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Synthetic Inorganic Chemistry: New Perspectives
 0128184299, 9780128184295

Table of contents :
Cover
Title page
Copyright
Contents
List of contributors
Foreword
Preface
Section 1 Non-precious metals in catalysis
1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules and biodegradable polymers
Section 2 Smart inorganic polymers
2. Polyphosphazenes: macromolecular structures, properties, and their methods of synthesis
Section 3 Inorganic chemistry in ionic liquids
3. Application of ionic liquids in inorganic synthesis
Section 4 Metal-organic frameworks
4. Wettability control of metal-organic frameworks
Section 5 Frustrated Lewis pairs and small molecule activation
5. Rivaling transition metal reactivity—an exploration of frustrated Lewis pairs chemistry
Section 6 New inorganic therapeutics, I
6. Ruthenium and iron metallodrugs: new inorganic and organometallic complexes as prospective anticancer agents
Section 7 New inorganic therapeutics, II
7. Functional nanocomposites: promising candidates for cancer diagnosis and treatment
Section 8 Advances in fundamental main group chemistry, I
8. Recent advances in the selective functionalization of anionic icosahedral boranes and carboranes
Section 9 Advances in fundamental main group chemistry, II
9. Coordination of N-heterocyclic carbene to Si-Si and P-P multiple bonded compounds
Section 10 Bioinspired inorganic synthesis
10. Bioinorganic and bioinspired solid-state chemistry: from classical crystallization to nonclassical synthesis concepts
Index
Backcover

Citation preview

SYNTHETIC INORGANIC CHEMISTRY

Developments in Inorganic Chemistry

SYNTHETIC INORGANIC CHEMISTRY New Perspectives

Edited by

EWAN J. M. HAMILTON The Ohio State University at Lima, Lima, OH, United States

SERIES EDITOR

NARAYAN S. HOSMANE

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2021 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-818429-5 For Information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Susan Dennis Acquisitions Editor: Emily M. McCloskey Editorial Project Manager: Lindsay Lawrence Production Project Manager: Bharatwaj Varatharajan Cover Designer: Mark Rogers Typeset by MPS Limited, Chennai, India

Contents

List of contributors Foreword Preface

ix xiii xv

Section 1 Non-precious metals in catalysis 1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules and biodegradable polymers Xiao Wu, Katie J. Lamb, Agustı´n Lara-Sa´nchez, Carlos Alonso-Moreno, Michael North and Jose´ A. Castro-Osma 1.1 Introduction 1.2 Aluminum-based catalysts 1.3 Iron-based catalysts 1.4 Conclusions References

3 4 20 33 33

Section 2 Smart inorganic polymers 2. Polyphosphazenes: macromolecular structures, properties, and their methods of synthesis Aitziber Iturmendi, Helena Henke, George S. Pappas and Ian Teasdale 2.1 Introduction 2.2 Synthesis of poly(organo)phosphazenes 2.3 Advanced architectures 2.4 Cyclomatrix organophosphazenes 2.5 (Bio)degradable poly(organo)phosphazenes 2.6 Water-soluble poly(organo)phosphazenes 2.7 Soft materials 2.8 Conclusions and outlook References

v

47 48 54 63 72 78 83 89 90

vi

Contents

Section 3 Inorganic chemistry in ionic liquids 3. Application of ionic liquids in inorganic synthesis Di Li and Wenjun Zheng 3.1 Introduction 3.2 Advantages and key factors of the structural regulation mechanism of ionic liquids in inorganic synthesis 3.3 Ionic liquids assisted synthesis of nanomaterials 3.4 Summary References

105 108 110 123 123

Section 4 Metal-organic frameworks 4. Wettability control of metal-organic frameworks Qi Sun and Shengqian Ma 4.1 4.2 4.3 4.4 4.5 4.6

Introduction Wettability of metal-organic framework surfaces Synthesis of hydrophobic metal-organic framework materials Linker-based hydrophobic metal-organic frameworks Induction of hydrophobicity by postsynthetic modification Introduction of external surface corrugation by use of a hydrophobic unit 4.7 Hydrophobic metal-organic framework composites 4.8 Potential applications of hydrophobic metal-organic frameworks and their composites 4.9 Gas separation/storage 4.10 Oil spill cleanup 4.11 Catalysis 4.12 Conclusions and perspectives References

131 133 134 136 140 144 147 154 154 157 158 160 161

Section 5 Frustrated Lewis pairs and small molecule activation 5. Rivaling transition metal reactivity—an exploration of frustrated Lewis pairs chemistry Meera Mehta and Christopher B. Caputo 5.1 Introduction

169

Contents

5.2 Evidence that unique chemistry was possible with main-group Lewis acids and bases 5.3 The discovery of reversible dihydrogen activation and catalysis 5.4 Small molecule activation 5.5 Mechanistic insights into frustrated Lewis pair small molecule activation 5.6 Frustrated Lewis pair mediated CsH bond activation 5.7 Immobilization of frustrated Lewis pairs 5.8 Unconventional Lewis acid partners 5.9 Transition metal frustrated Lewis pair systems 5.10 What are the requirements for frustration? 5.11 Outlook References

vii 170 172 174 185 187 189 192 202 206 209 210

Section 6 New inorganic therapeutics, I 6. Ruthenium and iron metallodrugs: new inorganic and organometallic complexes as prospective anticancer agents Andreia Valente, Taˆnia S. Morais, Ricardo G. Teixeira, Cristina P. Matos, Ana Isabel Tomaz and M. Helena Garcia 6.1 6.2 6.3 6.4

Introduction Novel octahedral Ru(III)/Fe(III)-based prospective drug candidates Designing metallodrugs with the {M(II)(Cp)} scaffold General synthetic procedures for ruthenium and iron prospective metallodrugs 6.5 Conclusions and final comments Acknowledgments References

223 233 242 259 265 266 266

Section 7 New inorganic therapeutics, II 7. Functional nanocomposites: promising candidates for cancer diagnosis and treatment Okan Icten 7.1 7.2 7.3 7.4

Introduction Synthesis techniques for preparation of nanocomposites Surface modification Cancer diagnosis and treatment applications of functional nanocomposites References

279 282 299 308 327

viii

Contents

Section 8 Advances in fundamental main group chemistry, I 8. Recent advances in the selective functionalization of anionic icosahedral boranes and carboranes Mustapha Hamdaoui, Rajesh Varkhedkar, Jizeng Sun, Fan Liu and Simon Duttwyler 8.1 Introduction 8.2 BsH activation for the functionalization of anionic boron clusters 8.3 Directing group-controlled formation of organometallic complexes of the monocarborane anion 8.4 Transition metal-catalyzed functionalization of anionic boron clusters 8.5 Outlook Acknowledgements References

343 349 354 364 384 385 385

Section 9 Advances in fundamental main group chemistry, II 9. Coordination of N-heterocyclic carbene to Si Si and P P multiple bonded compounds Anukul Jana 9.1 Introduction 9.2 NHC coordination to a Si Si triple bonded compound 9.3 Reversible NHC coordination to Si Si double bonded compounds 9.4 Reversible NHC coordination to PsP double bonded compounds 9.5 Conclusions References

393 396 398 400 425 425

Section 10 Bioinspired inorganic synthesis 10. Bioinorganic and bioinspired solid-state chemistry: from classical crystallization to nonclassical synthesis concepts Stephan E. Wolf 10.1 Introduction: creatures proficient in inorganic solid-state chemistry 10.2 Biominerals: basic principles of bioinorganic solid-state chemistry 10.3 From biomineralizing organism to bioinspired in vitro syntheses 10.4 From solutes to solids: conclusions and outlook References

Index

433 437 447 471 472

491

List of contributors

Carlos Alonso-Moreno Departamento de Quı´mica Inorga´nica, Orga´nica y Bioquı´mica, and Centro de Innovacio´n en Quı´mica Avanzada (ORFEO–CINQA), Facultad de Farmacia, Universidad de Castilla-La Mancha, Albacete, Spain Christopher B. Caputo ON, Canada

Department of Chemistry, York University, Toronto,

Jose´ A. Castro-Osma Departamento de Quı´mica Inorga´nica, Orga´nica y Bioquı´mica, and Centro de Innovacio´n en Quı´mica Avanzada (ORFEO–CINQA), Facultad de Farmacia, Universidad de Castilla-La Mancha, Albacete, Spain Simon Duttwyler P.R. China

Department of Chemistry, Zhejiang University, Hangzhou,

M. Helena Garcia Centro de Quı´mica Estrutural and Departamento de Quı´mica e Bioquı´mica, Faculdade de Cieˆncias, Universidade de Lisboa, Campo Grande, Portugal Mustapha Hamdaoui Hangzhou, P.R. China Helena Henke Linz, Austria Okan Icten

Department

of

Chemistry,

Zhejiang

University,

Institute of Polymer Chemistry, Johannes Kepler University,

Hacettepe University, Ankara, Turkey

Aitziber Iturmendi Institute University, Linz, Austria

of

Polymer

Chemistry,

Johannes

Kepler

Anukul Jana Tata Institute of Fundamental Research Hyderabad, Hyderabad, India Katie J. Lamb Green Chemistry Centre of Excellence, Department of Chemistry, The University of York, York, United Kingdom Agustı´n Lara-Sa´nchez Departamento de Quı´mica Inorga´nica, Orga´nica y Bioquı´mica, and Centro de Innovacio´n en Quı´mica Avanzada (ORFEO-CINQA), Facultad de Ciencias y Tecnologı´as Quı´micas, Universidad de Castilla-La Mancha, Ciudad Real, Spain Di Li

Institute for Energy Research, Jiangsu University, Zhenjiang, P.R. China

Fan Liu Department of Chemistry, Zhejiang University, Hangzhou, P.R. China

ix

x

List of contributors

Shengqian Ma Department of Chemistry, University of South Florida, Tampa, FL, United States Cristina P. Matos Centro de Cieˆ ncias e Tecnologias Nucleares (C2TN), Instituto Superior Te´ cnico, Universidade de Lisboa, Bobadela LRS, Portugal Meera Mehta Department of Chemistry, The University of Manchester, Manchester, United Kingdom Taˆnia S. Morais Centro de Quı´mica Estrutural and Departamento de Quı´mica e Bioquı´mica, Faculdade de Cieˆncias, Universidade de Lisboa, Campo Grande, Portugal Michael North Green Chemistry Centre of Excellence, Department of Chemistry, The University of York, York, United Kingdom George S. Pappas Linz, Austria Jizeng Sun P.R. China

Institute of Polymer Chemistry, Johannes Kepler University,

Department of Chemistry, Zhejiang University, Hangzhou,

Qi Sun Department of Chemistry, University of South Florida, Tampa, FL, United States; College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, P.R. China Ian Teasdale Institute of Polymer Chemistry, Johannes Kepler University, Linz, Austria Ricardo G. Teixeira Centro de Quı´mica Estrutural and Departamento de Quı´mica e Bioquı´mica, Faculdade de Cieˆncias, Universidade de Lisboa, Campo Grande, Portugal Ana Isabel Tomaz Centro de Quı´mica Estrutural and Departamento de Quı´mica e Bioquı´mica, Faculdade de Cieˆncias, Universidade de Lisboa, Campo Grande, Portugal Andreia Valente Centro de Quı´mica Estrutural and Departamento de Quı´mica e Bioquı´mica, Faculdade de Cieˆncias, Universidade de Lisboa, Campo Grande, Portugal Rajesh Varkhedkar Department Hangzhou, P.R. China

of

Chemistry,

Zhejiang

University,

Stephan E. Wolf Department of Materials Science and Engineering, Institute for Glass and Ceramics, Friedrich-Alexander-University Erlangen-Nu¨rnberg (FAU), Erlangen, Germany Xiao Wu Green Chemistry Centre of Excellence, Department of Chemistry, The University of York, York, United Kingdom

List of contributors

xi

Wenjun Zheng Department of Chemistry, Key Laboratory of Advanced Energy Materials Chemistry (MOE), TKL of Metal and Molecule-Based Material Chemistry, College of Chemistry, Nankai University, Tianjin, P.R. China; Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin, P.R. China

Foreword I was delighted to be asked to write this Foreword to Synthetic Inorganic Chemistry: New Perspectives, the first volume in the Elsevier series Developments in Inorganic Chemistry. The volume editor, Prof. Ewan J. M. Hamilton, the series editor, Prof. Narayan S. Hosmane, and I share several things—a fulfilling early-career association with the Department of Chemistry at the University of Edinburgh, Scotland; an enduring love of polyhedral boron chemistry; and the firm belief that a full appreciation of what inorganic chemistry is and can do naturally begins with the synthesis of new molecules and materials. In the last respect, it is entirely fitting that the first volume in this new series should be devoted to the art of inorganic synthesis. The tremendous diversity of synthetic inorganic chemistry is clearly evident from the range of subjects covered in the following 500 pages, organised into 8 themes and 10 chapters written by internationally leading experts. It will be both an invaluable reference work to those working in the specific areas covered and a clear beacon to others of the importance of synthetic inorganic chemistry as a key enabling interdisciplinary subject. Alan J. Welch Heriot-Watt University, Edinburgh, United Kingdom March 2021

xiii

Preface While august multivolume collections such as the Comprehensive Inorganic Chemistry series or Modern Synthetic Inorganic Chemistry represent tremendous resources that succeed in providing in-depth and somewhat exhaustive coverage of all aspects of inorganic chemistry, the aim of this book is somewhat different. If one were to ask a layperson to visualize and describe a chemist at work in their laboratory, one would likely hear a description of someone in a lab coat and goggles, with a suitably wild hairstyle, ministering over a collection of test tubes and other strange pieces of glassware filled with a variety of different colored (and most often bubbling!) liquids. The telling thing, however, is that the ubiquity of color in these compounds suggests that the “research” going on here revolves around inorganic compounds. Yet if we were to then ask the same layperson what this (inorganic) chemist may be seeking to make or to learn, or what advances or benefits to society accrue from chemical research, we are most likely to hear about the development of what are essentially organic pharmaceutical compounds. What, then, is our synthetic inorganic chemist up to? In this volume, we seek to give a broad sense of the themes, scale, scope, and excitement of today’s synthetic inorganic chemistry. The audience for the book are chemists and students of chemistry for whom inorganic chemistry may not (yet?) be their core subdiscipline. As will be clear from the following short introduction to some of the topics that lie within these pages, there exists a significant degree of crossover between synthetic inorganic chemistry and other disciplines such as catalysis, medicinal chemistry, and materials science, and, of course, between subdivisions of inorganic chemistry itself. Indeed, the observant reader will even find the authors of one chapter refer to the work of other authors, known for their work in what would appear at first glance to be a very different area of endeavor. (I will leave it to the reader to find this in the text!). While the preparation of new transition metal-based catalysts has been at the forefront of inorganic chemistry for decades, the need to develop catalytic systems around earth-abundant, nonprecious metals has never been greater. Chapter 1, Homogeneous Aluminum and Iron Catalysts for the Synthesis of Organic Molecules and Biodegradable Polymers, describes some recent progress in the preparation of homogeneous catalysts based

xv

xvi

Preface

on aluminum and iron for a variety of bond-forming and polymerization reactions. On the subject of polymers, Chapter 2, Polyphosphazenes: Macromolecular Structures, Properties, and Their Methods of Synthesis, provides an introduction to the synthesis of the class of inorganic polymers known as polyphosphazenes, based on an alternating P N backbone. Recent synthetic advances described herein have permitted rational design of a wide range of macromolecular structures with varied physicochemical properties, paving the way for continued growth in this area. Another area in which the development of new synthetic methods has enabled expansion into the production of materials with different structural motifs has been by the use of ionic liquids. Chapter 3, Application of Ionic Liquids in Inorganic Synthesis, provides an overview of the function of ionic liquids as solvents, templates, and also potential precursors in the synthesis of a variety of inorganic materials featuring 0D to 3D architectures that find application in, for example, a variety of photocatalytic processes. Metal-organic frameworks (MOFs) are a class of materials to which the talents of synthetic inorganic chemists have been brought to bear in recent years. A huge variety of these fascinating compounds have already been prepared, with a great range of potential applications in separations, sensing, catalysis, etc. A significant drawback to wider practical adoption of these materials, however, is their limited stability in aqueous (or merely ambient) environments. Control over the wettability of MOFs is, therefore, a crucial issue, and synthetic approaches toward this necessary goal are addressed in Chapter 4, Wettability Control of Metal-Organic Frameworks. The theme of catalysis is never far from the mind of the modern synthetic inorganic chemist, and this recurs in the work described in Chapter 5, Rivaling Transition Metal Reactivity—An Exploration of Frustrated Lewis Pairs Chemistry. While Chapter 1, Homogeneous Aluminum and Iron Catalysts for the Synthesis of Organic Molecules and Biodegradable Polymers, describes catalytic systems that avoid precious metals, the concept of frustrated Lewis pairs represents a completely different approach that arguably goes one better by using cleverly designed combinations of main group elements to effect small molecule activation. The frustrated Lewis pair concept is also extended to include Lewis acidic early transition metals as well as examples of later transition metals functioning in a Lewis basic role, so broadening our concept of what constitutes a frustrated Lewis pair. Chapter 6, Ruthenium and Iron Metallodrugs: New Inorganic and Organometallic Complexes as Prospective Anticancer Agents, and Chapter 7, Functional Nanocomposites: Promising Candidates for Cancer Diagnosis and Treatment, share the conceptual spirit of applying inorganic synthesis to the arena of anticancer therapeutics. These two

