoinactivation of microorganism [81]. Hyaluronic acid (HA) has been widely used for medical and biological applications contributed to its biocompatibility, biodegradability, non-toxicity, non-immunogenicity, and non-inflammatory properties. Interestingly, HA exhibits outstanding targeting activity for selectively binding to the surface of cancer cells that with overexpressed specific receptors such as cluster determinant and receptor for

Fig. 15 Preparation of fabric based on TPPS and CDs decorated polypropylene fibers coating components and its antibacterial mechanism. (Reproduced with permission [81]. Copyright 2017, American Chemical Society)

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hyaluronate-mediated motility. Taking advantage of host-guest interaction between CDs and guest moieties, HA grafted by functional group such as CDs and adamantane has been regarded as potential engineered nanocarriers for drug delivery and targeting agents [82]. Nanoparticles (HATXP), composed of PM-β-CD-modified HA (HApCD) and porphyrin-modified paclitaxel prodrug through host-guest and amphiphilic interactions, exhibited specific targeting internalization into cancer cells via HA receptor-mediated endocytosis effects. The cytotoxicity experiments showed that the HATXP exhibited similar anticancer activities but with much lower side effects than commercial anticancer drug Taxol. On the other hand, benefiting from the fluorescent porphyrin part, the location of the nanoparticles in cells, could be explicit [83] (Fig. 16). Another versatile tumor-specific theranostic nanoplatform based on mesoporous silica nanoparticles was obtained by coating tirapazamine (TPZ)-loaded mesoporous silica (MS) nanoparticles (TPZ@MS) with sequential assembled supramolecular

Fig. 16 The synthetic routes of HApCD, PorTaxol, and HATXP nanoparticle. (Reproduced with permission [83]. Copyright 2016, Nature Publishing Group)

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Fig. 17 Schematic illustration of TPZ@MCMSN-Gd3+ to achieve superior antitumor efficacy by the collaboration of supraPSs-based photodynamic therapy and bioreductive chemotherapy. (Reproduced with permission [84]. Copyright 2017, Elsevier)

photosensitizer through host-guest interaction of HA-CD and TSPP and the chelation with paramagnetic Gd3+. The resulting TPZ@MCMS nanoparticles (TPZ@MCMSN-Gd3+) could be specifically uptaken by luster determinant receptor overexpressed tumor cells and respond to hyaluronidase to trigger the release of therapeutics. In vivo studies showed that the TPZ@MCMSN-Gd3+ preferentially accumulated in tumor site and significantly inhibited the tumor progression by the collaboration of PDT and bioreductive chemotherapy under near infrared (NIR) fluorescence/magnetic resonance imaging guidance (Fig. 17) [84].

38.3.4 Catalysis Cytochromes P450 is a class of heme-dependent proteins, which natively functions as oxygenases and transfers oxygen to hydrocarbons or heteroatoms with high chemo- and regioselectivity [85, 86]. The water-soluble external rim and the hydrophobic and chiral cavity interior of CDs endow themselves remarkable inclusion capabilities with suitable organic molecules in water. This superiority enables CDs a good alternative for artificial enzymes and catalysis for chemical reactions. CDs have been used to catalyze conventional chemical reactions (such as hydrolysis, elimination, addition, substitution, oxidation, and reduction reactions) and as chiral reaction containers for the asymmetric oxidation in water [87]. The MnIII porphyrin

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Fig. 18 Schematic representation of the tubular self-assembly. (Reproduced with permission [88]. Copyright 2014, Wiley-VCH)

complexes carrying four or two β-CD rings can selectively bind substrates of appropriate length with two hydrophobic ends and then selectively oxidize them with good catalytic turnover [48]. Research on the application of CDs for catalysis is only beginning to be discovered. Employing a rigid siliconIV phthalocyanine axially bridged bis(PM-β-CD) to binding with an amphiphilic porphyrin which bears long hydrophobic tails, a hollow tubular structure was constructed as a supramolecular nanoreactor [88]. The Scanning Electron Microscopy (SEM), TEM, and X-ray diffraction (XRD) experiments inferred that the interior and exterior surfaces of the nanotubes are composed of the highly stable PM-β-CD/porphyrin-associated units with rigid phthalocyanine spacers, whereas the hydrophobic alkyl chains interlace with each other in the middle of the tubular walls (Fig. 18). The pendant carboxylic acid groups located at the periphery of the porphyrins that served as anchoring sites could immobilize various metal-based catalysts. The supramolecular nanotubes not only acted as supporting materials but also promoted the positive conversion from reactants to products without any adverse effect on catalytic activity and conversion. Exploration of functionalized CDs and their complexes with porphyrin through judicious design will continue to energize and expand into other fields of asymmetric synthesis and chiral materials.

38.3.5 Supramolecular Smart Materials Supramolecular smart materials that are responsive to light have attracted increasing interest due to its reversibility and remote-controlling properties [89–91]. The strong binding ability of PM-β-CDs toward porphyrin guests arising from the effect of multivalency is very useful for construction of controllable nanoarchitectures with three-dimensional periodicity and collective behaviors. Zinc phthalocyanine-grafted PM-β-CDs could be assembled into supramolecular nanowire where the pristine fullerene could be efficiently captured by the preorganized π-electronic cage in water [92]. Utilizing the ‘orthogonal’ host-guest interaction of the zinc phthalocyaninegrafted PM-β-CDs together with naphthyl bridged bis(α-CD)s toward porphyrin and

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Fig. 19 Photo-controlled reversible conversion of nanotube and nanoparticle mediated by cyclodextrin dimers. (Reproduced with permission [94]. Copyright 2018, Springer Nature)

azobenzene, a photoswitchable and reversible assembly/disassembly process was realized upon irradiation [93]. Linked PM-β-CD dimer with photo-responsive moiety (such as azobenzene and dithienylethene) can facilitate to control the properties of CD-porphyrin supramolecular systems by taking advantages of the strong binding affinity between PM-β-CD and water-soluble porphyrins. For example, a photochemically interconvertible supramolecular nanotube-nanoparticle system was constructed through secondary assembling of self-aggregates of amphiphilic porphyrin derivatives and mediated by trans- and cis-azobenzene-bridged bis(PM-β-CD) (Fig. 19). The designed porphyrin formed typical H-aggregates accompanied with fluorescence quenching in aqueous buffer and assemble into spherical nanostructures with an average diameter of

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ET

FR

650nm

422nm 650nm

UV Vis FR

ET

Fig. 20 Schematic representation for photo-controlling the FRET process of their assembly. (Reproduced with permission [97]. Copyright 2016, The Royal Society of Chemistry)

150 nm. The presence of monomeric PM-β-CD prevents self-aggregation of porphyrins(G) by forming 2:1 inclusion complex with binding constants as K1 = 3.4
108 M1 and K2 = 1.2
107 M1 by UV/vis titration. When bridged bis(PM-β-CD) binds with azobenzene, the Job’s analysis of the UV/vis spectral data indicated the stoichiometric 1:1 binding radio between H and G, and the apparent binding constant was calculated as 2.37
106 M1 and 8.45
106 M1 for the association of G with trans- and cis-isomer of H, respectively. SEM and TEM images showed hollow tubular structure of a uniform hollow size, and the average inner and outer diameters of the H-trans/G nanotubes were about 45 and 61 nm, respectively. After irradiation of the solution of H-trans/G at 365 nm for 20 minutes, the morphology interconverted into a number of solid nanoparticles with an average diameter of 180–200 nm, which is attributed to the photo-induced geometrical change of H from the trans-isomer (H-trans) to cis-isomer (H-cis) [95]. Dithienylethene is another one of the most attractive families because of their fatigue resistance, thermally stability, high photocyclization/cycloreversion quantum yields, and rapid response time [96]. Connected PM-β-CD onto dithienylethene unit can improve the water solubility of dithienylethene unit and form photo-controlled supramolecular complexes. As shown in Fig. 20, the dithienylethene-modified PM-β-CD host (DTE-PM-β-CD) exhibited reversible photoisomerization and photochromism behaviors in aqueous solution. The UV-vis titration spectra demonstrated the strong association of PM-β-CD with TSPP/ZnTSPP, with high binding constants (K = ~107–9 M1). The emission spectra also showed red shifts accompanied by the obvious intensity changes. The circular dichroism spectra showed relatively high circular dichroism signals in the presence of DTE-PM-β-CD. The TEM image that showed rodlike nanostructures indicated a possible secondary aggregation of the linear assemblies. The UV-vis spectra and fluorescence spectra exhibited significant photo-controlled Förster resonance energy transfer (FRET) behaviors. The near-infrared emission spectra of the complexes showed a photoswitchable, efficient, and reversible 1O2 generation property [97].

38.4

Conclusion

In this chapter, both non-covalent inclusion complexes and covalently linked CD-porphyrin conjugates are summarized as the main binding mode to form CD-porphyrin supramolecular complexes. The main driving forces to form inclusion

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complexes of CD-porphyrins are hydrophobic, van der Waals, hydrogen bond, and electrostatic interactions, or a cooperation of them. The high selectivity and binding affinity of β-CD derivatives with porphyrin derivatives enable access to supramolecular complexes with enhanced properties or a new one, such as molecular oxygen binding, electron/energy transfer, drug encapsulation, and catalysis. CD-porphyrin supramolecular complexes exhibit fascinating and practical application for biomimetics and functional materials. The target to mimic heme-copper oxidases in water has achieved breakthrough progress. In the light of accumulated research achievements, elaborately designing controllable supramolecular assembly through modification on the structure of CD and porphyrin building blocks has been proved to be a practical strategy. Many challenges have to be faced in the forthcoming studies on CD-porphyrin supramolecular complexes. Mimicking the function of a heme/copper heterobinuclear active site in water has been achieved, how to extend the retaining time of those CD-porphyrin supramolecular complexes in blood to perform their bioactivity without any side-effects? The hydrophobic interior cavity of CDs is favor to accommodate aromatic chromophores, how to sophisticatedly construct multilevel hetero donor-acceptor system utilizing CD-porphyrin supramolecular complexes with high electron/energy transfer? How to fabricate artificial enzyme based on CD-porphyrin supramolecular complexes and expend their application for catalysis? How to fabricate artificial enzyme in terms of chemo-, regio-, and stereoselectivity? Metalloporphyrins are ubiquitous in the naturally occurring enzyme, but research on the application of CDs for catalysis is only beginning to be discovered. With the rapid development of techniques in synthesis chemistry and materials manipulation, we believe that more exciting findings of CD-porphyrin supramolecular complexes with infinite potentiality will be discovered in the near future. Acknowledgments We thank NNSFC (21432004, 21672113, 21772099, 21801135) for financial support.

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Part VI Some Important Approaches in MacrocycleBased Supramolecular Chemistry

Molecular Simulations of Supramolecular Architectures

39

Wensheng Cai and Haohao Fu

Contents 39.1 39.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Computational Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.2.1 Molecular Dynamics Simulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.2.2 Free Energy Calculations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.3 Simulations of Supramolecular Architectures and Controllable Motion in Rotaxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.3.1 Formation of Micelles of Cholesteryl-Functionalized Cyclodextrins . . . . . . . . 39.3.2 Self-Inclusion of altro-α-Cyclodextrin Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.3.3 Solvent-Controlled Shuttling in a Molecular Switch . . . . . . . . . . . . . . . . . . . . . . . . . 39.3.4 The Lubricating Role of Water in the Motion of Rotaxanes . . . . . . . . . . . . . . . . . 39.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39.5 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

39.1

1107 1108 1108 1110 1111 1111 1117 1120 1125 1131 1131 1131

Introduction

Understanding the mechanism of a chemical process at the atomic level is of great importance without any doubt. In experiment, however, it is usually very difficult to observe directly the processes of supramolecular self-assembly and molecular movements in rotaxanes. Computational approaches, therefore, have been widely used to investigate the microscopic movements of the macrocycle-based supramolecular assemblies. Among different types of computational methods, molecular dynamics (MD) is regarded as “computational microscope” and has been broadly W. Cai (*) · H. Fu Research Center for Analytical Sciences, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_45

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employed to reveal in atomic detail the formation mechanisms of supramolecular architectures and the motion properties in rotaxane-based molecular machines [1, 2]. Through classical MD simulations, one can obtain a trajectory of the positions and velocities of atoms of a molecular assembly, from which the thermodynamic and kinetic properties can be calculated based on the theory of statistical physics. The mechanisms and the driving forces responsible for the formation of supramolecular structures, hence, can be investigated at the atomic level. However, the amenable timescale of a process in wall clock time that can be explored by brute force MD simulation usually ranges from microseconds to milliseconds, in contrast to minutes to hours for real chemical experiments [3]. To bridge this gap, importance sampling techniques can be adopted, by which sampling along one or more predefined geometrical variables that can properly describe the chemical processes is artificially accelerated [4]. One can further extract the free energy change along the geometrical variables, which includes major information of a process from the perspective of physicochemistry. In supramolecular chemistry, the important chemical processes include molecular self-assembly [5], host-guest complexation [6], and molecular motion in molecular devices/machines [7]. One may argue that if the supramolecular architectures have been successfully built and observed in experiment, why the view of computational chemistry is still so important? The reasons include three aspects: (i) to understand the atomic level of the mechanisms of self-assembly, molecular recognition, and controllable movements in molecular machines; (ii) to extract some general principles from the unveiled mechanisms, which can be used to guide the design of new architectures; and (iii) to provide computational approaches for rational design of novel supramolecular architectures/molecular machines endowed with specific functions. In this chapter, the computational methods, namely, MD simulations and importance sampling techniques, will be briefly introduced in the next section. Then a number of examples, such as studies of the formation mechanism of supramolecular architectures and the mechanism of controllable motion of rotaxanes, will be used to illustrate how these computational approaches are applied and what can be learned from the simulation results.

39.2

Computational Methods

39.2.1 Molecular Dynamics Simulations Considering the Born-Oppenheimer approximation, since electrons move much faster than atomic nuclei, the motion of nuclei and electrons in a molecule can be separated. In other words, if the forces on atoms can be evaluated, for example, using quantum theory, the motion of atoms can be calculated by integration of Newtonian equations:

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F i ðt Þ ¼ mai ðt Þ vi ðt þ Δt Þ ¼ vi ðt Þ þ

ai ðt Þ þ ai ðt þ Δt Þ Δt 2

(1)

1 ri ðt þ Δt Þ ¼ ri ðt Þ þ vi ðt ÞΔt þ ai ðt ÞΔt 2 2 F i ðt Þ ¼ ∇U i ðt Þ where Fi is the force on atom i; m, mass; ai, acceleration; vi, velocity; t, time; ri, position; and Ui, potential energy. Computationally, this integration, together with its extensions that control the temperature and pressure of the system, is achieved through numerical algorithms. In practice, however, since quantum chemistry calculation is computationally expensive, classical force fields may be used to evaluate the force on each atom. The function form of a force field is usually highly based on physical intuition. For instance, in Amber force field [8]: U FF ¼ U bond þ U angle þ U dihedral þ U Columbic þ U VDW

(2)

where U bond ¼

X1 k bond ðx  x0 Þ2 2 bond

U angle ¼

X1 k angle ðθ  θ0 Þ2 2 angle

U dihedral ¼

X X1 n

dihedral

U Columbic ¼

U vdw ¼

X atoms i,j

V n ½1 þ cos ðnω  γ Þ

(3)

X

qi qj 4πer i ,j atoms i,j

" ei,j

2

rm ri,j

12



rm 2 r i ,j

6 #

are the bond stretching, angle bending, torsional, Coulombic, and van der Waals energy, respectively. kbond, kangle, Vn, n, γ, q, ei, j, and rm are tunable parameters. Usually, these force field parameters are parameterized from quantum chemistry calculation, which means that UFF is an approximation of the result of quantum mechanism. Based on Eqs. 1, 2, and 3, the position and velocity of atom i at each time t, namely, ri(t) and vi(t), i.e., the trajectory of atoms, can be obtained. Thermodynamic

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and kinetic properties can, therefore, be calculated through the theory of statistical physics. For example, along a geometrical variable A, say, the distance between two atom groups, the distribution of sampling ρ(A) can be extracted from trajectory data. The free energy landscape along A, namely, the potential of mean force (PMF), can then be written as: ΔGðAÞ ¼ RT lnðρðAÞÞ (4) where R is the universal gas constant and T is temperature.

39.2.2 Free Energy Calculations In MD simulations, the sampling obeys the Boltzmann distribution, namely: e

pα ¼ P M

kU αT B

β¼1 e

Uβ BT

k

(5) where pα and Uα are the probability and energy of state α, respectively. kB is the Boltzmann constant. M represents the total number of states of the system. Equation 5 implies that the high-energy structures and the local minima separated from the initial structure by high free energy barriers are very difficult to sample in the timescale of classical molecular simulations. To address this issue, the importance sampling techniques, such as umbrella sampling (US) [9, 10], metadynamics (MtD) [11–13], and adaptive biasing force (ABF) [14, 15] and their variants [16–23], can be adopted. Here only classical ABF [14] is introduced as an example. Say that the motion of molecular assembly can be described by a chosen transition coordinate ξ. Using the classical ABF method, the free energy change ΔG along ξ is estimated by: ð ΔG ¼

ξ

   F ξ ξ dξ ¼

ð ξ



@U ðrÞ @ξ



 ! 1 @lnjJ j  dξ β @ξ ξ ξ (6)

where hFξiξ is the average force acting along ξ, obtained from unconstrained MD simulations, and |J| is the determinant of the Jacobian for the transformation from Cartesian to generalized coordinates, β = 1/kBT. The first term of the ensemble average corresponds to the physical forces exerted on the system, derived from the potential energy function, U(r). The second term mirrors the contribution of the geometrical entropies. In the course of the simulation, a biasing force F along ξ is rapidly estimated and applied to the system to erase the ruggedness of the free energy

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1111

surface and, hence, allow ξ to be sampled uniformly. A transition coordinate, ξ, is usually formed by one or a set of collective variables. It is not unexpected that the choice of ξ is extremely crucial in free energy calculations using ABF. It should be noted that sometimes, chemical intuition may lead to a not-so-good transition coordinate.

39.3

Simulations of Supramolecular Architectures and Controllable Motion in Rotaxanes

In this section, four computational studies of supramolecular assemblies and rotaxane-based molecular machines will be explained in detail. All the atomistic MD simulations presented herein are performed using the parallel, scalable program NAMD [24]. The r-RESPA multiple time-step algorithm [25] is employed to integrate the equations of motion with a time step of 2 and 4 fs for short- and long-range interactions, respectively. Chemical bonds involving hydrogen atoms are constrained to their experimental lengths by means of the SHAKE/RATTLE [26, 27] and SETTLE [28] algorithms for organic and water molecules, respectively. Longrange electrostatic forces are evaluated using the particle mesh Ewald (PME) [29] scheme. The short-range van der Waals and electrostatic interactions are calculated by the smoothed 12.0 Å spherical cutoff. The temperature and the pressure are maintained at 300 K and 1 atm, respectively, using Langevin dynamics [30] and the Langevin piston [31] method. Periodic boundary conditions (PBCs) are applied in the three directions of Cartesian space. Free energy calculations are carried out, utilizing either the adaptive biasing force (ABF) [14, 15] or extended ABF (eABF) [21, 32, 33] algorithm. Visualization and analyses of the MD trajectories are performed with the VMD package [34].

39.3.1 Formation of Micelles of Cholesteryl-Functionalized Cyclodextrins Amphiphilic cholesteryl 2,6-di-O-methyl-β-cyclodextrins (chol-DIMEB) (Scheme 1a) can self-aggregate into spherical micelles with core-shell structure in aqueous solutions [35]. The hydrophilic cyclodextrin (CD) shell being exposed to the aqueous medium making them available for the inclusion of hydrophobic drug molecules in the cavities and the hydrophobic cholesteryl core can also bind hydrophobic drugs [36]. Therefore, they have great potential to become drug carriers due to their high aqueous solubility and drug loading capacity. The details on the micellar structure formed by chol-DIMEB and the driving forces responsible for such aggregation are investigated [37]. MD simulations of chol-DIMEB micelles consisting of 4 and 24 monomers are carried out in water, as shown in Table 1. The results for system I in Table 1, consisting four monomers initially pointing outward as depicted in Fig. 1a, show that the chol-DIMEB can spontaneously form

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Scheme 1 Structure of chol-DIMEB (a), dosulepin (DOS) (b), progesterone (PRO) (c), and 4-tertbutyl benzoic acid sodium salt (TBA) (d)

Table 1 Total number of atoms, arrangement of initial structures, and overall simulation time for the two molecular systems System I: 4 monomers II: 24 monomers

Number of atoms 48345 51201

Arrangement of initial structures Cholesteryl moieties pointing outward Spherical

Simulation time (ns) 30 100

a compact, aggregated structure in water, as shown in Fig. 1b. To explore the compactness of the aggregate and the orientation of the monomer, two geometrical variables, i.e., R and cos θ described in the insert of Fig. 1c, d, are monitored during the simulation. Both R and cos θ vary largely in the first 15 ns and became stabilized later, indicating that the cholesterols changed their orientation from outward to inward for a tight and stable aggregate. It is apparent that chol-DIMEB exhibits a strong tendency toward self-assembly. An analysis of the interactions within all the monomers forming the micelle has been carried out (see Fig. 1e), revealing a sharp decrease of the total van der Waals energy after 15 ns, which comes from the

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favorable interactions of cholesteryl tails. This results clarify that the main driving force to for the self-assembly of chol-DIMEB is due to the van der Walls interaction of hydrophobic cholesteryl tails. These interactions lead to the formation of a hydrophobic inner core consisting of cholesteryl moieties and a hydrophilic outer shell formed by CDs. This segregation can also be mirrored by the solvent-accessible surface area (SASA). As depicted in Fig. 1f, the SASA of cholesteryl moieties greatly reduced after 15 ns, which implies a self-assembly of the hydrophobic tails. It is impractical to observe the spontaneous formation of a large micelle from a random distribution of monomers in an acceptable timescale. A 100 ns MD simulation of a preconstructed aggregate formed by 24 chol-DIMEB monomers (system II in Table 1) is performed in water to probe the structural properties of the micelle. From the analysis of MD trajectories, the micellar core-shell structure is found to be very stable, and the radius of gyration, Rg (see Fig. 2) of the hydrophobic core and the total radius of the micelle are calculated to be 16.3  0.2 and 29.4  0.3 Å, respectively, in reasonable agreement with the experiments. The analysis of the interaction energies indicates that van der Waals forces between cholesteryl moieties stabilize the micelle. The aqueous solubility of the micelle is examined by the SASA of the different components of the micelle and the interaction of micelle and water, as shown in Figs. 3 and 4, respectively. The SASA of CD moieties contributes the major part to the total value, indicating that the hydrophilic CD groups are exposed to water environment. Cholesteryl tails, on the contrary, are hydrophobic and encapsulated in the core of the micelle. Figure 4a shows the average hydration number per fragment, viz., the number of the water molecules bound to a given component of a monomer. It is not unexpected that the average hydration number per CD is much higher than that of other moieties since CD is very hydrophilic. The radial distribution functions (RDFs) of the hydrogen atom of water as a function of the distance from the oxygen atoms of the CDs were calculated. As depicted in Fig. 4b, a local maximum emerges between 1.5 and 2.5 Å and implies that the hydrogen bonds formed between CDs and water molecules contribute the most to the formation of the first hydration shell of the micelle. From the above simulations, chol-DIMEB is found to exhibit a strong tendency to form noteworthily stable and highly soluble core-shell structures, which is mainly due to the strong van der Waals interaction of cholesteryl moieties. The volumetric maps of occupancy for the micellar atoms are delineated in Fig. 5, indicating that in addition to the CD cavities, many other sites in the micelle can bind drugs, i.e., between the CD cavities or in the inner core of the micelle. Therefore, the micelle should possess high drug loading capacity. In the following part, MD simulations of the chol-DIMEB micelle with three drugs (Scheme 1b–d), dosulepin (DOS), progesterone (PRO), and 4-tert-butyl benzoic acid sodium salt (TBA), are performed in aqueous solution to explore the drug loading capacity of the micelle. The initial coordinates of chol-DIMEB micelle containing 24 monomers are taken from the above 100 ns MD final structure. Twelve or twenty four drug molecules are arranged randomly around the micelle, and six molecular systems in a periodic TIP3P water box are constructed (see Table 2).

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a

b

c

d

0.5

Center of Four Monomers

cos q

R (Å)

R

20

–0.5 0

5

25 0

10 15 20 Time (ns)

25

30

total elec CD vdw cholesteryl vdw

–25 –50 –75

–1.0

f

total vdw water-(chol-DIMEB) nonbounded

–1400 –1500

Center of Four Monomers

0

5

6000

10 15 20 Time (ns)

25

30

25

30

CD

5000 SASA (Å2)

E (kcal/mol)

e

Center of Chol

0.0

Center of CD

10 0

1.0

Center of Chol

30

4000 3000 cholesteryl

2000 1000

–1600 0

5

10 15 20 Time (ns)

25

30

0

5

10 15 20 Time (ns)

Fig. 1 (a) Initial arrangement of system I. (b) Last snapshot of system I after 30 ns. The hydrogen atoms and water molecules are omitted for clarity. (c) Time evolution of the average distance, R, separating the center of the cholesteryl moiety in each monomer from the center of the four monomers (as shown in the inset). (d) Time evolution of the orientation of chol-DIMEB measured in terms of the average of cos θ, where the definition of θ for each monomer is depicted in the inset. (e) Energy characterizing the interaction within the monomers and the interaction of water and the monomers: total vdw (red), total elec (black), cholesteryl vdw (blue), CD vdw (green), and water(chol-DIMEB) nonbonded (cyan) energies. (f) Time evolution of the solvent-accessible surface area (SASA) for the CD and the cholesteryl components in the micelle. (Reproduced with permission from Ref. [37]. Copyright (2011) American Chemical Society)

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25 total micelle

Rg (Å)

20

15

A

hydrophobic core 10

0

20

40 60 Time (ns)

80

100

Fig. 2 Time evolution of the radius of gyration of the total micelle and its hydrophobic core. All atoms are taken into account in the computation of Rg for the total micelle but only those atoms of cholesteryl group for Rg of the hydrophobic core. Based on the average radius of gyration, , the micellar radius, Rs, can be determined using Rs=(5/3)1/2. (Reproduced with permission from ref. 37. Copyright (2011) American Chemical Society)

35000

total micelle

30000 SASA (Å2)

Fig. 3 Time evolution of the SASA of the micelle and of the moieties thereof. (Reproduced with permission from Ref. [37]. Copyright (2011) American Chemical Society)

CD 25000 5000 cholesteryl

0

succinyl 0

20

40 60 Time (ns)

80

100

Na+ or Cl counterions are added to neutralize the solvated systems. 50 ns MD simulations are carried out for each assembly. The final structures after the 50 ns MD simulations are plotted in Fig. 6. Two binding modes of the drug molecules to the micelle, namely, binding inside the cavity of CD and binding in the inner core of the micelle, are found. The corresponding number of the drug molecules binding to the micelle in each mode is given in Table 2. The results indicate that DOS and TBA prefer to enter into the CD cavity and PRO prefers to adsorb in the inner core. This observation can be easily understood. The skeleton structure of PRO is similar as that of cholesteryl, and the favorable hydrophobic interaction between the two moieties makes it adsorb into

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b

22 20

CD

1.0 0.8

18 RDFs

Average Hydration Number

a

16 4

0.6 0.4

succinyl

0.2

2 cholesteryl

0 0

20

40 60 Time (ns)

0.0 80

100

0

1

2

3

4 5 6 7 Distance (Å)

8

9 10

Fig. 4 (a) Time evolution of the average hydration number per fragment. (b) The RDFs of the hydrogen atoms of water as a function of distance from the oxygen atoms in the CD moieties. (Reproduced with permission from Ref. [37]. Copyright (2011) American Chemical Society)

Fig. 5 100 ns MD simulation of system II. Volumetric maps of occupancy for different fragments in the micelle: CDs (blue), cholesteryls (green), and succinyls (red). Hydrogen atoms and water molecules are not shown for clarity. (Reproduced with permission from Ref. [37]. Copyright (2011) American Chemical Society)

the inner core. For DOS and TBA, their charged groups prevent the two drug molecules from entering deep into the inner core. The hydrophobic parts of DOS and TBA prefer to be included in the hydrophobic cavity of CD; meanwhile their charged groups point toward the exterior, interacting with water, making this binding mode energetically favorable. From Table 2 and Fig. 6, it can be concluded that increasing the concentration of PRO and TBA can enhance the drug loading capacity of the micelle, but the concentration of DOS has little effect on the drug loading capacity. In addition, as seen in Fig. 6, even at low concentration, PROs that are not captured by the micelle are easy to self-aggregate, but TBAs are not. For DOS, self-aggregation is only observed at high concentration.

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Table 2 Molecular assemblies and simulation results

System DOS-12 DOS-24 PRO-12 PRO-24 TBA-12 TBA-24

Drug molecule DOS DOS PRO PRO TBA TBA

Number of drug molecules 12 24 12 24 12 24

Number of atoms 54117 58418 54603 60468 44553 52921

Number of drug molecules bound in Cavity Core 4 1 4 2 1 3 3 6 5 3 9 2

To conclude, the MD simulations demonstrate that amphiphilic chol-DIMEB can self-aggregate into spherical micelles, ascribing to the strong interaction of cholesteryl moieties. Further simulations indicated that such chol-DIMEB micelles are potential drug carriers, possessing two possible binding sites, i.e., the CD cavity and the inner core. van der Waals interactions may constitute the main driving forces responsible for the formation of the complexes of the micelles and drugs.

39.3.2 Self-Inclusion of altro-a-Cyclodextrin Derivatives An altro-α-cyclodextrin (altro-α-CD) derivative bearing an adamantyl end group (see Fig. 7a) can form a pseudo[1]rotaxane through the self-inclusion of its arm into the CD cavity [38]. The mechanism of the bulky end group translocating from the secondary side of the altro-α-CD to its primary side to form the pseudo[1]rotaxane, however, remains somewhat unclear. In the altro-αCD derivative of Fig. 7a, the sugar unit bearing the arm moiety is an α-Daltropyranose unit, weakening hydrogen-bonding interactions with its neighboring glucopyranose units at the secondary hydroxyl side. Under these premises, the altro-α-CD macrocycle is more flexible than the native α-CD. On the basis of this analysis and subsequent experiments, Harada et al. put forth two possible mechanisms for different altro-α-CD derivatives, namely, threading and tumbling [38, 39], as illustrated in Fig. 7b, c. However, it is still unclear which is the true mechanism that underlies the formation of the pseudo[1] rotaxane in Fig. 7. To investigate the atomic-level mechanism that underlies the formation of the self-inclusion complex, namely, the pseudo[1]rotaxane depicted in Fig. 7, classical, all-atom MD simulations combined with microsecond timescale free energy calculations were performed [40]. The free energy profiles characterizing the threading and tumbling were determined, from where the most likely pathway toward the formation of the pseudo[1]rotaxane can be inferred. The coarse variables describing

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Fig. 6 Final structure of each system after 50 ns MD simulations. The micelle is shown in lines, drug molecules binding to micelle in VDW sphere, and others in sticks. (a) DOS-12 (b) DOS-24 (c) PRO-12 (d) PRO-24 (e) TBA-12 (f) TBA-24

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Fig. 7 (a) Chemical structure of the altro-α-CD derivative. Schematic illustration of the threading (b) and tumbling (c) pathways leading to the pseudo[1]rotaxane. (Reproduced with permission from Ref. [40]. Copyright (2014) American Chemical Society)

the threading and the tumbling were defined as ξ and θ, namely, the projection onto the z-axis of the distance between the center of mass of adamantane and that of the CD glycosidic oxygen atoms (Fig. 8a) and the dihedral angle between the altropyranose unit and the plane formed by the six glycosidic oxygen atoms of the altro-α-CD (Fig. 8b), respectively. The free energy profile along ξ, characterizing adamantane threading through the altro-α-CD cavity (see Fig. 8a), is depicted in Fig. 9a. Two relatively flat regions corresponding to the unbound states of adamantane, namely, 10  ξ  7 and +5  ξ  +10 Å, are separated by a sharply peaked, high free energy barrier spanning 4  ξ  +5 Å. When adamantane moves close to altro-α-CD and partially included in the altro-α-CD cavity, as shown in Fig. 9b, a global minimum at around 3.8 Å emerges, which is due to the favorable van der Waals interaction of the adamantine and the CD cavity. Further movement of adamantane toward altro-αCD cavity is hindered by steric hindrances, as mirrored by a significantly high free energy barrier. The most unfavorable structure corresponds to the free energy maximum at +0.8 Å, wherein the bulky adamantane molecule is completely encapsulated in the altro-α-CD cavity, as depicted in Fig. 9c, leading to a marked expansion of the cavity (Fig. 9d). The large free energy difference between the

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Fig. 8 Two simplified models utilized to explore the putative transition pathways. (a) Threading an adamantane through the altro-α-CD cavity. (b) Tumbling an altropyranose unit about the axis of an α(1,4) bond. To describe a continuous tumbling process, the transition pathway spans 300  θ  +100 . (Reproduced with permission from Ref. [40]. Copyright (2014) American Chemical Society)

stable and transition state is 53.6 kcal/mol, indicating a rare possibility of threading of adamantane through altro-α-CD. The PMF characterizing the tumbling of the altropyranose unit (see Fig. 8b) is depicted in Fig. 10a. The horizontal arrow denotes the tumbling direction of the altropyranose monomer. It can be seen that the free energy barrier for the tumbling from point A to point E is about 16.0 kcal/mol, which is much lower than that in the threading pathway (53.6 kcal/mol). This result clear suggests that the tumbling of the altropyranose connecting the arm moiety is the pathway of self-inclusion rather than the threading of the adamantyl group. In this section, the energetically favorable pathway of the formation of pseudo[1] rotaxane is investigated. The results show that the threading pathway is forbidden by the large steric hindrances. Tumbling is, hence, the true mechanism of the formation of pseudo[1]rotaxane. The free energy barrier against the self-inclusion of the altroα-CD derivative may arise from disrupted hydrogen bonds at the secondary side of the CD and the unfavorable interaction of the hydroxyl groups of the altropyranose unit with the hydrophobic cavity.

39.3.3 Solvent-Controlled Shuttling in a Molecular Switch Rotaxanes are mechanically interlocked molecular complexes composed by a linear (chain- or dumbbell-like) molecule with stoppers at both termini and a macrocycle threaded onto the latter [41]. The ring-like molecule can shuttle between different binding sites under external stimuli, such as pH [42], light [43], and solvents [44]. A cyclodextrin-based molecular shuttle designed by Harada and co-workers (Fig. 11) can be considered as a paradigm for solvent-driven rotaxanes [45]. Here, the effect

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Fig. 9 (a) Free energy profile characterizing the threading process along ξ. Snapshots of the inclusion complex of adamantane with altro-α-CD (b) at the global minimum of the PMF, ca. ξ = 3.8 Å, and (c) at the barrier of the PMF, ca. ξ = +0.8 Å. For clarity, water molecules are omitted. (d) Fluctuation in the course of the threading process of the area of the central plane formed by the six glycosidic oxygen atoms of the altro-α-CD. (Reproduced with permission from Ref. [40]. Copyright (2014) American Chemical Society)

of the temperature and solvent on the shuttling of the rotaxane was studied by MD simulations and free energy calculations [46]. Three different conditions were considered, namely, DMSO at 300 K, DMSO at 400 K, and water at 300 K, under which free energy calculations were performed. Moreover, the PMFs were decoupled into elementary contributions to clarify the driving force of the shuttling environmental effects. The structure of the rotaxane is presented in Fig. 11. The coarse variable, ξ, was chosen as the distance between the center of mass of the CD and that of the lefthanded 4,40 -bipyridinium group. Three ABF simulations, characterizing the shuttling of the rotaxane in DMSO at 400 K, in DMSO at 300 K, and in water at 300 K, were carried out. The three free energy landscapes describing the translocation movement of the αCD along the chain-like molecule under different conditions are shown in Fig. 12. These profiles reveal that (i) each profile possesses two stable states separated by

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Fig. 10 (a) Free energy profile characterizing the tumbling of the altropyranose monomer of altroα-CD along θ. The values of the dihedral angle corresponding to inflection points A to E of the PMF are 75 , 14 , 80 , 192 , and 276 , respectively. (b) Evolution of the average number of hydrogen bonds formed between the altropyranose unit and two neighboring glucopyranose units during tumbling. The hydrogen-bonding criteria are (i) the angle O–HO > 135 and (ii) the distance OO < 3.5 Å. Evolution of the solvent-accessible surface area (SASA) of (c) the primary hydroxyl group and (d) the secondary hydroxyl groups of the altropyranose unit in the course of tumbling. (Reproduced with permission from Ref. [40]. Copyright (2014) American Chemical Society)

Fig. 11 [2]Rotaxane molecule formed by an α-CD, two dodecamethylene moieties (stations), three 4,40 -bipyridinium moieties (linkers), and two 2,4-dinitrophenyl moieties (stoppers). (Reproduced with permission from Ref. [46]. Copyright (2012) American Chemical Society)

a significant barrier, (ii) the height of the barrier in DMSO at 400 is identical to that in DMSO at 300 K, and (iii) the barrier, relative to the minima of the free energy landscape in water at 300 K, is significantly higher than that in DMSO.

DG(x)(kcal/mol)

a

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20 15 10 5 0

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x(Å) Fig. 12 Free energy profiles delineating the shuttling process along ξ: (a) in DMSO at 400 K, (b) in DMSO at 300 K, and (c) in water at 300 K. The error bars represent the standard error of the free energy difference. (Reproduced with permission from Ref. [46]. Copyright (2012) American Chemical Society)

Table 3 Activation free energiesa System DMSO, 400K DMSO, 300K Water, 300K

ΔGforward(kcal/mol) 24.40.2 25.00.2 29.00.1

ΔGbackward(kcal/mol) 22.10.1 22.00.1 26.50.1

ΔG‡(kcal/mol) 23.30.2 23.50.2 27.50.1

Tshuttling (s) 0.034 2.7102 107

a

The experimental free energy of activation for the site exchange process in DMSO and 400 K is ca. 20 kcal/mol

In the PMF calculated under each condition, two local minima at ξ = 12 and ξ = 35 Å are separated by a free energy barrier spanning 15  ξ  29 Å. These minima correspond to the stable states of the rotaxane, in which the macrocycle binds to the dodecamethylene group. The free energy barrier mirrors a transition state, in which the center of mass of the ring-like molecule coincides with that of bipyridinium moiety. The height of the free energy barrier for the forward (ΔGforward) and the backward (ΔGbackward) shuttling is shown in Table 3. The activation free energy (ΔG‡) is defined as the average of the two value.

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The activation free energy corresponding the shuttling of the rotaxane in DMSO at 400 K is 23.3  0.2 kcal/mol, which coincides well with the value predicted by experiments. The calculated activation free energies in DMSO at 300 K and 400 K are almost the same. However, when calculating the characteristic time for shuttling through the Eyring equation, it can be found that the time needed for such process at 400 K is much less compared with that at 300 K, which indicates that the decrease of temperature can cause a significant change in the timescale of chemical process. This result agrees well with experiments, in which the site exchange of the rotaxane can be stopped by cooling the system from 400 to 300 K. The activation free energy calculated in water at 300 K is 4.0 kcal/mol higher than that determined in DMSO at the same temperature (Table 3). The increase in the free energy barrier leads to a sharp rise in the time needed for shuttling in water, which coincides with the experimental observation that no shuttling can be observed in the aqueous solution. To find out the reason of the relatively high activation free energy determined in water, the free energy landscape is decoupled into distinct contributions, as depicted in Fig. 13. The CD-thread interactions are similar in different conditions, as mirrored by the broad valley spanning 16  ξ  30 Å of the corresponding partial free energy profile. Further decomposition of the CD-thread interaction suggests that although

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x(Å) Fig. 13 Decomposition of the total free energy profile into van der Waals CD-thread, electrostatic CD-thread, and CD-solvent contributions for the shuttling process (a) in DMSO at 400 K, (b) in DMSO at 300 K, and (c) in water at 300 K. (Reproduced with permission from Ref. [46]. Copyright (2012) American Chemical Society)

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the solvents have different effects on van der Waals and electrostatics contributions, the changes of the two terms counterbalance each other, making the sum of them remains unchanged (Fig. 13b, c). As shown in Fig. 13, the CD-solvent interactions contribute the most to the final activation free energies, no matter what condition is. The average height of the peak with respect to the left and right local minimum is about 35, 35, and 40 kcal/mol in DMSO at 400 K, in DMSO at 300 K, and in water at 300 K, respectively. This difference, not unexpectedly, corresponds to the difference in the activation free energies shown in Table 3, which indicates that the distinct CD-solvent interactions lead to the change of the time needed for shuttling when altering solvent condition. In aqueous solution, the CD-solvent interaction is more unfavorable than in DMSO, when the α-CD passing through the central linker. The solvation of the hydrophobic alkyl chain and the desolvation of the positively charged bipyridinium moiety contribute predominantly to the increment of the free energy barrier, thus rationalizing that the free energy barrier arising from unfavorable CD-solvent interactions in water is higher than that in DMSO. In this section, the influence of the temperature and the solvent on the shuttling of rotaxanes has been investigated. The change of temperature has a negligible effect on the activation free energy of the shuttling of the rotaxane in DMSO, whereas increase of the temperature can accelerate the process kinetically. Altering the solvent condition from DMSO to aqueous solution can increase the free energy barrier for shuttling, hence, slowing down the shuttling speed.

39.3.4 The Lubricating Role of Water in the Motion of Rotaxanes For solvent-controlled rotaxanes, the translation of macromolecule is considered to be highly correlated to the polarity of the solvent. In the hydrogen-bonded supramolecular architecture investigated by Panman et al [47], however, the shuttling rate of the macrocycle can only be boosted up by water, whereas no significant effect is found when changing to other solvents. The reason of the unique lubrication role of water still remains unknown. The main goal of the section, therefore, is to explore the distinctive effect of water in amide-based rotaxanes on the shuttling process from the perspective of the configurational changes and the underlying thermodynamics [48]. The structure of the rotaxane investigated herein is shown in Fig. 14. The transition coordinate contains two primary coarse variables, namely, the distance, d, and the average dihedral angle, φ, defined in Fig. 14, which were adopted to describe the translation and the conformational change of the macrocycle, respectively. Four solvents with different properties, i.e., diethyl ether, acetonitrile, ethanol, and water, were applied in this study. The free energy landscapes characterizing the translation coupled with conformational change of the ring in different solvents are shown in Fig. 15a–d.

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Fig. 14 Upper panel, possible movements in the rotaxane. Red arrow, translation of the ring. Cyan arrow, rotation of the ring. Purple arrow, rotation of the stoppers. Lower left panel, isomerization of the macrocycle. Boat-I, boat-II: boat conformation facing to the left-hand and right-hand stoppers, respectively. Lower right panel, structure of the rotaxane and the coarse variables (d, φ) chosen to define the transition coordinate. φ = 0 denotes a boat-like conformation, while φ 20 or φ  20 indicates a chair-like conformation. Two binding sites on the thread are defined as “left-hand” and “right-hand.” The left-hand binding site is located at the succinamide group, while the right-hand one at the naphthalimide stopper. (Reproduced with permission from Ref. [48]. Published by the Royal Society of Chemistry)

As can be seen in Fig. 15a, in the nonpolar diethyl ether, two local minima, A1 and A2, which correspond to the left-hand binding site of the macrocycle, are located at d = 2–4 Å. These local minima can be also mirrored by the one-dimensional PMF shown in Fig. 15e. The three-dimensional arrangements corresponding to the local minima are shown in Fig. 16, wherein the ring-like molecule in the two structures shows a boat and a chair motif, respectively. Hydrogen bonds are found to be formed between the amino groups of the macrocycle and the carbonyl groups of the chain. The conformation of the ring-like molecule changes fast between the two stable states. This conversion stops when the macrocycle moves to the methylene chain,

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Fig. 15 Free energy calculations characterizing the translational movement and conformational change processes of the macrocycle (a–d). Free energy landscapes in diethyl ether, acetonitrile, ethanol, and water, respectively, obtained by 4  2.2 μs simulations. White characters denote the local (meta)stable structures (local minima) of the rotaxane in different solutions. The black dotted lines indicate the least free energy pathways connecting the local minima. (e) Projection of the twodimensional PMFs along the coarse variable d. (Reproduced with permission from Ref. [48]. Published by the Royal Society of Chemistry)

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Fig. 16 Representative threedimensional arrangements of the rotaxane in diethyl ether. The free energy differences between these structures are also shown. The activation free energy of the shuttling process is depicted in red. (Reproduced with permission from Ref. [48]. Published by the Royal Society of Chemistry)

where it adopts the boat conformation. Only one stable three-dimensional arrangement, A3, emerges at d = 21–22 Å, where the ring is now located at the right-hand binding site. The corresponding structure is depicted in Fig. 16. It is worth noting that the amino groups of the macrocycle and the carbonyl groups of the naphthalimide moiety can form hydrogen bonds. As a result, the steric hindrance of the bulky stopper arising from the close contact between the latter two objects prevents the macrocycle from adopting a chair conformation. Intermolecular hydrogen bonding is the driving force responsible for shuttling in the nonpolar solvent according to the breakdown of the one-dimensional free energy change. The intermolecular hydrogen-bonding interaction demonstrates that less hydrogen bonds are formed in structure A3 than in structure A1 and A2, thereby rationalizing the relative stability of the two binding sites observed in Fig. 15e. Further analysis of the conformational change reveals that the macrocycle experiences several times a boat–boat interconversion during shuttling along the reaction path. Such isomerization happens in all four solvents. The free energy landscapes describing the shuttling progress in acetonitrile and ethanol are somewhat similar as that in diethyl ether, indicating a similarity of the rotaxane conformation in diethyl ether, acetonitrile, and ethanol solvents. Compared with diethyl ether, however, acetonitrile and ethanol are polar solvents, in which there is solvophobic interaction. Stable structures B3, B4, C3, and C4, therefore, emerge on account of the affinities of the aromatic parts of the macrocycle and the aliphatic moieties of the dumbbell-like molecule in polar environments. The PMF describing the translation and conformational change of the macrocyclic molecule in aqueous solution differs significantly from those determined in diethyl ether, acetonitrile, and ethanol (Fig. 15d, e). In particular, as shown in Fig. 15e, by comparing the free energy barrier against shuttling of the rotaxane in water and other solvent, it is obvious that the translation of the macrocycle in aqueous solution is much faster, which agrees well with the so-called lubrication

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Fig. 17 Representative structures of the rotaxane in aqueous solution. The free energy differences between the distinct three-dimensional arrangements are shown. The activation free energies of the shuttling process are described in red. (Reproduced with permission from Ref. [48]. Published by the Royal Society of Chemistry)

effect by water found in experiments. Moreover, both the left- and right-hand binding sites shift leftward compared to other solvents. Analysis of the trajectory suggests that the isomerization of the macrocyclic molecule in water during shuttling differs significantly, compared with nonaqueous environments, as shown in Fig. 17. The ring binds to the succinamide moiety and shows a boat-I conformation in the three-dimensional arrangement D1. Such boat-I conformation of the macrocycle becomes unfavorable when the ring starts to translocate, and, on the contrary, the boat-II conformation is preferred in structure D2. The macrocycle remains in the boat-II conformation when it moves along the aliphatic chain, until it reaches the metastable state D4 at the right-hand binding site. Then, the ring-like molecule adopts quickly the structure D5, in which it shows a chair conformation and the amino groups of the benzylic amide ring unbind to the carbonyl groups of the naphthalimide moiety, as illustrated in Fig. 17. As depicted in Fig. 15e, the free energy barrier against the translocation of the ring from the left-hand to the right-hand binding site decreases along with the increases of the solvent polarity. Specifically, the free energy barrier drops significantly in aqueous solution, compared with other solvents, indicative of a sharply acceleration of shuttling. This lubrication by water can be explained by its inherent properties. The high polarity of water can greatly weaken the hydrogen bonds formed between the ring and the chain when the macrocycle interacts with the succinamide moiety. Hydrophobic interactions, therefore, become dominant and drive the shuttling of the macrocycle ring from left to right. In addition, the phenylene groups of the macrocycle can interact with the hydrophobic part of the

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Fig. 18 (a) Water stabilizes the amides of the macrocyclic ring- and the chain-like molecule. (b) The average number of hydrogen bonds between the amino groups of the ring and the oxygen/ nitrogen atom of the solvents when the coarse variable d = 12–16 Å, i.e., the ring, resides over the aliphatic part of the chain. (Reproduced with permission from Ref. [48]. Published by the Royal Society of Chemistry)

supramolecular assembly, either the aliphatic chain or the aromatic stopper, during shuttling. This solvophobic interaction significantly enhances in water. Moreover, water molecules can form hydrogen bonds with the carbonyl groups of the chain and the amino groups of the ring (Fig. 18) during the macrocycle moving away from the succinamide moiety to the alkyl chain, thus, compensating the energy loss due to breaking hydrogen bonds between the ring and the chain. The free energy barrier against translocating the macrocycle from the left-hand binding site to the right-hand one can, therefore, greatly reduce. In nonaqueous solution, forming hydrogen bonds between solvent molecules and the dangling carbonyl/amino groups are much more difficult compared with in water. This difficulty is mainly because (i) diethyl ether and acetonitrile are not hydrogen bond donors and, therefore, cannot stabilize the carbonyl moieties of the dumbbell-like molecule and (ii) compared with the water molecule, which is very small in volume, diethyl ether, acetonitrile, and ethanol are much larger. Hence, inserting the latter molecules into the cavity formed by the macrocyclic ring and the chain to form hydrogen bonds is difficult. Such volumetric effect can be mirrored by the analysis of the hydrogen bonds formed between the ring and the solvents, as illustrated in Fig. 18. It is clear that water can form more hydrogen bonds with the macrocycle than any other solvent due to its small volume, thereby act as an important lubricant of molecular machines. In this section, the lubrication by water for an amide-based rotaxane is investigated. The properties of water that make it unique among other solvents can be summarized as follows – a high polarity, the ability of being both a hydrogen donor

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and an acceptor, and a very small molecular volume. Synergy among the aforementioned properties can significantly reduce the free energy barrier against the shuttling of rotaxanes.

39.4

Conclusion

In this chapter, the methods of MD simulation and free energy calculation have been briefly introduced. These methods have been applied to investigate four macrocyclebased supramolecular assemblies as examples. The computational techniques applied in these applications are proven to be effective and robust to investigate micelles and molecular machines. The self-assembly mechanism of supramolecular architectures and the mechanism of the controllable motion in molecular machines at the atomistic levels which usually cannot be directly observed from experiments, can be extracted. The theoretical framework proposed in these applications, which allows us to not only reproduce within chemical accuracy the experimental data but also shed new light on the intricate movements in rotaxanes, is extremely useful in de novo design of smart supramolecular architectures and molecular machines. One may model an architecture and predict its properties in silico and then carry out experiments under the valuable guidelines provided by simulations.

39.5

Cross-References

▶ Cyclodextrin-Based Supramolecular Hydrogel ▶ Functional Rotaxanes ▶ Functionalized Cyclodextrins and Their Applications in Biodelivery ▶ Polypseudorotaxanes Constructed by Crown Ethers ▶ Thermodynamic Studies of Supramolecular Systems Acknowledgments We thank NNSFC (21773125) for the financial support.

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Thermodynamic Studies of Supramolecular Systems

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Contents 40.1 40.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thermodynamic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40.2.1 Various Methods for Determination of Thermodynamic Quantities . . . . . . . . . 40.2.2 Calorimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40.3 Applications of Thermodynamics in Supramolecular Systems . . . . . . . . . . . . . . . . . . . . . . . . 40.3.1 Cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40.3.2 Crown Ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40.3.3 Calixarenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40.3.4 Cucurbiturils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40.1

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Introduction

Supramolecular chemistry, known as “beyond molecular chemistry,” is one of the most popular and rapidly growing fields of chemistry. It focuses on the study of molecular recognition, molecular assembly, host-guest interaction, mechanically interlocked molecular architectures, drug delivery, molecular sensors, and so on. Hence, supramolecular chemistry is highly interdisciplinary in various areas such as N. Li School of Textile Science and Engineering, State Key Laboratory of Separation Membranes and Membrane Processes, Tianjin Polytechnic University, Tianjin, China Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_46

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physical chemistry, coordination chemistry, organic chemistry, materials science, biological science, polymer chemistry, crystal chemistry, etc. The importance of supramolecular chemistry was established by Jean-Marie Lehn, Donald J. Cram, and Charles J. Pedersen who were awarded Nobel Prize in 1987 for Chemistry [1]. The development of selective host-guest complexes particularly in which a host molecule recognizes and selectively binds a certain guest molecule was cited as a significant contribution [2, 3]. Non-covalent interaction plays a crucial role in the binding processes. Herein the study of host-guest complexes investigates non-covalent interactions such as van der Waals forces, hydrogen bonding, ion-dipole interactions, dipole-dipole interactions, metal coordination, hydrophobic forces, π-π stacking, and electrostatic effects [4, 5]. Moreover, the formation of a host-guest complex via supramolecular interactions is fast, facile, and stable [6]. Therefore supramolecular chemists have designed and synthesized a wide variety of modified macrocyclic hosts such as crown ethers, cyclodextrins, calixarenes, cucurbiturils, and so on for delivery, sensing, and recognition toward specifically targeted guests [7–10]. Due to these non-covalent interactions, the free energy change (ΔG) is either increased or decreased in supramolecular systems. Moreover, binding constant (K ) of complex formation serves crucial information for investigation and characterization of host-guest models. By using thermodynamic analysis, we can investigate binding mechanisms between macrocyclic hosts and a number of guests [11–13]. It should be explicitly stated that the role of thermodynamics in understanding the factors contributing to complex stability and selectivity is important. Large amounts of thermodynamic data were collected in many papers to examine the validity of the enthalpy-entropy compensation relationship in the complexation reactions [8, 14]. Thus, thermodynamics leads us to a better and deeper understanding of supramolecular chemistry. In this chapter, calculations of thermodynamic parameters and microcalorimetry will be reviewed. And we will discuss applications of thermodynamics in supramolecular systems.

40.2

Thermodynamic Studies

It should be noted that the thermodynamic parameters, such as the heat capacities, enthalpies, entropies, and free energies, have been studied by various experimental methods for complexation reactions and binding strength. The selection of technique is based on the selection of physical property of the receptor and host. The most commonly used experimental techniques for the determination of thermodynamic parameters are electronic absorption (UV-Vis), nuclear magnetic resonance (NMR), mass spectrometry, fluorescence, conductometry, potentiometry, polarography, chromatography, electrophoresis, and calorimetry [15–18]. The choice of the spectroscopic methods depends on the properties of the host and guest used. Experimental methods mentioned above should be used with the proper skills to obtain reliable thermodynamic data. Moreover, calorimetry is the method for the simultaneous determination of the change in enthalpy (ΔH ) and binding constant (K ) associated with formation of the complex [19]. In particular, titration microcalorimetry is

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employed as an important and sensitive tool when attempting to measure comparatively weak interactions [20]. The section of this chapter is concentrated on calculation of thermodynamic parameters and microcalorimetry.

40.2.1 Various Methods for Determination of Thermodynamic Quantities A wide variety of experimental techniques have been used in the determination of thermodynamic quantities for host-guest complexes. The most commonly methods are as follows: NMR titration is one of most popular and capable methods for determination of thermodynamic quantities [21]. It is suitable for obtaining the information about the small structural changes of guests [22]. Compared with other techniques such as UVVis and fluorescence, NMR spectroscopy is more reliable in the presence of minor impurities [23]. In general, NMR titration techniques are suitable for systems with equilibrium constants in the range 10–104 M
1 [24]. Because the interactions involved in these systems lie in slow exchange region, NMR titration techniques are not suitable for the intramolecular chelate systems [6]. However, this method is widely used in chiral discrimination studies with cyclodextrins [25]. The drawback of NMR method is the poor solubility of the host/guest in deuterated water. Thus, other solvents may be added in solutions, which may modify the host-guest interactions. Due to limited information about structural changes, UV-vis titration is more useful and fast for thermodynamic analysis [26]. Because of the operational simplicity of the instrument, UV-vis spectroscopy is suitable for systems with high equilibrium constants and micromolar concentrations, especially for determination of chromophoric compounds with macrocyclic hosts. Both the stoichiometry (N ) and the stability constant (K ) of the host-guest complex can be measured from the continuous variation methods (Job’s plot). Fluorescence spectroscopy is another useful tool for the investigation of complexation reactions due to its high sensitivity and operational simplicity. In the excited state, the important process is fluorescence resonance energy transfer (FRET). This process occurs when the emission spectrum of a fluorophore (the donor) overlaps with the absorption spectrum of another compound (the acceptor) which does not need to be fluorescent [27]. FRET is the result of long-range dipoledipole interactions between the donor and acceptor without the transfer of a photon. FRET has been used in the determination of distances between donors and acceptors. Circular dichroism spectroscopy (CD) is a capable method based on the measurement of differences in the absorption of left-handed polarized light versus righthanded polarized light inducing from structural asymmetry, for the determination of the complex formation of chromophoric guests with macrocyclic hosts. Because CD spectroscopy is sensitive to intermolecular interactions, it plays a key role to detect chiral complexes with stoichiometric ratios, thermodynamic parameters, and supramolecular structures [28, 29].

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Electron spin resonance spectroscopy (ESR) is a spectroscopic technique used for characterizing molecules containing unpaired electrons, including free radicals, which provided information about binding constants and structures of complexes [30]. Capillary electrophoresis (CE) has also been employed in determination of pKa values, which relies on finding the relationship between electrophoretic mobility and pH, and fitting a sigmoidal curve with the inflection point that indicates pKa [31]. A full thermodynamic characterization of a complexation reaction means the determination of K, ΔG, ΔH, ΔS, and stoichiometry (N). K, ΔH, and N are measured or fitted by experimental data. ΔS and ΔG are calculated from these following relationships: ΔG ¼
RT lnK ΔH ¼
R ΔS ¼ R

d ðlnK Þ d ð1=T Þ

d ðlnK Þ ΔH
ΔG ¼ d ðlnT Þ T

(1) (2)

(3)

It is not directly determined from a single experiment for all thermodynamic data by all of the experimental methods mentioned above. Thus, we emphasize that calorimetric methods, in which K and ΔH are directly determined by a single experiment, have advantages over other methods [32]. In fact, ΔH is best measured directly by calorimetry. In contrast to spectroscopic methods, calorimetric methods can be used to measure the interaction between molecules which are with no chromophore or fluorophore tag or in buffer conditions. Then, we will introduce the calorimetric methods.

40.2.2 Calorimetry As mentioned above, calorimetry is the only method which can simultaneously determine all thermodynamic data in a single experiment. In the early seventeenth century, the idea of latent heat was very crude and was necessary to develop objective standards. Calorimeter was invented to improve accuracy in 1780s by Lavoisier and Laplace [33]. In the last few decades, calorimetric techniques have started to become a powerful analytical tool for a variety of applications, particularly in biological sciences [34]. Moreover, microcalorimetry, based on the exchanges of heat accompanying the interaction between hosts and guests, was first described 50 years ago [32]. Figure 1 shows the development of calorimeter. The performance of calorimeters was improved since 1780s (Fig. 1). It has then become a capable technique for characterizing label-free host-guest interactions to evaluate many thermodynamic parameters. There are many calorimeters in two widely used systems: differential scanning calorimetry (DSC) and isothermal

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Fig. 1 Development of calorimeter [33]

titration calorimetry (ITC) [35, 36]. DSC has been used in the determination of enthalpy and heat capacity of thermal denaturation [34]. ITC is an easy-to-use and important instrument for the study of the thermodynamics of complexation formation of guests with macrocyclic hosts. In an ITC experiment, two reactants are titrated against one and the other, and full thermodynamic characterization is determined by direct measurement of heat exchange [37]. ITC has broad scope in the analysis of binding stoichiometries and thermodynamic parameters, including ΔH and ΔS in a single experiment. It has the additional advantages that the experiments can be performed in a range of conditions such as different pH values, temperatures, and buffers. Application of ITC as a useful tool can be used to study in diverse fields in science such as biological systems, chiral chemistry, and supramolecular systems [38].

40.2.2.1 Isothermal Titration Calorimetry and Titration Curves ITC measures the heat (Q) taken from the system to maintain a constant temperature (T). The molar heat of a complexation reaction is equal to the molar standard variation enthalpy and can be calculated from the following relation: q = dQ/ dυ = ΔH  , and ʋ is the number of moles. In an ITC experiment, each titration of guest/host molecules into the sample cell gives a reaction heat caused by the formation of inclusion complex. The reaction heat decreased after each injection of guest/host molecules because less and less host/guest are available to form inclusion complexes, so the all heat is given by q = n  ΔH  p, where n is concentration and p is the number of titrations. The binding constant (K ) and the reaction enthalpic changes (ΔH  ) enabled the calculation of standard Gibbs free energy changes (ΔG ) and entropic changes (ΔS ), according to equation, where R is the gas constant and T is the absolute temperature. ΔG ¼
RT lnK ¼ ΔH 
T ΔS 

(4)

The change heat capacity (ΔCp) is determined from ITC measurements at different temperatures, according to ΔCp = dH/dT [37].

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Fig. 2 MicroCal VP-ITC titration microcalorimeter

The titration calorimeter was first introduced by Christensen and Izatt 50 years ago [39]. In 1989, the first commercially titration calorimeter became available from MicroCal [34]. Since then ITC instruments were significantly improved, and thermodynamic data were analyzed by modern analysis software. Thus, sensitive ITC instrument is able to measure heat effects as small as 0.1 μcal. A typical MicroCal VP-ITC titration microcalorimeter is shown in Fig. 2. ITC instrument contains a thermal core of two identical cells which are sample cell and reference cell with a volume of 0.2–1.5 mL. The thermal core keeps these two cells at the same temperature and atmospheric pressure by a thermocouple device. All solutions are degassed by a ThermoVac accessory before titration experiments. The solution of host/guest is loaded into injection syringe with a volume of 40–500 μL, which is inserted into the sample cell with a long and stirring needle. The syringe is continuously rotated during each run, leading to complete mixing in the sample cell. The heat sensing devices can detect temperature differences between these two cells when the complexation reaction occurs. Then it provides feedback of temperature differences for compensation which makes the cells to the same desired temperature. Therefore, the ITC can measure heat effects when the first injection is made (Fig. 3). To obtain high-quality data, the VP-ITC instrument is calibrated chemically by the measurement of the complexation reaction of β-CD with cyclohexanol in supramolecular systems, and the obtained thermodynamic data are in good agreement (error < 2%) with the literature data. All solutions have to be thoroughly degassed by a ThermoVac accessory before titration experiments. Any air in the

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Fig. 3 Typical diagram of MicroCal VP-ITC titration microcalorimeter. Major features include the sample and reference cells, syringe, and adiabatic shield. The diagram illustrates the signal resulting by the instrument to maintain constant temperature between the sample and reference cells [38]

solutions can cause variation in the volume and interfere with the thermal contact. As a rule of thumb, if the guest is easily soluble, it is possible to load the solution into the syringe and be added to the sample cell with host and vice versa. Thus, the titration experiment should be planned by optimizing host and guest concentrations and the injection volume. This would need a sufficient number of data points to reach thermal equilibrium for data analysis. In general, each microcalorimetric titration experiment consists 25 successive injections of a constant volume of guest/host solution into the reaction cell. Moreover, the time interval between successive injections is important to the titration experiment. If association is slow, the instrument baseline will be equilibrated in a long time. In contrast, heat signals of rapid processes require less time to reach equilibrium. The experimental data are presented as a plot of power against time until the reaction reaches equilibrium. Typical titration curves are shown in Fig. 4. Each titration of guest molecules into the sample cell gives a reaction heat caused by the formation of inclusion complex between macrocyclic hosts and guest molecules. The reaction heat decreases after each injection of guest molecules because less and less macrocyclic hosts are available to form inclusion complexes [8]. ITC instrument detects the total heat effect in binding reactions, which contains reaction heat and dilution heat. The dilution heat of host/guest solution when added to the pure buffer/water solution is determined in each run. The dilution heat determined in these control experiments are subtracted from the reaction heat measured in titration experiments to give the net reaction heat. The net heat in each run is analyzed by using “one set of binding sites” model with Origin software which is provided by MicroCal Inc. To check the accuracy of calculated

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Fig. 4 Microcalorimetric titration of macrocyclic host and guest. (a) Raw data for sequential 25 injections of guest into host solution. (b) Apparent reaction heat obtained from the integration of the calorimetric traces [8]

thermodynamic quantities, it would need several independent titration runs to obtain average values. A representative curve fitting result for the complexation of macrocyclic hosts with guest is shown in Fig. 5.

40.2.2.2 Analyzing Thermodynamic Data Thermodynamic data of complexation reactions can determine the mechanism of binding, including enthalpic contributions of bond formation, entropic effects, and so on. A full thermodynamic characterization of a complexation reaction means the determination of K, ΔG, ΔH, ΔS, and stoichiometry (N ). As previously mentioned, the binding constant (K ) is linked to the Gibbs free energy changes (ΔG) by the wellknown van’t Hoff relationship ΔG ¼
RT lnK

(5)

in which R is the gas constant (8.314 J K
1 mol
1) and T is the absolute temperature in Kelvin. ΔG is again composed of enthalpy changes (ΔH ) and entropy changes (ΔS), related by another fundamental relation

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Fig. 5 (a) Heat effects of dilution (I) and complexation (II) of macrocyclic hosts with guest for each injection during microcalorimetric titration experiment. (b) “Net” heat effect obtained by subtracting the dilution heat from the reaction heat, which was fitted by computer simulation using the “one set of binding sites” model [8]

ΔG ¼ ΔH
T ΔS

(6)

ΔG is temperature dependent and is described by the following equation, where T0 is an appropriate reference temperature: ΔGðT Þ ¼ ΔH ðT 0 Þ þ

ðT0

ΔCpdT
T ΔS ðT 0 Þ


ðT 0

T0

ΔCpdlnT

(7)

T0

  T ΔGðT Þ ¼ ΔH ðT 0 Þ
T ΔS ðT 0 Þ þ ΔCp T
T 0
T ln T0

(8)

Equation (8) shows ΔH and ΔS are dependent on T through ΔCp. ΔH ðT Þ ¼ ΔH ðT0 Þ þ ΔCpðT
T0 Þ

(9)

ΔS ðT Þ ¼ ΔS ðT0 Þ þ ΔCpðInT
lnT0 Þ

(10)

ΔG of complexation reaction is the significant thermodynamic description of binding, since it determines the stability of host-guest complex. The thermodynamic analysis involves different binding models, such as simple single-site, two-site binding model, and more sophisticated models. Due to conformational transitions and loss of translational and rotational degrees of freedom, ΔG are related to van der

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Waals, hydrogen bonding, hydration, conformational entropy, electrostatic, and ionization effects [40]. Moreover, compensate enthalpy and entropy are contributed to ΔG in complexation reactions. Thus, ΔH and ΔS are important for understanding of ΔG of binding [41]. In general, ΔH represents the changes in non-covalent bond energy occurring during the interaction [34]. The measured enthalpy must be the result of the hostguest formation in aqueous medium. The enthalpy change of binding reflects the non-covalent interactions, which may produce either favorable or unfavorable contributions. According to Eq. (6), ΔS is directly calculated from ΔH and ΔG, which represents all other negative and positive driving forces that contribute to ΔG [34]. Hydration effects are main factor contributing to ΔS in host-guest formation. An additional factor for ΔS is the reduction of the number of particles in solution and their degrees of freedom [42]. ΔCp is almost always negative in the complexation reactions, because there is strong correlation between ΔCp and the surface area with forming a complex [43]. Thus, ΔCp provides a link between thermodynamic data and structural information of macromolecules. The determination of binding stoichiometries (N ) is important for the characterization of binding mechanisms of supramolecular systems. Due to the computercontrolled injection of definite volumes, ITC can directly show the binding stoichiometry which is determined from the molar ratio at equivalence point. There are a number of possible reasons for deviation of N, such as ratio error in concentration of macromolecule and guest, unspecific binding, and uncertainty of the data set. Thus, the parameter N can be determined by iterative fitting or fixed as equal to the number binding sites in fitting procedures. It is recommended to corroborate the parameter N by additional experimental techniques. If the binding model is verified, ITC can be used as an excellent instrument for the study of the thermodynamics of complexation formation of guests with macrocyclic hosts. The interpretation of the obtained thermodynamic data can indicate the physical phenomena driving the complexation formation. Large favorable enthalpic contributions are related to hydrogen bonding, van der Waals interactions, or electrostatic interactions which are contributed by the unfavorable enthalpic change related to the desolvation of polar groups. Large entropy-dominated processes are assigned to changes in the salvation of lipophilic and/or hydrophobic groups that originates from the release of water molecules from the complexation formation. Additionally, unfavorable enthalpic change is associated with conformational changes involving the loss of degrees of freedom [44].

40.2.2.3 Enthalpy-Entropy Compensation In general, a phenomenon about enthalpy-entropy compensation had been widely observed in thermodynamic parameters related to diverse equilibria and reactions. This relationship between ΔH and ΔS is first proposed and extensively analyzed as an empirical rule in 1955 [45]. It is characterized by the linear relationship between ΔH and ΔS, which favorable changes in binding enthalpy are compensated by opposite changes in entropy and vice versa, resulting in small changes in binding affinity over a range of temperature [34]. It is believed that enthalpy-entropy

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compensation plays an important role in the complexation reactions in solution. The relationship of enthalpic and entropic changes observed was mutually compensatory (Eq. 11) and showing a linear TΔS versus ΔH plot (Eq. 12) after being integrated. T δðΔS  Þ ¼ αδðΔH  Þ

(11)

T ΔS  ¼ αΔH  þ T ΔS 0

(12)

ΔG ¼ ð1
αÞΔH 

(13)

Therefore, the slope (α) and the intercept (TΔS0) of the compensatory plot can be interpreted as measures of the extent of desolvation effect and conformational changes for complex formation. Thus, (1
α) of the enthalpic gain can contribute to the enhancement of complex stability. The intercept (TΔS0) represents the hostguest complex stability at ΔH = 0, if the TΔS0 term is positive [14]. The slope (α) and intercept (TΔS0) can determine the changes of conformation and desolvation with host and guest in supramolecular system.

40.2.2.4 Scope and Limitations ITC as a new and powerful tool offers a good way to measure the interactions of the thermodynamics of complexation formation of guests with macrocyclic hosts. Moreover, ITC experiments can yield a complete set of thermodynamic parameters relevant to complexation interactions in macrocyclic chemistry. There are three important areas for ITC experiments: (1) investigations of the thermodynamic properties of host-guest complex formation, (2) thermodynamic characterization of macrocyclic molecules with their intermolecular interactions in the condensed state and in solutions, and (3) determination of interactions between biological systems and macrocyclic hosts [46]. In general, a simple 1:1 host-guest complex model can be easily determined by iterative fitting in fitting procedures. In contrast, more sophisticated models with 1:2 or 2:1 stoichiometry may lead to ratio error in the mathematical treatments. Thus, appropriate precautions should be exercised to obtain reliable thermodynamic data from these more sophisticated models. Additionally, ITC is not an independent technique and always requires the support of different techniques to explain the binding event. In thermodynamic experiments, heat of reaction depends on ΔH, given the relation between ΔH and Q with the same K. In other words, the heat change will vary linearly with ΔH [47].