Preface

xvii

chapters, however, take radically different approaches to this crucially important problem. In Chapter 6, Ruthenium and Iron Metallodrugs: New Inorganic and Organometallic Complexes as Prospective Anticancer Agents, we are introduced to two broad classes of new molecular compounds based on iron and ruthenium as potential metallodrugs, which might circumvent the significant drawbacks associated with prevailing platinum-based chemotherapy. Chapter 7, Functional Nanocomposites: Promising Candidates for Cancer Diagnosis and Treatment, describes the methods of synthesis of nanocomposite materials and their use in an array of diagnostic and multimodal therapeutic techniques, including MRI, fluorescence imaging, hyperthermia, boron and gadolinium neutron capture therapy, and photodynamic therapy. The mention of boron neutron capture therapy brings us neatly to Chapter 8, Recent Advances in the Selective Functionalization of Anionic Icosahedral Boranes and Carboranes, the first of our chapters on fundamental main group synthesis. Here, new methodologies are presented that describe the selective functionalization of icosahedral (monocarbon) carborane and borane clusters. Despite these cluster cores having been known for decades, the work described in Chapter 8, Recent Advances in the Selective Functionalization of Anionic Icosahedral Boranes and Carboranes, represents an important stride in their controlled derivatization and opens the door to their continued development. Our second chapter on fundamental main group synthesis describes work aimed at understanding the nature of multiple bonds between nonmetals. Specifically, Chapter 9, Coordination of N-Heterocyclic Carbene to Si Si and P P Multiple Bonded Compounds, describes the manner in which multiply bonded Si Si and P P moieties interact with N-heterocyclic carbenes and the careful study required to reveal the complex nature of these (often equilibrium-based) systems. The book concludes with Chapter 10, Bioinorganic and bioinspired solid-state chemistry: from classical crystallization to nonclassical synthesis concepts, developing the concepts of bioinspired solid-state chemistry. This new branch of bioinorganic chemistry investigates biomineralization and the application of nonclassical biomimetic techniques that are capable of producing solid-state inorganic materials under much milder conditions than those typically employed in traditional solid-state synthetic protocols. It has been my great pleasure to work with all of the authors who have contributed these fine chapters. I have learned a great deal about many aspects of synthetic inorganic chemistry from them, and I am humbled by their expertise and dedication to their respective fields of study. I believe we are very fortunate to have succeeded in enlisting experts of their caliber to write these enlightening chapters for us. Ewan J. M. Hamilton The Ohio State University at Lima, Lima, OH, United States March 2021

S E C T I O N

1

Non-precious metals in catalysis

C H A P T E R

1 Homogeneous aluminum and iron catalysts for the synthesis of organic molecules and biodegradable polymers Xiao Wu1, Katie J. Lamb1, Agustı´n Lara-Sa´nchez2, Carlos Alonso-Moreno3, Michael North1 and Jose´ A. Castro-Osma3 1

Green Chemistry Centre of Excellence, Department of Chemistry, The University of York, York, United Kingdom, 2Departamento de Quı´mica Inorga´nica, Orga´nica y Bioquı´mica, and Centro de Innovacio´n en Quı´mica Avanzada (ORFEO-CINQA), Facultad de Ciencias y Tecnologı´as Quı´micas, Universidad de Castilla-La Mancha, Ciudad Real, Spain, 3Departamento de Quı´mica Inorga´nica, Orga´nica y Bioquı´mica, and Centro de Innovacio´n en Quı´mica Avanzada (ORFEO CINQA), Facultad de Farmacia, Universidad de Castilla-La Mancha, Albacete, Spain

1.1 Introduction The use of metal complexes as catalysts in organic synthesis and polymer chemistry has attracted much attention over the last few decades and there have been remarkable achievements in this area.1 20 However, most catalytic processes rely on the use of precious metals such as iridium, ruthenium, platinum, and palladium among others.21 27 Moreover, the price of transition and rare-earth elements has increased over the last decade. Therefore the development of inexpensive and Earth-abundant metal-containing

Synthetic Inorganic Chemistry DOI: https://doi.org/10.1016/B978-0-12-818429-5.00002-8

3

© 2021 Elsevier Inc. All rights reserved.

4

1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules

complexes as industrial catalysts for the production of organic molecules or biodegradable polymeric materials has increased in recent years.28 31 Aluminum and iron are among the most abundant metals in the Earth’s crust and are significantly cheaper than noble metals that are currently used in chemical processes.28 In these metal complexes, the metal center is generally stabilized by the coordination of a broad variety of ligands that allow their use as catalysts for both achiral and asymmetric transformations.32 34 In this chapter, we will focus on the use of aluminum and iron complexes as catalysts for CsC and C heteroatom bond forming and ring-opening polymerization (ROP) and copolymerization (ROCOP) reactions.

1.2 Aluminum-based catalysts Aluminum compounds have been used as catalysts for a broad range of chemical transformations and some excellent reviews regarding aluminum-catalyzed reactions have been reported in the literature.35 38 In this section we will cover some of the most important reactions catalyzed by aluminum such as reactions of three-membered ring heterocycles with heterocumulenes, hydroelementation reactions, and ROP processes.

1.2.1 Reaction of three-membered ring heterocycles with heterocumulenes Salen and related ligand-based aluminum complexes are wellstudied catalysts for the reaction between epoxides and carbon dioxide. The general mechanism for the synthesis of cyclic carbonates from epoxides and carbon dioxide is presented in Scheme 1.1. Thus the catalysts

SCHEME 1.1

General mechanism for cyclic carbonate synthesis.

1. Non-precious metals in catalysis

1.2 Aluminum-based catalysts

5

could either be a Lewis or Brønsted acid, which activate the epoxide. A good nucleophile then ring-opens the activated epoxide to form an alkoxide and CO2 is inserted to produce a carbonate. Finally, the intramolecular ring-closing step provides the target cyclic carbonate, with catalyst regeneration. Bimetallic aluminum salen complex 1 (Fig. 1.1) was found to be an excellent catalyst in the presence of tetrabutylammonium bromide

FIGURE 1.1 Aluminum salen and salphen complexes 1 and 2.

(TBAB) as a cocatalyst for this transformation at ambient temperature and pressure.39 41 Typically, 2.5 mol% of aluminum complex 1 and TBAB proved to be an effective catalytic system for a range of terminal epoxides. Aluminum complex 1 is also able to catalyze the reaction without the use of a cocatalyst, although harsher reaction conditions are required.42 Subsequently, the formation of an unusual Al-carbonato species, resulting from carbon dioxide insertion into one of the Al O bonds of complex 1, was proposed and observed. Hence, a different reaction mechanism for the transformation of epoxides into cyclic carbonates in the absence of a cocatalyst was proposed.43 Later, a more active (compared to complex 1) diamino aluminum salphen complex 2 was developed.44 In this case, 1.5 mol% of aluminum complex 2 and TBAB were able to convert terminal epoxides and carbon dioxide into their corresponding cyclic carbonates. Furthermore, aluminum complex 2 was also active toward a range of internal epoxides, giving substituted cyclic carbonates in good to excellent yields. Bimetallic aluminum salphen complex 3 was also shown to be an effective catalyst for the production of various cyclic carbonates from epoxides and carbon dioxide in the presence of TBAB (Fig. 1.2).45 The reaction conditions (50 C, 10 bar carbon dioxide pressure) were slightly harsher than those required for catalyst 1 and 2. Nevertheless, both terminal and internal epoxides were transformed into their corresponding cyclic carbonates using bimetallic aluminum salphen complex 3. Mechanistic studies revealed that both aluminum centers were involved in an intramolecular cooperative catalysis pathway. Interestingly, monometallic aluminum salen complex 4 together with TBAB is a

1. Non-precious metals in catalysis

6

1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules

FIGURE 1.2 Aluminum salphen and salen complexes 3 and 4.

suitable catalytic system for the kinetic resolution of epoxides through enantioselective carbon dioxide coupling, giving the highest relative rate of reaction for the two epoxide enantiomers (krel) of 15.4 and an enantiomeric ratio (er) for the cyclic carbonates of 93:7.46 One-component aluminum salen complex 5 bearing appended pyridinium salt substituents was shown to be an effective catalyst for the coupling of epoxides and carbon dioxide (Fig. 1.3).47 The nature of the

FIGURE 1.3 Aluminum salen complexes 5 and 6.

cation proved to be important as decreasing the acidity of the pyridinium salts decreases the catalyst activity. Similarly, aluminum salen complex 6, which possesses intramolecular quaternary ammonium salts as cocatalysts, was used in the regioselective ring-opening of epoxides in a coupling reaction with carbon dioxide, affording cyclic carbonates with complete retention of configuration.48 Notably, this catalyst system exhibited nearly 100% regioselectivity for ring-opening at the methylene C O bond for various terminal epoxides, such as styrene oxide and epichlorohydrin, which contain electron-withdrawing groups. This provided access to various enantiopure cyclic carbonates that were hitherto difficult to access.

1. Non-precious metals in catalysis

1.2 Aluminum-based catalysts

7

Kleij and coworkers developed a class of well-defined aluminum complexes derived from aminotriphenolate ligands, as shown in Scheme 1.2.49,50 Complex 7 was shown to be highly active for cyclic

SCHEME 1.2

Reaction between 1,2-epoxyhexane and carbon dioxide catalyzed by

complex 7.

carbonate formation from epoxides and carbon dioxide (Scheme 1.2). Initial experiments were carried out using 1,2-epoxyhexane as a substrate and the reaction was examined at 90 C and 10 bar carbon dioxide pressure. At a catalyst loading of 0.05 mol% and cocatalyst loading of 0.25 mol%, quantitative conversion to cyclic carbonate 8 was achieved after 2 h, giving a turnover frequency (TOF) of 906 h21. In the presence of 0.0520.1 mol% of aluminum aminotriphenolate complex 7 together with tetrabutylammonium iodide as a cocatalyst, a range of highly functionalized terminal epoxides could be transformed into their corresponding cyclic carbonates in good to excellent yields (40%298%).49 Internal epoxides are widely considered to be very challenging substrates for the formation of cyclic carbonates. However, the combination of aluminum aminotriphenolate complex 7 together with tetrabutylammonium bromide as a catalyst system has proven to be most beneficial for such transformation, using a very low catalyst loading of 0.120.5 mol%.50 Furthermore, a binary catalyst comprising a Lewis acidic aluminum aminotriphenolate complex 7 and a nucleophilic cocatalyst, bis(triphenylphosphine)iminium chloride (PPNCl), is able to mediate the challenging coupling of highly substituted cyclic and acyclic terpene oxides, and carbon dioxide into bio-based cyclic organic carbonates (Scheme 1.3).51 While cyclic terpene oxides exhibited excellent conversion to the organic carbonate product with high diastereoselectivity, acyclic terpene oxides showed inferior chemoselectivity. More recently, the binary aluminum aminotriphenolate complex 7 with PPNCl as cocatalyst has been reported to be a highly active system for the conversion of fatty acid derived epoxides into their cyclic carbonates under relatively mild reaction conditions (70 C285 C, 10 bar carbon dioxide pressure).52 More specifically, various mono-, di-, and tris-epoxy substrates have been transformed into the corresponding cyclic carbonates while maintaining high levels of

1. Non-precious metals in catalysis

8

1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules

SCHEME 1.3

Reaction between terpene derived epoxides and carbon dioxide.

diastereoselectivity with cis/trans ratios of up to 99:1 in the cyclic carbonate products (Scheme 1.4).

SCHEME 1.4

Reaction between epoxidized methyl oleate and carbon dioxide.

Recent benchmarking studies among a series of aluminum-based binary catalysts using different epoxides under various reaction conditions demonstrated that binary catalysts 7/TBAB and porphyrin-based complex 9/PPNCl (Fig. 1.4) display the highest catalytic activity.53 A series of aluminum(heteroscorpionate) catalysts have been developed for the formation of cyclic carbonates from epoxides and carbon dioxide (Fig. 1.5).54 57 Generally, an elevated temperature and pressure (50 C285 C, 10220 bar carbon dioxide pressure) were required to convert both terminal and internal epoxides into their corresponding cyclic carbonates. The effect of adding water to the reaction mixtures using complexes 10 and 11 was also investigated. It was found

1. Non-precious metals in catalysis

1.2 Aluminum-based catalysts

9

FIGURE 1.4 Porphyrin aluminum complex 9 for the synthesis of cyclic carbonates.

FIGURE 1.5

Aluminum(heteroscorpionate) catalysts for cyclic carbonate formation.

that small amounts of water were beneficial for the catalytic activity, increasing the conversion of styrene oxide to styrene carbonate. However, a further increase in the amount of water added was detrimental and the conversion decreased due to hydrolysis of the aluminum alkyl groups. Other reactions between epoxides and heterocumulenes (also known as heteroallenes), such as carbon disulfide and isocyanates, afford cyclic di- or trithiocarbonates and oxazolidinones, respectively, and these have been studied using various aluminum-based catalysts (Scheme 1.5).

SCHEME 1.5 Reaction between epoxides and heterocumulenes.

These include aluminum complex 1,58 61 aluminum complex 7,62 and aluminum heteroscorpionate complexes.63

1. Non-precious metals in catalysis

10

1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules

1.2.2 Hydroelementation reactions Hydrosilylation of alkenes and alkynes is one of the most effective and convenient methods for the synthesis of organosilanes, which have great versatility as building blocks in organic synthesis. A number of catalytic systems, involving radical initiators,64,65 metal catalysts,66,67 and Lewis acids,68,69 have been investigated for the addition of hydrosilanes to multiple bonds. Yamamoto and coworkers reported the use of AlCl3 and trialkylsilanes for the hydrosilylation of alkynes, leading to cis-alkenylsilanes with very high regio- and stereoselectivities in good to high yields.70 As a representative example, 0.2 mol% of AlCl3 catalyzed the hydrosilylation of 1-dodecyne in the presence of 1.2 equivalents of triethylsilane at 0 C for 1 h, affording the corresponding cis-alkenylsilane in 95% yield (Scheme 1.6).

SCHEME 1.6 Lewis acid catalyzed hydrosilylation of 1-dodecyne with Et3SiH.

Similarly, Jung and coworkers investigated the hydrosilylation of cyclic and linear alkenes with trialkylsilanes in the presence of Lewis acid catalysts under mild reaction conditions, giving the corresponding trialkylsilylalkanes in good yields.71 As an example, 0.2 mol% of AlCl3 was required at 0 C for 3 h for the hydrosilylation of 1-methylcyclohexene with Et3SiH to give cis-1triethylsilyl-2-methylcyclohexane in 74% yield, consistent with a trans-hydrosilylation pathway. The authors suggested that  the reaction proceeds by the from AlCl3 and the silane, formation of a silylenium ion Et3 Si1 AlCl2 4 which then adds to the alkene to generate a carbocation (Scheme 1.7).

SCHEME 1.7

Proposed reaction mechanism for the hydrosilylation of 1-methylcyclohexene.

Recently, well-defined aluminum species have been investigated for the hydrosilylation of unsaturated carbon carbon bonds. Chen and coworkers isolated and fully characterized a frustrated Lewis-pair catalyst for the hydrosilylation of unactivated alkenes by mixing an excess of Et3SiH with

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Al(C6F5)3 in hexane.72 With the super Lewis acidity of Al(C6F5)3, the silane alane system exhibits high catalytic activity. Indeed, 98% conversion during the hydrosilylation of 1-hexene was achieved using 5 mol% of silane alane complex [Et3SiH_Al(C6F5)3] in 30 min, with a TOF value of 39 h21 (Scheme 1.8). Noticeably, the silane borane complex [Et3SiH_B(C6F5)3],

SCHEME 1.8 Hydrosilylation of 1-hexene using silane alane complex.

a superior catalyst for hydrosilylation of carbonyl substrates, showed a much slower catalytic activity for 1-hexene with TOF 5 1.5 h21. Nikonov and coworkers reported the use of [AlH(nacnac)][B(C6F5)4] (nacnac 5 CH{C(Me)N(2,6-iPr2C6H3)}2) 15 for alkene hydrosilylation.73 Using 1 or 5 mol% of catalyst 15 in the presence of Et3SiH, a range of terminal alkenes and cyclohexene all showed quantitative conversion to the alkylsilanes in less than 10 min at room temperature. Complex 15 is also effective in catalyzing the hydrosilylation of aliphatic alkynes at room temperature albeit with much longer reaction times of 24 h. Despite the observed high conversion to the hydrosilylation products for both alkenes and alkynes, the isolated yields for the target silanes were rather low due to formation of redistribution products. Mechanistic studies suggest that Lewis acid activation by the cationic aluminum center was involved in the process (Scheme 1.9).

SCHEME 1.9 Proposed mechanism for complex 15 catalyzed hydrosilylation.

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1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules

Roesky and coworkers showed that the well-defined aluminum dihydride LAlH2 (L 5 CH(CMeNAr)2, Ar 5 2,6-Et2C6H3) 16 (3 mol%) was able to catalyze the hydroboration of terminal alkynes with HBpin (pinacolborane) at 30 C for 12 32 h (61% 82% yields), affording the trans-vinylboronate ester arising from the anti-Markovnikov addition of the borane (Scheme 1.10).74 Quantum mechanical calculations indicate

SCHEME 1.10

Hydroboration of alkynes catalyzed by aluminum catalysts 16 and 17.

that the alkyne is activated by the catalyst, leading to the formation of an aluminum acetylide intermediate. In comparison, the catalytic activity of the N-heterocyclic imine-substituted aluminum hydride 17 toward the hydroboration of terminal alkynes is inferior, requiring a higher temperature (80 C) and extended reaction time of 40 h to produce high conversions (Scheme 1.10).75 More recently, Cowley and coworkers developed a catalytic system based on either the commercially available aluminum hydride DIBAL-H (iBu2AlH) or bench-stable Et3Al DABCO (DABCO 5 1,4-diazabicyclo [2.2.0]octane) (10 mol%) and HBpin, which was efficient for alkyne hydroboration (Scheme 1.11).76 In the presence of HBpin (1.2 equivalents)



SCHEME 1.11 Hydroboration of alkynes catalyzed by DIBAL-H.

at 110 C for 2 h in toluene, a series of functionalized and unfunctionalized alkynes was hydroborated in 40% 2 89% yields. Notably, the addition of the HsB bond is chemoselective to the alkynes in the presence of alkenes. Both DIBAL-H and Et3Al DABCO showed equal catalytic activity across all substrates tested, which strongly suggests a shared mode of operation. The reaction mechanism is thought to be different from that with aluminum dihydride complex



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16. A series of mechanistic studies revealed that the hydroboration proceeds through initial hydroalumination, followed by σ-bond metathesis with HBpin, where the alkenyl substituent undergoes transmetallation from aluminum to boron, thus regenerating the aluminum hydride (Scheme 1.12).

SCHEME 1.12 Proposed mechanism for aluminum hydride catalyzed hydroboration.