40.3

Applications of Thermodynamics in Supramolecular Systems

ITC is a powerful technique based on the measurement of the heat generated, which can be applied in various fields from chemistry to cellular biology. One of the classic applications of ITC concerns its use for the supramolecular systems, such as

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macromolecular complex formation, characterization of the interaction mechanisms of macrocyclic hosts with guests, and applications in drug delivery [48]. Measurement of the heat absorbed or generated when molecules bind allows for measurement of the host-guest interactions, accurate determination of the host-guest complex stoichiometry and association constants, and evaluation of ΔH and ΔS can be obtained by a single experiment and a complete thermodynamic profile [49]. Moreover, each ITC run just requires only a few hours, and compared to other traditional tools, a smaller amount of sample is needed. In general, the ITC experiments are conducted in aqueous media, such as water or phosphate buffer. Because many macrocyclic hosts are hydrophilic and biocompatible, but many guest molecules have limited water solubility. Thus, it should be added other organic solvent in the cells to increase the poor concentration of the guest in aqueous media. A co-solvent can be wildly used in the ITC experiments. For example, a water/ethanol (50/50%, v/v) co-solvent was used to investigate the interaction between paclitaxel and bis-β-cyclodetrins [50].

40.3.1 Cyclodextrins Shaped as a hollow truncated cone, cyclodextrins (CDs) are a class of cyclic oligosaccharides, which are constituted of 6, 7, and 8 glucopyranose units linked by α (1,4)- glycosidic bonds. They correspond to α-, β-, and γ-CD, respectively. The exterior of CDs is formed by the secondary 2- and 3-hydroxyl groups and the hydrophobic inner cavity of CDs by the primary 6-hydroxyl groups. Owing to this special conformation, CDs are used to interact with hydrophobic guests by hostguest complexation to increase the solubility of the guest molecule. However, natural CDs, and particularly β-CD, have limited aqueous solubility related to the relatively strong intramolecular hydrogen bonds between the secondary hydroxyl groups. Therefore, many modified CD derivatives have been developed to improve the physicochemical properties of natural CDs. Therefore, CDs play an important role of mediators between supramolecular chemistry and other sciences.

40.3.1.1 Natural Cyclodextrins Natural CDs are obtained by degradation of starch by the enzyme. The chemical and physical properties of α-, β-, and γ-CD are given in Table 1 [51]. The formation of host-guest complexes is one of the most interesting properties of CDs. The hostTable 1 Chemical and physical properties of α-, β-, and γ- CD [51] The property No. of glucopyranose unites Molecular weight (g/Mol) Central cavity diameter (Å) Water solubility at 298.15 K (g/100 mL)

α-CD 6 972 4.7–5.3 14.5

β-CD 7 1135 6.0–6.5 1.85

γ-CD 8 1297 7.5–8.3 23.2

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guest complexes affect their physicochemical properties, such as aqueous solubility and rate of dissolution, when a guest molecule is incorporated in the cavity of CD. The ITC has been widely used for characterization of host-guest complexes with natural CDs. The thermodynamic data for a very wide variety of guest compounds were compiled by Inoue and Rekharsky [14]. They discussed structural and electronic features of the guest molecules, and matched size of host-guest complexes affects the inclusion behavior with natural CDs. In general, the thermodynamic quantities are correlated with the extent in which the guest molecule has penetrated into the cavity of CD. For example, alkyl chains with a maximum of five or six carbon atoms are accommodated in the α-CD cavity. Both the alkanol’s hydroxyl group and the alkanoate’s carboxylate moiety remain in the bulk water even after inclusion complexation and that only the alkyl groups interact with the cavity of CD [14]. As mentioned above, the affinity of guests toward CDs depends on matched size between the guest molecule and the cavity of CD. In general, the smallest cycloalkanol, acyclic guests, and imidazole prefer α-CD cavity, while adamantane derivatives, cyclic aliphatic compounds, and guest molecules carrying a phenyl moiety prefer β-CD cavity [52]. γ-CD has the highest water solubility among natural CDs. Natural CDs are widely for enhancing properties of drugs, such as hydrosolubility, bioavailability, and controlled release properties. Moreover, natural CDs and some modified CDs are approved by the Food and Drug Administration. Thus, a great number of studies are reported for the complexation between natural CDs and drugs with the use of thermal methods. It is emphasized that thermal methods are valuable techniques for analyzing CD complexes and with other methods can complete the information related to the host-guest inclusion process and the specific properties of CD complexes [53]. Kumar et al. [54] studied the formation of complexes of sanguinarine, a putative anticancer agent, with natural α-, β-, and γ-CD by means of ITC, fluorescence, UVvis spectroscopy, and circular dichroism. The three natural CDs form sanguinarine with 1:1 stoichiometry, and the binding affinity followed the order β > α > γ-CD. Due to the perfect cavity size for sanguinarine, β-CD exhibits the best binding ability compared to the other two CDs. The complexation of α- and β-CD with sanguinarine is driven by a greater entropy, whereas it is driven by a greater both enthalpy and entropy for γ-CD. Wszelaka-Rylik et al. [55] studied the inclusion complex formation of natural CDs with three drugs in aqueous solutions by means of ITC. For natural β-CD, the stoichiometry of host-guest complexation is 1:1, whereas the smaller α-CD with bigger drug molecules of a stoichiometry is 2:1 or 1:2. The different thermodynamic properties of the complexation are related to the stoichiometry. Wszelaka-Rylik et al. [56] investigated the inclusion complex of natural α- and β-CD with three tropane alkaloids in aqueous medium. β-CD forms inclusion complexes of 1:1 stoichiometry with atropine sulfate and scopolamine and 1:2 with homatropine hydrobromide. α-CD forms inclusion complexes of 1:2 stoichiometry with homatropine hydrobromide but forms very weak inclusion complexes with tropane alkaloids due to the smaller size of cavity. The driving force for the complexation is entropy for CDs with three tropane alkaloids.

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Holm et al. [57] investigated the thermodynamics of the formation of the complex of bile salts with natural γ-CD. This study has presented 1:1 stoichiometry and thermodynamic parameters for the binding behavior. The complexation is driven by both enthalpy and entropy for all the bile salts, which is in contrast to reported data on β-CD, due to the dehydration effects. Roy et al. [58] investigated the inclusion complexes of natural α- and β-CD with two amino acids in aqueous medium. The host-guest complexation with the stoichiometric 1:1 is determined by NMR technology. The driving force for the complexation is the release of water molecules from the hydrophobic cavity into the bulk. Benkö et al. [59] studied the complexation thermodynamics of β-CD with series of anionic, cationic, and nonionic surfactant homologs, which consist of a hydrophilic headgroup and a hydrophobic tail. The stability of the complexation is influenced by the number of carbon atoms in the alkyl chains of the surfactants.

40.3.1.2 Modified Cyclodextrins Natural CDs are probably widely used in various fields, owing to the suitable size. However, natural CDs are of limited usage mainly due to their limited solubility and complexation capability. Fortunately, the hydroxyl H atoms at the narrower primary rim and the wider secondary rim of CD can be substituted by various functional groups. The resulting chemically modified CDs, with better physical and chemical properties such as solubility, stability, and spectral properties, are much more desirable for many applications [60]. Matencio et al. [61] investigated the inclusion of piceatannol with different natural and modified CDs. This bioactive molecule forms a 1:1 complex with all the natural and modified CDs. Among natural CDs, the binding affinity of β-CD with piceatannol is the most efficient. However, almost all the modified CDs show higher binding constants than natural β-CD. Moreover, during the encapsulation process, it exhibits negative entropic and enthalpic changes and a negative Gibbs free energy value. The obtained results support the use of piceatannol as an ingredient of new foods. Deng et al. [62] studied the inclusion behavior of β-CD derivatives with benzophenone, which is mainly used as a photoinitiator, and pharmaceutical intermediates. The inclusion complexes with a stoichiometric ratio of 1:1 are driven by enthalpy at different temperatures. The water solubility of benzophenone is enhanced by β-CD derivatives, which can reduce the harm in environment and organisms.

40.3.2 Crown Ethers Possessing multiple oxygen heteroatoms incorporated in a monocyclic carbon backbone, crown ethers were firstly synthesized by Pedersen [63]. Crown ethers display a strong affinity and high selectivity for ammonium, alkali, and alkaline earth metal ions, due to a hydrophilic cavity delineated by a lipophilic envelope. A great number of papers in the thermodynamic aspects of the complexation with crown ethers and various guests have been reported [64].

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Irandoust et al. [64] studied the thermodynamics of complexation of Rb+ with 18crown-6 in a number of binary dimethyl sulfoxide-nitrobenzene mixtures by means of 1H NMR technique. The formation of complexation is enthalpy stabilized, but entropy destabilized in different solvent mixtures with the stoichiometric ratio 1:1. The plot between ΔH and TΔS of all thermodynamic data shows a fairly good linear correlation indicating the existence of enthalpy-entropy compensation in the hostguest complexation. Vendilo et al. [65] studied the complexation of 18-crown-6 with cesium ion in different solutions by means of 1H NMR technique at different temperatures. The K values of host-guest complexes are decreased as temperature is increasing. This paper exhibits that enthalpic change promotes complex formation, while the negative change of entropy provides the decomposition of complex. Taghdiri et al. [66] investigated the complexation reactions between 40 ,400 (500 )ditert-butyldibenzo-18-crown-6 and Li+, Na+, and K+ ions in different acetonitrilenitromethane mixtures at various temperatures. Thermodynamically, the host-guest complexation with the stoichiometric 1:1 is related to the solvent. It is found that the stability of the host-guest complexes increased with increasing nitromethane in the solvent mixture. The plot between ΔH and TΔS of all thermodynamic data shows a fairly good linear in the complexation reactions. Usacheva et al. [67] investigated the thermodynamics of the formation of the complex of 18-crown-6 ether with glycine in the mixed solvents. The stability of the host-guest complex is improved with increasing DMSO concentrations. The enthalpy contributions of the reagents influence on the complexation due to the changes in the solvation state. In 2015, they also studied the thermodynamics of the complexation between 18-crown-6 ether with various amino acids in the binary aqueous organic solvents [68].

40.3.3 Calixarenes Calixarenes, along with cyclodextrins, crown ethers, and cucurbiturils, represent a significant class of the host molecules in supramolecular chemistry. Owing to easy functionalization and different sizes, calixarenes are used to become important receptors for synthesis, molecular recognition, drug delivery, sensing, and selfassembly [69]. Various tools have been employed to investigate the binding behaviors of calixarenes with guest molecules. Thus, thermodynamic data can be applied in host-guest complex stability and selectivity based on calixarenes and functionalized calixarenes.

40.3.3.1 p-Tert-Butylcalixarenes Liu et al. [70] investigated the thermodynamic parameters for the complexation of light lanthanoid nitrates with p-tert-butylcalix[4]arene, shown in Fig. 6. Using the ITC experiments, the cyano analogue shows low and invariant K values for all light lanthanoids, whereas the vanillino analogue shows enhancement of K for all light lanthanoids. It indicates that the three-dimensional induced fit to lanthanoid ions by

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Fig. 6 Structures of five familiar p-sulfonatocalixarenes

the lower-rim and side-arm donor atoms, which play a decisive role upon recognition of trivalent lanthanoid ions by the calix[4]arenes with flexible donating side arms. Thus, the complexation is driven by the favorable enthalpic changes with negative entropic changes. Danil de Namor et al. [71] investigated the interaction of p-tert-butylcalix[n]arene (n = 4–6) tertiary amide derivatives with uni- and bivalent cations in protic (methanol) and dipolar aprotic (acetonitrile) media. It is demonstrated that as the number of phenyl units in the macrocyclic host increases, the feature of the cyclic tetramer host for selective recognition of cations decreases for the cyclic pentamer and almost disappears for the hexamer. This study displays the growth of interest in macrocyclic chemistry involving neutral receptors with ionic species. Sharma et al. [72] investigated the host-guest complexation properties of ptertbutylcalix[4]arene against the five ions by means of 1H NMR, circular dichroism, and UV-Vis. p-Tertbutylcalix[4]arene complex with the metal ion through charge transfer from the phenol oxygen lone pairs and the stoichiometric of host-guest complexation is 1:1. Thus, the strongest binding ability of p-tertbutylcalix[4]arene for the trivalent Tl3+ ion is due to the largest amount of charge transfer. These experiments confirm the utility of this supramolecular compound for topical radiological decontamination formulations.

40.3.3.2 p-Sulfonatocalixarenes Among different calixarene derivatives, p-sulfonatocalixarenes are water soluble and biocompatible. Possessing three-dimensional, flexible, π-electron-rich cavities, p-sulfonatocalixarenes are capable to complex with numerous guest molecules, including inorganic cations, neutral molecules, organic ammonium cations, pyridiniums/viologens, dyes, and biological or pharmaceutical molecules [73]. Figure 7 shows the structures of five familiar p-sulfonatocalixarenes. Liu et al. [74] summarized the binding abilities and thermodynamic origins of psulfonatocalixarenes and with guest molecules, including inorganic cations, organic ammonium cations, pyridiniums and viologens, neutral organic molecules, and dye molecules. Thermodynamically, the complexation of p-sulfonatocalix[4]arene with monovalent cations is enthalpy-driven accompanied with negative or small positive entropy changes, whereas the complexation of p-sulfonatocalix[4]arene with divalent and trivalent cations is entropy-driven accompanied with unfavorable enthalpy changes. Therefore, the binding geometries between monovalent and multivalent

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Fig. 7 Structures of five familiar p-sulfonatocalixarenes

cations with p-sulfonatocalix[4]arene make a difference. Owing to the cationπ interactions, the monovalent metal ions are included into the cavity of p-sulfonatocalix[4] arene, while the association of p-sulfonatocalix[4]arene with multivalent metal ions occurs outside the cavity due to strong electrostatic interactions [74]. Due to π-stacking and charge interactions, p-sulfonatocalixarenes display strong binding abilities and high molecular selectivity for organic cations. The complexes of p-sulfonatocalix[4]arene with organic ammonium cations are entirely formed by enthalpy-driven accompanied with some either positive or negative entropic changes [74]. Liu et al. [75] investigated the thermodynamic parameters for the complexation of p-sulfonatocalix[4]arene and thiacalix[4]arene tetrasulfonate with diazacycloalkane guests in pH both 2.0 and 7.2 phosphate buffer solutions. Thermodynamically, the host-guest complexation with the stoichiometric 1:1 was driven by the favorable enthalpic changes, accompanying either positive or negative entropy changes. In addition, p-sulfonatocalix[4]arene with diazacycloalkane guests exhibited more stable than an thiacalix[4]arene tetrasulfonate in both 2.0 and 7.2 buffer solution due to its smaller cavity that fits the size of diazacycloalkane guests better. Liu et al. [74] have also studied the interactions of p-sulfonatocalix[4]arene, p-sulfonatocalix[6]arene, and thiacalix[4]arene tetrasulfonate with quaternary ammonium cations in a neutral buffer. The formations of the stoichiometric 1:1 complexes are driven by favorable enthalpy changes which are due to π-stacking and van der Waals interactions, which are accompanied with negative entropy changes attributed to the loss of conformational freedom. Liu et al. [76–78] investigated the thermodynamic parameters for the complexation of various p-sulfonatocalixarenes with pyridiniums and viologens guests by the NMR spectroscopy and ITC method in pH both 2.0 and 7.2 phosphate buffer solutions. The host-guest complexation with the stoichiometric 1:1 is driven by favorable enthalpic changes, accompanied with negative or slightly positive entropic changes. The 1H NMR data indicate that pyridinium ions penetrate into the cavity of host from the para-position of N atom, which contributes to the electrostatic interactions between protonated N atom of guest and anionic sulfonate group of host. Moreover, the binding abilities of p-sulfonatocalixarenes enhance continuously accompanied with the increasing number of methyl group of guests. Liu et al. [79] reported the interactions of p-sulfonatocalixarenes with some dye guest molecules by fluorescence spectroscopy. The study shows p-sulfonatocalixarenes could form stable complexes and dye guest molecules with similar molecular selectivity. The values of K increase with increasing the ring size and the length of the hydrophobic alkyl chain.

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In the last several years, a number of papers related to p-sulfonatocalixarenes have been published in several fields including pharmaceutical chemistry, biological chemistry, and environmental chemistry. Liu et al. [80] investigated the thermodynamic parameters and binding geometries of p-sulfonatocalixarenes with five local anesthetics by 1H NMR spectroscopy and ITC. Local anesthetics are used to relieve unpleasant sensations, such as pain, burning, and itching. 1H NMR spectroscopy indicated that p-sulfonatocalixarenes included local anesthetics by triethylammonium moieties which immersed into the cavities of p-sulfonatocalixarenes, except that psulfonatothiacalix[4]arene prefers binding the butylanilinium group of tetracaine in a neutral buffer. p-Sulfonatocalixarenes bind the triethylammonium moieties of procaine and procainamide but unselectively bind the tertiary ammonium and butylanilinium/ butyloxy moieties of tetracaine/dibucaine in acidic buffer. It indicates that the protonated extent of the guest molecules is an important factor in the host-guest complexes based on p-sulfonatocalixarenes. Moreover, the formations of the complexes are dominantly driven by the enthalpic term, and the binding abilities become stronger and stronger with decreasing cavity size. This paper provides a potential clinical application in pharmaceutical studies. Zhang et al. [81] investigated the complexation of p-sulfonatothiacalix[4]arene with L-tyrosine in aqueous solutions by means of spectrofluorometric titration. The experimental data showed that p-sulfonatothiacalix[4]arene forms stoichiometric 1:1 complexes with L-tyrosine in water, and the part of benzene ring of L-tyrosine partially penetrated into the hydrophobic cavity of p-sulfonatothiacalix[4]arene and charged aliphatic chain of L-tyrosine stick out of the cavity. Thermodynamically, the formation of the complex is driven by the favorable entropy changes, and the related mechanism is hydrophobic interaction and electrostatic interaction. Therefore, it will be potential applications in the further biological pharmaceutical development. Mc Dermott et al. [82] investigated the interactions between p-sulfonatothiacalix [4]arene and diquat in an aqueous solution as a function of the ionic strength. The host-guest complexation displays the stoichiometric 1:1 by means of UV-vis spectroscopy. The ionic strength exhibits a significant influence on the value of K, which is decreasing with an increase in the ionic strength. As an antidote toward viologen poisoning, p-sulfonatothiacalix[4]arene can reduce the amount of this toxic species formed in the body. However, in the case of other p-sulfonatocalixarenes, such as p-sulfonatocalix[6] arene and p-sulfonatocalix[8]arene, the binding of alkaline cations has not been widely explored in detail. Garcia-Rio et al. [83] investigated the complexes between p-sulfonatocalix[n]arenes (n = 6, 8) and lucigenin by means of NMR and fluorescence spectroscopy. The host-guest complexations display the stoichiometric 1:1 or 1:2, and the binding stability is dependent on the concentration of metal cations and these anionic calixarenes.

40.3.4 Cucurbiturils Cucurbiturils are well-known in supramolecular chemistry as molecular containers, which possess a relatively rigid structure with hydrophobic cavity and polar carbonyl

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groups surrounding both portals. The development of water-soluble cucurbiturils and their derivatives has various applications in the areas of supramolecular chemistry, including molecular recognition, sensors, catalysts, drug and gene carriers, nanomaterials, and so on. In 1905, cucurbit[6]uril was firstly synthesized by condensation reaction of glycoluril and formaldehyde during an acid-catalyzed reaction [84]. The binding behaviors of guests and cucurbit[6]uril are a combination of electrostatic interactions with the carbonyl rims and hydrophobic interactions with the cavity. In recent years, the family of cucurbituril (Fig. 8) has been enhanced with several functionalized cucurbit[n]urils, where n is a number of units ranging from five to ten. The variable cavity sizes of cucurbiturils lead to well-adjustable recognition properties, and different cucurbiturils accommodate different guest molecules. The thermodynamics of host-guest chemistry of cucurbiturils have constituted the topics of many studies. Buschmann et al. [85] investigated a thermodynamic study of complex formation of cucurbit[6]uril and some amino acids, dipeptides, and short polypeptides in aqueous formic acid solutions by means of calorimetric titrations, due to the low solubility of cucurbit[6]uril in water. The host-guest complexation with the stoichiometric 1:1 was favored by enthalpic and entropic contributions. For the native amino acids, ion-dipole interactions are lowered owing to the electrostatic repulsion between the carbonyl groups and the carboxylic groups of cucurbit[6]uril. For the peptides, the K values and the reaction entropies did not show differences. Nau et al. [85] reported a supramolecular tandem enzyme assay for the accurate determination of amino acids enantiomeric excess. Thus, they utilized cucurbit[7] uril with the high selectivity for enzymatic reactions. Cucurbit[7]uril was used to complex a dye by monitoring the fluorescence change accompanying the enzyme decarboxylation of the amino acid to determine amino acids enantiomeric excesses. The K values and the thermodynamic parameters for the complexation between cucurbit[7]uril with amino acids and their decarboxylated products were determined by ITC and fluorescence titrations. Urbach et al. [86] investigated the high-affinity and site-specific molecular recognition of phenylalanine derivatives and their peptides by the synthetic receptor cucurbit[7]uril. Owning to the N-terminal ammonium group, the side chain ammonium group and the peptide backbone, the complexes obtain the extraordinary Fig. 8 Structures of familiar cucurbiturils

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stability. The high affinity, single-site selectivity, and small modification in this complexation make it potential for the development of minimal affinity tags in vivo. Mendicuti et al. [87] have studied the thermodynamics of binding of a neutral polarity-sensitive guest with cucurbit[6]uril, cucurbit[7]uril, and cucurbit[8]uril in water. The guest complexed with cucurbit[7]uril exhibited a 1:1 stoichiometry, whereas it could not complex with cucurbit[7]uril or cucurbit[8]uril. The complexation of cucurbit[7]uril with the neutral polarity-sensitive guest is accompanied by a small unfavorable enthalpy change. Buczkowski et al. [88] have studied the thermodynamics of stable binding of cucurbit[7]uril and gemcitabine by means of ITC and mass spectrometry in an aqueous high acidic solution. The formations of complexes display different stoichiometrys in different pH solutions and different concentrations. The process of complexation is spontaneous (ΔG < 0), exothermal (ΔH < 0) and accompanied by an increase in the degree of the unordered state of reagents (ΔS > 0). Urbach et al. [85] investigated the complexation of amino acids with cucurbit[8] uril and cucurbit[8]uril methyl viologen by means of ITC and 1H NMR spectroscopy in purely aqueous solution. With the stoichiometric 1:1, both hosts exhibit high selectivity for aromatic amino acids. In this study, ternary complexes were formed by electrostatic interactions of terminal peptide ammonium groups or free amino acid with carbonyl groups of cucurbit[8]uril. Miskolczy et al. [89] have studied the complexation of protonated ellipticine with cucurbit[8]uril by means of ITC and fluorescence spectroscopic in water at pH 4. The different binding stoichiometries of inclusion complexes are depended on the host and guest concentrations. The driving force of the 1:1 guest-host complex formation is much higher than that of 1:2 encapsulation.

40.4

Conclusion

In summary, supramolecular systems is a hot and rapidly growing field, which focuses on the research of host-guest interaction, molecular recognition, molecular assembly, drug delivery, molecular sensors, and so on. The development of selective host-guest complexes, particularly in which a host molecule selectively recognizes, discovers the great possibilities for variety of related fields. By using thermodynamic analysis, we can investigate binding mechanisms between supramolecular hosts and various guests. A wide variety of experimental techniques have been used in the determination of thermodynamic quantities for supramolecular systems. As a highsensitivity calorimetry instrument, ITC is a widely used technique for studying the formation or dissociation of molecular complexes. A full thermodynamic characterization of a complexation reaction can be obtained in a single ITC experiment, including the determination of K, ΔG, ΔH, ΔS, and stoichiometry (N ). Additionally, ITC always requires the support of other techniques to explain the interaction mechanisms. We discuss applications of thermodynamics in supramolecular systems. The examples presented throughout this chapter show that thermodynamic studies will be instrumental as one of the crucial techniques required to tackle the

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complexity in supramolecular chemistry. Thus, thermodynamic analysis will play an invaluable role in supramolecular systems. Acknowledgments We thank NNSFC (21432004, 21672113, 21772099, 21861132001) for financial support.

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Spectroscopy Studies of Macrocyclic Supramolecular Assembly

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Zixin Yang, Hao Tang, and Yu Liu

Contents 41.1 41.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Absorbance and Fluorescence Spectroscopies in Supramolecular Chemistry . . . . . . . . . 41.2.1 General Preparation for Spectroscopies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.2.2 The Qualitative Spectroscopic Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.2.3 The Quantitative Spectroscopic Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.3 NMR Spectroscopies in Supramolecular Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.3.1 1D NMR Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.3.2 2D NMR Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.3.3 DOSY Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.3.4 NMR Titration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.4 CD Spectroscopy in Supramolecular Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.4.1 Generation of ICD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.4.2 Kodaka’s Rules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.5 Dynamic Study in Supramolecular Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Z. Yang College of Science, Huazhong Agricultural University, Wuhan, China e-mail: [email protected] H. Tang School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, China e-mail: [email protected] Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_47

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Introduction

Supramolecular chemistry, which evolved from host-guest chemistry, has been prospering in many rapidly expanding fields, such as molecular machines and motors, molecular sensors, dynamic combinatorial chemistry, and supramolecular polymers [1]. In supramolecular systems, various building blocks are held together and organized by many simultaneous intermolecular forces and therefore generate new and exciting properties and functions that surpass those of the blocks. A supramolecular system is of structural complexity and dynamic reversibility, and thus detailed information on these aspects allows chemists to have a deep understanding of the relationship among the properties of supramolecular system, the underlying microstructure of assemblies and the molecular structure of the blocks [2]. Spectroscopies are important and effective methodologies to deeply reflect the molecular structure characteristics and various dynamic processes proceeded within and between molecules. As a result, they have been widely used in the study of supramolecular chemistry [3–7]. In this chapter, absorbance, fluorescence, NMR, and ICD spectroscopies in supramolecular chemistry are introduced. With practical examples, some fundamental and common techniques of these four spectroscopies are discussed. The chapter begins with absorbance and fluorescence spectroscopies, which are proven powerful tools to study the characteristics of supramolecular microenvironment as well as the supramolecular interaction between the building blocks. The ultraviolet-visible spectrophotometer and the spectrofluorophotometer are two of the most commonly used spectroscopic instruments in the laboratory. Therefore the basic principles of the experimental design and conduction, the qualitative and quantitative analysis are introduced in detailed. Next, 1D and 2D NMR spectroscopies including COSY, NOESY, ROESY, and DOSY are introduced as powerful techniques for the structure investigation. Then CD spectroscopy for supramolecular conformation changes are introduced. Finally, the supramolecular dynamics on different timescales are introduced briefly. In short, this chapter focuses on the fundamental spectroscopic principle, the most commonly used instruments, the experimental design and conduction, and the qualitative and quantitative analysis. Moreover, state of art and perspectives of studies using these spectroscopies are presented.

41.2

Absorbance and Fluorescence Spectroscopies in Supramolecular Chemistry

The absorbance and fluorescence spectroscopies are two commonly used methodologies to study the supramolecular chemistry including the molecular recognition, the self-process, and constitutional dynamic chemistry. These methodologies require that the system contains chromophores (to absorb light) or fluorophores to (emit light). Moreover, the signals of these materials should be changed during the supramolecular process. For those supramolecular systems that contain no chromophores or fluorophores, it is necessary to introduce into the systems the probes that

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are sensitive and responsive to the change of their microenvironments triggered by the supramolecular processes. During the last decade, with the development of new technologies, transient spectroscopies were developed to probe and characterize the transient state (short-lived excited state) of the probe molecules on different time scales from nanosecond to microsecond and successfully employed to study the supramolecular processes. In this section, several absorbance and fluorescence spectroscopies and their applications in the supramolecular study will be introduced.

41.2.1 General Preparation for Spectroscopies 41.2.1.1 The Selection of Probes The probes need to be sensitive to the change of its microenvironment and selective to the specific binding sites. The probes could be an inherent part of the supramolecular systems. For example, a fluorescent-cavity pillararene was designed and synthesized by conjugating a chromophore to the host cavity, as shown in Fig. 1 [8]. This host can selectively detect succinonitrile with fluorescence enhancement at lower concentration of probes (5 μM) and malononitrile with fluorescence quenching at higher concentration of probes (0.1 mM). Such dramatically different signal responses on the guests with a subtle difference of one methylene group were attributed to the subtle difference of guest locations within the cavity. On other hands, the probes need to be introduced into the supramolecular systems if the original systems are optically silent. The probes are diffused and then located in some specific locations mainly driven by the supramolecular interactions between the probes and the binding sites of the supramolecular systems. In general, one might be tempted to assume that the binding sites where the probes are located are identical and homogeneous. However, there might be many different binding sites with different sizes and binding affinities for the probes. For example, as shown in Fig. 2, there are at least five binding sites with different sizes and different hydrophobicities in human serum albumin (the host). As a result, the mobility and the dimerization reactivity of 2-anthracenecarboxylate (the guest) are different when located in different binding sites [9]. Another concern regarding the selection is the stability of the probes. The probes might become reactive when excited or suffer from photobleaching, adsorption, and precipitation. As a result, the probe signals detected for a supramolecular system might be artifacts or unrelated to the supramolecular processes, and thus interfere with the interpretation of the results. For example, during the study of the binding dynamics of 2-naphthyl-1-ethylammonium cation with cucurbit[7]uril, a product that emits at 450 nm was detected under the continuous irradiation of the aerated samples at high photon flux (Fig. 3) [10]. This probe was related to the presence of oxygen, the concentration of the host-guest complex, and the photon flux. However, it was not useful for probing the host-guest binding in the project and thus need to be suppressed.

Fig. 1 Molecular structure of a fluorescent-cavity pillararene, its fluorescence response to different guests, and electrostatic potentials mapped on the electron isodensity surface of H1
guests Ref. [8]

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Fig. 2 Enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylate (AC) mediated by different binding sites of human serum albumin (HAS) in aqueous solution Ref. [9]

Fig. 3 Artifact observed at 450 nm over time during the binding of cucurbit[7]uril to 2-naphthyl-1ethylammonium cation (NpH+) in the presence of Na+ in the aerated samples at high photon flux Ref. [10]

41.2.1.2 The Selection of Media Important principles on the selection of solvents need to be considered including: (i) the solubility of the supramolecular components such as host molecules and guest molecules, (ii) the inertia to react with the supramolecular components, (iii) the inability to absorb or emit light at certain wavelengths that interfere with the spectra of the supramolecular systems, and (iv) the extra driving force from the interactions between the solvent molecules and the supramolecular components. For example, the per-methoxylated pillar[5]arene-guest complex were destabilized in polar solvents due to the strong interaction between the polar guests (dicyanoethane, 1,4dibromobutane and 1,3-dicyanopropane) and the polar solvent. Moreover, when the solvent molecule was changed from p-xylene (that can bind into the host cavity) to oxylene (that cannot bind into the cavity due to the steric hindrance effect), the binding affinity between the per-methoxylated pillar[5]arene and guests increased at least ten fold, showing a competition between the solvent molecule p-xylene and the guest for the binding site of the host. As a result, the binding affinity between permethoxylated pillar[5]arene and dicyanoethane can change from 42 M1 in acetonitrile to 1.8  106 M1 in o-xylene, as shown in Fig. 4 [11]. Indeed, the host-guest complexation could even lead to the precipitation that can be easily observed by naked eyes [12]. In some cases, cosolvent or coion was added into the supramolecular system to solubilize the supramolecular components. For example, in the cucurbituril chemistry, the addition of metal ions or hydronium was necessary to solubilize the host

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Fig. 4 Solvent effect on the binding affinity of per-methoxylated pillararene to dicyanoethane, and the goodness of fit of data when considering the dual roles of solvent molecules as the media and the competitor of the guest Ref. [11]

Fig. 5 The effect of Na+ concentration on the distribution of species and the binding mechanisms for the Ph-H+-Np/CB[7] system Ref. [17]

molecules in aqueous solutions. The presence of cocations (or hydronium) in general leads to the decrease of the binding affinity of host to guest because of the competition between the cocations and the guest to the binding sites of the host [10, 13–16]. Interesting, the presence of cocations with different concentrations can induce the formation of different types of host-guest complexes. For example, as shown in Fig. 5, at lower concentration of Na+ (5 mM), the naphthyl unit of N-phenyl-2naphthylammonium cation (Ph-AH+-Np) bind to the cavity of cucurbit[7]uril. In contrast, at higher concentration of Na+ (25 mM), the binding of Na+ to CB[7] stabilized the binding of phenyl unit of Ph-AH+-Np, and thus lead to the formation of Na+•CB[7]@Ph-AH+-Np@CB[7] 2:1 host–guest complex (where “@” and “•” represent an inclusion complex and an exclusion complex, respectively) [17].

41.2.1.3 The Selection of Laboratory Tools Cuvettes are used to hold samples for the spectroscopic test. Theoretically they can be made by any materials that do not absorb the light at certain wavelengths. There are mainly three types of cuvettes including quartz, glass and plastic ones. Quartz cuvette can be used for the test from 190 nm – 2500 nm, but are quite expensive.

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Glass one can be used in the range of 340 nm – 2500 nm and less expensive. Plastic cuvettes are transparent in the visible light range (380 nm – 780 nm), cheap and disposable with the cross-contamination of samples being avoided. However, they are unsuitable for the UV light range and can be corroded by many organic solvents. When choosing the right cuvette for the experiment, the researchers need to check the wavelength ranges, the solvents, and the photophysical properties of the samples. Another issue is related to the adsorption of the probe to glass and plastic surfaces that continuously decrease the concentration of probe in the solution and therefore decrease the absorbance or fluorescence signal. For example, the fluorescence of 1 μM Rhodamine 6G (the probe) decreased at least 15% and 40% within 5 h when hold in a quartz cuvette and in a borosilicate vial, respectively. The decrease was more dramatical when using a plastic vial. [18] The adsorption issue of probe becomes worse with a lower concentration of the dye prepared: In the same study, more than 90% of 10 nM Rhodamine 6G were lost during the sample preparation with glass or plastic containers [18]. The adsorption of Rhodamine 6G to the surfaces of equipment was suppressed in the presence of cucurbit[7]uril due to the host-guest complexation between the cucurbit[7]uril and Rhodamine 6G. Nevertheless, one might keep in mind that the concentration of hydrophobic dyes in aqueous solution might be largely overestimated especially when preparing the samples at low concentrations (μM or lower) or handling the samples with plastic laboratory tools such as plastic pipettes or cuvettes.

41.2.2 The Qualitative Spectroscopic Study The signal changes of the probes upon supramolecular interactions could be the intensity changes for certain bands, or the wavelength shifts, or both. Several mechanisms for the signal changes were listed as examples.

41.2.2.1 The Intensity Changes One general mechanism related to the intensity enhancement for the fluorescence of the probe is that the host cavity provides a protection for the excited-state probe against quenching by the quencher (such as oxygen or ions) in the solvents. In other cases, the energy transfer process (ET) or the charge transfer process (CT) between donor and acceptor could occur if the donor and the acceptor are in close proximity during the host-guest binding, leading to the fluorescence quenching of the donor. For the acceptor, the fluorescence could be enhanced in case of ET or quenched in case of CT. Furthermore, the close proximity of the polar moiety of one supramolecular component with the fluorophore of another component can be realized during the supramolecular process and leads to a polarity-induced fluorescence quenching. Another mechanism related to the intensity change is the Ham effect proposed by Ham in 1953 [19, 20]. During the determination of the absorption of benzene, Ham found that the absorption band at 260 nm was enhanced with the solvent changing from a hydrocarbon solvent to carbon tetrachloride. This absorption enhancement of forbidden transitions of the solute was attributed to the overlap between the wave

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functions of the excited-state solutes and those of the ground-state solvents with a positive electron affinity or a moderate ionization potential or both. This Ham effect was observed later for many symmetry aromatic molecules including naphthalene and pyrene since their first electronic transition are symmetry forbidden and can be enhanced when located in polar environments. Indeed, the strength of the 0–0 band for pyrene is very sensitive to the solvent polarity. As a result, the intensity ratio of the 0–0 band and the third band in vibronic fine structure of the fluorescence spectra of pyrene was developed as a “pyrene scale” to characterize the polarity of solvents [21, 22]. The “pyrene scale” was later employed to study the polarity of the host cavities for a synthetic cavitand octa acid [23, 24], β-cyclodextrin and so on [25]. The intensity change could be related to the aggregation process. In general, the fluorescence is often quenched for fluorophore at high concentrations due to the formation of aggregates, which is referred to as “aggregation-caused quenching” (ACQ). In contrast, a newly developed mechanism for the fluorescence enhancement is related to the aggregation induced emission (AIE), where the related materials are more emissive in the aggregated state [26–32]. Whether AIE or ACQ prevails in the systems depends on the molecular structure. For example, planar fluorophores tent to aggregate with the strong π-π stacking interactions between them, which leads to the fluorescence quenching, whereas the nonplanar fluorophores might have AIE properties due to the restriction of intramolecular rotation, the restriction of intramolecular vibrations, or both (i.e., the restriction of intramolecular motions). In the supramolecular system, the fluorescence enhancement might be observed during the binding of host to a guest with ACQ property, or during the crosslinking of polymeric host with AIE property by the binding of multitopic guest, or both [33, 34]. Recently, the concept of the assembling-induced emission was reported where the molecular motions and the emission are both controlled by the supramolecular dynamic assembling [35, 36].

41.2.2.2 The Wavelength Shifts The general mechanism related to the wavelength shifts for the probes is the FranckCondon principle in solvation. As shown in Fig. 6, the probes could interact with the solvent molecules via weak interactions with the energy of the interaction being Fig. 6 Energy diagram for the Franck-Condon principle in solvation

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minimized (energy level E0). Upon the excitation of the probes, the electronic transition occurs at 1015 second timescale, during which the positions of the probes and the solvent molecules stay the same (energy level E1). The dipole moment of the excited state of probes may be different from that of the ground state of probes. As a result, the solvent molecules will rearrange around the probes to minimize the interaction energy (energy level E2). If the lifetime of the excited state of the probe is longer than the time for the rearrange of the solvent molecules, the excited state of the probe would decay from E2 to the ground state (energy level E3), during which the positions of the probes and the solvent molecules stay the same. The interaction energy will be minimized by the rearrangement of the solvent molecules such that the system reaches E0. If the excited state of the probe has a dipole moment larger than the ground state, the energy level E2 and E0 will be significantly lower than E1 and E3 in the presence of polar solvents, respectively. On the other hand, the absorption band of the probe is related to the transition from E0 to E1, while the fluorescence band is related to the transition from E2 to E3. Therefore, the fluorescence band for the probe with excited state more polar than its ground state will be red shifted in the presence of polar solvents. Moreover, the stoke shift will increase with the polarity of the solvents. In the case that the ground state of probes has a dipole moment larger than the excited state, a blue shift of the fluorescence band could be observed in the presence of polar solvents. Upon complexation, the probes move into the host cavities which are in general more hydrophobic than the solvent phase and have polarities different from the solvent phases, which could lead to a shift observed for the spectra.

41.2.3 The Quantitative Spectroscopic Study 41.2.3.1 The Relationship between the Signals and the Probe Concentration The value of absorbance determined for a probe by using a colorimeter is independent on the equipment and proportional to the concentration of the probe according to Beer’s law, (Eq. 1). It is convenient to determine the concentration of sample by the absorbance spectroscopy. For example, Kaifer developed a methodology to determine the purity of cucurbit[7]uril and cucurbit[8]uril [37]. The absorbance of the organometallic cobaltocenium cation decreased linearly with the addition of cucurbituril sample and reached a plateau when one equivalent of cucurbituril was added. The plot of absorbance against the concentration of cucurbituril was straightforwardly characterized by two straight lines with the intersection of two lines at the equivalence point. A¼eLc

(1)

where A, e, L, and c represent the absorbance of the probe, the molar extinction coefficient, the light path length of the sample, and the concentration of the probe, respectively.

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In general, the fluorescence spectroscopy is more sensitive than the absorption spectroscopy. The value of fluorescence intensity, in contrast to that of absorbance, depends not only on the photophysical property (i.e., the fluorescence quantum yield) and the concentration of the probe but also on the setting of the fluorimeter such as the photon flux of lamp, the slit widths, the voltage applied to the photomultiplier, etc. Therefore, the values of fluorescence intensity for samples can be compared only when the experimental conditions are the same. The reason is discussed below.
 I F ¼ I 0  1  10A  ΦF

(2)

where IF, I0, and ΦF represent the fluorescence intensity, the intensity of the incident light at the excitation wavelength, the fluorescence quantum yield of the probe, respectively. Mathematical approximation (Eq. 3) is valid when the absorbance of the probe at the excitation wavelength is less than 0.2. 1  10A  R  A

(3)

where R = 2.205 when A < 0.2. The linear relationship between the fluorescence intensity (IF) and the concentration of probe (C) is achieved (Eq. 4) by combining the Eqs. 1, 2, and 3. I F ¼ I 0  R  e  L  ΦF  c

(4)

It is worth noting that Eq. 4 is valid only under the condition that the absorbance of the probe at the excitation wavelength is less than 0.2. Higher absorbance values lead to deviation from the linear dependence of the fluorescence intensity on the concentration of the probe. Several methods can be used to lower the absorbance values at the excitation wavelength, including (i) shifting the excitation wavelength to a region where the absorbance is lower, (ii) diluting the solution, and (iii) using a cuvette with shorter light path (e.g., 1 mm or 2 mm) than the standard cuvette (10 mm).

41.2.3.2 The Determination of Lifetime of the Singlet Excited State The fluorescence quantum yield ΦF in Eq. 2 is related to the rate constant for the fluorescence from the singlet-excited species (kF) and the lifetime for the singletexcited species (τ), as shown in Eq. 5. The rate constant kF is related to the refractive index of the medium, the oscillator strength, and the wavenumber corresponding to the maximum wavelength of absorption [38]. In general, the oscillator strength of fluorescence dyes are insensitive to the environment where the dyes are located [39]. The lifetime τ is the reciprocal of the sum of rates for all possible deexcitation pathways and can be determined by using the single photon counting technique. ΦF ¼ k F  τ

(5)

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For a supramolecular system where multiple fluorescent species (i) coexist, the fluorescence decays are fit to a sum of exponentials (Eq. 6) with the lifetimes (τi) and the pre-exponential factors (Ai) being determined. The quality of each fit was judged by the residuals plot and the value of χ 2. The number of exponentials (n) for each fit was increased until the residuals were random and the χ 2 values were between 0.9 and 1.2. It is worth noting that evaluating the goodness of the fit solely by the value of χ 2 is sometimes misleading since the value of χ 2 can be within the range of 0.9–1.2 even when the goodness of fit is poor with the residuals being non-random. Therefore, always check the residuals plot during the data treatment. It ¼ I0 

n h i X t Ai  e τ i

(6)

i¼1

The fluorescence intensities for each species (e.g., a system with two species i and j) can be related to the pre-exponential factor and singlet-excited state lifetime τ by Eq. 7. Equation 8 is then derived from Eq. 7.  Ð1  τt i A  e i I F ,i 0  ¼ t I F ,j Ð 1 A  e  τ j j 0 I F,i Ai τi ¼ I F,j Aj τj

(7)

(8)

According to Eq. 4, the fluorescence intensities for each species can be related to the concentration of each species by Eq. 9. I F ,i e i  k F ,i  τ i  ½ i  ¼ I F ,j e j  k F ,j  τ j  ½ j 

(9)

Eq 10 can be derived by associating Eqs. 8 and 9. Ai ¼ Aj

g i ,j 

½i ½j

(10)

g i ,j ¼

e i  k F ,i e j  k F ,j

(11)

where

As a result, the ratio of pre-exponential factors for different species could be used to probe the ratio of concentrations for those species. For example, each enantiomer of 2-naphthyl-1-ethanol (R-NpOH or S-NpOH) binds to β-cyclodextrin to form two type of 1:1 complexes (N and E) [40]. N and E referred to the complexes with the naphthyl unit and with the ethanol unit of NpOH being deeply embeded into the βcyclodextrin cavity, respectively. N and E could associate with each other to form

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Table 1 Lifetimes and pre-exponential factors for the emission of NpOH obtained from the global analysis for the decay excited at 277 nm and measured at 380 nm [40] NpOH RS-

τ1/ns 25.4 25.4

A1 0.17 0.21

τ2/ns 38.0 38.0

A2 0.11 0.38

τ3/ns 72.7 72.0

A3 0.72 0.42

three type of 2:2 complexes, i.e., NN, EE, and NE, where the EE complexe exhibited excimer emission. The time-correlated single-photon counting experiments were conducted for the β-cyclodextrin/NpOH systems. The decays traces determined were fit by Eq. 6 with the parameter n being increased. The residuals between the data and the fit was not random until n was assigned to 3, implying a “best fit” with three fluorecent species being identified. The shortest lifetime, τ1, was assigned to NpOH free in water, while the second lifetime, τ2, was assigned to NpOH in the 1:1 host/guest complex. The longest lifetime, τ3, corresponds to the excimer emission of NpOH in the 2:2 host/guest complex. The A3 value is significantly higher for RNpOH than for S-NpOH, indicating that more 2:2 host/guest complexes were formed for R-NpOH than for S-NpOH, and thus a chiral recognition (Table 1).

41.2.3.3 The Determination of Equilibrium Binding Constant The absorbance or fluorescence intensity change at certain wavelength upon the host-guest complexation can be used to quantitatively study the host-guest binding. The host-guest binding ratio can be determined by a Job plot [41]. In the experiments, the samples are prepared with the concentration of guest varied but the total concentration of host and guest remaining constant. The signal change of absorbance or fluorescence intensity is then plotted against the mole fraction. The mole fraction with the maximum of the signal change in the plot implicates the host-guest binding ratio. The Job plot is simple and straightforward methodology to determine the binding ratio. However, one could determine the binding ratio and the equilibrium binding constant for the host-guest binding simultaneously by a titration experiment. In the titration experiment, the concentration of the probe (either host or guest depending on which one is detectable) is in general kept constant while the concentration of the other species is varied. The signal changes are then plotted against the concentration of the titrant and the binding isotherm was fit with several binding models until the best fit was achieved. The goodness of the fit of a binding model is judged by the randomness of the distribution of residuals between the data and the fit. For example, the binding isotherms for the interaction of pillararene unit with multitopic guests were determined and fit with different binding model (Fig. 7) [33]. Only the fit with 2:1 host/guest binding model showed random residuals for the pillararene/ditopic guest complex and the fit with 3:1 host/guest binding model showed random residuals for the pillararene/tritopic guest complex, respectively. It is worth noting that some traditional fitting methods, e.g., the BenesiHildebrand treatment for a 1:1 host-guest complex (Eq. 12) [42], are still employed nowadays. These methods are convenient and straightforward to fit the data using linear regression. However, these methods give higher weight to the lower signal

Spectroscopy Studies of Macrocyclic Supramolecular Assembly

Fig. 7 The fit of binding isotherm with different host-guest binding models by the nonlinear regression Ref. [33]

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changes which are determined at lower concentration of titrant and thus have the higher uncertainty. As a result, the equilibrium binding constant recovered by the linear regression (e.g., Eq. 12 for a 1:1 host-guest complex) is not so accurate as that determined by the nonlinear regression (e.g., Eq. 13 for a 1:1 host-guest complex). 1 1 1 ¼ 0þ Δ Δ K  Δ0  c Δ¼

Δ0  K  c 1þK c

(12) (13)

where Δ, Δ0 , K, and c represent the signal changes determined for each sample, the signal change between the free and complexed probe, the equilibrium binding constant, and the concentration of titrant, respectively.

41.3

NMR Spectroscopies in Supramolecular Chemistry

NMR spectroscopy is the very important and powerful methodology for the investigation of supramolecular systems. Various NMR techniques are applied to develop detailed structural elucidation of supramolecular systems and to study their thermodynamic and dynamic properties [5]. In this section, some most common NMR techniques and their applications in supramolecular systems will be given brief introduction. Before beginning, it needs to be aware of that the host-guest complexation is a dynamic process. If there is a slow exchange between the free and bound species, separated NMR resonances will be observed for all species involved in the hostguest bonding equilibrium. However, the most common situation in host-guest complexation is a fast exchange, and the observed chemical shifts in this case is a weighted average of the values in the free and bound states [6].

41.3.1 1D NMR Spectroscopy Changes in the 1D spectra of the molecules during a molecular assembly process can present the information about the resulting structure. Chemical shift change is usually an indicator of the formation of a host-guest complex, and more if it is informative on the binding mode analysis [5]. A recent and typical example has been provide by Yu liu and co-workers [43], where a variety of morphologically interesting aggregates have been constructed using bipyridinium-modified diphenylalanine derivative (BP-FF) and macrocyclic hosts (cucurbit[7]uril (CB[7]), cucurbit[8]uril (CB[8]), pillar[5]arene (WP5A), or tetrasulfonated crown ether (DNC)). There is the 1:1 complex stoichiometry between BP-FF and four macrocycles. Their binding modes were investigated by 1H NMR spectroscopy. The NMR spectra of free host or guest molecules without binding were shown in Fig. 8a, c, e, g, i, respectively. The

Spectroscopy Studies of Macrocyclic Supramolecular Assembly

Fig. 8 1H NMR spectra (400 MHz, D2O) of (a) free CB[7], (b) BP-FF CB[7] complex, (c) free BP-FF, (d) BP-FF CB[8] complex, (e) free WP5A, (f) BPFF WP5A complex, (g) free BP-FF, (h) BP-FF DNC complex, and (i) free DNC at 25 C (The concentration is 2 mM of all substances) Ref. [43]

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resonances of an included guest are usually shifted to upfield compared with the free molecule, due to the anisotropic effect of a rich electronic cavity of the host, such as the host with the aromatic walls [44]. When BP-FF CB[7] complex formed, the protons (Hb and Hc) of the pyridinium moiety in BP-FF exhibited a large upfield shift in the presence of CB[7], while the protons of the phenyl rings were essentially unchanged (Fig. 8b, c). Therefore, it can be deduced that pyridinium moiety was bound to CB[7], but the diphenylalanine moiety is outside the cavity. In BPFF CB[8] complex, both pyridinium (Ha, Hb and Hc in Fig. 8d) and partial phenyl protons shifted to higher field in the presence of CB[8], indicating that the pyridinium moiety and phenyl ring of diphenylalanine were concurrently included in the cavity of CB[8]. As shown in Fig. 8f, when WP5A was added, the proton peaks of the pyridinium ring of BP-FF underwent an upfield shift, which demonstrate the host-guest inclusion between WP5A and the pyridinium moiety of BP-FF in water. Similarly, as can be seen from Fig. 8h, the chemical shifts of aromatic protons in DNC and all protons in bipyridinium moiety of BP-FF showed an upfield shift upon complexation with each other, by the anisotropic effect between naphthalene and pyridinium rings. Chemical shift changes in 1D NMR spectroscopy are also usually utilized to study stimulus-response behaviors, intra- and intermolecular [6]. For example, the changes can reveal the conformational variation of host/guest, or the relative motions between molecules in a supramolecular system, such as in a rotaxane or catenane. As shown in Fig. 9, OPVEx2Box4+ is a semi-rigid tetra-cationic cyclophane with a rectangle-like geometry [45]. It comprises oligo(p-phenylenevinylene) pyridinium units and the biphenylene-bridged 4,4-bipyridinium extended viologens, where the stilbene part is photo- and thermal-responsive. (EE)-OPVEx2Box4+ can undergo (E)$(Z) isomerization of vinyl group upon light irradiation or on heating. The photoisomerization can be displayed by 1H NMR spectroscopy. The 1H NMR spectrum of a freshly prepared (EE)-OPVEx2Box4+ sample under blue light (450–460 nm) irradiation showed two distinct proton resonances shifts to upfield of hydrogen in the alkene group (Hk and Hl), indicative of (EE)-OPVEx2Box4+ undergoing isomerization. More specifically, the resonances of the protons Hk and Hl were split into two sets: the original set was assigned to the unreacted E conformation, while the other set of proton resonances (Fig. 9b), Ho (d, J = 12.9 Hz) and Hp (d, J = 12.8 Hz), was corresponding to the transformation of OPVEx2Box4+ from the (EE)- to the (EZ)-isomer. On heating of the solution of the (EZ)-OPVEx2Box4+ at 70 C for 16 h, the 1H NMR spectra (Fig. 9c) was restored to the same as the (EE)OPVEx2Box4+, which indicated almost quantitative thermalisomerization from the (EZ)-isomer to the (EE)-isomer. In supramolecular chemistry study, it is a matter of great concern to study the controlled motion between molecules, because it is an important foundation of molecular machine research [46]. As mentioned above, certain chemical shift changes in 1D NMR spectroscopy are signs to tracking the relative motions between molecules. Wei jiang and co-workers has reported a rotaxane-based molecular shuttle that can achieve directional shuttling of a cone-like “rotor” on a symmetric “axle” [47]. The “rotor” was a naphthotube macrocycle, and the “axle” possessed

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Fig. 9 1H NMR spectra (500 MHz, CD3CN, 25 C) of (EE)-OPVEx2Box4PF6 (a) before and (b) after blue light irradiation (450–460 nm, 12 W, 12 s). (c) Spectrum after heating the solution of (b) for 16 h at 70 C. (d) Spectrum of (EZ)-OPVEx2Box4PF6 Ref. [45]

two phenyl triazole stations arranged in opposite orientations and one di(quaternary ammonium) station in the middle (Fig. 10a). The stimuli-responsive motion between the “rotor” and the “axle” in the rotaxane (R2+) could be manipulated by the acid/ base adding as shown in Fig. 10b. Its unique directional shuttling was discovered and supported from its 1H NMR experiments. The addition of three equivalents TFA

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Fig. 10 (a) Chemical structure and cartoon of rotaxane R2+ with PF 6 as the counterions. (b) Cartoon representation of acid/base controlled shuttling of rotaxane R2+. 1H NMR spectra (400 MHz, CD2Cl2, 2.0 mM, 25 C) of rotaxane R2+ with PF 6 in (c) the absence or (d) the presence of TFA Ref. [47]

into the solution of R2+ was able to cause the protonation of macrocycle and then the relocation of macrocycle to the two phenyl triazole stations. Because the upfield peaks of H atoms (Hj, Hk, Hl, Hk’, and Hl’) from the alkyl in the “axle” was disappeared, indicating the shielding effect faded away, that is, the electron-rich cavity of macrocycle moved away from the alkyl. It might result in the formation of two possible isomers RA-2H4+ and RB-2H4+, if the movement of macrocycle was nondirectional onto the “axle.” However, the 1H NMR spectrum of R2+in the presence of TFA was quite well-defined and clean, and only one set of isomer’s signals was observed, standing for only one isomer exists. As regards peaks, protons in left phenyl triazole part underwent very large upfield shift, where He shifted upfield (1.55 ppm), Hf (4.72 ppm) and Hg (3.47 ppm). These chemical shift changes revealed only RA-2H4+ was formed form the directional shuttling in the R2+.

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41.3.2 2D NMR Spectroscopy 2D NMR spectroscopy gives data plotted in a space defined by two frequency axes rather than one. The development from 1D to 2D NMR has opened a broader prospect for the application of nuclear magnetic technology. 2D NMR techniques have become very popular because they can easily and clearly show the interaction within or between molecules. The interactions through scalar couplings between nuclei can be detected mainly by COSY, TOCSY, HMQC, and HMBC experiments, while ones through space couplings is usually detected by NOESY and ROESY experiments. 2D COSY, called correlation spectroscopy, experiment is the simple and widely used 2D NMR experiment. It is an homonuclear chemical shift correlation experiment based on the transfer polarization by a mixing pulse between directly J-coupled spins, and homonuclear through-bond interactions can be trace out in its map if their cross-peak exists [48]. Thus, the spectral assignment in a complicated system can be made with the help of 2D COSY spectrum. In the work just mentioned about the directional shuttling of rotaxane R2+ [47], the identification of its 1H NMR peaks to corresponding hydrogens of R2+, especially the peaks of right (or left) “axle,” is very difficult. To minimize form complexity, it is necessary to determine the peaks derived from the hydrogens on adjacent carbon (e. g., Hj – Hk) through the crosspeaks in the 2D COSY map, as shown as in Fig. 11. NOESY, called nuclear overhauser enhancement spectroscopy, is based on nuclear overhauser effects (NOE), and the NOE is defined as the change in the intensity of one spin when the spin transition of another nuclei nearby is perturbed from equilibrium population [48]. The NOE decreases rapidly with the increment of the distance between the nuclei, and thus the NOE cross peak in 2D map only relates protons which are spatially close to each other (closer than 0.4 nm), even if no chemical bonds connection, and the relative intensities of these cross-peaks depend on the spaces between the corresponding nuclei. When the molecules with a mass of 1000 Da – 2000 Da, it is worth noting the NOE can become very weak or even vanish. In that case, the spin-lock experiments such as the rotating frame NOE (ROESY) should be used instead of NOESY. Thus, NOESY and ROESY are very useful for judging protons that are close to each other in the supermolecular structure. For example, the structure of β-cyclodextrin/BPA complex was investigated in water solution by ROESY experiments at 25 C in D2O [49]. As shown in Fig. 12, β-cyclodextrin is a cyclic oligosaccharide with seven D-glucose units linked by α-1,4-glucose bonds and has the H3/H5 inside its hydrophobic cavity. H3 locates at the secondary ring side, while H5 at the primary ring side. β-cyclodextrin can form 1:1 complex with BPA, and the ROESY spectrum of the complex displayed clear NOE cross-peaks between the Ha proton of BPA and the H3/H5 protons of βcyclodextrin (peaks A and B), as well as, between the Hb protons of BPA and the H3/H5 protons of β-cyclodextrin (peaks C and D). These NOE cross-peaks indicate the structure of the complex, where the phenyl ring of BPA is deeply included into the β-cyclodextrin’s cavity. Moreover, considering the comparable intensity of peaks E and F (peaks E assigned to the NOE cross-peaks between the Hc and H3, peaks F

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Fig. 11 2D 1H-1H COSY spectrum of (400 MHz, CD2Cl2, 2.0 mM, 25 C) of rotaxane R2+ with PF 6 Ref. [47]

assigned to the NOE cross-peaks between the Hc and H5), the BPA molecule can puncture simultaneously into the β-cyclodextrin’s cavity both from the primary ring side and the secondary ring side. From a NOESY spectrum, similar information can be obtained. As shown in Fig. 13, the pillararene (WP5-P) and the guest (G1) displayed NOE cross peaks between protons Ha, Hb, and Hc of WP5-P and protons H1 and H4 of G1 in their NOESY spectrum, indicating the complex can be formed and has the structure as presented in Fig. 13a [50].

41.3.3 DOSY Technique The diffusion coefficients (D) can be calculated by the Stokes-Einstein equation (Eq. 14): D¼

kBT 6πηr

(14)

where kB is the Boltzmann constant, T is the absolute temperature, η is the dynamic viscosity, and r is the hydrodynamic radius of the species [51]. The diffusion

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Fig. 12 (a) 1H ROESY spectrum of the β-cyclodextrin/BPA complex (8 mM in D2O at 25 C with a mixing time of 200 ms). (b) Possible structure of the complex in aqueous solution [49]

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Fig. 13 (a) Structures and cartoon representations of WP5-P/G1, (b) 1H NOESY spectrum of a mixture of WP5-P (10.0 mM) and G1(10.0 mM). The NOE correlation signals that confirm the hostguest interactions are marked on the spectrum Ref. [50]

coefficients, in a given situation can reflect on the size and shape of species. Since molecular aggregations and complexations in solution will cause a change in the diffusion coefficients, diffusion measurements are attracting more attention in supramolecular chemistry. Many NMR techniques are developed for diffusion measurements to investigate molecular interactions, such as DOSY. DOSY, called diffusionordered NMR spectroscopy, is also presented as a 2D map with the chemical shift in the horizontal axis and the diffusion coefficient of the component in the vertical axis [52], so it shows the separation of the components in a complex mixture according to their diffusion coefficient just like a “NMR chromatography” and make an evaluation of the species in equilibrium. Cohen and co-workers confirmed the hexameric capsules of M1 formed in CDCl3 by the DOSY experiment using M2 as an internal

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Fig. 14 1H DOSY of a mixture of M1 (20mM) and M2 (20mM) in CDCl3 at 25 C. Structures of M1 and M2 as shown on top Ref. [53]

reference [53]. The DOSY spectrum of the 1:1 mixture of M1/M2 (Fig. 14) shows three diffusing sets of peaks. M2 is known to form robust hexamers when dissolved in CDCl3, so the horizontal purple line represents the diffusion value of its hexamers. The diffusion coefficient of the slower diffusing set of peaks of M1 (green line) is approximate to that of the hexamer of M2, indicating the hexamers M1 formed. In addition, the red line indicates the diffusion value of the dimer of M1.

41.3.4 NMR Titration NMR titration is measurement of chemical shift changes as a function of concentrations of species. As mentioned above, if host-guest complexation is a fast exchange, the observed chemical shift in this case is a weighted average of the values in the free and bound states. Thus, in that situation, the association constant (K ) of host-guest complexation can then be obtained from a series of NMR spectra measured at different initial concentrations of host and guest. The data treatment

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with Benesi-Hildebrand equation is recommended and like that of the spectral methods in previous section (Eq. 6). The advantage of NMR technology is that it can provide more microscopic information for complicated supramolecular structures and avoid mistakes attributed to the presence of impurities. For example, Yuliu and co-workers employed a 1H NMR titration to investigate the association constants (K ) of CPT-CD and ADA-EDA [54]. CPT-CD and ADA-EDA are derivatives of β-cyclodextrin and adamantane, respectively. Firstly, the stoichiometry between CPT-CD and ADA-EDA was determined as 1:1 according to the Job’s plot where the maximum was observed at a molar fraction of 0.5. As shown in Fig. 15, the concentration of ADA-EDA was fixed at 0.5 mM, and the concentration of CPTCD increased from 0 to 3.0 mM. The proton signals of ADA-EDA shifted downfield gradually for the inclusion of ADA part into the cavity of CPT-CD. The peak at δ = 1.86 ppm is assigned to ADA-EDA, and its chemical-shift changes is chosen as the function of the concentration of CPT-CD by analyzing the nonlinear leastsquares fit. Finally, the binding constant (K ) between ADA-EDA and CPT-CD was calculated as (1.8 0.2)  103 M1.

41.4

CD Spectroscopy in Supramolecular Chemistry

41.4.1 Generation of ICD Circular dichroism (CD) is a chiroptical spectroscopy, and the phenomenon of CD is derived from the differential absorption, usually in the UV-Vis wavelength region, of molecules with left- and right-circularly polarized light (CPL) [55]. Its signal can be positive or negative, depending on whether left-CPL is absorbed to a greater extent than right-CPL. A chiral molecule is optically active, so CD spectroscopy is a sensitive spectroscopic tool for determining its absolute configurations and conformations. Nevertheless, an achiral molecule can be induced optical activity by a chiral and transparent molecule as result of the appropriate coupling between the electrical transition moments of the former and of the latter, that is, it displays induced circular dichroism (ICD) signals in absorption bands after complexation with a chiral inducing molecule [7, 56]. The basic idea of ICD is shown in Fig. 16. A good example for ICD caused by hosts is that achiral naphthalene derivatives can be endowed ICD property by the complexation with cyclodextrins [57]. Cyclodextrins are chiral molecules but do not absorb in the UV-Vis region and consequently do not show CD over there. Achiral naphthalene derivatives can absorb in this wavelength range, but CD inactive. When the naphthalene guest complexes with a cyclodextrin, it arises the ICD in the UV-Vis region [58–61].

41.4.2 Kodaka’s Rules Kodaka proposed some general rules for ICD of an achiral chromophore caused by a chiral macrocycle host, in particular for cyclodextrins [58–60]. (1) For the guest included in the host, an electronic transition of achiral guest parallel to the axis of

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Fig. 15 1H NMR titration of ADA-EDA with CPT-CD. (a) 1H NMR spectra of ADA-EDA (0.5 mM) upon the addition of 0, 0.1, 0.3, 0.5, 0.8, 1.0, 1.2, 1.5, 1.8, 2.0, 2.2, 2.5, and 3.0 mM CPT-CD (spectrum 1 to 13) in D2O containing 3% DMSO-d6 at 25 C. (b) Nonlinear least-squares fit of the chemical-shift changes of the ADA-EDA with the initial concentration of CPT-CD. Structures of ADA-EDA and CPT-CD as shown on top Ref. [54]

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Fig. 16 Simplified representation of generation of ICD

host gives positive ICD while that perpendicular to the axis gives negative ICD. (2) When a chromophore is situated outside the cavity of the host, the sign of ICD becomes reversed to that inside. (3) The magnitude of the ICD signal is greater when the movement of the guest inside the host is hindered. The application of the rules will be explained through the ICD studies of 2,3dimethyl naphthalenedicarboxylate (23DMN) with 2-hydroxypropyl-α-, β-, and γ-cyclodextrins (HPCDs) in aqueous solution [61]. As shown in Fig. 17a, 23DMN do not have any CD signal itself, but it can be induced ICD signals in the presence of α-, β-, and γ-HPCD. The ICD spectra for 23DMN:β-HPCD and 23DMN:γ-HPCyD systems exhibit a positive peak around 240 nm, which is corresponding to 1Bb band of 23DMN. It indicates that 23DMN penetrates inside the cavities of β- and γ-HPCD with its 1Bb transition parallel to the axis of HPCDs (Fig. 17b). The higher magnitude of the ICD for the 23DMN:β-HPCD suggests a better size-fit and less movement freedom of 23DMN within β-HPCD than γ-HPCD. This host-guest geometry is further confirmed by the molecular mechanics calculations (Fig. 17c). In contrast, the 23DMN with α-HPCD shows a weak negative peak for its 1Bb band. For the relatively small size of α-HPCD, the 23DMN can not penetrates inside with its 1Bb transition perpendicular to the axis of α-HPCD. Based on Kodaka’s rules, it should be that the 23DMN has most of its chromophore part situated outside the cavity of the α-HPCD (Fig. 17b). In addition, the calculation of the binding constant of hostguest complexes also can be performed by using the ICD technique [62]. From the ICD intensity change of the intensity of the 23DMN upon β-HPCD addition (Fig. 17d), the binding constant, as (910 50) M1, can be fitted out by a nonlinear equation for a 1:1 complex (Eq. 13).

41.5

Dynamic Study in Supramolecular Chemistry

One crucial feature of supramolecular system is its dynamic characteristics [63]. The intermolecular interactions between the chemical components in the systems are noncovalent and relatively weak compared to the covalent bond in the molecular

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Fig. 17 (a) CD spectra of 23DMN and 23DMN in the presence of α-, β-, and γ-HPCD water solutions. Absorption spectrum for a 23DMN water solution and the orientations of the absorption transition moments of 23DMN are shown in the inset. (b) Schematic structures of the 23DMN complex with HPCDs. (c) Minima binding energy conformation structure for the 23DMN complex with β-HPCD by the molecular mechanics calculations. (d) Nonlinear least-squares fit of the ellipticity values with the initial concentration of β-HPCD for the 23DMN/β-HPCD system Refs. [61, 62]

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systems. Therefore, the chemical components in supramolecular systems associate and dissociate with each other reversibly. As written by Jean-Marie Lehn, “indeed, supramolecular chemistry is intrinsically a dynamic chemistry in view of the lability of the non-covalent interactions connecting the molecular components of a supramolecular entity.” [64] The dynamic of supramolecular system might be crucial to the application scenarios. For example, a drug delivery system might require the release of drugs in the timescale of hours [65], while a dye stabilizing system might require the release of dyes in the timescale of days or even months [18]. However, the information provided by dynamic studies cannot be inferred from thermodynamic studies or structural studies. For example, the trend for the rate of complexation process can be opposite from that for the stability of the complex [66]. In contrast, the information provided by the dynamic study can be employed to infer or explain the results from the thermodynamic study and the structural study. The dynamic study in the supramolecular chemistry has not been developed to the same extent as the thermodynamic study or the molecular structural design. This situation may be due to fact that the complexity and the diversity of the supramolecular systems limit the equipment and the technique that can be employed. For example, the dissociation of complex can proceed very fast (e.g., within 0.1 μs for the β-cyclodextrin-xanthone complex [67]) or very slow (e.g., >27 h for the CB[7]1,10 -bis(trimethylammoniomethyl)ferrocene complex [68]). The slow dynamic process (e.g., equilibrating on a timescale longer than minutes) is convenient to be studied by the techniques aforementioned in this chapter, e.g., steady-state fluorescence and absorbance spectroscopies or NMR. During data collection for the supramolecular system, the concentration of the species can be approximately treated as being constant because the time of determination is too short for the process to proceed (known as psudoequilibrium state). Thus, the data points collected at each sampling time can be used to study supramolecular dynamics. In contrast, the fast process cannot be studied by those techniques because the process equilibrates within the determination time and no dynamics information can be obtained. To study the fast process, some relaxation techniques were developed [69]. In 1950s, Manfred Eigen developed a method of “kinetic relaxation” (or known as “chemical relaxation”) to study very fast reactions, e.g., the neutralization process of hydronium ion and hydroxide ion [70, 71]. In brief, the methodology of chemical relaxation studies includes perturbing a system at equilibrium, recording the relaxation process (i.e., the process for the system to re-achieve the equilibrium) as the kinetic trace, and analyzing the kinetic trace. The binding mechanism for the supramolecular system and the related association and dissociation rate constants for the relevant reactions in the system are determined during the analyzing process. The perturbation process, which must be faster than the relaxation process, can be achieved by changing temperature (i.e., “temperature jump”), changing pressure (i.e., “pressure jump”), changing the concentration of supramolecular components (i.e., “stopped flow”) or changing the energy state of the chemical species (e.g., generating significant amount of excited state of species by the laser flash photolysis experiments (Fig. 18) [72].

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Fig. 18 Techniques suitable for the supramolecular dynamics study at different timescales Ref. [69]

In general, the binding process between the guest and the host molecules proceeds by two steps: (i) the formation of intermediates driven by the host-guest recognition according to the surface properties of the guest and the host molecules (i.e., an exclusion complex), and (ii) the formation of the final host-guest complexes whose geometry and structural distribution depend on the dynamic properties of the complex (i.e., an inclusion complex) [73]. Whether the exclusion complex is detectable or not is different, case by case. For example, the guests with different charge states could associate with cucurbit[6]uril (CB[6]) by different mechanisms: Charged guests with large size bind to CB[6] by forming exclusion complexes firstly and then inclusion complexes, whereas neutral guests with similar sizes move into the cavity of CB[6] directly without the formation of detectable exclusion complexes [13]. For a simple system with two supramolecular components, the binding process could be very fast and equilibrate within 1 millisecond, e.g., the association rate constant for binding of some guests to cyclodextrins and cucurbit[7]uril could be within the range of 4  108 M1 s1 –109 M1 s1 [10, 74]. With the increase of complexity of supramolecular assemblies, the assembling process dramatically slows down from a sub-millisecond timescale to a millisecond or longer timescale [23, 75]. It is worth noting that some picosecond and femtosecond studies have been conducted for the supramolecular systems [76]. In these cases, the time window of the measurement is too short for the association and dissociation between guest and host cavities. Rather, the ultrafast dynamic studies examined the effect of the host cavities on the vibrational relaxation process of the tripped guests.

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Conclusion

Overall, this chapter introduces four basic and common spectroscopies, i.e., absorbance, fluorescence, NMR, and ICD spectroscopies and their applications in supramolecular chemistry. These spectroscopies are profusely and successfully used in structural, thermodynamic and dynamic studies of supramolecular systems. Absorbance, fluorescence and classic 1D NMR spectroscopies are useful tools to monitor the formation of host-guest assemblies with the binding mechanism and the binding affinity being determined. 2D NMR techniques are convenient ways to reveal the intermolecular interactions as well as the position of guest within the host cavity. ICD experiments are often performed for supramolecular conformation characterization. And with the dynamic methodologies at different timescales, the characteristics of the dynamic process in supramolecular systems and the binding mechanism could be clarified. Moreover, the basic principles in the experimental design and practical operation of spectroscopic experiments were introduced in detailed with specified examples. This knowledge is very important to make the experimental design and data collection rightly especially for beginners. In all, the comprehensive and rational use of these methods and techniques will help us to obtain more complete and accurate insights in supramolecular chemistry. Acknowledgments We thank National Natural Science Foundation of China (21502059), Natural Science Foundation of Guangdong Province, China (2018A0303130007), and Fundamental Research Funds for the Central Universities, China (2018MS38).

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Contents 42.1 42.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protein Modifications via Host-Guest Interactions and Their Applications . . . . . . . . . . . 42.2.1 Host-Guest Recognition-Driven Protein Assemblies . . . . . . . . . . . . . . . . . . . . . . . . . 42.2.2 Host-Guest Mediated Protein Modifications and Purifications . . . . . . . . . . . . . . . 42.2.3 Macrocycle-Modified Proteins for Biological Activation and Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.2.4 Proteins/Peptides Recognition via Water-Soluble Cavitands and Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.3 Carbohydrates Recognition and Modification by Synthetic Macrocycles . . . . . . . . . . . . . 42.3.1 Mono- and Disaccharide Recognition by Synthetic Macrocycle in Water . . . 42.3.2 Polysaccharide Recognition and Modification with Synthetic Macrocycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.4 DNA Modifications with Macrocyclic Hosts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

The birth of host-guest chemistry and supramolecular chemistry was marked by the accidental discovery of crown ethers half a century ago, since then rapid development has been made for the synthetic macrocyclic compounds who has played an important role in the fabrication of advanced supramolecular systems or host-guest based materials with tunable, selective, and stimuli-responsive recognition motifs that can drive self-assembly or other functionality [1–5]. While continuous interests have been paid to the investigation of structural diversity and properties of the T.-G. Zhan · K.-D. Zhang (*) College of Chemistry and Life Science, Zhejiang Normal University, Jinhua, China e-mail: [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_48

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original macrocycles [3], exploring the application scope of host-guest chemistry has been recognized as a major thrust in the development of supramolecular chemistry. In particular, the combination of specific host-guest interactions and biomolecules has recently been emerged as an exciting discipline [2, 4, 5]. Although covalent strategies based on small molecules are traditionally used, these methods often need tedious chemical synthesis, harsh reaction conditions, and the use of large metal ions, which may ubiquitously bring drawbacks to the chemically modified biomolecular systems such as the impairment of protein activities. To address these challenges, supramolecular approaches involving specific hostguest interaction have been developed for the advantages of easy preparation, mild condition, as well as high selectivity and binding affinity. More importantly, benefiting from the nature of noncovalent interaction, noticeable features such as stimuli responsiveness, modification reversibility, and functional adaptability can provide various opportunities for guiding the modification and functional regulation of biomolecules including proteins and peptides [6–9], carbohydrates [10], as well as DNA and nucleic acids [11]. In this content, synthetic water-soluble macrocyclic molecules with well-defined cavities and recognition motifs such as calixarenes (CAs), cyclodextrins (CDs), cucurbit[n]urils (CB[n]s), and deep-cavity cavitands are among the commonly used supramolecular hosts in biomolecular modifications [2]. In the next few sections, we are going to discuss how these wholly synthetic macrocyclic molecules can be utilized in the modification of biomacromolecules in widespread applications ranging from self-assembled biomaterials to drug delivery and biomedicine. It should be pointed out that although convergent properties including outstanding recognition properties, nontoxicity, as well as synthetic modularity could also be found for some acyclic host molecules, especially the acyclic CB[n]-type receptors, they are outside the scope of this chapter [12].

42.2

Protein Modifications via Host-Guest Interactions and Their Applications

Among the biomolecules, proteins have become the key role whose modification is of central importance in the fields of chemical biology and biomaterials science in the postgenomic era. Although traditional covalent chemistry has offered useful techniques for the protein modifications, the rise of supramolecular chemistry, in particular, the host-guest chemistry, has provided more promising strategies for the modification of complex proteins with introducing different degrees of reversibility and functionalities simultaneously [6–9]. In this section, we will highlight the recent advances on the host-guest assisted protein immobilization and modification for ordered protein assemblies, protein purification, and enrichment, as well as their wide applications including biosensors, catalysis, biological activations, and drug delivery.

42.2.1 Host-Guest Recognition-Driven Protein Assemblies Proteins with ordered assembled architectures have played a vital role in many important life processes. The manipulation of proteins with the chemical tools,

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Fig. 1 (a) The heterodimerization of eCFP and eYFP induced by the host-guest interactions between β-CD and LA. (Reprinted with permission from Ref. [14]. Copyright 2007 John Wiley and Sons). (b) The heterodimerization of mCFP and mYFP induced by the host-guest interactions between CB[8] and FGG. (Reprinted with permission from Ref. [15]. Copyright 2010 John Wiley and Sons). (c) Multicomponent protein assembly directed synergistically by the CB[8] and 14-3-3 protein dimer. (d) The formation of cytochrome c tetramers mediated by sulfonato-calix[8]arene (sclx8) macrocycle in solution. (Adapted with permission from Ref. [18]. Copyright 2018 John Wiley and Sons)

particularly the specific host-guest chemistry, can provide unique supramolecular approach to create highly ordered protein assemblies and modify their interaction properties [13]. Among the synthetic macrocyclic hosts, the cone-shaped cyclodextrins (CDs) and pumpkin-shaped cucurbit[n]urils (CB[n]) are the most optimal platforms for protein assembly. Brunsveld and co-workers performed the pioneering proof-of-principle studies on host-guest induced protein dimerizations [14–16]. As illustrated in Fig. 1a, they selected the enhanced cyan fluorescent protein (eCFP) and enhanced yellow fluorescent protein (eYFP) as the model proteins, which were modified with lithocholic acid (LA) and β-CD, respectively. Then protein heterodimers capable of functioning intracellularly could be formed driven by the hydrophobic inclusion of the LA moiety into the cavity of β-CD. They also demonstrated another way to dictate protein self-assembly by using CB[8], who could selectively associate with two tripeptide phenyalanine-glycineglycine (FGG) motifs [15, 16]. It was found that both the homodimerization of two monomeric FGG-mYFP proteins or the heterodimerization of one FGG-mCFP and one FGG-mYFP could be induced by the addition of equimolar CB[8], which resulted in the occurrence of a strong homo/hetero-FRET (Fig. 1b). Furthermore, multicomponent supramolecular protein assembly system could also be obtained by taking advantage of the highly specific host-guest interaction of FGG/CB[8] pair. For example, Ottmann and co-workers

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have demonstrated that binary bivalent supramolecular assembly platform could be constructed based on the host-guest interactions between CB[8] and dimeric adapter protein 14-3-3 to form a CB[8]-induced ternary complex, whose crystal structure revealed multiple supramolecular interactions between the protein, peptide, and CB [8] (Fig. 1c) [17]. In spite of dimerization, supramolecular tetrameric protein assemblies could also be fabricated through the conjugation of protein-host pair [18, 19]. Recently, Crowley et al. have reported that novel auto-regulated protein assembly could be achieved mediated by a flexible macrocycle of sulfonato-calix[8]arene (sclx8), which could act as a scaffold for the formation of cytochrome c tetramers in solution (Fig. 1d) [18]. Tetramer was found to be disassembled spontaneously at high concentrations of sclx8, in this case the protein surface was masked which prevented the oligomerization of protein. Therefore, the assembly-disassembly behaviors of such host-mediated protein tetramer could be regulated by changing the concentration of host molecule, which provided a means to control assembly without the need for competitive inhibitors. CB[8] could also be applied in the construction of protein assemblies with more complicated ordered architectures from 1D to 3D [13, 20]. In this content, significant advances have been made by the Liu group; in 2013, they have designed and synthesized 1D supramolecular protein polymers by using the CB[8]-FGG pair as an external inducer (Fig. 2a) [21]. The N-termini at each side of the dimeric glutathione S-transferase (GST) was firstly fused with FGG peptides, then protein nanowires were formed driven by the highly specific host-guest interactions of the CB[8]-FGG pair. By using this strategy, 1D protein assemblies with fine control of the conformational changes responsive to external stimulus (Ca2+) could be further constructed [22]. Although the FGG tags can be selectively encapsulated by CB[8] with strong association constant (Kter = 1.5
1011 M2), they are typically fixed to the N-termini via genetic fusion before being utilized. In order to overcome such spatial limitation which greatly confined the availability of the CB[8]-FGG pair in the construction of more sophisticated protein nanostructures, Liu et al. have recently designed and synthesized a maleimide functionalized FGG tag as a versatile CB[8]-based site-specific protein modification tool to construct smart dynamic protein self-assembly system with distinctive morphological diversities ranging from nanorings, nanospirals, nanowires to superwires [23]. As good glue molecules, CB[n]s/CDs could be modified to construct well-defined arrays with potential application in the design of 2D/3D protein assemblies in solution or on the surface. For example, Brunsveld and co-workers have demonstrated that CB [7] could self-assembled on the Au surface to form 2D monolayer, which was able to bind the ferrocene-incorporated proteins (Fc-YFP) through the strong host-guest interaction of CB[7]/Fc pair (Fig. 2b) [24]. They also demonstrated that CB[8]induced 2D protein assembly onto lipid bilayers could be achieved, which can serve as a new supramolecular strategy for the immobilization of proteins [25]. In addition, uniform fluorescent protein patterns could also be generated by using patterned β-CD surfaces to specifically capture the adamantine (Ad) functionalized proteins through the strong β-CD/Ad host-guest interactions (Fig. 2c) [26].

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Fig. 2 (a) CB[8]-induced self-assembly of FGG-GST into protein nanowires. (Reprinted with permission from Ref. [20]. Copyright 2016 American Chemical Society). (b) The immobilization of protein Fc-YFP onto a CB[7] monolayer. (Reprinted with permission from Ref. [24]. Copyright 2010 John Wiley and Sons). (c) Bisadamantane functionalized fluorescent SNAP-tag fusion proteins (CFP and YFP) for immobilization on β-CD monolayer surfaces and β-CD vesicles. (Adapted with permission from Ref. [26]. Copyright 2012 John Wiley and Sons). (d) 3D protein assemblies of supramolecular amphiphile vesicle induced by CB[8]-based host-guest interactions. (Adapted with permission from Ref. [27]. Copyright 2012 John Wiley and Sons)

Well-defined 3D protein assemblies could also be constructed by using CB[8]based host-guest interactions. A representative contribution on this aspect comes from the Scherman group; they have exploited a CB[8]-based supramolecular approach to fabricate self-assembled amphiphilic peptide vesicles (Fig. 4d) [27]. Such noncovalent peptide amphiphiles were likely to undergo a self-assembly step and form vesicles in water, which could be taken up by the HeLa cells and serve as potential peptide delivery agents in the living cells. By controlling the dissociation of the CB[8]-based ternary host-guest complexes using external competitive guests as triggers, the peptide release process could be induced, which could switch on the fluorescence as well as the cytotoxicity in cells.

42.2.2 Host-Guest Mediated Protein Modifications and Purifications The development of new techniques for protein modification and immobilization is of great important in the field of proteomics, drug delivery, and environmental

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science. Ideal protein modification reactions are required to not only provide chemical orthogonality to other functional groups existing on the protein surfaces or in the biological mixtures, but also ensure that proteins only be modified at a single site of interest, so as to generate homogeneous product with nonuniform properties instead of heterogeneous mixtures. To achieve these goals, the hostguest based supramolecular strategies have been developed which can offer alternative and complementary controllable bioconjugation approaches for sitespecifically conjugating proteins with functions that would be difficult to replicate using traditional covalent methods. Generally, there have been two host-guest based approaches explored prevalently in this regard [9]: one is related to the modification of the protein and substrate as two guests that are capable of being encapsulated by a synthetic macrocyclic host simultaneously; and the other involved the formation of a binary host-guest complex with a respective partner bound to a synthetic substrate. Modification of proteins with poly(ethylene glycol) (PEG), also known as PEGylation, is one of the most common strategies for protein functionalization, which can bring distinct physicochemical properties such as temporarily reduced immunogenicity/toxicity and increased solubility of the protein. To overcome the problem of decreasing protein activity during the protein PEGylation, Scherman and co-workers have described a CB[8]-based host-guest approach for the reversible PEGylation of bovine serum albumin (BSA) in water (Fig. 3a) [28]. Both BSA and PEG were functionalized with either an electron-deficient viologen or electron-rich naphthalene, respectively. In this system, strong and specific binding interaction can only occur between the complementary labeled polymers and proteins in the presence of CB[8]. In 2016, Langer, Anderson and coworkers reported the supramolecular PEGylation of therapeutic proteins by using a CB[7]-PEG conjugation approach [29]. PEG was covalently attached to CB[7] whose cavity can bind the N-terminal aromatic residue leading to the PEGylation of protein with CB[7]-PEG. Remarkable enhancement in stability and therapeutic properties of the PEGylated proteins could be observed. Compared to the direct covalent PEGylation, this approach may have significant benefits. For instance, in the case of insulin, the higher-affinity of the formed CB[7] complex makes it possible to prolong the therapeutic effect in the body after injection. Specific biofunctions could be achieved benefiting from the combined advantageous properties of proteins and mechanical bonds [30]. Aiming at making protein-based biomaterials, the Francis group has developed a rotaxanes-based ä Fig. 3 (a) CB[8] mediated stable ternary complex both for small molecules and functionalized BSA proteins in aqueous solution with high binding specificity. (Reprinted with permission from Ref. [28]; Copyright 2011 The Royal Society of Chemistry). (b) Aqueous synthesis of rotaxanes via bioconjugation to oligopeptides and proteins. (Adapted with permission from Ref. [31]. Copyright 2016 American Chemical Society). (c) CB[6]-promoted click chemistry for protein modification. (Adapted with permission from Ref. [32]. Copyright 2017 American Chemical Society)

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strategy to make protein bioconjugates containing mechanical bonds for the first time [31]. As revealed in Fig. 3b, water-soluble rotaxanes containing CB[7] or CBPQT4+ macrocycles could be near-quantitatively and rapidly synthesized by employing an efficient stoppering protocol under mild conditions. In this new class of hybrid molecular system, it was possible to harness the controlled mechanical motion of the ring component to regulate the functions of a protein. Later, they reported another supramolecular approach based on CB[6]-promoted copper-free click reaction for the near-quantitative azide-modification of proteins (Fig. 3c) [32]. Featured with simple operation and sufficiently occurred under mild conditions, this CB[6]-promoted click reaction could be expended to construct more complex biological systems without interrupting the biomolecular structures. In chemical proteomics, labeled proteins are often enriched by the combination of click chemistry and the natural biotin-streptavidin (Bt-SA) binding pair which is the highest affinity complexes known in nature (Ka = 1013 M1). However, the incomplete conversion of the protein modification reactions often yields inseparable mixtures of labeled and unlabeled proteins, making it very difficult to separate the target proteins while maintaining their folded and native structures under mild enough conditions. To address these challenges, host-guest based supramolecular strategy was developed for the purification of fluorescently labeled proteins. For instance, the β-CD/Azo pair could be tagged to the proteins as a specific affinity handle, which was further used to isolate proteins via affinity chromatography resulting in a sample of protein with a well-defined number of modifications [33]. This CD-based method was particularly applicable to the systems such as protein homomultimers where chemically identical subunits are impossible to be discerned. Specially, the Kim group has developed a supramolecular latching system based on the CB[7]-mediated ultrastable artificial binding pair (Ka = 1012–1017 M1), which can replace the biotin-(strept)avidin system in diverse areas of research [7]. Initially, they demonstrated a novel plasma membrane protein isolation method by using the strong and specific host-guest interactions between a CB[7]-immobilized bead and “ferrocenylated” plasma membrane proteins (Fig. 4a) [34]. This CB[7]-Fc based plasma membrane isolation method may serve as novel “supramolecular fishing” system, which provide enhanced sensitivity and specificity than those analogous extractions performed using biotinylated proteins in plasma membrane protein analysis (Fig. 4b), for example, enriching the histone deacetylases (HDACs) from cell lysates [35] or increasing the signal abundance and sequence coverage of peptic peptides during the MS analysis of peptic digests [36]. With the ability of simultaneously accommodating two guests, CB[8] also showed great potential in recognition and enrichment of proteins. Recently, Scherman and co-workers presented the first example of conjugating small short amino acid motif expressed within a protein domain mediated by the CB[8] macrocycle, without the restriction and difficulty arising from chemical modifications or aromatic residue insertion at the N-terminus [37].

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Fig. 4 (a) Strategy for the isolation of plasma membrane proteins using an ultrastable synthetic host-guest binding pair system. (Reprinted with permission from Ref. [34]. Copyright 2010 Springer Nature). (b) Schematic illustration of spatiotemporal labeling of proteins using orthogonal binding pairs and isolation and analysis of the labeled proteins. (Adapted with permission from Ref. [7]. Copyright 2017 American Chemical Society)

42.2.3 Macrocycle-Modified Proteins for Biological Activation and Drug Delivery Although several chemical approaches have been developed to activate proteins and modify their functions, the modifications of proteins with synthetic macrocyclic molecules have also been proved to be powerful methods for the functional activation of proteins [8]. In 2003, Tsukube and co-workers reported a novel supramolecular method for the activation of cytochrome c proteins via crown ether complexation (Fig. 5a) [38]. It was found that the crown ether can serve as an artificial factor to activate the cytochrome c proteins as cold-active synzymes in promoted asymmetric oxidation of several organic sulfoxides, sulfides, and anthracene in methanol. Issacs et al. have demonstrated that the enzyme activity could be “switched on” by releasing an inhibitor from the active site through CB[7]-based competitive binding (Fig. 5b) [39]. In this system, a series of two-faced guests containing both enzyme inhibitor and CB[7] binding domains were prepared, which can inhibit enzymatic activity by binding to the enzyme active site (BCA)

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Fig. 5 (a) Chemical activation of cytochrome c proteins via crown ether complexation. (Adapted with permission from Ref. [38]. Copyright 2003 American Chemical Society). (b) Biological catalysis regulated by CB[7] molecular containers. (Reprinted with permission from Ref. [39]. Copyright 2010 American Chemical Society). (c) Schematic representation of N-terminal FGGbearing monomeric caspase-9 and its dimerization into an enzymatically active homodimer by supramolecular-induced host-guest complexation with CB[8]. (Adapted with permission from Ref. [40]. Copyright 2013 John Wiley and Sons)

or peripheral sites (AChE). After adding CB[7], activation of enzyme (with limited up to 45%) could be achieved. Furthermore, by the sequential addition of the competitive guest and CB[7], the on-off cycle can be performed repetitively. It should be pointed out, although limited activation was observed and some of the limitations of this approach were illustrated by attempted regulation of acetylcholine esterase (AChE), this work was successfully implemented and the results to a certain extent speculated on why nature has evolved allosteric systems to regulate enzyme catalysis. Since activating enzymes in nature often evolves the recruitment and subsequent dimerization of enzyme factors, the CB[8]-based supramolecular protein dimerization approach (as introduced in section “Host-Guest Recognition-Driven Protein Assemblies”) is expected to be used for the activation of enzyme activity. Brunsveld and co-workers have described a concept of CB[8]-based supramolecular protein dimerization to control enzyme activity (Fig. 5c) [40]. Two inactive FGG-incorporated caspase-9 monomers could be facilitated to form an enzymatically active homodimer induced by the CB[8]-mediated host-guest complexation. The resulting CB[8]-bridged caspase-9 dimers exhibited more than 50 times increase in activities over the caspase-9 monomers, and the full and reversible control over caspase activity could be achieved. What’s more, such supramolecular controlled protein

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Fig. 6 (a) Schematic of the gold nanoparticle and surface groups, and the use of intracellular hostguest complexation to trigger nanoparticle cytotoxicity. (Reprinted with permission from Ref. [42]. Copyright 2010 Springer Nature). (b) Structure of a mixed monolayer-protected AuNP featuring pentanethiol (C5) and diaminohexane (DAH) terminated thiol ligand, as well as the schematic of the protein-NP interactions in the absence and presence of the guest molecules CB[7]. (Reprinted with permission from Ref. [43]. Copyright 2014 The Royal Society of Chemistry). (c) Bioorthogonal nanozyme design and supramolecular regulation of intracellular catalysis. (Reprinted with permission from Ref. [44]. Copyright 2015 Springer Nature)

dimerization approach could be applied in where classical protein engineering techniques are not accessible such as the construction of activation controllable supramolecular split-luciferase complementation system [41]. The advantages of trigger-induced association and disassociation properties have made the host-guest chemistry a useful tool in drug activation and delivery applications [2]. Among the macrocyclic host molecules, CB[7] and CB[8] have received numerous attentions in the application of drug activation and delivery, because of the good water solubility of CB[7] and the unique ternary binding properties of CB[8], as well as their low cytotoxicity toward animal cells and bacterials. In particular, the excellent biocompatibility of CB[7] even makes it an ideal excipient to improve the stability and efficiency of drugs, meanwhile minimize the adverse effect. The Rotello group has made significant progress in this aspect; in 2010, they have initially reported a novel CB[7]-mediated switchable drug delivery system through the complementary host-guest interaction between the diaminohexane-terminated gold nanoparticles (AuNP-NH2) and CB[7] (Fig. 6a) [42]. Such surface-CB[7]-modified gold nanoparticles could be readily taken up by cells, and therapeutic effect was then achieved by intracellularly release of cytotoxic AuNP-NH2 upon the administration of 1-adamantylamine (ADA) as a trigger. This CB[7]-based supramolecular strategy for intracellular activation could also be associated with protein-sized gold nanoparticles, the aim of which was to induce protein assembly to tune the enzyme

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activities (Fig. 6b) [43]. Remarkably, they have designed a protein-sized bioorthogonal catalytic system in cells by using nanoparticle-embedded transition metal catalysts (Fig. 6c) [44]. In this nanozyme system, the hydrophobic transition metal (Ru) catalysts were able to be encapsulated by water-soluble AuNPs, and the activity of the resulting NP-Ru catalysts could be controlled reversibly through the regulation of CB[7]-based binding behaviors on the monolayer surface of Ru-loaded AuNPs. More importantly, this CB[7]-gated nanoenzymatic platform has showed potential in vivo applications of bioimaging and therapeutics, as well as pharmacological treatments [45].

42.2.4 Proteins/Peptides Recognition via Water-Soluble Cavitands and Applications Although the above mentioned synthetic cavity-containing macrocyclic molecules such as calixarenes, cyclodextrins, as well as cucurbiturils could serve as promising hosts for the recognition proteins under aqueous conditions, it is still highly desirable to develop novel macrocyclic molecules, particularly those with small spaces revealing molecular behavior that is inaccessible in bulk solution. As a unique class of synthetic macrocyclic host molecules which have one open end that allowing small molecules to go in and out, cavitands have recently been emerged as ideal hosts for exploring the weak intermolecular forces of molecular recognition in water [46]. In 2014, Rebek and co-workers have found that this ionic cavitand showed good affinity for normal octanoyl groups, specifically the gastric peptide ghrelin could be bound through its O-octanoyl group on the third serine residue (Fig. 7a) [47]. Recently, Hooley, Zhong, and co-workers have showed that water-soluble deep cavitands (such as 1 in Fig. 7b) can act as fluorescent indicator displacement assay systems for the detection of posttranslationally modified (PTM) peptides, for example, the detection of peptide trimethylations and the determination of histone demethylase activity (Fig. 7b) [48], the discrimination of different lysine methylation states [49], as well as the phosphorylated peptides and monitoring kinase and phosphatase activity [50]. Notwithstanding that most relevant protein involved biological recognition processes are happened in membrane environments, it is found far less common and far more difficult to study protein recognition at biomimetic membrane bilayers with synthetic receptors compared to that in the free solution. The major challenge is that ä Fig. 7 (a) The structure and modeled complex of a water-soluble cavitand with the gastric peptide ghrelin through the O-octanoyl group. (Adapted with permission from Ref. [46]. Copyright 2018 American Chemical Society). (b) Structures of cavitand hosts, fluorophore guest, and their minimized model of host-guest complex; and the supramolecular tandem assay for the site-selective sensing of a lysine demethylase enzyme. (Reprinted with permission from Ref. [48]. Copyright 2017 American Chemical Society). (c) Labeled protein recognition at a membrane bilayer interface by embedded synthetic receptors

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the common water-soluble small molecule hosts are incompatible with membrane based recognition, since they are often unable to be successfully incorporated into the membranes, which makes the hydrophobic effect cannot be exploited to induce effective binding. Hooley et al. have found that this problem could be solved through the combination of deep, self-folded cavitands and the supported lipid bilayers (SLBs) [51–53]. They found that the tetracarboxylated water-soluble deep cavitand could be incorporated into a membrane bilayer to fabricate a cavitand-incorporated SLB membrane-mimicking system, which was then successfully used for a widely applications including the real-time analysis of proteins [51], monitoring protein recognition from aqueous solution (Fig. 7c) [52], as well as the immobilization of unmodified proteins and enzymes at a supported lipid bilayer interface [53].

42.3

Carbohydrates Recognition and Modification by Synthetic Macrocycles

As important biomacromolecules for fuel and building materials in nature word, carbohydrates are often found in the plasma membranes of eukaryotic cells in the form of glycolipids or glycoproteins embedded in cell membranes. The recognition of carbohydrates plays a prominent role in a wide range of biological processes. In nature, most carbohydrate recognition involves oligosaccharides which could bind to many proteins, notably the group called lectins, which are ubiquitous in nature and are found in many foods (Fig. 8a). As carbohydrate binding proteins, although lectins are highly specific for sugar moieties of other molecules, they often show nonideal selectivity and notoriously weak affinities for carbohydrates on the general scale of biomolecular interactions (lectins often bind monosaccharides with Ka < 103 M1) [54]. On the other hand, the structural complexity and stereochemical diversity make carbohydrates exceptionally challenging guest targets for the synthetic lectins, especially in the natural medium of water. Therefore, it is of great importance to develop synthetic biomimetic systems (“synthetic lectins”) that are capable of binding carbohydrates with competitive binding strength and lectin selectivity [55], since the synthetic carbohydrate receptors can provide valuable model systems to study the underlying principles of carbohydrate-based molecular recognition processes by using noncovalent interactions for sugar binding (Fig. 8b).

42.3.1 Mono- and Disaccharide Recognition by Synthetic Macrocycle in Water Compared to the well-studied synthetic carbohydrate receptors with acyclic scaffolds [56], the development of macrocyclic receptors is expected to be a more powerful strategy for the effective and selective recognition of carbohydrates by employing a combination of multiple hydrogen bonds and C. . .H-π interactions [57], which are the main involved noncovalent interactions during the recognition of carbohydrates. A general strategy is to use multiple hydrogen bonding interactions

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Fig. 8 (a) The structure of leucoagglutinin, a toxic phytohemagglutinin found in raw fava bean. Picture reprinted from Wikipedia. (b) Representation of the interactions of D-glucose with functional groups inside the active center of the D-galactose binding protein. (Reprinted with permission from Ref. [55]. Copyright 2009 John Wiley and Sons)

in apolar organic media. Since the initial studies on carbohydrates recognition were achieved by Aoyama and co-workers [58], a research was booming in this topic and many macrocycles have been designed for carbohydrate binding in organic media [59]. Although synthetic macrocyclic receptors have been reported to operate well in organic solvents for effective carbohydrates binding, recognizing carbohydrates in water still remains a notoriously challenge since the macrocyclic hosts are forced to selectively discriminate the target carbohydrates from the competitive water molecules. So far, there are still few reports on macrocycles binding carbohydrates in water through noncovalent interactions [60–62]. In the 1990s, cyclodextrins were firstly employed by several groups for the selective binding of sugar and glucose in water [60], but they exhibited relatively low affinity toward the carbohydrate targets. Early in this century, Schmidtchen and coworkers have prepared macrocyclic porphyrin sandwich systems, which were examined as saccharide receptors to selective binding of saccharides in highly competitive media, revealing a trend increasing from mono- to trisaccharide [61]. Recently, Kim and co-workers demonstrated that the uncharged and water soluble macrocyclic host CB[7] was able to bind protonated amino saccharides with excellent affinity (Ka = 103–104 M1) (Fig. 9) [62]. The affinity of CB[7] for amino saccharides is expected to offer new opportunities in glycan analysis, as well as the delivery and sensing of aminoglucoside antibiotic drugs. Among the effective “synthetic lectins” over the past few decades, the most spectacular advances come from the Davis’ group. Noticed that the glucose with the β-anomer is an “all-equatorial” carbohydrate whose polar groups directed away from the center and the axial C-H groups acted as two small patches of hydrophobic, they assumed that a “temple-like” receptor with two apolar surfaces set parallel to

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Fig. 9 CB[7] as a high-affinity host for encapsulation of amino saccharides in water and the proposed model for the CB[7] and saccharide inclusion complex. (Adapted with permission from Ref. [62]. Copyright 2013 John Wiley and Sons)

Fig. 10 (a) The design and cartoon showing interactions in “temple-like” synthetic lectins for allequatorial carbohydrates. (Reprinted with permission from Ref. [63]. Copyright 2009 John Wiley and Sons). (b) A biomimetic receptor for glucose. (Adapted with permission from Ref. [64]. Copyright 2018 Springer Nature). (c) A synthetic lectin for O-linked β-N-acetylglucosamine. (Reprinted with permission from Ref. [63]. Copyright 2009 John Wiley and Sons). (d) High-affinity disaccharide binding by tricyclic synthetic lectins. (Reprinted with permission from Ref. [66]. Copyright 2012 John Wiley and Sons)

each other separated by rigid polar spacers, and these apolar surfaces should be aromatic so as to facilitate the C. . .H-π interaction (Fig. 10a) [63]. Based on this complementarity recognition principle, the Davis’ group has designed a series of caged receptors that are likely to create cavities which might bind the β-glucose derivatives well in aqueous solution. For example, they recently reported a synthetic

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receptor with simple and symmetrical core structure for glucose recognition (Fig. 10b) [64]. Such novel receptor was biomimetic in both design and capabilities, which could provide a cavity almost perfectly complemented the all-equatorial β-pyranoside substrate (with affinity for glucose at Ka ~ 18,000 M1) comparing well with natural receptor systems. Specially, they found that the biphenyl-based water soluble cage could serve as a strong and selective receptor for β-GlcNAc (Fig. 10c) [63], suggesting that biomimetic carbohydrate receptors can and may point to a general strategy for discovering tools for studying O-GlcNAc and other forms of glycosylation. Compared to monosaccharide, disaccharide substrates were representative of major biopolymers. Aiming at binding all-equatorial disaccharides such as cellobiose, a tetracyclic receptor has been designed and synthesized [65]. This macrocyclic host revealed a dramatic leap in performance, showing both good affinities and outstanding selectivities for the chosen substrate, which is remarkably close to true biomimicry and provides a realistic synthetic model for protein/carbohydrate recognition. In addition, by employing a less preorganized but more accessible tetracyclic synthetic cage-like receptor (Fig. 10d), increased Ka values up to 4500 M1 and extreme selectivity for disaccharides versus monosaccharides could be achieved [66]. The authors pointed out that such “conformational selection” approach based on the less-connected receptor structures was superior to rigid preorganization in carbohydrate recognition, which may bring about novel simpler systems with potential applications.

42.3.2 Polysaccharide Recognition and Modification with Synthetic Macrocycle A long term objective for work on synthetic lectins is the recognizing of cellulose, chitin, and related polysaccharides, which are the key renewable resources and the dominant organic molecules in the biosphere. The major obstacle comes from the extreme insolubility of these biomicromolecules in water; this makes it of great challenging to mobilize these materials in water under mild conditions. The breakthrough comes from the Davis’ group, who have adumbrated a strategy for the dissolution of cellulose and the related polysaccharides (Fig. 11b) through the application of synthetic cage-like receptor (Fig. 11a) that could thread onto the polysaccharides to form polypseudorotaxanes [67]. By taking advantage of the threaded topology, the receptor molecules could bind to one polysaccharide chain and surround the polymer with hydrophilic groups (Fig. 11c). In this way, the hostguest binding strength was strong enough (Ka value above 104 M1) to counteract the crystal-packing forces of polysaccharide molecules, resulting in the dissolution of the target polysaccharides. Evidence implied that the polycationic analogue of chitosan could also be recognized by this receptor through the formation of polypseudorotaxanes (Fig. 11d). The formation of such polypseudorotaxane was expected to provide a novel way to moderate the properties of the important

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Fig. 11 The chemical structures of (a) polysaccharide receptor and (b) all-equatorial polysaccharide guests; (c) the schematic design strategy with cellulose depicted as the substrate; and (d) the AFM image of chitosan (n = 375–750) (1 nM glucosaminyl) with receptor (0.01 nM) deposited from aqueous. (Adapted with permission from Ref. [67]. Copyright 2015 Springer Nature)

biomicromolecules of cellulose and chitin. For example, threading onto nascent chitin chains could provide a promising approach to antifungal agents. Despite the role of fuel and building materials in biology, the natural existing polysaccharides are ideal candidates in the fabrication of biocompatible materials such as supramolecular hydrogels. In 2012, Kim and coworkers have developed a facile modular modification of biocompatible hydrogels by using CB[6]-conjugated hyaluronic acid (CB[6]-HA), diaminohexaneconjugated HA (DAH-HA), and tagsCB[6] for cellular engineering applications [68]. In this system, the strong and selective host-guest interaction between CB[6] and DAH was responsible for the formation of the CB[6]/DAH-HA hydrogels in the presence of cells and even under the skin of nude mice (Fig. 12a). Moreover, the 3D environments of such resulting in situ formed cell-entrapped hydrogels could be further modularly modified by the simple treatment with various multifunctional tags-CB[6]. Such CB[6]/DAH-HA hydrogels might be feasibly exploited as a 3D artificial extracellular matrix for various biomedical applications from in vitro studies on cellular behaviors and cell therapy to the tissue engineering. Alternatively, the Scherman group has found that after modifying the cellulosic derivatives and commercial poly(vinyl alcohol) polymers with electron-rich naphthalene (Np) and electron-deficient methyl viologen (MV) as strongly binding guests, respectively, hydrogels with extremely high water content (up to 99.7%

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Fig. 12 (a) The chemical structures of CB[6] derivative and polyamines, the schematic representation for the host-guest interaction of DAH-HA with CB[6], and the chematic representations for in situ formation of supramolecular biocompatible hydrogel and its modular modification using highly selective and strong host-guest interactions. (Adapted with permission from Ref. [68]. Copyright (2012) American Chemical Society). (b) The synthesis of the peptide-polysaccharide conjugation and schematic representation of supramolecular hydrogels formation by physically cross-linking phenylalanine functionalized polysaccharides with CB[8] in water. (Adapted with permission from Ref. [70]. Copyright 2015 American Chemical Society)

water by weight) could be fabricated when these polymers were mixed in the presence of CB[8] [69]. Other polysaccharides such as hyaluronic acid (HA), carboxymethyl cellulose (CMC), and hydroxyethyl cellulose (HEC) could be easily modified with the dipeptide Phe-Cys by employing a two-step method (Fig. 12b)

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[70]. After adding the CB[8] macrocycles to these functional polysaccharides, the physical cross-linking took place by the strong 2:1 “homoternary” host-guest complexations between two pendant Phe residues and CB[8]s, leading to the formation of CB[8]-mediated polysaccharide hydrogels. Such dynamical CB[8]-mediated host-guest conjugation could be further used in the fabrication of cellulosecontaining hybrid supramolecular hydrogels [71].

42.4

DNA Modifications with Macrocyclic Hosts

Benefiting from the ease of synthesis and base-pairing loyalty with sequence programmability, DNA has also been selected as a distinctive biomacromolecular tool for the rational construction of artificial functional molecular architectures in the fields of supramolecular chemistry and chemical biology. In this area, the host-guest chemistry provides attractive supramolecular approaches to set up functionalized DNA by conjugating natural DNA scaffolds with macrocyclic host molecules [11]. The introduction of specific host-guest interaction will enhance the stability of the DNA supramolecular structures, enabling the resulting DNA-host systems to be applicable in a wide range of research fields such as sensors, delivery vehicles, supramolecular catalysts, as well as synthetic transducers, which will be briefly discussed in this section. So far, the majority of DNA-host assembly systems have focused on using β-CDs as the host molecule. For instance, Inouye and co-workers have demonstrated that the CD host incorporated DNA duplex assembly could serve as versatile fluorescent sensor [72]. They also illustrated that the CD hosts could be clicked to the 50 or 30 ends of the pyrene-modified short complementary oligodeoxynucleotides (ODNs) to generate CD-ODNs (Fig. 13a) [73], which could form linear end-to-end type supramolecular assemblies of short DNA duplexes, showing increased melting temperature (Tm) values compared to the corresponding natural hybrids. Recently, Varghese and co-workers demonstrated that size controllable DNA nanogels could be fabricated from the self-assembly of DNA nanostructures driven by multivalent host-guest interactions [74]. As shown in Fig. 13b, the obtained DNA-nanogels exhibited excellent biocompatibility, good cell permeability, and high drug encapsulation ability, which are promising features for their application as a drug carrier. In addition, they also showed a special β-CD/Ad host-guest interaction based noncovalent approach for the synthesis of DNA amphiphiles, which could spontaneously undergo the amphiphilicity-driven self-assembly to form DNA decorated and thermally stable nano-to-micro-sized vesicles (Fig. 13c) [75]. Through the sequence specific DNA hybridization of such novel vesicles with Au-NPs, functional gold nanoparticles (Au-NPs) with DNA-based surface addressability could be obtained. Recently, Zhou and co-workers have developed another CB[7]-based supramolecular approach for the reversible conformation change of the DNA helical structures [76]. In their systems, the CB[7] was found to encapsulate the central butanediamine moiety of spermine to form an inclusion complex of CB[7]-spm, which could reverse the Z-DNA back to B-DNA caused by spm (right-to-left in Fig. 13d). Although it is

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Fig. 13 The self-assembly of DNA-host conjugates: (a) schematic illustration of an end-to-end self-association of DNA hybrids based on β-CD/Ad complexation. (Reprinted with permission from Ref. [73]. Copyright 2013 The Royal Society of Chemistry). (b) Self-assembled nanogel based on β-CD tethered four-way DNA junction and an adamantane projecting PEG polymer. (Adapted with permission from Ref. [74]. Copyright 2018 The Royal Society of Chemistry). (c) Schematic representation of DNA-decorated vesicle that is self-assembled from the β-CD modified supramolecular DNA amphiphile. (Reprinted with permission from Ref. [75]. Copyright 2018 The Royal Society of Chemistry). (d) The CB7-based supramolecular approach designed for reversible B/ZDNA transition

yet to understand whether such a strategy is operative in vivo, the findings in this work can offer a general and facile way toward reversible and accurate control of DNA helical structure. As a rapidly growing research area, such DNA-host conjugates have also been demonstrated to be used for the construction of advanced self-assemblies and nanostructures with exciting functions. For example, Ihara and co-workers have developed an elegant design of cooperative DNA probe to discriminate single nucleotide polymorphisms (SNPs) by using β-CD-DNA conjugate and a nucleobase-specific fluorescent ligand (Fig. 14a) [77]. In this system, the hybridization of a short β-CD-DNA (CyD-CD) conjugate strand and another short “mask”

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Fig. 14 (a) A mechanical DNA “arm” based on b-CD/ferrocene tethered DNA scaffolds. (Adapted with permission from Ref. [77]. Copyright 2009 American Chemical Society). (b) Switchable supramolecular catalysis using DNA-templated scaffolds. (Reprinted with permission from Ref. [78]. Copyright 2015 The Royal Society of Chemistry). (c) A β-CD conjugated circular bivalent DNA aptamer used for enhanced therapeutics delivery. (Adapted with permission from Ref. [80]. Copyright 2018 American Chemical Society). (d) A DNA-small molecule chimera (DC) transducer based on a split DNA aptamer that converts an ATP input into functional release of a CAII inhibitor from the CB[7] host. (Reprinted with permission from Ref. [81]. Copyright 2017 American Chemical Society)

strand could form a ternary DNA scaffold, in which the two shorter strands were apart from each other in one nucleobase distance with the β-CD oriented adjacent to the gap nucleobase (C-gap duplex showed in left Fig. 14a). When the nucleobasespecific fluorescent ligand (MNDS) was introduced, its AcMND moiety can bind to the gap nucleobase (guanine), with the formation of a luminous inclusion complex between the dansyl group and nearby β-CD host (G-gap duplex right in Fig. 14a). Through the integration of DNA-templated scaffolds with β-CD/Ad host-guest binding, Willner and co-workers have demonstrated the construction of novel switchable supramolecular catalytic systems [78], by which the hydrolysis of m-tert-butylphenyl acetate could be catalyzed. They also demonstrated that the incorporation of hemin into the G-quadruplex unit could generate a more complexed supramolecular β-CD/DNAzyme catalytic system, which exhibited dual switchable catalytic functions in the presence of K+ ion/18-crown-6 ether as stimuli (Fig. 14b). The β-CD/Ad host-guest recognition motif could be further harnessed to combine with DNA to achieve more complicated biofunctions. For instance, Jayawickramarajah and co-workers have demonstrated that the modification of DNA with

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β-CD/Ad host-guest interactions could provide a proof-of-concept strategy to develop DNA-chimera (DC) with protein-binding ability inducible by selected nucleic acid inputs [79]. Very recently, a novel β-CD modified circular bivalent aptamer (cb-apt-CD) was reported by the Tan group (Fig. 14c) [80]. In their design, the β-CD host was first conjugated to a single-stranded aptamer, which was then cyclized with a complementary sequence to form cb-apt-βCD. It was found that the incorporation of β-CD with cb-apt could not only retain the high serum stability of the circular bivalent aptamer, but also enable the encapsulation of a hydrophobic small-molecule or Ad-modified protein to form a supramolecular ensemble. In this way, small molecules or cytotoxic proteins could be efficiently delivered for targeted cancer therapy. The authors expected that the development of such supramolecularly engineered circular bivalent aptamer ensemble can provide a general platform for the creation of functional and stable synthetic aptamer, which is capable to address the biological and physiological challenges in the clinical translation of aptamer-based molecular medicine. Aiming to expand the scope of DNA-host systems, Jayawickramarajah and coworkers have designed a novel CB[7]-modified DC transducer which featured as the first example of a covalent CB-DNA conjugate that was capable of converting a chosen biological input (ATP) into functional release of a CA-II inhibitor [81]. As displayed in Fig. 14d, a pair of single strand DNA chimeras could be prepared from the modification of a split ATP binding DNA aptamer with CB[7] (DC2) and Ad (DC3), respectively. The activity of the protein (carbonic anhydrase II, CA-II) inhibitor (1 in Fig. 14d) could be turned off when encapsulated by CB[7] of DC2 to form a binary complex (DC21). However, the addition of ATP (cannot bind to CB [8]) as a chosen biological input could induce the duplex formation where the intramolecular CB[7]/Ad interactions occurred simultaneously. This may result in the turn-on of the inhibitor by releasing it from the cavity of CB[7]. The ATP selective aptamer domain has played a key in this system, and new host-guest derived DC transducers could be developed by exploring alternative aptamers against other biomolecular targets as biologically/clinically relevant stimuli.

42.5

Conclusion

The past two decades have witnessed the rapid development of a particularly interested and underexplored aspect of supramolecular chemistry and biochemistry, that is, the modification and functional regulation of biomolecules with artificial synthetic host molecules. In this chapter, we provide an overview on the current research progresses in this exciting research field mainly including synthetic host molecules modifying important biomacromolecules of proteins/peptides, carbohydrates, and DNA. The modification of these biomacromolecules with macrocyclic host molecules can introduce specific host-guest interactions, which allow for greater control over their bio functions. Although the present extensively published scientific studies have showed widespread applications ranging from specific biomolecular recognition, well-defined nanostructure assemblies, small bioactive molecule

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and drug delivery, as well as supramolecular bioactivation or catalysis, the exploration of novel macrocycle-modified biomacromolecular systems are highly demanded and still facing many practical challenges. From the protein perspective, despite impressive progresses have been made on using host-guest chemistry strategies for protein modification and immobilization in recent years, further substantial efforts are still required to explore details about the cooperative and synergistic activities of the host-modified proteins, which is particularly needed in understanding the multiple noncovalent dominated interactions between heterogeneous protein-protein interfaces. On the other hand, the pharmaceutical/biomedical studies employed in vivo models are limited. In the case of carbohydrate recognition, available synthetic macrocyclic receptors with high selectivity and affinity in aqueous conditions are extremely limited. Besides, there is a huge gap in the field of functional regulation of carbohydrates with synthetic macrocyclic receptors in comparison with the situation of proteins. For the conjugation of hosts with oligonucleotides, DNA-host conjugates are most concerned cases which still in its infancy, and the development of functional RNAhost conjugates is another open challenge. Finally, although these host-modified biomolecular systems have been successfully applied for drug delivery or bioactivation intracellularly, there is still a long way to go to realize practical clinical usage of such supramolecular systems in vivo. Many key issues such as long-term toxicity effect, immunological reaction, biodegradation, and so forth still need to be resolved. The development of biocompatible and biodegradable host-modified biomolecular systems will be a major focus in future research. Throughout the full text of this chapter, another more intuitive problem is that only a limited number of synthetic macrocyclic molecules (in most cases, CDs and CBs) can be used for the modification of boimacromolecules. From a chemical point of view, more versatile synthetic macrocyclic molecules with improved water solubility, biocompatibility, targeting properties, as well as stimuli-responsiveness and even potentially additional bioactivity are highly desired.

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52. Ghang Y-J, Lloyd JJ, Moehlig MP, Arguelles JK, Mettry M, Zhang X, Julian RR, Cheng Q, Hooley RJ (2014) Labeled protein recognition at a membrane bilayer interface by embedded synthetic receptors. Langmuir 30:10161 53. Ghang Y-J, Perez L, Morgan MA, Si F, Hamdy OM, Beecher CN, Larive CK, Julian RR, Zhong W, Cheng Q, Hooley RJ (2014) Anionic deep cavitands enable the adhesion of unmodified proteins at a membrane bilayer. Soft Matter 10:9651 54. Lis H, Sharon N (1998) Lectins:carbohydrate-specific proteins that mediate cellular recognition. Chem Rev 98:637 55. Kubik S (2009) Synthetic lectins. Angew Chem Int Ed 48:1722 56. Mazik M (2009) Molecular recognition of carbohydrates by acyclic receptors employing noncovalent interactions. Chem Soc Rev 38:935 57. Laughrey ZR, Kiehna SE, Riemen AJ, Waters ML (2008) Carbohydrate-π interactions: what are they worth?. J Am Chem Soc 130:14625 58. Aoyama Y, Tanaka Y, Toi H, Ogoshi H (1988) Polar host-guest interaction. Binding of nonionic polar compounds with a resorcinol-aldehyde cyclooligomer as a lipophilic polar host. J Am Chem Soc 110:634 59. Davis AP, Wareham RS (1999) Carbohydrate recognition through noncovalent interactions: a challenge for biomimetic and supramolecular chemistry. Angew Chem Int Ed 38:2978 60. Aoyama Y, Nagai Y, Otsuki J-i, Kobayashi K, Toi H (1992) Selective binding of sugar to β-cyclodextrin: a prototype for sugar-sugar interactions in water. Angew Chem Int Ed 31:745 61. Král V, Rusin O, Schmidtchen FP (2001) Novel porphyrin-cryptand cyclic systems: receptors for saccharide recognition in water. Org Lett 3:873 62. Jang Y, Natarajan R, Ko YH, Kim K (2014) Cucurbit[7]uril: a high-affinity host for encapsulation of amino saccharides and supramolecular stabilization of their α-anomers in water. Angew Chem Int Ed 53:1003 63. Ferrand Y, Klein E, Barwell NP, Crump MP, Jiménez-Barbero J, Vicent C, Boons G-J, Ingale S, Davis AP (2009) A synthetic lectin for O-linked β-N-acetylglucosamine. Angew Chem Int Ed 48:1775 64. Tromans RA, Carter TS, Chabanne L, Crump MP, Li H, Matlock JV, Orchard MG, Davis AP (2019) A biomimetic receptor for glucose. Nat Chem 11:52 65. Ferrand Y, Crump MP, Davis AP (2007) A synthetic lectin analog for biomimetic disaccharide recognition. Science 318:619 66. Sookcharoenpinyo B, Klein E, Ferrand Y, Walker DB, Brotherhood PR, Ke C, Crump MP, Davis AP (2012) High-affinity disaccharide binding by tricyclic synthetic lectins. Angew Chem Int Ed 51:4586 67. Mooibroek TJ, Casas-Solvas JM, Harniman RL, Renney CM, Carter TS, Crump MP, Davis AP (2016) A threading receptor for polysaccharides. Nat Chem 8:69 68. Park KM, Yang J-A, Jung H, Yeom J, Park JS, Park K-H, Hoffman AS, Hahn SK, Kim K (2012) In situ supramolecular assembly and modular modification of hyaluronic acid hydrogels for 3D cellular engineering. ACS Nano 6:2960 69. Appel EA, Loh XJ, Jones ST, Biedermann F, Dreiss CA, Scherman OA (2012) Ultrahigh-watercontent supramolecular hydrogels exhibiting multistimuli responsiveness. J Am Chem Soc 134:11767 70. Rowland MJ, Atgie M, Hoogland D, Scherman OA (2015) Preparation and supramolecular recognition of multivalent peptide-polysaccharide conjugates by cucurbit[8]uril in hydrogel formation. Biomacromolecules 16:2436 71. Janeček E-R, McKee JR, Tan CSY, Nykänen A, Kettunen M, Laine J, Ikkala O, Scherman OA (2015) Hybrid supramolecular and colloidal hydrogels that bridge multiple length scales. Angew Chem Int Ed 54:5383 72. Fujimoto K, Yamada S, Inouye M (2009) Synthesis of versatile fluorescent sensors based on Click chemistry: detection of unsaturated fatty acids by their pyrene-emission switching. Chem Commun 45:7164

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Controllable Synthesis of Polynuclear Metal Clusters Within Macrocycles

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Siqi Zhang and Liang Zhao

Contents 43.1 43.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Macrocyclic Ligands in Metal Cluster Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.2.1 Sulfur-Containing Macrocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.2.2 Oxygen Donor Macrocycle Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.2.3 Neutral N-Containing Macrocycle Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.3 Applications of Metal Cluster-Macrocycle Adducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.3.1 Platform for Organometallic Transformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.3.2 Stabilization of Intermediate Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.3.3 Macrocycle-Assisted Bulk-to-Cluster-to-Nanoparticle Transformations . . . . . 43.4 Conclusions and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.5 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43.1

1223 1224 1225 1230 1231 1242 1242 1242 1245 1248 1248 1248

Introduction

The history of macrocyclic complexes dates back a long time to the biologically occurring macrocycles such as porphyrins and corrins, which function to bind metal ions at the active sites in a variety of nature systems (e.g., hemoglobin, cytochrome C, and vitamin B12) [1, 2]. These natural macrocycles are taken as models in the early synthetic macrocyclic chemistry and give rise to an evolution of mimicking the metal-macrocycle active centers in biological systems. During the last few decades, significant progresses have been made in organic synthetic chemistry; thus a variety of macrocycles with internal anionic moieties such as -OH groups or neutral ones have been successfully fabricated [3–5] and applied in recognizing metal ions as S. Zhang · L. Zhao (*) Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, China e-mail: [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_49

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well as stabilizing short-lived reactive species [6–8]. Such remarkable stability of these metal-macrocycle complexes comes from the known macrocyclic effect [9], which often brings about an enhanced kinetic and thermodynamic stability for the macrocycle systems compared with their open-chain analogues, thus making them ideal for mimicking the active sites of metalloenzymes in nature. By virtue of these outstanding properties of macrocyclic ligands, it is envisioned that the employment of macrocycles may provide a feasible method to achieve highly active models for metallobiosites in a convenient way. Recent studies in the field of metal-macrocycle complexes synthesis have illustrated that the size-tunable macrocyclic ligands possess a good prospect in adjusting the nuclearity number of the resulting metal ion species based on size-match principle [10]. Therefore, we anticipate that the characteristic flexible conformations of large macrocyclic ligands would make them easily adapt to diversiform metal cluster aggregates, which play a significant role in mimicking the active sites of metalloenzymes on account of their fantastic properties. Since the structure diversities in nuclearity number and geometry largely affect the properties of metal cluster aggregates, it is essential to develop an efficient synthetic approach toward the controllable synthesis of metal clusters for further studies of their properties and applications. In this chapter, special attention is paid to the controllable synthesis of metal clusters based on macrocyclic template. Accordingly, reactivity studies and applications of the metal-macrocycle species are also exemplified.

43.2

Macrocyclic Ligands in Metal Cluster Synthesis

Polynuclear metal clusters have attracted intense interests of chemists in many interdisciplinary areas of chemistry owing to their fantastic catalytic properties, especially for mimicking the active sites of metalloenzymes which are ubiquitous in nature [11–14]. For instance, the widely studied copper-containing enzymes such as multicopper oxidases (MCOs) [15] and particulate methane monooxygenase (pMMO) [16] have exhibited efficient catalytic reactivities in the oxidation of phenol or methane. The active sites in these species are proposed to be polynuclear copper clusters. Thus, the designed synthesis of metal clusters with structural diversity plays an important role in studying the fundamental chemistry of enzyme-catalyzed reactions and developing new catalysts. Apart from the high reactivity empowered by their unique structures, however, the formidable structural complexity makes the rational design and controllable synthesis of polynuclear metal clusters very challenging. In this regard, the employment of structurally well-defined macrocyclic ligands has many advantages. Macrocyclic ligands could not only facilitate the formation of unique architectures based on their multiple coordination sites but also largely enhance their affinity for metal ions and form metal clusters with high kinetic inertness and thermodynamic stability due to the macrocyclic effect. Aside from this, the great advances in organic synthetic chemistry make it feasible to design and synthesize various desired macrocyclic compounds [17–19]. Recent studies in the field of metal-macrocycle complexes synthesis have illustrated that

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the restricted conformational flexibility associated with the size-tunable macrocyclic ligands possess a good perspective in matching the cavity size of the macrocycle to the steric and electronic requirements of the resulting metal cluster species based on the size-match principle. Several metal cluster-macrocycle systems and single metal coordination complexes of oversized macrocycles are summarized below based on the classifications of coordination donor atoms within macrocycles.

43.2.1 Sulfur-Containing Macrocycles Sulfur-containing macrocycles (thiamacrocycles) have been widely studied and often shown unusual coordination behavior toward soft metal ions such as Ag(I) and Cu(I) due to their well-documented affinity for soft sulfur donors, giving rise to a variety of supramolecular complexes with structural diversity. Besides, the latter dblock elements that are free of crystal field influences could readily adopt variable coordination numbers or geometries, which is conducive to the construction of uncommon structures. Molecular structures of several characteristic sulfurcontaining macrocycles related to the synthesis of polymetallic species are presented here (Fig. 1). Structure identification of blue copper proteins such as plastocyanin, azurin, and rusticyanin has illustrated that thiaether moieties play an important role as the coordination ligands to the copper centers. The construction of S-coordinated copper species as models of the active sites in “blue” copper proteins offers an efficient way to study the relationship between the coordination geometry and the redox behavior of the copper ions. To date, a number of sulfur-containing macrocycles have been applied to the study of copper species. For example, the S6-donor ligand [21]aneS6 has been successfully employed to investigate the active sites of the “blue” copper proteins [20]. It is intriguing that the Cu(I) complex is found to be more stable than the Cu(II) complex by 12 orders of magnitude in the stability constant, which is probably attributed to the favor of tetrahedral geometry for copper(I) ions within this large flexible macrocycle. The structure of Cu(I) complex 1 (Fig. 2) shows that four adjacent sulfur donor atoms of [21]aneS6 participate in the coordination to the Cu(I) ion, giving a common distorted tetrahedral coordination geometry. The remaining two sulfur atoms in the ligand are free of coordination. Cyclic voltammetry measurement has revealed that the redox potential of the Cu(I)/Cu(II)couple in this system is 0.89 V (vs. SHE), which at the time is the highest reported value for a Cu(II/I) system in aqueous media. An intriguing feature of thiamacrocycles is the ability to stabilize a variety of metal species with uncommon oxidation states. As in the following example, the first +2 oxidation-state silver complex [Ag[18]aneS6]2+ has been successfully isolated and characterized by using [18]aneS6 [21]. The single-crystal structure of [Ag[18] aneS6](ClO4)2 (2) confirms an octahedral homoleptic thioether coordination of the silver center with Ag(II)-S distances (2.569(7) Å and 2.720(6) Å) shorter than that in Ag(I) species (2.6665(12) Å and 2.7813(10) Å) (Fig. 3). Further DFT computations and EPR spectroscopy characterizations are performed to investigate the structure,

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Fig. 1 Sulfur-containing macrocycles discussed in this chapter

S

S S

[9]aneS3

S

S

S

S

S

S

S

[14]aneS4 H N

S S S

S

S

[12]aneS4

S

S

S

S

S

S

S

S S

S

N H

[18]aneS6

[18]aneS4N2

S

[21]aneS6

S

Ha S

S

S

N Ar

n

N S

S

nAr

S

Cl

Ar=

Hb

(n=0) S6N2-0

Fig. 2 The structure of Cu(I) complex encircled by [21]aneS6 macrocyclic ligand

Cl

Ar=

Hc

(n=1) S6N2-1

S S

Cu

S

S S

S

1

which is in agreement with the XRD analysis. It is envisioned that the stereochemical flexibility of the crown ligands and their encapsulation of reactive metal ions by polarizabale S-donors are conducive to stabilize uncommon oxidation-state metal species.

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Fig. 3 Crystal structure of [Ag[18]aneS6](ClO4)2 (2). Color coding: Ag, pink; C, gray; S, yellow

Fig. 4 Crystal structures of binuclear silver complexes 3 and 4 based on azathiacrown ethers. Color coding: Ag, pink; C, gray; N, blue; S, yellow; Cl, green

Many kinds of large azathiacrown ethers have also been prepared to encapsulate several Ag ions. An investigation on two azathiacrown ethers with N-appended side arms (S6N2–0 and S6N2–1) shows that they both form 2:1 (metal/ligand) silver(I) complexes based on 1H NMR titration and X-ray diffraction studies [22]. The structural studies of the binuclear silver complexes show that both Ag(I) ions are placed in the cavity of the macrocyclic ring and each silver(I) ion adopts a distorted trigonal bipyramidal geometry. Therein, three equatorial coordination sites and one axial position are taken up by three S atoms and one N atom from the macrocyclic ring, respectively (Fig. 4). Aside from the group 11 metal complexes mentioned above, a series of cadmium (II) complexes containing differently sized thiamacrocyclic ligands have been reported. One goal of this study is to examine how structural modifications of thiamacrocycles affect their ability to bind toxic heavy metal ions [23]. Various Cdmacrocycle complexes of the thiamacrocyclic ligands illustrated in Fig. 1 have been successfully isolated. X-ray crystallographic structure of [Cd([9]aneS3)2](PF6)2 (5) (Fig. 5a) shows that two [9]aneS3 ligands bind facially via their three sulfur atoms to a

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Fig. 5 Crystal structures of (a) [Cd([9]aneS3)2](PF6)2 (5), (b) [Cd([12]aneS4)2](ClO4)2 (6), and (c) [Cd[18]aneS4N2](PF6)2 (7). Color coding: Cd, light blue; N, blue; C, gray; S, yellow

Cd by a common distorted octahedral coordination geometry. As to an analogue complex [Cd([12]aneS4)2](ClO4)2 (6) containing a larger thiamacrocycle [12]aneS4, a sandwich-like structure is obtained as each [12]aneS4 binds the central Cd(II) ion via its four sulfur atoms to form an unusual eight-coordination square antiprismatic geometry (Fig. 5b). The Cd(II) complex 7 of the mixed azathiacrown [18]aneS4N2 crystallized as a hexafluorophosphate salt (Fig. 5c). The coordination geometry of the Cd(II) center is found to be a severely distorted octahedral mode due to the mixed S/N donor system. The 113Cd NMR chemical shifts of these Cd(II) complexes containing differently sized thiamacrocyclic ligands are in the range of 225 to 731 ppm. It is notable that the decrease in the number of thioether sulfur donors or the replacement of a thioether by a secondary nitrogen donor often causes upfield chemical shift in the 113 Cd NMR spectra. This finding provides a promising method for relating the 113Cd NMR shift behaviors to the coordination environments in Cd(II) complexes involving thiamacrocyclic ligands. Thiamacrocycles have also been widely applied to synthesize ruthenium(II) complexes. For example, the employment of differently sized thiamacrocycles [9]aneS3, [12]aneS4, and [14]aneS4 has led to [(Ru[9]aneS3Cl)2(bpta)](PF6)2 (8), [(Ru[12] aneS4)2(bpta)](PF6)4 (9), and [(Ru[14]aneS4)2bpta](PF6)4 (10) (bpta = 3,6-bis (2-pyridyl)-1,2,4,5-tetrazine) [24]. These complexes have a common bridged structure as shown in Fig. 6a–c. Various characterizations have been employed to probe the relationship between the electronic properties of bpta-bridged dinuclear Ru complexes and thioether ligands. X-ray crystallographic analysis of complex 8 has revealed that each Ru(II) ion is in a distorted octahedral coordination geometry and is coplanar with the bpta ligand. Three trans angles at the Ru(II) site (N-Ru-S, 176.56(15)
and 172.87(14)
; S-Ru-Cl, 175.20(6)
) have a slight variation away from the ideal octahedral coordination geometry. Compared with the relatively long bond lengths of Ru1-S1 and Ru2-S6, the shorter one of Ru1-S2 (2.3033(17) Å) results from the greater trans effect of chlorine. In complex 9 that contains a larger macrocycle [12]aneS4 with four sulfur donors, there is an obvious difference among three trans angles at the Ru(II) site (N-Ru-S, 177.96(18)
and 171.71(19)
; S-Ru-S, 176.34(8)
). These distortions are probably due to the increased steric hindrance of the large macrocycle, in which all

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Fig. 6 Crystal structures of (a) [(Ru[9]aneS3Cl)2(bpta)](PF6)2 (8) (b), (Ru[12]aneS4)2(bpta)] (PF6)4 (9), and (c) [(Ru[14]aneS4)2bpta](PF6)4 (10). Color coding: Ru, orange; N, blue; C, gray; S, yellow; Cl, green

the four sulfur donor atoms are confined to a relatively small host cavity. The structure of complex 10 is very similar to that of 9 with each Ru(II) coordinated by four sulfur donor atoms. However, the larger and more flexible conformation of [14]aneS4 makes it better satisfy the octahedral coordination geometry. Furthermore, the UV-vis spectroscopy and electrochemical studies are then performed on these Ru complexes. Compared with chlorine-coordinated complex 8, the significant changes for complexes 9 and 10 are the anodic shift of the bpta/bpta – couple and the RuIII/II couple, which may be related to the

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bonding properties of thiacrown ligands. Due to the poor σ-donors but good π-acid characteristic of thioether ligands, the electron density on the Ru center in 8 would be decreased by introducing the chloride ligand. On the other hand, the decreased electron density could be achieved through increasing the backbonding to the thiacrowns, which then leads to a lowered intermetallic electronic coupling.

43.2.2 Oxygen Donor Macrocycle Systems Macrocycles involving phenoxy bridges have been investigated for long time in supermolecular chemistry due to their persistent shape and a hydroxyl-based crown ether-like interior, which possess a great potential to coordinate with metal ions. A number of studies have demonstrated that oxygen-containing macrocycles could be used as scaffold to template the formation of various metal cluster aggregates. For example, some Zn(II) [25] or Cd(II) [26] acetate clusters could be obtained by using the phenoxy-based macrocyclic ligands. Single-crystal X-ray diffraction studies of 11 reveal that each zinc ion is supported by a N2O2 unit of the macrocycle, finally resulting in a distorted tetrahedral [Zn4O] cluster in cooperation with the bridged acetate ligands (Fig. 7a). Besides, this phenoxybased macrocyclic scaffold could also be applied to Cd(OAc)2 H2O system to obtain a heptacadmium carboxylate cluster (12). As shown in Fig. 7b, the macrocycle in 12 exhibits a bowl-shaped configuration to adapt to the formed Cd-oxygen cluster. Three Cd(II) ions each is coordinated by a N2O2 unit, and the remaining four central cadmium ions are coordinated by several oxygen atoms. This coordination scenario is analogous to the Zn(II) system. The 113Cd NMR studies of 12 further confirm that the cadmium ions therein are located in three coordination environments with a ratio of 3:1:3, which is in agreement with the X-ray crystallographic structure. Moreover, the individual cluster-embedded bowls would corporate in pairs to form a capsule-like structure through hydrogen bonding, which is significantly influenced by different solvent systems. In addition to the trap of homonuclear metal cluster species, such oxygencontaining macrocycles could also be applied to achieve heteronuclear cluster aggregates. One example is the macrocycle-involved tetranuclear mixed-metal complex 13, which is composed of zinc and erbium ions in a 3:1 ratio [27]. Crystal structure of 13 indicates that both the tetradentate and hexadentate coordination modes are included in the macrocyclic ring. The former N2O2 is adopted by three Zn(II) ions, while the remaining Er(III) ion is joined by six phenoxy oxygen atoms of the macrocycle (Fig. 7c). In this way, the Er(III) ion is nine coordinated by six bridging oxygen atoms at equatorial positions and three oxygen atoms from a bidentate nitrato anion and water at the axial positions. The equatorial plane of the six phenoxy oxygen atoms is slightly bent with two oxygen atoms located above the ideal plane and the other four oxygen atoms below the plane. However, such deviations are neglectable in comparison with the remarkably different Er-O distances, which could be attributed to the strong equatorial ligand field of six phenoxy oxygen donors. The Zn(II) ions are in a square pyramidal coordination geometry

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Fig. 7 Crystal structures of (a) [Zn4O(OAc)6] (11), (b) [Cd3O(OAc)6Cd(H2O)3] (12), and (c) [ErIIIZnII3(OAc)(NO3)2(H2O)1.5(MeOH)0.5] (13) clusters based on oxygen-containing macrocycles. Color coding: Zn, dark green; Cd, light blue; Er, dark blue; N, blue; C, gray; O, red

with a square N2O2 coordination site on the macrocyclic ligand and other molecules (acetate, nitrate, or methanol) at axial positions. In a short summary, macrocycles with pendant oxygen donors facilitate the formation of various homonuclear or heteronuclear metal cluster aggregates through the coordination and electrostatic attraction of bridging phenoxy oxygen atoms. Novel metal clusters with structure diversity have been achieved by this kind of macrocyclic templates.

43.2.3 Neutral N-Containing Macrocycle Systems Aside from the widely utilized negatively charged macrocycles containing oxygen donors, neutral N-containing polydentate macrocycles have also been extensively employed in the assembly of metal cluster aggregates. Azacalix[n]pyridines (Py[n]s) [28] as a new kind of neutral macrocycles have been successfully applied in the

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controllable synthesis of many anion-centered polynuclear metal clusters [10]. Taking advantage of the characteristic flexible conformation and tunable size of Py[n]s, they could easily adapt to structurally diversified metal cluster aggregates with different nuclearity numbers and coordination geometries. For example, a variety of Py[n]based polynuclear silver clusters with many externally introduced mono-, di-, or multitopic anions (e.g., acetylides, thiolates, and halides) have been isolated and characterized [10]. It is noteworthy that the solubility of stoichiometric silver complexes of these anions is usually very poor (e.g., Ksp(Ag2S) = 8  1051 at 25
C). However, the use of Py[n] macrocycles could largely enhance the solubility of related silver compounds due to the remarkable cooperative coordination effect. For example, the polymeric silver acetylide complex [AgC  CtBu]n has poor solubility in common solvents. Nevertheless, treatment of a suspension of insoluble [AgC  CtBu]n and silver triflate with Py[8] leads to a clear pale-yellow solution immediately [29]. The crystallized product is subsequently obtained by the diffusion of diethyl ether into the solution. As shown in Fig. 8a, the formula of this crystalline complex 14 is revealed as [(CF3SO3)Ag4(tBuC  C)(Py[8])](CF3SO3)2, which contains a square planar tetranuclear silver aggregate bridged by a tBuC  C anion through σ and π interaction. Relative to the tBuC  C anion, a triflate group is coordinated to an edge of the Ag4 plane at the opposite side. Besides, the Py[8] macrocyclic ligand functions as an outer template to stabilize the Ag4 aggregate based on the size-match principle. Notably, the linear [(CF3SO3)Ag4(tBuC  C)] moiety with the tBuC  C anion and the triflate group bonded to the Ag4 plane on either side is threaded through the Py[8] macrocycle, thus giving rise to a clustercentered organometallic rotaxane structure. In contrast to the parallelogram 1,3,4,6alternate conformation of free Py[8] macrocycle, the Py[8] in complex 14 is in a cylinder-belt-like conformation. It is intriguing that only one set of broad proton signals corresponding to the Py[8] ligand are observed in the 1H NMR spectrum of 14 (Fig. 8b), which conflicts with its coordination behavior in the crystalline structure. In crystalline solid structure of 14, two kinds of pyridine rings that are coordinated or uncoordinated with Ag can be clearly discriminated. Further variable temperature NMR studies show that the broad signals gradually split into several sharp doublets and triplets as the temperature decreases, suggesting that the Py[8] in 14 is fluxional in solution, and eight pyridyl nitrogen atoms undergo a rapid dissociation-recombination equilibrium to coordinate with the central Ag4 aggregate. Encouraged by the successful synthesis of the cluster-centered organometallic rotaxane 14, a specific angled ditopic ligand is then applied to construct desired metal cluster-centered supramolecular architectures. As shown in Fig. 8c, the employment of the extending conjugated ligand 1,3-bis((3-ethynylphenyl)ethynyl) benzene affords two [(C  C)-Ag4(CF3SO3)] aggregates at each anionic center, which is threaded through a Py[8] macrocycle to generate a pseudorotaxane structure in complex 15 [29]. In contrast to complex 14, the two cluster-centered pseudorotaxane moieties constitute a semicircular [3]-pseudorotaxane structure based on the angled phenylene-acetylene linker. Furthermore, two semicircles are linked together by the FF interactions between the attached triflates to finally yield a nanometer-sized hexagonal catenane-like structure (Fig. 8d).