Similarly, Cowley and coworkers also demonstrated the use of commercially available aluminum hydrides for the hydroboration of alkenes.77 Thus by using 10 mol% of LiAlH4 and 1.2 equivalents of HBpin, the hydroboration of alkenes can be performed at 110 C in 3 h, giving the linear boronic ester in excellent yields with a regioselectivity of 99:1 over branched products. Bergman and coworkers described well-defined four coordinate aluminum complexes bearing a dianionic phenylene-diamine-based ligand, which were active in the intramolecular hydroamination of aminoalkenes (Scheme 1.13).78 Specifically, aluminum complex 18 (10 mol%) was

SCHEME 1.13

Hydroamination of aminoalkenes catalyzed by complex 18.

able to promote the hydroamination of primary aminoalkenes bearing geminal substituents on the backbone to give 5- and 6-membered rings in moderate to good yields, when performing the reaction at 150 C over extended reaction times. It was proposed that the reaction mechanism involved an Al-NMe2/H-NHR metathesis pathway to give an

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1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules

aluminum olefin-amide species, followed by cyclization with the pendent olefin group. Wehmschulte and coworkers investigated cationic dialkylaluminum and m-terphenylalkylaluminum compounds as catalysts for the intramolecular hydroamination of primary and secondary aminopentenes (Scheme 1.14).79 It was found that reaction rates were dependent on the

SCHEME 1.14

Aluminum catalyst for the hydroamination of primary and secondary

aminopentenes.

substrate and the catalyst substituents. The most sterically hindered species 19 was the most active of the catalysts tested. Thus using 10 mol% of catalyst 19 at 135 C afforded the targeted pyrrolidines in good yields over a short reaction time (0.2521.5 h). Dun˜ach and coworkers reported the use of aluminum trifluoromethanesulfonate, Al(OTf)3, as an efficient catalyst for the intramolecular hydroalkoxylation of unactivated alkenes.80,81 The reaction can be performed in the presence of 5 mol% of Al(OTf)3 under mild conditions with a range of γ,δ-unsaturated alcohols, leading to the corresponding tetrahydrofurans and tetrahydropyrans in high yields with Markovnikov regioselectivity (Scheme 1.15). The reaction mechanism is said to proceed via Lewis superacid-type

SCHEME 1.15

Hydroalkoxylation of 2-allylphenol catalyzed by Al(OTf)3 and Al(OiPr)3.

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catalysis. Similarly, William and coworkers also reported the intermolecular hydroalkoxylation of alkenes catalyzed by Al(OTf)3.82 More recently, Hintermann and coworkers described the use of aluminum iso-propoxide, Al(OiPr)3, as a catalyst for the hydroalkoxylation of 2-allylphenols.83 In contrast to the reaction conditions reported by Dun˜ach and coworkers, drastic reaction conditions were required to achieve similar conversions of the target products. The reaction tolerates a number of functional groups, such as halogens, methoxy, and cyano. However, substrates capable of forming stable chelates with aluminum(III), such as 6-methoxy- and 6-formylsubstituted allylphenols, and benzylic alcohol could not be cyclized.

1.2.3 Polymerization reactions In the past decades, alkyl and alkoxide aluminum complexes have been developed as catalysts for the ROP of cyclic esters.84 88 In particular, aluminum alkoxide complexes generated in situ from the reaction of an alkyl aluminum complex with an alcohol have been successfully used for the stereoselective ROP of rac-lactide (rac-LA), affording stereoenriched polylactides (PLA). The stereoselectivity is determined by the presence of a chain-end control mechanism or a site control mechanism.86 88 In general, the ROP of cyclic esters catalyzed by aluminum complexes occurs via a coordination insertion mechanism (Scheme 1.16). In the first step, the

SCHEME 1.16

Ring-opening polymerization of cyclic esters.

monomer coordinates to the aluminum center. Then, the nucleophile ringopens the activated monomer affording an aluminum alkoxide complex that can undergo successive ring-opening reactions of cyclic esters to afford the desired biodegradable polyester materials. The coordinated ligands on the aluminum center have a great effect on the catalytic activity since they allow the fine-tuning of the electronic and steric properties and stability of the resulting aluminum complexes. A broad range of ligands have been used for the preparation of aluminum complexes that act as catalysts for the ROP of cyclic esters. Salen and related ligands are

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among the most studied ligand precursors for the synthesis of aluminum catalysts due to their straightforward synthesis from an aldehyde and a diamine and their high versatility as they allow the facile modulation of the steric and electronic properties.89 In 2010 Darensbourg reported the use of chiral and achiral half-salen aluminum complexes for the stereoselective ROP of racLA.90 All complexes were found to be catalytically active in toluene at 70 C, providing PLA with experimental molecular weights close to the theoretical values, narrow polydispersity index (PDI) and a Pm value (isotactic selectivity as defined by the probability of meso linkages, as determined by NMR) up to 0.76, indicating that these complexes catalyze the stereoselective ROP of racLA. These studies were extended to investigate the ROP of trimethylene carbonate (TMC), δ-valerolactone (δ-VL), rac-β-butyrolactone (rac-β-BL), and ε-caprolactone (ε-CL), using complex 20 as catalyst, obtaining the corresponding polycarbonates or polyesters (Fig. 1.6).91 A detailed kinetic study con-

FIGURE 1.6 Aluminum complex 20 for the ROP of cyclic esters.

firmed that the ΔG‡ values are in the order rac-LA  rac-β-BL . δ-VL . TMC  ε-CL. The ROCOP of rac-LA and δ-VL provided a tapered polylactide polyvalerolactone copolymer due to the higher reactivity of the catalyst toward the rac-LA unit over the δ-VL monomer. Salen alkyl aluminum complexes were developed as highly stereoselective catalysts for the stereoselective ROP of rac-LA at 70 C in toluene, producing quasi-isotactic PLAs, (Pm 5 0.94 0.97) at high conversions with narrow PDIs (Scheme 1.17).92 The high crystallinity of the polymer was

SCHEME 1.17

Stereoselective ROP of rac-LA catalyzed by complex 21.

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confirmed by its high melting point (Tm) of 205 C. Salen and salan aluminum complexes have also been used as catalysts for the ROP of rac-β-BL, forming high-molecular-weight polyhydroxybutyrate (PHB).93 It is important to note that these complexes catalyze the immortal ROP of rac-β-BL since the addition of an excess of benzyl alcohol (BnOH) did not have a detrimental effect on the catalytic activity. Gradient copolymers with narrow polydispersities could be obtained when the ROCOP of rac-LA and rac-β-BL was performed in toluene at 85 C. Aluminum salalen complexes were investigated as catalysts for the homo- and copolymerization of L-, D-, rac-, and meso-LA and ε-CL.94 As expected, the homopolymerization of L- and D-LA afforded isotactic PLLA and PDLA, respectively, while the ROP of rac- or meso-LA produced isotactic- or heterotactic-enriched PLAs, respectively. The ROCOP of L-LA and ε-CL was studied, obtaining random copolymers with very similar average lengths of the caproyl and lactidyl units. Thomas and coworkers reported on the mechanism for the ROP of racLA at room temperature using a highly efficient salen chloride aluminum catalyst in combination with PPNCl in propylene oxide as solvent.95 The proposed mechanism involves the formation of salen aluminate species by two different pathways (Scheme 1.18). The salen chloride aluminum

SCHEME 1.18

Formation of salen aluminate species in the ROP of rac-LA at room

temperature.

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1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules

complex can react with PPNCl to form the bis-chloride aluminate species 4a that can react with two molecules of epoxide to form a six-coordinated bis-alkoxide aluminate species 4c, which is in equilibrium with the mono-alkoxide species 4d and PPNOR. Density functional theory (DFT) calculations were performed to study the origin of the high catalytic activity displayed by this catalyst system. It was concluded that the extraordinary performance is due to the formation of external nucleophilic alkoxide, which decreases the energy barrier for the ring-opening of the lactide monomer by 5.7 kcal mol21. Aluminum complexes containing a range of N,O ligands have been designed and used as catalysts for the ROP of cyclic esters. Phenoxyimine alkyl aluminum complexes in combination with BnOH cocatalysts displayed high catalytic activity toward the ROP of rac-LA,96 the ROP of rac-β-BL,97 and ROCOP of L-LA and rac-β-BL.97 The use of a bulky o-SiPh3 substituent in the phenoxy moiety allowed the synthesis of a stereoselective ROP catalyst, obtaining PLA with Pm up to 0.80 and good control over the molecular weight of the polymer and narrow polydispersities.96 Milione and coworkers have used phenoxyimine aluminum catalysts for the ROP of rac-β-BL in toluene at 100 C obtaining PHB with medium to high molecular weight and narrow PDI.97 The ROCOP of L-LA and rac-β-BL was also studied using 100 equivalents of both monomers, obtaining random copolymers with a glass transition temperature (Tg) of 31 C.97 Five-coordinated salicylbenzoxazole aluminum complexes were used as catalysts for the ROP of rac-LA and ε-CL, obtaining the corresponding polyesters with molecular weights close to the theoretically predicted values and narrow PDIs.98 Interestingly, these complexes catalyzed the stereoselective ROP of rac-LA, obtaining PLAs with Pm 5 0.64 2 0.75, which is higher than the Pm achieved by the corresponding four-coordinated aluminum analogs (Pm 5 0.54 2 0.70). Carpentier et al. developed a range of fluorinated alkoxyimino aluminum complexes for the ROP of rac-LA (Scheme 1.19).37,99 The use of

SCHEME 1.19 ROP of rac-LA catalyzed by fluorinated alkoxyimino aluminum complexes.

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1.2 Aluminum-based catalysts

19

dialkylaluminum complexes, {ON}AlMe2, in combination with BnOH produced essentially atactic PLAs.99 However, when a bridge between the two alkoxyimino moieties was used, isotactic-enriched PLAs were obtained with Pm between 0.78 and 0.87 due to the higher conformational rigidity.37 Aluminum complexes supported by β-ketiminato ligands were developed by Li and coworkers.100,101 These complexes very efficiently catalyzed the ROP of ε-CL and L-LA in the presence of isopropyl alcohol (iPrOH) as a cocatalyst, giving 94% conversion for the ROP of 1000 equivalents of ε-CL in 30 min and complete conversion of 100 equivalents of L-LA in 1 h at 80 C.100 Block and gradient copolymers of ε-CL and L-LA could be obtained with the most active catalyst. In an extension of this work, quasi-random copolymers of ε-CL and L-LA could be prepared by modifying the β-ketiminato ligand.101 The copolymers obtained showed similar average lengths of the caproyl and lactidyl sequences and reactivity ratios of the two monomers of rLA 5 1.31 and rCL 5 0.99, confirming the essentially random copolymerization of the two monomers. A range of copolymers with different thermal properties were obtained by variation of the ε-CL:L-LA ratio. Random copolymers of ε-CL and rac-LA were prepared by using pyrrolylpyridylamido aluminum catalysts in toluene at 70 C using iPrOH as cocatalyst (Scheme 1.20).102 The reactivity ratios obtained for each

SCHEME 1.20 Preparation of random copolymer PCL PLA catalyzed by complex 24.

monomer were close to 1, indicating a random copolymerization. In all cases, amorphous materials were obtained with Tg values from 246 C to 30 C. Otero and coworkers have reported several families of scorpionate aluminum complexes as catalysts for the formation of polyesters by ROP and ROCOP of rac- or L-lactide and/or ε-caprolactone and epoxides with cyclic anhydrides.103 108 The molecular weight, molecular weight distribution, and tacticity of the homopolymers and copolymers obtained could be modulated by changing the design of the scorpionate ligand (Scheme 1.21). For the ROP of cyclic esters, the aluminum

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1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules

SCHEME 1.21

Scorpionate aluminum complexes for the ROP and ROCOP of cyclic

esters.

complex did not require the presence of a cocatalyst to perform a living polymerization. Interestingly, complex 25 allowed the preparation of cyclic polycaprolactones instead of a linear PCL via ring-expansion polymerization (Scheme 1.21).

1.3 Iron-based catalysts Transition metals are widely used in catalysis to promote a broad range of chemical transformations.109 The use of iron catalysts in organic synthesis is a huge field of interest. Iron catalysts have been used in Alder-ene-type, addition, annulation, cross-coupling,110 cyclization, cycloaddition, domino, elimination, (de)hydrogenation,31 hydrometalation,111 isomerization, metathesis, oxidation, polymerization, rearrangement, reduction,111,112 and substitution reactions (amongst others).113 Iron is a nontoxic, air-stable, and inexpensive metal, which is readily abundant across the globe, environmentally benign, and plays an important part in numerous biological catalytic systems.114 Iron is therefore an ideal transition metal in terms of Green Chemistry

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principles115 and sustainability, compared to traditionally used transition or precious metals.116 In this section, only iron-catalyzed cross-coupling (i.e., CsC bond formation), CsX heteroatom bond formation, polymerization and dehydrogenation reactions will be discussed, with a focus on research reported over the last 15 years. This review will not give a comprehensive review of all reported procedures but hopes to give a flavor of iron-catalyzed reactions. For those seeking more indepth background information on iron-catalyzed reactions, readers are encouraged to consult the following reviews.31,110 114,116 132

1.3.1 Cross-coupling reactions Cross-coupling reactions occur when two reagents, both with activating groups, react together with a metal catalyst to form a new covalent bond, driven by loss of the activating groups. Iron cross-coupling reactions were first reported in the 1940s by Kharasch and Fields, when investigating the reaction of Grignard reagents with organic halides in the presence of metallic halides.133 Iron cross-coupling was then studied thoroughly and brought to the forefront by Kochi and Tamura in the 1970s,134 136 which led to a vital turning point for iron-catalyzed crosscoupling reactions and iron catalysis in general, when they reported the alkenylation of alkyl Grignard reagents with vinyl bromides using Fe (III) chloride (Scheme 1.22).136

SCHEME 1.22

Iron-catalyzed alkenylation of alkyl Grignard reagents with vinyl

bromides.

Although iron-catalyzed cross-coupling reactions preceded palladium- and nickel-catalyzed reactions, interest waned until the start of the millennium,113 when it again increased especially with a view to formation of CsC bonds in pharmaceuticals128 and natural products. Iron-catalyzed cross-coupling reactions include CsX/C metal crosscoupling, CsC bond formation by CsH bond activation,129 and decarboxylative and decarbonylative coupling reactions.113 Those interested in these iron-catalyzed cross-coupling reactions are recommended to read the following articles.110,118 121,128,132 Perhaps one of the most important iron catalysts used in crosscoupling reactions for pharmaceutical128 and natural product synthesis is tris(acetylacetonato)iron(III) (Fe(acac)3) (Scheme 1.23A D). In 2008 a

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SCHEME 1.23 Pharmaceuticals, natural products, and vital compounds that have been synthesized using Fe(acac)3.137,139 141

key synthetic step in making the anticancer agent Combretastatin A-4 was achieved using Fe(acac)3 (Scheme 1.23A).137 That same year, a route to the immunosuppressive agent FTY720 was devised by reacting octyl magnesium bromide with an aryl triflate and Fe(acac)3.138 A more recent alternative route was reported by Feng in 2012, via an ironcatalyzed cross-coupling reaction between methyl 4-chlorobenzoate and octyl magnesium bromide (Scheme 1.23B).139 In 2012 the perfume ingredient and dusk musk odorant (R,Z)-5-muscenone, aka Muscenone, was synthesized via a cross-coupling reaction with Fe(acac)3 (Scheme 1.23C).140 Also in 2012, iron-catalyzed aryl alkyl cross-coupling reactions were used to synthesize nine examples of pentapodal ω-functional derivatives of corannulene, important building blocks for synthesis and supramolecular chemistry, in good to high yields (Scheme 1.23D).141 Besides the iron catalyst Fe(acac)3, other simple iron-based salts, such as FeF2, FeF3, FeCl2, FeCl3, FeBr2, FeBr3, and Fe(OAc)2, have been used in cross-coupling reactions.113 There has also been success in using more well-defined iron complexes as catalysts in cross-coupling reactions (Scheme 1.24A C). In 2013 Bedford et al. reported that iron

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1.3 Iron-based catalysts

SCHEME 1.24 Iron complex-catalyzed cross-coupling reactions.142

144

phosphine catalysts 26 and 27 could perform cross-coupling reactions over a broad substrate scope in superb yields (Scheme 1.24A).142 The year prior, Deng et al. reported that dinuclear iron complex 28 could successfully cross-couple primary alkyl fluorides with aryl Grignards (Scheme 1.24B).143 In 2013 iron(III)amine-bis(phenolate) complex 29 was reported by Kozak et al. in the cross-coupling of benzyl halides (Scheme 1.24C).144 Success in using iron salen145 and iron(III) amine-bis(phenolate)146 complexes for these reactions has also been reported.

1.3.2 C heteroatom bond forming reactions CsX heteroatom bond formation is another area of huge interest for iron-catalyzed reactions. Carbon heteroatom bonds are important components in many organic compounds used in pharmaceutical and biological research.116 Iron catalysis has been successfully employed in

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1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules

forming CsN, CsO, and CsS bonds via N-arylation, hydroamination, aziridination, allylic amination, addition, O-arylation, CsH oxidation, alkene oxidation, rearrangements, S-arylation, and Michael addition116 (some examples are shown in Schemes 1.25 and 1.26).116 Those

SCHEME 1.25 Iron catalyzed CsN, CsO, and CsS bond formation.148

151

SCHEME 1.26 Synthesis of methanol using iron scorpionate complex 32.

interested in XsX heteroatom formation reactions are advised to consult Bolm’s 2008 and Melen’s 2016 reviews.116,147 In 2018 Bernskoetter reported the iron-catalyzed N-formylation of amines (CsN bond formation) using iron pincer catalyst 30 (Scheme 1.25A).148 This catalyst was

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compatible with a broad range of substrates and reactions only required 0.02 mol% of complex 30. Imines are another interesting class of compounds, as they are used in pharmaceutical, dye, polymer, and pigment syntheses. In 2017, Milstein used iron pincer complex 31 to produce secondary aldimines via a hydrogenative cross-coupling reaction between nitriles and amines (Scheme 1.25B).149 This reaction could be performed under mild conditions with numerous nitriles and amines, and was the first ever metal catalyst reported to perform this reaction. In 2008 Bolm et al. reported that the simple iron salt FeCl3 (when .98% pure) could be used to generate CsO and CsS bonds, by reacting aryl iodides with phenols150 and aromatic thiols,151 respectively (Scheme 1.25C and D). In 2017 the iron scorpionate complex 32 was reported to convert carbon dioxide and hydrogen into methanol via a selective reductive amination/hydrogenative cross-coupling reaction (Scheme 1.26).152 This is a reaction of huge interest, as not only does the conversion of carbon dioxide into methanol provide the opportunity to reduce carbon dioxide emissions, but it also recycles this “waste” gas into an alternative fuel, fuel additive, and intermediate in the production of, for example, plastics, paints, and textiles.153 This reaction required no solvent, an extremely low catalytic loading of 32 and was the first ever report in the literature of a scorpionate catalyst accomplishing this reaction. The use of pentaethylenehexamine (PEHA) was required to increase the yield of methanol from 28% to 46%, but the reaction could be performed under amine free conditions if desired. Catalyst 32 can be made via a simple one-pot process, making this catalyst extremely green. While the mechanism of this reaction remains unknown,152 this work is extremely interesting as the substitution of rare or precious metal catalysts with iron species is often problematic and does not result in active catalysts.154 Alternative routes to CsX (as well as CsC) bond formations are via CsH activation or transformation reactions,114,129 which were first reported by Nakamura et al. in 2008.155 In the decade following this discovery, numerous iron catalysts have been used in CsH activation reactions, with many of these catalysts requiring only low temperatures and often giving quicker conversions than the equivalent palladium, ruthenium, and rhodium catalysts.129 Reactions such as CsH bond amination, borylation, silylation, and tritiation have all been performed using iron catalysts (Scheme 1.27).129 Tritiation reactions are particularly interesting and are vital in drug research, as converting a CsH bond into a CsH3 bond (tritium labeling) enables the pharmacokinetics and pharmacodynamics of new drug candidates to be studied.156 In 2016 Chirik et al. reported the ability of iron catalyst 34 to label the calcimimetic drug Cinacalcet,157 which is used to treat hyperparathyroidism (overactive functioning of the parathyroid glands) during the end-stages of

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1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules

SCHEME 1.27

Iron catalysts reported in the formation of CsN, CsSi, and Cs3H

157,159,160

bonds.

renal disease (Scheme 1.27C).158 The tritium labeling ability of catalyst 34 was comparable to the state-of-the-art iridium catalyst (Crabtree’s catalyst), which requires dichloromethane as the reaction solvent to function.157 Iron-catalyzed radical reactions can also form CsX bonds via CsH bond halogenation and oxidation via Gif or Fenton chemistry.129 Those interested in these processes are recommended to read the articles by Barton,161 Tapper,162 and Sawyer.163

1.3.3 Polymerization reactions Iron complexes have been used as catalysts for a range of polymerization processes.164 169 In this section, recent advances on the ROCOP

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of epoxides and CO2 to afford polycarbonates and the ROCOP of epoxides and cyclic anhydrides to produce polyester materials catalyzed by iron complexes will be described (Scheme 1.28).

SCHEME 1.28 ROCOP of epoxides with CO2 or cyclic anhydrides.

In 2011 Williams et al. reported the first example of an iron catalyst for the reaction of epoxides and CO2 to afford either cyclic- or polycarbonates.170 In this contribution, the bimetallic air-stable Fe(III) complex 36 catalyzed the production of poly(cyclohexene carbonate) (PCHC) at 80 C with high selectivity (Scheme 1.29). The catalyst was found to be

SCHEME 1.29

Synthesis of poly(cyclohexene carbonate) catalyzed by complex 36.

active even at 1 atm of CO2 pressure providing a copolymer in 93% yield but with only 66% of carbonate linkages. However, when the reactions were carried out at 10 atm of CO2 pressure, PCHC was obtained with selectivities greater than 99% and no trans-cyclic carbonate

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formation was observed, obtaining a turnover number (TON) value of 694 and a TOF value of 29 h21 using 0.1 mol% catalyst loading. Reducing the catalyst loading from 0.1 to 0.01 mol% resulted in an increase of the TON and TOF values to 2570 and 107 h21, respectively. Pescarmona, Kleij, and coworkers reported the synthesis of aminotriphenolate171 and pyridylamino-bisphenolate172 iron complexes for the synthesis of PCHC from cyclohexene oxide (CHO) and CO2 (Fig. 1.7).

FIGURE 1.7 Aminotriphenolate and pyridylamino-bisphenolate iron complexes for polycarbonate formation.

The selectivity toward the production of PCHC can be controlled by changing the nucleophile source and the catalyst:cocatalyst ratio using supercritical CO2 as reaction medium. When the reactions were carried out at 85 C and 80 bar of CO2 using a combination of 0.1 mol% of complexes 37 and 38 and Bu4NCl or PPNCl, medium- to high-molecularweight PCHC was obtained with selectivities higher than 92% and narrow PDI values.171 Poly(vinylcyclohexene carbonate) (PVCHC) could be prepared by reacting 1,2-epoxy-4-vinylcyclohexane and CO2 at 85 C and 80 bar of CO2 using 0.5 mol% of complex 39 and 0.5 mol% of TBAB. The presence of vinyl groups allowed the postpolymerization of the polycarbonate in order to prepare cross-linked polycarbonates. Thus, by reacting PVCHC and 1,3-propanedithiol in the presence of azobisisobutyronitrile (AIBN) as radical initiator, a cross-linked material was obtained showing an improvement of the thermal properties, increasing the glass transition temperature from 75 C in PVCHC to 130 C in the cross-linked polymeric material.172 The use of iron(III) and iron(IV) corrole complexes allowed the first reported examples of the synthesis of polycarbonate materials derived from terminal epoxides such as propylene oxide and glycidyl phenyl ether and CO2 catalyzed by iron complexes (Scheme 1.30).173 The combination of complex 41 and PPNCl as cocatalyst at 80 C and 20 bar of CO2 allowed the production of a high-molecular-weight polyetherpolycarbonate material with a PDI value of 1.32 and a TOF value of 1314 h21. On the other hand, the use of phenyl glycidyl ether gave

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1.3 Iron-based catalysts

SCHEME 1.30

29

ROCOP of terminal epoxides and CO2 catalyzed by corrole iron

complexes.

copolymers with lower molecular weights and broader PDI values. However, it was possible to obtain a crystalline copolymer with Tg and Tm values of 11 C and 180 C, respectively. Capacchione and coworkers have recently reported the use of bisthioether-diphenolate OSSO-iron(III) complexes (Scheme 1.31) for the

SCHEME 1.31 ROCOP of cyclohexene oxide and CO2 catalyzed by complex 46.

reaction between CHO and CO2 for the synthesis of PCHC at 80 C and one bar pressure of CO2 using a combination of 0.1 mol% of complex 46 and 0.1 mol% of Bu4NCl, under solvent-free conditions, achieving 40% yield in 1 h and TOF values up to 400 h21.174 Kinetic experiments and DFT calculations suggested that the rate-limiting step for the production of PCHC is the monometallic insertion of CHO into the growing polycarbonate chain.

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1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules

Merna et al. developed salen and salphen iron(III) complexes 47 2 49 as catalysts for the ROCOP of CHO and phthalic anhydride (PA) obtaining purely alternating copolymers with narrow PDI values (Scheme 1.32).175

SCHEME 1.32 ROCOP of epoxides and cyclic anhydrides catalyzed by salen or salophen iron complexes.

The reactions were carried out in toluene at 110 C using a combination of 0.4 mol% of iron complexes and PPNCl or DMAP (4-dimethylaminopyridine) as cocatalyst, obtaining selectivities higher than 99% toward the polyester. In most cases PPNCl showed to be a better cocatalyst than DMAP and higher conversions were obtained resulting in polyesters with higher molecular weights. Aminotriphenolate iron complex 37 developed by Kleij and coworkers176 allowed the use of renewable monomers derived from terpene oxides to prepare bio-based polyesters. This complex was used as catalyst in combination with PPNCl as nucleophile for the ROCOP of limonene, carene, and menthene oxides and a range of aromatic cyclic anhydrides for the preparation of a broad range of bio-derived polyesters (Scheme 1.33). The reactions were carried out at 65 C using a

SCHEME 1.33 ROCOP of epoxides and cyclic anhydrides catalyzed by aminotriphenolate iron complex 37.

1. Non-precious metals in catalysis

1.3 Iron-based catalysts

31

catalyst loading of 0.5 mol% of both the iron complex and PPNCl in THF. Under these reaction conditions, medium- to high-molecularweight polyesters were isolated with a selectivity higher than 98%. The use of a broad range of epoxides and aromatic anhydrides allowed the synthesis of a wide variety of polyesters with modulable thermal properties and glass transition temperatures from 53 C to 243 C. This catalyst was also used for the synthesis of aliphatic polyesters from propylene oxide (PO) or CHO and tricyclic anhydrides derived from renewable resources.177 The methodology provided a wide range of polyesters with Mn up to 32.2 kDa and polydispersities lower than 1.58. It is worth noting that the polyesters derived from PO had lower Tg values than those obtained from CHO showing the importance of the starting materials on the thermal properties of the isolated polyesters. In 2018 Jiang reported the use of bimetallic iron(III) complexes in combination with PPNCl as catalyst systems for the ROCOP of CHO with CO2 or PA for the preparation of either polycarbonates or polyesters (Scheme 1.34).178 It is worth highlighting that the bimetallic

SCHEME 1.34 ROCOP of epoxides and CO2 or cyclic anhydrides to produce either polycarbonates or polyesters.

complex was shown to be more active than the monometallic analogue, indicating intramolecular cooperation between the metal centers. Polycarbonates were efficiently prepared from CHO and CO2 at 90 C and 45 bar pressure of CO2 using a combination of 0.01 mol% of the bimetallic iron complex and 0.02 mol% of PPNCl under solvent-free conditions obtaining PCHC in 78% conversion with selectivities higher than 99% and TOF values up to 260 h21. This complex was shown to be versatile as it also catalyzed the formation of polyesters derived from CHO and PA, obtaining polymeric materials with Mn up to 22.5 kDa and narrow polydispersities using 0.2 mol% of both iron complex and

1. Non-precious metals in catalysis

32

1. Homogeneous aluminum and iron catalysts for the synthesis of organic molecules

PPNCl in toluene at 100 C in 3 h. The catalyst system displayed excellent catalytic activity and selectivity even under neat conditions, obtaining TOF values up to 1100 h21 at 100 C.

1.3.4 Dehydrogenation reactions Iron catalysts have been reported in the dehydrogenation, or dehydrocoupling, of amine-boranes.179 181 These reactions create interesting amineborane trimers, which are currently being investigated as alternative hydrogen storage carriers, because they can easily release hydrogen on demand in the presence of a catalyst.147 Hydrogen is viewed as an alternative, renewable, nontoxic, and clean energy source and energy carrier for a future green economy, as it releases no carbon emissions upon combustion. The long-term storage and transportation of hydrogen is still an issue however, as its low density means that hydrogen must be stored under increased pressures and cooled to lower temperatures. This is an undesirable scenario in terms of both safety and energy efficiency.182 In 2011 Warner reported that the iron carbonyl dimer [CpFe(CO)2]2 (complex 50) could photocatalytically dehydrocouple primary and secondary amineboranes, as well as ammonia-borane itself, to form cyclic and polymeric nitrogen-borane compounds (Scheme 1.35).180 This was the first report

SCHEME 1.35

Photoactivated dehydrogenation of amine-boranes using iron catalyst 50.

of the use of iron catalysts for this reaction. The reaction also required only mild conditions and a low catalytic loading of 50 (5 mol%). This research also highlighted that iron catalysts could potentially replace similar, more expensive rhodium catalysts, which are traditionally used in this process.109,180

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1.4 Conclusions Aluminum and iron catalysts are active toward a wide range of chemical transformations such as CO2 fixation, hydroelementation and cross-coupling reactions, CsX heteroatom bond formation, polymerization, and dehydrogenation reactions. The current success in employing aluminum and iron catalysts as substitutes for more rare and precious metals is extremely promising. These reactions often have broad substrate compatibility and can occur rapidly even under mild reaction conditions in good to excellent yields. The transition from academic research to large-scale industrial implementation, however, is still a major hurdle and more research is required to fully understand the reaction mechanisms of these processes. The development of more heterogeneous-based catalysts for these reactions, rather than reliance on homogenous-based catalysts, is also a likely venue of exploration. Many reagents used in these processes are also now considered unsustainable, such as 1-methyl-2-pyrrolidone (NMP), which was recently added to the “REACH” restricted chemicals list.183 The sustainability of these reactions will therefore need to be considered more carefully in the future. Despite the encouraging and vast quantity of research that has been performed in aluminum and iron catalysis, there are still only a few large-scale global applications of iron catalysis in use today, namely the venerable Fischer Tropsch and Haber Bosch processes.111 The development of more large-scale and industrially viable catalytic systems is thus an absolute necessity.

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87 Mecerreyes, D.; Je´roˆme, R.; Dubois, P. Novel Macromolecular Architectures Based on Aliphatic Polyesters: Relevance of the “Coordination-Insertion” Ring-Opening Polymerization. Macromolecular Architectures; Springer: Berlin, Heidelberg, 19991 59. 88. Wei, Y.; Wang, S.; Zhou, S. Aluminum Alkyl Complexes: Synthesis, Structure, and Application in ROP of Cyclic Esters. Dalton Trans. 2016, 45, 4471 4485. 89. Cozzi, P. G. Metal Salen Schiff Base Complexes in Catalysis: Practical Aspects. Chem. Soc. Rev. 2004, 33, 410 421. 90. Darensbourg, D. J.; Karroonnirun, O. Stereoselective Ring-Opening Polymerization of rac-Lactides Catalyzed by Chiral and Achiral Aluminum Half-Salen Complexes. Organometallics 2010, 29, 5627 5634. 91. Darensbourg, D. J.; Karroonnirun, O.; Wilson, S. J. Ring-Opening Polymerization of Cyclic Esters and Trimethylene Carbonate Catalyzed by Aluminum Half-Salen Complexes. Inorg. Chem. 2011, 50, 6775 6787. 92. Chen, H.-L.; Dutta, S.; Huang, P.-Y.; Lin, C.-C. Preparation and Characterization of Aluminum Alkoxides Coordinated on Salen-Type Ligands: Highly Stereoselective Ring-Opening Polymerization of rac-Lactide. Organometallics 2012, 31, 2016 2025. 93. Cross, E. D.; Allan, L. E. N.; Decken, A.; Shaver, M. P. Aluminum Salen and Salan Complexes in the Ring-Opening Polymerization of Cyclic Esters: Controlled Immortal and Copolymerization of rac-β-Butyrolactone and rac-Lactide. J. Polym. Sci. Part A Polym. Chem. 2013, 51, 1137 1146. 94. Pilone, A.; De Maio, N.; Press, K.; Venditto, V.; Pappalardo, D.; Mazzeo, M.; Pellecchia, C.; Kol, M.; Lamberti, M. Ring-Opening Homo- and Co-Polymerization of Lactides and ε-Caprolactone by Salalen Aluminum Complexes. Dalton Trans 2015, 44, 2157 2165. 95. Robert, C.; Schmid, T. E.; Richard, V.; Haquette, P.; Raman, S. K.; Rager, M.-N.; Gauvin, R. M.; Morin, Y.; Trivelli, X.; Gue´rineau, V.; del Rosal, I.; Maron, L.; Thomas, C. M. Mechanistic Aspects of the Polymerization of Lactide Using a Highly Efficient Aluminum(III) Catalytic System. J. Am. Chem. Soc. 2017, 139, 6217 6225. 96. Normand, M.; Dorcet, V.; Kirillov, E.; Carpentier, J.-F. {Phenoxy-Imine}aluminum versus -Indium Complexes for the Immortal ROP of Lactide: Different Stereocontrol, Different Mechanisms. Organometallics 2013, 32, 1694 1709. 97. Garcı´a-Valle, F. M.; Tabernero, V.; Cuenca, T.; Mosquera, M. E. G.; Cano, J.; Milione, S. Biodegradable PHB from rac-β-Butyrolactone: Highly Controlled ROP Mediated by a Pentacoordinated Aluminum Complex. Organometallics 2018, 37, 837 840. 98. Sumrit, P.; Chuawong, P.; Nanok, T.; Duangthongyou, T.; Hormnirun, P. Aluminum Complexes Containing Salicylbenzoxazole Ligands and Their Application in the Ring-Opening Polymerization of rac-Lactide and ε-Caprolactone. Dalton Trans. 2016, 45, 9250 9266. 99. Bouyahyi, M.; Roisnel, T.; Carpentier, J.-F. Aluminum Complexes of Bidentate Fluorinated Alkoxy-Imino Ligands: Syntheses, Structures, and Use in Ring-Opening Polymerization of Cyclic Esters. Organometallics 2012, 31, 1458 1466. 100. Huang, H.-C.; Wang, B.; Zhang, Y.-P.; Li, Y.-S. Bimetallic Aluminum Complexes with Cyclic β-Ketiminato Ligands: The Cooperative Effect Improves Their Capability in Polymerization of Lactide and ε-Caprolactone. Polym. Chem. 2016, 7, 5819 5827. 101. Huang, H.-C.; Li, Z.-J.; Wang, B.; Chen, X.; Li, Y.-S. Synthesis of Lactide/ ε-Caprolactone Quasi-Random Copolymer by Using Rationally Designed Mononuclear Aluminum Complexes with Modified β-Ketiminato Ligand. J. Polym. Sci. Part A Polym. Chem. 2018, 56, 203 212. 102. Li, G.; Lamberti, M.; Pappalardo, D.; Pellecchia, C. Random Copolymerization of ε-Caprolactone and Lactides Promoted by Pyrrolylpyridylamido Aluminum Complexes. Macromolecules 2012, 45, 8614 8620.