Controllable Synthesis of Polynuclear Metal Clusters Within Macrocycles

Fig. 8 (a) Crystal structure and (b) 1H NMR of [(CF3SO3)Ag4(tBuC  C)(Py[8])](CF3SO3)2 (14). (c) Crystal structure and (d) assembled hexagonal catenanelike structure of [(CF3SO3)Ag4-{C  C-(m-C6H4)-C  C-(m-C6H4)-C  C-(m-C6-H4)C  C}Ag4(CF3SO3)(Py[8])2](CF3SO3)4 (15). Color coding: Ag, pink; N, blue; C, gray; O, red; the acetylide group is highlighted in green. (Reprinted with permission from [10, 29]. Copyright 2018 and 2011 American Chemical Society)

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Fig. 9 Crystal structures of (a) [(CF3SO3)1.5Ag3.5(tBuC  C)(Py[6])-(CH3OH)0.5](CF3SO3) (16) and (b) [Ag3( p-MeOC6H4C  C)(Py[6])](CF3SO3)2 (17). Color coding: Ag, pink; N, blue; C, gray; O, red; the acetylide group is highlighted in green. (Reprinted with permission from [10]. Copyright 2018 American Chemical Society)

The size-tunable Py[n] macrocycles have a remarkable advantage in adjusting the nuclearity number of encapsulated polynuclear metal clusters. The employment of a smaller macrocycle Py[6] in place of Py[8] results in a trinuclear silver aggregate (16 and 17) [30, 31]. As shown in Fig. 9, a Ag3 aggregate is held together by the t BuC  C group or CH3O-( p-C6H4)-C  C group and coordinated by three alternate pyridyl nitrogen atoms of the Py[6] ligand. The 1H NMR spectra of 16 and 17 show two sets of well-resolved peaks for the coordinated and uncoordinated pyridine rings of Py[6] due to the excellent size match between Py[6] and the Ag3 aggregate. It is noteworthy that such excellent size matching makes the Ag3 aggregate to be the most favorable structure within Py[6] no matter what kind of and not affected by the external anions are introduced. In summary, the nuclearity number of metal cluster aggregates could be finely adjusted by altering the size of Py[n]s. Taking advantage of the good ability of Py[n]s to stabilize reactive species and adjust the nuclearity number of silver clusters, it is envisioned that such fantastic protective effect of Py[n]s could facilitate the construction of metal cluster aggregates with higher nuclearity numbers and structural diversity by employing more complicated anion centers with di- or multiacetylide groups. For instance, a dumbbell-like structure containing two [C  CAg3]  Py[6] moieties (18) is formed by using a 1,4-phenylenediacetylide dianion and Py[6] ligand. As shown in Fig. 10a, the two Py[6] macrocycles are in the arrangement of a parallel face-to-face geometry. Besides, the employment of 1,3-butadiynediide, which has a shorter linkage carbon chain between two acetylide groups, results in a C42 bridged Ag3-Py[6] unit (19) in a clam-like structure (Fig. 10b) [30]. Therein, the two Py[6] ligands in 19 shows an eclipsed face-to-face configuration with a dihedral angle of 23
. Further shortening the length of carbon linker leads to a fusion of the bridged C  CAg3 aggregates,

Controllable Synthesis of Polynuclear Metal Clusters Within Macrocycles

Fig. 10 Crystal structures of (a) [Ag6(C  C-( p-C6H4)-C  C)(Py[6])2](CF3SO3)42CH2Cl2 (18), (b) [(CF3SO3)4Ag8(C  C-C  C)(Py[6])2](CF3SO3)2 (19), (c) {[Ag5(C  C)(Py [6])2](CF3SO3)3}0.7{[Ag6(C  C)(Py-[6])2](CF3SO3)4}0.3 (20), (d) [Ag10{1,4-(C  C)2C6H4}2(Py[8])2(CH3OH)2](BF4)62H2O (21), and (e) [(CF3SO3)4Ag6(C  C-C  C)(Py[8])(H2O)5] (22). Color coding: Ag, pink; N, blue; C, gray; O, red; the acetylide group is highlighted in green. (Reprinted with permission from [10]. Copyright 2018 American Chemical Society)

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finally generating a C22-centered silver cage in 20 encircled between two Py[6] macrocycles (Fig. 10c) [30]. In this C2@Ag5–6 cluster, the silver aggregates are encapsulated by two parallel bowl-shaped Py[6] ligands that are associated together by multiple C-Hπ and C-HN interactions. A brief conclusion states that the relatively small Py[6] macrocycle tends to form an acetylide-centered Ag3 aggregate and the length of linkage carbon chain between two acetylide groups would significantly affect the structure of metal cluster complexes. Thus, reactive and unstable metal cluster aggregates with structural diversity could be fabricated by using this macrocyclic template-directed strategy. For Py[8] macrocycle with a larger cavity size, the study with these ditopic anioncentered silver cluster aggregates ([1,4-(C  C)2C6H4]2 and [C  C-C  C]2 in 18 and 19) is carried out to gain further insights into the coordinative relationship between multitopic anions and differently sized Py[n]s. As shown in Fig. 10e, the employment of [1,4-(C  C)2C6H4]2 brings about the formation of [Ag3C  C-C6H4-C  CAg3] aggregate, which is beyond the limit of Py[8], thus leading to a fusion of two [Ag3C  C-C6H4-C  CAg3] aggregates to a bigger [Ag5(C  C-C6H4-C  C)2Ag5] cluster in 21 with a zigzag-chain-like structure stabilized by two Py[8] macrocycles [32]. Besides, in contrast to the C2@Ag5–6 cluster stabilized by two Py[6], a dumbbell-like [Ag3C  C-C  CAg3] aggregate in 22 is encapsulated by one parallelogram-shaped Py[8], resulting in a discrete cocoon-like structure (Fig. 10d). It is noteworthy that the larger macrocycle Py[8] is more flexible and could easily adapt to different cluster aggregates based on the extraordinary conformational tunability. Moreover, the nuclearity number and geometry of the encapsulated clusters would be finely adjusted by the anion center, shedding lights on the synthesis of a wide range of metal cluster aggregates. For the Py[n]-based polyacetylide anion systems, some special metal clustercentered metallosupramolecular architectures with high nuclearity number have been fabricated by altering the ring size. Taking the employment of the panel-like polyacetylide anion [1,3,5-(C  C)3C6H3]3 as an example, a series of metal clustercentered metallocages are obtained based on differently sized Py[n] (n = 6–8) macrocycles (Fig. 11a) [33]. Structural studies reveal that the Ag3-Py[6] unit is bonded to each acetylide moiety in the Py[6]-encircled complex 23, and the resulting [1,3,5-(Ag3C  C)3C6H3]6+ aggregate is then encapsulated by three Py[6] macrocycles to achieve a trefoil geometry (Fig. 11b). The employment of a larger macrocycle Py[7] also gives rise to the same [1,3,5-(Ag3C  C)3C6H3]6+ species (Fig. 11c), but the three Py[7] ligands in complex 24 exhibit different conformations. 1H NMR spectrum shows that the signals of proton of Py[6] in 23 are sharp and wellresolved. But for complex 24, the mismatch between the large Py[7] and the relatively small Ag3 aggregate results in very broad proton NMR signals of Py[7]. When an even larger macrocycle Py[8] is employed to the multitopic anionic system, two [1,3,5-(Ag3C  C)3C6H3]6+ aggregates fuse together to a Ag5 aggregate as mentioned before, which is further encircled in the large cavity of Py[8] to form complex 25. In this case, a triangular prism structure is generated based on three Py[8]-encapsulated Ag5 clusters and two [1,3,5-(C  C)3C6H3] units, which function as the pillars and panels, respectively (Fig. 11d). Moreover, as evidenced by

Controllable Synthesis of Polynuclear Metal Clusters Within Macrocycles

Fig. 11 (a) Scheme of the synthesis of metal cluster-centered metallocages with polyacetylide anion [1,3,5-(C  C)3C6H3]3 and differently sized Py[n] (n = 6–8) macrocycles. Crystal structures of (b) [Ag9{1,3,5-(C  C)3C6H3}(Py[6])3](CF3SO3)6 (23), (c) [Ag20.5{1,3,5-(C  C)3C6H3}2(Py[7])6(CF3SO3)4](CF3SO3)10.5 (24), and (d) [Ag15{1,3,5-(C  C)3C6H3}2(Py[8])3(CF3SO3)3](CF3SO3)6 (25). Color coding: Ag, pink; N, blue; C, gray; O, red. (Reprinted with permission from [10, 33]. Copyright 2018 American Chemical Society. Copyright 2012 Royal Society of Chemistry)

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DOSY NMR spectrum and high-resolution ESI-MS, such complicated 3D structure shows fantastic stability and structural integrity in solution despite of the complex composition involving 3 Py[8] macrocycles, 15 silver atoms, 2 [1,3,5(C  C)3C6H3] units, and triflate anions. Therefore, it is envisioned that macrocycle-based synthetic strategy is conducive to access a variety of metal clustercentered polygonal and polyhedral architectures, which could enlarge the library of the extensively reported single-metal-based structures. Ag2S nanoclusters have attracted considerable attentions due to their intriguing near-infrared photoluminescent properties, semiconductor properties, and low toxicities to living tissues. However, it is still a challenge to prepare Ag2S nanoclusters with tunable sizes under mild conditions. Inspired by the extraordinary property of size-tunable Py[n]s in the fabrication of polynuclear silver clusters of various acetylides, it is envisioned that such synthetic method could be applied to achieve the silver thiolate cluster precursors in a controllable manner, which would further facilitate the construction of desired Ag2S nanoclusters. As shown in Fig. 12a, a typical-Ag3 cluster aggregate 26 is established by using the Py[6] macrocycle [34]. X-ray diffraction studies present that such a Ag3 aggregate is coordinated to the sulfur center through a μ3-mode and is encapsulated by the Py[6] macrocycle via the coordination of three alternate pyridyl nitrogen atoms (Fig. 12a). The remaining three pyridine rings interact with the silver atoms based on the silver-aromatic π interactions. In contrast to previously reported μ3 silver-thiolate cluster species, the Ag-S bond distances in 26 (2.339(3)–2.394(2) Å) are found to be shorter by 0.1–0.2 Å, indicating the strong size restriction effect of the peripheral coordinative Py[6] macrocycle. In another case, a Ag5 cluster complex 27 is obtained based on a

Fig. 12 Crystal structures of (a) [Ag4(tBuS)(CF3SO3)2(Py[6])](CF3SO3) (26) and (b) [Ag5S(Py [6])](CF3SO3)3CH3OH (27). Color coding: Ag, pink; N, blue; C, gray; S, yellow; the acetylide group is highlighted in green. (Reprinted with permission from [10]. Copyright 2018 American Chemical Society)

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single-atom dianion S2 with three silver atoms coordinated by a bowl-shaped Py[6] macrocycle similar to that in complex 26 (Fig. 12b) [35]. Obviously, both the argentophilic interactions and silver-aromatic π interactions account for the stabilization of such a Py[6]-encircled Ag5 cluster aggregates. Therefore, the size-tunable Py[n]s could be finely employed to access metal cluster aggregates with different kinds of external anion centers in a controllable way. Further study involving a macrocycle Py[7] and halide anions has been carried out to investigate how the central anion variations within Py[n] macrocycles affect the structure of metal cluster aggregates [36]. As shown in Fig. 13a–c, the resulting silver halide clusters [Ag3–4X] (X = Cl, Br, I) all comprise a central halide-coordinated Ag3 or Ag4 aggregate inside Py[7] (complex 28–30). Each silver atom bonded with the halide center is also supported by one or two nitrogen atoms of pyridine rings and further interact with the aromatic π systems (Ag-C distances, 2.515–2.705 Å). The Ag-Cl bond lengths in 28 are approximately 0.2 Å shorter than that in other reported pyramidal [Ag3Cl] clusters, and the chlorine atom is 0.34 Å above the Ag1-Ag2-Ag3 plane due to the restricted coordination of Py[7] (Fig. 13a). For a larger bromide center, the long Ag-Br lengths lead to an increased distance between the bromine atom and Ag3 plane in 29 (Fig. 13b). Because of the small size of the [Ag3Cl] and [Ag3Br] clusters relative to the cavity size of Py[7], one or two additional silver atoms are also included in the macrocyclic ligand. Moreover, the even larger atomic size of iodine leads to a longer Ag-I bond and an expanded Ag3 triangle, resulting in the encapsulation of one more silver atom capping on the silver triangle. Thus, a trigonal bipyramidal [IAg4] cluster 30 is finally obtained with the iodide anion 0.92 Å above the Ag3 plane (Fig. 13c). It is suggested by this study that the metal-anion bonding distances could be finely adjusted by the coordination restriction Py[n]s, which provides a potential method to access metal clusters with novel intrinsic properties. Another new kind of neutral N-containing macrocyclic ligands has been developed to construct novel dicobalt amido complexes [37]. The geometric flexibility of the sizetunable macrocyclic ligands could easily adapt to various coordination environments of the metal ions by adjusting the number of catenated methylene units between imino nitrogen atoms. X-ray diffraction studies reveal that a chloride bridged dicobalt complex 31 is obtained with a folded structure by treatment of the ligand with CoCl2, in which an acute angle of the macrocyclic plane is formed to satisfy the coordination environment of the dinuclear dicobalt complex (Fig. 14a). Substitution of the bridging chloride unit in 31 gives rise to the dark red azido complex 32 with a folded geometry similar to that of 31. It is noteworthy that a pseudo-octahedral geometry is obtained for the CoII ions in 32 (Fig. 14b), suggesting the lability of the coordinated phosphine moiety. Besides, the azido complex is stable under the addition of excess PR3 (R = Me, Et), indicating that the PMe3 ligation seems to be inert on 32. Furthermore, when the azido complex 32 is heated with PMe3, a diamagnetic amido complex 33 is formed in C2v symmetry similar to that of complex 31 (Fig. 14c). 1H NMR spectrum shows that the bridged amido NH2 in 33 resonates at δ = 4.56 ppm. Moreover, a μ-phosphinimido dicobalt species 34 could also be fabricated by altering the number of catenated methylene units to an ethylene group in a similar synthetic method. Due to the relatively short linker, the macrocycle in 34 with weak flexibility displays a structure somewhere

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Fig. 13 Crystal structures of (a) [Ag4Cl(CF3SO3)3(Py[7])(CH3OH)] (28), (b) [Ag5Br (CF3SO3)2(H2O)4(Py[7])](CF3SO3)2H2O (29), and (c) [Ag4I(H2O)2(Py[7])](CF3SO3)3 (30). Color coding: Ag, pink; N, blue; C, gray; O, red; Cl, green; Br, brown; I, light blue. (Reprinted with permission from [10]. Copyright 2018 American Chemical Society)

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Fig. 14 Crystal structures of (a) [(3PDI2)Co2(μ-Cl)-(PMe3)2][OTf]3 (31), (b) [(3PDI2)Co2(μ-N3) (PMe3)2][OTf]3 (32), (c) [(3PDI2)Co2(μ-NH2)(PMe3)2][OTf]3 (33), and (d) [(2PDI2)Co2(μ-NPMe3) (PMe3)2][OTf]3 (34) (PDI = 2,6-pyridyldiimine). Color coding: Co, purple; N, blue; C, gray; Cl, green; P, brown

in between the unfolded and folded geometries (Fig. 14d). The successful isolation of these structurally diversified dicobalt species suggests that both the ring size and reaction conditions would influence the product distributions, which could be applied to alter the Co2(μ-N) core reactivity based on the reorganization abilities of differently sized macrocyclic ligands.

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Applications of Metal Cluster-Macrocycle Adducts

43.3.1 Platform for Organometallic Transformations In view of the abovementioned controllable synthesis of polynuclear metal clusters based on Py[n]s, the resulting metal-macrocycle capsules with high flexibility hold a great potential to conduct organometallic transformations for polymetalated heteroaromatic compounds. To date, many metal-ligand container architectures have been reported to encage guest molecules and stabilize highly reactive transition states of substrate molecules. Besides, a variety of reactions (e.g., Diels-Alder reaction [38], electrocyclization [39], and reductive elimination [40]) have been performed within organometallic capsules, and the resulting products show unusual selectivity and/or enhanced activity. However, the structurally well-defined reaction intermediates are rarely isolated due to the lack of flexible supramolecular coordination capsules with different cavity sizes. Inspired by the remarkable dynamic feature of capsule-like Py[8]-Ag3 cluster, which suggests an interconversion of various conformations of Py[8]-Ag3 capsule at room temperature and a fixed rigid form at low temperatures, it is envisioned that such flexibility would allow this capsule to easily adapt to diverse polymetalated heteroaromatic compounds by organometallic transformations. For example, intramolecular an 5-endo-dig cyclization is observed to form a polymetalated indole complex 35 upon treatment of o-ethynylaniline with a solution of Py[8]-Ag3 capsule and additional silver triflate [41]. The resulting dianionic indole ring in 35 is negatively charged at two vicinal carbon atoms and stabilized by a coplanar Ag4 rectangle based on Py[8]. Notably, the structure of 35 features the first example of well-defined organosilver intermediate derived from Ag(I)-involved aminoalkyne cyclization transformations [42]. Additionally, the Py[8]-Ag3 capsule-triggered cyclization can also be applied to other substrates containing both amine and ethynyl groups (Fig. 15), which experiences a new 6-endodig cyclization or cascade or multistep cyclization pathway triggered by the Py[8]-Ag3 capsule to achieve the quinolinium, 2,20 -biindole, and benzo[a]carbazole architectures in 36–38, respectively. Such macrocycle-based dynamic coordination capsule provides a feasible way to trigger cyclization reactions for various alkyne substrates under mild conditions. The isolation of these unprecedented structurally well-defined polysilver heteroaromatics and related theoretical studies deepen our understanding of multicentered bonding nature and metal-perturbed aromaticity in stabilization of the polysilver aromatic complexes, which could provide a probable way to develop more efficient and useful synthetic methods.

43.3.2 Stabilization of Intermediate Species Copper-catalyzed oxidations have many significant applications in biological and synthetic systems. In view to get insights into the mechanisms of such oxidation catalysis, the synthesis and reactivity studies of various copper-oxygen intermediates have been widely carried out. Macrocycle-based copper systems have provided an

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Fig. 15 Molecular structures of substrates and polysilver-bonded heteroaromatics formed within a Py[8]-Ag3 capsule. Crystal structures of [Ag5(C8NH5)(Py[8])](CF3SO3)3 (35), [Ag5(C9NH5)H(Py [8])](CF3SO3)4 (36), [Ag5(C16N2H10)(Py[8])](CF3SO3)3 (37), and [Ag5(C16NH9)(Py[8])] (CF3SO3)3) (38). Color coding: Ag, pink; N, blue; C, gray; O, red; the acetylide group is highlighted in green. (Reprinted with permission from [10, 41]. Copyright 2018 American Chemical Society. Copyright 2018 The Royal Society of Chemistry)

efficient tool to address this goal due to the extraordinary protective effect on reactive species. For example, a binuclear [CuII(μ-OH)Na] species encircled by a macrocyclic ligand (complex 39) has been found to stabilize the hydroxylation product of THF, resulting in a 2-hydroxytetrahydrofuran complex (THF-2-ol) protected by macrocycle in complex 40 [43]. X-ray crystal structure studies of 39 (Fig. 16a) reveal that the CuII ion is bonded to three neighboring N atoms on the macrocyclic ligand and is bridged by a hydroxyl

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Fig. 16 Crystal structures of (a) the monor and (c) the dimer of [CuII(μ-OH)Na] species (39) and (b) the monor and (d) the dimer of [CuII(μ-O-THF)Na] species (40). Color coding: Cu, dark green; Na, light pink; N, blue; C, gray; O, red

group to a NaI ion with a CuNa distance of 3.568(2) Å. It is intriguing that the complex crystallizes as a dimer as shown in Fig. 16c due to the interactions between the carboxamide carbonyl in one “monomer” and the Na+ ion in the other, resulting a five-coordinate NaI ion in a distorted square-pyramidal geometry. Surprisingly, when complex 39 is treated with CuI in THF/CH3CN in an attempt to substitute a CuI ion for the NaI ion, only the deprotonated product of THF (complex 40) is formed. X-ray crystal structure analysis shows that the THF-2-ol is bridged to the CuII and NaI ions with a weak interaction between CuII and the O atom on THF (Fig. 16b, d). Isotopelabeling studies suggest that the oxygen atom in THF-2-ol is the source of the O atom in complex 39. It is noteworthy that such hydroxylation of THF is not observed in THF solutions of Cu(III) with acyclic multidentate ligand, implying the unique role of such macrocycle-bonded metal systems in C-H activation process.

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43.3.3 Macrocycle-Assisted Bulk-to-Cluster-to-Nanoparticle Transformations On account of the coordination restriction of macrocyclic Py[n]s, the abovementioned silver cluster aggregates show unique metal-anion bond lengths and uncommon elemental ratios between the central anions and silver atoms. Therefore, it is envisioned that such distinctive metal cluster aggregates could be utilized as starting materials to access new functional compounds. For example, the abovementioned Py[7]-based silver halide clusters [Ag3–4X] (X = Cl, Br, I) can be further transformed to nonstoichiometric silver halide nanoparticles [AgmXn](m-n)+ (m > n; X = Cl, Br, I) by adding tetrafluoroboric acid to interrupt the coordination between the central silver aggregates and the surrounding Py[7] (Fig. 17a) [36]. The nonstoichiometric silver chloride nanoparticles are finally obtained after the protonation process together with the addition of the stabilizing surfactant polyvinylpyrrolidone (PVP). Moreover, the newly fabricated nonstoichiometric silver halide nanoparticles [AgmXn](m-n)+ (m > n; X = Cl, Br, I) hold a great potential to act as an highly efficient electrocatalyst for the chlorine evolution reaction (CER), which is a fundamental and important electrochemical reaction in industry because of the extensive application of chlorine (e.g., in polymers and drugs). Besides, the nonstoichiometric elemental ratio between silver and halogen atoms results in the positively charged nature of the [AgmXn](m-n)+ nanoparticles, which accelerates the transport process of chloride drived by electrostatic attraction and thus facilitates the formation of the catalytically active silver polychloride species. Such enhanced catalytic efficiency also results from the formation of uncommon nonstoichiometric nanoparticles, which makes the coordinatively unsaturated silver active sites easily access to catalyze the chloride oxidation (Fig. 17b). In this regard, the involvement of the [AgmXn](m-n)+ nanoparticles could provide an efficient tool to catalyze the CER at a very low overpotential. In addition, the positively charged surface of the nonstoichiometric [AgmXn](m-n)+ nanoparticles makes it attract chloride anions more easily than neutral water molecules, leading to a high selectivity for the CER over the oxygen evolution reaction (Fig. 17c). Given that silver sulfide has long been investigated as a type of narrow bandgap semiconductor owing to its good stability, low toxicity, and widespread potential applications in photovoltaic cells, photoconductors, and near-infrared imaging [44], the construction of diversiform silver sulfide species has attracted tremendous research interests. Besides a bandgap of 0.9–1.1 eV for bulk α-Ag2S [45], the synthesis of nano-sized Ag2S provides an efficient method to finely enlarge the bandgap based on the quantum confinement effect, which brings about many fantastic size-specific optical and optoelectronic properties [46]. Therefore, it is necessary to develop an effective method to access uniformly sized Ag2S nanocrystals. However, among the previously explored methods (e.g., the microemulsion approach [47] and the hot injection method [48]), the use of exotic ligand- or surfactant-stabilized silver and sulfide ions or their precursors as well as the requirement of elevated temperature and high pressure in most cases impedes the synthesis of uniformly sized Ag2S nanocrystals [49]. Thus, an alternative method that direct transform bulk Ag2S

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Fig. 17 (a) Scheme for the formation of nonstoichiometric silver halide nanoparticles as CER reaction electrocatalysts. (b) Cyclic voltammograms (CVs) at a glassy carbon electrode in an aqueous solution of NaCl (1 M). (c) CVs at a glassy carbon electrode in an aqueous solution of NaCl with the nonstoichiometric [AgmCln](m-n)+ nanoparticle (cAg+ = 0.53 μM) as a catalyst after degassing (red) or after bubbling oxygen (black). (Reprinted with permission from [10, 36]. Copyright 2018 American Chemical Society. Copyright 2017 The Royal Society of Chemistry)

solid into its nano-sized prototype would be a convenient and ideal synthetic strategy. In this case, the abovementioned macrocycle-assisted bulk-to-cluster-to-nanoparticle transformation could also be applied to the silver sulfide systems. Taking into consideration that the [Ag5S]-containing complex 27 could be stabilized by macrocyclic Py[6], this macrocyclic ligand is thus utilized to produce two new precursor clusters 41 and 42 by varying its amount [35]. As shown in Fig. 18b, a dumbbell-shaped [Ag12S2] silver sulfide cluster aggregate is found to be embraced by two macrocyclic Py[6]s at the upper and nether sides in complex 41. For complex 42, the [Ag5S] cluster aggregate is protected by two face-to-face Py[6] macrocycles (Fig. 18c). It is worth noting that the Ag-S bond lengths in 41 and 42 are 0.2 Å shorter than that in bulk Ag2S due to the coordination restriction of Py[6] [50]. In view of the fact that the single [Ag5S] and joint [Ag12S2] silver sulfide clusters can be successfully isolated by varying the amount of protective Py[6], the coalescence and fusion of Py[6]-encapsulated [Ag5S] clusters are suggested as a promising tool to access nonstoichiometric Ag-S binary nanoparticles. For the bulk-to-cluster-to-nanoparticle transformation of Ag2S (Fig. 18a), protonation of these macrocycle-encircled complexes results in the release of the deprotected silver sulfide clusters, which will further undergo the formation of silver sulfide nanoparticles. Further characterization by energy-dispersive

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Fig. 18 (a) Schematic diagram for the bulk-to-cluster-to-nanoparticle transformation of Py[6]protected Ag2S species. (b) Crystal structures of [Ag12S2(Py[6])2](CF3SO3)8H2OCH3OH (41) and [Ag5S(Py[6])2](CF3SO3)3 (42). Color coding: Ag, pink; N, blue; C, gray; S, yellow

X-ray measurements reveals the existence of Ag and S and further offers the Ag/S atomic ratio of 3.5. Additionally, X-ray photoelectron spectroscopy suggests a + 1 oxidation state of the silver atoms in the nanoparticles, and the Ag/S molar ratio is determined to be 3.7, which is comparable to the energy dispersive X-ray spectroscopy result of 3.5 and larger than the values of around 2.0 in bulk Ag2S [47]. It is conjectured that such a high Ag/S ratio is actually resulted from the Py[6]-encapsulated silver-rich Ag-S clusters. The bandgap energy of the nanoparticle with a high Ag/S ratio is thus deduced to be 4.0 eV, leading to a large blueshift relative to that of bulk α-Ag2S. Theoretical calculation for HOMO-LUMO gap of silver sulfide clusters with different Ag/S ratios is carried out to clarify the relationship between the energy gap and the Ag/S ratio in silver sulfide clusters. DFT calculations show that the cluster with a higher Ag/S ratio

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has more localized HOMO-LUMO orbital and a larger energy gaps correspondingly. On account of such advantages mentioned above, this new synthetic method provides a viable tool to tune the bandgap of binary nanomaterials by different element ratios instead of the size. Aside from this, the present macrocycle-assisted bulk-to-cluster-to-nanoparticle transformation is also applicable to the efficient synthesis of alkynyl-protected silver nanoclusters and thiolate-protected Ag2S nanoclusters.

43.4

Conclusions and Perspectives

This chapter highlights the employment of polydentate macrocycles as an outer template to direct the construction of various polynuclear metal clusters in a controllable manner. Clearly, the intrinsic macrocyclic effect and the cooperative coordination effect of macrocyclic ligand systems contribute to their superiority in metal cluster assemblies. In particular, neutral polydentate macrocycles have shown good behaviors in the assembly of metal cluster aggregates containing various externally introduced anions, which provide an efficient method to achieve structurally diversified metal cluster aggregates. Preliminary application studies of the macrocycle-encapsulated metal clusters have also been described, such as the uncommon organometallic transformations and a Py[n]-assisted bulk-to-cluster-to-nanoparticle transformation that can be used to fabricate novel nanomaterials with unique physical and catalytic properties. It is envisioned that many other symmetric or unsymmetric macrocycles could be elaborately designed and synthesized as templates to direct the synthesis of metal clusters with homo- or heteronuclear metal atoms in a controllable way. In this way, the macrocycle-protected metal clusters with structural diversity would provide an ideal molecular platform to study the structure-property relationship of metal clusters in view of their satisfying stability.

43.5

Cross-References

▶ Emerging Macrocyclic Arenes Related to Calixarenes and Pillararenes ▶ Stimuli-Responsive Self-Assembly Based on Macrocyclic Hosts and Biomedical Applications Acknowledgments Financial support by the National Natural Science Foundation of China is gratefully acknowledged.

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27. Yamashita A, Watanabe A, Akine S, Nabeshima T, Nakano M, Yamamura T, Kajiwara T (2011) Wheel-shaped ErIIIZnII3 single-molecule magnet: a macrocyclic approach to designing magnetic anisotropy. Angew Chem Int Ed 50:4016–4019 28. Wang M-X (2012) Nitrogen and oxygen bridged calixaromatics: synthesis, structure, functionalization, and molecular recognition. Acc Chem Res 45:182–195 29. Gao C-Y, Zhao L, Wang M-X (2011) Designed synthesis of metal cluster-centered pseudorotaxane supramolecular architectures. J Am Chem Soc 133:8448–8451 30. Gao C-Y, Zhao L, Wang M-X (2012) Stabilization of a reactive polynuclear silver carbide cluster through the encapsulation within a supramolecular cage. J Am Chem Soc 134:824–827 31. Guo H, He X, Wan C-Q, Zhao L (2016) A stepwise bulk-to-cluster-to-particle transformation toward the efficient synthesis of alkynyl-protected silver nanoclusters. Chem Commun 52:7723–7726 32. Gao C-Y, He X, Zhao L, Wang M-X (2012) Dual template synthesis of silver acetylide clusterencapsulated supramolecular boxes. Chem Commun 48:8368–8370 33. He X, Gao C-Y, Wang M-X, Zhao L (2012) Designed synthesis of a metal cluster-pillared coordination cage. Chem Commun 48:10877–10879 34. Chen H-Q, He X, Guo H, Fu N-Y, Zhao L (2015) Designed synthesis of size-tunable Ag2S nanoclusters via distinguishable C-S bond cleavage reaction of alkyl- and aryl-thiolates. Dalton Trans 44:3963–3966 35. He X, Wang Y, Gao C-Y, Jiang H, Zhao L (2015) A macrocycle-assisted nanoparticlization process for bulk Ag2S. Chem Sci 6:654–658 36. Zhang Q-Y, He X, Zhao L (2017) Macrocycle-assisted synthesis of non-stoichiometric silver(I) halide electrocatalysts for efficient chlorine evolution reaction. Chem Sci 8:5662–5668 37. Cui P, Wang Q, McCollom SP, Manor BC, Carroll PJ, Tomson NC (2017) Ring-size-modulated reactivity of putative dicobalt-bridging nitrides: C@H activation versus phosphinimide formation. Angew Chem Int Ed 56:15979–15983 38. Inokuma Y, Yoshioka S, Fujita M (2010) A molecular capsule network: guest encapsulation and control of Diels-Alder reactivity. Angew Chem Int Ed 49:8912–8914 39. Hastings CJ, Pluth MD, Bergman RG, Raymond KN (2010) Enzyme-like catalysis of the nazarov cyclization by supramolecular encapsulation. J Am Chem Soc 132:6938–6940 40. Kaphan DM, Levin MD, Bergman RG, Raymond KN, Toste FD (2015) A supramolecular microenvironment strategy for transition metal catalysis. Science 350:1235–1238 41. He X, Xue Y, Li C-C, Wang Y, Jiang H, Zhao L (2018) Synthesis of stable polymetalated aromatic complexes through metal-macrocycle capsule-triggered cyclization. Chem Sci 9:1481–1487 42. van Esseveldt BCJ, van Delft FL, Smits JMM, de Gelder R, Schoemaker HE, Rutjesa FPJT (2004) Transition metal-catalyzed synthesis of novel biologically relevant tryptophan analogues. Adv Synth Catal 346:823–834 43. Halvagar MR, Tolman WB (2013) Isolation of a 2-hydroxytetrahydrofuran complex from copper promoted hydroxylation of THF. Inorg Chem 52:8306–8308 44. Sadovnikov SI, Gusev AI (2017) Recent progress in nanostructured silver sulfide: from synthesis and nonstoichiometry to properties. J Mater Chem A 5:17676–17704 45. Kershaw SV, Susha AS, Rogach AL (2013) Narrow bandgap colloidal metal chalcogenide quantum dots: synthetic methods, heterostructures, assemblies, electronic and infrared optical properties. Chem Soc Rev 42:3033–3087 46. Wang RY, Tangirala R, Raoux S, Jordan-Sweet JL, Milliron DJ (2012) Ionic and electronic transport in Ag2S nanocrystal-GeS2 matrix composites with size-controlled Ag2S nanocrystals. Adv Mater 24:99–103 47. Jiang X, Xie Y, Lu J, Zhu L, He W, Qian Y (2001) In-situ interface self-assemblies of nanocrystalline Ag2E (E = S, Se, or Te) via chalcogen directional transfer agents. J Mater Chem 11:584–588

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Molecular Recognition with Helical Receptors

44

Dan-Wei Zhang, Hui Wang, and Zhan-Ting Li

Contents 44.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44.2 Poly(m-arylene ethynylene)s and Analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44.3 Aromatic Amide Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44.4 Aromatic Hydrazide Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44.5 Aromatic Urea Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44.6 Aromatic Triazole Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44.7 Aromatic Oxadiazole Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44.8 Conclusion and Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

44.1

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Introduction

Helix is the key structural motif of DNA and proteins and plays an essential role in life on, such as, molecular recognition, catalysis, replication, and signal transduction. Chemists have a long-standing interest in developing artificial helical polymers for mimicking the biological helices as well as for the development of synthetic systems that exhibit new interesting functions. In this category, a variety of nonaromatic polymers that possess helical conformations and high degree of polymerization (DP) have been developed, which, however, are not able to generate tubular cavity. Foldamers are synthetic oligomers that adopt folded conformations due to the induction of intramolecular non-covalent interactions [1]. Owing to their conjugated coplanarity nature, foldamers that are composed of meta-substituted aromatic units usually possess predictable folded or helical conformations [2–5]. The width of the

D.-W. Zhang · H. Wang · Z.-T. Li (*) Department of Chemistry, Fudan University, Shanghai, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_51

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compact structures is defined by the size and geometry of the repeat units. By elaborate combination of the repeat units, currently chemists can obtain hollow structures with well-defined cavity size. The depth or length is varying but can be easily modulated by controlling the number of the aromatic components of the backbones. In principle, long tubular foldamers can be prepared through multistep organic synthesis. However, the synthesis would be time-consuming and challenging for enabling large amounts for property or function investigation. Polymeric foldamers can be prepared much more quickly through the polymerization of rationally designed monomers, which not only endows the backbones with defined inner diameter comparable with that of the short analogues but also realizes much longer depth due to elongation of the backbones (Fig. 1) [6–8]. Moreover, polymeric helical tubes are stabilized by intramolecular non-covalent interactions and thus, different from those obtained by self-assembly of molecular components and concentration-independent. Although non-covalent interactions are sensitive to the polarity of the media, by choosing a suitable non-covalent interaction, stable helical structures can be constructed in a specific medium. In the past two decades, among others, conjugated m-arylene ethynylene [9], amide [4], hydrazide [4], urea [4], triazole [10, 11], and oxadiazole [12] segments have been utilized to build tubular polymeric helices. Many of these hollow structures have been revealed to function as macromolecular receptors for various guests or transmembrane transporters for different ions. The advances are described in this chapter.

44.2

Poly(m-arylene ethynylene)s and Analogues

Moore et al. developed the strategy of utilizing oligo(m-phenylene ethynylene)s (m-PEs) to construct aromatic helices that are stabilized by solvophobicity in polar organic solvents [13]. From the coupling reaction of compounds 1 and 2, Hecht et al. prepared polymer P3 (Fig. 2) [8], which had a number-average DP of 60 and a typical polydispersity index (PDI) of 1.3. Solvent denaturation experiments in acetonitrile, with the addition of benign chloroform, revealed that polymer P3 formed a stable helical conformation, because the occurrence of denaturation required large percentage of chloroform. The cinnamate groups in the helical conformation could further undergo light-initiated [2 + 2] photodimerization reaction to cross-link the backbone to afford polymer P4. UV/Vis titration experiments Fig. 1 The extension of an oligomeric foldamer leading to the generation of a polymeric tubular helix with comparable inner diameter and DP-dependent depth

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O

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OR [Pd(PPh3)4], CuI +

I

H

SiMe3 2

I

DBU, H2O MeCN, reflux

1 O

R R R R R R R R

OR

hv MeCN H n P3

P4

Fig. 2 Synthesis of polymers P3 and P4 (R = CO2(CH2CH2O)3Me). DBU = 1,8-diazabicyclo [5.4.0]undec-7-ene

of this polymer in acetonitrile revealed no significant spectral changes with the addition of the chloroform denaturant, which supported the locking of the helical conformation. Molecular modeling revealed that one turn of this kind of folded structures has six repeat units [13]; the DP of 60 of this polymer showed ca. 10 turns, which correspond to a depth of 3.5 nm for the helical tube by assuming a typical distance of 3.5 Å between two adjacent turns. Poly(propylene oxide)-poly(mPE) block and graft copolymer P7 could be prepared from the reaction of polymer P5 and 1-ethynyl-3-iodobenzene 6 (Fig. 3) [14]. The reactions of polymer P5 of different length gave rise to polymer P7 of comparable DP (m = 8–11). The poly(mPE) backbone of the copolymer was partially folded into a helical conformation in methanol. In methanol or chloroform, the poly (mPE) backbone was flexible. Thus, its circular dichroism (CD) spectrum only exhibited a positive signal in the region of the polyethylene glycol backbone absorption, but not a bisignate exciton couplet expected for a poly(mPE) backbone of helicity bias. Thus, chirality transfer only took place in the flexible conformation of the poly(mPE) backbone in methanol. Inouye et al. prepared polymer P8 from the corresponding 2-ethynyl-6iodopyridine derivative [15]. In chloroform the poly(m-ethynylpyridine) backbone adopted unfolded conformations as a result of the orientation of the pyridine nitrogen atoms on the opposite side of the ethynediyl bonds in order to avoid the dipoles. Adding β-D-glucoside 9 induced the backbone to fold into helical state in chloroform through hydrogen-bonding interactions between the OH groups of saccharides and the pyridine nitrogen atoms (Fig. 4). The saccharide was encapsulated in the cavity of the helix and thus induced the latter to produce helicity bias. Different n-

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O BbO

O

[Pd(PPh3)4], CuI THF, MeCN

+

n I

P5

I

H

6

(n = 100, 200, 300)

r.t., 3 days, 57%

O BbO

O

n I m

P7

Fig. 3 The coupling reaction of polymers P5 and 6 to afford copolymer P7

OH OBu-n

I

HO HO

N n

O OH

OC8H17-n 9

hydrogen bonding

P8 Mn= 2200, Mw = 4500 Fig. 4 Helix formation of polymer P8 induced by β-D-glucoside 9 through multiple hydrogen bonds. (Adapted with permission from [15]. Copyright 2004, ACS)

octyl pyranosides were investigated, but 9 was found to induce the helicity bias most effectively. The encapsulation could lead to extraction of native monosaccharides into less polar organic solvents like chloroform. Similar polymers with the pyridine ring bearing poly(ethylene glycol) chains at the 4-position were soluble in water, which could complex native saccharides in water in the helical conformation. In this case, inter-turn aromatic stacking might contribute significantly to the formation of the helical conformation. R- and S-polymers P10 that bear chiral oligo(ethylene glycol) side chains were also soluble in water. By using gel permeation chromatography (GPC), fractions of different molecular weight could be separated for the polymers [16]. Depending on their molecular size and the solution temperature, the shape of their CD spectra in water changed considerably, and that of the heaviest fractions was responsive to the addition of mannose, cyclodextrins, and polysaccharides such as glycogen. The change of their higher-order chiral structures from single helix to more complicated entangled intramolecular duplex and then to guest-entrapping helix had been

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proposed to rationalize this change (Fig. 5). S-Polymer P11 bearing chiral amide and oligo(ethylene glycol) side chains alternately was soluble in both polar and apolar organic solvents. Adding metal salts to its solution in pure water or in binary water and ethanol could cause a positive Cotton effect and hypochromism enhancement around 360 nm, which was attributed to the coordination of metal ions to the amide side chains and consequent stabilization of the helical structure. Polymer P12 also adopted a flexible conformation due to the electrostatic repulsion of the dipoles of the adjacent pyridine units [17]. In dichloromethane, this polymer exhibited pH-regulating binding to 9 or other monosaccharides also through the helical conformation. Adding trifluoroacetic acid (TFA) to their complexes caused the ICD of the polymer to enhance gradually and the stability of the complexes to increase until the amount of the acid reached ca. 0.5 molar equivalent of its pyridine rings. These results had been rationalized by considering half-protonation of the pyridine rings, which stabilized the helical structure that consisted of cisoid conformations for each of the adjacent pyridine pairs (Fig. 6). More TFA

8

Me

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O

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H

OMe

O

C8H17

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Me

H N

N n

H

S-Polym 11 O

Me O

I n

Polym 12

7

Fig. 5 Tentative mechanism for temperature- or guest-responsive conformational change of R- or S-polymer P10. (Reproduced with permission from [16]. Copyright 2012, RSC)

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Me

N

R

Me

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N N

N

nH+

N

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H N+

N+ H

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N

N H

Me

R

N

R N Me

R

H N+

N+ H

R = n-C8H17

zigzag N

helical

Me

N

R

Fig. 6 Partial (half) and complete protonation of the pyridine rings of polymer P12 leading to the helical or zigzag conformation, respectively

suppressed the ICD as well as weakened the stability of the complexes because further protonation of the pyridine rings favored the formation of the flexible zigzag conformation. Polymer P13 that bears amino side chains has been revealed to exhibit memorization of achirality and chirality of meta-ethynylpyridine polymer with amino side chains through cross-linking with Cu(OTf)2 outside the helical backbone (Fig. 7) [18]. When chiral guest 9 and Cu(OTf)2 were added to its solution in chloroform in order, the guest-induced CD band around 340 nm for the resulting helix was enhanced by the addition of the salt through Cu2+-N coordination. However, changing the addition order of the two species only caused a weak CD band. It was proposed that achirality was memorized due to the above coordination, and subsequent addition of the chiral guest could only induce weak CD signal. For the chiral CD-enhanced helical complex, the addition of β-L-9 caused very slow decay of the CD band, pointing to a significant chiral memorization effect. Moore et al. also expanded the helical state of oligo(mPE)s to other polymeric structures through partially changing the backbones. One interesting example involved the coordination of the appended pyridines of oligomers 14a-c to transdichlorobis(acetonitrile)palladium [19]. For 14a and 14b, this coordination led to the formation of polymers P15a and P15b (Fig. 8), which resembled the longer oligomers to adopt helical conformations in acetonitrile. In contrast, oligomer 14c, which bears six aromatic rings, was found to coordinate to one Pd atom with its two pyridines to form a coordination macrocycle due to the suitable length of the oligomer for macrocyclization [9, 20]. Moore et al. further prepared imine-derived oligomers 16a and 16b [9], both of which were revealed to be conformationally flexible. In acetonitrile in the presence of 0.5 mM oxalic acid as a catalyst, the two oligomers (1,1 equivalent at 5 mM)

44

Molecular Recognition with Helical Receptors

Fig. 7 Chiral guest and coordination-induced helix of polymer P13 exhibiting chiral and achiral memorization

1259 O

MeO MeO

O

N

N

O

N

N

N

O

N

N

N

O

N

N

N Cu2+

MeO MeO

N

guest N

O

CO2R

RO

OR

n N

N

14a: n = 2 14b: n = 6 14c: n = 4

R = (CH2CH2O)3Me

OR

OR

Ar Cl N Pd N Cl

PdCl2(MeCN)2 2

N Ar

Ar = mPE oligomer

Ar RO

Fig. 8 Palladium-pyridine coordination of 14a and 14b to form polymers P15a and P15b that folded into hollow helices in acetonitrile. (Adapted with permission from [45]. Copyright 2006, ACS)

underwent imine metathesis to afford high molecular weight products, because high polymers could allow the formation of intra-chain non-covalent interactions, which drove the metathesis equilibrium to shift from shorter conformationally flexible oligomers to high helical polymers (Fig. 9). In less polar chloroform, similar metathesis also took place. However, after equilibrium was reached, the reaction mixture contained only starting materials, their dimers and trimers, together with a small amount of higher oligomers. The content of the products was well consistent with the theoretically calculated statistical distribution in a closed system in which all the components did not obtain stacking energy [21]. Further polymerization experiments in a series of solvents revealed a good

1260

D.-W. Zhang et al. CO2R X

X N

N 2 CO2R

16a: X = NO2 16b: X = OMe

CO2R

R = (CH2CH2O)3Me

metathesis metathesis

Fig. 9 Imine metathesis in 16a and 16b (1.1) afforded the formation of longer helical polymers due to the stabilization of cross-turn stacking interaction. (Adapted with permission from [21]. Copyright 2002, ACS)

correlation of the molecular weight of the products with the stability of the resulting helical products and important dependence of the equilibrium state of the metathesis reaction on the chain length of the starter sequences [9]. It was also proposed that the elongation process might involve unfolding or partial unfolding of the backbones by reducing possible steric hindrance produced by aromatic stacking in the helical state. Hecht et al. introduced ethylene and azo units to the m-PE backbones to prepare polymers P17a and P17b to exploit the influence of the linkers on the formation and stability of m-PE-based helices [22]. In polar solvents such as acetonitrile, both polymers folded to form stable helical conformations. It was found that the introduction of the extended diacetylene linkers in polymer P17b could strengthen aromatic stacking of the backbone, which increased the aggregation tendency of the backbone as well as suppressed the photoisomerization of the azobenzene units in the folded state. Yashima and Hecht et al. also investigated the self-assembly morphology of R- and S-polymer P18 on surface [23]. Both polymers exhibited Cotton effect in polar and nonpolar organic solvents, reflecting the formation of helicity bias in solution through the induction of the chiral side chains. High-resolution atomic force microscopy (AFM) images showed the helical structures of molecular resolution in two-dimensional crystalline layers. Absolute helical senses could be observed, which solidly confirmed the formation of the helical conformations.

44

Molecular Recognition with Helical Receptors

RO O

O

1261

O

N

m

O

N

2

n

n

OR

R- or S-P18

P17a: m = 1 P17b: m = 2 R = (CH2CH2O)3Me

O

O Me

O Me

O RO

H N

O

OR

Liu et al. conducted the living polymerization of optically active and amphiphilic 19 by using alkyne-Pd(II) 20 as the initiator to afford well-defined polymer P21 (Fig. 10) [24], which was found to form a stable helical conformation in polar organic solvents including THF, 1,4-dioxane, and MeCN. The Cotton effects appeared in the range of 245–400 nm. The positive first Cotton effect was observed around 308 nm, while the negative second Cotton effect showed the maximum peak around 289 nm. This helix also showed effective solvent-dependent helicity inversion in THF with the addition of chloroform. Treatment of polymer P21 with isocyanate 22 produced amphiphilic polymers P23a-c. These block copolymers was H N

O H N

O

R

PEt3 Pd Cl 20 PEt3

MeO

PEt3 Pd Cl Et3P m

PPh3, CuI, NEt3, THF, 55 °C

I

R

P21

19

MeO O

O

H N

+ 1) C N

22

THF, 55 °C

R

X H m

2) MeOH

n

N X MeO

R=

O

OMe

P23a: X = OC10H21 P23b: X =

3

P23b: X =

Fig. 10 The preparation of polymers P21 and P23a-c

O

N H

CO2C10H21

N H

CO2C10H21

1262

D.-W. Zhang et al.

found to self-assemble into well-defined spherical nanostructures in binary THF and methanol, which was independent of the side chains on the second benzene ring. It is unclear if the poly(m-PE) segments could keep the helical conformation. Schanze et al. prepared water-soluble anionic polyelectrolyte polymer P24 and studied its interactions with alkynyl-Pt(II) terpyridine complexes 25a and 25b [25]. Polymer P24 existed in the helical conformation. Its interactions with the Pt complexes were found to occur through the intercalation of the planar complexes within the polymer helix, which was considered as a specific “guest-host” ensemble. Titration of Pt(II) complexes into an aqueous solution of the polymer led to efficient quenching of the fluorescence of the polymer, and triplet metal-metal-to-ligand charge transfer (3MMLCT) state emission from the intercalated Pt(II) complexes was observed when the ensembles were excited into the absorption band of the polymer. The generation of the 3MMLCT state emission supported that the Pt(II) complexes aggregated or dimerized within helical scaffold. This helical polymer and Pt(II) complex ensembles were also found to be responsive to various proteins, and under physiological pH, negatively charged proteins recovered the polymer fluorescence more than the positively charged ones, which was attributed to the electrostatics between the ensembles and the proteins. O

SO 3-Na+ N N

2TfO -

N

Pt+

N

3TfO -

Pt+

NMe 3+ N P24

n

NMe 3+

N 25a

NMe 3+

25b

Ito et al. prepared polymer P26 from the coupling of the corresponding 1,3diethynylbenzene precursor [26]. This polymer consisted of repeated m-phenylene diethynylene (m-PDE) units which bear chiral amide side chains. It was revealed that cross-turn hydrogen bonding induced the backbone to adopt a helical conformation (Fig. 11). The helical backbone could undergo light-induced cross-linking at longitudinally aligned 1,3-butadiyne moieties to form covalently helical tubes. This crosslinking could take place in solution or the solid state. The chiral side chains allowed easy analysis of both the helical conformation and the covalent organic nanotubes.

44.3

Aromatic Amide Polymers

Since 2001, several groups have developed a variety of aromatic amide sequences that are induced by intramolecular hydrogen bonds to form folded or helical conformations [4]. On the basis of the early studies on oligomers, quite a number of backbones have been expanded to produce polymeric systems [6, 7]. As their oligomeric analogues, some of the hollow polymeric helices have been revealed to function as good receptors for discrete guests.

44

Molecular Recognition with Helical Receptors

1263

Fig. 11 (a) Schematic representation of the synthetic approach toward covalent nanotubes. (b) Hydrogen bonding induced formation of helical structure by polymer P26 and subsequent photochemical cross-linking between longitudinal diacetylenes. (Adapted with permission from [26]. Copyright 2016, ACS)

Zhang et al. had prepared aromatic amide-based polymers from the solid-state condensation of isophthalic acid and benzene-1,3-diamine at 350–400
C [27]. The resulting poly(m-phenylene isophthalamide) (polymer P27) had a maximum inherent viscosity of 0.55 dL/g. With a trade name of Nomex, polymer P27 is prepared in industry from the condensation of isophthaloyl dichloride and benzene-1,3-diamine under milder conditions [28]. Using dimethylacetamide as solvent in the presence of LiCl, the above reaction gave rise to both macrocycles of different sizes (6–20 benzene rings) and short oligomers. All the oligomers and polymers are insoluble in either water or polar organic solvents due to strong intra- and/or intermolecular and π-stacking [4]. When flexible side chains are introduced, the resulting polymers may become soluble in organic or aqueous solution, which depend on the polarity of the side chains. These polymers can be driven by intramolecular hydrogen bonding, solvophobicity, or guest induction to give rise to different helical conformations.

H N

HO O

H N

OH O

O

n

O

P27

Guan et al. tried to prepare polymer P29 from the self-coupling of 28 in Nmethylpyrrolidone (NMP) in the presence of LiCl and triphenylphosphine (TPP) (Fig. 12) [29]. The reaction actually mainly afforded polymer P29’ due to the decomposition of the methoxy groups (71%) to the hydroxyl groups. However, treatment of polymer P29’ with excess of methyl sulfate could lead to the

1264

D.-W. Zhang et al. Me

Me

O

4% LiCl PPh3, NMP

HO

NH2 O

HO

110 °C, 6 h

N H

O MeO

OMe 28

H

O

H N H 0.71n

0.29n

P29'

Me

Me O

Me2SO4 K2CO3, DMF

O N

Me 60 °C, 12 h

O

O H Me

O Me OMe

N H

Me n-2

O Me

NMe2

P29

Fig. 12 The synthesis of polymer P29 from 28 through polymer P29’ as a polymeric intermediate

methylation of the hydroxyl groups, as well as the free amino group, to yield the originally designed polymer P29. The number-average molecular weight (Mn = 2.43 KD, PDI = 1.47) of polymer P29 was apparently lower than that of polymer P29’ (Mn = 3.75 KD, PDI = 1.72), which was attributed to the linear conformation of the former polymer due to the different hydrogen-bonding motif of the hydroxyl group [4]. As expected, polymer P29 was revealed to adopt a helical conformation. Zeng et al. established that, for this family of linear aromatic amides, five benzene segments form one turn. Thus, the above molecular weight of polymer P29 showed that the backbone had about three helical turns and a cavity depth of 1.1 nm, by assuming an average pitch of 3.5 Å. Because the intramolecular hydrogen-bonded segments are located inward, helical polymer P29 has a very small cavity. However, chiral R- and S-1-phenylethan-1-amine (30) still could induce it to exhibit helical handedness by forming intermolecular hydrogen bonding, which was proposed to take place at the two ends of the polymer helix. Typically, the aromatic units of amide oligomers and polymers are all intramolecularly hydrogen bonded to induce the backbones to form stable folded or helical conformations. To exploit the effect of other interactions, Zhu et al. prepared polymer P33 from 31 and 32 (Fig. 13) [30]. The alkoxy groups on the isophthalamide units form stable intramolecular six-membered N-HOR’ hydrogen bonding, whereas the 3,5-diaminobenzamide moieties may only form intermolecular hydrogen bonding. Thus, the polymer was envisioned to undergo solvent-dependent folding. The number- and weight-average molecular weights (Mn and Mw) of the crude polymer, obtained by evaporating the reaction mixture, were evaluated to be 2.17 and 1.47 KD by GPC, while its high molecular weight dispersity was determined to be 6.80, which indicated a wide distribution of lengths. The crude polymer was further treated by repeated dissolution in chloroform and precipitation in ethanol. In this way, three fractions were obtained as polymers P33a-c, the Mn’s of which were determined to be 35.1, 18.6, and 10.2 KD, respectively, and

44

Molecular Recognition with Helical Receptors

1265 O

NHR

NHR

O

R'O + H2N

NH2 31 R=

OR'

Cl

NEt3, DMA

Cl 0 °C to r.t., 8 h O

32

O H

O

R' =

O

N H

N H

O R' P33a: 18 turns P33b: 9 turns P33c: 5 turns

O OH OR' n

Fig. 13 The coupling of 31 and 32 to afford polymers P33a–c

corresponded to a helix of 18, 9, or 5 turns. 1H NMR dilution experiments in CDCl3 indicated that the side-chain amide units formed cross-turn hydrogen bonding to stabilize the helical conformation. The CD spectra of polymers P33a-c in chloroform all exhibited strong positive and negative Cotton effects at 275 and 300 nm, and the intensity was correlated with the molecular weight. Thus, all the three fractions formed a helical conformation of twist-sense bias, which was attributed to the cooperative induction of the chiral side chains. Zhao et al. showed that, in the absence of stable intramolecular hydrogen bonding, 3- to 13-mer aromatic amide oligomers did not form folded or helical conformation in organic solvents [31]. To test if solvophobicity was able to drive aromatic amide polymers to fold, Li et al. prepared polymer P34 from the coupling of the corresponding diamine and diacid precursors [32]. This polymer was soluble in both water and all organic solvents studied due to the introduction of the tetraethylene glycol side chains. Its Mn and Mw were determined by GPC to be 32.0 and 59.0 KD, respectively, which pointed to a weight dispersity of 1.8. By assuming six aromatic units forming one turn, the Mn value suggested the formation of a helix of nine turns with a depth of ca. 3.1 nm (Fig. 14), whereas molecular dynamics modeling revealed the cavity had a size of 1.3 nm. The fluorescent spectra of polymer P34 in water and nine organic solvents of varying polarity revealed that it folded into a tubular helix in all the solvents. Solvophobicity and cross-turn hydrogen bonding should contribute to stabilize the helix. Treatment of the polymer with methyl iodide afforded polymer P34’, which contained approximately 90% of methylated amide units. Fluorescence experiments showed that, in polar organic solvents like methanol, this N-methylated polymer still could fold into a helical conformation, which should be mainly driven by solvophobicity. Polymer P35 was also prepared to test whether it could be induced by a guest to form a helical conformation [33]. Its Mn and Mw were determined by GPC to be 8.6 and 16.0 KD, respectively, which corresponded to the weight dispersity of 1.86 and a helix of four turns. 1H NMR in CDCl3 showed that this polymer formed multiple intermolecular N-HO and C-HO hydrogen bonds with racemic dianionic aspartate 36. The fluorescence of polymer P35 in chloroform exhibited the excimer emission of the naphthalene unit around 460 nm. Adding 36 to the solution caused the excimer emission to increase and approximately 8 equivalents of 36 led to

1266

D.-W. Zhang et al.

a

b

Fig. 14 (a) Side and (b) top view of the optimized right-handed helix formed by polymer P34 of 54 subunits. The long side chains were replaced with methyl groups for clarity. (Reproduced with permission from [32]. Copyright 2015, RCS)

maximum emission, whereas control compound 37 of the identical concentration of the naphthalene unit (30 μM) did not exhibit similar excimer emission without or with the addition of 36. Thus, it was proposed that in chloroform 36 could induce polymer P35 to form a helical conformation through intermolecular hydrogen bonding. This compact helical conformation facilitated the excimer emission of the naphthalene units through cross-turn stacking, whereas 8 equivalents of 36 caused full folding of the backbone. The CD spectra of the mixture of polymer P35 and enantiomeric L- and D-36 in chloroform exhibited large Cotton effects of rough mirror symmetry, supporting twist-sense bias of the induced helical conformation. In accordance with the above fluorescence enhancement, the Cotton effects reached maximum after about 8 equiv. of the chiral guest was added, supporting that polymer P35 already formed a fully folded helix. When the spectra were recorded for the mixture of polymer P35 and 36 with increased enantiomeric excess (ee) of the latter, the Cotton effects were nonlinearly enhanced with the increase of the ee of 36, and 70% ee led to maximum Cotton effect. Thus, the induction of the twist-sense bias of the helix obeyed the so-called majority role.

44

Molecular Recognition with Helical Receptors

O

1267

NR2

O

H N O

O P35

H N

NR2 H N

HO n

O

R = (CH2CH2O)4Me

NH2

O 37

To explore new strategies of controlling the hollow helical conformations of aromatic amide polymers, Li et al. prepared R- and S- polymer P38 from the coupling reaction of the chiral precursor (R- or S-) 39 and 2,20 -bipyridine (BIPY)-4,40 -dicarboxylic acid 40 [34]. The long flexible amphiphilic side chains provided the polymers with highly soluble in water as well as organic solvents. The Mn and Mw of the two polymers were determined by GPC to be 5.9 and 6.0 KD and 9.3 and 9.4 KD, respectively, which corresponded to a weight dispersity of 1.57 and 1.55 and a DP of ca. 22. In organic solvents, their CD spectra displayed no or very weak Cotton effects. However, in water both polymers exhibited strong positive or negative Cotton effect within 250 nm and 350 nm. As expected, chiral control compound R- or S-39 did not. These observations indicated that the two polymers formed a helical conformation in water with important twist-sense bias, which was expected to be driven hydrophobically because the high polarity of water should not allow the formation of important cross-turn hydrogen bonding. To avoid electrostatic repulsion of the two nitrogen atoms, the BIPY units in the polymer should exist in the anti-configuration, which enabled a large cavity of 2.5 nm, while the DP of 22 could produce a helix of about 3.5 turns. Adding Ni2+ (as ClO4 salt, 1.0 equivalent relative to [BIPY]) to the aqueous solution of R-polymer P38 led to the inversion of the CD signals. This process took about 12 h to reach equilibrium, reflecting the stability of the helical conformation. Ni2+-N(BIPY) coordination-induced formation of another helical conformation of small cavity was proposed to account for the helicity inversion (Fig. 15). Adding 1.0 equivalent of ethylenediaminetetraacetate (EDTA) sodium could recover the original spectrum due to its increased ability for complexing Ni2+.

44.4

Aromatic Hydrazide Polymers

Meta-phenylene-derived aromatic hydrazides have planar rigid conformation and are good segments for the construction of hydrogen-bonded foldamers that form a large cavity of about 1 nm inner diameter [35]. Zhang et al. further prepared water-soluble polymers P43a–c from the coupling reaction of monomers 41a,b and 42a,b (Fig. 16) [36]. These polymers have a Mn value of 14.4, 12.2, and 7.2 KD, respectively, and a Mw value of 31.2, 31.1, and 2.1 KD, respectively, which corresponded to an average length of 26, 24, and 14 aromatic segments and 4.3, 4.0, or 2.3 turn, respectively, for a helical conformation. The repeated benzene rings of polymers P44a–c bear three, two, or one chiral side chains. The intramolecular six-membered hydrogen bonds of benzene A

1268

D.-W. Zhang et al. O O

NR2

R = (CH2CH2O)4Me

NH

O

NR2 NH

O N

O *

N H

N H

* N

O

H 2N

n R- and S-P38

O NH

R2N

NH R2N NH

O

O

O O

NH

O R2N

N

H N

NH

O

O

NH

N

N H

N H N

H N

N O

O

HN

HN

N

O N

O

N H

N

N

Ni2+

O

EDTA

Ni2+

N

N

O

HN

O

O

NH O

N H

N

NH

O

O N

O

NH

O

NR2 O

NR2

NH

N

O

R-and S-39

N

O

O

NH2

H N O

Ni2+ N

H N O O

HN O

HN O

NR2

NR2

O NR2

Fig. 15 Ni2+ and EDTA-tuned conversion of two helical conformations of polymer P38 in water

H2N

H N

R1 O

R1 O

OR2 H N

+ NH2

P(OPh)3, NMP, LiCl, Py HO

O 41a,b O

O N H

H N

R1 O

R1 O A

O

O

H N

O

42a,b

120 °C, 42 h

O

P43a: R1 = R2 =

O N H

OH

B OR2

n

P43b: R1 = P43c: R1 =

OMe

O

4

O

OMe R2 =

O

4

O 4 Me

R2 =

O

4 Me

OMe 4

Fig. 16 The synthesis of polymers P43a–c from the coupling reaction of precursors 41a,b and 42a,b

favored the formation of helical conformation. In polar organic solvents such as methanol or acetonitrile, all the polymers formed helical conformation. However, the helical conformation did not exhibit twist-sense bias. In water their CD spectra exhibited one bisignate Cotton effect and thus twist-sense bias, which should be induced by the chiral side chains. The twist-sense bias of polymers P43a and P43b was quite

44

Molecular Recognition with Helical Receptors

1269

comparable and greater than that of polymer P43c, which was consistent with their higher percentage of chiral side chains and suggested that the chiral side chains on the 5postion of benzene B contributed little in inducing the twist-sense bias. Dong et al. prepared polymer P44a from the corresponding dialdehyde and diacylhydrazine precursors [37]. The Mn of this hydrazone-derived polymer was determined by GPC to be 31 KD. The intramolecular N-HN and C-HN hydrogen bonds and the electrostatic repulsion between the imine and connected pyridine nitrogen atoms induced the backbone to adopt a tubular helical conformation of 1.0 nm cavity diameter. The hollow helix was found to catalyze the oxidation of benzenethiol into diphenyl disulfide in the presence of hydrogen peroxide. The polar microenvironment inside the helical backbone was proposed to enable the catalysis. The aldehyde units at the end of the backbone were further treated with chiral amine R- or S-30 to form the related imine bonds. With the introduction of the chiral group at the ends, the resulting polymers P44b and P44c gave rise to strong induced CD signals, suggesting the formation of important twist-sense bias.

O N

H

N

OR

OR

N

N HN

Me

H

O N

34

P44a: R = O

N

N

N

N

N O

NH

R

Me N

N

OR

OR

O

P44b: R =

NH

P44c: R =

NH

R = n-C12H25

Hou et al. prepared polymer P45 which bears tripeptide side chains that promote their ability of inserting membranes [38]. The molecular weight of this polymer was approximately 15.8 KD, which corresponded to DP of about 10 and 3.5 helix turns. The helical backbone of this polymer was found to be able to insert into lipid bilayers. The resulting unimacromolecular channels exhibited an NH4+/K+ selectivity that was higher than that of natural gramicidin A. Patch clamp experiments revealed that channels formed by polymer P45 were of long open duration. The varying length of different polymeric components led to a trace of multiple currents, whereas oligomers and macrocycles with the same repeat segments and peptide side chains produced only one conductance state. It was proposed that, for both polymeric and molecular channels, the tripeptide side chains converged on the two sides of the backbones to form deformable pores, which enabled good to high transport selectivity for different ions.

1270

D.-W. Zhang et al.

O RO

H

N

O N

H

O N H N H OR Me

O RO H O

N N

O

O

O P45 (n = 9)

H OMe

H N

R=

CO2H

44.5

n

O

OR H

N NH2 O N H Ph

Ph H N

O OH

O

Ph

Aromatic Urea Polymers

Meijer et al. prepared polymers P46a–c from the reactions of the corresponding ureidophthalimide diamines and diisocyanates [39]. These polymers bear chiral side chains of different polarity and stacking tendency. The crude polymer P46a was separated by column chromatography to divide into high, intermediate, and low molecular weight fractions. In THF, the high molecular weight fraction (n = ~30) could fold into a chiral helical structure, whereas the intermediate molecular weight fraction (n = ~7) showed a minor Cotton effect in the CD spectrum. These results were consistent with that these two fractions formed helical states of more than one pitch, which allowed chirality transfer from the CD-silent peripheral side chains to the accurately positioned, CD-active phthalimide chromophores. Molecular modeling showed that the helix created a cavity of ca. 1.4 nm.

O O Ar

N

H N

Ar N

H N

OR O

a: Ar =

N

O

O

H N n-4

O

OR N

H N

O N H

OR R =

N H

N O

O

O

Me 4

OR

N H O

O

b: Ar =

O P46a-c

O N

OR

N H O

Ar

Ar O

O

H N

OR R =

H

Ar

O

c: Ar =

OR OR O R = n-C12H25

OR

44

Molecular Recognition with Helical Receptors

1271

Polymer P46b [40], with a DP of about 20, bears chiral oligo(glycol) side chains and thus was soluble in both water and THF. Its CD spectra in water exhibited a Cotton effect that was independent of temperature or concentration within the studied range, supporting the formation of a very stable helical conformation of twist-sense bias. Both intramolecular hydrogen bonding and cross-turn stacking were proposed to stabilize the chiral helix. The polymer also gave rise to a helix in THF. However, the sign of its bisignated Cotton effect was opposite to that in water. Polymer P46c bears large oligo( p-phenylene vinylene) (OPV) chromophores, which possess strong stacking tendency and short chiral aliphatic chains. The crude polymer product was separated by column chromatography to longand short-chain fractions. The OPVs of the long-chain sample was revealed to arrange helically in THF, but not in chloroform. In apolar heptane, the CD spectrum of a sample with a THF history exhibited a bisignate Cotton effect, whereas the sample with a chloroform history did not, which indicated that the original solvent dictated the expression of supramolecular chirality in the helical conformation.

44.6

Aromatic Triazole Polymers

Inter- and intramolecular hydrogen bonding can induce meta-phenylene-linked 1,2,3-triazole oligomers to fold into compact conformations [10, 41]. Hecht et al. prepared polymers P47a and P47b which consisted of 1,2,3-triazole and pyridine units alternately [42]. Due to the dipole of the triazole and pyridine units, the triazole-pyridine repeat units have a strong preference to adopt an anti-anti conformation. Thus, both polymers adopted the helical conformation in acetonitrile and the chiral side chains were able to induce twist-sense bias for the helical structures. It was also found that transition metal ions such as Fe3+ could lead to coordinative cross-linking of the backbone, which resulted in the gelation of its acetonitrile solution. R'

N N N N

N

N

n

N N

R

O

N N N

O

R

n OR"

P47a: R' = R" = (OCH2CH2)3OMe P47b: R' = CO2(CH2CH2O)3Me R" = (OCH2CH2)3OMe

NH2

O S-, or R-P48a: R =

O

O(CH2CH2O)3Me

O P48b: R = O(CH2CH2O)6Me

Klumperman et al. reported that para-phenylene-linked S- and R- polymers P48a and P48b prevailed as random, flexible coils in N,N-dimethyl formamide (DMF) [43]. In binary DMF and water (>10%), S- and R-polymers P48a could fold into the

1272

D.-W. Zhang et al.

helical conformation, and 28% of water caused intact stacking and stable helical conformation, as indicated by the CD spectra, which exhibited water contentdependent Cotton effect. Molecular modeling study showed that about 14.5 repeat units formed one turn, which had a large internal diameter of ca. 31.6 Å (Fig. 17). The longer side chains in polymer P48b provided high water solubility. Its coil-tohelix transition midpoint occurred at 19% H2O. With the increase of water content (>40%), the helical structure further stacked to produce higher-order nanotubes. The diameter of hydrophobic poly(γ-benzyl-L-glutamate) (PBLG) α-helix, which has a diameter of about 1.6 nm, matched well with the calculated helical cavity of the helix of polymer P48b. CD spectroscopy revealed that chiral information transfer of chiral PBLG to achiral polymer P48b took place in the binary medium, starting at 18% H2O, which was attributed to the encapsulation of PBLG by the helical nanotube of polymer 48b.

44.7

Aromatic Oxadiazole Polymers

Dong et al. prepared polymers P49a–c and chiral S- and R-polymers P50 which consisted of alternately linked 1,3,4-oxadiazole and pyrido[3,2-g]quinolone segments [12]. Polymer P49a had a DP of up to 30. Its Mn and PDI were estimated to be 6000 and 1.16, respectively. Scanning tunneling microscopy images showed that all the polymers underwent intramolecular stacking into small helical structures, with a diameter of ca. 0.55 nm. CD studies in dichloromethane showed that the helix of S- and R-polymers P50 exhibited twist-sense bias. These two chiral helices could also assemble to form double helix, which exhibited supramolecular chirality that was different from that observed for the single helix.

Fig. 17 Calculated helix formed by polymer P48 series. (Adapted with permission from [43]. Copyright 2013, Wiley)

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Molecular Recognition with Helical Receptors

N N

RO

O N

RO N O

X

Me

1273

OR

n

P49a: R = i-Bu, X = OH P49b: R = n-C12H25, X = OH (n ≈30) OR P49c: R = n-C12H25, X = OH (n ≈ 13)

N Me

N X

S- and R-P50: R = i-Bu, X = O

N H

The long n-dodecyl side chains of polymers P49b and P49c provided good solubility in organic solvents [44]. Polymer P49b had a Mn of 18700 and an PDI of 1.21. The Mn value corresponded to about 3.3 nm of depth for its helical conformation, which is longer than naturally occurring peptide gramicidin A dimer. This helix was found to be able to span lipid bilayers to produce unimacromolecular channels of extraordinary stability, long lifetime, and high transporting efficiency for protons and cations. The shorter polymer P49c formed channels through dimerization, which was similar to natural gramicidin A. Both polymers exhibited high selectivity for H+ over alkali cations. For both unimacromolecular and dimeric channels, the ions transport took place through the interior of their helical conformation. Different from the polymers, oligomers of the same backbone were found to selectively transport K+ over Na+ [45]. Concerning the synthesis of new backbones, this oxadiazole-based strategy has been extended to other systems [46].

44.8

Conclusion and Prospects

This chapter summarizes the advance of the construction of aromatic polymeric helices and their applications in molecular recognition. The rigidity of the aromatic enables defined inner diameter of such helical tubes, whereas the long polymeric backbones allow for the formation of deep hollows or pores. Currently, the function investigations for such kind of unimacromolecular structures have mainly focused on their encapsulation for small ions or molecules. One conceptual extension of such function is to exploit the entrapment of long oligomeric or even polymeric guests. Molecular and supramolecular capsules have been an important topic in molecular recognition. The long tubular cavity of polymeric helices also provides new confined space for hosting more than one guest. Studies along this line may lead to new interesting binding selectivity. In the category of transmembrane transport, several structures have demonstrated their efficiency and selectivity. Further modification of the backbones and incorporation of the backbones into two-dimensional systems may lead to new transport or separation materials.

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25. Wang S, Zeman CJ, Jiang J, Pan Z, Schanze KS (2017) Intercalation of Alkynylplatinum(II) Terpyridine Complexes into a Helical Poly(phenylene ethynylene) Sulfonate: Application to Protein Sensing. ACS Appl Mater Interfaces 9:33461 26. Maeda K, Hong L, Nishihara T, Nakanishi Y, Miyauchi Y, Kitaura R, Ousaka N, Yashima E, Ito H, Itami K (2016) Construction of Covalent Organic Nanotubes by Light-Induced CrossLinking of Diacetylene-Based Helical Polymers. J Am Chem Soc 138:11001 27. Zhang C, Shoji Y, Higashihara T, Tsukuda A, Ochi T, Ueda M (2011) Synthesis of poly (m-phenyleneisophthalamide) by solid-state polycondensation of isophthalic acid with m-phenylenediamine. J Polym Sci Part A Polym Chem 49:4725 28. Garcia JM, Garcia FC, Serna F, de la Pena JL (2010) High-performance aromatic polyamides. Progr Polym Sci 35:623 29. Lu YX, Shi ZM, Li ZT, Guan Z (2010) Helical polymers based on intramolecularly hydrogenbonded aromatic polyamides. Chem Commun 46:9019 30. Cao J, Kline M, Chen Z, Luan B, Lv M, Zhang W, Lian C, Wang Q, Huang Q, Wei X, Deng J, Zhu J, Gong B (2012) Preparation and helical folding of aromatic polyamides. Chem Commun 48:11112 31. Xu YX, Zhan TG, Zhao X, Li ZT (2014) Hydrogen bonding-driven highly stable homoduplexes formed by benzene/naphthalene amide oligomers. Org Chem Front 1:73 32. Zhang P, Zhang L, Wang H, Zhang DW, Li ZT (2015) Helical folding of an arylamide polymer in water and organic solvents of varying polarity. Polym Chem 6:2955 33. Zhang P, Zhang L, Wang ZK, Zhang YC, Guo R, Wang H, Zhang DW, Li ZT (2016) GuestInduced Arylamide Polymer Helicity: Twist-Sense Bias andSolvent-Dependent Helicity Inversion. Chem Asian J 11:1725 34. Zhang P, Wang Z, Zhang L, Wang H, Zhang D, Hou J, Li Z (2016) Aromatic Amide Polymers that Form Two Helical Conformations with Twist Sense Bias in Water. Chin J Chem 34:678 35. Hou JL, Shao XB, Chen GJ, Zhou YX, Jiang XK, Li ZT (2004) Hydrogen Bonded Oligohydrazide Foldamers and Their Recognition for Saccharides. J Am Chem Soc 126:12386 36. Guo R, Zhang L, Wang H, Zhang DW, Li ZT (2015) Hydrophobically driven twist sense bias of hollow helical foldamers of aromatic hydrazide polymers in water. Polym Chem 6:2382 37. Li W, Zhang C, Qi S, Deng X, Wang W, Yang B, Liu J, Dong Z (2017) A folding-directed catalytic microenvironment in helical dynamic covalent polymers formed by spontaneous configuration control. Polym Chem 8:1294 38. Xin P, Zhu P, Su P, Hou JL, Li ZT (2014) Hydrogen-Bonded Helical Hydrazide Oligomers and Polymer That Mimic the Ion Transport of Gramicidin A. J Am Chem Soc 136:13078 39. Sinkeldam RW, Hoeben FJM, Pouderoijen MJ, De Cat I, Zhang J, Furukawa S, De Feyter S, Vekemans JAJM, Meijer EW (2006) Chiral Alignment of OPV Chromophores: Exploitation of the Ureidophthalimide-Based Foldamer. J Am Chem Soc 128:16113 40. Sinkeldam RW, van Houtem MHCJ, Pieterse K, Vekemans JAJM, Meijer EW (2006) Chiral Poly(ureidophthalimide) Foldamersin Water. Chem Eur J 12:6129 41. Liu YH, Zhang L, Xu XN, Li ZM, Zhang DW, Zhao X, Li ZT (2014) Intramolecular C–H  F hydrogen bondinginduced 1,2,3-triazole-based foldamers†. Org Chem Front 1:494 42. Meudtner RM, Hecht S (2008) Responsive Backbones Based on Alternating Triazole-Pyridine/ Benzene Copolymers: From Helically Folding Polymers to Metallosupramolecularly Crosslinked Gels. Macromol Rapid Commun 29:347 43. Pfukwa R, Kouwer PHJ, Rowan AE, Klumperman B (2013) Templated Hierarchical SelfAssembly of Poly(p-aryltriazole) Foldamers. Angew Chem Int Ed 52:11040 44. Lang C, Li W, Dong Z, Zhang X, Yang F, Yang B, Deng X, Zhang C, Xu J, Liu J (2016) Biomimetic Transmembrane Channels with High Stability and Transporting Efficiency from Helically Folded Macromolecules. Angew Chem Int Ed 55:9723 45. Lang C, Deng X, Yang F, Yang B, Wang W, Qi S, Zhang X, Zhang C, Dong Z, Liu J (2017) Highly Selective Artificial Potassium Ion Channels Constructed from Pore-Containing Helical Oligomers. Angew Chem Int Ed 56:12668 46. Wang W, Zhang C, Qi S, Deng X, Yang B, Liu J, Dong Z (2018) A Switchable Helical Capsule for Encapsulation and Release of Potassium Ion. J Org Chem 83:1898

Supramolecular Interface for Biochemical Sensing Applications

45

Xu Yan, Wenwei Pan, Hemi Qu, and Xuexin Duan

Contents 45.1 45.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Supramolecular Interface for Gas Sensor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.2.1 Cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.2.2 Calixarenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.2.3 Cavitands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.2.4 Cryptophane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.2.5 Supramolecular-Based Sensor Array . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.3 Supramolecular Interface for Ion Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.3.1 Crown Ether . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.3.2 Cyclodextrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.3.3 Calixarene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.3.4 Pillararenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.4 Supramolecular Interface for Protein and DNA Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.4.1 Protein Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.4.2 DNA Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45.6 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45.1

1277 1278 1282 1286 1290 1292 1295 1297 1297 1300 1301 1301 1303 1303 1309 1309 1311 1311

Introduction

Biochemical sensing represents one of crucial technologies that will have dramatic influence on our society, which has been widely used in environmental monitoring, industrial quality control, and point-of-care diagnostics. Accordingly, the demand of reliable sensors for the rapid, sensitive, and specific detection of various analytes both in vapor and liquid phase is quite urgent. This requires a successful integration X. Yan · W. Pan · H. Qu · X. Duan (*) Tianjin University, Tianjin, China e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_52

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Fig. 1 Operating principle of supramolecular-based sensors

of sensitive materials and transduction devices. Inspired by the wisdom of biological system in nature, chemists developed a supramolecular system that mimics the exquisite specific behavior of biological receptors, exploiting the concepts of shape recognition and binding site complementarity. In recent years, many groups have approached biochemical sensing with these macrocycles, mainly using crown ether, cyclodextrins, calixarenes, pillararenes, cavitands, cryptophanes, etc. All these classes of compounds share the presence of an enforced cavity of molecular dimensions which acts as molecular recognition site for the incoming analytes. The majority of supramolecular-based sensors contain a macrocycles sensitive layer tunable for the detection of different analytes and a transducer which can transform these biochemical interactions into a readable signal (Fig. 1).

45.2

Supramolecular Interface for Gas Sensor

Chemical detection in the vapor phase is critical in many fields, including pharmaceuticals [1], foods [2], the environment [3], the security [4], and the petroleum industry [5]. While benchtop equipment is the workhorse in the lab-based analysis, chemical vapor sensing technology is the most promising method to address these needs in the field. Chemical vapor sensors have demonstrated several favorable characters for field application, such as low cost, minimal personnel, small size, and remote control. The majority of chemical vapor sensors are composed by the transducer and the sensitive layer. The sensors work by the interaction of vapor analyte with sensitive materials, which lead to the materials property variations. Such variations are then transformed into readable signals by transducers. The optimal sensor performance, in terms of sensitivity and selectivity, is the result of comprehensive considerations in both transducing modes and sensitive layers. Current chemical vapor sensors are frequently troubled with false-positive and falsenegative signals. The origin of such troubles comes from the lack of sensor selectivity, which is directly related with sensitive materials. Supramolecular materials, such as cyclodextrins, calixarenes, and cavitands, have been extensively studied for selective sensing in the vapor phase. Those

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supramolecular macrocycles are regarded as synthetic receptors with tunable cavities for host-guest specific interactions being similar with receptors in biological system like enzyme-substrate and antigen-antibody. For example, phosphonate cavitands have demonstrated to be selective toward low-chain alcohols with the synergistic presence of H-bonding and CH-π interactions within the rigid cavity [6]. Being different from biological system in the solution, where nonspecific interaction is alleviated due to the presence of solvent, gas sensors with supramolecular macrocycles interact with vapor analyte in the gas-solid interface, where the analyte experiences a dramatic increase in nonspecific dispersion interactions when moving from vapor to the condensed phase. Therefore, enabling selectivity of supramolecular macrocycle toward analytes in the vapor phase requires that the specific hostguest interaction overwhelms nonspecific interactions. The weak interactions between supramolecular macrocycles and analytes can be summarized in the linear sorption energy relationship equation (LSER) [7], which indicates the sorption behavior of supramolecular macrocycles sorbent layer toward different analytes: H H 16 log K p ¼ rR2 þ sπ H 2 þ aα2 þ bβ 2 þ l log L þ c 16 H H where Kp is the layer coefficient partition and rR2, rπ H 2 , aα2 bβ2 , and l log L are solvation parameters for characterizing the solubility properties of the vapor in the H sorption layer. The rR2 provides an indication of polarizability. The aαH 2 and bβ2 are H related with hydrogen-bond basicity and acidity. The sπ 2 is related to the sorbent phase dipolarity/polarizability. The l log L16 is related to dispersion interactions. The term c is a constant obtained in linear regression. The first four terms are relative to specific binding modes, and the term l log L16 characterizes the nonspecific dispersion interaction. Besides the supramolecular recognition system, the choice of transducer is also highly critical to the sensor performance. Acoustic wave transducers are the main component of the supramolecular-based sensors for gas sensing owing to their high level of sensitivity as well as working without the need of extra receptor derivatization. When exposed to analytes, the mass accumulation on these devices surface leads to a frequency decrease which is proportional to the mass change. This is the basis for detection of VOCs and can be quantitative according to Sauerbrey’s equation [8]:

Δf ¼

2Δmf 0 2 pffiffiffiffiffi A ρμ

where Δf denotes the frequency shift induced by the mass accumulation, f0 is the fundamental operating frequency of the acoustic wave devices, Δm presents the mass change during the exposure, A is the surface area for effective sensing, ρ is the density of the material, and μ is the Young’s modulus of the device along the direction of acoustic wave propagation. It is clear that better sensitivity is available by the enhancement of f0.

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According to the direction and depth of acoustic wave propagation, these transducers can be broadly classified into two categories: bulk acoustic wave (BAW) and surface acoustic wave (SAW) devices [9]. Quartz crystal microbalances (QCMs), with a thickness shear mode (TSM) acoustic wave propagates into the bulk medium, are the most widely used BAW devices as mass sensitive sensors [10, 11]. They are composed of a bulk piezoelectric layer (quartz crystal) in the middle and two gold electrodes on both top and bottom side (Fig. 2a). The operating frequency of QCM is general 5–20 MHz, and their sensitivity is closely related to the thickness of quartz crystal plates. As the development of thin film technology, the emergence of film bulk acoustic resonators (FBARs) with higher frequency (from sub-GHz to tens of GHz) can satisfy the requirement of enhanced sensitivity. A typical FBAR device shows a sandwiched structure which consists of a thin piezo-electric layer (aluminum nitride (AlN) or zinc oxide (ZnO)) and two gold electrodes (Fig. 2b). The application of an electrical signal across the electrodes generates a thickness longitudinal mode (TLM) wave by the piezoelectric layer, and this acoustic wave can be isolated by the air cavity beneath the AlN film. FBAR has recently been extensively investigated for gas sensing applications because of the advantage of ultrahigh sensitivity as well as being several orders of magnitude smaller than QCM [12–14]. Moreover, piezotransduced silicon bulk acoustic wave resonators (PSBARs) are also a type of thin film BAW resonators (Fig. 2c), providing independent multimode resonances frequency ranging from tens to hundreds MHz. Zhao et al. used PSBAR as a virtual sensor array (VSA) for the discrimination of VOCs [15, 16]. In comparison with the BAW transducer, the acoustic wave in SAW device propagates along the surface and penetrates to only one acoustic wavelength depth into the surface [9]. Most of SAW devices are based on the Rayleigh mode, which can be divided into longitudinal and vertical shear modes. SAWs are fabricated on a piezoelectric substrate with a fundamental frequency from 80 MHz to 1 GHz, and their sensitivity depends on the structure and size of the comblike interdigitated transducers (IDTs) (Fig. 2d). Love mode SAW is another transducer based on the typical shear horizontal SAW (SH-SAW) device. A wave-guiding layer which has a very low acoustic velocity is added on the surface of the SH-SAW to trap the acoustic waves (Fig. 2e). As a result of this waveguide effect, an obvious sensitivity improvement for gas sensing is achieved by this design [17, 18]. The performance in sensitivity of the different acoustic wave transducers versus their common operational frequency ranges is illustrated in Fig. 3. In addition, surface plasmon resonance (SPR) can also be implemented with supramolecular compounds for safe, remote, and nondestructive means of gas sensing [19]. The setup for SPR measurement is based on Kretschmann configuration where a sensing layer and a prism are placed on either side of the metal layer (Fig. 4). SPR is a strong coupling phenomenon between the light and plasmon waves, and it results in a loss of energy and therefore a reduction in the intensity of the reflected light which is measured by a CCD chip. An evanescent electrical field associated with the plasma wave travels for a short distance into the medium from the metallic film. Consequently, the SP (surface plasmon) is sensitive to changes in the environment near the interface, which allows vapor detection at

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Fig. 2 The schematic of acoustic wave transducers: (a) QCM, (b) FBAR, (c) PSBAR, (d) SAW, and (e) Love wave device

ppb levels using thin films as receptor layers. Hence, when a sensing layer of receptors deposited on the metal film is exposed to a gaseous analyte, the molecular recognition process induces a change in the refractive index providing a selective signal for the receptor-analyte interaction [20]. The SPR method is found to be more attractive for studying adsorption behavior of organic molecules in supramolecular

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Fig. 3 Performance in sensitivity of acoustic wave transducers versus their operating frequency

Fig. 4 The schematic of the SPR transducer

films, and supramolecular-coated SPR transducers are also promising gas sensors with the advantages of high sensitivity and drastic reduction in nonspecific interactions [21–23].

45.2.1 Cyclodextrins Cyclodextrins (CDs), including six (α-CD), seven (β-CD), and eight (γ-CD) glucose moieties (Fig. 5), are natural oligosaccharides with rigid units in torus shape. The hydrocarbon walls of inner cavity are well suited for vapor detection at the solid-gas interface, where the recognition is driven by size fit and van der Waals interactions. On the other hand, the hydroxyl groups at cavity rims are highly tunable by chemical modification which affects the flexibility and geometry of the ring [24–26]. In their pioneering work on vapor detection using CD derivatives, Stoddart et al. [27] coated piezoelectric crystal transducers with three chemically modified cyclodextrins, namely, DSαCD, DAαCD, and DMβCD-B7 (Fig. 6a). Among those three supramolecular compounds, DSαCD was found to be the best for the detection of benzene in the concentration range between 0.08 and 400 mg/dm3. Moreover,

O

HO

O OH

OH

HO

O

O

HO

OH

O

OH

a-CD

OH

O

OH

HO

OH

O

OH

O

OH

O

O

OH

HO

O

HO

O OH

OH

O OH

HO

O

Fig. 5 Structural formulas of the α-CD, β-CD, and γ-CD

HO

O

O OH

HO

OH

HO

O

O OH

OH

O

b-CD

OH HO

O

HO

OH O

O

OH

OH OH O

OH

O

OH

OH O

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OH

OH HO

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OH O OH

O OH

HO

OH

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OH

HO

O O HO

OH

O

OH

Y-CD

OH

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OH

OH

OH O

OH

HO

OH O

O

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OH O OH

O

OH

OH

45 Supramolecular Interface for Biochemical Sensing Applications 1283

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b

a

NH

OR6

N

O R3O OR2 O n n

R2

R3

R6

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6

TBDMS

H

TBDMS

DAaCD

6

CH2CH=CH2

H

CH2CH=CH2

DMbCD-B7

7

Me

PhCO

Me

mono(6-phenylamino6-deoxy)-b-cyclodextrin (1)

NH

NH

mono(6-cyclohexylamino6-deoxy)-b-cyclodextrin (3)

mono(6-benzylamino6-deoxy)-b-cyclodextrin (4)

d

c 220 200

100 compound 1 compound 2 compound 3 compound 4

180 160 140

a)

50 0

b)

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Frequency shift/Hz

mono(6-benzylimino6-deoxy)-b-cyclodextrin (2)

80 60

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c)

–150

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CLF

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Δf [kHz]

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–60 –80 –100

30

–120 –140

20

0

time [s] 10

80

301 433

1000 f0 [MHz]

Fig. 6 (continued)

200

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the response of DSαCD modified sensor to toluene was much smaller than that of benzene ( 0.05; **: 0.05 < p  0.01; ***: p  0.001)

OH

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RO

d) NaOMe (cat.), MeOH

HO

B

A

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rhamnose and IgM. The strategy of using supramolecular assemblies of a saccharide to suppress immunity provided a novel approach for immunomodulation.

53.8

Conclusion

The pioneering works introduced in this tutorial review have demonstrated that selfassembling peptides are powerful nanomaterials for immune modulation, which are very useful for vaccine development and antibody production. However, challenges still remained as formidable tasks. Peptides and proteins are needed to be folded into correct conformation to stimulate specific antibody [40]. While nanomaterials formed by self-assembling peptides are metastable materials [41, 42], their property will be significantly affected by the pathway of preparation [36, 43, 44]. In order to assist peptide folding, the kinetics of peptide self-assembly, pathway to prepare selfassembled nanomaterials, and presence of additives are needed to be screened and optimized. For antibody production, complete Freund’s adjuvant is very powerful but is still unable to enhance the proportion of specialized antibody for phosphorylated and acetylated proteins. Self-assembling peptides may prevent the dephosphorylation and deacetylation of the antigens and therefore specifically evoke antibody production for these proteins. Besides, a perfect mixed of multiple adjuvants may further increase the efficiency of antibody production [45]. Combination therapy will generally lead to better therapeutic effects for cancer treatment. The effect of combination of cancer vaccine with chemotherapy, cell therapy, or other immunotherapy on cancer treatment is worth investigating. Though many challenges remained, we image a brilliant future of self-assembling peptides in the development of novel vaccines and peptide-based therapeutics.

References 1. Plotkin SA (2005) Vaccines: past, present and future. Nat Med 11:S5–S11 2. Rappuoli R, Aderem A (2011) A 2020 vision for vaccines against HIV, tuberculosis and malaria. Nature 473:463–469 3. Germain RN (2010) Vaccines and the future of human immunology. Immunity 33:441–450 4. Reed SG, Bertholet S, Coler RN et al (2009) New horizons in adjuvants for vaccine development. Trends Immunol 30:23–32 5. Bachmann MF, Jennings GT (2010) Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat Rev Immunol 10:787–796 6. Goldberg MS (2015) Immunoengineering: how nanotechnology can enhance cancer immunotherapy. Cell 161:201–204 7. Hu C-MJ, Fang RH, Luk BT et al (2013) Nanoparticle-detained toxins for safe and effective vaccination. Nat Nanotechnol 8:933–938 8. Moon JJ, Suh H, Bershteyn A et al (2011) Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses. Nat Mater 10:243–251 9. Collier JH, Rudra JS, Gasiorowski JZ et al (2010) Multi-component extracellular matrices based on peptide self-assembly. Chem Soc Rev 39:3413–3424 10. Du X, Zhou J, Shi J et al (2015) Supramolecular hydrogelators and hydrogels: from soft matter to molecular biomaterials. Chem Rev 115:13165–13307

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11. Ulijn RV (2015) Molecular self-assembly. Best of both worlds. Nat Nanotechnol 10:295–296 12. Zelzer M, Ulijn RV (2010) Next-generation peptide nanomaterials: molecular networks, interfaces and supramolecular functionality. Chem Soc Rev 39:3351–3357 13. Versluis F, van Esch JH, Eelkema R (2016) Synthetic self-assembled materials in biological environments. Adv Mater 28:4576–4592 14. Tao K, Levin A, Adler-Abramovich L et al (2016) Fmoc-modified amino acids and short peptides: simple bio-inspired building blocks for the fabrication of functional materials. Chem Soc Rev 45:3935–3953 15. Yuan Y, Wang L, Du W et al (2015) Intracellular self-assembly of Taxol nanoparticles for overcoming multidrug resistance. Angew Chem Int Ed 54:9700–9704 16. Zhao F, Ma ML, Xu B (2009) Molecular hydrogels of therapeutic agents. Chem Soc Rev 38:883–891 17. Luo Z, Zhang S (2012) Designer nanomaterials using chiral self-assembling peptide systems and their emerging benefit for society. Chem Soc Rev 41:4736–4754 18. Boekhoven J, Stupp SI (2014) 25th anniversary article. Supramolecular materials for regenerative medicine. Adv Mater 26:1642–1659 19. Wang Y, Cheetham AG, Angacian G et al (2017) Peptide–drug conjugates as effective prodrug strategies for targeted delivery. Adv Drug Deliver Rev 110:112–126 20. Wen Y, Collier JH (2015) Supramolecular peptide vaccines: tuning adaptive immunity. Curr Opin Immunol 35:73–79 21. Rudra JS, Tian YF, Jung JP et al (2010) A self-assembling peptide acting as an immune adjuvant. Proc Natl Acad Sci 107:622–627 22. Chen J, Pompano RR, Santiago FW et al (2013) The use of self-adjuvanting nanofiber vaccines to elicit high-affinity B cell responses to peptide antigens without inflammation. Biomaterials 34:8776–8785 23. Rudra JS, Mishra S, Chong AS et al (2012) Self-assembled peptide nanofibers raising durable antibody responses against a malaria epitope. Biomaterials 33:6476–6484 24. Rudra JS, Sun T, Bird KC et al (2012) Modulating adaptive immune responses to peptide selfassemblies. ACS Nano 6:1557–1564 25. Hudalla GA, Sun T, Gasiorowski JZ et al (2014) Gradated assembly of multiple proteins into supramolecular nanomaterials. Nat Mater 13:829 26. Cui H, Webber MJ, Stupp SI (2010) Self-assembly of peptide amphiphiles: from molecules to nanostructures to biomaterials. Biopolymers 94:1–18 27. Zhu X, Ramos TV, Gras-Masse H et al (2004) Lipopeptide epitopes extended by an Nϵ-palmitoyl-lysine moiety increase uptake and maturation of dendritic cells through a tolllike receptor-2 pathway and trigger a Th1-dependent protective immunity. Eur J Immunol 34:3102–3114 28. Black M, Trent A, Kostenko Y et al (2012) Self-assembled peptide Amphiphile micelles containing a cytotoxic T-cell epitope promote a protective immune response in vivo. Adv Mater 24:3845–3849 29. Manolova V, Flace A, Bauer M et al (2008) Nanoparticles target distinct dendritic cell populations according to their size. Eur J Immunol 38:1404–1413 30. Singh A, Peppas NA (2014) Hydrogels and scaffolds for immunomodulation. Adv Mater 26:6530–6541 31. Bencherif SA, Sands RW, Ali OA et al (2015) Injectable cryogel-based whole-cell cancer vaccines. Nat Commun 6:7556 32. Medina SH, Li S, Howard OZ et al (2015) Enhanced immunostimulatory effects of DNA-encapsulated peptide hydrogels. Biomaterials 53:545–553 33. Tian Y, Wang H, Liu Y et al (2014) A peptide-based nanofibrous hydrogel as a promising DNA nanovector for optimizing the efficacy of HIV vaccine. Nano Lett 14:1439–1445 34. Wang H, Luo Z, Wang Y et al (2016) Enzyme-catalyzed formation of supramolecular hydrogels as promising vaccine adjuvants. Adv Funct Mater 26:1822–1829

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Macrocycle-Based Synthetic Ion Channels

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Harekrushna Behera and Jun-Li Hou

Contents 54.1 54.2 54.3 54.4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ion Channels Developed from Face-to-Face Stacking of Macrocycles . . . . . . . . . . . . . . . . Ion Channels Developed from Columnar Assembly of Macrocycles . . . . . . . . . . . . . . . . . Ion Channels Developed from Tunnel or Pore Type of Cylindrical Molecules by Using Macrocycles as Central Relay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54.5 Ion Channels Developed from Macrocycles Appended with Membrane-Compatible Channel Walls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54.5.1 Resorcin[4]Arene-Based Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54.5.2 Calix[4]Arene-Based Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54.5.3 Cyclodextrin-Based Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54.5.4 Crown Ether Peptide Hybrid Channel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54.6 Ion Channels from Covalent Organic Cages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54.7 Metal Organic Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54.8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54.1

1519 1521 1525 1532 1539 1539 1540 1542 1543 1544 1545 1548 1548

Introduction

Natural ion transporters are membrane-bound proteins that facilitate transport of ions/molecules across the cell membranes. These proteins play a vital role in many complex biological processes such as neuronal proliferation and differentiation, synaptic plasticity, muscular control, regulation of hormonal secretion, electrical excitability and pH values, maintaining osmotic balance, transferring information in the nervous system, cell-to-cell communications, maintaining the cell volume in living organisms, etc. [1–6]. Malfunction of these transporters is closely associated with life-threatening diseases such as Bartter syndrome, Gitelman syndrome, H. Behera (*) · J.-L. Hou Department of Chemistry, Fudan University, Shanghai, China e-mail: [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_64

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deafness, epilepsy, renal tubular acidosis, thyroid diseases, cystic fibrosis, and blindness [2–4, 7–11]. Significant efforts have been devoted to develop transporter replacement therapies that can alleviate the symptoms of channelopathies caused by these faulty proteins [7, 12]. However, the use of natural proteins in commercial applications is limited as it is difficult to reconstitute the proteins in their active form in vitro [13]. Hence, there is a growing interest toward the synthesis of stable artificial ion transporters that could mimic the function of natural ion transporters. Ion transport through artificial ion transporters typically occurs either via a channel or carrier mechanism (Fig. 1). The channel mechanism involves continuous flow of ions through a pore formed by a single molecule (Fig. 1a) or multiple molecules coming together (Fig. 1b–e). In the carrier mechanism, the ion is bound to the molecule, transported across the lipid bilayer, and released. The free carrier is again active to bind to another ion, and the cycle repeats (Fig. 1f). Ion transport through relay mechanism was also developed, where ion has to accelerate dynamically through the membrane to the opposite leaflet, from donor molecules to acceptor molecules [14]. Synthetic ion channels that mimic the ion selectivity of natural proteins have found applications as biosensors [15], ionic devices [16], and therapeutic agents [17, 18]. Synthetic ion channels can also be used as model systems to understand the transport mechanism of natural ion channels in living organisms [1]. Out of several artificial ion transporters, macrocycle-based ion channels remain much attractive as it has defined cavity to accommodate specific ions and its structural simplicity could provide a more accurate manipulation of the transporter in the bilayer. Hence, macrocycle-based ion channels that transport ions through either unimolecular channels or supramolecular self-assembled channels will be discussed in this chapter. Supramolecular self-assembled channels can further be envisioned according to

Fig. 1 Ion transport through lipid membranes by (a–e) channel; (f) carrier mechanism

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the way of their aggregation through non-covalent interactions such as face-to-face stacking, columnar assembly, or tail-to-tail dimer suprastructures in lipid bilayer.

54.2

Ion Channels Developed from Face-to-Face Stacking of Macrocycles

In 1974, De-Santis and co-workers have theoretically recognized that cyclic D,L-αpeptides can undergo ring stacking to form hollow cylindrical structures with minimized side-chain interactions as amino acid side chains radiate outward [19]. In 1993, Ghadiri’s group has successfully synthesized cyclic peptide 1 [(D-Ala-LGlu-D-Ala-L-Gln-)2] containing even number of alternating D- and L-amino acids through standard solid-phase synthetic methodology, which they have characterized by electron microscopy, electron diffraction, and FT-IR spectroscopy (Fig. 2) [20, 21]. The cyclic peptide (CP) 1 adopt low-energy ring-shaped or disc-shaped flat conformations with the side chains pointing outside of the ring, while the carbonyl and amide functionalities remain perpendicular to the plane of the peptide ring. Ring stacking by antiparallel β-sheet like hydrogen bonding by the amide groups leads to formation of extended three-dimensional hollow nanotubes having length of 100 nm long and internal diameter 7–8 Å. The cyclic peptide was designed in such a way that affords unique pH-dependent solubility properties such as the CP 1 is water soluble under basic conditions and self-assembled upon acidification to afford nanotubes. The main advantage of these cyclic peptides is that the pore size and the external functionality of the self-assembled nanotubes could be easily controlled by varying the number and nature of amino acids, respectively. Therefore, cyclic peptides that

Fig. 2 Schematic representation of cyclic peptide 1 that self-assemble by face-to-face stacking through multiple hydrogen bonding interactions to form nanotube structure. (Reprinted with permission from Ref. [22]. Copyright 2013, American Chemical Society)

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can self-assemble to form hollow nanotubes have been found to mimic ion channels and also have been used as antibacterial agents and sensors [18, 22–26]. In order to facilitate the integration of the self-assembled peptide nanotubes in the nonpolar environment of the lipid bilayer, Ghadiri’s group has taken advantage of the hydrophobic nature of tryptophan and leucine amino acids to decorate the external surface of the cyclic peptide nanotubes (Fig. 3) [21, 22]. Eight to ten flat conformations of cyclic peptide 2 undergo enthalpy-driven self-assembly in lipid bilayer through multiple hydrogen bonding interactions to afford a hollow cylindrical nanotube that would be long enough to span the thickness of average biological membranes, where each subunit is separated by inter distance of 4.7–5 Å (Fig. 3). Fluorescence and UV absorption spectroscopy were used to access the incorporation ability of these peptide nanotubes into the lipid bilayer membrane of large unilamellar vesicles (LUVs). The FT-IR spectroscopy confirms the formation of hydrogen-bonded transmembrane channel structure, where the observed band at 1624 cm 1 correlated well with hydrogen-bonded amide I and amide II bands and an NH stretching band at 3272 cm 1 strongly support the formation of a tight network of hydrogen bonds [21]. The proton transport ability of this peptide channel was accessed by using a dye-entrapped vesicle-based fluorescence assay, where 5(6)-carboxyfluorescein (CF) dye was used as fluorescence probe. The channelforming peptide was added to the CF-loaded vesicles with an induced pH gradient of 1 unit (pHout = 5.5; pHin = 6.5), which immediately triggered the influx of protons from the extra-vesicular medium resulting in quenching of the fluorescence intensity of the internal pH-sensitive CF dye. The formation of supramolecular channel by CP 2 was further unambiguously proved by conductance experiments in planar bilayer membranes (BLMs), where addition of CP 2 into the micro patch clamp device spontaneously gave single-channel events of open-closed channel transitions. The structural flexibility of the CP ring facilitates the assembly and disassembly of channel structures resulting in open and closed transitions. The

Fig. 3 Effect of nanotube outer surface hydrophobicity on the ion transport rate; schematic representations of CP ion channels 2–6

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recorded conductance values for equimolar concentrations of NaCl and KCl were 55 and 65 pS, respectively. The rates of ion transport for K+ and Na+ were found to be three times faster than for natural ion channel gramicidin A under similar conditions [21, 27]. In order to investigate the effect of nanotube outer surface hydrophobicity on the ion transport rate, conducting properties of a series of CPs 2–6 with different amino acid compositions were accessed. This study extensively concluded that the channel dwell opening time (τ) was found to be inversely proportional to the hydrophilicity of the amino acid side chains of CPs [22]. This family of peptides is found to transport alkali metal cation selectivity over anions and is also impermeable to divalent metal cations such as calcium [22]. Transmembrane transport of small polar molecules across the cell membranes constitutes an essential metabolic process in living beings. Apart from the nanotube characterization and transport of metal ions by these cps, significant efforts have been dedicated to exploit this tubular assembly for the selective membrane transport of polar molecules [28]. Molecular modelling suggested that a pore diameter greater than 9 Å is required for the passage of glucose through the cylindrical self-assembled peptide nanotubes. Therefore, the cyclic peptide 7 made of 10-amino acid residues with an internal diameter of 10 Å was chosen for this study (Chart 1). This cyclic decapeptide 7 also undergoes self-assembly in a similar way to produce tubular ensembles having an uniform internal diameter of 10 Å. Glucose transport activity through CP 7 was accessed by using an enzyme-coupled assay, where glucoseentrapped unilamellar vesicles were charged with various concentrations of CP 7. Glucose efflux was measured by spectrophotometrically at 340 nm for the production of NADPH, which confirms the glucose transport with first-order kinetics [28]. On the other hand, neither gramicidin A (pore internal diameter of approximately 4.5 Å) nor the similar type of smaller cyclic peptide 2 (pore internal diameter of

NH O O HN

H N

O

O

NH

H N O

NH2 O

HN

10 Å

O

O

H2N NH

NH

HN

O

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NH

O HN HN

H N

O

N H

NH O O

HN

7

Chart 1 Cyclic peptides with different diameters as ion channels

NH2 O 8

N H

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approximately 7.5 Å) showed any glucose transport activity under similar conditions, which strongly supports the size-selective pore-mediated glucose transport mechanism. Cyclic decapeptide 7 was also found to transport small charged molecules like glutamic amino acids with a rate of 2.7  104 molecules per second per 1.0 mM CP 7 concentration [29]. The effect of pore size on transport selectivity could further be seen by comparing Ghadiri’s D, L-cyclic decapeptide 7 and Kodama’s cyclic tetrapeptide 8 (Chart 1) [29–31]. The larger internal diameter of cyclic decapeptide 7 was found to transport large molecules such as glucose and glutamic acid across unilamellar vesicles, whereas the small cyclic tetrapeptide 8 was shown to transport Cl¯ ions selectively across the lipid bilayer [31]. Gong and co-workers have developed a family of oligoamide- and acetylenebased macrocycle 9 and 10 with a membrane-compatible exterior to mimic the masstransport characteristics of biological channels and pores (Fig. 4) [32, 33]. Cofacially stacking of these shape-persistent macrocycles enforced by the cooperative interactions such as pi-pi stacking as well as multiple hydrogen bonding interactions results in cylindrical assembly to form organic nanotubes with modifiable surfaces (Fig. 4). The hydrophilic cavity of 9 (~8 Å) due to inward carbonyl oxygen was found to transport Na+ and K+ ions across the lipid bilayer, whereas the hydrophobic cavity of channel 10 (~6.5 Å) was found to have a high proton selectivity over chloride and potassium ions, i.e., exhibiting a permeability PH+/PCl ratio of greater than 3000 and PH+/PK+ ratio of ~2000. This result strongly supports the formation of hydrogenbonded chains of water along the hydrophobic channel 10. Significant efforts have been devoted by supramolecular chemists to engineer internally functionalized ion channels, as it has a broad range of applications such as selective filter of ions, catalysis, and biosensors [13, 34–39]. In order to enable the chemical modification of the inner cavities of previously described CP nanotubes, Granja’s group has developed internally functionalized cyclic peptide nanotubes made from α- and γ-amino acids (Chart 2). The additional Sp3 C of cis-3aminocycloalkenecarboxylic acid of CP 11 results in hydrophobic pore cavity, whereas 4-amino-3-hydroxytetrahydrofuran-1-carboxylic acid of CP 12 affords hydrophilic cavity by directing its hydroxyl group to the center of the pore. The importance of internal functionalization could be well understood by comparing the

OR

H3CO H N

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NH OCH3

O H3CO

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OR R

9: R =

R

R OR

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10: R =

R

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OC4H9 O

Fig. 4 Schematic representations of supramolecular face-to-face stacking of ion channels 9–10

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Macrocycle-Based Synthetic Ion Channels

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NH O

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O

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13 N H

Chart 2 Granja’s pore-forming cyclic α,γ-peptides and Roesky’s functionalized cyclic peptide ion channel

ion selectivity properties of these cyclic peptides 11 and 12. The hydrophobic inner wall of cyclic peptide 11 allows to transport Na+, K+, and Cs+ ions, whereas hydrophilic inner wall of cyclic peptide 12 transports halide ions selectively across the lipid bilayer [40]. Roesky’s group has also developed functionalized cyclic dodecapeptide 13 composed of a repeating L-L-L-D sequence of amino acids, where polar amino acid side chains faced the channel pore that could interact with the ions (Chart 2) [41]. The cyclic peptide 13 was found to transport cations selectively across the lipid bilayer. The main advantage of this cyclic peptide is that the ion selectivity can be tuned by changing the pH of the solution. Matile’s group has developed peptidomimetic oligourea/amide hybrid macrocycles 14–15 with urea and/or amide NH linkages and aromatic side chains (Fig. 5) that can undergo face-to-face self-assembly to form parallel and antiparallel nanotubes [42]. These nanotubes are found to bind selectively with anions and facilitate anion transport across the lipid bilayer. Anion transport by macrocycles 14 and 15 exhibited anti-Hofmeister (Cl¯ > Br¯ > I¯) and Hofmeister (Cl¯ > I¯ > Br¯) selectivity, respectively. Ion transport activity was found to be strongly influenced by the strength of the anion-receptor interaction, i.e., the anions that are more strongly bound by the macrocycle are being transported more efficiently. The size of anions was found to be too large as compared to the internal diameter of nanotubes formed by self-assembly of macrocycles. Therefore a Jacob’s ladder mechanism was proposed for anion transport, wherein the individual macrocycles in the transmembrane stack would bind with the anion first and then rotate around their own axis to flip their dipole, resulting in handover of anions to the neighboring molecules without moving themselves (Fig. 5).

54.3

Ion Channels Developed from Columnar Assembly of Macrocycles

Barboiu’s group has reported a series of heteroditopic alkylureido crown ether-based self-organized ion channels that prefer to transport potassium ions over sodium ions across the lipid membrane (unique phenomena that mimic natural KcsA K+ channel)

N

N

O

Fig. 5 Chemical structures of oligourea/amide hybrid macrocycles 14–15 and Jacob’s ladder mechanism for the transport of anions by macrocycle 14 (A–E). (Reprinted with permission from Ref. [42]. Copyright 2009, American Chemical Society)

15

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[43–48]. These types of supramolecular channels are constructed by considering three fundamental facts such as (i) either benzo-15-crown-5 or benzo-18-crown-6 macrocycles were used as cationic binding domain, (ii) urea/amide groups for guided H-bond interactions, and (iii) a membrane-compatible hydrophobic tail, where nature of the tail determines the dynamics of the channel suprastructures across the lipid bilayer. Either parallel or antiparallel dynamic self-assembly of these macrocycle monomers through hydrogen bonding between the urea and amide functional groups leads to formation of columnar arrays of crown ether transmembrane supramolecular channels that are aligned around a central pore (Fig. 6a–c). Compounds 16–29, where either rigid benzo-15-crown-5 or benzo-18-crown-6 macrocycles are decorated with membrane-compatible linear or branched alkyl tails of different lengths for the development of K+ ion-selective channel systems (Chart 3a) [43, 44, 46, 48]. Multivalent macrocyclic systems based on triarylamine pillars (28–29) have also been developed for the construction of directional ion-transporting channels [45]. The single-crystal structure of crown ether-triarylamine complex 29.K+ showed that the K+ ions are equatorially surrounded by benzo-18-crown-6 macrocycles, while the water molecules coordinated at apical positions that act as H-bonded bridges to vicinal crown ethers (Fig. 6d) [45]. Minimal electrostatic repulsion between the cations due to alternating positioning of K+ cations and H2O molecules allows to build K+-H2O channel suprastructure that allows K+ H2O co-translocation along the channel. Zeng’s group has used monopeptide-based scaffold that appended with crown ethers for the construction of K+selective ion channels (Fig. 6e) [49]. A directional self-assembly through amide NH hydrogen bonding facilitates a highly robust supramolecular H-bonded 1D ensemble, where crown ethers stack on top of each other to form a columnar channel for facilitated ion transport across the membrane (Fig. 6e). Membrane transport activity of compounds 16–29 was accessed form vesiclebased fluorogenic assays and single-channel conductance measurements. Selfassembly of these oligomers to form variable adaptive suprastructures was found to be strongly dependent on their concentration. Membrane disruption behaviors of 16–29 over regular translocation at low macrocycle concentrations were significantly changed to a rich array of interconverting regular channel conductance states with multiple conductance activity values and lifetimes at high concentration. These results strongly suggested that the formation of several types of active suprastructures depends on the concentration. The transport activity of this family of channels was strongly dependent on the lipophilicity of ionophores, where longer and shorter alkyl chains showed low activity and optimal activity was found for octyl-substituted macrocycles. Hexylureidobenzo-15-crown-5-ether 18 was found to transport smaller Li+ or the fittest Na+ cations with a slower rate, whereas K+, Rb+, and Cs+ cations, which are dimensionally bigger than the 15-crown-5 hole, are transported with a faster rate. This macrocycle was also found to actively transport K+ ions even without a pH gradient. Structural studies suggested that the macrocycle 18 binds with the Na+ cation via equatorial coordination by the oxygens of the crown ether, where the dehydration sphere around the cation is not totally coordinated by the receptor binding sites that face difficulties in recovering the hydration sphere of

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Fig. 6 (a) Dynamic self-assembly of crown ether molecules to form channel suprastructures; (b–c) single-crystal X-ray structural packing (side and top views) of macrocycle ionophores 16 (b) and 18 (c) in stick representation; (d) structure of the 29.K+ complex; (e) directional assembly of Zeng’s peptide appended with crown ether ion channel; (f) lateral view (left) and top view (center) of the double-barreled model and top view of the toroidal model (right) for the organization of 18 in the bilayer. (Reprinted with permission from Ref. [44, 45, 51]. Copyright 2003, 2006, 2017, and 2018, American Chemical Society)

the cation [50]. In case of bigger K+ cations, close proximity of two 15-crown-5ethers to binding site is found tenfold-coordinated to K+ ion in a sandwich-type geometry, where K+ ions are completely surrounded by the macrocycle oxygens that result in replacing the waters coordinating to the cations in aqueous solution.

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Macrocycle-Based Synthetic Ion Channels

R

H N

H N

O

O

O

16: n= 1; R = -C6H5 17: n= 1; R = -C3H7 18: n= 1; R = -C6H13 19: n= 1; R = -C8H17 20: n= 1; R = 2-iC8H17

O O

1529

n

O

21: n= 1; R = -C12H15 22: n= 1; R = -C18H5 23: n= 2; R = -C3H7 24: n= 2; R = -C6H13 25: n= 2; R = -C18H37

O O

HN O

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26

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O O

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27: R = -Cholesteryl

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NHCOCH3

O

O O

29

Chart 3a Barboiu’s columnar crown ether-based ion channels 16–29

However, it would be difficult to describe the transport mechanism through X-ray structures and binding behaviors. It is most probably possible that the cations can diffuse along the channels formed by crown ether aggregates through a series of K+sandwiching sites that facilitate the macrocycles in close spatial proximity. Therefore, from the Na+ and K+ ion conductance behavior of compounds 18 and 24, two types of channel suprastructures are proposed, i.e., a possible stacked crown ethers to form double-barreled channels and large toroidal pores (Fig. 6f) [44, 51]. The rate of K+ ion transport through the channels formed by hexylureidobenzo-15crown-5-ether 18 was found to be 1 order of magnitude higher than the initial K+ transport rates through cholesterylthioureidoethylamido-15-crown-5 27 and squalylamidobenzo-15-crown-5 26, respectively. The higher activity of 18 is attributed to the flexibility of its self-assembled aggregates that facilitate the exposure of dynamic channel suprastructures within the bilayer membrane. A clear regular channel activity with good K+ to Na+ selectivity was found for 18 (SK+/Na+ = 3–17) and Zeng’s octylphenylalanineamidobenzo-15-crown-5-ether (SK+/Na+ = 10) [49]. Squalylamidobenzo-15-crown-5-ether 26 has showed an interesting selectivity of K+ over Na+ transport (SK+/Na+ = 58.3), which is the highest selectivity ever reported among the crown ether families [48]. Benzo-18-crown-6-based compound 28 also could form sandwich-type Rb+(18-crown-6)2 complex and was also found to selectively transport Rb+ cations that are dimensionally bigger than the hole of the coordinating macrocycle, over other alkali metal ions [45]. Voyer’s group has developed linear peptide 30 made of leucine amino acids that appended with six

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crown ether units in such a position (i, i + 4) that the crown ether units in the peptide scaffold align on one side of the α-helix to form a cation-selective columnar membrane-spanning pore. The peptide 30 was found to transport alkali metal cations across the lipid bilayer [51] (Fig. 7). Bao, Zhu, and co-workers have developed 18-benzo-crown-6-ether appended with photocleavable o-nitrobenzyl group supramolecular ion channel 31 formed through columnar stacking of crown ethers in the lipid bilayer (Fig. 8a) [52]. The K+ ion transport rate for channel 31 was found to be blocked by irradiation of UV light. The loss of activity is attributed to the intramolecular photoinduced cleavage of the o-nitrobenzyl group that triggers disassembly of the channel suprastructure across the lipid bilayer. Crown ether was also appended with a photoresponsive group such as acylhydrazone to construct light-gated supramolecular ion channel (Fig. 8a) [53]. The gating behavior of the channel 32 was observed by the photoinduced cis/trans isomerization of the C=N bond of acylhydrazone unit of 32 that facilitates the channel to assemble and disassemble in the lipid bilayer (Fig. 8b). The gating process was found to be reversible by irradiation of the channel with alternating 320 and 365 nm UV light (Fig. 8b). Hall et al. have developed a hydrophilic artificial ion channel containing a redoxactive ferrocene unit, which would act as an electrochemical switch [54]. In this channel model, two diaza-18-crown-6 residues were connected with each other through a central ferrocene unit which would also act as a cation relay (Chart 3b). Each of diaza-18-crown-6 residues was further connected with head group macrocycle unit through an aliphatic spacer chains. The length of the resultant channel formed by the columnar assembly of crown ethers would be approximately equal to O

H N

R

N

(a) O

O O

O

O N H

O

O O

O O2N

NH

N

O O

O

O

31

HN

R

R

OC12H25

O

32: R =

O

O O

(b) UV light (λ1) Disassembly Assembly UV light (λ2) Transport Off

Fig. 7 Schematic representation of Voyer’s oligopeptide ion channel

O

O O

Transport On

N

O

54

Macrocycle-Based Synthetic Ion Channels

1531 ions

O

OR OR O

O

O

Membrane insretion

O

O

RO RO

═

O

O

O

O

O

O

OR OR

37: R = HO O

O O O

38: R = S

O

O O

O

O S

OH

O O

O O

39: R = S

O

O

O

O O

OH

HO S

OH O

OH

O

Fig. 8 (a) Chemical structures of light-responsive ion channel 31–32; (b) schematic representation of photoinduced assembly and disassembly of channel 32 in the lipid bilayer. (Reproduced from Ref. [53], The Royal Society of Chemistry)

O O

N H

O

H N

H N

N H

O

O N H

O

H N

O O

N H

O

O 3

O

O O

O

O

O O

O

O

O

O

O 30

O

O

Chart 3b Chemical structures of crown ether-based ion channels 33–36

the thickness of a typical biological membrane. The ferrocene can undergoes oxidative loss of an electron from the neutral Fe(II) state to afford a positive ferricinium [Fe(III)] species. The presence of an integral positive charge of the channel molecule at the bilayer midplane could tune the channel selectivity. The channel 33 was found to transport K+ ions at both negative and positive potentials across the lipid membrane [54]. Gokel’s group has developed a series of hydrophilic channel molecules 34–36 based on a three-macrocycle concept to effectively span the 30–35 Å length lipid bilayer membrane (Chart 3b) [55, 56]. This family of molecules was designed based on a chemical intuition that an ion would face difficulties when traveling through a distance of 30–35 Å without some energy-

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lowering element at the bilayer midplane. A polar macrocycle such as crown ether was incorporated at the bilayer midplane for stabilization of ions, whereas two similar crown ethers were incorporated on the either side at a distance of about 15 Å to serve as amphiphilic head groups that would anchor at membrane water interface. All of these three macrocycles were connected to each other by appropriate spacer chains. It was expected that this design would allow the macrocycles to arrange themselves parallel to the membrane’s surface and stabilize the position of the channel structure within the lipid bilayer. Structure-activity relationship was carried out by varying the crown size, length, as well as type of the side arms or spacer chains and functional groups to find an optimal ion channel structure and their selectivity and biological activity [57]. Planar bilayer conductance experiment proves the unimolecular channel mechanism with open and close behaviors [58]. This family of channels is found to transport Na+ and K+ ions across the lipid bilayer and has shown antibacterial activity [55, 57, 59]. Extensive biophysical studies confirmed that the central macrocycle was parallel to the axis of the fatty acid chains and perpendicular to the head group macrocycles [60, 61]. Ion passage can be blocked either by a side chain that facilitates H-bond across the distal macrocycles or by strong complexation with Ag+ ions [62].

54.4

Ion Channels Developed from Tunnel or Pore Type of Cylindrical Molecules by Using Macrocycles as Central Relay

Supramolecular chemists have been using two very basic design elements for the development of ion transporters such as a hydrophobic domain to facilitate membrane insertion and an ion recognition domain such as macrocycles to enhance ion selectivity. In this section, we will be discussing the use of macrocycles as a central relay for the construction of supramolecular tunnel/pore-type ion channels. Fyles and Frye groups have developed tartaric acid – 18-crown-6-based ion channel 37–39 – where central crown ether macrocycle was appended with either six cholesterol units or six bolaamphiphile walls (Fig. 9) [64–67]. These molecules form a cylindrical pore in the lipid bilayer, where three of its amphiphilic walls are faced in one direction from the planar macrocycle, while the other three are faced in the opposite direction. Crown ether moiety remains at the midplane of the bilayer, while

HO OH

HO OH

OH Side-chain

*

Covalently appending

n HO

OH HO

Lipid bilayer insertion

OH HO

PA[n] (n = 5, 6)

Fig. 9 Schematic representation for Fyles’ and Frye’s crown ether ion channel

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Macrocycle-Based Synthetic Ion Channels

1533

amphiphilic walls terminated with a polar head group would remain perpendicular to the plane of the macrocycle that interacts with the nonpolar part of the phospholipid bilayer. The metal ion transport ability of 37 across the phospholipid bilayer was accessed by dynamic NMR methods, which confirms the Li+- and Na+ ion-mediated transport. Alkali metal cation transport activity for this family of molecules 38–39 is highly controlled by their structural variables. A combined effect of hydrophilic head groups, length of channel wall, and balance of hydrophilic and lipophilic groups in the wall units detects/controls their activity and transport pathways [65–67]. Pillar[n]arenes (PA[n]s) contain rigid backbones that is composed of hydroquinone units linked at the para positions through methylene units. Hou’s group has designed a family of unimolecular artificial channels from well-defined tubular pillar [5]arene and pillar[6]arene rigid frameworks that decorated with various ester, hydrazide, and short peptide chains (Fig. 10). The intramolecular N H


O=C hydrogen bonding among the appended chains enhances the stability of tubular conformation of the whole molecule across the lipid bilayer, where PA[n]s act as central relay that anchor at the midplane of the bilayer. These pillar[n]arene derivatives with straight or extended unimolecular tubes facilitated the passage of ions and small organic molecules in a selective and/or controllable manner across the bilayer. The ester-attached PA [5] derivative 40 was found to stack cofacially in the solid state to adopt a tubular conformation of infinite uniform organic tubes, wherein, water molecules were associated by continuous high strength of hydrogen bonds to form single wires (Fig. 11a) [67]. This unique pore-water wire hybrid suprastructure of 40 was found to incorporate into planar lipid bilayers to serve as proton channels O EtO

O

O EtO EtO O OO

*

EtO O OO EtO O

OO

OEt O O OEt

OO

OOEt O OEt

O 40

R R R R R

H O N N O H O H N N H H O ON N O H H O N H N N H NO O H

O EtO

O

O EtO EtO O OO

*

EtO O OO EtO O

OEt

O O N H O H ON OH OO NN N O H H O O

H N H O OO NN N H H O O

OEt O O OEt

OO

OOEt O OEt

O

O H N

OO

*

OO

OO O

42: R = (CH2)2COOMe

O EtO

O

*

O EtO EtO O OO

EtO O OO O O

O n O 41a-e: n = 2-6

OO

OEt O O OEt

OO

OOEt O OEt

O

H O N O NH O HN N O H

O

O H ON NH N O NH HH O O N N O H

O

H N HN O NH N O O H

H N N O HH O N N O H HO N N H O

OEt O

R R R

R R

Fig. 10 Schematic representation of the construction of PA-based unimolecular tubular channels. (Reprinted with permission from Ref. [70]. Copyright 2015, American Chemical Society)

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O

O

O

O

O

C10H21 N

O

O N

O

(CH2)12 N

N O

O

O

O

O

O

O

O

O N

(CH2)10

N

O

O

O

Fe N O

O

O

34: R = H, 35: R = CH2Ph 36: R = (CH2)CH3

N N

C10H21 N

(CH2)12 N

(CH2)10

O

O

N O

O

O

O N R

33

Chart 4 Chemical structures of PA-based ion channels 40–42

a

b H

O H

H

H O

H O H

H

H

O H

H

H O

H H O H

H

H

O H

H

O

H O H

H

Fig. 11 (a) Crystal structure of compound 40. The O atoms of the entrapped water molecules are highlighted using CPK spheres. H atoms have been omitted for clarity. (Reproduced from Ref. [69] and [66]. Copyright 2015 and 2011, American Chemical Society and Elsevier Ltd. respectively.) (b) Schematic representation for mechanism of proton channel

[68]. It was found that the dissociation of O H bonds was involved in the proton transport process, where rearrangement of the hydrogen bonds of two adjacent water molecules facilitates the migration of a proton from one water molecule to the next one (Fig. 11b). However, the low water solubility of 40 severely affects its membrane incorporation capability, which led to difficulty in determining the

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Macrocycle-Based Synthetic Ion Channels

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molecularity of the proton channel. Therefore, unimolecular channels were constructed by connecting two PA units through an appropriate alkyl spacer chain to overcome such problems [68]. The proton transport activity of compound 41a–41e strongly depends on the length of the linker alkyl chain, and compound 41c was found to be the highest active proton transporter. The hexamethylene linker of compound 41c has the appropriate length for best-matched face-to-face stacking of the two PA [5] units, while the shorter or longer spacers disfavor such face-to-face stacking. The proton transport ability was completely diminished when the PA unit of compound 42 was connected with longer polyhydrazide units [69]. The alternating hydrophobic and hydrophilic structural domains along the cylindrical structure of 42 were found to strongly disrupt the continuous water wires within the inner core of the channel, which might block the proton flux. However, the longest hydrazidepillar[5]arene 42 was found to be an excellent transporter for water and hydroxyl anions through unimolecular translocation mechanism. Peptide chains made of alternating L- and D-amino acids were also attached to the backbone of PA [5] or PA [6] of 43–46 to transport ions and molecules across the bilayer [70, 71]. The D-L-D sequence of peptide chains was chosen because molecular modelling showed that all of the side chains of the amino acid pointed to the outside surface of the tubular structures formed by these PA derivatives (Fig. 12). Out of several peptide chains with different lengths, the channel with tripeptides has the appropriate length (3.2 nm) that well matched with the thickness of the hydrophobic part of the bilayer, which results in the highest membrane incorporation ability and so on. The hydrophobic Phe residues and hydrophilic terminal carboxylic acid groups were favorable for the insertion of the channel molecules into the lipid

Fig. 12 Schematic representations of (a) PA-based ion channels 43–46; (b) voltage-responsive ion channel 44 (Reproduced from Ref. [72]. Copyright 2014, John Wiley and Sons)

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bilayer. Low concentration of tripeptide appended with PA[5]-derived 43a favored the transport of small amino acids such as Gly and Ala, whereas PA[6]-derived 43b could allow the flux of the larger Phe amino acids. The chirality of the cavity due to chiral peptide of the channel 43b facilitates transport of chiral amino acid selectively, i.e., transport of the D isomers of Ala, Ser, Thr, Val, and Leu was notably faster than that for their L isomers. Arg-incorporated peptides were appended to the PA scaffold to design voltage-gated channels [72]. Each peptide chain of compound 44 consists of two neutral Phe residues and one positively charged Arg residue [72]. Membrane insertion capability of 44 that contains ten positively charged Arg residues was very poor at positive potential and significantly increased in the presence of a negative membrane potential. Thus, altering applied voltages of 100 and + 100 mV, compound 44 was found to reversibly insert into and depart from the lipid bilayer, respectively, which results in switching transmembrane K+ transport on and off, as demonstrated by patch clamp experiments (Fig. 12b). Trp-containing peptide chains with different lengths were installed on PA scaffold for tuning the membrane insertion selectivity of compounds 45a–45c [73]. These tubular molecules are also found to insert into the lipid bilayer and form unimolecular transmembrane K+ ion channels. Channel 45a was found to specifically insert into the bilayer of the Gram-positive bacteria but not into the membranes of the mammalian rat erythrocytes even at the very high concentrations. All of the three channels 45a–45c showed efficient antimicrobial activity for the Gram-positive bacteria without drug resistance but could not inhibit the growth of Gram-negative bacteria. The high membrane selectivity combined with low hemolytic toxicity for mammalian erythrocytes of these compounds provides a new avenue for development of pillar[5]arene-based antibiotics without drug resistance. PA-based tubular molecule 46, appended with peptides that terminated with positively charged amino groups, selectively insert and function as unimolecular channel in mammalian cell membranes composed of phosphatidylcholine lipids [74]. The channel 46 was found to insert in the HepG2 cancer cell and facilitate ion flux to destroy the cell environments that result in killing them. Barboiu’s group also used PA [5] as support for the self-assembly of crown ether macrocycle into channel-type oligomers in membrane for the cation-file diffusion [75]. Bis(benzo-15-crown-5-ether-ureido)-pillar[5]arene compound 47, composed of a central pillar[5]arene scaffold with two benzo-15crown-5 cation binding sites, forms ion channels in lipid membrane that prefers to transport K+ ions over Na+ ions (Fig. 13) [75]. Recently, Chen et al. have developed pillar[5]arene-cyclodextrin hybrid tubular molecules 48–50 that efficiently insert into the lipid bilayers and displayed high selectivity for K+ ions over Na+ ions (Fig. 13) [76]. The bucket-shaped cavity of α-cyclodextrins (α-CDs) decorated with primary and secondary hydroxyl groups together with the oxygen atoms of glucopyranosyl ring provides multiple binding sites for hydrated alkali metal ions and is responsible for high cation selectivity for these molecules. The cation transport selectivity of compounds 48–50 was found to be strongly dependent on the length of the linkers between pillararene and cyclodextrin. The conductance and selectivity preference for K+ ions were found to be much higher for shortest channel 48 over other two channels. The highest activity of channel 48 is attributed to its

54

Macrocycle-Based Synthetic Ion Channels

1537

Fig. 13 Schematic representations of crown ether or α-CDs appended with PA ion channels (Reproduced from Ref. [76]. Copyright 2019, John Wiley and Sons)

shortest linker, which enables it to form a more rigid tubular structure that facilitates transport of K+ ions, whereas longer linkers in 49 and 50 might enhance the flexibility of the molecule that results in formation of nonrigid tubular structures. The high selectivity for K+ over Na+ ions of this artificial channels 48–50 results in the specific transmembrane translocation of K+ ions that generate a stable membrane potential across lipid bilayers. Chen and Hou’s group has used shape-persistent aromatic hydrazide macrocycle as central relay for construction of unimolecular ion channels [78–80]. Phe-based tripeptides were attached to the macrocycle to improve its membrane penetration ability. Tripeptide appended with hydrazide macrocycles 51–52 were also prone to form tubular structure in lipid bilayer similar to the PA scaffold through the multiple intramolecular H-bonding [77]. Patch clamp experiments reveal that both the macrocycles could transport all alkali metal cations that follow Eisenman I sequence (NH4+ > Cs+ > Rb+ > K+ > Na+). This result provides a strong evidence that the cations moved across the cavity of the macrocyclic channels after being dehydrated, where lower activity of smaller alkali cations is due to its higher hydration energy. The channels 51–52 were found to transport alkaline cation selectivity over the chloride anion and displayed the highest selectivity for NH4+/K+ ions. The easiest way to access these macrocycles through one-step condensation method coupled with ease of its backbone modification

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makes them attractive scaffold for the development of gated ion channels. Therefore Chen’s group has internally functionalized these hydrazide macrocycle-based ion channels 53–54 by successfully installing either amino or carboxylic acid groups for the development of pH-responsive ion channels [78, 79]. The K+/Cl¯ selectivity for these compounds was found to be strongly dependent on the pH of the buffer and was highest at alkaline pH. The variation of pH led to protonation and deprotonation of multiple amines or carboxyl groups in the cavity of channels that changes the charge distribution as well as ion selectivity. At alkaline pH, the deprotonated carboxylic groups create negative charge at opening and/or center of the tubular channel, which in turn creates an electrostatic barrier to the entry of Cl¯ ions into the channel pore, whereas K+ ion transport was preferred. Lower selectivity for K+/Cl¯ at lower pH is due to the protonation of amine and/or carboxyl groups and led to decrease of negative charge density at channel openings and enhancement of positive charge density at inner cavity of channel that increases the affinity for the Cl¯ ions and obstructs K+ ions to pass through them to transport across the membrane (Fig. 14). Calixarene scaffold has also been used as a central relay for the construction of tunnel or pore-like ion channels. In these calix[4]arene hybrid derivatives 55–58, central calix [4]arene unit was appended with either dodecyl chains terminated with 10-benzyl-1,10diaza[18]crown-6 units, cholic acid, or oligoether derivatives in an 1,3-alternate conformation, respectively (Chart 5) [5, 81–85]. The length of these molecules would be sufficient to completely span the thick lipid bilayer and transport Na+ ions selectively through unimolecular channel pathway across the lipid bilayer. When the calixarene cavity was substituted with bulky tert-butyl groups in compound 56, the central relay faces obstruction, and cation transport rate was severely hampered.

Fig. 14 Schematic representations of hydrazide-based macrocycle ion channels 51–54 (Reproduced from Ref. [77], The Royal Society of Chemistry)

54

Macrocycle-Based Synthetic Ion Channels

54.5

1539

Ion Channels Developed from Macrocycles Appended with Membrane-Compatible Channel Walls

54.5.1 Resorcin[4]Arene-Based Ion Channels Kobuke’s group has reported a pair of synthetic ion channels derived from resorcin [4]arene (Fig. 15) [85, 86]. The resorcin[4]arene would serve as a head group that anchors at the membrane aqueous interface, while the alkyl chains anchor the structures in the nonpolar part of the bilayer [85, 86]. Compounds 59 and 60 containing flexible C17 alkyl and rigid cholic acid chains, respectively, formed a tail-to-tail dimer in the lipid bilayer to match the length of the membrane and form a stable pore to transport ions. The channel activity could only be observed when the compounds were added to both sides of the lipid bilayer, which strongly suggest that each monomer is only capable of spanning half of the membrane thickness. The rapid molecular motion of the flexible alkyl side chains of 59 makes the channel rapidly switched between the open and closed states, resulting in short-lived open states, whereas the rigidity of cholate derivative 60 and on supplement with additional polar interaction that made the channel structure more stable in the lipid

Chart 5 Chemical structures of calix[n]arene-based ion channels 55–58

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═

Fig. 15 Schematic representations of resorcin[4]arene ion channels 59–64

bilayer results in long-lasting open state. The K+ ion transport was found to be entirely blocked by Rb+ ions, which suggested a single conducting portal. Beer and co-workers have installed aromatic rings at the lower rim of the resorcin[4]arene to rigidify the pore and to improve its cation selectivity via weak cation-π interactions. The channels 61–64 were found to transport K+ ion selectively across the lipid bilayer with an outstanding K+/Na+ flux selectivity (Fig. 15) [87]. The potassium ion conductance across the lipid bilayer for long-chain phenoxyalkyl resorcin[4]arenes 62 was found to be comparable to that of natural systems gramicidin A.

54.5.2 Calix[4]Arene-Based Ion Channels Carreira’s group has appended four amphotericin B (AmB) molecules with the calix [4]arene scaffold (Fig. 16) [88]. These calix[4]arene channels 65 and 66 were found to be ten times less hemotoxic as compared to AmB molecules. All the four Amb molecules in 65 and 66 were arranged on one side of the calix[4]arene to match the

54

Macrocycle-Based Synthetic Ion Channels

1541

═

Fig. 16 Schematic representation of calix[4]arene and AmB hybrid ion channel

Chart 6 Chemical structures of calix[n]arene-based ion channels 67–73

thickness of the membrane and form unimolecular potassium ion channel across the lipid bilayer. Jin has reported a photoresponsive Na+ ion transporter 67, where ion and electron fluxes across the membrane could be regulated by light (Chart 6) [89]. The anthracene photodimerization was used to open and close the channel. The ion transport experiments were conducted by voltage clamp technique on a planar bilayer membrane. The effect of photons on the membrane currents was studied by irradiating UV radiation (>310 nm) to the bilayer membrane containing 67. The Na+ currents were immediately switched off upon UV irradiation, and the transport activity was again resumed after the

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light-off. Calix[6]arene-Triton-X100™ conjugate 68 has also been developed to afford Na+ ion-selective channels across the lipid bilayer (Chart 6) [5, 83–85]. Calix[6]arene 68 was found to transport Na+ ions selectively over K+ ions. Davis and co-workers have developed a family of anion-selective channels from 1,3-alt, cone, and paco calix[4] arene derivatives by installing amide groups in the scaffold (Chart 6) [82, 91–95]. Ion transport assays by using either intravesicular lucigenin or HPTS dye indicated that the channels 69–71 selectively transport Cl¯ ions across the EYPC liposome lipid bilayer. The chloride ion transport through molecule 71 that contain an acidic OH group on its lower rim could be tuned by using pH. Izzo, Tecilla, De Riccardis, and co-workers have developed a pair of 1,3-alternate calix[4]arene derivatives 72 and 73 containing spermidine side chains (Chart 6) [95]. The cationic side chains functioned as anion binding sites that drag the anions from the membrane-water interface and improved the anion selectivity of the resulting channels. The halide transport rates increased with the increased lipophilic nature of the halide ions, i.e., I¯~ Br¯ > Cl¯.

54.5.3 Cyclodextrin-Based Ion Channels Tabushi’s group has reported the first synthetic ion channel 74, which is made from β-cyclodextrin that appended with four membrane permeating hydrophobic groups (Fig. 17) [96]. The hydrophilic hydroxyl groups of the cyclodextrin derivative 74 were envisioned to be located at the lipid-water interface at the surface of the membrane that could serve as the entrance of the ion channel, and four hydrophobic alkyl tails were long enough to span a single leaflet of a lipid bilayer. The molecule formed tail-to-tail active dimeric structure and transported Co2+ and Cu2+ ions across the lipid bilayer.

═

Fig. 17 Schematic representation of Tabushi’s β-cyclodextrin ion channel

54

Macrocycle-Based Synthetic Ion Channels

1543

═

Fig. 18 Schematic representation of Gin’s β-cyclodextrin ion channel

Gin’s group has reported a synthetic oligoether attached aminocyclodextrin-based anion-selective channel 75 (Fig. 18) that discriminates among halide ions (I¯ > Br¯ > Cl¯) [97, 98]. 23Na NMR- and lucigenin-based fluorescence assays were used to study the pH dependence on the transport activity, which indicated that the rates of cation as well as anion transport for channel 75 increased with an increase in pH. The ion selectivity of the channel 75 is attributed to the presence of acid-sensitive amine groups inside the channel pore at the lower rim of the macrocycle. At lower pH, protonation of amine groups leads to slower cation transport due to electrostatic repulsion, while high electrostatic attraction was mentioned to explain the slower anion transport rate at the lower pH [98]. After developing pH-gated ion channel, the author has successfully installed a photoswitchable azobenzene group at the upper rim of the cyclodextrin to develop a synthetic light-gated ion channel [99]. A perfect matching of trans-azobenzene within the macrocycle cavity of 76 allowed transport of smaller cations while hindering the larger anions. This ion selectivity was completely lost upon photochemical isomerization into the cis-channel 77, due to the release/evacuation of the azobenzene from the interior cavity of the cyclodextrin macrocycle.

54.5.4 Crown Ether Peptide Hybrid Channel Antibiotic gramicidin A (gA) is a pentadecapeptide composed of alternating D- and L-amino acids that have been shown to have a β-helix conformation [100]. The dimeric membrane-spanning pore formed by two units of gA was found to transport

1544

H. Behera and J.-L. Hou

═

Fig. 19 Schematic representation of aza-crown ether-gA dimeric ion channel

alkali metal ions selectively over halide ions [101]. To improve the ion selectivity of gA, an aza-crown ether ring was attached to terminal point of gA (Fig. 19) [102]. The gA hybrid 78 was found to transport alkali metal ions across the lipid bilayer in the order K+ > Cs+ ions, which was opposite to the selectivity of gA. This reversal in selectivity is due to the smaller size of K+ ions that exactly fit into the aza-crown ether cavity of 78 and easily passed through it. In contrast, the larger ionic diameter of Cs+ ions prevented it from passing through the crown ether cavity.

54.6

Ion Channels from Covalent Organic Cages

Cucurbit[n]uril (CB[n], n = 5 and 6) are macrocyclic cavitand comprising of either five or six glycoluril units, which have hydrophobic cavity diameter of ~5.5 Å. Supramolecular chemists have also utilized these large internal cavities of more complex macromolecules for the development of selective membrane transporters (Chart 7) [103]. The rigid structure of Cucurbit[n]uril contains an attractive cavity that can bind with molecules and ions. HPTS assay and planar bilayer conductance experiments were performed to access their ion transport activity across the membrane. CB [6] 79 was found to transport proton as well as alkali metal cations across the lipid bilayer through unimolecular channel mechanism. The metal ion transport activity of CB [6] 79 follows the order of Li+ > Cs+  Rb+ > K+ > Na+, which is opposite to the binding affinity of CB [6] 79 toward alkali metal ions [103]. The smaller carbonyl-fringed portal size of CB [5] 80 (diameter 2.4 Å) than the diameters of alkali metal ions makes it inactive for transporting K+, Rb+, and Cs+ ions. The 3D shape-persistent organic cage of a porphyrin box 81 was used for the development of

54

Macrocycle-Based Synthetic Ion Channels

1545

Chart 7 Chemical structures of Kim’s organic cage-based ion channels 79–81

anion-selective unimolecular channel (Chart 7) [104]. Attachment of multiple alkyl chains to the cage of 81 made it hydrophobic enough to be incorporated into the lipid bilayer. This cage of 81 has not only displayed a transport preference for anions over cations but also discriminates among the various inorganic anions that follow the Hofmeister series, I¯ > NO3¯ > Br¯ > Cl¯ > SO42¯. This transport activity strongly depends on the ion dehydration energy, i.e., the highest transport activity was observed from the weakly hydrated iodide and the lowest from the strongly hydrated sulfate anion. The cage of 81 was also found to transport the iodide ion about 60 times more efficiently than chloride ion.