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103. Martı´nez de Sarasa Buchaca, M.; de la Cruz-Martı´nez, F.; Martı´nez, J.; AlonsoMoreno, C.; Ferna´ndez-Baeza, J.; Tejeda, J.; Niza, E.; Castro-Osma, J. A.; Otero, A.; Lara-Sa´nchez, A. Alternating Copolymerization of Epoxides and Anhydrides Catalyzed by Aluminum Complexes. ACS Omega 2018, 3, 17581 17589. 104. Martı´nez, J.; Martı´nez de Sarasa Buchaca, M.; de la Cruz-Martı´nez, F.; AlonsoMoreno, C.; Sa´nchez-Barba, L. F.; Fernandez-Baeza, J.; Rodrı´guez, A. M.; Rodrı´guezDie´guez, A.; Castro-Osma, J. A.; Otero, A.; Lara-Sa´nchez, A. Versatile Organoaluminium Catalysts Based on Heteroscorpionate Ligands for the Preparation of Polyesters. Dalton Trans. 2018, 47, 7471 7479. 105. Castro-Osma, J. A.; Alonso-Moreno, C.; Lara-Sa´nchez, A.; Otero, A.; Ferna´ndezBaeza, J.; Sa´nchez-Barba, L. F.; Rodrı´guez, A. M. Catalytic Behaviour in the RingOpening Polymerisation of Organoaluminiums Supported by Bulky Heteroscorpionate Ligands. Dalton Trans. 2015, 44, 12388 12400. 106. Castro-Osma, J. A.; Alonso-Moreno, C.; Garcı´a-Martinez, J. C.; Ferna´ndez-Baeza, J.; Sa´nchez-Barba, L. F.; Lara-Sa´nchez, A.; Otero, A. Ring-Opening (ROP) Versus RingExpansion (REP) Polymerization of ε-Caprolactone To Give Linear or Cyclic Polycaprolactones. Macromolecules 2013, 46, 6388 6394. 107. Castro-Osma, J. A.; Alonso-Moreno, C.; Ma´rquez-Segovia, I.; Otero, A.; Lara-Sa´nchez, A.; Ferna´ndez-Baeza, J.; Rodrı´guez, A. M.; Sa´nchez-Barba, L. F.; Garcı´a-Martı´nez, J. C. Synthesis, Structural Characterization and Catalytic Evaluation of the RingOpening Polymerization of Discrete Five-Coordinate Alkyl Aluminium Complexes. Dalton Trans. 2013, 42, 9325 9337. 108. Otero, A.; Lara-Sa´nchez, A.; Ferna´ndez-Baeza, J.; Alonso-Moreno, C.; Castro-Osma, J. A.; Ma´rquez-Segovia, I.; Sa´nchez-Barba, L. F.; Rodrı´guez, A. M.; Garcia-Martinez, J. C. Neutral and Cationic Aluminum Complexes Supported by Acetamidate and Thioacetamidate Heteroscorpionate Ligands as Initiators for Ring-Opening Polymerization of Cyclic Esters. Organometallics 2011, 30, 1507 1522. 109. Leitao, E. M.; Jurca, T.; Manners, I. Catalysis in Service of Main Group Chemistry Offers a Versatile Approach to p-Block Molecules and Materials. Nat. Chem. 2013, 5, 817 829. 110. Fu¨rstner, A.; Martin, R. Advances in Iron Catalyzed Cross Coupling Reactions. Chem. Lett. 2005, 34, 624 629. 111. Wei, D.; Darcel, C. Iron Catalysis in Reduction and Hydrometalation Reactions. Chem. Rev. 2019, 119, 2550 2610. 112. Chakraborty, S.; Bhattacharya, P.; Dai, H. G.; Guan, H. R. Nickel and Iron Pincer Complexes as Catalysts for the Reduction of Carbonyl Compounds. Acc. Chem. Res. 2015, 48, 1995 2003. 113. Bauer, I.; Knolker, H. J. Iron Catalysis in Organic Synthesis. Chem. Rev. 2015, 115, 3170 3387. 114. Sun, C. L.; Li, B. J.; Shi, Z. J. Direct C-H Transformation via Iron Catalysis. Chem. Rev. 2011, 111, 1293 1314. 115. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, 1998. 116. Correa, A.; Mancheno, O. G.; Bolm, C. Iron-Catalysed Carbon-Heteroatom and Heteroatom-Heteroatom Bond Forming Processes. Chem. Soc. Rev. 2008, 37, 1108 1117. 117. Fu¨rstner, A. From Oblivion into the Limelight: Iron (Domino) Catalysis. Angew. Chem. Int. Ed. 2009, 48, 1364 1367. 118. Rudolph, A.; Lautens, M. Secondary Alkyl Halides in Transition-Metal-Catalyzed Cross-Coupling Reactions. Angew. Chem. Int. Ed. 2009, 48, 2656 2670. 119. Sherry, B. D.; Fu¨rstner, A. The Promise and Challenge of Iron-Catalyzed Cross Coupling. Acc. Chem. Res. 2008, 41, 1500 1511.

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142. Bedford, R. B.; Carter, E.; Cogswell, P. M.; Gower, N. J.; Haddow, M. F.; Harvey, J. N.; Murphy, D. M.; Neeve, E. C.; Nunn, J. Simplifying Iron-Phosphine Catalysts for Cross-Coupling Reactions. Angew. Chem. Int. Ed. 2013, 52, 1285 1288. 143. Mo, Z. B.; Zhang, Q.; Deng, L. Dinuclear Iron Complex-Catalyzed Cross-Coupling of Primary Alkyl Fluorides with Aryl Grignard Reagents. Organometallics 2012, 31, 6518 6521. 144. Chard, E. F.; Dawe, L. N.; Kozak, C. M. Coupling of Benzyl Halides with Aryl Grignard Reagents Catalyzed by Iron(III) Amine-Bis(Phenolate) Complexes. J. Organomet. Chem. 2013, 737, 32 39. 145. Bedford, R. B.; Bruce, D. W.; Frost, R. M.; Goodby, J. W.; Hird, M. Iron(III) SalenType Catalysts for the Cross-Coupling of Aryl Grignards with Alkyl Halides Bearing Beta-Hydrogens. Chem. Commun. 2004, 2822 2823. 146. Chowdhury, R. R.; Crane, A. K.; Fowler, C.; Kwong, P.; Kozak, C. M. Iron(III) Amine-Bis(Phenolate) Complexes as Catalysts for the Coupling of Alkyl Halides with Aryl Grignard Reagents. Chem. Commun. 2008, 94 96. 147. Melen, R. L. Dehydrocoupling Routes to Element-Element Bonds Catalysed by Main Group Compounds. Chem. Soc. Rev. 2016, 45, 775 788. 148. Jayarathne, U.; Hazari, N.; Bernskoetter, W. H. Selective Iron-Catalyzed N-Formylation of Amines Using Dihydrogen and Carbon Dioxide. ACS Catal 2018, 8, 1338 1345. 149. Chakraborty, S.; Leitus, G.; Milstein, D. Iron-Catalyzed Mild and Selective Hydrogenative Cross-Coupling of Nitriles and Amines to Form Secondary Aldimines. Angew. Chem. Int. Ed. 2017, 56, 2074 2078. 150. Bistri, O.; Correa, A.; Bolm, C. Iron-Catalyzed C-O Cross-Couplings of Phenols with Aryl Iodides. Angew. Chem. Int. Ed. 2008, 47, 586 588. 151. Correa, A.; Carril, M.; Bolm, C. Iron-Catalyzed S-Arylation of Thiols with Aryl Iodides. Angew. Chem. Int. Ed. 2008, 47, 2880 2883. 152. Ribeiro, A. P. C.; Martins, L. M. D. R. S.; Pombeiro, A. J. L. Carbon Dioxide-toMethanol Single-Pot Conversion Using a C-Scorpionate Iron(II) Catalyst. Green Chem. 2017, 19, 4811 4815. ´ . Process Advantages of Direct CO2 to 153. Marlin, D. S.; Sarron, E.; Sigurbjo¨rnsson, O Methanol Synthesis. Front. Chem. 2018, 6, 446. 154. Kar, S.; Sen, R.; Goeppert, A.; Prakash, G. K. S. Integrative CO2 Capture and Hydrogenation to Methanol with Reusable Catalyst and Amine: Toward a Carbon Neutral Methanol Economy. J. Am. Chem. Soc. 2018, 140, 1580 1583. 155. Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. Iron-Catalyzed Direct Arylation Through Directed C-H Bond Activation. J. Am. Chem. Soc. 2008, 130, 5858 5859. 156. Isin, E. M.; Elmore, C. S.; Nilsson, G. N.; Thompson, R. A.; Weidolf, L. Use of Radiolabeled Compounds in Drug Metabolism and Pharmacokinetic Studies. Chem. Res. Toxicol. 2012, 25, 532 542. 157. Yu, R. P.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Iron-Catalysed Tritiation of Pharmaceuticals. Nature 2016, 529, 195 199. 158. Torres, P. U. Cinacalcet HCl: A Novel Treatment for Secondary Hyperparathyroidism Caused by Chronic Kidney Disease. J. Ren. Nutr. 2006, 16, 253 258. 159. Barton, D. H. R.; Doller, D. The Selective Functionalization of SaturatedHydrocarbons - Gif Chemistry. Acc. Chem. Res. 1992, 25, 504 512. 160. Stavropoulos, P.; Celenligil-Cetin, R.; Tapper, A. E. The Gif Paradox. Acc. Chem. Res. 2001, 34, 745 752. 161. Sawyer, D. T.; Sobkowiak, A.; Matsushita, T. Metal ML(x); M 5 Fe, Cu, Co, Mn/ Hydroperoxide-Induced Activation of Dioxygen for the Oxygenation of Hydrocarbons: Oxygenated Fenton Chemistry. Acc. Chem. Res. 1996, 29, 409 416.

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162. Bianchini, C.; Giambastiani, G.; Rios, I. G.; Mantovani, G.; Meli, A.; Segarra, A. M. Ethylene Oligomerization, Homopolymerization and Copolymerization by Iron and Cobalt Catalysts with 2,6-(Bis-Organylimino)Pyridyl Ligands. Coord. Chem. Rev. 2006, 250, 1391 1418. 163. Matyjaszewski, K.; Wei, M.; Xia, J.; McDermott, N. E. Controlled/“Living” Radical Polymerization of Styrene and Methyl Methacrylate Catalyzed by Iron Complexes. Macromolecules 1997, 30, 8161 8164. 164. Ando, T.; Kamigaito, M.; Sawamoto, M. Iron(II) Chloride Complex for Living Radical Polymerization of Methyl Methacrylate 1. Macromolecules 1997, 30, 4507 4510. 165. Britovsek, G. J. P.; Bruce, M.; Gibson, V. C.; Kimberley, B. S.; Maddox, P. J.; Mastroianni, S.; McTavish, S. J.; Redshaw, C.; Solan, G. A.; Stro¨mberg, S.; White, J. P.; Williams, D. J. Iron and Cobalt Ethylene Polymerization Catalysts Bearing 2,6-Bis (Imino)Pyridyl Ligands: Synthesis, Structures, and Polymerization Studies. J. Am. Chem. Soc. 1999, 121, 8728 8740. 166. Britovsek, G. J. P.; Gibson, V. C.; McTavish, S. J.; Solan, G. A.; White, A. J. P.; Williams, D. J.; Britovsek, G. J. P.; Kimberley, B. S.; Maddox, P. J. Novel Olefin Polymerization Catalysts Based on Iron and Cobalt. Chem. Commun. 1998, 849 850. 167. Small, B. L.; Brookhart, M.; Bennett, A. M. A. Highly Active Iron and Cobalt Catalysts for the Polymerization of Ethylene. J. Am. Chem. Soc. 1998, 120, 4049 4050. 168. Buchard, A.; Kember, M. R.; Sandeman, K. G.; Williams, C. K. A Bimetallic Iron(III) Catalyst for CO2/Epoxide Coupling. Chem. Commun. 2011, 47, 212 214. 169. Taherimehr, M.; Al-Amsyar, S. M.; Whiteoak, C. J.; Kleij, A. W.; Pescarmona, P. P. High Activity and Switchable Selectivity in the Synthesis of Cyclic and Polymeric Cyclohexene Carbonates with Iron Amino Triphenolate Catalysts. Green Chem. 2013, 15, 3083. 170. Taherimehr, M.; Serta˜, J. P. C. C.; Kleij, A. W.; Whiteoak, C. J.; Pescarmona, P. P. New Iron Pyridylamino-Bis(Phenolate) Catalyst for Converting CO2 into Cyclic Carbonates and Cross-Linked Polycarbonates. ChemSusChem 2015, 8, 1034 1042. 171. Nakano, K.; Kobayashi, K.; Ohkawara, T.; Imoto, H.; Nozaki, K. Copolymerization of Epoxides with Carbon Dioxide Catalyzed by Iron-Corrole Complexes: Synthesis of a Crystalline Copolymer. J. Am. Chem. Soc. 2013, 135, 8456 8459. 172. Della Monica, F.; Maity, B.; Pehl, T.; Buonerba, A.; De Nisi, A.; Monari, M.; Grassi, A.; Rieger, B.; Cavallo, L.; Capacchione, C. [OSSO]-Type Iron(III) Complexes for the Low-Pressure Reaction of Carbon Dioxide with Epoxides: Catalytic Activity, Reaction Kinetics, and Computational Study. ACS Catal. 2018, 8, 6882 6893. ˇ enkova´, I.; Merna, J. Alternating Ring-Opening 173. Mundil, R.; Hoˇst’a´lek, Z.; Sedˇ Copolymerization of Cyclohexene Oxide with Phthalic Anhydride Catalyzed by Iron (III) Salen Complexes. Macromol. Res. 2015, 23, 161 166. 174. Pen˜a Carrodeguas, L.; Martı´n, C.; Kleij, A. W. Semiaromatic Polyesters Derived from Renewable Terpene Oxides with High Glass Transitions. Macromolecules 2017, 50, 5337 5345. 175. Sanford, M. J.; Pen˜a Carrodeguas, L.; Van Zee, N. J.; Kleij, A. W.; Coates, G. W. Alternating Copolymerization of Propylene Oxide and Cyclohexene Oxide with Tricyclic Anhydrides: Access to Partially Renewable Aliphatic Polyesters with High Glass Transition Temperatures. Macromolecules 2016, 49, 6394 6400. 176. Shi, Z.; Jiang, Q.; Song, Z.; Wang, Z.; Gao, C. Dinuclear Iron(III) Complexes Bearing Phenylene-Bridged Bis(Amino Triphenolate) Ligands as Catalysts for the Copolymerization of Cyclohexene Oxide with Carbon Dioxide or Phthalic Anhydride. Polym. Chem. 2018, 9, 4733 4743. 177. Luo, W.; Campbell, P. G.; Zakharov, L. N.; Liu, S. Y. A Single-Component LiquidPhase Hydrogen Storage Material. J. Am. Chem. Soc. 2011, 133, 19326 19329.

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1. Non-precious metals in catalysis

S E C T I O N

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Smart inorganic polymers

C H A P T E R

2 Polyphosphazenes: macromolecular structures, properties, and their methods of synthesis Aitziber Iturmendi, Helena Henke, George S. Pappas and Ian Teasdale Institute of Polymer Chemistry, Johannes Kepler University, Linz, Austria

2.1 Introduction Polymers play a ubiquitous role in modern society as easily processable, versatile materials and have become almost indispensable for wide-ranging applications from simple inert plastic containers to complex advanced functional materials. However, while the vast majority of polymers are organic macromolecules based on carbon backbones, with the obvious exception of polysiloxanes, commercially relevant polymers containing inorganic elements remain almost unknown. Nevertheless, the incorporation of inorganic elements into polymer main-chains, that is, inorganic polymers, can not only complement organic polymers, but also potentially offer properties that go beyond those where classical carbon-based polymers have reached their upper limits. This opportunity, in combination with the ever-advancing synthetic methods that allow easier preparation on the larger scales required of materials chemistry, is allowing inorganic polymers to emerge as an extremely valuable class of players in current and future polymeric materials.

Synthetic Inorganic Chemistry DOI: https://doi.org/10.1016/B978-0-12-818429-5.00009-0

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© 2021 Elsevier Inc. All rights reserved.

48

2. Polyphosphazenes: macromolecular structures

Inorganic polymers can be particularly useful as functional polymers, whereby not only structural characteristics but also chemical properties that are responsive to their environment are required.1 Emerging synthetic inorganic polymers include those containing metal centers, incorporating the functionality of metal centers into tough, ductile, and processable macromolecular materials. Further examples include boroncontaining polymers,2 which are promising for electronic devices and biomedical applications, as well as the large range of phosphoruscontaining polymers,3 including the phosphate-based polyphosphoesters4 and nitrogen-phosphorus-containing polyphosphazenes. Polyphosphazenes consist of an alternating phosphorusnitrogen main-chain, commonly bearing two organic substituents on each phosphorus center, hence referred to as poly(organo)phosphazenes (Fig. 2.1).

FIGURE 2.1 General structure of poly(organo)phosphazene.

While somewhat obscure compared to organic polymers, among inorganic polymers polyphosphazenes are relatively well developed in terms of the variety of structures on offer, and the synthetic methods available. In the first part of this chapter, the key synthetic considerations are described, including descriptions of the state-of-the-art methods of synthesis. These include mild methods with excellent control of the polymerization processes, through to methods conducive to industrial-scale production. This is followed by a discussion on how these advanced methods can be used to prepare advanced macromolecular architectures. A recent rapid development in nanomaterials based on cyclomatrix phosphazenes is also described, including a discussion on the structure property relationships that underlie their preparation and properties. Degradable polyphosphazenes are then discussed, this property being a major driving force behind their recent development in medicinal applications where the predictable degradation rate to biologically benign compounds is of high importance. Finally, the preparation of watersoluble polyphosphazenes is discussed, as well as elastomers, representing two important materials classes for poly(organo)phosphazenes.

2.2 Synthesis of poly(organo)phosphazenes Poly(organo)phosphazenes can be synthesized by a variety of routes,5,6 for example, directly via thermal condensationpolymerization of

2. Smart inorganic polymers

2.2 Synthesis of poly(organo)phosphazenes

49

(CF3CH2O)(R1)(R2)PQNSiMe3 type monomers7 and via phosphitemediated chain-growth polycondensation of BrR1R2PQNSiMe3 type monomers.8 However, a two-step method is most commonly employed in which the polymeric precursor poly(dichloro)phosphazene, [NPCl2]n, is first prepared, followed by nucleophilic substitution of the chlorine atoms, often referred to as macrosubstitution.9

2.2.1 Synthesis of the precursor [NPCl2]n A variety of procedures are known for the synthesis of [NPCl2]n5,9 with the ring-opening polymerization (ROP) of hexachlorocyclotriphosphazene ([NPCl2]3) and living cationic polymerization of trichloro(trimethylsilyl)phosphoranimine (Cl3PQNSiMe3) being the most widely used approaches.