54.7

Metal Organic Framework

Fyles’ group has first used the heavy metal-based supramolecular self-assembled coordination squares for the construction of synthetic ion channel. The square planar palladium with two exchangeable ligands forms coordination bonds with bipyridine to afford 82, a square planar geometry that proposed to anchor at the membranewater interface (Chart 8) [105]. The long alkyl tails were attached to this scaffold to facilitate membrane insertion. The channel gave modest selectivity between Cs+, K+, Cl¯, and Br¯ ions. However the activity could be obtained in the absence of bipyridine that clearly suggests that a self-assembled square is not the only mechanism for conductance. Kobuke’s group has used zinc tris-porphyrin-based supramolecular macrocycle 83 where three zinc porphyrins are connected through aromatic turns [106]. The structure assembles in solution to a cyclic trimer in which the pendant imidazole ligands at both ends of zinc porphyrin facilitate axial coordination to the terminal Zn-porphyrin units that result in a trimeric pore in solution. Grubbs ring-closing metathesis was used to freeze the structure via covalent linkages

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Chart 8 Chemical structures of metal organic framework-based ion channels 82–83

between the monomer units. The macromolecule is having six carboxylic acid groups directed up and down, whose height is estimated to be 21 Å, almost equal to half of the thickness of a membrane. Therefore, two macrorings interact with each other through cooperative hydrogen bonds to give a transmembrane pore. The carboxylic acid groups are found to be essential for formation of transmembrane nanopore. Similar kind of porphyrin-based pore was also developed by Tecilla’s group where peripheral pyridines are coordinated to Re(I) to form stable porphyrin tetramers with large pores [107]. The self-assembled dimer spans the membrane and transports ions with very high activities [107]. Kim’s group has developed metal organic cage 84 through self-assembly from 5-dodecoxybenzene-1,3-dicarboxylic acid (isophthalate amphiphile) and Cu(OAc)2 (Fig. 20) [108]. This metal organic polyhedra (mop) 84 has a hydrophilic cavity with a diameter of 13.8 Å, which is accessible through eight triangular and six square windows each with a diameter of 3.8 and 6.6 Å, respectively. The overall size of the mop 84 including the long alkyl chains decorating outside of the cage is enough to span the lipid bilayers that transport proton and alkali metal ions across lipid membranes. The cation transport activity of mop 84 follows the order Li+>Na+ > K+ > Rb+ > Cs+, which strongly suggests that cations are binding strongly to the channel depending on their size. Gokel’s group has developed pyrogallolarene-based metal capsules, where copper-mediated assembly of pyrogallarene 85 results in metallocapsules that exhibit channel activity across the lipid bilayer [109]. The capsule is approximately 17 Å in diameter and has six openings of approximately 3.8 Å diameter on opposite faces. The hydrocarbon chains radiating outward facilitate insertion of capsule into the phospholipid bilayer. Planar bilayer conductance measurement experiments showed that the single-channel conductance levels were small, ohmic, cation-selective, and voltage-dependent gating (i.e., dependence of channel opening on applied voltage). The selectivity order among alkali metal cations was found to be Na+ > K+ Cs+. The lowest transport rate for Cs+ ion is attributed to the pore blockage by the large Cs+ ion. Although channel mechanism was confirmed from patch clamp experiment,

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Fig. 20 Schematic representation of Kim’s mop-based ion channel 84 (Reproduced from Ref. [108]. Copyright 2008, John Wiley and Sons)

a

b

Fig. 21 Schematic representation of Gokel’s mop-based ion channel; (a) unimolecular channel mechanism; (b) bimolecular channel mechanism (Reproduced from Ref. [109]. Copyright 2009, John Wiley and Sons)

the gating mechanism was proposed through two possible conductance pathways, such as single-capsule (unimolecular) and double-capsule (bimolecular) mechanisms (Fig. 21a and b, respectively). In the unimolecular mechanism, single capsule could easily fit within the membrane, and the rocking motion of the capsule would

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change accessibility to either the entry or exit portal or both that facilitates the gating mechanism. Alternatively, two molecules of capsule could stack with each other to form a conductance pathway to match 30–35 Å thickness of lipid bilayer. A movement of one molecule with respect to the other could either align or offset each other that leads to open or closed gating behavior, respectively.

54.8

Conclusion

In this chapter, a variety of macrocycle-based supramolecular synthetic ion channels have been developed to mimic the ion selectivity of natural proteins. Cyclic peptides containing sequences with repeating LD- and LLD-amino acid units have been shown to transport ions across the lipid bilayer. The cavity of these cyclic peptides has been engineered to obtain internally functionalized channels for tuning their ion selectivity. However, the synthesis of these cyclic peptides is not trivial. Therefore, an emphasis has been given to construct ion channels from other easily accessible macrocycle derivatives. Aza-crown ether group was attached to the acyclic peptide scaffold made of alternating LD-amino acid unit to improve its selectivity for cations. Columnar self-assembly of crown ether moiety also leads to cation-selective ion channels that prefer to transport K+ over Na+ ions, a unique function that mimics natural KcsA K+ channel. Macrocycles have also been used as central relay to construct tunnel/pore kind of cylindrical channels in the lipid bilayer. The macrocycle present at midplane of the bilayer was found to stabilize the polar ions and accelerate their transport. The membrane-compatible chains appended with macrocycle ion channels were developed where macrocycle anchors at membrane-water interface at the surface of lipid bilayer that dehydrates the transported ions. Ion transport functions were also accessed from the macromolecules such as either from large covalent organic cages or from metal organic frameworks. Although much more work has already been done, there are a lot of challenges that need to be taken care of for the development of gated or responsive ion channels to mimic the function of natural ion channels.

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Construction and Biomedical Applications of Macrocycle-Based Supramolecular Topological Polymers

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Wenzhuo Chen, Chengfei Liu, Xin Song, Xuedong Xiao, Shuai Qiu, and Wei Tian

Contents 55.1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55.1.1 Macrocyclic Hosts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55.1.2 Supramolecular Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55.1.3 Macrocycle-Based Supramolecular Topological Polymers . . . . . . . . . . . . . . . . . . . 55.2 Construction of Macrocycle-Based Supramolecular Topological Polymers . . . . . . . . . . . 55.2.1 Crown Ether-Based Supramolecular Topological Polymers . . . . . . . . . . . . . . . . . . 55.2.2 Cyclodextrin-Based Supramolecular Topological Polymers . . . . . . . . . . . . . . . . . 55.2.3 Cucurbituril-Based Supramolecular Topological Polymers . . . . . . . . . . . . . . . . . . 55.2.4 Calixarene-Based Supramolecular Topological Polymers . . . . . . . . . . . . . . . . . . . . 55.2.5 Pillararene-Based Supramolecular Topological Polymers . . . . . . . . . . . . . . . . . . . . 55.2.6 Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55.3 Biomedical Application of Macrocycle-Based Supramolecular Topological Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55.3.1 Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55.3.2 Gene Transfection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55.3.3 Bioimaging and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55.4 Summary and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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W. Chen · C. Liu · X. Song · X. Xiao · S. Qiu · W. Tian (*) MOE Key Laboratory of Material Physics and Chemistry under Extraordinary Conditions, Shanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi’an, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_65

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Introduction

55.1.1 Macrocyclic Hosts Supramolecular interactions based on macrocyclic molecules could provide reversible linker for the fabrication of supramolecular systems via noncovalent interactions mainly including electrostatic interactions, π-π stacking, hydrogen bonding, hydrophobic interactions, and host-guest interactions, which have attracted more and more attention arising from their distinctive properties such as good selectivity, high efficiency, and stimuli responsiveness [1, 2]. For decades, a number of macrocyclic host molecules with cavities have been exploited to encapsulate the guests for the construction of novel supramolecular structures and great potential applications in various fields such as biomedicine, photoelectricity, and catalysis [3–6]. Among the macrocyclic host molecules, crown ethers, cyclodextrins (CDs), calix[n]arenes (C[n] As), cucurbit[n]urils (CB[n]s), and pillar[n]arenes (P[n]As) are the most common and deep-researched examples (Table 1). They all have well-established and hydrophobic cavities which can encapsulate hydrophobic guests and provide ideal platforms for the fabrication of functional supramolecular materials [7]. As the Nobelist Charles Pedersen discovered the crown ethers in 1967, the deep of supramolecular chemistry has been revealed [8]. Crown ethers are a family of cyclic oligomer composed of repeating ether units, which are usually recognized as the first-generation macrocyclic host molecules. Due to the rich lone pair electrons of oxygen in crown ether, they have strong ability to complex with cations like metal ions, ammoniums, and paraquat derivatives via host-guest interactions. In this way, diverse topological structures can be firmly constructed to create new supramolecular materials [9]. But unfortunately, only a few biomedical applications have been reported since the crown ethers are an inherent degree of toxicity [10]. CDs, as one of the key macrocyclic host molecules mentioned above, have been wildly researched since they were found by Villiers in the end of nineteenth century [11]. The most commonly used CDs are α-, β-, and γ-CD, which contain 6, 7, and 8 1,4-linked D-glucopyranosyl residues, respectively. All of them have hydrophilic external surface and hydrophobic hollow cavities, so not only a series of guests (adamantane, azobenzene, ferrocene, etc.) can be encapsulated into the cavity in aqueous conditions but also good water solubility of the system can be achieved [12]. Moreover, the good biocompatibility and nontoxicity nature of CDs and their derivatives make them ideal candidates for biomedical applications. A variety of functionalized CD-based supramolecular systems have been developed in the field of artificial enzymes, biosensors, and drug delivery [13–15]. Came on the heels of CDs, C[n] As are the third-generation macrocyclic host molecules in supramolecular chemistry [16]. They are phenol-derived cyclic oligomers constructed by methylene-linked phenolic units at the meta-positions. So C[n]As have flexible conformational isomers and variable cavity dimensions as per the repeat unit number (commonly 4, 5, 6, or 8). And C[n]As own a corn shape with a hydrophobic hollow cavity and two rims in each side which can be modified to kinds of functional groups. A variety of neural and ionic guests can be incorporated into the cavity of C[n]As [17]. Except for

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Table 1 Several typical host molecules and their corresponding guest molecules. (Reprinted with permission from Ref. [4]. Copyright 2015, American Chemical Society)

Host molecules

Molecular structures

Typical gust molecules

Crown ether

Viologen, charged amine

β-Cyclodextrin

Adamantane, coumarin

Calixarene

Charged alkane, viologen

Methyl viologen, Cucurbit[8]uril

charged naphthalene, anthracene, and alkane

Pillararene

Charged imidazole and DABCO

being the macrocyclic host molecules, C[n]As and their derivatives also reveal instinctive inhibition abilities toward virus, bacterial, and some cancers. That makes the C[n]As0 great potentials in biomedical applications such as the improvement of drug solubility, construction of ion channels, and drug/gene delivery [17, 18]. As early as 1905, CB[n]s, mainly including CB[5], CB[6], CB[7], and CB[8], had been synthesized by Behrend [19]. But they had been confirmed and became the fourth-generation macrocycles by Mock until 1981 [20]. The rigid outwall, highly polar symmetrical carbonyl openings, and hollow cavity with hydrophobicity make CB[n]s highly specific which recognize and strongly incorporate with guest molecules by shape matching, hydrogen bond and ion/dipole-dipole interactions, and hydrophobic interactions, respectively [21]. Therefore, CB[n]s could specifically bind a range of size-matched guests from cation such as metal ion, alkylammonium to neutral molecules including gas, ferrocene, and even small molecular drugs.

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And it is intriguing that CB[n]s have the ability to form binary and ternary host-guest complexes as the cavity size increases from CB[5] to CB[8] [22, 23]. These unique characters of CB[n]s not only enriched the building block of supramolecular chemistry to construct novel supramolecular polymeric materials but also versatile applications including catalysis, sensing, drug delivery, and pollutant absorption [24–26]. Other than the macrocyclic molecules noted above, the P[n]As have been synthesized and characterized by Ogoshi until 2008 [27]. But they soon became very popular as brand new supramolecular macrocyclic building blocks due to their attractive properties. As the name says, the P[n]As own highly symmetrical pillarshaped structures with two same openings and a hollow cavity, constructed by phenolic moieties at the para-positions, whose structure is similar to the combination of C[n]As and CB[n]s in some degree. The rich phenolic hydroxyl group on both rims could be easily functionalized just like the hydroxyl groups on rims of P[n]As [28, 29]. Hence, P[n]As and their derivatives have inherited various characteristic features from former macrocycles such as rigid and electron-rich skeleton for specific binding to guests, easy to multiple functional group modification, and good solubility in different solvents [30, 31]. These merits endow P[n]As with application potentials in field of biomedicine, catalysis, sensors, and other responsible and tunable materials [32–34].

55.1.2 Supramolecular Polymers Great attentions have been attracted by supramolecular polymers (SPs), which is the intersection of supramolecular chemistry and polymer science. SPs can be defined as polymeric arrays composed of monomeric units, which are connected by reversibly noncovalent interactions such as π-π stacking, hydrogen bonding, host-guest interactions, metal coordination, or electrostatic interactions [35]. Generally, supramolecular linear polymers are generally classified into five types including AA type, AB type, AA/BB type, ABBA type, and aromatic-stacking type (Table 2) [4]. On the other aspect, supramolecular nonlinear polymers mainly have star, cyclic, dendritic structures, and so on [36]. SPs exhibit polymeric properties not only in the bulk but also in diluted or concentrated solutions [37–41]. And their senior structures are responsive and reversible according to different non-covalent interaction conditions. So their properties including degradability, self-healing, and self-adaptation may be adjusted by all kinds of stimulus, including but not limited to redox, pH, magnetism, light, stress, temperature, and biological signaling molecules. For this reason, SPs possess promising platform to be investigated for the development of functional supramolecular materials [42–44].

55.1.3 Macrocycle-Based Supramolecular Topological Polymers The properties and functions of SPs are strongly affected by their higher-level topological structures. Compared with linear SPs, these macrocycle-based

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Table 2 Supramolecular liner polymers, taking CD and CB[8] as examples. (Reprinted with permission from Ref. [4]. Copyright 2015, American Chemical Society)

supramolecular topological polymers (STPs) are superior in the complication and hierarchy of structures due to more diverse possible combinations between unique topological structures and macrocycle-based interactions [9, 16, 45]. Some major types of macrocycle-based STPs can be summarized as follows (Fig. 1): macrocyclebased supramolecular dendritic polymers [46], macrocycle-based star-shaped SPs [47], and macrocycle-based cross-linked SPs [48]. Macrocycle-based STPs with supramolecular interactions lead to advantages both in structure and properties such as rich functional groups, good solubility, and more recognition sites of building blocks. Positive cooperative merits such as inherent degradable polymer backbones, smart controllable and tunable responsiveness to specific biological stimuli, facile multifunctional module modifications, and unique chemical physical properties can also be achieved, showing great potential for the development of novel biomedical materials [49]. A number of publications related to the biomedical applications of macrocyclebased STPs have been reported in recent years due to the good biocompatibilities and feasibilities to design stimuli-responsive supramolecular structures [6, 50]. Specifically, poorly soluble drugs/genes/proteins/bioimaging reagents can be encapsulated into the macrocycle-based STP nanoparticles constructed by nontoxic and

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Fig. 1 Classes of main macrocycle-based STPs with different topological structures. (Reprinted with permission from Ref. [50]. Copyright 2018, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)

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water-soluble macrocyclic host molecules like CDs, which can be used to improve the solubility/stability and loading efficiency of therapeutic agents in physiological environment [51]. Furthermore, various therapeutic elements such as therapeutic agents, targeting groups, or imaging molecules can be grafted to the backbone of macrocycle-based STPs via modifying the macrocyclic host molecules and designed hierarchical self-assembly [50]. Moreover, controlled release of the loaded drugs can be realized through the responsiveness under different stimuli (pH, biological signaling molecules, redox conditions, enzymes, etc.) or exogenous stimuli (magnetic field, light, heat, etc.) [37, 52]. For these reasons, macrocycle-based STPs may have distinct biomedical potential including drug delivery, gene transfection, bioimaging, and diagnosis due to their prominent advantages [6, 50, 53]. In this chapter, we aim to summarize the construction and biomedical applications of macrocycle-based STPs (Fig. 2). Herein, we will summarize the macrocyclebased STPs with diverse structures and responsive functional characteristics and their latest applications in the biomedical applications. We want to clarify the distinct structure property features of macrocycle-based STPs and reveal their promising potential in biomedical applications.

Fig. 2 Schematic illustration of the relationship of structures, properties, and applications in macrocycle-based STPs

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Construction of Macrocycle-Based Supramolecular Topological Polymers

The influence of topology on polymers is the brisk research direction today [54, 55]. Benefiting from the unique encapsulation properties, controllable permeability, and surface functionality of macrocyclic structures, macrocycle-based STPs have demonstrated their unique advantages in construction, self-assembly behavior, and functional application, which attract great interests [4, 39, 46, 56]. In general, there are two main methods for constructing macrocycle-based STPs. One route is to directly use macrocyclic molecules as the building blocks to construct STPs. The other strategy is to incorporate macrocyclic molecules into the backbone or terminals of STPs. In this section, we will discuss the construction of macrocycle-based STPs on the basis of crown ethers, CDs, CB[n]s, C[n]As, and P[n]As.

55.2.1 Crown Ether-Based Supramolecular Topological Polymers As the earliest class of macrocycle host, the crown ether molecular has usually been used to construct host-guest-type STPs [57–59], such as supramolecular hyperbranched polymer (SHP) and supramolecular networks or gels [60–62]. In 2004, Huang and Gibson [57] prepared an AB2-type SHP based on the host-guest interaction between one bis-(m-phenylene)-32-crown-10 and two paraquat moieties (Fig. 3a). Liu et al. [58] developed responsive supramolecular gels constructed between dibenzylammonium salt-terminated two-arm A2 monomer and dibenzo[24]crown-8-terminated four-arm B4 monomer. Furthermore, the cavities in the supramolecular networks could be facilely adjusted through changing the arm lengths of A2 and B4 monomers. This model showed unique advantages as smart nano-carriers in delivery and release field. Fan and Tian [59] designed an A2–B3-type SHP from host-guest recognition moiety between benzo-21crown-7 and a secondary ammonium salt (Fig. 3b). This resulting topological polymers exhibited stimuli-responsive behavior. Recently, Bu and Zhang [60] constructed star multiple-arm topology supramolecular polymer with the polyoxometalate cluster as the core and the dibenzo[24]crown-8 moiety as the shell (Fig. 3c). The resulting polymer was then functionalized with dibenzyl ammonium ions to form supramolecular networks, which showed remarkable enhancement and rational control of proton conductivity. However, due to low toxicity and poor solubility in aqueous solution, crown ether-based STPs are little used as biomaterials.

55.2.2 Cyclodextrin-Based Supramolecular Topological Polymers As a kind of biological macromolecule and unique hydrophilic, CDs have powerful advantages in constructing functional STPs and biological materials [63–65]. Benefiting from their easy modification process, Zhu et al. [66] designed miktoarm star terpolymer via the molecular recognition between β-CD and adamantine (Fig. 4a). Zhou et al. [67] constructed the supramolecular vesicles by Janus hyperbranched block polymers. Due

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Fig. 3 (a) Schematic illustration of the formation of a crown ether-based SHP from AB2 monomer. (Reprinted with permission from Ref. [57]. Copyright 2004, American Chemical Society). (b) Graphical representation of the crown-based SHP constructed from monomers A2 and B3. (Reproduced with permission from Ref. [59]. Copyright 2014, Royal Society of Chemistry). (c) Secondary dialkylammonium salt/crown ether supramolecular topological polymers as nanostructured platforms for proton transport. (Reproduced with permission from Ref. [60]. Copyright 2018, Royal Society of Chemistry)

to typical host-guest interaction between Azo and β-CD moiety on each hyperbranched block polymers, respectively, the self-assembly/disassembly process could be regulated by UV/Vis light (Fig. 4b). Next, their group prepared a dandelion-like supramolecular polymer through host-guest interaction between the β-CD-functionalized HBPO-starPEO and Ada-functionalized triple dodecyl chains [68]. Our group constructed a series of CD-based stimuli-responsive STPs [69–73]. We constructed a nonionic binary supramolecular system from the β-CD trimer, and double-naphthalene-terminated poly(ethylene glycol) presented reversible upper critical solution temperature (UCST)lower critical solution temperature (LCST) transitions (Fig. 5a) [69]. Our group also reported a series of controlled self-assembly morphology transitions of SHPs based on AB2-type monomers under ultrasonication [70], the addition of the competitive guest [71], or changing the solution conditions [72]. For example, we found that the morphology transitions of SHPs could be induced by double supramolecular driving force of host-guest and the hydrophilic-hydrophobic interactions (Fig. 5b) [71]. Recently, we have successfully prepared a series of SHPs using an ABx-type (x > 2) amphiphilic macromonomer containing β-CD and azobenzene (Fig. 5c) [73]. These obtained SHPs present an adjusted self-assembly behavior as the unimolecular micelles in salt and branched aggregates in aqueous solutions. The above SHP self-assemblies possess photo-tunable reversibility result from the reversible host-gust interaction between β-CD and azobenzene.

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Fig. 5 (a) Typical turbidity-temperature curves of a nonionic binary supramolecular system upon heating and cooling process. (Reprinted with permission from Ref. [69]. Copyright 2014, American Chemical Society). (b) Schematic representation of the possible morphology transition mechanism from SHPs to nanoparticles. (Reproduced with permission from Ref. [71]. Copyright 2015, Royal Society of Chemistry). (c) Construction and controlled self-assembly of an ABx-type amphiphilic macromonomer-based supramolecular hyperbranched polymer. (Reproduced with permission from Ref. [73]. Copyright 2017, Royal Society of Chemistry)

55.2.3 Cucurbituril-Based Supramolecular Topological Polymers CB[n]s are an important class of macrocyclic hosts; the high binding constant makes the CB[n]s as an ideal model molecule for the study of supramolecular polymerization [74–76]. CB[8] has an ability to bind two guests in its relatively large cavity contributing it the most potential host in the CB[n] family. Thus, Zhang et al. [74] have studied the construction of SHPs driven by CB[8]-based supramolecular interaction. They prepared a SHP in aqueous solution on the basis of a B3 molecule with three arms in which everyone possesses one guest moiety (Fig. 6a). In a similar way to construct the SHPs using naphthyl-substituted porphyrin derivative as the B4 monomers, the CB[8] could bind two naphthyl moieties to form SHPs by supramolecular cross-link strategy [75]. This supramolecular polymeric structure could decrease the porphyrin aggregation, thus leading to enhancement of their 1O2-generation efficiency. Furthermore, as showed in Fig. 6b, CB [8]-based SHPs can be switched into covalent hyperbranched polymers by introducing the azastilbene unit as a guest moiety [76]. Owing to the strong binding force of CB[8] to guest molecules, it has unique advantages in constructing framework of 2D materials [77]. A unique water-soluble two-dimensional SHP was constructed from the recognition of a 4,4-bipyridin-1-ium (BP)-containing ä Fig. 4 (a) Construction of the supramolecular ABC miktoarm star terpolymer based on host-guest inclusion complexation. (Reprinted with permission from Ref. [66]. Copyright 2012, American Chemical Society). (b) Self-assembly/disassembly process of the Janus-type supramolecular hyperbranched block polymer. (Reprinted with permission from Ref. [67]. Copyright 2013, American Chemical Society)

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Fig. 6 (a) Illustration of the formation of SHPs through the recognition of CB[8] and a naphthalene-containing three-arm monomer. (Reproduced with permission from Ref. [74]. Copyright 2013, Royal Society of Chemistry). (b) Illustration of the transformation from SHPs into covalent hyperbranched polymers by UV irradiation. (Reproduced with permission from Ref. [76]. Copyright 2014, Royal Society of Chemistry)

tritopic molecule and CB[8]. Recently, the responsiveness study of CB[7]-based STPs has obtained progress. Zhang et al. [78] reported a novel multi-responsive dodecaborate-CB[7]-based supramolecular networks allowed exclusion and inclusion complexation.

55.2.4 Calixarene-Based Supramolecular Topological Polymers C[n]As are phenol-derived cyclic oligomers, which possess flexible structural design and phenolic hydroxyl groups that could be easily modified with other functional molecular [79]. These properties endow C[n]As with an excellent structural unit to

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construct STPs with complex structure [47, 80]. In 2005, Böhmer et al. [80] designed the supramolecular dendrimers using double-block strategy. Firstly, the block contained one triurea derivative moiety and three urea-substituted C[4]As to form primary dimers and then self-assembled to uniform supramolecular dendrimers (Fig. 7a). Besides the common organic small molecules, C[5]As can encapsulate spherical organic compounds (e.g., C60) due to their asymmetric structure [81, 82]. Haino et al. reported the supramolecular polymeric network and constructed by direct molecular encapsulation between bis(C[5]As) and C60 moieties grafted onto the polymer chain (Fig. 7b) [82]. In addition to organic media, since C[n]As can be easily designed or modified to be a water-soluble structure, their water-soluble derivatives could also be good candidates for fabricating STPs. The typical 2D network polymers were constructed between water-soluble bis(p-sulfonato-C[5] As) and four-armed cationic porphyrins reported by Liu’s group [83].

55.2.5 Pillararene-Based Supramolecular Topological Polymers P[n]As with high binding abilities for guests have been used to construct host-guest interaction-based supramolecular polymers because of their special structures that can be conveniently modified at the hydroquinone unit [31, 84–86]. In early stage, Li [85] synthesized an AB2-type heterotritopic copillar[5]arene monomer, which could spontaneously self-assemble to form SHP in chloroform solution via hostguest interactions. Furthermore, Li0 s group has explored an AA/BB-type and an A2/B3-type supramolecular polymer from pillar[5]arene dimer and ditopic/tritopic guests [86] (Fig. 8a). The stimuli-responsive and functional application of P[5] A-based STPs have achieved breakthrough in recent years [87–89]. Wang and coworkers [88] designed and synthesized a brush P[5]A-modified-conjugated polymer and further prepared polypseudorotaxanes by threading the n-octylpyrazinium axle into the P[5]A units on the basis of the host-guest interaction (Fig. 8b). Moreover, the disassembly behavior would be achieved by adding Cl to destroy the host-guest complexation of pillar[5]arene and n-octylpyrazinium. Huang and Hua [89] reported a novel fluorescent supramolecular cross-linked polymer network based on the host-guest interaction between pillararene units of conjugated poly (tetraphenylethene) and double cyano-terminated cross-linker (Fig. 8c).

55.2.6 Others In recent years, the concept of self-sorting assembly has expanded the construction of macrocycle-based STPs [90–93]. Our group proposed a three-monomer system based on self-classification to avoid cross-linking [94]. Two rigid homotritopic monomers tris(per-methylated P[5]A) (D3) and tris(benzo-21-crown-7) (E3) and two ends of the AC monomer which modified with a typical guest unit that selectively binds crown ether and PA were synthesized (Fig. 9a). Through the selfclassification recognition between the two host-guest interactions, those three

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Fig. 7 (a) Schematic representation of the chemical structure and building methods for supramolecular dendrimers. (Reprinted with permission from Ref. [80]. Copyright 2005, American Chemical Society). (b) The specific recognition process between bis(calix[5]arenes) molecules and C60 moieties to form supramolecular topological polymer. (Reproduced with permission from Ref. [82]. Copyright 2010, John Wiley and Sons)

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Fig. 8 (a) Schematic illustration of an A2 + B3 route to construct SHPs. (Reproduced with permission from Ref. [86]. Copyright 2013, John Wiley and Sons). (b) Representation of the formation of pillar[5]arene-modified polypseudorotaxanes and their disassembly induced by chloride anion. (Reproduced with permission from Ref. [88]. Copyright 2013, Royal Society of Chemistry). (c) Chemical structures of P5-TPE and double cyano-terminated cross-linker, as well as the formation of an aggregation-induced enhanced emission fluorescent supramolecular polymer network. (Reproduced with permission from Ref. [89]. Copyright 2018, Royal Society of Chemistry)

monomers were copolymerized to form the hyperbranched alternating copolymer structure. We also report a transformation from a supramolecular hyperbranched homopolymer to alternating polymers by the “competitive self-sorting” strategy [95] (Fig. 9b). The macrocyclic-based STPs can also be combined with inorganic metal ions to form an organic-inorganic hybrid system [96, 97]. Yang [96] presented a highly efficient approach for the construction of multiple P[5]A species (Fig. 10a). Tian and Liang [97] reported a new fluorescent SHP prepared by orthogonal selfassembly of P[5]A-based host-guest interaction and metal ion coordination complexation (Fig. 10b).

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Fig. 9 (a) Graphical representation of the supramolecular hyperbranched alternating polymer constructed from monomers D3, AC, and E3 by self-sorting assembly. (Reproduced with permission from Ref. [94]. Copyright 2016, Royal Society of Chemistry). (b) Schematic representation of the transformation from a supramolecular hyperbranched homopolymer to a supramolecular hyperbranched alternating copolymer. (Reproduced with permission from Ref. [95]. Copyright 2017, John Wiley and Sons)

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Fig. 10 (a) Construction of the hexagonal metallacycle and the formation of supramolecular polymer gels. (Adapted with permission from Ref. [96]. Copyright 2014, American Chemical Society). (b) Schematic depiction of the fluorescent SHP prepared from monomer B3, AC, and metal ion by orthogonal self-assembly. (Reproduced with permission from Ref. [97]. Copyright 2018, John Wiley and Sons)

55.3

Biomedical Application of Macrocycle-Based Supramolecular Topological Polymers

The above macrocycle-based STPs with lots of impressive performances such as stimuli responsiveness, drug-loading ability, self-healing behavior, and good mechanical properties [98, 99] have great potential applications in drug delivery [98–102], gene transfection [103–106], bioimaging, diagnosis [107–110], and so on.

55.3.1 Drug Delivery The drug delivery platforms constructed by macrocycle-based STPs not only overcome the drawback of chemical agents but also add new functions [54, 111–114]. Therefore, they have been used as potential multifunctional chemotherapy agents carries for diverse cancer therapy [111–115]. Zhao et al. [115] designed prodrug vesicles based on supramolecular linear-dendritic block copolymers to fight against cervical cancer by co-delivering camp to the cin and SiRNA. Benefiting from the host-guest interactions, the assembly can be easily formed and enhanced the

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dissociation of the prodrug combined with the disulfide bond cleavage under high concentrated intracellular GSH in cancer site (Fig. 11). Mao et al. [111] designed supramolecular star-shaped polymers co-delivery system by coupling β-CD and amino acids to the quantum dots (QDs). The star-like morphology with β-CD terminal provides large loading quantities of mdr1 SiRNA and DOX via electrostatic interaction and host-guest interactions, respectively. Liu’s group [112] has constructed supramolecular cross-linked polymers by fluorescent β-CD-containing supramolecular assemblies, which could efficiently load DOX into cancer cells. Our group [113, 114] designed supramolecular branched copolymer self-assemblies with a light-triggered reversible morphology transition feature, which can be used to construct a switch-controlled drug release system (Fig. 12).

55.3.2 Gene Transfection Gene delivery vectors often divided into two types: viral and nonviral [116]. Considering the safety concern of viral vectors, nonviral gene vectors might be a wonderful choice for gene transfection due to their low immunogenicity, ease of preparation, large gene payloads, and flexible structures [103–106]. As a nonviral gene delivery vectors, macrocycle-based STP has gained significant attention because of their high transfection efficiency and high biocompatibility. For example, Zhu and coworkers [117] developed a charge-tunable supramolecular dendritic polycation for the gene delivery via the host-guest interactions (Fig. 13). This class of supramolecular dendritic polycations shows controlled pDNA condensing ability and enhanced in vitro transfection efficiency. Tian and Xu et al. [118] reported a novel self-assembled supramolecular polycations with hyperbranched topological structures by the self-assembly of AB2 macromonomers with one Ad group and two β-CD-PGEA arms between Ada and β-CD (Fig. 14). They possessed a higher pDNA condensation ability and much better gene transfection efficiency than the dissembled AB2- type counterparts.

Fig. 11 Schematic illustration of the self-assembly process of the vesicle and its therapeutic agent release and fluorescence imaging in vivo. (Reproduced with permission from Ref. [115]. Copyright 2017, American Chemical Society)

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Fig. 12 (a) Schematic illustration of the switch-controlled release of DOX through light-triggered reversible morphology transitions. (b) Illustration of the typical TEM images for light-triggered reversible morphology transitions. Bottom right illustration of the cumulative release curves of DOX under different UV/visible light irradiation times. (Reproduced with permission from Ref. [113]. Copyright 2015, The Royal Society of Chemistry)

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Fig. 13 (a) Charge-tunable supramolecular dendritic polymer constructed through β-CD/AD hostguest interactions. (b) Luciferase expression (top) and green fluorescent protein expression (bottom) of these supramolecular polycations in COS-7 cells. (Reproduced with permission from Ref. [117]. Copyright 2011, Royal Society of Chemistry)

55.3.3 Bioimaging and Diagnosis Bioimaging and diagnosis play a major role in bioscience research and clinical applications because it is rapid, highly sensitive, and inexpensive [119–122]. In recent years, macrocycle-based STPs have been employed as bioimaging and diagnosis reagents because of their stability, improved targeting specificity, prolonged plasma half-lives, and reduced toxicity [107–110]. For example, Zhu and coworkers [123] prepared a new class of supramolecular fluorescent nanoparticles by the self-assembly of β-CD-grafted hyperbranched polyethylenimine, AD-functionalized calcein, AD-functionalized PEG derivative, and AD-functionalized folate based on host-guest interaction (Fig. 15a). The introduction of the folate receptor endowed these supramolecular fluorescent nanoparticles with excellent bioimaging efficacy in HeLa cancer cells (Fig. 15b). Huang and co-workers [124] constructed an amphiphilic supramolecular brush copolymer, which self-assembled into highly emissive SNPs by taking advantage of the aggregation-induced emission (AIE) effect (Fig. 16). The hydrophobic core of the SNPs was utilized to encapsulate the anticancer drug DOX, affording a self-imaging DDS.

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Fig. 14 Preparation processes of PGEA-based supramolecular hyperbranched polycations and their resultant pDNA delivery process. (Reproduced from Ref. [118], with permission from the Royal Society of Chemistry)

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Fig. 15 (a) Schematic illustration of supramolecular fluorescent nanoparticles (SFNPs) formed from PEI-CD, CA-AD, mPEG-AD, and FA-AD via β-CD/AD host-guest interaction. (b) Confocal laser scanning microscopy (CLSM) images of HeLa cells that incubated with excess folate (top panel). (Reproduced with permission from Ref. [123]. Copyright 2012, American Chemical Society)

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Fig. 16 (a) Chemical structures and cartoon representations of M, P5, P5-PEG-Biotin, and PTPE. (b) Schematic illustration of the formation of SNPs self-assembled from the amphiphilic supramolecular brush copolymer P5-PEG-BiotinPTPE. (c) Time-dependent in vivo fluorescence imaging of tumor-bearing mouse treated with free DOX•HCl and DOX-loaded SNPs. (Reproduced with permission from Ref. [124]. Copyright 2016, The Royal Society of Chemistry)

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Summary and Outlook

In summary, by combining merits of macrocyclic host and supramolecular topological polymers, macrocycle-based STPs have been developed to be good candidates for biomedical applications. The 3D topological structures, multifunctional properties, water solubility, and stability make them meet the requirements of biomedicine. On the other aspect, they have an ability to respond to multiple external stimuli in biological environment due to the reversible and dynamic noncovalent interactions, leading to the morphological transformation and further releasing drugs. In this chapter, we have discussed the current progress of macrocycle-based STPs including synthesis, relationships of structures, properties, functions, and their biomedical applications in several important fields such as drug delivery, gene transfection, bioimaging, diagnosis, and so on. However, from molecular architecture aspect, the functionality of current macrocycle-based STPs is still relatively simple and not intelligent for complex biosystems. Besides, it is difficult to completely clarify the structure-function relationship and further construct macrocycle-based STPs with rational molecular design. Furthermore, the majority of macrocycle-based STPs have been constructed by polymeric building blocks due to their facile fabrication and relatively good stable properties. Alternatively, the small molecule-based or inorganic componentcontaining SPs with well-defined structures usually have better blood elimination performance and lower cytotoxicity to normal cell due to the smaller particle size and precise block composition. So they are even superior in biomedical applications in comparison with polymer-based ones. However, macrocycle-based STPs on the basis of the small molecule-based or inorganic building blocks have rarely been reported. Additionally, the combination of host-guest interactions and other noncovalent interactions is urgent and expected for constructing hierarchical selfassemblies, which may be more biomimetic and have unexpected synergetic effects for disease therapy. Speed development of new kinds of macrocyclic host molecules with favorable biological properties and specific responsiveness should also be taken into account. Switch to clinical use perspective, the safety and therapeutic performance of the macrocycle-based STPs have rarely been fully evaluated in clinical trials since they are rising star in nanomedical field. Therefore, the research on therapeutic applications of macrocycle-based STPs is still at the preliminary stage, and lots of obstacles need to be overcome such as therapy efficacy, safety, and commercial process. In order to clarify the relationship between structure and function for biomedical applications, organic-inorganic hybrid complex can be introduced into the construction of macrocycle-based STPs as a new biofunctional building block. Moreover, by the cooperation between molecular biology and medicine knowledge, more intelligent macrocycle-based STPs can be designed with high sensitivity to a specific disease, realizing the effective and precise therapy. The continuous research on macrocycle-based STPs will bring a widespread clinic biomedical application in the coming years.

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Acknowledgments We thank National Natural Science Foundation of China (21674086, 21374088) and Natural Science Basic Research Plan in Shaanxi Province of China (2018JZ2003) for financial support.

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Contents 56.1 56.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Supermolecules as Antitumor Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.2.1 Macrocycle-Based Supermolecules as Antitumor Agents . . . . . . . . . . . . . . . . . . 56.2.2 Metal-Based Supermolecules as Antitumor Agents . . . . . . . . . . . . . . . . . . . . . . . . . 56.2.3 Polymer-Based Supermolecules as Antitumor Agents . . . . . . . . . . . . . . . . . . . . . . 56.3 Supermolecules as Antiinflammatory and Analgesic Agents . . . . . . . . . . . . . . . . . . . . . . . . . 56.4 Supermolecules as Antimalarial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.5 Supermolecules as Antibacterial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.5.1 Quinolone-Based Supermolecules as Antibacterial Agents . . . . . . . . . . . . . . . . . 56.5.2 Sulfanilamide-Based Supermolecules as Antibacterial Agents . . . . . . . . . . . . . 56.5.3 Schiff Base-Based Supermolecules as Antibacterial Agents . . . . . . . . . . . . . . . . 56.5.4 Hydrazone-Based Supermolecules as Antibacterial Agents . . . . . . . . . . . . . . . . . 56.5.5 Thiosemicarbazone-Based Supermolecules as Antibacterial Agents . . . . . . . 56.5.6 Macrocycle-Based Supermolecules as Antibacterial Agents . . . . . . . . . . . . . . . . 56.5.7 Other Supermolecules as Antibacterial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.6 Supermolecules as Antifungal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.7 Supermolecules as Antituberculosis Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.8 Supermolecules as Antiviral Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.9 Supermolecules as Antiepileptic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.10 Supermolecules as Cardiovascular Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.11 Supermolecules as MRI Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.12 Supermolecules as Other Medicinal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.13 Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.14 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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C.-H. Zhou (*) · Y.-F. Sui Institute of Bioorganic and Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, China e-mail: [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_66

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Introduction

Supramolecular chemistry is a rapidly expansive scientific interdiscipline, strongly promoting the development of chemistry at a revolutionary pace [1–3]. Numerous efforts have been devoted to the study of supramolecular chemistry, which has been extended and developed in many disciplines such as materials science, biology, medicine, and pharmaceuticals [4–6]. Many outstanding achievements have been made [7–9]. Generally, supermolecules are described as aggregates formed by two or more molecules through noncovalent bonds. According to this definition, the inorganic and organic complexes could be attributed to supermolecules. The main driving force for the formation of inorganic complex supramolecular aggregates is coordination bonds, whereas the driving force for organic supramolecular aggregates is mainly hydrogen bonds, ionic bonds, and van der Waals forces. The inorganic complexes or aggregates formed by inorganic compounds or organic compounds can be regarded as inorganic supermolecules. The anticancer drug cisplatin is an example. This drug is usually considered to be the inorganic metal complex formed by one molecule of the inorganic compound PtCl2 and two NH3 molecules through coordination bonds; this complex is an aggregate of three molecules formed through noncovalent bonds (here generally considered to be coordination bonds). Therefore, cisplatin could be called an inorganic (complex) supermolecule. Similarly, the organic complexes or aggregates formed by organic compounds and organic compounds could be regarded as organic complexes or supermolecules. Considering the complex of β-cyclodextrin with the anticancer drug adriamycin, it was found that the organic molecule β-cyclodextrin, with another organic molecule, the anticancer adriamycin, in aqueous solution formed a 1:1 host–guest complex. The drug adriamycin is generally considered to enter into the cavity of macrocyclic cyclodextrin, often called an (organic) inclusion complex. This complex is an aggregate formed by one molecule of β-cyclodextrin and one molecule of adriamycin, mainly through noncovalent bond forces such as hydrophobic interaction or van der Waals forces. Thus, such a complex should be an organic supermolecule. Supermolecules or polymolecular assemblies formed by the weak interactions of noncovalent bonds via self-process, self-assembly, or self-organization show distinct chemical, physical, and biological properties in comparison with their precursor molecules. These supramolecular systems exhibit some specific functions, being capable of being used as conductors, magnetic materials, or sensors, and thus they have wide potential applications in chemistry, physics, the medical sciences, and other fields [10–12]. It is well known that supermolecules have important roles in living biological systems. Chlorophyll in plant photosynthesis is the magnesium tetrapyrrole complex supermolecule, heme in hemoglobin in uptake and transport of oxygen is the iron complex supermolecule with porphyrin ring, and vitamin B12 is the cobalt macrocyclic complex supermolecule. Therefore, to some extent, the living biological system is a huge and particularly excellent biological supramolecular system in which the supramolecular hosts are various kinds of enzymes, receptors, genes, antibodies of the immune system, or ionophores, whereas the guests are substrates,

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inhibitors, antigens, drugs, and so on. The synergistic cooperation between hosts and guests supports biological processes in living biological systems. Utilization of interactions of noncovalent bonds, in attempts to study molecular recognition, regulation, and control, modeling or mimicking enzyme catalysis in biological processes, DNA binding, membrane transport, cell–cell recognition, as well as investigating drug interactions, has become an unusually active research area of supramolecular chemistry in the life sciences, providing a new approach for the development of new drugs. The highly interdisciplinary research in this field is considered to be an important source for new concepts with high technology. The noncovalent interactions in biological supramolecular systems should be highly useful for the development of supramolecular drugs. However, surprisingly, the word “supramolecular drug” has seldom been mentioned. The concept of supermolecular drugs, as described by Prof. Cheng-He Zhou early in 2009, was defined that a supramolecular drug was formed by two or more molecules through noncovalent bonds [13, 14]. The wide extension and rapid development of supramolecular chemistry into scientific disciplines have attracted much exploration toward applying supramolecular systems in pharmaceutical sciences. Since the discovery of the inorganic platinum complex cisplatin as an anticancer agent, research for medicinal application of inorganic metal complex supermolecules has been active. The two inorganic compounds, PtCl2 and NH3, are not anticancer drugs, but their cisplatin complex formed through noncovalent bonds is used widely clinically as an anticancer drug. The anticancer drug cisplatin has thus opened up a new era for the research and development of new medicinal drugs, with numerous endeavors toward inorganic complex supermolecules as drugs formed by inorganic metal compounds with inorganic compounds such as NH3 or organic compounds such as diamines and porphyrins. In particular, supramolecular inclusion complexes, formed by organic macrocyclic compounds such as cyclodextrins and their derivatives as hosts with guest drugs, not only could improve the water solubility of original drugs, control drug release in the body, assist drug delivery to the target organ, and even eliminate abnormal flavors of drugs, but also effectively improve the pharmacokinetics properties of drugs, increasing their bioavailability and efficacy. These special advantages for drugs have encouraged and attracted numerous workers to engage in research and development of supramolecular drugs. Currently, research in supramolecular drugs is quite active and the progress is unusually rapid, becoming an emerging highly interdisciplinary field with enormous potential and gradually becoming a relatively independent scientific area. To date, a large number of supermolecules as medicinal drugs have been widely used in clinics. Supermolecules as medicinal drugs show not only less expense, shorter time, and greater possibility as clinic drugs with their successful research and development, but also safety, lower toxicity, less adverse effect, higher bioavailability, better biocompatibility and drug targeting, less drug resistance, and better curative effects, exhibiting extensive potential for clinical use. This chapter provides a comprehensive summary of supramolecular drugs, including antitumor, antiinflammatory, analgesic, antimalarial, antibacterial, antifungal, antivirus, antiepileptic, and

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cardiovascular agents and agents for magnetic resonance imaging . The foreseeable perspectives for future development of supermolecules as medicinal drugs are also presented.

56.2

Supermolecules as Antitumor Agents

Cancer is a frequently occurring and formidable disease that seriously threatens human health. The development of anticancer drugs has become an important issue in the world. In recent years, various achievements have been obtained in seeking drugs and methods for treating cancers, such as apoptosis antileptics, signal conduction blockade agents, angiogenesis inhibitors, and chemotherapy and radiotherapy protectants. Supermolecules as anticancer drugs have become highlighted, especially cyclodextrin inclusion compounds, liposomes, nanometer particles, and metal complexes such as platinum, as representative supramolecular chemical drugs important in treating cancers [15, 16].

56.2.1 Macrocycle-Based Supermolecules as Antitumor Agents Organic macrocyclic compounds are excellent hosts to form supermolecules. Macrocycles such as cyclodextrins (CDs), cyclophanes, crown ethers, calixarenes, porphyrins, phthalocyanines, cyclopeptides, and cucurbiturils, for example, provide rich host resources. The CDs are a class of D-glucopyranose-based special macrocyclic hosts with a hydrophilic exterior and a hydrophobic cavity. These cavities with appropriate size enable them to form inclusion complex supermolecules with various hydrophobic drugs, resulting in improvement of the drug properties such as solubility, chemical stability, bioavailability, drug release control, or even elimination of abnormal drug flavor. Therefore, the CDs possess good application prospects in oral administration preparation, and they have also become important useful functional excipients in modern pharmaceuticals because of their features, such as being easy to obtain, better biocompatibility, almost no adverse effects, and stable chemical properties as well as clathration simplicity with guest drugs. Cyclodextrin derivatives with different solubilities can meet the requirements of appropriate drug release. The extensively used cyclodextrins are β-CD, especially its derivatives such as hydroxypropyl-β-CD (HP-β-CD), hydroxyethyl-β-CD (HE-β-CD), and trimethyl-β-CD (TM-β-CD). The β-CD with an appropriate cavity size and shape could bind efficiently with a series of hydrophobic aromatic guests, and also is widely investigated and applied because of its low price. For instance, anticancer drug doxorubicin 1 and β-CD could form a 1:1 inclusion complex. Prof. Yu Liu and coworkers found that this supermolecule remarkably improved the water solubility of doxorubicin and enhanced its efficacy as a drug.

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HOH2C HO

OH

O

OH

O

H2N O HO O

OMe

1

Me

One highlight is to modify the structures of CDs in various ways to increase their drug-loading capability. Much work on the structural modifications of methylation, hydroxymethylation, sulfonylation, and sulfur alkylation is hoped to improve the water solubility and inclusion capability of β-CDs; some good results in enhancement of water solubility and the complexation capability of CDs have been obtained to different extents. The β-CD dimers and linear polymers could serve as potent selective carriers of drugs such as the anticancer agent busulfan, and improve the physicochemical properties of drugs. Prof. Liu Yu et al. used bis(β-CD)s with paclitaxel to form inclusion complex supermolecules, hoping to improve the water solubility and antineoplastic activity of paclitaxel. Among these supermolecules, the complex of ethylenediamine-bridged β-CD dimer significantly increased the water solubility and thermal stability of paclitaxel, and exhibited antiproliferative activity against the human K562 erythroleukemia cell line (IC50 value, 0.6 nmol
l1), which was even better than that of free paclitaxel (IC50 value, 0.98 nmol
l1). The bridged CD could also greatly increase complexation ability to drugs by interactions of the drug molecule with two adjacent hydrophobic cavities. Supramolecular nano-assemblies responding to multiple stimuli exhibit high therapeutic efficacy against malignant tumors. A new type of supramolecular nanofiber integrated targeting peptide 2-coated magnetic nanoparticles with β-cyclodextrin-bearing polysaccharides in a complex held together by multivalent interactions. The nanofibers markedly suppressed invasion and metastasis of cancer cells both in vitro and in vivo. Furthermore, in comparison with control mice, tumor-burdened mice treated with the nanofiber assembly showed a lower rate of mortality from the metastatic spread of tumor cells [17].

HN H2N

H

H N

H N

OH

HO

NH2

O

O O

HN

NH

O

O H N

N H

O

O 2

HN

OH

NH

O 2

NH2 HN HN

NH N H O

4

O O N H

3

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A recent study developed a β-CD-functionalized Ru(II) polypyridyl complex supermolecule with an adamantane-appended tumor-targeting c(RGDyK) peptide 3. The host–guest system can form stable phosphorescent nanostructures with quantitative drug loading. The formed nanoparticles, Ru-CD-RGD, displayed high selectivity for integrin αvβ3-rich U87MG cancer cells as compared with integrin αvβ3-deficient cancer cells. Mechanistic studies showed that Ru-CD-RGD could induce apoptotic cell death through lysosomal damage, reactive oxygen species (ROS) elevation, and caspase activation [18].

N

H N

N

N

O

4

β-CD

Supramolecular assembly with tumor-targeting properties or photodynamic therapy (PDT) ability has recently become a focus of interest in the biomaterial field because of its high therapeutic efficacy against tumor cells. A β-cyclodextrin-functionalized compound 4 formed a ruthenium complex that acted as the targeted sites for tumor cells, the coordinated Ru (II) centers acted as the PDTactive sites, and the biocompatible polysaccharide β-cyclodextrins acted as the noncovalent linkers. Significantly, the resultant Ru/polysaccharide/protein complex exhibited not only specific targeting properties toward tumor cells but also high PDT ability under visible light irradiation. Furthermore, the assembly showed selective killing toward tumor cells combined with negligible toxicity toward normal cells [19]. The porphyrin ring possessed the structural features of both macrocycles and multidentes. Porphyrins and their metalloporphyrins may offer many distinct physicochemical properties and functions when changing substituents in the porphyrin ring, adjusting the electron–donor ability of four nitrogen atoms, introducing different center metal ions, or changing the affinity of axial ligands [20]. In recent years, PDT has become the fourth new and reliable treatment for cancer, after surgery, radiotherapy, and chemotherapy. Porphyrin-based anticancer drugs generally act as photosensitizers to generate photodynamic reactions when light at the appropriate wavelength is applied, give highly active oxygen singlets, and then destroy the target cells. The widely used drugs in the clinic are hematoporphyrin derivatives, the first generation of photosensitizers with high phototoxicity and dark toxicity. Recently, principal studies have been focusing on exploring new photosensitizers with singlet oxygen in high yields, with strong absorption at or near the infrared region, as well as better targeted intelligence carriers.

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Camptothecin (CPT) selectively traps topoisomerase 1-DNA cleavable complexes (Top1cc) to promote anticancer activity. A new class of neutral porphyrin derivative, 5,10-bis(4-carboxyphenyl)-15, 20-bis(4-dimethylaminophenyl)-porphyrin as a potent catalytic inhibitor of human Top1, was designed and synthesized. In contrast to CPT, compound 5 reversibly binds with the free enzyme, inhibits the formation of Top1cc, and promotes reversal of the preformed Top1cc with CPT. Compound 5-induced inhibition of Top1cc formation in live cells was substantiated by fluorescence recovery after photobleaching (FRAP) assays. The study established that MCF7 cells treated with compound 5 trigger proteasome-mediated Top1 degradation, accumulate higher levels of ROS, PARP1 cleavage, and oxidative DNA fragmentation, and stimulate apoptotic cell death without stabilizing apoptotic Top1–DNA cleavage complexes. Finally, compound 5 shows anticancer activity by targeting cellular Top1 and preventing the enzyme from directly participating in the apoptotic process [21]. H 3C

CH3

N

H 3C N

CH3

N HN

NH N

5 HOOC

COOH

Identification of the molecular target(s) of anticancer metal complexes is a formidable challenge because most of them are unstable toward ligand-exchange reaction(s) or biological reduction under physiological conditions. Gold(III) tetraphenylporphyrin 6 is notable for its high stability in biological milieux and potent in vitro and in vivo anticancer activities. Herein, extensive chemical biology approaches employing photo-affinity labeling, click chemistry, chemical proteomics, cellular thermal shift, saturation-transfer difference, nuclear magnetic resonance imaging (NMR), protein fluorescence quenching, and protein chaperone assays were used to provide compelling evidence that heat-shock protein 60 (Hsp60), a mitochondrial chaperone and potential anticancer target, is a direct target of 6 in vitro and in cells. Structure–activity studies with a panel of nonporphyrin gold(III) complexes and other metalloporphyrins revealed that Hsp60 inhibition is specifically dependent on both the gold(III) ion and the porphyrin ligand [22].

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N N

Au 3+ N

Cl

N

6

The bis-NHC complexes exhibited potent dark cytotoxicity toward a panel of cancer cells with IC50 values at submicromolar levels. The cytotoxicity of these complexes could be further enhanced upon light irradiation, with IC50 values as low as nanomolar levels in association with the light-induced generation of ROS. Bioimaging indicates that the Ir complex mainly targets the endoplasmic reticulum. It catalyzes the photoinduced generation of singlet oxygen and triggers protein oxidation, cell cycle arrest, apoptosis, and the inhibition of angiogenesis. It also causes pronounced photoinduced inhibition of tumor growth in a mouse model of human cancer [23]. Other macrocycles such as cyclophanes, calixarenes, and cucurbiturils as hosts to form supramolecular drugs were also extensively investigated.

56.2.2 Metal-Based Supermolecules as Antitumor Agents Metal anticancer complexes are a vigorous research field. Noble metal-based complex supramolecular drugs especially have achieved great success. Many metal complex supramolecular drugs such as cisplatin and carboplatin have been widely used clinically. Numerous researchers have been encouraged to develop precious metals as anticancer drugs. Platinum complexes are widely used clinically. So far, fewer non-platinum metal anticancer drugs have been approved for cancer chemotherapy, but some metal complex supermolecules of ruthenium, titanium, or gallium have already been tested in clinical phases. It is well known that a series of platinum complexes has been investigated extensively since the inorganic coordination complex of platinum, cisplatin, was found to exhibit antitumor activity in 1969. Cisplatin 7 as an anticancer drug was approved by the United States (USA) in 1978, and it is also widely used to treat many kinds of malignancies, including testicular, ovarian, cervical, and bladder types. The distinct anticancer mechanism, wide anticancer spectrum, and different toxicity spectrum of platinum complexes from many natural and nonnatural

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drugs, has focused more and more studies on platinum complexes. After cisplatin, several other platinum complexes such as carboplatin 8, nedaplatin 9, oxaliplatin 10, sunpla 11, and lobaplatin 12 have been approved for current tumor therapy. O

7

Pt

N H2

O

H3N

Cl

O

O

8

O

O

NH2

10

O

O

Pt2+

Pt2+ O

Me

O

H3N

O

9 NH2

O

NH2

O

O

Pt2+

O

Me

O

H3N

Pt2+

2+

Pt2+

H3N

H2 N

O

H3N

Cl

H3N

O 11

O

NH2

Me

12

O

Although cisplatin and carboplatin are the first choice as anticancer drugs, they have side effects of nephrotoxicity, neurotoxicity, and poor targeting. Therefore, much research based on the structures of cisplatin and carboplatin, according to the classic structure–activity relationship, has designed and synthesized new platinum complexes to decrease their toxicity. A cisplatin-type complex containing a ferrocenylphosphine moiety was linked with a nucleoside to give the new derivative 13. This supermolecule could improve significantly the physicochemical properties of the complex with better water solubility, longer half-life, and ease of binding to DNA. O Fe P

Ph

P Pt2+

Ph

Ph

OH

HO

NH

O

N

Me

OH

Ph

13

Cl

Cl

O

HN

N H

O

O

A unique class of estradiol-Pt(II) hybrid complex 14, which binds DNA indirectly through hydrogen bonds, showed good potential in vitro and in vivo for the treatment of hormone-dependent cancers, in particular for breast cancer, without any apparent side effects. When n was 4, complex 14 was more effective against several types of cancers than cisplatin. HO

OH

Me

n HN

Cl

N Pt2+ Cl

N

Pt2+ Cl

N Fe2+

N N

14 HO

15

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In addition to DNA binding, azole-based platinum supermolecules can also kill cancer cells by photodynamic therapy. The platinum (II) supermolecule 15 was obtained by ferrocene-modified terpyridine and carbazole derivatives, which could kill human skin keratinocytes under light (400–700 nm). The mechanism of action showed that ferrocene acted as a photoinitiator in the molecule, and after illumination, ferrocene ions were formed. This ion eventually reacted with molecular oxygen to form hydroxyl radicals, oxidizing the surrounding active molecules, causing irreversible damage and thereby killing cells [24]. The synthesis of a unique platinum (II) tethered to a cholesterol backbone was carried out via a unique monocarboxylate and O ! Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)2000]. The formed nanoparticles of 16 exhibited lower IC50 values in comparison with carboplatin or cisplatin in vitro and were active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibited significantly enhanced in vivo antitumor efficacy in murine 4 T1 breast cancer and in K-RasLSL/+/Ptenfl/fl ovarian cancer models with decreased systemic and nephrotoxicity. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicated that the constructed nanostructure could translate into a next-generation platinum-based clinical agent [25]. O

O H

H HN CH3 HN

O O H2N

CH3

CH3

H 3C

O Pt

H

16

CH3

NH2

Platinum(IV) complexes possess octahedral geometry. The introduction of two extra ligands, compared to Pt(II) complexes, enhanced their lipophilicity, and offered the opportunity to overcome some problems of platinum(II) drugs. A four-armed amphiphilic copolymer with a metallocycle was established in which the tetraphenylethene derivative acted as an aggregation-induced emissive fluorescent probe for live cell imaging and the 3,6-bis[trans-Pt(PEt3)2]phenanthrene (PhenPt) was an anticancer drug. This copolymer was further self-assembled into nanoparticles of different sizes and vesicles depending upon the experimental conditions, and the self-assemblies were further employed to encapsulate doxorubicin (DOX) to achieve a synergistic anticancer effect. The controlled drug release was also realized via amphiphilicity changes and was driven by a glutathione-induced cascade elimination reaction. The DOX-loaded nanoparticles of about 50 nm in size exhibited excellent antitumor performance as well as low systemic toxicity by the enhanced permeability and retention effect [26].

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Multifunctional supramolecular self-assembled nanoparticles were successfully constructed by host–guest interactions. The platinum(IV) prodrug 17 and the porphyrin photosensitizer 18 served not only as the building blocks but also the cargoes of the delivery system. The cellular platinum uptake derived from complex 17–compound 18 assemblies was much higher than that derived from cisplatin, and visible light irradiation induced the rise of cellular ROS. Therefore, a synergistic enhancement of anticancer efficacy has been achieved. The combination of chemophotodynamic dual therapy was proved to have great potential in overcoming cisplatin resistance [27]. O

O

+ N

+ N

N

HN

NH

HN

O O N

β-CD

β-CD O

Cl

Cl

O Pt4+ O H3N NH3

O 17

O

N +

N +

18

O

The successful exploitation and wide use of platinum supermolecules as anticancer drugs attracted great interest to investigate other transition metals instead of platinum. Ruthenium complexes have become one of the promising anticancer drugs because of their hypotoxicity and easier absorption by tumor tissue. Currently, most synthesized complexes were monocaryon, including ammonia (imine), multipyridine, ethylenediaminetetraacetic acid, and dimethyl sulfoxide complexes. Generally, the cytotoxicity of ruthenium complexes is related to DNA binding. The anticancer mechanism is that the complexes bind with DNA (covalent bond of guanine residue N7) by cross-linking adjacent Gua once entering into the caryon and then inhibiting the replication of DNA. Since the initial discovery that [Ru(η6-C6H6)(DMSO)Cl2] could inhibit topoisomerase II, three types of derivatives have been prepared by replacing the DMSO ligand with 3-aminopyridine, p-aminobenzoic acid, or aminoguanidine. These analogues enhanced the efficacy of topoisomerase II inhibition and showed higher cytotoxicity against breast and colon carcinoma cells. The aromatic Ru(II) complex 19 also gave good activity against human ovarian cancer cells and showed similar activity to that of carboplatin with no cross-resistance to cisplatin.

Ru3+

X R

N H

R Ph R R = H or Et , X = Cl or I N arene = p-cumene or biphenyl en = ethylendiamine or N-ethylenediamine Me 19

Me

OEt O

O Ti2+

O

O 20

OEt

Ph

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Furthermore, titanium and gallium complex supermolecules have also received much attention and some have been entered into clinical trials. For instance, budotitane 20, first discovered by Keppler in 1982, showed good activity against ascites cancer and solid tumor and better activity against colon cancer than 5-fluorouracil. Most gallium anticancer compounds in clinical phase I and II studies are inorganic salts of gallium such as gallium nitrate or gallium chloridate. These compounds have better anticancer activity accompanied by stronger toxic side effects. To diminish their toxicity, many organic gallium complex supermolecules were prepared. Complex 21 is now being tested in clinical phases, and the results have shown that the supermolecule 21 could inhibit prostate cancer and multiple myeloma. The activity of nitrogen heterocyclic carbene supermolecule 22 on ovarian cancer TOV21G is comparable to that of the reference drug cisplatin, a promising antiovarian cancer drug. Further studies revealed that when there is no substituent on the phenyl ring or an electron-withdrawing group instead of the methoxyl group, the supramolecular anticancer activity is significantly reduced. Me

O

O

Ga3+

O

O

O

O

O

O

N

Me

O O

Pd Cl

21

Me

N

H3C

2+

N N

O

N N

N

N 2NO 3

N

Cu 2+ N

N N

22

N

N 23

Pyrazole derivative 23 exhibits broad-spectrum anticancer activity and is effective in inhibiting the proliferation of glioma U373-MG cells, ovarian cancer A2780 cells, leukemia K562 cells, rectal cancer HCT15 cells, breast cancer MCF-7 cells, prostate cancer PC-3 cells, and lung cancer Hop62 cells with a GI50 value of less than 10 mol/l. The supramolecular molecule exhibits anticancer activity by inhibiting the activity of topoisomerase I.

56.2.3 Polymer-Based Supermolecules as Antitumor Agents The solubility, stability, targeting, or safety of some anticancer drugs seriously influences the therapeutic efficacy. These problems could be solved with the help of new drug delivery systems. The most extensive investigation was to use polymers as drug carriers. Drugs were encapsulated into the carrier to form various kinds of supramolecular drugs, such as liposomes and nanoparticles. The delivery systems of liposomes and nanoparticles have the merits of increasing solubility, prolonging retention time in vivo, enhancing drug targeting, decreasing toxicity, and overcoming anticancer multidrug resistance. So far many of these supramolecular

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preparations such as liposomes or nanoparticles have been used clinically. They effectively diminished the side effects, provided prophylaxis of cancer, relieved pain caused by cancer deterioration and chemotherapy, and made it possible to adopt original and better chemotherapy methods for current drugs. It has long been an important research area worldwide that antitumor agents could be developed as liposomal drugs. Many antitumor liposomes have been developed, such as platinum liposomes, paclitaxel magnetism liposomes, cisplatin invisible liposomes SPI-077, oxaliplatin liposomes (lipoxal), doxorubicin temperature-sensitive liposomes, and doxorubicin long-circulation liposomes (DOXILR). Research showed that encapsulation of doxorubicin in polyethylene glycol-coated liposomes could enhance the safety and efficacy of conventional doxorubicin. In preclinical models, liposomal doxorubicin could produce remission and cure against many cancers including tumors of the breast, lung, ovaries, prostate, colon, bladder, and pancreas, as well as lymphoma, sarcoma, and myeloma. It was also effective as adjuvant therapy. In addition, it was found to penetrate into the blood–brain barrier and inhibit the growth of tumors in the central nervous system. The combination of liposomes with vincristine or trastuzumab resulted in synergistic effects and better efficacy. Liposomes appeared to overcome multidrug resistance, possibly as the result of increased intracellular concentrations and an interaction between the liposome and P-glycoprotein, and showed favorable applications for treating a variety of cancers. Therefore, it is an important trend to improve anticancer drugs by developing liposomes as long-lasting circulation preparations, exploiting a variety of liposomes that are new and aggregate in high concentration in a local tumor. Nanoparticles are submicron-sized polymeric colloidal particles. In recent years, the clinical values of nanomaterials have been becoming more and more important, and nanoparticles received more attention to act as anticancer drug carriers. Nanotherapy enhanced the drug accumulation in tumor tissue and slowed tumor growth. Some anticancer nanoparticles have been approved by the US FDA for clinical use. Currently, much work focused on nanoparticles of paclitaxel, mitomycin, 5-fluorouracil, doxorubicin, and platinum drugs. Some nano-techniques were also employed to improve PDT therapy. Research revealed that paclitaxel nanoparticles prepared by the nano-precipitation method have activity comparable to traditional formulations, such as the introduction of a solubilizing agent or preparation of cyclodextrins inclusions, with much faster drug-release rate and prolonged action time. Cellular studies showed as much as a 70% loss of viability in NCI-H69 human small cell lung cancer cells at levels of 0.025 μg
ml1. An innovative drug delivery system based on a self-assembling amphiphilic dendrimer was developed that can generate supramolecular nanomicelles with a large void space in their core to encapsulate anticancer drugs with high loading capacity. The resulting drug-encapsulated nanomicelles can effectively enhance drug potency and combat drug resistance by promoting cellular uptake and decreasing the efflux of the anticancer drug. Moreover, this drug delivery system can significantly reduce the systemic toxicity of the free drug [28].

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56.3

Supermolecules as Antiinflammatory and Analgesic Agents

Inflammation is now recognized as a type of nonspecific immune response to a destructive stimulus, and is a basic way to protect the body from infection, irritation, or other injuries. Its clinical appearance includes redness, warmth, swelling, and pain as well as functional disturbance. Antiinflammatory and analgesic drugs are a class of drugs acting against fever and pain, inflammation, and rheumatism. Because of their exceptional antiinflammatory activity, this class of drugs was named nonsteroidal antiinflammatory drugs (NSAIDs) in the 1974 international conference at Milan in Italy. Aspirin is the representative of this type of drug. Aspirin, the first NSAID used clinically, was a milestone for the use of synthetic drugs to treat inflammation. Subsequently, the NSAIDs expanded to more than 100 varieties and became the first choice to treat osteoarthritis and arthritis pauperum. However, the high gastrointestinal side effects restricted their application. The complexation of NSAIDs with metal ions could significantly reduce gastric toxicity, and some even enhance analgesia and antiinflammatory activities. Copper–NSAIDs complexes were extensively investigated beginning in 1976. It was found that the antiinflammatory activities of Cu–NSAIDs complexes in animal models were better than the parent NSAIDs. For example, the antiinflammatory activity of the Cu(II) complex of aspirin was shown to be 30 times higher than the free drug aspirin. Other NSAIDs–metal complexes such as Zn(II), Pd(II), Sn(IV), and Ru(II,III) also decreased toxicity and enhanced the activities of parent compounds. The zinc complex supermolecule formed with aspirin or niacinamide not only could ameliorate the irritation of aspirin in the gastrointestinal tract but also significantly enhanced antiinflammatory activity. The manganese complex of compound 24 displayed antiinflammatory response as good as that of the parent NSAID sulindac. In addition, the silver (I) complex of compound 25 displayed an antiinflammatory response as good as that of the parent NSAID ibuprofen, respectively [29]. Ruthenium complexes with isonicotinic and nicotinic acids showed antinociceptive and antiinflammatory activity and the mechanism of antinociceptive effect involved in reducing neutrophil migration and inhibiting PKC activation in vivo [30]. Rhodium(III) 26, in the mice model, showed similar antiinflammatory activity to mesalazine [31]. F

H 3C O

O

S 24

CH3

N H

N

CH3 O N

N

CH3 25

H N

N

N

Rh CH3

NH

N 3+

OCH3

N

PF6 26

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Not only could the NSAIDs metal complexes lower the gastrointestinal damage of NSAIDs, but also the organic complex supermolecules, formed by CDs and their derivatives with NSAIDs, could improve their pharmacodynamics and pharmacokinetics properties. The indomethacin-CD inclusion complex has no anabrosis side effect. Naproxen-β-CD significantly increased the water solubility, raised the dissolution rate, facilitated absorption, degraded gastrointestinal damage of naproxen, and also possessed lower photoxicity after complexation with β-CD. In addition, the ibuprofen–β-CD complex also increased the aqueous solubility, absorption rate, and bioavailability of ibuprofen. Coating with pH-sensitive CD derivatives is a method of drug delivery to the site of action, for example, the antiinflammatory effect of the prednisolone succinate/α-CD(PDsuc/α-CD) inclusion complex, was comparable to those of prednisolone (PD) alone, although its systemic side effect was much lower than that of PD alone when administered orally, which might be related to the specific degradation of the inclusion complex in the large intestine. Superoxide dismutase (SOD), a new type of antiinflammatory preparation, is an important oxygen free radical scavenger, mainly used for the treatment of patients with inflammation. However, its shortcomings such as high cost, large molecular weight, and low stability prevent its wide use. Many studies have confirmed that nonsteroidal antiinflammatory drugs containing carboxylate ligands and Cu2+ ion could form a metal supermolecule, which displayed SOD activity. The nonsteroidal antiinflammatory drug ibuprofen forms copper (II) complexes 27 and 28 with imidazole and caffeine, respectively: these can inhibit the conversion of oxygen free radicals with IC50 values of 0.70 and 0.24 μg/ml, respectively, which are equivalent or lower than the reference drug ibuprofen calcium salt and natural SOD (IC50 = 0.70 μg/ml). O

H3C O

PhO O HN

N

O Cu2+

O

H3C N N

O OPh

NH

56.4

N

CH3

N

O

O H3C

28

CH3

Cu2+ O O H3C

H3C 27

PhO

N

CH3

N

N

O

N

OPh O

CH3

N CH3

Supermolecules as Antimalarial Agents

Malaria, one of the most challenging public health problems all over the world, is the most common hazardous parasitic disease worldwide. The rapid expansion of multidrug-resistant parasites has seriously weakened the therapeutic efficacy of

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antimalarial agents. Thus, it is quite urgent to find new antimalarial agents with different structures and mechanisms for clinical use. Exploring novel antimalarial agents is important for controlling malaria. Cinchonine 29 is an earlier drug for treating malaria. To improve its water solubility, CDs were employed to form inclusion complexes with cinchonine that might give three types of supermolecules, and these supermolecules improved its solubility significantly. Artemisinin is one of the most widely used antimalarial drugs. However, its low aqueous solubility and shorter half-life resulted in poor and erratic absorption upon oral administration. After encapsulation with CDs, its solubility and oral bioavailability were greatly enhanced. HO

HN

H

N Fe

Me H N

Me

Cl

F3C

N N 29

Cl

N 30 Ferroquine(FQ)

N

Cl 31

Organic metal complexes as a novel class of antimalarial supermolecules have received close attention. Ferrocene, with its distinct features of sandwich structure and electrochemical behavior, is widely used in biological research and drug design. Ferroquine 30 is an earlier antimalaria complex containing a ferrocene structure. The survival of mice by treatment with ferroquine was far greater than that of current standard drugs, and it also displayed long-term stable antimalarial activity in the biosystem. Trifluoromethylbenzimidazole 31 is an anti-protozoal agent that effectively kills protozoa such as Giardia intestinalis, Entamoeba histolytica, Trichomonas vaginalis, and Leishmania mexicana. However, its clinical application has been limited by its low water solubility. An effective way to increase the water solubility, stability, and bioavailability of drugs is to form supermolecules with cyclodextrin. The study showed that complex 31-Mβ-CD formed by compound 31 and methyl-βcyclodextrin (Mβ-CD) had an IC50 value of 1.9 μg/ml against Leishmania, and its insecticidal effect is far superior to the reference drug amphotericin B (IC50 = 6.5 μg/ ml) and glucantime (IC50 = 18.4 μg/ml). At the concentration of 100 μg/ml, 31-MβCD (82%) showed much better inhibition than the reference drugs nifurtimox and benznidazole (inhibition rate < 50%) against American trypanosomiasis (Chaga disease). In vitro cytotoxicity studies revealed that 31-Mβ-CD showed a hemolysis reaction greater than 500 μg/ml. These studies indicated that 31-Mβ-CD was expected to be developed as an anti-pathogenic drug.

56.5

Supermolecules as Antibacterial Agents

The frequencies and types of life-threatening infections have been increasing, especially in recent years with the high incidence of multidrug-resistant (MDR), having broken the last line of defense of vancomycin as the antibacterial drug of last

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report for the treatment of MDR. The synthetic antibacterial agents being used extensively in clinics, such as quinolones and sulfonamides, and antibiotics such as β-lactam antibiotics and aminoglycoside antibiotics, could not effectively inhibit these bacterial strains; even oxazolidinon, with its new mode of action, cannot meet clinical needs. It is quite urgent to develop novel antibacterial agents with a new mechanism of action and effectively decrease drug-resistant strains. Numerous investigations have proved that the complexation of antibiotics or potent antibacterial agents to various kinds of metal ions enhances activity and, in some cases, the complexes possessed even more healing properties than the parent drugs. Therefore, to develop and screen new therapeutic antibacterial agents from these active supermolecules is being extensively investigated. According to the structures of the ligands, the supermolecules as antibacterial agents can be divided into the following categories: quinolones, sulfanilamides, Schiff bases, thiosemicarbazides, and macrocycles [32].