2.2.2 Ring-opening polymerization ROP of hexachlorocyclotriphosphazene [NPCl2]3 is the traditional route used to synthesize high-molecular-weight [NPCl2]n. The [NPCl2]3 precursor is required to be carefully purified (recrystallized from dry heptane, followed by vacuum sublimation at 50 C60 C and completely free of moisture to avoid any hydrolysis products, usually evidenced by hydroxyl groups, which would lead to undesired cross-linking. In the first step of the ROP of [NPCl2]3, the ionization of a chloride ion from the phosphorus atom occurs (Fig. 2.2). A reaction between the phosphazenium cation and

FIGURE 2.2 Synthetic route for the synthesis of poly(dichloro)phosphazene [NPCl2]n via the ring-opening polymerization of hexachlorocyclotriphosphazene [NPCl2]3.

another trimer then takes place leading to ring-opening, followed by cation transfer to the terminal phosphorus. Chain propagation subsequently occurs from the cationic site. Termination occurs when a chloride ion is abstracted from another [NPCl2]3. Typically, polymerization of molten [NPCl2]3 is carried out under vacuum in a sealed glass tube at 250 C for around 8 h and must be terminated before cross-linking, and hence gelation, occurs.9 The polymerization time can vary depending on different factors, such as the purity of [NPCl2]3. At higher temperatures, the polymerization rate is accelerated, but

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unfortunately the degree of cross-linking is also increased, so careful control over reaction temperatures is essential for successful polymerization. Similarly, the polymerization rate decreases rapidly at temperatures below 250 C, with approximately 230 C being the lowest reported temperature for uncatalyzed polymerization in a prudent period of time. The polymerization temperature can be lowered to 210 C and the relative amount of cross-linking reduced by the addition of Lewis acid catalysts, such as BCl3 and AlCl3.9 In this case, precise control over the organic solvents is necessary as the PCl bond in [NPCl2]3 is sensitive to side reactions with some solvents (e.g., toluene, tetrahydrofuran, nitrobenzene, alkyl ester, and ethers) at high temperatures liberating hydrogen chloride. In the last few years, a mild route to the complete synthesis of high-molecular-weight [NPCl2]n was reported, using 1,2-dichlorobenzene at 25 C with 10 mol% of N-silylated derivatives.10 Additionally, different cyclotriphosphazenes, such as bromocyclophosphazenes [NPBr2]3 and fluorocyclophosphazenes [NPF2]3, are available for the synthesis of poly(organo)phosphazenes via ROP.9 [NPBr2]n is more sensitive to cross-linking than [NPCl2]n, but due to the difference in reactivity of the PBr and PCl bonds, mixed bromochlorophosphazenes could be achieved by copolymerization of [NPCl2]3 and [NPBr2]3 leading to selective substitution by different nucleophiles.11 Furthermore, the unique solubility of [NPF2]n in fluorinated solvents also allows for selective substitution by different nucleophiles. However, higher temperatures (350 C) and longer reaction times are necessary than with [NPCl2]3, presumably due to the greater bond strength of PF compared to the PCl bond.

2.2.3 Living cationic polymerization A different route to [NPCl2]n is via living cationic polymerization of the monomer trichloro(trimethylsilyl)phosphoranimine (Cl3PQNSiMe3) at room temperature. This can be carried out in solution or in bulk, and is usually initiated using phosphorus pentachloride (PCl5). The ambient temperature synthesis of [NPCl2]n with controlled molecular weight via living cationic polymerization of Cl3PQNSiMe3 was first reported in 1995 by Honeyman et al.12 Controlled polymerization is possible by varying the monomer to initiator ratio. Cl3PQNSiMe3 in the presence of two equivalents of PCl5 forms a cationic species [Cl3PNPCl3]1 with PCl62 as the counterion (Fig. 2.3A).13 Further equivalents of Cl3PQNSiMe3 can react with the cationic species in a living cationic polymerization until the monomer is consumed. This living chaingrowth allows the synthesis of polymers with controlled molecular weights and narrow dispersities. However, such procedures give

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FIGURE 2.3 Schematic illustration of the synthesis of poly(dichloro)phosphazene [NPCl2]n by living cationic polymerization of trichloro(trimethylsilyl)phosphoranimine (Cl3PQNSiMe3) with (A) phosphorus pentachloride (PCl5) as initiator and (B) triphenylphosphine dichloride (Ph3PCl2) as initiator.

polymer chains in a controlled manner only up to n  75, probably due to the presence of side reactions.14 Although reaction times can vary depending on different factors such as monomer concentration, solvent, and desired polymer chain length, the polymerization rate can be reasonably fast in dichloromethane and toluene.13,15 Furthermore, extremely anhydrous solvents are required as any trace of water could inhibit the polymerization. Alternatively, the same reaction in the absence of solvent results in longer polymer chains albeit with some reduction in control of the molecular weight.10 The bulk polymerization of Cl3PQNSiMe3 with trace amounts of PCl5 forms a two-phase mixture. The lower, denser, and more viscous part corresponds to the desired [NPCl2]n product, while the upper and liquid phase corresponds to the side product ClSiMe3. In contrast to ROP, such methods allow the synthesis of polymers with high molecular weights in which the complete polymerization of [NPCl2]n is carried out at room temperature. In both cases, in solution or in bulk, the monomer Cl3PQNSiMe3 needs to be of high purity and in sufficient quantity for practical preparation of polymer materials. The most widely used route to synthesize Cl3PQNSiMe3 is via reaction of LiN(SiMe3)2 with PCl3 in diethyl ether, followed by the addition of the strong chlorinating agent SO2Cl2.16 Although good yields (above 80%) are reported, the indispensable vacuum distillation for the purification of Cl3PQNSiMe3 can still represent a limitation to upscaling. Consequently, a new approach was presented in which the well-established living cationic polymerization of [NPCl2]n and the synthesis of Cl3PQNSiMe3 were combined in a one-pot route.17 Contrary to the well-known method for Cl3PQNSiMe3 synthesis, distillation of the monomer is avoided and it is instead reacted with trace amounts of PCl5 to form [NPCl2]n in situ. However, such a synthetic route should be optimized if strict control over the molecular weights is required.

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Although the living cationic polymerization of [NPCl2]n is a wellestablished method and promising route to the synthesis of poly(organo)phosphazenes with controlled architectures, the bidirectional chain growth limits the synthesis of polymers with more complex architectures (e.g., block copolymers).18 Therefore a variety of blocked phosphoranimines with the structure R3PQNSiMe3 has been applied in order to achieve monodirectional growth.19 After reaction of R3PQNSiMe3 with PCl5, the resulting cationic species initiates the polymerization of Cl3PQNSiMe3 but only in one direction, as the R group prevents one end from initiating. Thereby, after total reaction of the first monomer, a second and different phosphoranimine, such as Cl(PhMe) PQNSiMe3, can be added to prepare block copolymers.20 A more recent alternative method to synthesize poly(organo)phosphazenes with defined chain ends is established by the addition of chlorinated tertiary phosphines, such as triphenylphosphine dichloride (Ph3PCl2), as initiator (Fig. 2.3B).21,22 It is well known that Ph3PCl2, for example, exists predominantly in the ionized form, [Ph3PCl]1 [Cl]2, in polar solvents,23 which can initiate the polymerization of Cl3PQNSiMe3. The species [Ph3PNPCl3]1 is obtained upon addition of Cl3PQNSiMe3 resulting in the monodirectional growth of the polymer ensuring the controlled chain growth and narrow dispersities. Moreover, the length of the polymer can be determined by the addition of commercially available monofunctionalized phosphine compounds,22 thus providing the opportunity to modify the functional group at one chain terminus and offering access to block copolymers.

2.2.4 Macromolecular substitution of [NPCl2]n [NPCl2]n is a macromolecule with reactive chlorine atoms, which must be isolated under anhydrous conditions due to its high reactivity toward atmospheric moisture. Consequently, [NPCl2]n has commonly been reacted immediately upon synthesis. Special methods have been developed to store the precursor, for example, Andrianov et al.24 discovered that [NPCl2]n can be stored in solution in the presence of diglyme over 4 years. While its sensitivity to hydrolysis causes storage challenges, the high reactivity of [NPCl2]n allows ready replacement of the halogen atoms by a variety of organic or organometallic nucleophiles, such as RONa, RNH2, or RLi. The key advantage of this approach is that it permits tailoring of the properties of the final polymer without changing its chain length, backbone architecture, and molecular weight distribution, assuming that no backbone cleavage occurs during the halogen substitution process. This is in contrast to the majority of polymerization methods

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in which the desired side groups have to be incorporated into the starting monomer. Furthermore, more than one organic side group can be introduced either simultaneously or sequentially, resulting in mixed substituted polymers and avoiding issues related to the copolymerization of different monomers of differing reactivities. Reaction conditions such as time, temperature, and nucleophilicity are essential to replace all the chlorine atoms, as remaining halogen atoms will yield an unstable polymer, which will be susceptible to cross-linking and/or degradation. Furthermore, steric hindrance of the nucleophiles is also an important consideration, as it may limit the number of chlorine atoms that can be replaced along the polymer chain, though the remaining halogen atoms can sometimes ultimately be replaced by less hindered nucleophiles.25 31P{1H}-NMR spectroscopy can be used to follow the progress of the macromolecular substitution of [NPCl2]n to yield the final [NPR2]n polymer.26 31P NMR chemical shifts are sensitive to the nature of the side groups attached to the phosphorus atoms in the backbone, allowing the monitoring of the conversion of phosphorus attached to chlorine to phosphorus linked to the organic side groups as the reaction progresses. Although the substitution pattern during the reaction appears to be complex, the complete substitution of all chlorine atoms can be readily identified by this technique, at least up to the sensitivity limits of the measurements. Macromolecular substitution is generally limited to monofunctional nucleophiles, as di- or trifunctional groups will promote the crosslinking of the polymer chains, causing a precipitation of the partially substituted polymer and preventing the replacement of all of the chlorine atoms. Thereby, if reactive functional groups are desired in the final polymer, they often need to be incorporated after the macromolecular substitution step or protected during the substitution. An exception to this has been achieved with the amino acid serine, whereby the high reactivity of the amine compared to the hydroxyl nucleophile allowed complete substitution by amine groups, leaving the hydroxyl moieties free.27

2.2.5 Direct polymerization to poly(organo)phosphazenes The direct synthesis of poly(organo)phosphazenes was achieved in 1977 by the uncatalyzed thermal polymerization (B200 C) of Me3NQP (OCH2CF3) to obtain poly(bis(2,2,2-trifluoroethoxy)phosphazene).28 Matyjaszewski and coworkers subsequently improved the method using anionic initiators such as tetrabutylammonium fluoride to lower the polymerization temperature to 130 C and thus achieved polymers with Ð

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between 1.30 and 1.44.29 Most recently, a method for the synthesis of poly (bistrifluoroethoxy)phosphazene with controlled Mw, low Ð (,1.15), and high conversion at readily accessible temperatures (125 C) has also been developed.30 In this case, it was found that the polymerization of a trimethylsilyl phosphoranimine monomer in presence of small quantity of water and catalytic amounts of N-methylimidazole in diglyme resulted in the controlled formation of poly(bistrifluoroethoxy)phosphazene in high conversion (Fig. 2.4).

FIGURE 2.4 Schematic illustration of the synthesis of poly(bistrifluoroethoxy)phosphazene from tris(2,2,2-trifluoroethyl)trimethylsilyl phosphorimidate monomer initiated by water and catalytic amounts of N-methylimidazole.30

The direct synthesis of polyphosphazenes with PC bonds can be also achieved via thermal condensationpolymerization of phosphoranimine monomers (CF3CH2O)(R1R2)PQNSiMe3) that bear alkyl and/ or aryl groups linked directly to the phosphorus atom (R 5 alkyl or aryl group).7 Similarly, a novel poly(phospholenazene) was also synthesized in which the phosphorus atom from the backbone is part of a heterocyclic ring (Fig. 2.5).31 Moreover, X(R1R2)PQNSiMe3 (X 5 Cl, Br; R 5 alkyl or aryl group) type monomers can also polymerize to poly(alkyl/aryl)phosphazenes using trimethylphosphite (P(OMe)3) as initiator at room temperature.8

FIGURE 2.5 Direct synthesis of the novel poly(phospholenazene) via thermal condensationpolymerization.31

2.3 Advanced architectures Polyphosphazenes with a variety of architectures have been prepared (Fig. 2.6) and are discussed in this section. First, postpolymerization substitution of the poly(dichloro)phosphazene [NPCl2]n opens up the

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FIGURE 2.6 Different architectures achieved by poly(organic)phosphazenes: bottlebrush (A), barbwire bottlebrush (B), block copolymer (C), three-arm star (D), six-arm star (E), and dendrimer (F).

possibility of different architectures via the choice of substituents and their characteristics. Second, phosphine-mediated polymerization can yield a variety of quite intricate architectures, and third, different approaches to block copolymers will be discussed, ranging from end group functionalization of the nonpolyphosphazene block to living cationic polymerization with subsequential addition of different phosphoranimine monomers. The densely branched architecture of poly(organo)phosphazenes can be utilized to yield bottlebrush polymers, where short polymer chains are grafted onto the polyphosphazene backbone.14 A doubling in branching can be achieved by increasing the multifunctionality from two arms per repeat unit to four by thiol-yne photochemistry using propargyl alcohol as a macrosubstituent and thiol end-capped Jeffamine M1000 (Fig. 2.7),14 obtained by in situ ring opening of a thiolactone32 with the amine of the Jeffamine M-1000, yielding barbwire bottlebrushes (Fig. 2.6B), a combination of starlike and bottlebrush polymers.33 Three-arm polyphosphazene stars (Fig. 2.6D) can be obtained by polymerization from a central core, namely 1,1,1-tris(diphenylphosphino)methane, with three diphenylphosphine moieties acting as a polymerization mediator upon chlorination with hexachloroethane (C2Cl6). With the addition of the monomer Cl3PNSi(CH3)3, [NPCl2]n arms are grown from the diphenylphosphine chloride moieties (Fig. 2.8). Macrosubstitution of the [NPCl2]n, in this case a grafting onto approach, with Jeffamine M-1000 gives star-shaped molecular brushes. Macrosubstitution of the same three-arm

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FIGURE 2.7 Synthesis of polyphosphazenes with four arms per repeat unit via in situ ring opening of a thiolactone, followed by a thiol-yne reaction.14

FIGURE 2.8 Synthesis of three-arm polyphosphazenes grown from a central core bearing three diphenylphosphine moieties.34

[NPCl2]n with 3-(diphenylphosphino)propylamine on each repeat unit, results in macroinitiators. Each phosphine along the main chain can act as a initiator and hence two [NPCl2]n chains can be grown from every repeating unit (Fig. 2.9). Subsequent substitution with Jeffamine M-1000 yields star dendritic molecular brushes, a form of architecture not only hitherto unattainable for polyphosphazenes, but an intricate structure for any type of polymer. The substituted polyphosphazene branches emanating from a starshaped polyphosphazene backbone yield extremely densely branched polymers with relatively narrow dispersities (Ð 1.21.6) and an extremely large number of end-groups. Dynamic light scattering (DLS) measurements of 2. Smart inorganic polymers

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FIGURE 2.9 Synthesis of star dendritic molecular brushes. (i) Chlorination of a diphenylphosphine bearing macroinitiator, (ii) addition of the Cl3PNSi(CH3)3 monomer, and (iii) postpolymerization substitution with Jeffamine M-1000.34

these polymers in water showed a hydrodynamic diameter in the range of 20-70 nm, which was also confirmed via atomic force microscopy measurements, where the polymers appear as unimolecular globular shapes.34 This grafting-from method is not only limited to three-arm stars, but can be extended to six arms by substituting the hexachlorophosphazene trimer [NPCl2]3 with 3-(diphenylphosphino)propylamine resulting in a hexainitiator for growing six [NPCl2]n arms from the cyclic core (Fig. 2.6E). The postpolymerization of the six-arm [NPCl2]n with propargylamine offers two alkyne functionalities per repeat unit for further thiol-yne reactions with 3-amino1,2-propandiol yielding eight hydroxyl functional groups per repeat unit, which can be regarded as a degradable branched polyol (Fig. 2.10).35 A simi-

FIGURE 2.10 Synthesis of dendritic polyols via thiol-yne reaction of six-arm star poly (propargylamine)phosphazenes. Source: Reproduced with permission from Linhardt, A.; Konig, M.; Iturmendi, A.; Henke, H.; Bruggemann, O.; Teasdale, I. Degradable, Dendritic Polyols on a Branched Polyphosphazene Backbone. Ind. Eng. Chem. Res. 2018, 57, 36023609. r (2018) American Chemical Society.

lar grafting approach, albeit with organic side-arms, has also been utilized by synthesizing ATRP (atom transfer radical polymerization) macroinitiators. This was achieved by the functionalization of both the [NPCl2]3 trimer and polymer with tertiary alkyl bromides, which can be used as macroinitiators 2. Smart inorganic polymers

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FIGURE 2.11 Schematic representation of the synthesis of block copolymers. (A) Combination of two polymers, (B) end-capped polyphosphazene block from which the other block is grown, and (C) end-capped nonpolyphosphazene block from which the polyphosphazene is grown.

to polymerize various monomers, such as styrene, N-isopropylacrylamide, and tert-butyl acrylate, and create star-shaped and comb-shaped brushes with a polyphosphazene core and organic polymers as arms.36 Another important type of advanced architectures is block copolymers (Fig. 2.11). For an in-depth description of the versatility of polyphosphazenes for block copolymers and self-assembly, the reader is referred to the work of the Soto group and their latest review on this topic.37 For block copolymers the control of end group functionality is imperative. One approach is to employ phosphines as a terminal group on the nonpolyphosphazene block from which the polyphosphazene block can be grown using the aforementioned phosphine-mediated polymerization (Fig. 2.11C). This method is employed to achieve polyphosphazene-b-polyferrocenylsilane block copolymers. The polyferrocenylsilane (PFS) block is prepared first by living anionic polymerization of dimethylsila[1]ferrocenophane initiated with n-butyllithium (n-BuLi). Chain end functionalization is achieved by quenching the living end of the resulting polymer with chlorodiphenylphosphine (ClPPh2), from which, after chlorination, the [NPCl2]n block can be grown via living cationic polymerization of the trichlorophosphoranimine Cl3PNSi(CH3)3 monomer (Fig. 2.12), and subsequently be substituted to yield the desired poly(organo)phosphazene blocks. These materials benefit from the tunability of the polyphosphazene block, as well as the crystallinity of the polyferrocenylsilane block, and show well-defined structures and narrow dispersities.21 Such polyphosphazene-b-polyferrocenylsilane block copolymers are used to gain access to micelles with a distinct pointed oval shape by 2. Smart inorganic polymers

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FIGURE 2.12 Synthesis of polyphosphazene-b-polyferrocenylsilane block copolymers.21

crystallization-driven living self-assembly, where two different PFS block copolymers, one featuring a polyphosphazene block and the other synthesized with a poly(2-vinylpyridine) (P2VP) block, are generated in a selective solvent, here 2-propanol. This distinct shape is achieved by using micelles formed by the PFS-b-P2VP block copolymer as seeds where polyphosphazene-b-PFS chains formed micellar structures with the PFS block forming around this seed and the polyphosphazene blocks forming the outer layer.38 Polyphosphazene block copolymers can also be achieved by synthesizing the chain endfunctionalized poly(organo)phosphazene block first (Fig. 2.11B). For this, propargylamine is reacted with bromophosphoranimine, and subsequently reacted with phosphorus pentachloride, PCl5, yielding the initiator for the polymerization. Upon addition of the Cl3PNSi (CH3)3 monomer, the [NPCl2]n chains are formed. Subsequent postpolymerization substitution with the preferred side group, in this case NaOCH2CF3, yields alkyne chain endfunctionalized poly(organo)phosphazenes. This alkyne chain end is then used to perform an azide-alkyne click reaction to functionalize this chain end with an ATRP initiator from which an organic polymer block, in this case poly[(dimethylamino)ethyl methacrylate] is grown, yielding amphiphilic block copolymers with narrow dispersities, which in aqueous medium self-agglomerated into micelles.39 The more common approach to block copolymers with one polyphosphazene block is the functionalization of the end-group of the nonpolyphosphazene block with a phosphoranimine species, and react this end-group then with the living end of the [NPCl2]n block, which is subsequently substituted to yield the poly(organo)phosphazene block (Fig. 2.11A). This method is used to synthesize different block copolymers with one polyphosphazene block, from polyesters and polycarbonate blocks,40 to polystyrene.41 The phosphazene block of these polyphosphazene-b-polystyrene copolymers have been functionalized with adamantyl groups enabling later reaction with β-cyclodextrin for micelle formation, which is controllable via the concentration of the β-cyclodextrin.41 Polystyrene-b-polyphosphazene blocks have more recently been synthesized, where a lithiated phosphine is on one hand used to initiate the polymerization of styrene and, after quenching of the polystyrene chain, the phosphine is then used to grow polyphosphazenes via the aforementioned phosphine-mediated polymerization, yielding products of low dispersities (Ð 5 1.2).42 In the same vein, polyphosphazene-b-poly(2-vinylpyridine) has been prepared very recently, leading to cylindrical micelles.43 2. Smart inorganic polymers

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FIGURE 2.13 Schematic representation of the synthesis of triblock copolymers. (A) End capping of the polyphosphazene block with end groupfunctionalized nonpolyphosphazene blocks (A-B-A type), (B) reaction of two polyphosphazene blocks with an α,ω-chain endfunctionalized nonpolyphosphazene block (B-A-B type), and (C) α,ω-chain endfunctionalized nonpolyphosphazene block from which two polyphosphazene blocks can be grown.