56.5.1 Quinolone-Based Supermolecules as Antibacterial Agents Quinolones are an important class of synthetic antibacterial agents. Since the introduction of nalidixic acid into clinical practice in 1962, quinolones have been developed from the first generation to the fourth generation and are used to treat various kinds of infections. Many researchers have reviewed the mode of action, structure–activity relationship, and activity of these quinolones. It is found that quinolones can bind with DNA mediated by a transition metal. Therefore, it is important to study the coordination chemistry of quinolone antimicrobial agents with metal ions and their antibacterial activities in biology and pharmacy. Oxolinic acid, OXO, a first-generation quinolone antimicrobial drug, is used for the treatment of urinary tract infections. The complex of oxolinic acid 32a, Cu (OXO)2(H2O), MoO2(OXO)2, and UO2(OXO)2 showed decreased biological activity in comparison to the free oxolinic acid. Copper(II) complexes of oxolinic acid did not affect the inhibition of the growth of microorganisms significantly when other ligands were introduced, such as 1,10-phenanthroline, 2,20 -bipyridine, and 2,20 dipyridylamine. The complex of cadmium as soft acid and toxic metal ion 32b showed activity against many gram-negative bacteria and Pseudomonas aeruginosa similar to that of cinoxacin. O

O

O O O Et

N

O

N

Et

45 32a, X = C 32b, X = N

O O

N

O O

N N H

Et

N

N

M2+ O O

X

O X

N

M2+ O O 33

Et

H N

N N

N

O

Pipemidic acid is a second-generation quinolone antimicrobial drug that is used to treat gram-negative urinary tract infections and severely damages DNA in the

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absence of an exogenous metabolizing system. It could form complexes with a series of metal ions such as Ca(II), Sr(II), Ba(II), Sn(IV), La(III), Ce(III), Pr(III), Nd(III), Sm(III), Tb(III), Dy(III), Y(III), Cu(II), and Mn(II) ions. The reported results suggest that metal ion coordination functions in the antibacterial activity. It was found that among a series of complexes of pipemidic acid with VO(II), Mn(II), Fe(III), Co(II), Ni(II), Zn(II), MoO2(II), Cd(II), and UO2(II), the best inhibition is provided by the UO2(II)complex of supermolecule 33 (MIC = 8 μg ml1) against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. Norfloxacin is a widely used broad-spectrum antibacterial clinical drug. Many studies have reported the biological activities of the metal complex of norfloxacin, such as silver, tungsten, copper, and auric complexes as well as ternary complexes of copper(II) with norfloxacin. Silver complex 34 of norfloxacin was reported to prevent bacterial infection for humans during burn treatment, and its antibacterial property in topical applications is superior to that of silver and zinc sulfadiazine. In particular, these complexes have better antibacterial activities against P. aeruginosa than the free ligand norfloxacin, but lower against Bacillus subtilis. O

O HOOC

F

N Et

Et

N O O NH Ag

N

N

N

NH F

34

COOH O

56.5.2 Sulfanilamide-Based Supermolecules as Antibacterial Agents Sulfonamides are the first synthetic antibacterial agents used in clinics as therapeutic agents against various bacterial infections. In recent years, some metal sulfonamides have attracted much attention because complex supermolecules showed greater activity than both free ligands and the corresponding metallic salts. In particular, Ag-sulfadiazine has been proved to be an effective topical antimicrobial agent, of significance in burn therapy, better than the free ligand or AgNO3. Moreover, some metal complexes of heterocyclic sulfonamides, such as sulfisoxazole, sulfapyridine, sulphadiazine, and sulfathiazole, have been extensively investigated. The metal sulfisoxazole complex 35 presented effective antibacterial activity against Staphylococcus aureus, E. coli, and Mycobacterium tuberculosis. Complex 35a presented the same activity against S. aureus and E. coli as sulfisoxazole, whereas the structurally similar complex 35b was more active against the foregoing bacteria than the free ligand and had no activity against M. tuberculosis. Probably the good antimicrobial result occurred because the copper complex 35b can penetrate easily into a less lipophilic cell wall and ionize into the active compounds inside the cell. New gold(I) and silver(I) complexes of sulfamethoxazole 36 showed better activity against E. coli, P.

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Supermolecules as Medicinal Drugs

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aeruginosa, and S. aureus than their ligands, which suggested that metal sulfonamide complexes provide possibilities for the development of new antibacterial drugs. Me

HN O

Me

OH2

Me

M2+

N

Me

N

O

O

OH2

S

Me NH O

S

O

HN O S

O

O

NH2 H2N 35a, M = Ni 35b, M = Cu

35

O N

NH2

36

Sulfadiazine-derived complex 37 exerted good inhibitory activity against some bacteria; especially, the zinc complex exhibited the best bactericidal potency against Bacillus subtilis and Staphylococcus aureus. These metal complexes performed stronger biological activities than the corresponding ligands and deserved further exploration. H N N

Br

O S N

O

N

O

H2O

M2+ O

H2O

N

O S

H N

N

O Br

M = Co; Ni; Cu; Zn

N

37

56.5.3 Schiff Base-Based Supermolecules as Antibacterial Agents The metal complexes containing oxygen and nitrogen donor Schiff bases possess unusual configuration and structural lability, and they are sensitive to the molecular environment. The environment around the metal center, for example, coordination geometry, the number of coordinated ligands and their donor groups, is the key factor for metalloproteins to carry out specific physiological functions. The Schiff base, containing a phenolic hydroxyl group or aromatic heterocycle with three nitrogen atoms, phosphoric acid, and phosphonate ester as well as their corresponding metal complexes, showed significant antibacterial activities that received considerable attention. Among these complexes, copper complexes were the most important class with good antibacterial activity, and the related work is reviewed here in detail. The oxygen and nitrogen donor atoms in Schiff bases containing a phenolic hydroxyl group could chelate with many transition metals, showing their biological

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C.-H. Zhou and Y.-F. Sui

activity. For example, the Ru(II)-complex of Schiff base derived from vanillin 38 showed significant activity against Staphylococcus aureus and Escherichia coli, and its antibacterial efficacy was higher than that of corresponding ligands. Structurally similar ligand naphthylideneimine derivatives exhibited little biological activity, but their Ru(II)-complex 38 showed moderate activity against S. aureus and E. coli. Ph R CO Cl R

N

N

Ph3Z

Ru2+

O

PPh3

O

CO Ru2+

N OMe 37

38

N

N Cl

ZPh3

R Z = P, As

N N N S

Zn2+

S

N N N

Ph

Ph

N

N

N

39a: R = H 39b: R = CH3

R Ph

Zinc supramolecular complex 39a showed a better inhibitory ability against Staphylococcus aureus and Bacillus subtilis, with both minimum inhibitory concentration (MIC) values of about 10 μg/ml, than the reference drug ciprofloxacin. The inhibitory activity of compound 39a against Escherichia coli and Pseudomonas aeruginosa was not ideal. The structure–activity relationship revealed that the supramolecular complex 39b obtained by introducing a methyl group into the 3position of the pyrazole ring showed equivalent anti-Escherichia coli potency in comparison to ciprofloxacin. The antibacterial activity toward Pseudomonas aeruginosa was also improved. Therefore, complexes 39a and 39b had the potential to become a new type of antibacterial drug after further research. Moreover, some nonionic Schiff bases showed antibacterial and antifungal potency. The biological activity of their Cu(II) as well as their Fe(III) complexes being synthesized in ML2 and ML3 stoichiometry have been studied in detail. Comparing with the different Schiff bases, the antimicrobial activity against the fungi Aspergillus niger and A. flavus, and the bacteria Candida albicans, Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, was enhanced with increasing length of the alkyl chain. Furthermore, after complexation with Cu(II) or Fe(III) ion, the antibacterial and antifungal activities increased as well. In contrast to the other metal complexes, the Cu(II) complexes showed higher activity against bacteria and fungi. The biological activity of the metal complexes was interestingly decreased when the chain length of the hydrophobic moieties was increased, whereas the contrary trend was observed for the ligands. This difference could be explained by micelle formation occurring more easily for the amphiphilic metal complexes with longer alkyl chains [33]. Complex 40 was found to specifically inhibit the growth of gram-positive bacteria Staphylococcus aureus with MIC50 values of 2–5 μg/ml and completely abolished its growth at 10 μg/ml (MIC100). This activity is comparable but slightly lower than the antibacterial activity of a well-known benchmarked antibiotic ciprofloxacin. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 40, including the role of ribonucleotide reductase (RNR)

56

Supermolecules as Medicinal Drugs

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inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways [34]. Cl Cu2+ N

S

N N

O

N H

40

56.5.4 Hydrazone-Based Supermolecules as Antibacterial Agents The β-nitrogen atom in carbohydrazones coordinated to the metal atom has an interesting stereochemistry, whereas the α-nitrogen remains uncoordinated. Complex supermolecules of carbohydrazones showed significant antibacterial, antifungal, and antiproliferative activities, so their research and application suggested enormous potential in the medicinal area. The complexes of ferrocenyl carbohydrazone or thiocarbohydrazone 41 displayed moderate antibacterial and antifungal activity, and their activities increased significantly in comparison with their ligands. Ruthenium complexes have been applied in many research areas. The complex 42 of Schiff base hydrazone containing quinolines showed more effective antibacterial activity. Transition metal complexes of hydrazides and sulfonamides also were found to be used as chemotherapy. The nickel(II) complex of new sulfonyl hydrazone 43 exhibited moderate activities against grampositive bacteria including Staphylococcus aureus, Bacillus subtilis, Bacillus megaterium, and the gram-negative bacteria Salmonella enteritidis and E. coli. N

X

Me HN N Cl N

Fe

HN

O

R2 C

N

N H

Ni 2+ O

Me

S 43

O

N

O M 2+

Cl

Fe

O

H N O

Cl N

NH

HN Me

X M= Co, Ni, Zn

R

NH

N Cl N

M2+

Me

1

Me

NH

42

41

M = Cu, Ni, Co, Fe N

X = O, S

S O

N

C H

1

2

O

O N

Me

R , R = H, CH3

R1

N Me

S N H

O 44

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C.-H. Zhou and Y.-F. Sui

The cobalt(II), nickel(II), copper(II), or zinc(II) complex of isatin derivative 44 exhibited a strong inhibition of the growth of Haemophilus influenzae with MIC values of 0.15–1.50 μg
ml1, and good antibacterial properties toward B. subtilis with MIC values of 3–25 μg
ml1. These supermolecules also showed good activities against the dermatophyte mold Epidermophyton floccosum.

56.5.5 Thiosemicarbazone-Based Supermolecules as Antibacterial Agents Thiosemicarbazones have been considered to be good chelating ligands since the activity of metal complexes of 2-formyl and 2-acetylpyridine thiosemicarbazones was demonstrated in clinically isolated bacteria in the 1990s. Many studies showed that thiosemicarbazones had antimicrobial activity, and exhibited significant inhibitory activity to gram-positive bacilli but poor activity to gram-negative bacilli. Some studies have pointed out that the copper complexes of thiosemicarbazones could be used as novel antimicrobial agents to treat the infectious diseases caused by drug-resistant fungi and bacteria. The copper complexes of pyridine-derived thiosemicarbazones were found to exhibit broad-spectrum antimicrobial activities. The copper complex of compound 45 gave a MIC value of 5 μmol
l1 against the growth of Salmonella typhimurium and 0.5 μmol
l1 against the growth of Candida albicans. The bismuth(III) complexes of morpholine-substituted compound 46 showed highly selective inhibition toward the growth of gram-positive bacteria Staphylococcus aureus and Bacillus subtilis. Me Ph N

H N

N

O

H N S

45

H N

N

Me CO N N

S Me

ZPh3

S

46 H2N

O

O

Ru2+ N Me N Z = P, As ZPh3

O 47

The interaction of small molecules such as CO and O2 with transition metal complexes, particularly those containing a ruthenium metal center coordinated to nitrogen and oxygen donor ligands, has attracted great interest in recent years. Complex 47 showed good activity against Staphylococcus aureus, Escherichia coli, Candida albicans, and Aspergillus fumigatus. The derivative of 2-hydroxyacetophenone N(4)-substituted thiosemicarbazone 48, and their copper complex showed significant growth inhibitory activity against the bacteria E. coli and S. aureus and the fungi C. albicans and A. flavus. Steroidal thiosemicarbazone palladium complex 49 had the same antibacterial activity as amoxicillin against E. coli, Streptococcus pyogenes, and Staphylococcus aureus. The copper complex of pyrrole-2-carbaldehyde thiosemicarbazone 50 was confirmed to be a broad-spectrum antibacterial agent, with an MIC value of 12 μg
ml1 against Bacillus subtilis and S. aureus. Interestingly, it could effectively inhibit the growth of both penicillin-

56

Supermolecules as Medicinal Drugs

1609

susceptible and -resistant Staphylococcus strains, acted as 25 μg
ml1 toward S. cerevisiae, and 50 μg
ml1 toward C. tropicalis and A. fumigatus. Cl Pd 2+

Cl CH3 N

OH 48

Me NH

S

Me

Me

Me N

N

H N

NH

S

S

HN NH

Me

49

NH2

50

Me

R

56.5.6 Macrocycle-Based Supermolecules as Antibacterial Agents Macrocyclic complexes have attracted great attention because of their pharmacological properties against bacterial and fungal growth. Porphyrins are a class of good photodynamic photosensitizers that can be used for research of the inhibition of bacteria and treatment of various kinds of bacterial infections, and can be also used as a sterilizing agent and antiseptic in hospitals. The macrocyclic complex 51 derived from benzil and oxalyldihydrazide was found to exhibit remarkable antibacterial activities against Salmonella typhi, Staphylococcus aureus, and Escherichia coli, and some complexes were equal to standard antibiotic linezolid against the same bacterial strains. Novel macrocyclic Co(II) compounds derived from o-phthalaldehyde showed remarkable antibacterial activity; for example, complex 52 was more active against S. aureus, E. coli, and P. aeruginosa, compared to streptomycin and ampicillin, and also showed very good efficacy on clinically resistant strains. Nickel(II) complexes of macrocyclic ligand derived from semicarbazide and thiodiglycolic acid 53 showed that the percentage inhibition of bacterial growth of S. aureus was 90% at the concentration of 0.5 mg
ml1, and showed good antifungal activity against A. fumigatus. O

O

HN Ph

N

NH X

N

N

M2+ Ph

N HN

51

N NH

O

O

S

Ph HN HN Cl

Co 2+

Ph X

Cl N

N

Cl

N

S

NH

52 O O M = Cr, Mn, Fe X = Cl, NO3, CH3COO

Cl HN M

M

Cl

Cl

HN

NH S

S

O 53 M = Co2+ , Ni2+ , Cu 2+, Ru3+, Ir 3+ O

Nickel(II) complexes of polyaza macrocycle 54 were found to decrease in antibacterial activity upon coordination in all cases. However, the macrocyclic

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C.-H. Zhou and Y.-F. Sui

dinuclear complex 55 gave selective antibacterial activity with moderate inhibition toward the growth of S. aureus. Me H

R

Me

N

Me

N

N

Me Me

Me

Ni N

N

Me Me 54

Me

Cu2+ H Me

N M = Zn, Pb R = CH2CH2N(CH2Ph)CH2CH2 CH2CH2N(CH2CH2Ph)CH2CH2 55

N

N NH

O

O

2+

Me

N M Me

N

M2+

NH N

N

NH

M2+ NH NH

56 56a: M = Zn, 56b: M = Cu

The macrocyclic polyamine 1,4,7,10-tetraazacyclododecane has been extensively studied for its strong ionic coordination ability and important antimicrobial activity. Supramolecular molecule 56, a complex formed by macrocyclic polyamine 1,4,7,10tetraazacyclododecane and benzoimidazole derivatives, showed relatively weak inhibitory activity to Escherichia coli and Bacillus subtilis, but had a good growth inhibitory effect on Staphylococcus aureus, Xanthococcus aureus, Pseudomonas aeruginosa, Bacillus proteus, and other strains. The structure–activity analysis found that both metal ion species and bridging benzene linkers had an effect on the antibacterial activity. Complex supermolecule 56a had a very strong inhibitory ability against Pseudomonas aeruginosa and B. proteus, with MIC50 values of 1 and 0.5 μg/ml, respectively, being 32 fold and 4 fold better than that of the reference drug chloramphenicol, respectively. However, the antibacterial activity of 56b with a different central ion was significantly reduced, and the MIC50 value of anti-Pseudomonas aeruginosa activity was more than 512 μg/ml [35].

56.5.7 Other Supermolecules as Antibacterial Agents Some other metal complexes formed with other structures, including the drug ligands such as tetracycline and vitamins, and others such as chalcone and phenanthroline, also showed antibacterial potential. Tetracyclines (TC) are broad-spectrum antibacterial agents with effective activity against both gram-positive and gram-negative bacteria, Chlamydia, Mycoplasma, Rickettsia, and protozoan parasites. Other antibiotics of this TC family, doxycycline and chlortetracycline (Chl), showed the same antibacterial activity. Compared to the tetracycline compounds, their corresponding Pd(II) complex 57 resulted in a significant change of biological activity against E. coli. Practically, complex 57a was 16 fold more effective in inhibiting the growth of E. coli strains, whereas complex 57b increased its activity in the resistant strain by a factor of 2 fold. Curiously, complex 57c did not improve its activity against the E. coli strain.

56

Supermolecules as Medicinal Drugs

Me R2 R 1 CH3

Me Cl

N

C

OH

O

B OH

A OH

O

OH2

O O

O D

1611

M

O O

Pd 2+

NH2

NH

Cl

O 57

57a, R1 = OH, R2 = H 57b, R1 = R2 = H 57c, R1 = OH, R 2 = Cl

O

OH2

N O O N 58 H H 2+ 58a, M = UO2 , 58b, M = VO 2+ 58c, M = ZrO2+

N

NH

Cl

O2N

O

59

Me Me

N

N Cl

N

O2N

N

Vitamin B13, belonging to pyrimidine bases in nucleinic acid, is important for cell regeneration in older persons, especially the liver and gastrointestinal tract cells, and is also valuable to be used as an anticancer drug. It is of importance that vitamin B13 and its derivatives could coordinate with many metals to form active biological complexes. The biological assay showed that the synthesized complex 58 has enhanced activity compared to vitamin B13. The biological activities of metal complexes increase in the order 58a > 58b > 58c. Not all the complexes showed better antibacterial activity than their ligands, such as copper and nickel complexes of bis-nitroimidazole 59 with weaker activity. Other complexes of imidazole and picolinamide have also been extensively investigated. Among these studies, many reports concerned copper complexes with stronger biological activity. Most of them showed broad-spectrum antibacterial and antifungal activities and were superior to other metal complexes and their corresponding ligands. The possible reasons are (1) the copper complexes have a proper lipid–water partition coefficient, which enables these compounds to penetrate more easily into the cell and release active matter; and (2) the activated oxygen on the copper surface can inhibit bacterial growth. With the rapid progress of supramolecular chemistry, it would certainly be possible to develop supramolecular antibacterial agents with high efficacy, low toxicity, and a broad spectrum and novel mode of action, to overcome the problem of microbial resistance to current antimicrobial drugs. The N-propenyl-substituted imidazolium nitrogen heterocyclic carbene silver (I) supramolecular complex 60a can inhibit the growth of Staphylococcus aureus and Pseudomonas aeruginosa by destroying the bacterial cell walls, with MIC values for both species about 4 μg/ml. The structure–activity relationship showed that the supramolecular complex 60b obtained by substituting Au+ ions for Ag+ ions showed better antibacterial activity than 60a, and the inhibitory potencies against these two bacteria increased by two- and fourfold, respectively. When using the ligand of 60a to form a binuclear macrocyclic supramolecular complex 61, its antibacterial activity was significantly lower than that of 60, and the MIC values for both S. aureus and P. aeruginosa were greater than 100 μg/ml [36].

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C.-H. Zhou and Y.-F. Sui

CH3

CH3

N

H2C

N N

M+

Br

CH2

N +M

Br

60 60a: M = Ag 60b: M = Au H2C

N Me

N

N

N

M+

Me H2C

N

Me

2PF6N

CH2

M+

Me CH2

N

N 61: M = Ag, Au

Superamolecule 62 is formed by a terphenyl-substituted methylene-bridging bipyrazole ligand. Supramolecular complex 62c had weak inhibitory activity against Bacillus subtilis, but it had a strong inhibitory effect on the growth of Staphylococcus aureus, with an MIC50 of 0.58 μg/ml; the inhibitory activity was equivalent to that of chloramphenicol. Compounds 62a and 62c effectively inhibited Pseudomonas putida growth with MIC values of 0.011 and 0.042 μg/ml, respectively, and the activity was 16 and 4 fold stronger, respectively, than that of the reference drug chloramphenicol. However, the supramolecular complex 62b, obtained by replacing chlorine with bromine, showed almost no inhibitory activity on either strains, indicating that the chlorine ligand was of great significance to enhance the antibacterial activity of the supramolecular complex, and that supermolecule 62a had potential to be developed as an antibacterial drug [37]. NH

X

N

N

2+

Zn X

N N

62a: X = Cl 62b: X = Br 62c: X = I

N

N

Cl

N 63a: M = Cu 63b: M = Zn

M2+ Cl

N H2O

Phenanthroline is a widely used organic ligand; the Cu2+ ion can cleave DNA by oxidation. The supramolecular complex 63a has a broad antibacterial spectrum and strong antibacterial ability. It exerted comparable inhibitory potency against Pseudomonas aeruginosa and Escherichia coli to the reference drug tetracycline, and the inhibitory ability against Pantoea dispersa and Bacillus subtilis was twice that of tetracycline. The structure–activity relationship study revealed that the complex 63b formed by replacing the central ion with the Zn2+ ion showed lower inhibitory ability

56

Supermolecules as Medicinal Drugs

1613

on the foregoing four bacteria than that of 63a, but its activity was still stronger than tetracycline. This finding is important for the further development of triazole antibacterial drugs. Some chalcone complex supermolecules also showed moderate antibacterial activity against Escherichia coli and Staphylococcus aureus. The octahedral complex proved to inhibit a human rhabdomyosarcoma cell line to nearly the same extent as the cisplatin control, with higher inhibition capacity than the related Cr(III), Fe (III), and Co(II) complexes [38].

56.6

Supermolecules as Antifungal Agents

Fungal infections are one of the leading causes of death of immunocompromised patients. Azole drugs such as ketoconazole and fluconazole are currently prescribed to treat fungal infections caused by the pathogenic yeast Candida albicans. However, many antimicrobial agents are toxic, and their extensive therapeutic use is often accompanied by problems of drug resistance, unwanted side effects, and other difficulties. It is quite urgent to develop new and highly effective antifungal agents. Mononuclear silver (I) complexes with 1,7-phenanthroline exhibited selectivity toward Candida, effectively inhibiting the growth of Candida albicans, C. parapsilosis, C. glabrata, and C. krusei with MICs ranging from 1.2 to 11.3 μM; C. krusei and C. albicans especially were the most sensitive. Complex 64 showed the lowest MIC values and the lowest cytotoxicity against healthy human fibroblasts with SI of more than 30, and it had the ability to attenuate C. albicans virulence and reduce epithelial cell damage in a cell infection model. In comparison to silvadene, complex 64 showed a fivefold lower MIC value against C. albicans and displayed fourfold lower cytotoxicity. Considering the remarkable activity against all tested Candida species, coupled with the fact that structural differences to other complexes were in the different counterion, complex 64 could be selected for further activity research [39].

N N

N N

Ag + NO3 64

N

N

N

65

N Zn2+ N

N N N

O

O

I

N CH3

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C.-H. Zhou and Y.-F. Sui

Photodynamic inactivation of pathogenic fungi as a novel antifungal strategy was found to have tempting characteristics such as the avoidance of drug resistance, narrow impairment to the host tissues, and broad-spectrum activity. Furthermore, phthalocyanines have been considered as highly potential second-generation photosensitizers because of their intensive absorption in the red visible light region and high competence in generating ROS. The cationic α-mono-substituted Zn2+ phthalocyanine 65 was not only observed with noticeable antifungal photoactivity, with an IC90 value against C. albicans as low as 3.3 mM, but also presented good photocytotoxicity with high cellular uptake. However, tetra-substitution and β-substitution with a morpholinyl moiety as well as non-quaternization would cause an adverse effect on its potency attributable to the caused change on hydrophilicity. All these results indicated that complex 65 holds great potentiality as an intriguing candidate for future studies as an antifungal photosensitizer [40]. The macrocyclic dinuclear Zn2+ complex 56a, produced by combining polyamine with benzoimidazole via a xylyl bridge, possessed low MICs, 0.5 and 8 μg/ml, respectively, toward Candida albicans and Aspergillus fumigatus, which was more active than fluconazole. The substitution of the xylyl fragment with the 2,6-dimethylpyridyl moiety was not favorable for antifungal efficiency, because the nitrogen in pyridine was likely to decrease the positive charge density and also hindered the approach between molecule and fungus through electrostatic interactions. Also, length was an influencing factor for lipophilicity or hydrophilicity between two metal nuclei, a significant antifungal property. It was also found to be likely to destroy the cell membrane as quaternary ammonium salt antimicrobial agents do. By contrast with the inhibitory action of the mononuclear complex, it was shown that dinuclear compounds exhibited more desirable potencies, indicating the importance of the metal ion in antifungal activity [35]. H N S N

N Cu2+

N

N S

N H

66

Thiabendazole, with structural similarity to the chelating agents 1,10phenanthroline and 2,20 -bipyridine, is a well-known anthelmintic agent and fungicide in agriculture with poor anti-Candida activity. However, its copper complex 66 was an activity-strong supermolecule with effective inhibition of the growth of C. candida strains. Complexes 67a–c acted as inhibitors against the tested fungal strains with extremely remarkable rates, in the range of 85–99%, in order of Aspergillus sp. > Penicillium sp. > Rhizoctonia sp. The anion participating in chelation also was

56

Supermolecules as Medicinal Drugs

1615

critical in potency, whereas the acetate was a more beneficial ion for maintaining good activity. O

O R

N

2Cl Cr

O

NH

HN

N

N

N

X R

HN O

CH3

3+

H 3C

O

NH O

H3C Ir3+ CH3 HN N

F

R=

N H

67a: X = CH3COO 67b: X = Cl 67c: X = NO3

N

68

NH2

Novel organoiridium (III) antimicrobial complex 68, containing a chelated biguanide, including the antidiabetic drug metformin, exhibited high antifungal potent activity against C. albicans with MICs in the nanomolar range. The complexes exhibited high selectivity and low cytotoxicity toward mammalian cells. Investigations of reactions with biomolecules suggested that these organometallic complexes delivered active biguanides to the microorganisms, whereas the biguanides themselves were inactive when administered alone. The exchange of monodentate ligands had little effect on the antifungal activity (MICs = 1 and 0.5 μg/ml, respectively). However, the introduction of sulfonyl functional groups could lower the activity slightly [41]. The supramolecular complex 69, formed by the bipyridine-modified triazole and the Ni2+ ion, has strong inhibition ability against Aspergillus niger, Aspergillus flavus, and Candida albicans, and its activity is comparable to that of the reference drug fluconazole. The divalent iron supramolecular complex 70 obtained by introducing pyridine on its triazole ring is also more active against these three fungi. Further studies have found that the antifungal activity of 69 is stronger than that of 70, and the activities of the two complexes is significantly higher than that of the corresponding ligands. Ph NH N

NH2 N N

N

H2O N N 2+ Ni

H2O N N 2ClO4_

N N

N

NCS

N

Ag

Fe NH2

N

NCS

ClO4_ N

N

NH 69

70

Ph

N HN

N NH

N

71

The bis-imidazole silver supramolecular complex 71 has strong antifungal activity, and its MIC80 value for Candida albicans is about 7.6 mol/l. The activity is much better than the reference drug miconazole. The structure–activity relationship showed that when the terminal imidazole ring introduced a methyl group at the N-1 or N-4 position, the anti-Candida albicans activity of the complex supermolecules will be attenuated by sevenfold and onefold, respectively. The silver supermolecule 72, formed by hydrazine carboxylic acid and two molecules of imidazole derivatives, showed good inhibitory activity against

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C.-H. Zhou and Y.-F. Sui

Candida albicans. Further studies indicated that the antifungal activity of this complex is improved significantly when there is no substituent on the imidazole ring. However, the antifungal activity decreased when an electron-withdrawing group was introduced on the imidazole ring, which implied that the substituents affected the antifungal activity of the supermolecules. CH3

CH3 HN

N

Ag+

N

O

O

NH

72

56.7

Supermolecules as Antituberculosis Agents

Tuberculosis (TB) is considered to be a highly dangerous infective disease that causes death with a high mortality rate throughout the world. The traditional antiTB drugs, which have been used in clinics for several decades, display multidrug resistance to some extent, which has affected clinical therapeutic efficacy. The long treatment cycle of tuberculosis has increased drug resistance and decreased the effectiveness of most available antitubercular agents, resulting in the reemergence of tuberculosis to threaten humans. Isoniazid (INH) is still one of the important anti-TB clinical drugs because of its distinct antitubercule bacillus activity, and its combination with rifampicin is often used to treat TB in short-course chemotherapy. INH is a good metal ion chelator, and can be coordinated with Ru(II), Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Pb(II), and rare earth metal ions to form stable complexes and thus ameliorate their liposolubility. The complex 73 of INH with Cu(II), Ni(II), and Co(II) ions exhibited higher growth inhibition against Mycobacterium tuberculosis H37Rv than the parent drug. N

R

OH2 N

O

N M2+

N

O N

73

OH2

73a, M = Co , R = CF3 73b, M = Cu , R = F

N R

56

Supermolecules as Medicinal Drugs

1617

Ciprofloxacin (cf) is often used as an anti-TB drug in clinics. Its application is limited to some extent because of the rapid emergence of drug-resistant strains. Lately, its metal complexes have been found to enhance remarkably the anti-TB activities, such as copper(II) complex 74 of ciprofloxacin. The formation of organometal complexes possibly increased its liposolubility, making it easier to penetrate into the bacterial cell, and at the same time, Cu(II) ion was reduced to give copper(I) species intracellularly, resulting ultimately in oxygen activation that is detrimental to the Mycobacteria. This result revealed that metal complexes with reducibility should be valuable for the design of highly active antitubercular drugs. On the basis of this, a mixed-ligand Cu(II) complex 75 containing ciprofloxacin and phenanthroline was prepared, but this mixed-ligand Cu(II) complex did not enhance the antitubercular activity, which might be related to phenanthridine to stabilize the cupric species and degrade the reduction activity of cupric species.

N

N F4B

O

N O

56.8

O

N

Cu2+ O

O

HN

O

O

F

NH

BF4 74

N F

O

Cu 2+ O N X

N NH

75 X = Cl, H2O F

N

Supermolecules as Antiviral Agents

Viral infections often result in serious diseases such as hepatitis, acquired immune deficiency syndrome (AIDS), and severe acute respiratory syndrome (SARS) that threaten human health and life. In spite of this, the enormous viral harm to humans did not result in rapid development of antiviral drugs, because virus replication has a close relationship to normal human cells and would damage normal cells when inhibiting the viruses. Similar to other anti-infection drugs, in long-term use antiviral drugs easily lead to drug resistance, decrease the curative effect, and result in relapse. These effects have become quite urgent problems for clinical therapy and drug development to resolve. Disoxaril is an anti-rhinovirus agent with good activity that was withdrawn from clinical studies by the appearance of asymptomatic crystalluria with large dosages, and the concentration of the drug acting on nasal mucosa was very low. To improve the water solubility of disoxaril, 2,6-di-O-methyl-β-cyclodextrin (DM-β-CD) was employed to encapsulate the anti-rhinovirus drug disoxaril, forming a 1:1 inclusion complex. It was found that DM-β-CD was able to increase significantly the water solubility of disoxaril from 123 μg
ml1 to 471.42 μg
ml1 and efficiently improve the stability of the drugs. A bovine nasal mucosa trial revealed that the formation of

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C.-H. Zhou and Y.-F. Sui

inclusion complexes could control efficiently the disoxaril release rate, resulted in a lag time of 2 h, and enhanced the bioavailability of the drugs. The CD4 cell-surface molecules were the first target of HIV infection; thus, inhibiting the entry of HIV into the cells through receptor CD4 antagonism became a dramatic method to prevent human immunodeficiency virus (HIV) infection. The entry of HIV into cells requires the sequential interaction of the virus with a coreceptor CXCR4; therefore, CXCR4 can serve as a target for the research of new drugs, and this is a new breakthrough for anti-HIV therapy. Bicyclams AMD3100 is a favorable CXCR4 antagonist that can inhibit replication of both X4 and X4/R5 types of HIV. Compound AMD3100 displayed significant activity against the HIV virus; unfortunately, it was found to have significant heart side effects, leading to its withdrawal from further development as an anti-HIV agent in phase II studies. To improve the anti-HIV activity of AMD3100, the complexation of AMD3100 with metal Zn(II), Ni(II), Cu(II), Co(II), or Pd(II) ion produced the 1:2 complex 76, and it was found that the Zn(II) complex (AMD3479) and Ni(II) complex (AMD3462) were slightly more active than the parent ligand AMD3100. The Cu(II) (AMD3469) and Co(III) (AMD3461) complexes were less active than AMD3100, and Pd(II) complex (AMD3158) was virtually inactive. NH HN M2+ NH

N

HN 2+

M

N

NH HN

76 M = Zn, Ni, Cu, Co, Pd

It is has been reported that superoxide dismutase (SOD) can inhibit HIV replication, and an SOD mimic consisting of the manganese SOD complex of a pyridinefused macrocyclic polyamine can inhibit apoptosis in HIV-infected cells by reducing oxidative stress. Novel CXCR4-binding compounds possess anti-HIV activity by evaluating the activities of these macrocyclic polyamines and their complexes with Mn2+, Cu2+, Fe3+, and Zn2+ ions. The Mn2+ complex of a new penta-azacyclopentadecane with one fused carbocyclic ring has the greatest potency as an inhibitor of the chemokine receptor CXCR4. The Zn2+ complex 77 was the most potent, and showed that redox activity of the metal center was not associated with CXCR4 inhibitory activity [42]. N NH

HN HN

Zn N N

2+

O

NH N 2Cl

HN H2N

N O 78

NH3 N

N

N

N

Co3+ O O NH3

Me

HO 77

Me

79

Me

Me

N

Me

Me N

Cl

Br

N Co3+

O

Me Me

O N

Me

Me N

80

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Acyclovir (78) is an efficient nucleobase guanosine antiviral agent that can be transformed into disphosphonate in the body. It could inhibit the replication of herpes simplex virus (HSV) by interfering with DNA synthesis, and has become the first choice against herpesvirus infection. To improve the antiviral activity of acyclovir, many metal complexes of acyclovir with metal Cd(II), Co(II), Cu(II), Ni (II), Zn(II), and Hg(II) ions have been prepared and characterized; however, so far their antiviral properties have not been reported. Research showed that some Co(III) organic chelates also exhibited favorable antiviral activity. Complex 79 was the first reported Co(III) organic complex with antiviral activity, and it displayed moderate activity against HSV-1. Its analogue CTC-96 (80) exhibited the least toxicity and best activity among this series of complex supermolecules against HSV-1 and HSV-2. In addition to the foregoing complexes with antiviral activity, the cobalt(III) hexamine complex also exhibited significant antiviral activity. The IC50 values against Sindbis virus-infected cells is 0.13 mmol
ml1. Ruthenium(II) complex [H4Ru4(η6-p-benzene)4]2+ is active against the polio virus without inhibiting the growth of human cells.

56.9

Supermolecules as Antiepileptic Agents

A large number of experiments revealed that metabolic defects and glutamic acid anomaly may intensify or induce excitotoxicity, and thus result in some neurogenic diseases. Epilepsy is a common neurological disorder, characterized by myoclonus, absence of psychomotor ability, loss of consciousness, paraesthesia, and disorder of sensations and movement. Seriously ill patients may suddenly lose consciousness, with tonic-clonic (grand mal) symptom such as screaming, vultus cyanoderma, regurgitating foam, and pupil diffusion; if the seizure lasts for a long time, it may cause a threat to life. Carbamazepine, a widely used anticonvulsant drug, was absorbed slowly and gave low bioavailability in vivo by its poor water solubility and unstable metabolism. The 1:1 inclusion complex of carbamazepine, formed with β-cyclodextrin, increased its aqueous solubility, and could reach a sufficient concentration in a minidose through controlling the release rate. Aryl semicarbazones encapsulated with cyclodextrin or its derivatives also can improve the aqueous solubility and bioavailability. For example, the inclusion complex of benzaldehyde semicarbazone 81 with HP-β-CD, whose minimum dose necessary to produce activity decreased from 100 mg
kg1 for the free semicarbazone to 35 mg
kg1, indicating that this inclusion complex significantly increased water solubility, decreased the release rate, and then improved its bioavailability. H N

NH2

N 81

O

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Some metal–NSAIDs complexes possessed not only antiinflammatory and analgesic activity but also anticonvulsant potential. Many studies of anticonvulsant agents have focused on the copper and zinc supramolecular complexes of NSAIDs, especially the Cu2(aspirinate)4 complexes. The [Cu2(aspirinate)4(DMF)2] complex was more effective in inhibiting maximal electroshock seizure (MES)-induced seizures than other binuclear or mononuclear copper chelates of aspirin, but had no activity in the scMET model of seizure. [Cu2(niflumate)4] complexes, formed by cupric salt and niflumic acid, showed some activity in inhibiting grand mal and psychomotor-type seizures, and this was consistent with inhibition of electroshockmediated brain inflammation. However, no activity was found for the prevention of petit mal type seizures. Some Zn–NSAIDs complexes have also been proved to possess anticonvulsant activities. Complexes [Zn(aspirinate)2(H2O)2] and [Zn (salicylate)2(phen)] were found to have excellent rivalry activity without rotorod toxicity against psychomotor seizures, and complexes [Zn(3,5-DIPS)2(DMSO)2], [Zn(aspirinate)2(H2O)2], and [Zn(salicylate)2(phen)] exhibited particular useful efficacy in protecting against MES and scMET seizures. In view of the good potential of salicylato–metal complexes in antiinflammatory and anticonvulsant activities, a series of metal Zn(II), Co(II), Ni(II), and Mg(II) complexes with 5-nitrosalicylate was prepared. Only complex 82b was found to exhibit activity against MES-induced seizures, but all the complexes had activity in protecting against the less intense minimal clonic seizure. Their activity order was 82c > 83b, 83a > 82a, 82b, 82d. Complexes 82a and 83 showed moderate activity against MET-induced seizures, with the relative order of effectiveness of 83a > 83b > 82a. H2O

H2O OH 2

O

M2+ O H2O H 2O

O

NO2 NO2

82

O O 82a, M = Zn, 82b, M = Co 82c, M = Ni, 82d , M = Mg

H 2O

O

2+

M

H 2O

HO HO

H 2O

O O

H2O

83a, M = Zn 83b, M = Co

HO

NO2

O 2N

OH

83

56.10 Supermolecules as Cardiovascular Agents Cardiovascular disease is one of the major causes of death in developed countries all over the world, and also has gradually become the life-threatening first cause in some developing countries. The cardiovascular drugs have high requirements for drug release; some require quick drug release, whereas others require sustained drug release to decrease the times of administration. The inclusion complexation of cyclodextrin or its derivatives with the available cardiovascular drugs can meet these requirements. The inclusion complexes of cyclodextrins with the dihydropyridine calcium antagonist could overcome the problems of low solubility and easy oxygenolysis under light. The inclusion complexes of β-CD or HP-β-CD with the drugs nifedipine,

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nitrendipine, captopril, nicardipine, and nimodipine separately were confirmed to improve effectively the stability, bioavailability, and solubility of these drugs, and the double-layer tablets of nifedipine encapsulated by 2-HP-β-CD and hydroxypropyl cellulose could satisfy the need of differentiated release rate by changing their component ratio. The binary system formed by captopril with HPβ-CD or TB-β-CD and the ternary system of captopril/TB-β-CD/HP-β-CD has been prepared in different molar ratios, and their release behavior was investigated in dogs. It was found that the release rate of captopril from the binary HP-β-CD system was rather rapid, whereas that from the binary TB-β-CD system was comparatively slower, the retarding effect being dependent on the amount of TB-β-CD. The release rate from the ternary captopril/TB-β-CD/HP-β-CD system was slowed by the addition of small amounts of HP-β-CD, whereas the rate increased as the molar ratio of HP-β-CD further increased (>0.25 molar ratio). The oral administration of the ternary captopril/TB-β-CD/HP-β-CD system (molar ratio of 1:0.5:0.5) in dogs gave a plasma profile comparable to that of a commercially available sustainedrelease preparation. Some studies investigated comparably the solubility-enhancing efficacy of nimodipine by the use of several CDs including HP-β-CD and their derivatives, finding that HP-β-CD resulted in better solubilizing efficiency than methyl-β-CD, which may be acceptable for the injectable preparation of parenteral nimodipine solutions. The inclusion complex of triacetyl-β-cyclodextrin (TA-β-CD) with nicardipine hydrochloride (NC) was carried out dissolution investigation in simulated gastric and intestinal fluids in vitro. The results showed that the release rate of the inclusion complex was consistent with zero-order kinetics, and it was concluded that TA-β-CD can be used as a sustained-release preparation excipient. MeO N MeO

N

N N

Me

Cl

N 84 N H

Compound 84 is a novel cytoprotection agent for the treatment of acute ischemic stroke. Compared to neutral HP-β-CD, the electronegative SBE7-β-CD formed a more stable inclusion complex with 84, resulted in the significant enhancement of water solubility and light stability for drug 84, and also decreased the DY-9760einduced cytotoxicity toward HUVECs and vascular damage in rabbits. Boronic acid-containing macromolecules have been utilized in a number of biomedical applications, including use in dynamic covalent materials, dual thermoand saccharide-responsive hydrogels, sensors, and nanomaterials, often with the goal of detection and treatment of type 1 diabetes, which requires constant monitoring of blood glucose levels and proactive insulin management. The ability of boronic acids to bind with saccharides and potentially undergo an ionization transition makes

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the materials ideal for diabetes-related applications. Other biomedical applications of boronic acid containing macromolecules include use as potential HIV barriers, separation and chromatography, cell capture and culture, enzymatic inhibition, and in site-specific radiation therapy [43]. A closed-loop “smart” insulin delivery system with the capability to mimic pancreatic cells will be highly desirable for diabetes treatment. Researchers have reported a multi-stimulation-responsive insulin delivery platform based on a clear supramolecular strategy. Self-assembled from a well-designed amphiphilic host–guest complex formed by pillar arene and a diphenylboronic acid derivative, and loaded with insulin and glucose oxidase, the obtained insulin-GOx-loaded supramolecular vesicles can selectively recognize glucose, accompanied by the structure disruption and efficient release of the entrapped insulin triggered by the high glucose concentration. A hyperglycemic condition, as well as a low local pH and a high H2O2 environment generated during the GOx-promoted oxidation of glucose to gluconic acid could facilitate the rapid disassembly of the vesicles and achieve efficient insulin release. More importantly, in vivo studies by using a mouse model of type 1 diabetes further showed that the insulin-GOx-loaded vesicles could regulate the blood glucose levels to a normal range during prolonged periods with fast responsiveness [44]. Advanced therapeutic modalities such as heart transplantation have been developed and considered to be the optimum paradigm for the treatment of a diseased heart. However, such a surgical operation is applicable to only a small subset of patients because of donor organ shortages and the incidence of immune rejection. Therefore, the development of effective therapeutic strategies for the prevention and treatment of thrombotic diseases is a demanding priority. Recently, supramolecular hydrogels self-assembled from peptide derivatives have shown great promise in cardiovascular diseases and regenerative medicine. The researchers combined curcumin with NO in a mixed-component hydrogel 139 to treat myocardial infarction (MI) by intramyocardial injection [45]. A supramolecular hydrogel formed by self-assembly of folic acid (FA)-modified peptides by a biocompatible method (glutathione reduction) was reported that is suitable for cell encapsulation and transplantation. iPS cells labeled with CM-Dil were transplanted into MI mice hearts with or without FA hydrogel encapsulation. The results confirmed that FA hydrogel significantly improved the retention and survival of iPS cells in MI hearts after injection, resulting in enhanced therapeutic efficacy of iPS cells, including better cardiac function and less adverse cardiac remodeling, followed by cardiomyocytes [46]. The incidence of diabetes is becoming higher and higher, and the diabetes patients are being diagnosed younger and younger, which has aroused great concern around the world. Some related work has been devoted to the development of hypoglycemic drugs such as tolbutamide, metformin, and rosiglitazone, widely used in clinical practice. Studies have shown that azole heterocyclic complex supermolecules have high bioavailability and weak drug interactions. Azole heterocyclic complexes have an important role in reducing insulin resistance and enhancing insulin secretion, opening up a new orientation for the development of new and highly effective antidiabetic drugs [47].

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Angiotensin II (AII) causes vasoconstriction and increases blood pressure, leading to high blood pressure. Currently, the sartan type of drugs can be used orally for the treatment of hypertension, atherosclerotic lesions, and diabetes, when combined with the subtype AT1 receptor of the AII type. The antihypertensive drug telmisartan 85 is potent because of its strong binding to angiotensin II receptors. Studies have shown that after forming a complex with metal ions, the mechanism of action is not changed. When the divalent copper ion forms a complex with the telmisartan 85, its antihypertensive effect is enhanced. COOH N

H3C CH3

HN

N

COOH

N N N

N N N

Cl

N

85

86 H3C

The antihypertensive drug losartan 86 is a tetrazole derivative that forms a watersoluble inclusion complex with hydroxypropyl-β-cyclodextrin, where there is a short-range interaction between Los and hydroxypropyl-β-cyclodextrin. The antihypertensive activity of the formed inclusion complex was evaluated. The results showed that the oral effect was good, the antihypertensive control was effective, the action time was increased from 6 h to 30 h, and the time and extent of antagonism had been strengthened.

56.11 Supermolecules as MRI Agents Magnetic resonance imaging (MRI) is a special imaging technique with multiple parameters and polynucleation. Its physical principles are the use of a special frequency of electromagnetic waves to irradiate the human tissues placed in the magnetic field, resulting in the nuclear magnetic resonance of hydrogen atoms in different tissues. The electromagnetic waves are absorbed and then emit the socalled nuclear magnetic resonance (NMR) signal. This NMR signal shows the internal structural information of matter, and the latter is measured and analyzed for the corresponding physical and chemical information. Thus, this technique exhibits important application values in such fields as physics, chemistry, biology, and medicine. Since Lauterbur first used MRI in 1973, the MRI technique has been widely used in various biomedical domains as clinical diagnosis with no traumatic occlusion and multi-contrast. Whether in clinical diagnosis or fundamental research, MRI has currently become an indispensable tool. Its distinct feature is that the images are very clear for soft tissue. Up to the present, no other diagnostic imaging can be compared with MRI.

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Metal ions, such as Gd(III), Dy(III), Fe(III), and Mn(II) with large magnetic moments, could form stable chelates by chelation with appropriate ligands. These complex supermolecules may decrease toxicity and increase molecular volume, and have become the chief objects in the research of MRI contrast agents. Free Gd(III) with hydration water and most of its corresponding complexes were not compatible with venous blood, easily precipitated, and exhibited strong toxicity. Therefore, it was of importance to choose a series of Gd complexes that are stable in blood or humor. The first magnetic resonance contrast medium Gd-DTPA, the Gd(III) complex of diethylene triaminepentaacetic acid (DTPA), was developed by Schering AG, and was used in clinics in 1983. To date, nine Gd(III) complexes have been used as MRI contrast agents: Magnevist (87a), MultiHance (87b), Primovist (87c), Vasovist (87d), Omniscan (87e), OptiMARK (87f), Dotarem (88a), ProHance (88b), and Gadovist (88c). Besides Gd(III) complexes, the Mn-DPDP complex Teslascan (89) has also been entered into clinical practice. O

O

O

N N

O

87d (Vasovist),R = H, R1 =

O

O O

N

HN

O

O O O

O 2 O3PO

N Gd3+

N O O

Ph

O

O

N

O

Gd3+

O

P

O

O

O

N

O O

O

O

Ph

O R R1

N

87a (Magnevist), R = H, R1 = H 87b (MultiHance), R = CH2(CH2) 2Ph, R 1 = H 87c (Primovist), R = H, R1 = 3-OCH3 benzyl

O

N

O

O

Gd3+

O

N

O

N

Mn2+

X Y O O O O 88a (Dotarem), X = CH2, Y = CO Me R 87e (Omniscan), R = Me 89 (Teslascan) 88b (ProHance), X = CH(CH3), Y = CH2 87f (OptiMARK),R =CH2(CH2)2 OMe 88c (Gadovist), X = Y = CH(CH OH) 2 R

2 OPO3

N

NH

Me

Recently, the development and application research on contrast agents has mostly focused on the improvement of the ligands, and Gd(III) was generally chosen as the metal ion. The ligands included both linear and macrocyclic compounds. The current design has been primarily oriented on modifications of the structural motifs of DOTA and DTPA to improve their selectivity and biocompatibility. Much effort in the development and application of contrast agents has been mainly expended in two following aspects. The first is to modify the ligands to reduce their toxicities and increase their stability and selectivity. The introduction of some functional groups in the modification of the ligand backbone of the contrast agents could ameliorate their hydrophobicity to obtain tissue- or organ-specific contrast agents. Currently, major research fields are involved in three types of targeting contrast agents including liver-targeting agents, tumor-targeting agents, and blood pool agents. Some hydrophobic groups, such as long-chain bisamide, aliphatic moiety, and phenyl ring, have been incorporated into the backbone of these

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complexes to increase their hydrophobicity and facilitate their selective absorbance by hepatic cells, therefore possessing great potential as liver imaging contrast agents. The contrast agents Gd(BOPTA) and Gd(EOB-DTPA) are in the clinic trials stage. Supramolecular complex Gd-DTPA is a MRI contrast agent being used extensively in clinics. It is an ionic contrast agent with high osmotic pressure and short detention time in vivo, and is easy to eliminate through kidney metabolism, as well as having no tissue or organ specificity. Complex Gd-DTPA was modified to form electroneutral molecules, and thus exhibited much lower osmolality and toxicity in animals. The reaction of Gd-DTPA with bisamides produced bisamino non-ion ligands such as Gd(DTPA-BDMA), Gd(DTPA-BDEA), Gd(DTPA-BIN), and Gd (cyclic-DTPA-1, 2-pn). Animal experiments and MRI evaluation showed that four neutral Gd-DTPA bisamide derivatives gave good relaxation in bovine serum albumin, and possessed features of liver targeting, better water solubility, hypotoxicity, and long detention time in vivo. The Gd-DTPA derivative 87d showed favorable binding ability with human serum albumin (HSA) by using a bulky hydrophobic residue consisting of two phenyl rings attached to a cyclohexyl moiety link, and reduced filtration of the glomerulus monomer, which resulted in low renal excretion rate and prolonged half-life time in blood vessels. Complex 87d is also the first Gd(III)-based contrast agent for angiographic applications to proceed to human trials. A series of DOTA derivatives 90–93 has been prepared with liver targeting; their supramolecular complexes displayed higher relaxivity than standard Gd (DTPA) and Gd(DOTA). The Gd(III) complexes of the piperidine-backboned PIPDOTA and PIP-DTPA displayed reduced kidney accumulation, compared with the nonspecific Gd(DOTA). The strategy to increase lipophilicity and rigidity of the chelate system and thus enhance hepatobiliary clearance and complex stability by incorporating either a piperidine or an azepane ring into the DTPA system appears desirable for the design of liver-specific MRI contrast agents. Gd(III) complexes of compounds 90–93 are promising to act as MRI liver agents or nonspecific agents in the clinic. HOOC N N N HOOC COOH COOH HOOC COOH 90 AZEP-DTPA

N N

N COOH HOOC COOH HOOC COOH 91 PIP-DTPA

COOH

N N

CO2H

N

N COOH

HOOC COOH 92 PIP-DOTA

N

N

N

N COOH n 93 COOH 93a, n = 0 NETA 93b, n = 1 NPTA

Recently, many studies have focused on Gd-DOTA derivatives. The complex P760 (94), a gadolinium macrocycle based on a DOTA structure that is substituted by hydrophilic bulky groups, had higher relaxivity and good biocompatibility. In rabbits, 5 min after the injection of 94, the blood concentration of 1036  105 μmol
kg1 was equivalent to the blood concentration of Gd-DOTA 1 min after injection. Furthermore, the slow permeability process increased the

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sensitivity of 94 for revealing permeability abnormalities, especially for tumor detection, and it displayed potential application. COO

COO COOR

ROOC N

O

N

R=

Gd3+ N

COOR COO

CON[CH2(CHOH) 4CH2OH] 2 Br

HN N

ROOC COO

Br H N

Br

CON[CH2(CHOH) 4CH2OH] 2

94

Another aspect in the exploitation and application of contrast agents is to couple with macromolecule covalently, resulting in enhanced relaxation efficiency and targeting property. The DTPA and DOTA were introduced by polyester or polyamide into the backbone of a polymer, or coupled covalently with natural or artificial synthetic polymers, to be capable of forming macromolecular MRI contrast agents. They could decrease molecular spin rate, increase relaxivity, maintain stable concentration for prolonged times in blood vessels, and further profit angiography; thus, these compounds were called blood pool contrast agents. In addition, when an organ- or tissue-targeting group was attached to this macromolecular metal complex, it could be endowed with an organ- or tissue-targeting property. The Gd chelates of DTPA derivatives coupled with the deoxycholic acid moiety had a higher relaxivity and longer half-life in human blood. Preliminary clinical tests showed that Tl decurtated to about 100 ms when injected at 50 mmol
kg1, and had good visualization effective for arteria coronaria in 30 min. The Gd-DTPA derivatives in covalent conjugation with the surface of polyamidoamine dendrimer separately form dendritic chelates that exhibited higher relaxivities than Gd-DTPA. The macrocyclic Gd(III) complexes formed by the conjugates of polyamidoamine (PAMAM) backbone with macrocyclic polyamine Gd(III) complexes could decrease the internal mobility of the MRI photographic developer, enhance its relaxivity efficacy, and could be used as a pH-responsive MRI contrast agent in vivo. The excellent efficacy of MRI contrast agents enables them to be an important assistant method in daily application. The first liver-targeting contrast agent is on the market, and lymph and blood pool contrast agents will also be marketed soon. In the near future, diseased region- or organ-targeting contrast agents with wide application will become a basic tool in medical diagnosis imaging. With the development of new MRI techniques, such as MR angiography (MRA), perfusion MRI, and diffusion-weighted MRI and their extensive use in clinical diagnosis, the research and development of MRI contrast agents will be faced with greater challenges. The major trends in the research and development of MRI contrast agents will focus on tissue- or organ-targeting materials with high relaxivity and specificity, high contrast enhancement with low doses, low toxicity and side effects, and minimal expense. Along with the progress of biocoordination chemistry, NMR spectroscopy, and medicine, there is no doubt that more and more

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novel, highly effective, and low-toxicity contrast agents will be used in the clinic and bring more human benefits. Dinuclear (Ir
Ln) and trinuclear (Ir
Ln2) complexes, in which a phosphorescent Ir (III)-based unit is connected to one or two water-stable lanthanide/aminocarboxylate units via a rigid, conjugated bridging connection, have been prepared. The dinuclear complexes performed better than their trinuclear counterparts for luminescence cell imaging and also in terms of relaxivity (for Gd complexes). Dinuclear (Ir
Ln) complexes performed best in cellular studies, exhibiting good solubility in aqueous solutions, low toxicity after 4 and 18 h, respectively, and punctate lysosomal staining. For dual (luminescence + MRI) imaging applications, the complex Ir
Gd is a promising candidate. With excellent luminescence imaging capabilities and low toxicity, it also displays unusually high relaxivity for a small molecule containing just one Gd(III) center. Variations in luminescence lifetime allow it to be used as a sensor toward molecular oxygen, an important biological analyte, in solution and in vitro [48].

56.12 Supermolecules as Other Medicinal Agents Diabetes mellitus has become one of the most serious diseases threatening human health, and research and development of antidiabetic drugs has become increasingly active [49]. Insulin is the most effective and the first choice in the treatment of advanced-stage diabetes. However, polypeptide drugs such as niditas insulin can aggregate by the interaction of internal hydrophobic residues and are often accompanied by drastic reduction of biological potency. The application of CD complexation represents a unique and effective strategy for improving drug solubility and activity by stabilizing against aggregation. The prepared HP-β-CD–insulin complex, encapsulated mucoadhesive nanoparticles, could protect the insulin from proteolytic degradation, resulting in good oral insulin delivery systems. With polypseudorotaxanes of pegylated insulin with CDs as the supramolecular system, it was found that the release rate of insulin in the γ-CD polypseudorotaxane was lower than that of insulin alone, and the γ-CD polypseudorotaxane could prolong the hypoglycemic effect of insulin in rats. The results indicated that the pegylated insulin/CD polypseudorotaxanes could work as a sustained drug-release system. Tolbutamide (TBM) was used clinically in tablet form as an oral hypoglycemic agent, and the inclusion complex of TBM with β-CD or HP-β-CD increased its aqueous solubility, dissolution rate, and oral absorption rate. Metal vanadium, a trace metal ion in higher animals, was well known to be essential to some organisms, and the vanadium complex VO-Hglu of D-gluconic acid as an antihyperglycemic agent showed good efficacy, with the need for further development as a potential drug. Inclusion research on tacrolimus showed that the complex of β-CD with tacrolimus gave the highest stability constant among natural α-, β-, and γ-CDs, which indicated that the cavity of β-CD matched well with tacrolimus. Rocuronium bromide is frequently used as a neuromuscular blocking agent in surgery. However, a reversal agent, for example, neostigmine as inhibitor of acetylcholinesterase (AChE) with side effects of bradycardia, nausea, and vomiting, was often administered to

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facilitate rapid neuromuscular recovery after surgery and to prevent residual blockade. However, the reversal agent could cause the side effects of bradycardia, nausea, and vomiting. The prepared γ-CD-rocuronium bromide inclusion complex as revealed by X-ray crystallography analysis showed that the complex was stable in the cavity of γ-CDs, which blocked the pharmacoactivity of rocuronium indirectly. The γ-CD derivative rapidly reversed the neuromuscular blocking effect of rocuronium bromide in vitro (mouse hemi-diaphragm) and in vivo (anaesthetized monkeys), and appeared to be superior to neostigmine without any toxicant side effects; it now has entered into the clinical trial stage. Alzheimer’s disease (AD) is a common neurological disease that is associated with depositional oxidative damage of insoluble β-amyloid (Aβ40, Aβ42) and decrease in acetylcholine. To date, clinical drugs have not been able to cure Alzheimer’s disease, but only to maintain the function of acetylcholine and glutamate channels to limit the side effects of the disease. Recent studies have found that the histidine that acted on insoluble β-amyloid can significantly reduce the neurotoxicity of β-amyloid. Therefore anti-insoluble β-amyloid deposition is currently the main target for the development of AD drugs. The development of supramolecular drugs has become an active field in the treatment of AD. Although metal chelators are rarely explored as AD therapies, copper complexes could feasibly mediate ADassociated Aβ aggregation, ROS generation, and oxidative stress in addition to addressing metal dysregulation [50]. Such studies have been successfully carried out on several platinum complexes. It was also found that the complex of imidazole and ruthenium showed greater toxicity than that of imidazole and platinum (the toxicity of ruthenium compounds was lower than that of platinum). Complex 95, formed by RuCl2 and thiazole, can also treat AD by forming an adduct with β-amyloid and scavenging β-amyloid. CO CO S

N

CO Ru2+ Cl

Cl

95

Buserelin acetate, an artificial synthetic nonapeptide, could form an inclusion complex with DM-β-CD. Ultraviolet absorption and circular dichroism (CD) spectroscopies indicated that the aromatic rings in side chain residues of L-tryptophan and L-tyrosine and the butyl group in serine were incorporated into the hydrophobic cavity of DM-β-CD, and resulted in space conformational change of the peptide chain, prevented unstable sites from being attacked by protease, and thereby enhanced the stability of buserelin [36]. Flutamide (FLT) is a nonsteroidal antiandrogen, and the formed FLT-HP-β-CD complex could improve oral bioavailability relative to FLT suspension. Intravenous pharmacokinetic profiles for both FLT and FLT-HP-β-CD were identical. The effect of HP-β-CD on the bioavailability of hydrocortisone (HC) as ophthalmology administration was investigated in the New Zealand rabbit, and HP-β-CD was found to increase the bioavailability of HC in the cornea by 75% and greatly enhance the permeability of the cornea.

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56.13 Conclusions and Outlook The foregoing discussion shows that supermolecules as medicinal drugs formed by two or more molecules through the weak interactions of noncovalent bonds, such as coordination bonds, hydrogen bonds, ion-dipole cation-π, π–π stacking, hydrophobic effect, and van der Waals forces, have been a quite rapidly developing, increasingly active, and newly rising interdisciplinary focus. Supramolecular drugs have shown positive roles in many medicinal aspects such as antitumor, antiinflammatory, analgesic, antimalarial, antibacterial, antifungal, antivirus, antiepileptic, cardiovascular agents, and magnetic resonance imaging agents. In particular, many supramolecular drugs such as antitumor, antiinflammatory, and magnetic resonance imaging agents have been extensively used in clinics and brought benefits to human health. The supramolecular drugs might effectively enhance stability and safety, decrease toxicity, eliminate abnormal flavor, overcome multidrug resistance, reduce adverse effects, and improve drug targeting, biocompatibility, and bioavailability. All these excellent properties could improve greatly the therapeutic efficacy of drugs. More important is that numerous supermolecules as clinical candidates are in actively ongoing research and development, and supermolecules as medicinal drugs have been shown to possess enormous potential. In addition, supramolecular drugs might require less expense, take shorter time in action, and have greater possibilities as clinical drugs. These virtues have strongly encouraged numerous researchers to engage in the research and development of novel supramolecular drugs. There is no doubt that in future, the research and development of supermolecules as medicinal drugs will become more and more active. Currently, much important progress has been made in the research of supermolecules as chemical drugs. The hosts of supramolecular drugs were involved in cyclodextrins, porphyrins, polymers, and some other structural compounds, and the guests themselves were drugs or non-drug molecules, but major research in this field focused on the cyclodextrin, porphyrin, and metal complexes. Thus, it should be fairly said that the research of supramolecular drugs is still in the initial stage. With the further expansion of supramolecular chemistry and the deep investigation of the supramolecular drugs, the research and development to access supermolecules as medicinal drugs will continue to be a hot topic and will become more and more active. The main aspects for research in the future might include the following 10 topics: 1. Continuous effort toward clinical drugs as guests to prepare supramolecular medicinal drugs with an attempt to obtain better drugs, especially those with good bioavailability, biocompatibility, and drug targeting, no obvious multidrug resistance, low toxicity, less adverse effect, and good curative effects as well as safety. 2. More work employing nondrug molecules as guests with the hope to discover new supramolecular medicinal drugs, especially those with a novel mechanism of action. 3. Important research to find low-toxicity components of supramolecular medicinal drugs.

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4. More exploration to seek low-toxicity hosts to form supramolecular medicinal drugs. 5. Active topic to use metal ions to produce supramolecular medicinal drugs. 6. Studies toward drugability such as bioavailability, biocompatibility, multidrug resistances, low toxicity, adverse effects, and curative effects and safety. 7. Discovery of a novel unique mechanism of action for supramolecular medicinal drugs. 8. Development of highly drug-loaded hosts able to load more drugs and the study of these hosts as drug carriers. 9. Evaluation of the physicochemical properties of supramolecular medicinal drugs, such as solubility, stability, drug dissolution, and selectivity. 10. Investigation to identify the action targets of supramolecular medicinal drugs. Supramolecular drugs are a very rich field of research topics. To some extent, their research is just beginning, and much more work is needed. It is inevitable that more and more workers will engage in the research and development of supermolecules as medicinal drugs. More and more supramolecular medicinal drugs with good efficacy, low toxicity, and good pharmacokinetics properties will then enter into clinical use to serve human health.

56.14 Cross-References ▶ Application of Anion-π Interaction on Supramolecular Self-Assembly ▶ Cyclodextrin Hybrid Inorganic Nanocomposites for Molecular Recognition, Selective Adsorption, and Drug Delivery ▶ Functionalized Cyclodextrins and Their Applications in Biodelivery ▶ Preparation of Biosensor Based on Supermolecular Recognization ▶ Stimuli-Responsive Self-Assembly Based on Macrocyclic Hosts and Biomedical Applications

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Nanoscaled Cyclodextrin Supermolecular System for Drug and Gene Delivery

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Xianyin Dai, Yong Chen, and Yu Liu

Contents 57.1 57.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nanoscaled Cyclodextrin Supramolecular System for Drug and Gene Delivery . . . . . 57.2.1 Nanoscaled Cyclodextrin Supramolecular System for Drug Delivery . . . . . . . 57.2.2 Nanoscaled Cyclodextrin Supramolecular System for Gene Delivery . . . . . . . 57.2.3 Nanoscaled Cyclodextrin Supramolecular System for Synergistic Drug and Gene Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

Supramolecular chemistry has made great progress and drawn more and more attention from scientists in many fields since 1987 when Lehn, Cram, and Pedersen won the Nobel Prize for their pioneering research in the host guest systems [1]. Scientists make full use of the noncovalent interactions such as π π stacking interaction, hydrogen-bonding interaction, electrostatic interaction, van der Waals force, and hydrophobic/hydrophilic attraction to construct various and advanced supramolecular materials from bottom to top [2, 3]. In particular, supramolecular materials are capable of being easily modified, reproducible, as well as diversiform. Furthermore, the dynamic and adaptive nature of supramolecular system in response to environmental conditions that can change their molecular arrangement and the morphology leading to the structural change of supramolecular materials and then

X. Dai · Y. Chen · Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_67

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the specific function could be switch on, perfectly suitable for their applications in biological field, smart drug and gene delivery, etc. [4, 5]. In recent years, various macrocyclic hosts have been designed and synthesized, and these macrocycles exhibit abundant host guest properties, which greatly facilitate the development of supramolecular chemistry [6, 7]. Among various macrocycles, crown ether, cyclodextrin, calixarene, cucurbituril, and pillararenes are typical macrocyclic hosts. Cyclodextrins are a family of macrocyclic molecules composed of α-1,4 glycosidic bond-linked oligosaccharides, which can be readily acquired from enzyme-triggered starch degradation [8]. Moreover, cyclodextrins could be easily obtained from their starch precursors, like potato and rice, making them be a low cost for broad applications. Since discovered by Villiers as early as 1891, CDs have undergone extensive studies in a variety of fields. Within the CDs family, α-, β-, and γ-CDs are most commonly used, which contain six, seven, and eight glucose units, respectively [9, 10]. Furthermore, they are all recognized as safe by the FDA. It is worth mentioning that cyclodextrins have drawn extensive attention from various research fields due to their excellent properties such as wide-ranging practicality, easy modification, and low immunogenicity, thus endowing them ideal candidates for biological applications [11, 12].

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Nanoscaled Cyclodextrin Supramolecular System for Drug and Gene Delivery

57.2.1 Nanoscaled Cyclodextrin Supramolecular System for Drug Delivery 57.2.1.1 Enzyme-Responsive System for Drug Delivery As we all know, enzymes are of great importance in regulating the function of human body for their participation in most biological reactions, and the abnormal activity of enzymes has always been associated with many diseases. Enzyme-responsive assemblies have caught much more attention due to their several inherent advantages: (1) the loaded drugs can be released from the broken assemblies triggered by specific enzymatic reactions at the enzyme-overexpressed sites; (2) avoiding tedious covalent syntheses in preparing desired assemblies as well as with good biocompatibility, high degree of sensitivity, and selectivity. In this regard, kinds of supramolecular assemblies based on enzyme-responsive property have been constructed. Among the various enzymes, cholinesterases (ChEs) are the family of serine enzymes that show desirable behaviors. Typically, myristoylcholine can be cleaved to myristic acid and choline in the presence of butyrylcholinesterase (BChE). Liu and co-workers [13] fabricated a BChE-responsive supramolecular nanoparticle composed of macrocyclic host hepa-carboxyl-modified cyclodextrins (carboxyl-CDs) and a cationic enzyme-cleavable guest. The carboxyl-CDs greatly lower the critical concentration (CAC) of myristoylcholine and then highly induce the molecular aggregation of myristoylcholine. On account of the hydrophobic interactions

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among the aliphatic tails of myristoylcholine, many molecules subsequently integrate together to form a large aggregate that curves to a spherical nanostructure. The trisodium salt of 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) is chosen as a model drug to evaluate the enzyme-responsive property of the nanoparticles. With BChE, the carboxyl-CD/myristoylcholine system shows a remarkable high release of entrapped HPTS, indicating that the nanoparticles are broken due to the imbalance between hydrophilic and hydrophobic. This work offers a convenient way to fabricate enzyme-responsive system for drug delivery (Fig. 1). Based on this concept, Liu and co-workers [14] reported another supramolecular assembly based on sulfato-β-cyclodextrin (SCD) and a water-soluble prodrug, i.e., choline-modified chlorambucil (QA-Cbl). They first design and synthesize a prodrug containing a quaternary ammonium group and an anticancer drug chlorambucil moiety which has been approved by the FDA by introducing a cleavable ester bond spacer. Due to the electrostatic interactions between SCD and QA-Cbl, SCD greatly lowers the critical aggregation concentration (CAC) of prodrug QA-Cbl. Thus SCD and QA-Cbl can assemble to form nanoparticles with high drug-loading efficiency that have not only enhanced permeability and retention (EPR) effect but also the reverse cancer multidrug resistance. In addition, butyrylcholinesterase (BChE) can cleave QA-Cbl into the anticancer drug chlorambucil (Cbl) and choline, leading to the disassembly of the SCD/QA-Cbl supramolecular nanoparticle, and then free Cbl can be released to kill the cancer cells. This work provides a simple, efficient, safe, and nontoxic method for cancer therapy (Fig. 2). Protamine is a biocompatible natural protein with promising biological functions. For one thing, it can bind DNA and then provide a highly compact configuration of chromatin in the nucleus of the sperm; for another thing, it can also be used as an excipient in insulin formulations. Moreover, protamine is also a natural trypsinresponsive biological cationic protein, but it is unable to form trypsin-responsive

Fig. 1 Schematic illustration of the carboxyl-CD/myristoylcholine supramolecular nanoparticles

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Fig. 2 Schematic illustration of the construction of cholinesterase-responsive SCD/QA-Cbl drug delivery system

amphiphilic assembly independently due to its high hydrophilic ability. Benefiting from the strong binding affinity of anionic cyclodextrin, Liu and co-workers [15] develop a trypsin-responsive supramolecular amphiphilic assembly. A novel trypsin-responsive protein/polysaccharide supramolecular assembly (protamine/SCD) from sulfato-β-cyclodextrin (SCD) and protamine is constructed. The higher negative charge density of SCD leads to higher induced aggregation efficiency to cationic protamine. The trypsin can cleave protamine to amino acids and peptides with excellent specificity, thus leading to the enzyme-responsive protamine/SCD nanoparticles being apart. Similarly, the trisodium salt of 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) is selected as a model molecule to assess the drug release. Without trypsin, a very low release of entrapped HPTS is observed. In contrast, the release rate is significantly enhanced when the protamine/SCD assembly is treated with trypsin (Fig. 3).

57.2.1.2 pH-Controlled System for Drug Delivery The pH-sensitive nanosystems have drawn greater attention for biological applications, and the acid-labile substituent groups have been widely used to construct pH-sensitive nanosystems for drug delivery. The pH of the human body is stable within the normal range via acid–base homeostasis. In addition, a series of changes in pH will occur when the human body has a disease. For instance, the pH value of the tumor environment (ca. 6.8) is slightly lower than that of normal tissues (ca. 7.4). These small differences provide a favorable advantage to build pH-responsive supramolecular materials.

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Fig. 3 Schematic illustration of the fabrication of protamine/SCD supramolecular nanoparticles

Benzimidazole (BM) exhibits great pH-sensitive host–guest interaction with β-cyclodextrin (β-CD). At the physiological pH (7.4), the BM can bind to the β-CD tightly via host–guest interactions. On the contrary, the BM unit is hydrophilic under acidic conditions (pH < 6), leading to the binding constant between BM and β-CD decreasing dramatically and thus causing the dissociation of the complex. Taking good advantage of these special properties, Chen and co-workers [16] constructed pH-sensitive supramolecular block amphiphiles consisting of benzimidazole (BM) modified poly(3-caprolactone) (BM-PCL) and β-cyclodextrin (β-CD) terminated dextran (Dex-β-CD). They design and synthesize dextran modified β-cyclodextrin via “click” reaction and benzimidazole (BM) modified poly (3-caprolactone) through ring-opening polymerization. Then by dissolving equal amounts of BM-PCL and Dex-β-CD into DMSO, dropping into PBS and dialyzing against deionized water to remove DMSO, they obtain the micelle solution finally. Doxorubicin (DOX) is employed as a model drug and loaded into the micelles to verify the self-assembled supramolecular micelles for intracellular drug delivery in cancer chemotherapy. Dependent on the low pH of cancer cells, cell experiments show that DOX-loaded micelle exhibits faster DOX release behavior in HepG2 cells than those pH-insensitive micelles (Fig. 4).

57.2.1.3 Voltage-Responsive System for Drug Delivery Membrane potential plays an important role in cell biomembrane system, which triggers lipid bilayer activities, such as membrane fusion and disassembly. Voltage

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Fig. 4 The schematic illustration of DOX-loaded Dex-β-CD /BM-PCL micelle

stimulus is considered as a clean and simple method for designing a voltageresponsive biomaterial, which is of great significance for simulating biological responses. So it is very convenient and efficient to achieve drug loading and controlled release by preparing voltage-responsive biomaterials. In this system, β-cyclodextrin (β-CD) and ferrocene (Fc) have always been demonstrated to be convenient units for constructing the voltage-responsive biomaterials. Generally, neutral Fc species or its derivatives bind strongly in the cavity of β-CD, whereas the charged species (Fc+) dissociate rapidly from the cavity. This process can be regulated by external voltage. In addition, β-CD and ferrocenyl derivative are all commercially available and have low hypotoxicity and facile functionalization. Yuan and co-workers [17] reported a voltage-responsive vesicle based on orthogonal assembly of two homopolymers. They employ poly(styrene) with β-CD end-decoration (PS-β-CD) and poly(ethylene oxide) containing Fc uncharged end-capping (PEO-Fc) as construction units for the fabrication of vesicles. Mixing an equal amount of PEO-Fc aqueous solution and PS-β-CD enables the formation of vesicles, which are quite stable for 3 months without any external stimuli. Moreover, these vesicles can reversibly switch on and off under external voltage. Cyclic voltammetric (CV) analysis is used to prove that the vesicles undergo an electrochemically controlled assembly–disassembly process. This kind of voltage-responsive supramolecular assembly opens a new window for electrochemical therapeutics (Fig. 5). In another work, Yuan and co-workers [18] also fabricated an electrochemical redox-responsive polymeric micelle formed from amphiphilic supramolecular brushes. In this work, electrochemical redox responsiveness is incorporated into a new supramolecular polymer brush in order to realize the voltage-controlled dynamic association and dissociation of the polymer chain consisting of complexes between β-cyclodextrin (β-CD) and ferrocene (Fc). First, they prepare two polymeric components through reversible addition-fragmentation chain transfer (RAFT) and ring-opening polymerization (ROP) with favorable biocompatibility, which is conducive to further biological applications. Likely, a series of experiments show that

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Fig. 5 The chemical structures and schematic illustration of the voltage-responsive controlled assembly and disassembly of PS-β-CD/PEO-Fc supramolecular vesicles

Fig. 6 Schematic illustration of the formation of electrochemical redox-responsive micelles from brush-like supramolecular block copolymers and their controlled assembly and disassembly

the supramolecular brushes can self-assemble into a micellar structure and exhibit voltage-triggered reversible self-degradable and self-repairable properties (Fig. 6). Cuo and co-workers [19] reported a voltage-responsive micelle prepared from noncovalently grafted amphiphilic polymers, and this smart nanocapsule is very suitable for electrochemical applications. They prepare β-cyclodextrin (β-CD) grafted dextran (Dex-CD) and ferrocene terminated poly(ε-caprolactone) (PCL-Fc). Then, they successfully construct micelles via mixing these two components. The reversible formation and disassembly of the micelles can be controlled by an external stimulating voltage because of the voltage responsiveness of Fc. Next, meloxicam (MLX) is used as a model drug to characterize the drug loading and control release performance of the prepared micelles. The sample with voltage stimuli shows a higher release rate and an equilibrium release content of ca. 83% after 10 h, whereas the control sample shows lower release rate. It is mainly due to

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Fig. 7 Schematic illustration of the voltage-responsive micelles through the self-assembly of noncovalently grafted polymer

the disassembly of micelles in the stimuli of voltage thus releasing the active drug (Fig. 7).

57.2.1.4 Photo-Controlled System for Drug Delivery Among the most external stimuli such as pH, redox, and enzymes, light is of particular interest due to its noninvasive, clean, and remote-controlling properties, which is utilized by more and more scientists to construct intelligently responding biological materials. Additionally, a wide variety of light-triggered drug delivery systems have been established based on the photoinduced isomerization. Due to the distinctive binding affinities of azobenzene with cyclodextrins upon reversible transand cis-photoisomerization, this unique property has always been used for the construction of CD-based photoresponsive supramolecular systems. Yan and co-workers [20] fabricated a photo-responsive vesicles with narrow size distribution via a supramolecular janus hyperbranched polymer through specific AZO/CD host guest interactions. First of all, they prepare a hydrophilic part hyper-branched polyglycerol with a β-cyclodextrin apex (CD-g-HPG) through ring-opening polymerization of glycerol and a hydrophobic part poly(3-ethyl-3oxetanemethanol) (HBPO) with an apex of an azobenzene group (AZO-g-HBPO). By virtue of the specific AZO/CD host guest interactions, they can self-assemble into vesicles in water. The morphology of the aggregates is observed and verified by kinds of characterization such as SEM, TEM, and AFM, which indicates the particles are vesicles or hollow spheres. At the same time, computer simulation results also confirm that. Interestingly, these vesicles can be disassembled under irradiation of UV light because of the photoinduced isomerization of AZO. This work has an important role in designing synthetic light-responsive vesicles for further biological application (Fig. 8). Different morphologies will greatly affect the function of the supramolecular assemblies. Yuan and co-workers [21] reported another light-controlled smart

Fig. 8 Schematic illustration of the fabrication of pH-responsive supramolecular polymer based on a bis-p-sulfonatocalixarene host and a tetraphenylethylene derivative guest

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nanotube based on the orthogonal assembly of two homopolymers. They synthesize single trans-Azo end-capped poly(acrylic acid) (PAA-tAzo) and α-CD terminated poly(caprolactone) (PCL-α-CD). Through the strong host–guest interaction of α-cyclodextrin (α-CD) and azobenzene, they can form an exact 1:1 inclusion complex with (Azo). The trans-azobenzene is strongly bound in the cavity of α-CD, whereas the cis-form (cAzo) can rapidly slide out of the cavity due to the different molecular configurations. This isomerization can be reversibly switched upon external photoirradiation. Further investigation shows that they can selfassemble into in particular tubular morphologies in water. It is worth mentioning that the shape of the assembly changes with the change of illumination time. At last, the bilayers are gradually destroyed, and the tubular morphologies completely dissociated. Interestingly, the previous tubular structure reappears similar to the original ones by applying visible light (Fig. 9).

57.2.1.5 Dual Responsive System for Drug Delivery Several tumor cell lines could consecutively produce certain amounts of ROS during their growth, and they also exhibit several times higher concentrations of glutathione (GSH) than normal cells in the cytoplasm. Considering the characteristic levels of ROS and GSH in cancer cell lines, many studies have focused on the construction of ROS or GSH-responsive drug delivery systems for cancer therapy. The ferrocene unit and disulfide bonds are usually designed to form supramolecular materials in response to cancer cells with a distinctive microenvironment in situ. Neutral ferrocene groups can be bonded to the cavity of the cyclodextrin tightly via host–guest interaction. Conversely, the ferrocene group will detach from the cyclodextrin cavity quickly when the ferrocene group is oxidized to its ionic form. The disulfide bonds are relatively stable in normal cells (10 μM of GSH), whereas it can be degraded to free thiols by an elevated concentration of GSH (approximately 10 mM in the cytoplasm) in cancer cells. Based on the above considerations, Wei and co-workers [22] constructed a dual redox-responsive supramolecular system using a reducible β-cyclodextran-ferrocene

Fig. 9 Schematic illustration of the reversible assembly and disassembly of light-responsive nanotubes on the basis of orthogonal host–guest interactions

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double-head unit (Fc-SS-β-CD) and ferrocene group terminated hydrophilic polymer chain (Fc-P(OEGMA)). The double-head unit Fc-SS-β-CD is a hydrophobic part, and Fc-P(OEGMA) is a hydrophilic part. By adjusting the ratio of the two assembled block, they can obtain two supramolecular assemblies of micelles and vesicles, respectively. Well-defined supramolecular micelles and vesicles are obtained under the molar mixed ratios of 1:1 and 3:1, and DOX and DOX
HCl are encapsulated into the supramolecular micelles and vesicles for further simulated drug release test. Furthermore, the resulting supramolecular self-assemblies can respond rapidly to both intracellular reducing and oxidizing environments due to the integration of a reduction-sensitive covalent disulfide link and oxidation-sensitive noncovalent β-CD/Fc joint in the polymer backbone, thus leading to the structural disassembly and accelerated drug release. This work provides a new method for GSH along with ROS-triggered anticancer drug delivery (Fig. 10). Li and co-workers [23] fabricated another dual redox-responsive supramolecular assembly for drug delivery and controllable release. Different from the work described above, they designed and synthesized a prodrug of camptothecin, ferrocene (Fc) modified on camptothecin (CPT), Fc-CPT, which are connected by disulfide bond that can be cleaved by GSH selectively that overexpressed in cancer cells. At the same time, the higher level of ROS generated by cancer cells will facilitate the oxidation of ferrocene, resulting in the dissociation between β-CD and Fc. Compared with traditional physical drug loading, the drug loading can be greatly improved by the design of the prodrug. Moreover, β-cyclodextrin (β-CD) at the end of methoxy polyethylene glycol (mPEG) was designed to form a more stable supramolecular assembly with prodrug molecules. In vitro cell experiments showed that this mPEG-β-CD/Fc-CPT supramolecular assembly has higher in vivo efficacy without side effects (Fig. 11). Carrying the drug to the cancer cells site accurately is still a problem that needs to be solved urgently. Hyaluronic acid (HA), a sort of polysaccharide with excellent biocompatibility, is a great choice for nanosized assemblies construction for drug and gene delivery due to its targeting capability toward HA receptors (CD44 receptors) overexpressed on the surface of malignant cancer cells. Li and Fig. 10 Schematic illustration of the fabrication of supramolecular amphiphilic block copolymer and its self-assembled micelle and vesicle

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Fig. 11 Schematic illustration of the fabrication of mPEG-β-CD/Fc-CPT supramolecular complex micelle

Fig. 12 Schematic illustration of the fabrication of β-CD-g-OX-HA/ADACPT supramolecular inclusion micelles

co-workers [24] reported novel pH and glutathione dual-triggered supramolecular assemblies as synergistic and controlled drug release carriers. Similar to the previous work, they designed and synthesized a prodrug of camptothecin, adamantane (ADA) modified on camptothecin (CPT), ADA-CPT, linked by a glutathione-responsive disulfide bond. Cyclodextrin is modified on hyaluronic acid (HA) via an imine bond as an intracellular acid-sensitive bridge. Due to the host–guest interactions between the adamantane (ADA) on camptothecin (CPT) and β-cyclodextrin (β-CD) on the side chain of the backbone of hyaluronic acid (HA), the supramolecular assembly β-CD-g-OX-HA/ADA-CPT is formed in water. In addition, this assembly can release active drugs precisely and rapidly due to the acidic environment and the presence of a high concentration of GSH. This work provides a new strategy to target cancer cells precisely and achieve controlled release of drugs efficiently (Fig. 12).

57.2.2 Nanoscaled Cyclodextrin Supramolecular System for Gene Delivery The fabrication of gene nanoscaled supramolecular systems via noncovalent interactions has been proved to be a convenient strategy for scientists in the chemical and

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biological fields. In particular, cyclodextrins and their derivatives have become an important building block for constructing gene delivery systems due to its good biocompatibility, low toxicity, and excellent host–guest properties.

57.2.2.1 Gene Delivery Based on Polyrotaxane The cyclodextrin-based polyrotaxane has attracted more and more attention due to its unique topology and good biocompatibility, which are often designed as a variety of biological materials for gene delivery. Cyclodextrins on the polyrotaxane still retain its original advantages such as facilely decorated for multi-functionality, low toxicity to organisms, and so on. Xu and co-workers [25] constructed an excellent cationic polyrotaxane (PP-PGEA) terminated with polypeptides as a nucleic acid delivery system. They designed and synthesized a cyclodextrin-based pseudopolyrotaxane and degradable polypeptides poly(aspartic acid) (PAsp) as terminated group via the end-capping reaction of pseudo-PR. Cyclodextrin on polyrotaxane as microinitiator can initiate polymerization of GMA through atom transfer radical polymerization (ATRP). PGMA can be converted to PGEA by subsequent reaction. The purpose for the arrangement is that the degradability of the PAsp segment can promote the slip of low-molecular-weight CD-PGEA from the main PEG chain, thus leading to the disintegration of the assemblies and further release the nucleic acids. The PP-PGEA polyrotaxanes display excellent effective antioncogene p53 delivery in vitro and in vivo for antitumor activities. This work provides a convenient strategy for the design of novel efficient nucleic acid delivery systems (Fig. 13). Yui and co-workers [26] have developed new cytocleavable cationic polyrotaxanes (PRXs) including N,Ndimethylaminoethyl (DMAE) group-modified α-cyclodextrins (CDs), and the PEG chain is capped with a bulky stopper using a cleavable disulfide linkage for siRNA delivery. In this study, they conduct a detailed investigation on the relationship between the chemical structure of the polyrotaxane and its siRNA delivery efficiency. The polyrotaxanes present better capability in forming the complex with siRNA with increasing dimethylaminoethyl (DMAE)-α-CD threaded on the PEG. Additionally, the introduction of biocleavable disulfide group enhances the gene silencing compared to the polyrotaxanes with no disulfide bonds (Fig. 14). Fig. 13 Schematic illustration of the synthesis process of cationic polyrotaxanes (PP-PGEA) and delivery process of pDNA

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Fig. 14 Schematic illustration of supramolecular polyplex formation between siRNA and DMAE-PR

57.2.2.2 Gene Delivery Based on Supramolecular Nanoparticles Among a series of supramolecular interactions, adamantane and β-cyclodextrin have often been employed to construct supramolecular systems due to their large association constant and high reliability of the interactions. Making full use of the interaction between them, a wide variety of supramolecular assemblies are designed for gene delivery. More recently, Liu and co-workers [27] reported a supramolecular nanoparticle composed of doubly positively charged adamantane (ADA2+) and β-CD modified hyaluronic acid (HACD). HACD is used to target cancer cells for targeted gene delivery. ADA2+ bearing two quaternary ammonium ions will turn into a zwitterionic molecule when its ester group is hydrolyzed to a negatively charged carboxyl. The nanoparticle named ADA2 + @HACD is formed by simply mixing ADA2+ and HACD together, which have a negatively charged HA shell and a positively charged quaternary ammonium chain core. The positively charged core can bind negatively charged plasmid DNA (pDNA) and then released when the ester group is hydrolyzed to make ADA2+ form a zwitterionic group. This work provides an attractive strategy and platform for targeted delivery and controllable release of nucleic acids (Fig. 15). Xu and co-workers [28] developed a PGMA-based supramolecular hyperbranched polycations for efficient gene delivery. They synthesize adamantane bridged cyclodextrin by click reaction. After subsequent modification, the macroinitiator named Ad-(CD-Br)2 is successfully obtained. Then a series of AB2 macromonomers (Ad-(CD-PGEA)2, ACP) with one adamantane (Ad) group and two CD-PGEA arms with different lengths are synthesized for next assembly. Depending on the interaction between cyclodextrin and adamantine, this ACP self-assembles into supramolecular hyperbranched polymers (S-ACP) in aqueous solution which had admirable DNA condensation ability and transfection performances. Moreover, the supramolecular hyperbranched polymers can be dissociated in the presence of sodium adamantane (Ad-Na) due to the competitive inclusion and thus leading to the controllable release of nucleic acids (Fig. 16).

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Fig. 15 The synthetic route for the ADA2 + @HACD nanoparticles

Fig. 16 Schematic illustration of the preparation of PGMA-based supramolecular hyperbranched polycations and their resultant pDNA delivery process

57.2.3 Nanoscaled Cyclodextrin Supramolecular System for Synergistic Drug and Gene Delivery Fabricating both drug and gene codelivery with stimuli-responsive release manner for synergistic cancer therapy is really desirable because of their enhancement effects. The accurate construction of this kind of supramocular system through non-covalent host–guest interaction is a simple and effective method.

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Fig. 17 Schematic illustration of the fabrication of supramolecular selfassembly process for formation of the γ-CD-OEI-SS-FA/PTX complex

57.2.3.1 Supramolecular System for Synergistic Drug and Gene Delivery Li and co-workers [29] recently reported a synergistic therapy by combining anticancer drugs paclitaxel (PTX) and p53 gene in nanoparticles for potential cancer therapy. They designed and synthesized a new star-shaped cationic polymer γ-CD-OEI-SS-FA which contains a γ-cyclodextrin (γ-CD) core and multiple oligoethylenimine (OEI) arms with folic acid (FA) linked via a disulfide linker. Through the host–guest interaction between the PTX and γ-CD, the PTX can bind deeply into the hydrophobic cavity of γ-CD core of the star polymer, thus resulting in the formation of inclusion complex termed as γ-CD-OEI-SS-FA/PTX. What’s more, this γ-CD-OEI-SS-FA/PTX carrier can specifically target and deliver DNA to cancer cells that overexpress folate receptors and reach a 10.4 wt% loading level of PTX as well as good solubility in water. This system shows great synergistic cancer therapy that delivers p53 gene into cancer cells effectively at low N/P ratios to induce an efficient cell apoptosis (Fig. 17). 57.2.3.2 Hybrid Supramolecular System for Synergistic Drug and Gene Delivery Inorganic nanoparticles especially silica nanoparticles have been widely applied in biomedical areas due to their high specific surface area, low toxicity, as well as easy surface modification. However, it is difficult for silica nanoparticles to degrade in the body, which greatly limited its application in vivo. In this regard, Xu and co-workers [30] designed redox-responsive and drugembedded silica nanoparticles, which contain disulfide (S-S)-bridged silsesquioxane with S-S bonds for efficient gene/drug codelivery. There are three obvious advantages for this silica nanoparticle: (1) they will undergo a self-destruction process under the higher concentration of glutathione (GSH) within cancer cells; (2) doxorubicin (DOX) can be embedded in the biodegradable silica nanoparticles (DS-DOX) by a facile one-pot method; and (3) the surface of the DS-DOX could be modified with adamantane to bind with CD-PGEA via host–guest interaction for realizing drug/gene codelivery. The CD-PGEA consists of one β-cyclodextrin core

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Fig. 18 Schematic illustration of the preparation of DS-DOX-PGEA and the resultant stimuliresponsive drug/gene codelivery process

and two ethanolamine-functionalized poly(glycidyl methacrylate) arms, which can form a stable nanoparticle DS-DOX-PGEA with adamantine modified DS-DOX and efficiently deliver genes by itself. This smart system can deliver DOX and antitumor gene p53 into tumor cells at the same time and exhibit superior antitumor effect. This work opens new avenues for the fabrication of synergistic drug/gene delivery systems (Fig. 18).

57.3

Conclusion

In summary, this chapter mainly summarized nanoscaled supramolecular systems based on cyclodextrins for drug and gene delivery. CD-based nanoscaled supramolecular systems with multifunctional properties have shown great potentials for biomedical applications. The design and construction of smart CD-based drug and gene delivery systems that can respond to external or internal stimuli, such as pH, light, and redox, is a desirable strategy toward high-efficiency cancer therapy. Although a great number of works have been reported about the biomedical applications of supramolecular systems, their clinical applications still have many practical challenges such as immunological reaction, excretion, and so on. However, all these research have certain directive significance for the clinical applications. CD-based advanced nanoscaled supramolecular systems will be generated to achieve more extensive functions and definitely play an increasingly important role in combating cancer.

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Immunity Regulation by Supramolecular Assemblies

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Qilin Yu, Yong Chen, Bing Zhang, Nali Zhu, Hangqi Zhu, Henan Wei, and Yu Liu

Contents 58.1 58.2 58.3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunomodulation of Antimicrobial Supramolecular Assemblies . . . . . . . . . . . . . . . . . . . . Overview of Antimicrobial and Immunomodulatory Supramolecular Assemblies . . . 58.3.1 AMP-Based Antimicrobial Supramolecular Assemblies . . . . . . . . . . . . . . . . . . . . . 58.3.2 HACD-Based Antimicrobial Supramolecular Assemblies . . . . . . . . . . . . . . . . . . . 58.4 Design and Immunomodulation of Supramolecular Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . 58.4.1 Overview of Supramolecular Assemblies for Vaccine Engineering . . . . . . . . . . 58.4.2 β-Sheet-Induced Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58.4.3 Peptide Amphiphile-Induced Nanomicelles/Nanoparticles . . . . . . . . . . . . . . . . . . . 58.4.4 Supramolecular Hydrogel for Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Q. Yu · N. Zhu · H. Zhu · H. Wei Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, China e-mail: [email protected]; [email protected]; [email protected]; [email protected] Y. Chen · Y. Liu (*) College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China e-mail: [email protected]; [email protected] B. Zhang College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_68

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Introduction

Supramolecular assemblies are formed by building blocks of molecules/inorganic nanocrystals into a structurally regular nano-aggregate via non-covalent molecular interactions, e.g., host-guest interactions, hydrogen bonds, electrostatic interactions, π-π stacking, metal-ligand coordination, van der Waals forces, etc. [1]. These assemblies may be nanofibers, nanovesicles, nanotubes, nanoparticles, hydrogels, etc., exhibiting various mechanical and physicochemical properties [2]. Owing to the dynamic properties of non-covalent interactions, supramolecular assemblies have good reversibility and responsiveness to environmental stimuli, such as temperature, light, pH, competitive host/guest molecules, and other physical/chemical/biological environments [3]. Similar to supramolecular assemblies, the immune systems are also dynamic and well-controllable during their interaction with environmental stimuli, especially with pathogenic microbes. Therefore, supramolecular assembly materials may have a great biological potential in immune regulation and are being used to develop strategies for fighting against a variety of immune-related (especially infectious) diseases.

58.2

Immunomodulation of Antimicrobial Supramolecular Assemblies

Undoubtedly, the infections caused by various pathogenic microbes (e.g., pathogenic bacteria, viruses, and fungi) are always the globally great challenge that threatens people health. With the increasing drug resistance, the efficiency of traditional antimicrobial drugs (antibiotics) used in clinic to fight against pathogenic microbes is frequently compromised [4]. Furthermore, with the increasing immunecompromised populations, more and more peoples are suffering from the risk of difficult illness. Supramolecular assemblies, especially antimicrobial and immunemodulatory supramolecular hydrogels, are being concerned widely in the medical profession. Since pathogenic microbes are one of the key factors that induce immune response, the incorporation of antimicrobial supramolecular assemblies during antimicrobial therapies is inevitable to modulate the immune system.

58.3

Overview of Antimicrobial and Immunomodulatory Supramolecular Assemblies

Supramolecular assemblies constitute an important class of antimicrobial materials [5, 6]. These materials can form a variety of self-assembled structures by various supramolecular interactions [7, 8], displaying many strong advantages as compared to many conventional chemically crosslinked structures, especially high self-healing and biocompatible properties. Antimicrobial supramolecular assemblies are those containing antimicrobial components or immune response-regulating components, which could help the

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host to efficiently fight against the pathogenic infections. Antimicrobial supramolecular assemblies not only possess the surfaces that are easy to adsorb pathogenic microorganisms but also exhibit high microbe-specific toxicity owing to their inherent antimicrobial properties. Especially, the assemblies containing antimicrobial peptides (AMPs) or hyaluronic acid-modified cyclodextrin (HACD) have strong antimicrobial activity and low toxicity to mammalian cells and may activate the host immune system to strength antibacterial efficiency.

58.3.1 AMP-Based Antimicrobial Supramolecular Assemblies AMPs are the peptides that construct the important components of the host innate immune system, functioning as one of the significant barrier to inhibit the invading pathogens [9, 10]. There are abundant AMPs which may be produced by mammals, insects, and plants and have abundant secondary structures (Fig. 1). AMPs not only could kill the pathogens but also have immunomodulatory abilities, such as antiinflammation and immune stimulation, enabling them to regulate the host immune system for enhancement of antimicrobial efficiency and inhibition of adverse health effects (e.g., sepsis) [11, 12]. AMPs have a known antimicrobial mechanism that the interaction of positively charged side groups of their critical amino acids with negatively charged lipid head groups on the cell surface membrane of the microbes results in the suppression of cell wall biosynthesis, disruption of the plasma membrane structures, and consequent cytokinesis [13]. Therefore, AMPs are considered a powerful alternative to traditional antibiotics during antimicrobial therapy, especially during treatment of the drug-resistant pathogens. Evidence have shown that some AMPs function in fighting against microbes by self-assembling process [5]. Under specific environmental conditions (e.g., physiological solutions, the surface of microbial membrane), AMPs can self-assemble into a variety of specific secondary strucutures, including vesicles, micelles, fibris, and nanotubes. There are some researches revealed that the self-assembling structures of

Fig. 1 The structures of several representative natural AMPs, showing the secondary structures of the demonstrated AMPs

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Fig. 2 Schematic illustration of the Cip-Indo@HACD assemblies and their antimicrobial activity

AMPs could be used in tissue regeneration, drug delivery, and antimicrobial therapy [14, 15]. For example, Jiang et al. constructed the cationic supramolecular assemblies of multi-domain peptides (MDPs) and found that they have a broad-spectrum antimicrobial activity [16]. Schnaider et al. designed the self-assembled antibacterial nanostructures containing diphenylalanine, which exhibited strong activity of disrupting the bacterial membranes, leading to membrane damage, activation of stress response signaling pathways, and consequent bacterial cell death [17]. Therefore, the antimicrobial effect of abundant AMPs is associated with their self-assembling process.

58.3.2 HACD-Based Antimicrobial Supramolecular Assemblies Recently, we developed a variety of HACD-containing antimicrobial supramolecular assemblies that could strongly inhibit pathogenic growth and promote immune response. On the one hand, the cyclodextrin cavity of this polysaccharides may load not only some kinds of antibiotics (such as ciprofloxacin, piperacillin) but also some AMPs. On the other hand, HA may stimulate the immune response of the bodies, promoting the antimicrobial efficiency of the immune system. For example, HACD may co-carry both ciprofloxacin and the AMP indolicidin, forming the CipIndo@HACD antimicrobial supramolecular assemblies (Fig. 2). The assemblies could not only severely inhibit the growth of tested pathogens, such as clinically isolated strains of Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus, but also induce the proliferation of macrophages and neutrophils, promoting the antimicrobial activity of the assemblies.

58.4

Design and Immunomodulation of Supramolecular Vaccines

Vaccination is an old but vigorous strategy for maintaining the body health and has being playing a significant role in prevention of abundant serious infectious diseases caused by pathogenic bacteria, virus, and fungi. Vaccines are the agents used during vaccination that pre-inject into the bodies for activation the immune system of bodies

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to recognize and prevent specific infectious or mutation-related diseases (e.g., cancers, neurodegenerative diseases) [18]. For example, the vaccines of variola virus and poliovirus have been used for successfully eradicating human beings from smallpox and poliomyelitis, respectively [19, 20]. Herein, we will discuss supramolecular assemblies that are being investigated as vaccines or vaccine adjuvants for precisely regulating immune responses in the hosts that suffer from immune-related illnesses, including infectious diseases, cancers, and autoimmune diseases. Traditional vaccines are prepared by attenuation of live pathogenic organisms or thorough inactivation of the organisms [21]. Live vaccines can produce longtime protective immunity, but their safety could not be fully guaranteed. In contrast, inactivated vaccines usually exhibit only short-term immunity regulation function but have good biosafety [21, 22]. In recent years, a novel kind of vaccines, named subunit vaccines, has been developed. Subunit vaccines are mainly composed of purified or recombinant antigens and epitopes, which are based on the pathogen surface components (e.g., polysaccharides, proteins, and lipids) that could induce production of the host antibodies or stimulate T cell activation against the pathogens [23]. However, subunit vaccines are usually not sufficient to be immunogenic, and additional immune-stimulating components, known as adjuvants, are required for subunit vaccines to fully activate local inflammation and induce the immune response [24–27]. The widely used adjuvants are bacillus Calmette-Guérin (BCG) vaccine and AS-series adjuvants which are composed of monophosphoryl lipid A (MPL) and other components (e.g., saponin QS-21 for the lipososome adjuvant AS01, aluminum hydroxide for AS04) [28, 29]. Apparently, the binding of subunit vaccines and adjuvants is mainly based on supramolecular interaction. Most recently, researchers are paying great attention to develop novel protein/ peptide-based supramolecular vaccines.

58.4.1 Overview of Supramolecular Assemblies for Vaccine Engineering Supramolecular assemblies, owing to their high dynamics and good cotrollability of sizes, epitope types, adjuvant contents, and multivalencies, are very suitable for regulating immune responses, which can enhance stability and mediate long-term immunity to aimed pathogens or other antigens [21, 30, 31]. Nowadays, a series of supramolecular assemblies for vaccines or vaccine adjuvants have been developed, such as β-sheet-induced nanofibers, peptide amphiphile-induced nanomicelles/nanoparticles, and supramolecular hydrogels.

58.4.2 b-Sheet-Induced Nanofibers By the multiple epitopes may be simultanously displayed with precise ratios and controllable valency. Among various self-assembling domains, the β-sheets are wonderful tools to drive self-assembling and display functional amino acids on the surface

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Fig. 3 Schematic illustration of β-sheet formation of the peptides and self-assembling of nanofibers driven by β-sheet. (a) A versatile peptide sequence with alternating amino acids with both hydrophilic (X) and hydrophobic (Y) groups. (b) X/Y-driven self-assembly of the β-sheet containing a hydrophilic face and a hydrophobic face. (c) Self-assembly of tape, ribbon, fibril, and fiber driven by β-sheet with different packing densities [31]

of their self-assembled nanofibers (Fig. 3) [31]. For instance, if one of specific epitope sequence is conjugated to the peptide Q11 (QQKFQFQFEQQ), which have the selfassembling ability, the fusion peptides could form the nanofibers that strongly activate corresponding antibody production [31]. The nanofibers driven by β-sheets have been proven to be very efficient in construction of different vaccines, such as mixed B epitopes, cytotoxic T cell antigens, the Staphylococcus aureus antigens, malaria antigens, and tumor-associated antigen MUC1 glycopeptide antigens [32–36].

58.4.3 Peptide Amphiphile-Induced Nanomicelles/Nanoparticles Besides β-sheet-induced nanofibers, amphiphilic peptide-lipid conjugates can also induce strong immune responses [37, 38]. Under physiological solutions, these amphiphilic peptides could self-assemble into spherical or cylindrical micelles. Moreover, the secondary structure of β-sheet and immune-functional epitopes can be stabilized during the assembling process. For example, Tirrell’s group developed the amphiphilic peptide platforms by conjugation of peptide with a dialkyl lipid tail (diC16) to generate nanomicelles. The self-assembled micelles could function as selfadjuvants. When a specific T cell epitope was introduced into the peptide amphiphile assemblies, the system could induce the corresponding T cell response, followed by suppression of tumor growth [30, 39]. This study shed a novel light on the application of supramolecular assembly-based vaccines on anticancer therapy.

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Fig. 4 Illustration of SVLP assembling by the designed lipopeptide building blocks [37]

Another successful design of peptide amphiphile-induced nanomicelles is the synthetic virus-like particles (SVLPs) (Fig. 4) [37]. The two hydrophobic lipid tail is composed of Pam2Cys lipid with two Pam chains and the modifiable -COOH and -NH2 groups. The COOH or -NH2 group then could be convalently connected with the coiled coil peptide (IEKKIEA), the TH epitope (IEKKIAKMEKASSVFNVV), and the B-cell epitope. The designed lipopeptide could self-assemble with the hydrophobic lipid core and the hydrophilic epitopes, forming SVLP nanomicelles (with the diameters of 20–30 nm). After several round of immunization in the rabbits, the assembled nanoparticles could induce very high titers of antibodies against the specific antigens [40]. The introduction of other antigens (e.g., the V3 loop of the HIVenvelop glycoprotein gp120, the proline-rich region of pneumococcal surface protein A(PspA)) could render high titers of antibodies against HIV and Streptococcus pneumoniae, respectively [41, 42].

58.4.4 Supramolecular Hydrogel for Vaccines Hydrogel is a kind of polymer network with dynamic three-dimensional structure. Due to the presence of abundant hydrophilic groups (amine, hydroxyl, ether, sulfate, or carboxyl) in their backbones, hydrogels could absorb a large amount of water or biological liquid to maintain the swollen network [43]. Owing to good biocompatibility and high antigen-loading efficiency, hydrogels have a great potential in vaccine adjuvants. As an example, Wang et al. developed a peptide-protein co-assembling system to form the hydrogel composed of Nap-GFFpY-OMe and the ovalbumin (antigen) and investigated its application in vaccines. The assembling hydrogel could enhance antibody production gels by promoting antigen uptake and inducing dendritic cell maturation [44]. Tian et al. reported that a left-hand peptide-DNA co-assembling hydrogel could be used as the HIV vaccines to enhance immune response [45].

58.5

Conclusion

Supramolecular assemblies by polysaccharides, peptides, lipopeptides, and their complexes have been developed as antimicrobial/antitumor materials and vaccines/ vaccine adjuvants for modulation of immune response. On the one hand,

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antimicrobial supramolecular assemblies, especially antimicrobial hydrogels based on AMP and HACD, could simultaneously kill pathogenic microbes and stimulate host immune system to enhance the antimicrobial efficiency. On the other hand, peptide-based supramolecular assemblies, such as β-sheet-induced nanofibers, peptide amphiphile-induced nanomicelles/nanoparticles, and supramolecular hydrogels, have been developed as vaccines or vaccine adjuvants to elicit host immune response for production specific antibodies and preventing the host from infection of corresponding pathogens. Further studies may focus on mechanistic investigations of supramolecular assemblies in immune modification and development of novel supramolecular assemblies for regulating antibody-independent immune response. As the splendid biological properties of supramolecular assemblies, they will become important immune modulation agents to fight against difficult illness associated with immune disorders.

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16. Jiang L, Xu D, Sellati TJ, Dong H (2015) Self-assembly of cationic multidomain peptide hydrogels: supramolecular nanostructure and rheological properties dictate antimicrobial activity. Nanoscale 7(45):19160–19169 17. Schnaider L, Brahmachari S, Schmidt NW, Mensa B, Shaham-Niv S, Bychenko D et al (2017) Self-assembling dipeptide antibacterial nanostructures with membrane disrupting activity. Nat Commun 8(1):1365 18. Coffman RL, Sher A, Seder RA (2010) Vaccine adjuvants: putting innate immunity to work. Immunity 33(4):492–503 19. Rosenthal SR, Merchlinsky M, Kleppinger C, Goldenthal KL (2001) Developing new smallpox vaccines. Emerg Infect Dis 7(6):920 20. Kew OM, Sutter RW, de Gourville EM, Dowdle WR, Pallansch MA (2005) Vaccine-derived polioviruses and the endgame strategy for global polio eradication. Annu Rev Microbiol 59:587–635 21. Rehm BH (2017) Bioengineering towards self-assembly of particulate vaccines. Curr Opin Biotechnol 48:42–53 22. Mahmoud A (2016) New vaccines: challenges of discovery. Microb Biotechnol 9(5):549–552 23. Schmitz J, Roehrig J, Barrett A, Hombach J (2011) Next generation dengue vaccines: a review of candidates in preclinical development. Vaccine 29(42):7276–7284 24. O’Hagan DT, Fox CB (2015) New generation adjuvants–from empiricism to rational design. Vaccine 33:B14–B20 25. Mosca F, Tritto E, Muzzi A, Monaci E, Bagnoli F, Iavarone C et al (2008) Molecular and cellular signatures of human vaccine adjuvants. Proc Natl Acad Sci 105(30):10501–10506 26. Petrovsky N, Aguilar JC (2004) Vaccine adjuvants: current state and future trends. Immunol Cell Biol 82(5):488–496 27. Reed SG, Orr MT, Fox CB (2013) Key roles of adjuvants in modern vaccines. Nat Med 19(12):1597 28. Santos WR, de Lima VM, de Souza EP, Bernardo RR, Palatnik M, de Sousa CBP (2002) Saponins, IL12 and BCG adjuvant in the FML-vaccine formulation against murine visceral leishmaniasis. Vaccine 21(1–2):30–43 29. Garçon N, Chomez P, Van Mechelen M (2007) GlaxoSmithKline adjuvant systems in vaccines: concepts, achievements and perspectives. Expert Rev Vaccines 6(5):723–739 30. Wen Y, Collier JH (2015) Supramolecular peptide vaccines: tuning adaptive immunity. Curr Opin Immunol 35:73–79 31. Eskandari S, Guerin T, Toth I, Stephenson RJ (2017) Recent advances in self-assembled peptides: implications for targeted drug delivery and vaccine engineering. Adv Drug Deliv Rev 110:169–187 32. Rudra JS, Tian YF, Jung JP, Collier JH (2010) A self-assembling peptide acting as an immune adjuvant. Proc Natl Acad Sci 107(2):622–627 33. Chesson CB, Huelsmann EJ, Lacek AT, Kohlhapp FJ, Webb MF, Nabatiyan A et al (2014) Antigenic peptide nanofibers elicit adjuvant-free CD8+ T cell responses. Vaccine 32(10):1174–1180 34. Pompano RR, Chen J, Verbus EA, Han H, Fridman A, McNeely T et al (2014) Titrating T-cell epitopes within self-assembled vaccines optimizes CD4+ helper T cell and antibody outputs. Adv Healthc Mater 3(11):1898–1908 35. Rudra JS, Mishra S, Chong AS, Mitchell RA, Nardin EH, Nussenzweig V, Collier JH (2012) Self-assembled peptide nanofibers raising durable antibody responses against a malaria epitope. Biomaterials 33(27):6476–6484 36. Huang ZH, Shi L, Ma JW, Sun ZY, Cai H, Chen YX et al (2012) A totally synthetic, selfassembling, adjuvant-free MUC1 glycopeptide vaccine for cancer therapy. J Am Chem Soc 134(21):8730–8733 37. Zerbe K, Moehle K, Robinson JA (2017) Protein epitope mimetics: from new antibiotics to supramolecular synthetic vaccines. Acc Chem Res 50(6):1323–1331 38. Cui H, Webber MJ, Stupp SI (2010) Self-assembly of peptide amphiphiles: from molecules to nanostructures to biomaterials. Pept Sci Orig Res Biomol 94(1):1–18

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39. Black M, Trent A, Kostenko Y, Lee JS, Olive C, Tirrell M (2012) Self-assembled peptide amphiphile micelles containing a cytotoxic T-cell epitope promote a protective immune response in vivo. Adv Mater 24(28):3845–3849 40. Boato F, Thomas RM, Ghasparian A, Freund-Renard A, Moehle K, Robinson JA (2007) Synthetic virus-like particles from self-assembling coiled-coil lipopeptides and their use in antigen display to the immune system. Angew Chem Int Ed 46(47):9015–9018 41. Ghasparian A, Riedel T, Koomullil J, Moehle K, Gorba C, Svergun DI et al (2011) Engineered synthetic virus-like particles and their use in vaccine delivery. Chembiochem 12(1):100–109 42. Tamborrini M, Geib N, Marrero-Nodarse A, Jud M, Hauser J, Aho C et al (2015) A synthetic virus-like particle streptococcal vaccine candidate using B-cell epitopes from the proline-rich region of pneumococcal surface protein a. Vaccine 3(4):850–874 43. Gonçalves C, Pereira P, Gama M (2010) Self-assembled hydrogel nanoparticles for drug delivery applications. Materials 3(2):1420–1460 44. Wang H, Luo Z, Wang Y, He T, Yang C, Ren C et al (2016) Enzyme-catalyzed formation of supramolecular hydrogels as promising vaccine adjuvants. Adv Funct Mater 26(11):1822–1829 45. Tian Y, Wang H, Liu Y, Mao L, Chen W, Zhu Z et al (2014) A peptide-based nanofibrous hydrogel as a promising DNA nanovector for optimizing the efficacy of HIV vaccine. Nano Lett 14(3):1439–1445

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Industrial Applications of Cyclodextrins Qian Wang

Contents 59.1 59.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Applications of CDs in Foods and Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59.2.1 Applications in Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59.2.2 Applications in Food Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59.3 Applications of CDs in Pharmaceutical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59.3.1 Improvement in Solubility, Stability, and Bioavailability . . . . . . . . . . . . . . . . . . . . 59.3.2 Masking Bitterness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59.3.3 CDs-Based Drug Delivery Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59.4 Applications of CDs in Daily Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59.4.1 Applications in Cosmetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59.4.2 Applications in Textile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59.6 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations

HP-β-CD Me-β-CD RM-β-CD SBE-β-CD HP-γ-CD DM-β-CD HE-β-CD PUFA

Hydroxypropyl-β-CD Methylated β-CD Randomly methylated β-CD Sulfobutylether β-CD Hydroxypropyl-γ-CD Heptakis (2,6-di-O-methyl)-β-CD Hydroxyethyl-β-CD Polyunsaturated fatty acid

Q. Wang (*) School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 Y. Liu et al. (eds.), Handbook of Macrocyclic Supramolecular Assembly, https://doi.org/10.1007/978-981-15-2686-2_69

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59.1

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Introduction

Cyclodextrins (CDs) are cyclic oligomers of α-D-glucopyranose that can be produced due to the transformation of starch by certain bacteria such as Bacillus macerans [1]. The preparation process of CDs consists of four principal phases [2]: (i) culturing of the microorganism that produces the cyclodextrin glucosyl transferase enzyme (CGTase); (ii) separation, concentration, and purification of the enzyme from the fermentation medium; (iii) enzymatical conversion of prehydrolyzed starch in mixture of cyclic and acyclic dextrins; and (iv) separation of CDs from the mixture, their purification, and crystallization. CGTase enzymes degrade the starch and produce intramolecular reactions without the water participation. In the process, cyclic and acyclic dextrins are originated, which are oligosaccharides of intermediate size. The cyclic products are CDs, which are formed by the linkage of several glucopyranoses end-to-end through α-1, 4 bonds. By the production on an industrial scale, there are mainly three CDs, that is, α-, β-, and γ-CD, which contain 6, 7, and 8 glucopyranose units, respectively (Fig. 1). The three major CDs are crystalline, homogeneous, and nonhygroscopic substances, which are torus-like macro-rings. However, the purification of α- and γ-CD considerably increases the cost of production, so that 97% of the CDs used in the market are β-CD. Production of parent CDs and some of commercially important CD derivatives is represented in Fig. 2. In reality, the ring that constitutes the CDs is a conical cylinder, which is frequently characterized as a doughnut or wreath-shaped truncated cone. The cavity is lined by the hydrogen atoms and the glycosidic oxygen bridges. The nonbonding electron pairs of the glycosidic oxygen bridges are directed toward the inside of the cavity producing a high electron density there, thus leading to it some Lewis base characteristics [3]. The C-2-OH group of one glucopyranose unit can form a hydrogen bond with the C-3-OH group of the adjacent glucopyranose unit.

Fig. 1 Structures of α-CD (n = 6), β-CD (n = 7), and γ-CD (n = 8)

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Fig. 2 Parent and some representative modified CDs [RM-β-CD, randomly methylated β-cyclodextrin; DIME-β-CD, heptakis (2, 6-dimethyl)-β-cyclodextrin; HP-β-CD, hydroxy propyl-βcyclodextrin; HE-β-CD, hydroxyethyl-β-cyclodextrin; SBE-β-CD, sulfobutylether β-cyclodextrin]

Fig. 3 Approximate geometric dimensions of α-, β-, and γ-CDs

Among the three CDs, β-CD possesses complete secondary belt formed by these intramolecular H-bonds, resulting in a rather rigid structure and the lowest water solubility of all CDs. In the α-CD molecule, the H-bond belt is incomplete because one glucopyranose unit is in a distorted position; consequently, only four H-bonds can be fully established instead of six. While the γ-CD is a noncoplanar, more flexible structure, therefore, it is the most soluble of the three CDs. On the side where the secondary hydroxyl groups are situated, the diameter of the cavity is larger than on the side with the primary hydroxyls, since free rotation of the latter reduces the effective diameter of the cavity [2]. The approximate dimensions of CDs are shown schematically in Fig. 3. With a hydrophilic outer surface and hollow hydrophobic interior, CDs have the ability to form inclusion complexes with a wide variety of organic compounds,

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which enter partly or entirely into the relatively hydrophobic cavity of CDs simultaneously expelling the few high-energy water molecules from inside (Fig. 4). Thus, CDs have widespread utilizations in pharmaceutical, food, cosmetics, and other industrial areas. In the pharmaceutical industry, the natural and modified CDs have been used in drugs either for complexation or as auxiliary additives such as solubilizers, stabilizers, or tablet ingredients to improve the physical and chemical properties or to improve the bioavailability of poorly soluble drugs [2, 4]. In the food, cosmetics, toiletry, and tobacco industries, CDs have been widely used either for stabilization of flavors and fragrances or for the suppression or elimination of undesired tastes or odors, microbiological contaminations, and other undesired compounds [5]. In this chapter, the state of the art in CD science from the viewpoint of industrial application including food, pharmaceutical, cosmetics, and textile will be disclosed, and we hope it can provide inspiration for the new strategies based on CDs to overcome some important issues which we face today.

59.2

Applications of CDs in Foods and Packaging

An important step in the development of natural food additives or ingredients is the design of formulation procedures for their stabilization, solubilization, and delivery. The use of CDs as nano-encapsulating amphiphilic molecules for such purposes introduces a new concept in the food industries [6].

59.2.1 Applications in Foods Owing to the excellent inclusion ability, CDs could accommodate lots of active ingredients in food industry, to solubilize or stabilize active ingredients and passivate their photosensitivity, thermal sensitivity, as well as volatility. Moreover, CDs could mask or eliminate undesired tastes and odors and improve organization structure of

Fig. 4 Schematic illustration of the formation of an inclusion complex between CD (host) and a guest

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food. At present, a growing number of foods containing CDs or using technology about CDs appear on the international market [7].

59.2.1.1 Authorization and Evaluation of CDs as Food Additives Ten years ago, it was found that branched types such as glucosylated and maltosylated CDs were detected in various food products containing enzyme- and heat-processed starch [8]. Beer samples, corn syrups, and bread can contain minute amounts of the enzyme-modified CDs. According to these results, the humankind has been presumably consuming CDs for thousands of years. Even so, the authorization process has only a history of about 40 years [6]. • In Japan, the CDs were declared to be enzymatically modified starch, and, therefore, their use in food products has been permitted since 1978. • In Hungary, the Ministry of Health approved the use of β-CD for stabilization of natural flavors (flavor/β-CD complexes) in 1983. • In France, S.A.L. International in cooperation with Chinoin (Hungary) received a limited approval for the use of β-CD as a flavor carrier in 1986. • In the Netherlands, the Ministry of Health officially declared β-CD to be an enzymatically modified starch in 1986, and, as such, applicable in all those food products in which, according to the already existing regulations (positive lists of ingredients), the use of enzymatically modified starch is permitted. The corresponding authorities of the Benelux (Belgium, Luxemburg, and the Netherlands) countries followed this act with identical decisions. • In 1987, the Spanish authorities approved the utilization of β-CD in foods. • For α-CD and γ-CD, no toxicological findings were filed at FDA. • JECFA (Joint FAO/WHO Expert Committee on Food Additives) classified both α-CD and γ-CD as “ADI not specified” (ADI = Allowed Daily Intakes) which means both CDs can be used in food at any concentration and quantity (JECFA 1999 and 2001). • GRAS (generally recognized as safe in a wide range of intended use in food) approvals were obtained in the USA, and novel food applications are filed in Europe (FDA 2000, 2001, and 2004). The food categories and use levels accepted as GRAS are listed in Table 1.

59.2.1.2 Enhancement of Aqueous Solubility and Stability of Nonpolar Components The most common industrial use of inclusion complex formed with CDs is to increase solubilities of functional ingredients. Generally, the lower the water solubility of a compound, the greater the relative solubility increases gained by complexation. Moreover, CDs have been widely utilized in food technology mainly as carriers of food-related lipophiles such as flavors, vitamins, colorants, fats, and so on, inhibiting the volatilization of labile ingredients and the light- or heat-induced transformations of these sensitive food ingredients.

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Table 1 Food categories and use levels approved for the CDs

Food category Breads, rolls, cakes, baking mixes, refrigerated dough Brownies and bars Crackers (sweet and non-sweet) Diet soft drinks, beverage mixes, fruit juices, instant coffees and teas, coffee whiteners (dry), formula diets, meal replacements, and nutritional supplements Vegetable juices, soy milk, and non-soy (imitation) milk Ready-to-eat breakfast cereals Instant rice, pasta, and noodles (prepared) Condiments Reduced fat spreads Dressings and mayonnaise Yogurt, milk beverage mixes, and frozen dairy desserts Pudding mixes (dry) Snack foods Canned and dry soups (prepared) Hard candy Chewing gum Cheese Spices and seasonings Carrier for vitamins as dietary supplement Carrier for polyunsaturated fatty acids as dietary supplement Fat-based fillings, fruit-based fillings Dairy desserts Baked goods

Maximum use level, percent (w/w) α-CD β-CD γ-CD (FDA, (FDA, (FDA, 2004) 2001) 2000) 5 2 1 7 10 0.5 1 1 1 1

2 2 to 9 2 3 20 5 2.5 1 1 2 15 10

2 2

1

20

1 1 0.2 2 2 1

1 1 3 1 90 80 5/3 3 2

Stabilization of Flavors Flavor plays an important role in consumer satisfaction and influences further consumption of foods. Manufacturing and storage processes, packaging materials, and ingredients in foods often cause modifications in overall flavor by reducing aroma compound intensity or producing off-flavor components [9]. To limit the degradation or loss of aroma during processing or storage, it is beneficial to entrap volatile ingredients prior to use in foods and beverages. A variety of commercial encapsulation practices are currently followed, however, those involving the formation of CD/flavor complexes offer great potential for the protection of volatile and/or labile flavoring materials residing in a multicomponent food system throughout a variety of rigorous food-processing methods, such as freezing, thawing, microwaving, cooking, pasteurization, etc.

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With the aim of selecting appropriate applications of CDs in foods, Astray [10] et al. determined the binding constants of host-guest complexes between several different flavors (Fig. 5) and α-CD as well as β-CD by UV-Vis spectra, as shown in Table 2. As can be seen, the Ks values obtained show that all the studied flavors exhibit more affinity for β-CD than for α-CD. This greater inclusion complexes stability of β-CD-G versus α-CD-G would be related to the larger cavity of β-CD, which can locate more comfortably the guest molecule. However, for encapsulating flavors extracted from dried shiitake like lenthionine, α-CD is the most suitable agent. These flavors are encapsulated in powder form by spray drying with α-CD. The retention of flavor was markedly increased by using a combination of α-CD and maltodextrin as the encapsulant [11]. In Japan, CDs are used to maintain flavor of powdered green tea and simultaneously protect its color, which makes it possible to enjoy green tea flavor and color in ice cream, mousse, and other confectioneries [12]. The process for production of powdered tea is schematized in Fig. 6. Stabilization of Plant Oils Plant oils are always volatile and autocatalytically oxidized rapidly, which can be effectively prevented by complexation with CDs. For example, garlic oil (GO) extracted from garlic which is a widely distributed plant has a variety of antimicrobial and antioxidant activities because it is rich in organosulfur compounds. However, its volatility and low physicochemical stability limit its application as food functional ingredients. Wang et al. [13] demonstrated that GO could be efficiently complexed with β-CD to form an inclusion complex in a molar ratio of 1:1, and the aqueous solubility and stability of GO were significantly increased by inclusion in βCD. In addition, the GO release rate from the GO/β-CD complex could be well controlled. Some recent examples for plant oils stabilized by complexation with CDs are listed in Table 3. These stabilized plant oils are used as nutraceuticals or feed additives. Solubilization and Stabilization of Vitamins As well known, vitamins are essential for humans as they play important roles in different biological cell processes, in the immune system, etc., and additionally they possess antioxidant properties. Hence, the study of functional foods enriched with vitamins is an emerging area. However, the low stability and water solubility of certain vitamins make their incorporation in foodstuff difficult, especially in waterbased formulations. Gratifyingly, this limitation is typically overcome by using encapsulating systems such as CDs. For example, Vilanova and Solans [15] successfully prepared water-soluble inclusion complexes with vitamin A palmitate (VAP) and β-CD without the use of organic solvents. It has been found that the fat-soluble VAP can be dissolved in aqueous media through its inclusion within the cavity of β-CD. Owing to the inclusion, the VAP from the complex shows a higher stability against temperature and oxygen. In addition, the molecular entrapment of VAP within β-CD partially hinders the trans–cis isomerization of the molecule upon exposure to UV light and as a consequence the formation of further toxic photodegradation products. The surface activity and the emulsification ability of the

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Fig. 5 Chemical structures and geometric dimensions of several flavors

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Table 2 Binding constants of several flavors to CDs Flavor Maltol Furaneol Vanillin Methyl cinnamate Cineole Citral Menthol Geraniol Camphor Nootkatone Eugenol p-Vinyl guaiacol Limonene

λ (nm) 230 285 300 391 250 210 530 240 280 254 210 220 400

Ks (α-CD) 0.4  0.1 1.1  0.2 1.6  0.3 41 61 82 10  1 91 31 71 51 2.0  0.5 14  3

Ks (β-CD) 2.1  0.5 71 17  3 20  4 29  4 31  6 35  7 44  9 19  6 32  5 23  4 17  5 55  11

Fig. 6 Process for producing powdered tea

present inclusion complexes have also been confirmed. In a word, β-CD seems to be a promising vehicle to increase the water solubility, stability, and thereby bioavailability of VAP in food fortification to treat vitamin A deficiency.

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Table 3 Plant oils stabilized by complexation with CDs [6, 14, 78, 79] Plant oil Cinnamomum osmophloeum leaf oil Guava leaf oil Estragole-containing essential oils Nutmeg oil Perilla oil Sesame oil Tartary buckwheat bran oil Walnut and flaxseed oil Prickly ash seed oil Evening primrose oil Olive oil Cranberry seed oil Canola oil

Components stabilized Trans-cinnamaldehyde

CD type β-CD

Limonene, β-caryophyllene, 1,8-cineole, and αpinene Estragole

HP-β-CD

Polyunsaturated fatty acid (PUFA) α-Linolenic acid Linoleic acid, oleic acid, sesamol, vitamin E Oleic, linoleic, and linolenic acid and eicosenoic acid PUFA, tocopherol PUFA PUFA PUFA Oleic, linoleic, and linolenic acid, tocopherols, tocotrienols, phytosterols, and lecithin Oleic, linoleic, and linolenic acids, carotenoids, tocopherols

α-, β-, γ-CD, HPβ-CD, ME-β- CD β-CD β-CD β-CD β-CD HP-β-CD β-CD α-, β-, and γ-CD β-CD γ-CD α-CD

Solubilization and Stabilization of Phytosterols Phytosterols and their derivatives have been known for many years due to the ability of preventing cardiovascular diseases by lowering cholesterol. These compounds are water insoluble and always poorly soluble in fats and oils; hence, complexation with CD is one of the best practicable means to include them into foods. The most common phytosterols in the human diet, i.e., β-sitosterol, campesterol, and stigmasterol, could form complexes with β- and γ-CDs. Various complexes of phytosterol with CDs formed to enhance the nutraceutical value of food [16], and it has been disclosed by Schwarzer et al. that stable solid dispersions containing phytosterols and CDs are easy to disperse in beverages, such as milk and orange juice [17]. Wang et al. found that phytosterols from corn germ oil were stabilized by complexation with CDs [18]. In addition, the health-promoting effect of activated Lactobacillus plantarum is proved to be enhanced by phytosterols and CDs [19]. Solubilization and Stabilization of Fatty Acids Interestingly, natural CDs form water-insoluble complexes with fatty acids, while the derivatives of CDs form water-soluble complexes. To solubilize fatty acids, various CD derivatives with good water solubility were designed and used, such as hydroxypropyl α-, β-, and γ-CD (HP-α-, HP-β-, HP-γ-CD) and random methylated α-, β-, and γ-CD (RM-α-, RM-β-, RM-γ-CD). Bálint [20] et al. discovered that the solubilizing effect not only depends on the dimensions of the CD ring but also the chain length and the degree of unsaturation of the fatty acid. HP-α-CD is a better

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solubilizer than HP-β-CD in the case of saturated fatty acids, while HP-β-CD shows better solubilization for the polyunsaturated fatty acids (PUFAs), and HP-γ-CD hardly has any solubilizing effect for saturated or unsaturated fatty acids. Among PUFAs, ω3 PUFAs most abundant in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are very popular. Complexation with HP-β-CD could effectively enhance the water solubility and stability of ω3 PUFAs. Containing conjugated double bonds in their backbone, PUFAs are very sensitive to autooxidation. As a result of oxidative processes, many detrimental substances are produced that might be harmful to health, some of which should be responsible for the rancid, undesirable smell and taste of food products [6]. Complexation with CDs could not only improve the water solubility of PUFAs but also enhance their stability. For example, the stability of linoleic acid and linolenic acid was significantly improved in the form of a water-insoluble complex with β-CD (Fig. 7) compared to that of the non-encapsulated acids [21]. Enhanced thermal and acid stability of linoleic acid complexed by amylose/β-CD mixture has also been researched [22]. In summary, the advantages of CD-stabilized/CD-solubilized PUFAs as nutraceuticals are as follows [6]: (1) exact dosing can be realized; (2) no need of further antioxidants, because of the stabilizing effect; (3) reduced rancid/ fishy smell; and (4) as nutraceuticals, the use of the proper highly soluble CD derivatives would result in improved absorption of fatty acids.

As Green Extracting Agents Nowadays, the recycling of bioactive compounds from wastes and by-products of agroindustrial production may be helpful to add value through the production of natural additives for food or cosmetic products. However, the extraction solvents are always organic which may result in environmental pollution as well as personnel health risks. Therefore, there is a pressing need to replace the organic extraction solvents by green extracting agents with sufficient extraction yields. Owing to the Fig. 7 Scheme of structure of β-CD/linoleic acid complex

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good water solubility and nontoxicity, CDs are regarded as green extracting agents. The employ of CD solutions in the extraction processes is currently being studied to promote the aqueous extraction of both hydrophilic and hydrophobic compounds in a single stage, which is considered as a safe and nonpolluting method [23]. The βCD-assisted extraction processes of polyphenols from grape pomace, apple pomace, and vine shoot cultivars have been optimized recently [24, 80]. In addition, Cui et al. [25] demonstrated that β-CD offered a better yield to recover epigallocatechin from tea leaves than that obtained employing an aqueous 50% ethanol solution as extraction agent. Compared to organic solvents, it is obvious that the β-CD-assisted extraction is more economic, safe, and green. As Browning Inhibitors In the production of juices, the mechanical damage suffered by vegetable and fruit tissues often leads to rapid enzyme-catalyzed browning reactions. Thus, polyphenol oxidase converts the colorless polyphenols to color compounds. In order to avoid this phenomenon, fruit and vegetable juices can be treated with CDs which could remove polyphenol oxidase from juices, as well as protect phenolic compounds from enzymatic oxidation by complexation [2, 26]. Therefore, CDs are widely used as browning inhibitors in different fruit or vegetable juices. López-Nicolás [27, 81–83] et al. have done extensive studies to evaluate the color, aromatic intensity, and sensory quality of fresh juice of apple, peach, pear, as well as banana in the presence of different types of natural and modified CDs, which strongly determined the effectiveness of CDs as browning inhibitors. For instance, the addition of α-CD at 90 mM could prevent oxidation of the volatile precursors present in freshly squeezed pear juices. This resulted in juice with the best color, but with low aromatic intensity and low sensory quality. Addition of 15 mM α-CD, in contrast, could lead to a pear juice that not only had an acceptable color but also retained a high intensity of fruity and pear-like odors/aromas, making it the best appreciated juice by the panel [28]. Solubilization of Propolis It is well known that, as a multifunctional bioactivity ingredient, propolis is natural and safe. It possesses many beneficial biological activities, such as antimicrobial, antioxidant, anti-inflammatory, antitumor, hepatoprotective, local anesthetic, and so on. More than 300 compounds including polyphenols, terpenoids, steroids, sugar, amino acids, etc. have been detected in raw propolis. Their abundance is influenced by geographical factors and botanical origins, as well as by collection season. The propolis produced in southeastern Brazil is widely known as green propolis (BGP) because of its color, and the most important plant source is Baccharis dracunculifolia. Possessing various biological activities like antiulcer, anti-inflammatory, antimutagenic, antifungal/antibacterial, and antileishmanial/antiplasmodial, BGP has been extensively employed in food and beverages, thus helping improve health and preventing diseases. It is quite interesting that a great number of the lipophilic compounds of propolis attracting much interest because of the related biological activities are ethanol soluble; thus, the most common propolis extraction uses ethanol as solvent. However, the ethanolic extraction has some disadvantages

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such as strong residual flavor, adverse reactions, and intolerance to alcohol in some people. Water alone has been tested as extraction solvent but resulted in low extraction yield. Encapsulation in CDs is regarded as a solution to the limitations above. Rocha [29] et al. investigated the encapsulation and thermal characterization of chemical compounds of BGP extracted with HP-β-CD. The characterization of BGP/ HP-β-CD complex suggests that propolis was molecularly dispersed in the HP-β-CD matrix, providing an increasing of solubility of propolis compounds in water, but not for polar compounds such as caffeic and q-coumaric acids. Moreover, the HP-β-CD complexes improved the solubility of some water insoluble or less soluble components, such as cinnamic acid, aromadendrin, isosakuranetin, and artepillin C (Table 4). This fact can resolve the disadvantages of using the ethanol as extraction agent like strong residual flavor, adverse reactions, and intolerance to alcohol in some people. Stabilization of Chlorogenic Acids Hydroxycinnamic acids, such as caffeic and ferulic acids, and their esters with quinic acids are one of the most important groups of phenolic compounds. Because of their similar chemical and bioactive properties, they can be classified into one group of compounds and are referred to as chlorogenic acids (CHAs). They have a broad range of biological activities, such as antibacterial, antifungal, anti-inflammatory, hypoglycemic, and antioxidant, among which the antioxidant activity reduces the risk of several oxidative stress-related diseases, including atherosclerosis, some kinds of cancer, and Alzheimer’s disease. Coffee is one of the plants that contain CHAs in quantities adequate to have physiological effects, especially their green beans which contain 4–10% of CHAs. Due to the high concentration of CHAs in green coffee and their good water solubility, it is easy to gain water extracts with a high concentration of CHAs, which can be used as food components or food supplements. However, when Table 4 Quantitation of chemical constituents of extracts and total polyphenol and flavonoid contents

Total polyphenol (μg GAEa/mLb) Total flavonoids(μg QCEc/mLb) Caffeic acidd ρ-Coumaric acidd Cinnamic acidd Aromadendrind Isosakuranetind Artepillin Cd

Aqueous extract 650  26 116  3 52.4  2.798 236.5  0.246 11.0  0.465 26.7  1.404 23.8  0.475 0.0  0.000

Inclusion complex solution 620  24 290  7 41.5  0.248 194.0  0.180 14.6  0.216 70.9  0.282 180.6  4.487 169.7  1.434

Values are mean  SD obtained from analyses in triplicate (n = 3) GAE = gallic acid equivalent b ext. = propolis extract c QCE = quercetin equivalent d μg/mL of extract a

Increase of solubility – 2.5 0.8 0.8 1.3 2.6 7.5 17.0

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using CHAs as food additives, an issue of their interactions with amino acids, peptides, and proteins may occur, which limits the functionality of both proteins and CHAs, especially in decreasing their absorption and reducing antioxidant activity. Moreover, the presence of polyphenol oxidase, temperature rise, as well as a neutral or alkaline pH would promote the oxidation of CHAs to the corresponding products, i.e., quinones or semiquinones, and favor the formation of covalent bonds. Therefore, it may be beneficial to entrap CHAs into the cavity of β-CD and to add the CHAs/β-CD complex to foods and food supplements. It is reported that the aromatic ring of CHA located in the cavity of β-CD, can be protected against reactions with food proteins, on the promise that inclusion of CHAs into β-CD cavity does not limit their bioavailability and antioxidant activity [30]. Solubilization of Tertiary Butylhydroquinones Generally speaking, oxidation is one of the main causes for food spoilage as well as human aging; as such, the studies about antioxidants have become especially important. Tertiary butylhydroquinone (TBHQ) is a phenolic antioxidant with high efficiency and stability and can be used to increase shelf life of oil-rich foods and improve their safety [31]. TBHQ is mainly used in edible oils, fried or baked goods, and meat products to prevent foods from being oxidized and also widely used as an antioxidant in cosmetic products, such as lipsticks, perfumes, and skin care preparations. However, the application of TBHQ is limited because of its poor water solubility. Recently, the improvement of aqueous solubility of TBHQ by the encapsulation of three kinds of CDs (β-CD, DM-β-CD, and HP-β-CD) was investigated [32]. The research showed that the water solubility of TBHQ was improved after complexation with HP-β-CD and DM-β-CD, and the antioxidant activity of TBHQ in aqueous solution was increased in different degrees after complexation with the three CDs. The effects of the three inclusion complexes on ·OH-, ·O2- ABTS+ free radical scavenging activity were significantly improved. However, the scavenging effects of the inclusion complexes on DPPH free radicals were not evident. Besides, the stability of TBHQ in PVC plastic materials or aqueous solution improved, and cytotoxicity reduced by forming inclusion complexes.

59.2.1.3 Reducing Unwanted Components or Taste In the same way, CDs can eliminate some taste or ingredients of food. In fact, a bitter taste is the main reason for the rejection of various food products although exceptions to this rule are rooted in many cultures: in some foods and beverages, such as coffee, beer, and wine, a certain degree of bitterness is expected. Bitterness, however, has proved a major limitation in the acceptance of commercial food like citrus juices [2]. A commercial process is needed to remove the bitter components without adding anything while still keeping the expected flavor and nutritional value of foods. CDs can be employed for the masking of unpleasant taste or odor as well as the removal of undesirable components. The utility of CDs is a potential bitterness minimizing treatment by complexation with bitter molecules. The bitter taste is reduced probably because of the inability of the complexed molecules to bind to the taste receptors on the tongue. Ginseng is very

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famous for its health benefits such as aiding in overall improvement of health, alleviating health conditions like diabetes, and become one of the most popular functional ingredients found in energy drink formulations. However, ginseng gets a bad rap for imparting a bitter taste. Thus, incorporating ginseng into beverages without the bitterness, while still keeping its health benefits, is quite necessary for developing an acceptable product. As early as 1993, Yu reported that 5% to 12% CDs (type not specified in patent) decreased the bitterness of a ginseng drink [33]. The patent reported by Lee [34] et al. also claimed that the bitterness of 100 g ginseng extract in solution could be eliminated by the addition of approximately 1 g γ-CD. Tamamoto [35] et al. performed experiments to study the effectiveness of bitterness-minimizing treatments of γ-CD and β-CD, suggesting that 0.09 g γ-CD significantly reduce the bitter taste and aftertaste of ginseng in 0.052 g ginseng/ 100 mL solution, which is useful in selecting the minimum amount of CDs necessary to produce an acceptable energy drink. As we know, goat milk or goat cheese has a different flavor from cow milk, that is, “goaty flavor,” due to certain branched-chain fatty acids (BCFAs), which limits market possibilities. It was found that β-CD could form complexes with BCFAs such as 4-methyloctanoic acid and thus was useful in masking goaty flavor [36]. Food regulations in many countries preclude additives in primal foods like pure milk. However, there are fewer restrictions for products like yogurt or cheese. Moreover, the market price for these products is higher and more variable than for pure milk, and so can more easily tolerate the costs of additives like CDs that improve eating quality. With its GRAS status, β-CD could be used in commercial goat milk yogurts and similar products. If used in these products, the real or perceived nutritional advantages of goat milk would not lost to goaty flavor, and this was shown to be particularly true for female consumers. Cholesterol (Fig. 8) is an important constituent of the mammalian cell membranes and a starting material for hormone and vitamin D synthesis, but high cholesterol level in the blood can cause atherosclerosis and cardiovascular disease. Thus, there is a big market of the cholesterol-free or cholesterol-reduced products [6]. Cholesterol could form complexes with CDs, but only with β-CD and its derivatives. Because of adequate steric fit into the cavity, there is almost no interaction of cholesterol with αand γ-CD. Like the fatty acids mentioned above, cholesterol is precipitated with parent βCD, which is utilized in the production of various food products with reduced Fig. 8 Structure of cholesterol

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cholesterol content, while the complexes of cholesterol with the β-CD derivatives are well soluble in water, especially the methylated β-CD derivatives [37] (Table 5). Therefore, these β-CD derivatives can be used for removal and delivery of cholesterol from and into cell cultures. However, the cholesterol-solubilizing effect of the β-CD derivatives has not been used in food so far. As early as the 1990s, the natural β-CD has been utilized for the removal of cholesterol from dairy products, eggs, and so on [38]. The research is, however, continued especially in the east. For instance, treating milk with 0.6% β-CD, butter with reduced cholesterol content (by 95%) and no significant change in the fatty acid composition is obtained [39]. Treating butter with β-CD is another option using the coprecipitation technique, which is more efficient than kneading [40]. The low cholesterol egg yolk obtained by treatment with β-CD contained less lipid and protein and more carbohydrate and ash than the original egg yolk, which can be used for foods such as mayonnaise without causing any toxicity. Both free and esterified cholesterol in cholesterol-reduced egg yolk were reduced by about 90%. In some recent years, more economic technologies were worked out by using β-CD immobilized in chitosan beads or cross-linked β-CD [41]. More interestingly, a Korean patent claims that hens fed with β-CD laid eggs with reduced cholesterol [42]. Although the feed intake and egg production decreased with a diet of enhanced β-CD content, the cholesterol content of egg yolks was significantly decreased by 0.7–4.2 mg in eggs from hens maintained on 2–8% β-CD supplemented feed [43]. In a word, CDs have been widely used in the food industry to solubilize bioactive compounds as nutraceuticals and stabilize components avoiding the volatilization or destruction of certain flavors, colors, or vitamins associated with certain ingredients by processing or storage. Thus, CDs improve the shelf life of food products by protecting against light-, air-, or heat-induced decomposition. Besides, CDs are employed for the reduction of unwanted components in foods, as well as the modification or elimination of bitter and disgusting odors or tastes of foods and beverages.

59.2.2 Applications in Food Packaging A fascinating and challenging application of CDs in food industry is the CDcontaining food packaging materials. Traditional food packages are passive barriers Table 5 Solubility of cholesterol (mg/mL) in 5% aqueous solutions of CD derivatives Hydroxypropyl (HP)a Random methyl (RAME)b Dimethyl (DIME) Trimethyl (TRIME) a

α-CD