Different combinations of tribock polymers can also be obtained (Fig. 2.13). The living ends of the poly(dichloro)phosphazene can be reacted with phosphoranimine chain endfunctionalized polymers of a different composition, such as polystyrene44 and poly(ethylene oxide)45 yielding triblock copolymers of the type A-B-A with polyphosphazene as the middle block B (Fig. 2.13A). With polyphosphazenes as the outer blocks, type B-A-B triblock polymers can be prepared using different approaches (Fig. 2.13B and C). Functionalization of both chain ends of the middle bock with phosphoranimines can be used to terminate two polyphosphazene chains, as is the case with poly(propylene glycol)46 as middle block A (Fig. 2.13B). Both phosphoranimine-functionalized chain ends, of poly(ethylene oxide),45 for example, can also be initiated with phosphorus pentachloride (PCl5), and [NPCl2]n chains grown by addition of the Cl3PNSi(CH3)3 monomer, with subsequent substitution with the desired side group to yield poly(organo) phosphazene blocks (Fig. 2.13C). Chain end functionalization of the polyphosphazene block (B), for example, with an alkene to be reacted with siloxane (A), can give access to di- and triblock polymers of the A-B, A-B-A, and B-A-B varieties.47 2. Smart inorganic polymers

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As mentioned earlier, block copolymers entirely composed of poly (organo)phosphazenes can also be prepared. Here, the living character of the polymerization is utilized by sequential addition of different phosphoranimine monomers to gain phosphazene-b-phosphazene block copolymers (Fig. 2.14).19 To achieve monodirectional growth of the poly-

FIGURE 2.14 Schematic representation of the synthesis of polyphosphazene-b-polyphosphazene block copolymers utilizing the living cationic polymerization of different phosphoranimine monomers. Source: Reproduced with permission from Sua´rez-Sua´rez, S.; Carriedo, G.A.; Tarazona, M.P.; Presa Soto, A. Twisted Morphologies and Novel Chiral Macroporous Films from the Self-Assembly of Optically Active Helical Polyphosphazene Block Copolymers. Chem. Eur. J. 2013, 19, 56445653. Copyright (2013) Wiley-VCH.

phosphazene chains, initiators such as phosphines, which simultaneously work as end cappers are employed.22 These phosphines initiate the polymerization of the Cl3PNSi(CH3)3 monomer, and after all available monomer is incorporated into the polymer chain, a different monomer [in this case ClCH3PhNSi(CH3)3] is added to create the second block (Fig. 2.8). The [NPCl2]n block of the resulting [NPCl2]n-b-[NPCH3Ph]m block copolymers needs to be substituted with an appropriate organic side group to yield the finished poly(organo)phosphazene block with the desired characteristics. This method has been used to prepare helical structures when substituting the [NPCl2]n block with a chiral binaphtoxy substituent, due to the “sergeant-and-soldiers” mechanism, where the poly(binaphtoxy) phosphazene dictates the conformation of the poly(methylphenyl)phosphazene block, a previously unattainable effect for polyphosphazenes. These novel morphologies resemble a twisted pearl necklace and were achieved by self-assembly and confirmed by scanning electron microscopy.48 While the sequential addition of different monomers is 2. Smart inorganic polymers

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advantageous, the drawback lies in the lack of versatility of substituents for the non-[NPCl2]n block, where any type of side group modification involves the need for the synthesis, and sometimes even development, of a new monomer. Therefore the synthesis of polyphosphazene-b-polyphosphazene block copolymers where both blocks are derived from [NPCl2]n would be of interest, bringing with it the versatility of tunable characteristics and easy adaptability for both blocks resulting from the postpolymerization functionalization of [NPCl2]n. To the authors’ knowledge, this has not been achieved to date. The aforementioned approach of the end functionalization of a nonpolyphosphazene polymer with a phosphoranimine to later terminate the living end of a polyphosphazene chain has also been used to prepare polyphosphazene dendrimers. In this approach, diaminobutane poly(propyleneimine) is used as the core of the dendrimer and poly(diethylene glycol methyl ether)phosphazenes as the arms. These dendrimers are able to encase hydrophobic molecules in the dendrimer core and release them upon addition of a trigger, here a sodium chloride solution.49 The trimer [NPCl2]3 (hexachlorocyclotriphosphazene or HCCP) can also be used as a building block for dendrimers, and these materials have been heavily investigated by the group of Caminade (Fig. 2.15).50 Ideally,

FIGURE 2.15 Dendrimer synthesis from [NPCl2]3 with AB5 building blocks. Source: Reproduced with permission from Caminade, A.M.; Hameau, A.; Majoral, J.P. The Specific Functionalization of Cyclotriphosphazene for the Synthesis of Smart Dendrimers. Dalton Trans. 2016, 45, 18101822. Copyright (2016) Royal Society of Chemistry.

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[NPCl2]3 could be reacted with six diamines followed by the addition of six trimers, followed by the diamine addition and so forth, but problems arise from high excess and/or cross-linking of the reagents.5 To circumvent this, one chloride of the [NPCl2]3 is substituted with a different substituent than the other five chlorides, the order of which is not of significance, yielding AB5 building blocks with a much higher multiplication effect compared to organic building blocks (OBBs).51

2.4 Cyclomatrix organophosphazenes The versatility of the phosphazene chemistry originates mainly from the labile PCl bonds that offer multiple reaction pathways for the preparation of useful and functional phosphazene-based materials. As discussed in the previous sections, the linear inorganic poly(dichlorophosphazenes) can be further functionalized with organic substituents. An alternative pathway for the preparation of phosphazene-based materials is the direct bridging of the cyclic HCCP with organic linkers to afford a continuous network of inorganic and OBBs known as cyclomatrix organophosphazenes.52 Fig. 2.16A shows a generic structure for

FIGURE 2.16

The general structures of (A) cyclomatrix and (B) cyclolinear organophosphazenes with “X” representing the organic linker.

cyclomatrix organophosphazenes while a linear bridging of the phosphazene rings results in cyclolinear organophosphazenes, shown in Fig. 2.16B. The latter have hitherto not been widely used because of their relatively low molecular weights. However, some recent synthetic developments show promise for the preparation of useful long cyclolinear molecules.53 Compared to the vast literature referring to linear polyphosphazenes, dimensionally stable cyclomatrix organophosphazene nanomaterials (X-OPZs) are much less reported due to their relatively recent discovery (200607) when the first highly cross-linked X-OPZs were synthesized in the form of nanofibers54 and microspheres.55 To date, X-OPZs and their derivatives range from zero-dimensional to three-dimensional materials and their unique hybrid molecular structures open up applications in

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energy storage,56,57 catalysis,58,59 gas sorption,60 probes,61,62 and drug delivery systems.63 This section focuses on the different pathways for the preparation of X-OPZs as the synthetic parameters play a crucial role in the resulting structures and morphologies of these materials. For the different applications of the X-OPZs, the reader can find information in the references at the end of this section.

2.4.1 Synthetic routes for X-OPZ nanostructured materials 2.4.1.1 Direct nucleation and growth of oligomers to X-OPZ particles X-OPZ nano-/microspheres are mainly obtained through thenucleophilic attack of an organic molecule on the phosphorous atom S2N ðPÞ . To achieve a multisite reaction, and hence the cross-linked configuration of the X-OPZs, the OBB needs to bear at least two nucleophilic centers, as the HCCP already provides six available substitution centers (three disubstituted P atoms). For example, the base-accelerated nucleophilic reaction between 4,40 sulfonyldiphenol (BPS) and HCCP is given in Fig. 2.17 and the reaction

FIGURE 2.17 The base-assisted S2N ðPÞ reaction of HCCP with BPS.

pathways are described as follows: a deprotonation of the weakly acidic phenol group takes place assisted by the weak base triethylamine (Et3N). The resulting phenoxide anion acts as a strong nucleophile and attacks the P center of the HCCP ring, with the simultaneous elimination of one Cl2 anion to form the triethylammonium chloride (Et3N HCl) by-product.



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The substitution reaction takes place simultaneously on other P centers and induces the formation of HCCPBPS oligomers (precondensates). Under the specific synthetic conditions (solvent polarity and temperature) the solubility factor of the primary precondensates changes dramatically and clusters are formed. These clusters aggregate to minimize their high free energy forming the primary nuclei. The nuclei continue to grow by continuous adsorption and reaction of oligomeric species from the solution and finally, highly cross-linked X-OPZ spherical particles precipitate out from solution (Fig. 2.18).

FIGURE 2.18 The nucleation and growth mechanism of spherical X-OPZs. Source: Reproduced with permission Zhu, Y.; Huang, X.; Li, W.; Fu, J.; Tang, X. Preparation of Novel Hybrid InorganicOrganic Microspheres with Active Hydroxyl Groups Using Ultrasonic Irradiation via One-Step Precipitation Polymerization. Mater. Lett. 2008, 62, 13891392 [64]. Copyright (2008) Elsevier B.V.

Both the polarity of the solvent and the pKa value of the organic base play essential roles for the successful reaction of the precursors and their transformation into dimensionally stable X-OPZ materials. First, since the reaction is driven by a S2N -type mechanism, an aprotic polar solvent is needed to stabilize the phenoxide anions (when phenols are employed), which are the reactive species. Polar protic solvents such as water and alcohols tend to stabilize the phenol homologues and thus reduce the reactivity of the nucleophiles. Moreover, a high acid dissociation constant (pKa) of the base in the selected solvent is necessary for the complete deprotonation of the OBB. Additionally, a nonnucleophilic base such as Et3N is preferred to avoid any undesired substitution reaction with the HCCP ring. Due to its high reactivity and low cost, BPS is the most often reported OBB. Nevertheless, the synthetic pathway described earlier became the basic platform for the preparation of X-OPZ materials from other multireactive nucleophiles employed as OBBs. A summary of the different OBBs, material morphologies, and the targeted applications is presented in Table 2.1.

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TABLE 2.1 Summary of reported OBBs, the synthetic conditions, and observed morphologies of X-OPZs. OBB

Conditions

Morphology/functionality

4,4 -Sulfonyldiphenol (BPS)

MeCN, (acetone), [THF]/Et3N

Nanospheres,56 (microspheres),55 (nanotubes)65

4,40 (Hexafluoroisopropylidene) diphenol

MeCN/Et3N

MicrospheresB0.5 μm/ superhydrophobic surfaces66

4,40 -Oxydianiline (ODA)

MeCN/Et3N

Microspheres 0.52.5 μm67

Benzidine

MeCN/Et3N

MicrospheresB2.3 μm/fluorescencebased nitroaromatic sensor68

2,20 -Bis(trifluoromethyl)-4,40 diaminodiphenyl ether

MeCN/Et3N

MicrospheresB0.53.0 μm/ superhydrophobic surfaces69

3,5-(Ditrifluoromethyl) phenylhydroquinone

MeCN/Et3N

Microspheres 0.600.95 μm/ superhydrophobic surfaces70

Phloroglucinol

MeCN/Et3N

Microspheres 0.61.1 μm/fluorescent particles71

Melamine

Pyridine

Nanotubes ø 5 50250 nm, L . 2 μm72

Melamine

DMF/Et3N

Microspherical grumbled 2D sheets 12 μm (diluted reaction)73 or dense microspheres74

4,40 ,4v-(1,3,5-Triazine-2,4,6triyl)trianiline

DMF/Et3N

Microspheres/iodine removal74

1,3,5-Tri(4-hydroxyphenyl) benzene

MeCN/Et3N

Microspheres 0.51.0 μm/fluorescent probes75

0

(Continued)

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TABLE 2.1

(Continued)

OBB

Conditions

Morphology/functionality

Curcumin

MeCN/Et3N

MicrospheresB1 μm/fluorescent particles76

40 ,50 -Dibromo fluorescein

MeCN/Et3N

NanospheresB330 nm/fluorescent particles for cell imaging77

Trimethoprim

MeCN/Et3N

Microspheres 0.51.0 μm/drug release78

Oxyservatol

MeCN/Et3N

Nanospheres 200400 nm/fluorescent probes79

Quercetin

Acetone/Et3N

Submicron spheres/drug release80

40 ,7-Dihydroxyflavone

Acetone/Et3N

Microspheres80

5,10,15,20-Tetrakis(4hydroxyphenyl) porphyrin (TPP OH)4)

MeCN (acetone)/ Et3N

Hollow nanospheresB250 nm (solid microspheresB0.67 μm)/ fluorescent probes81

p-Phenylenediamine

THF/hydrothermal conditions

Microporous frameworks/uranium sorbents82

3,3-Diaminobenzidine (DAB)

DMF or DMSO/ hydrothermal conditions

Nano-/microspheres 801500 nm83 or hierarchically porous frameworks84/ CO2 and CH4 sorbents

1,1-Di(aminomethyl) ferrocene

Acetone-toluene/ Et3N/sonic 3 h

Nano-/microspheres 0.31.3 μm/ superparamagnetic, electrochemical, fluorescent, and adsorbent material85

MnMo6-PhOH polyoxometalates

MeCN/Et3N

Submicron spheres 800 nm/chargeselective dye adsorption86

(Continued)

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TABLE 2.1 (Continued) OBB

Conditions

Morphology/functionality

Cyclen

MeCN (acetone)/ Et3N

Microspheres/Cu-doped reduction catalyst of 4-nitrophenol87

Branched PEI

MeCN/Et3N

Submicron spherical particles 400900 μm88

The required reaction time in organophosphazene chemistry ranges from a few seconds to several hours and it is highly depended on the solvent polarity, base strength, and nucleophilicity (reactivity) of the OBB. As shown in Table 2.1, there is a wide diversity on chemical structure of the aromatic OBBs. Their nucleophilicity is strongly dependent on the type of the nucleophilic center (OH or NH2) as well as on the bridging group between the phenyl rings. In phenylamines, such as ODA, the donation of the nitrogen’s lone pair to the phenyl ring reduces the reactivity of the amine group. As a result, longer reaction times and high temperature (energy) are needed for the formation of X-OPZ materials from arylamine OBBs. Similarly, the reactivity of the nucleophilic center is also affected by the presence of bridging groups connecting the phenyl rings at the parapositions and other substituents at the ortho- and meta-positions. These groups carry electron-withdrawing heteroatoms (e.g., S, F, O) that attract the aromatic electron cloud and consequently alter the reactivity of the OH and NH2 nucleophilic centers. It is important to note that due to the steric hindrance of the bulky OBBs, nongeminal substitution is dominant, so not all PCl bonds are substituted in the final product. Finally, the polarity of the solvent is also an important factor. For example, BPS is less reactive and shows slightly increased reaction times when (less polar) acetone is used instead of MeCN. Ultimately, the reaction kinetics play an essential role on the nucleation and growth rate and consequently on the final particle size. The product mass yield also depends on the reaction kinetics and in most reports is found to be more than 85 wt.%. The highly and random cross-linked structures of the X-OPZs obtained by this standard method result in noncrystalline materials of relatively low specific surface area (360 m2 g21). Most of the X-OPZ materials exhibit intrinsic fluorescence and high photobleaching resistance originating from the aromatic π-conjugated system and the highly cross-linked structure, respectively. Moreover, the adjacent functional groups, such as OH, NH2, COOH, and CF3, furnish OPZs with additional physicochemical properties. A common characteristic between the OBBs 2. Smart inorganic polymers

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(including the nonaromatic Cyclen and PEI) shown in Table 2.1 is their rigid structure, which is an essential precondition for the realization of nucleation and growth of spherical particles. Less rigid cross-linkers usually result in amorphous and gel-like raw materials.89,90 The rigid crosslinked structure of X-OPZs allows their transformation into high surface area microporous carbon materials after a pyrolysis (carbonization) process at temperatures above 550 C.9194 Most importantly, the rich chemical composition of the X-OPZ becomes the source for the heteroatom doping of the carbon structure. It is known that the presence of heteroatoms, such as N, O, S, B, or P, induces changes in the electronic, chemical, and textural properties of the carbon materials. The potential advantage of X-OPZs relies on the direct multi heteroatom doping of the carbon while other methods are limited to only a few heteroatoms and/or require a costly postcarbonization doping process. Especially, the postdoping of carbons with heteroatoms of large atomic radius, such as P, is difficult and insufficient. 2.4.1.2 In situ self-templating in X-OPZs An interesting feature of this synthetic method is the morphological diversity available without the need for external morphology directing agents (MDAs, e.g., inorganic or polymer templates and surfactants) by simply controlling the solubility factors of the reaction species. Specifically, self-templated X-OPZ nanotubes are obtained from the reaction of HCCP and BPS in the presence of Et3N in tetrahydrofuran (THF).65 This phenomenon relies on the in situ formation of needlelike nanocrystals of Et3N HCl, which are insoluble in THF. As the reaction between HCCP and BPS proceeds, oligomers and nuclei are continuously absorbed on the surface of Et3N HCl nanocrystals where the growth takes place. Initially, X-OPZ nanofibers with trapped Et3N HCl salt are formed and subsequent washing with water results in the nanotube structure, as shown in Fig. 2.19.







FIGURE 2.19 In situ self-templating template method for the synthesis of the X-OPS nanotubes in THF. Source: Reproduced with permission from Zhu, L.; Xu, Y.; Yuan, W.; Xi, J.; Huang, X.; Tang, X.; Zheng, S. One-Pot Synthesis of Poly(cyclotriphosphazene-co-4,40 -sulfonyldiphenol) Nanotubes via an In Situ Template Approach. Adv. Mater. 2006, 18, 29973000. Copyright (2006) Wiley-VCH.

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There are cases where the intermolecular interactions of the reactants themselves form templates in situ. In particular, X-OPZ hollow nanospheres are formed in MeCN when the multifunctional tetrakis(4-hydroxyphenyl) porphyrin ((TPP-OH)4) is used as the OBB. The ππ interactions between the aromatic groups of (TPP-OH)4 promote the formation of templates, which is also by hydrogen bonding with the Et3N, while the subsequent addition of HCCP results in the formation of the usual cross-linked OPZ structure. Here, the (TPP-OH)4 serves both as a sacrificial template and OBB. Noticeably, dense spheres are obtained in acetone under the same synthetic conditions, highlighting the importance of solvent polarity and solubility parameters. Based on a similar in situ self-templated mechanism, melamine-based X-OPZ nanotubes can be prepared in pyridine.72 In this case, melamine nanocrystals are formed in pyridine at 0 C, driven by the same interactions as earlier. By adding HCCP to the mixture and gradually increasing the temperature, the nucleophilic substitution reaction and dissolution of the melamine nanocrystals take place simultaneously. Here, melamine served both as sacrificial MDA and OBB while pyridine served as both solvent and organic base. The morphological diversity between tubular and spherical X-OPZs can also be observed in mixtures of acetone/toluene taking into account the Hildebrand solubility parameter of the oligomeric species and capacity of the mixed solvents to solvate the Et3N HCl salt.95 It is noteworthy to mention that the final hollow X-OPZ products are free from the template or organic base salt since a washing step with water, methanol, or acetone efficiently removes the templates.



2.4.1.3 Self-assembly of organocyclophosphazene into cyclomatrix X-OPZ materials The self-assembly of presynthesized organocyclophosphazene (OCPZ) molecules (precursors) into dimensionally stable materials is an alternative approach that enriches the library of X-OPZs structures. The driving force behind the self-assembly of O-CPZs is based again on the solubility factors of mixed solvent systems. For example, the soluble oxazodiazol-based O-CPZs precursors form nanobelts and flowerlike structures in a solvent exchange from chloroform to ethanol. These interesting morphologies are mainly attributed to the ππ interaction of the aromatic units and the molecular conformations of the chemical structures.96,97 Interestingly, the oxadiazol-based X-OPZs show crystallinity, unlike the traditional amorphous X-OPZs obtained by the direct multisite substitution reaction described earlier. The cross-linking of the building blocks, and thus the preservation of the structure, can be achieved by (1) an intermolecular photochemical [2 1 2] cycloaddition reaction,96 (2) a nucleophilic reaction with additional HCCP monomers,98 and (3) a nucleophilic reaction on the unreacted PCl groups of

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the O-CPZ precursors.99 Additionally, weak intermolecular interactions between the O-CPZ molecules can also preserve the morphology of selfassembled X-OPZs.92 The self-assembly approach also enabled the preparation of X-OPZs from nonaromatic OBBs such as the amino acid derivative L-cystine, opening up their suitability for bioapplications.63,100 Noncovalent organophosphazene structures can be prepared using metal ions, which promote the self-assembly of O-CPZs into coordination polymers101103 and phosphazene-based metal organic frameworks.104 The morphology of these materials is determined by the coordination preferences of the metal ions as well as the molecular conformation/geometry of the OBBs, which serve as polytopic ligands in such cases. 2.4.1.4 Cyclomatrix organophosphazene frameworks By selecting the appropriate building blocks and reaction conditions, the chemical structure of the cyclomatrix organophosphazenes is organized so as to form stable covalent frameworks. There are two strategies to prepare cyclomatrix organophosphazene frameworks (CPFs): (1) direct reaction of HCCP with OBBs under hydrothermal conditions (Fig. 2.20)82,84,105,106 and (2) synthesis of O-CPZ precursors and their subsequent cross-linking with HCCP or other OBB.107110 In contrast to the amorphous and low-surface-area X-OPZs, the CPFs show crystallinity and/or high surface areas, which mainly arise from

FIGURE 2.20 Hydrothermal synthesis of two different CPFs from bi- and trifunctional OBBs. Source: Reproduced with permission from Zhang, M.; Li, Y.; Bai, C.; Guo, X.; Han, J.; Hu, S.; Jiang, H.; Tan, W.; Li, S.; Ma, L. Synthesis of Microporous Covalent Phosphazene-Based Frameworks for Selective Separation of Uranium in Highly Acidic Media Based on Size-Matching Effect. ACS Appl. Mater. Interfaces 2018, 10, 2893628947. r (2018) American Chemical Society.

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their microporous structure. The organized and microporous structure of CPFs is favorable for gas sorption and metal-removal applications. Inevitably, the structure and the spatial arrangements of the OBBs are critical for the physicochemical properties of the hybrid organophosphazene network and the morphology of the superstructures.

2.5 (Bio)degradable poly(organo)phosphazenes Poly(organo)phosphazenes have an inherent tendency toward hydrolysis, meaning that degradable polymers can be prepared, depending on the substituents at the phosphorus center. Upon hydrolysis they degrade into phosphates and ammonium salts35 via hydroxyphosphazene and phosphazane species (Fig. 2.21),111 creating a pH-buffered solution,112

FIGURE 2.21 Proposed degradation mechanism for poly(organo)phosphazenes. Source: Reproduced with permission from Rothemund, S.; Teasdale, I. Preparation of Polyphosphazenes: A Tutorial Review. Chem. Soc. Rev. 2016, 45, 52005215. r (2016) Royal Society of Chemistry.

with the products and intermediates being physiologically benign.113 With their almost unlimited variety of substituents, introducible during the postpolymerization of the poly(dichloro)phosphazene,5 poly(organo) phosphazenes exhibit a facile tunability of degradation rates via the substitution of the phosphorus atoms, be it the type of bond, steric hindrance of the side group or the chemical functionality.111 Indeed, degradation rates can range from hundreds of years to minutes. There are a number of factors that can be used to design polyphosphazenes with the desired hydrolysis rates. First, the polyphosphazene backbone can be substituted with alkoxides or amines, whereby the resulting POR bond is hydrolytically more stable than the PNHR bond.114 The degradation rate of the polyphosphazene is also heavily influenced by the polarity of the side group, with the access of water to the backbone being facilitated by the increasing hydrophilicity of the

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substituent. There are some exceptions to this however, where a few hydrophilic substituents such as methoxyethoxyethoxy and some polyethylene glycol ethers are reported to exhibit good aqueous solubility but, more interestingly, high stability in water. This may arise from the nature of the side chains shielding the backbone or the absence of hydroxyl or carboxylic acid functional groups.111 Another possibility for tuning the degradation rates of polyphosphazenes is by utilizing bulky side groups to sterically hinder the access of water to the backbone. For example, substitution of amino acid esters with a bulky group at the α-position results in a slower hydrolysis of the resulting poly(amino acid ester)phosphazenes compared to the polyphosphazenes with unsubstituted amino acid esters.115,116 Indeed, amino acid (ethyl) esters are widely investigated substituents for the degradation tunability of polyphosphazenes, relatable to both their availability and biocompatibility.116 It must be considered that each poly(amino acid ester) phosphazene exhibits a different hydrolysis rate, where the rate is controlled by both hydrophobicity and steric hindrance, ranging from a few months for glycinate to years for valinate derivatives.111 Since the degradation behavior of amino acids has been very well investigated, they can be introduced as cosubstituents with other side groups to fine-tune the degradation rate of the resulting polymers,117 or alternatively can be incorporated as spacers between the phosphorus of the backbone and the side group (Fig. 2.22) selected to provide the

FIGURE 2.22 Introduction of amino acid spacers resulting in an increase in degradation for poly(organo)phosphazenes with n 5 50. Source: Adapted with permission from Wilfert, S.; Iturmendi, A.; Schoefberger, W.; Kryeziu, K.; Heffeter, P.; Berger, W.; Bru¨ggemann, O.; Teasdale, I. Water-Soluble, Biocompatible Polyphosphazenes with Controllable and pH-Promoted Degradation Behavior. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 287294. r (2014) John Wiley & Sons, Inc.

desired polymer characteristics, such as water solubility113 or photochemically cross-linkable polymers via allyl groups.118 The degradation behavior of various polyphosphazenes at different pH values has been tested extensively and shows a much accelerated

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rate at acidic pH in comparison with neutral pH.113,119 Although the main focus lies on the degradation behavior of polyphosphazenes in neutral and acidic environments, due to its importance for biomedical applications, the degradation behavior under basic conditions should not be disregarded. For example, investigations into poly[di(carboxylatophenoxy)phosphazene] (PCPP)120 and N-ethylpyrrolidone-containing polyphosphazenes121 show some degradation under basic conditions, but with a significant increase in degradation rate at lower pH.120,121 On the other hand, poly[bis(glycine ethyl ester)phosphazenes] are reported to show the fastest rate under basic conditions at 20 C, 37 C, and 47 C, followed by acidic conditions, with the polymer being the most stable under neutral conditions.122 This behavior is presumably due to cleavage of the ester groups under basic conditions facilitating the main-chain degradation. The hydrolysis rates and degradation behavior of materials based on the cyclic phosphazene trimer and the polymers based thereon have not been as thoroughly investigated as the poly(organo)phosphazenes stemming from poly(dichloro)phosphazenes. Although a hydrolysis pathway of cleavage of one side group followed by ring opening and subsequent disintegration to phosphates and ammonium has been shown, this process appears to be slow and hence not useful for the preparation of materials that degrade in useable timeframes.123

2.5.1 Stimuli-responsive degradation of poly(organo) phosphazenes In the prior section, degradable poly(organo)phosphazenes showing a gradual degradation over time have been presented. A limitation of these polymers is the gradual loss of molecular weight, and hence degradation of their properties and desired structure before reaching the expected or desired usage lifetime. Therefore for many applications it would be advantageous to have stable polymers that degrade only upon external stimuli. Thereby, recent studies in the area of stimuliresponsive degradation have drawn considerable attention toward the controlled degradation of poly(organo)phosphazenes. Among the possible external stimuli for the triggered degradation of poly(organo)phosphazenes, control of pH is one of the most obvious tools, especially for biomedical applications. Several studies have shown enhanced degradation kinetics of polyphosphazenes under acidic conditions compared to neutral pH values, due to protonation of the nitrogen atom in the backbone assisting the nucleophilic attack of water124 (Fig. 2.23). Numerous amino acid esterbased119 and dipeptide ethyl estersubstituted125 poly(organo)phosphazenes, for example, show

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75

Proposed degradation mechanism of poly(organo)phosphazenes in

acidic media.

faster degradation at lower pH values. These polymers are usually hydrophobic and their degradation behavior is tested in solid state,126 but their sensitivity toward hydrolysis can be exploited via mixed substitution, by introducing hydrophilic side groups to prepare watersoluble polymers. Thereby, water-soluble polyphosphazenes have been synthesized by incorporation of amino acid spacers between the polymer backbone and the hydrophilic Jeffamine M-1000 polyetheramine (amine-capped copolymer of EO/PO).113 It has been shown that these polymers degrade faster at slightly acidic pH values (pH 5) than at physiological pH (pH 7.4), while undergoing complete degradation at pH 2 in the same time frame (Fig. 2.24).

FIGURE 2.24 Release of inorganic phosphate of M-1000-based polyphosphazene with glycine amino acid spacer at pH 2, pH 5, and pH 7.4, measured by a molybdate assay by UV-Vis spectroscopy. Source: Reproduced with permission from Wilfert, S.; Iturmendi, A.; Schoefberger, W.; Kryeziu, K.; Heffeter, P.; Berger, W.; Bru¨ggemann, O.; Teasdale, I. Water-Soluble, Biocompatible Polyphosphazenes with Controllable and pH-Promoted Degradation Behavior. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 287294. r (2014) John Wiley & Sons, Inc.

Although the PO bond is hydrolytically more stable than the PN bond, there are also some polyphosphazenes containing the PO linkage that are shown to degrade, especially at lower pH values. For example, the poly(di[2(2-oxo-1-pyrrolidinyl)ethoxy]phosphazene) (PYRP), a polyphosphazene with

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N-ethylpyrrolidone groups, displays faster polymer breakdown at pH 3 than at pH 7.4 or pH 9.3.121 Poly[di(carboxylatophenoxy)phosphazene] (PCPP) also shows a pH-dependent degradation, which in this case is presumably promoted by the close proximity of acidic groups to the polymer backbone,120 in accordance with early studies into the degradation of polyaminophosphazenes.123,127 The nitrogen atom from the backbone is protonated due to the presence of acid groups close to the backbone and attack by water is then promoted, leading to cleavage of the side group (Fig. 2.25).

FIGURE 2.25 Proposed mechanism for the self-catalyzed degradation of poly(organo) phosphazenes.

In this context, enzymatically sensitive side groups have been incorporated into the polymer backbone that, after enzymatic cleavage by papain, exposes the carboxyl group promoting the backbone degradation.127 The synthesized water-soluble and biodegradable hybrid polyphosphazenes, with the hydrophilic Jeffamine M-1000 oligomer alongside the tetrapeptide Gly-Phe-Leu-Gly sequence, showed faster degradation rates in presence of the activated papain than in its absence, confirming the pathway of the enzymatic degradation. Polymers with oxidation-responsive degradation have also drawn special attention for biomedical applications due to their propensity to degrade in the presence of biological agents such as reactive oxygen species (ROS).128,129 ROS, which includes, for example, superoxide, hydrogen peroxide, and the hydroxyl radical, plays important roles in a wide range of biological functions, but causes oxidative stress when overproduced, leading to several diseases. Therefore some poly(organo) phosphazenes with controlled synthesis and adjustable properties that degrade in presence of H2O2 have been reported recently.130 In this work, the carboxylic acid from a poly(glycine)phosphazene is caged by

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a phenylboronate moiety that is oxidized to a phenol in the presence of H2O2, undergoing its self-immolation and exposing the carboxylic acid that catalyzes the polymer degradation. Gel permeation chromatography and 31P NMR analyses confirmed the selective degradation of the polymers in the presence of 10 mM aqueous solution of H2O2, while no signs of degradation were observed in the absence of H2O2. Furthermore, the exclusive H2O2-triggered degradation of the polymer due to the presence of the self-immolative moiety was confirmed when a different polymer without the phenylboronate caging group was exposed to a 10-fold more concentrated (100 mM) aqueous solution of H2O2 and showed no sign of degradation. Using light as an external stimulus to trigger chemical or physical changes in polymers has attracted increasing attention for a number of applications due to the facile spatial and temporal control over the localization of the stimulus.131 In this respect, a photocleavable coumarinyl ester moiety, which is already known to be cleaved by a two-photon near-infrared (NIR) absorption,132 has been incorporated into a poly(organo)phosphazene as a photocage of carboxylic acid groups.133 Upon irradiation under visible light, the coumarin-based photocage is cleaved, exposing the carboxylic acid of the glycine moiety on the polymer backbone and catalyzing its own degradation (Fig. 2.26). By incorporation of

FIGURE 2.26 (A) Proposed reaction scheme of the photocleavage of the coumarin moiety exposing the carboxylic acid and catalyzing its own degradation. (B) SEC analysis of the polymer in the dark and after irradiation. Source: Adapted with permission from Iturmendi, A.; Theis, S.; Maderegger, D.; Monkowius, U.; Teasdale, I. Coumarin-Caged Polyphosphazenes with a Visible-Light Driven On-Demand Degradation. Macromol. Rapid Commun. 2018, 39, 1800377. r (2018) Wiley-VCH.

different substituents alongside the coumarin-based photocage, properties such as solubility, stability, and stimulated degradation rates of the polymers were tailored. While hydrolytic stability in the dark was observed

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for both polymers within the investigated time frame, the degradation was initiated upon exposure to visible light, providing an “on-demand” degradation of the polymers. While these developments are still in their infancy, the prospect of polymer materials which can be deliberately and rapidly degraded at the end of their lifetime is highly enticing.

2.6 Water-soluble poly(organo)phosphazenes This section aims to summarize the availability of some water-soluble poly(organo)phosphazenes and their synthetic pathways.

2.6.1 Ionic poly(organo)phosphazenes Anionic poly(organo)phosphazenes are a class of water-soluble polyelectrolytes capable of association with biomacromolecules via (sodium) carboxylate groups (Fig. 2.27).

FIGURE 2.27 General chemical structure of the sodium salt of polyphosphazene polyacids. R 5 Ph (for poly[di(carboxylatophenoxy)phosphazene], PCPP), PhCH2CH2 (for poly[di(carboxylatoethylphenoxy)phosphazene], PCEP).

One of the most investigated polyelectrolytes is poly[di(carboxylatophenoxy)phosphazene] (PCPP), exploited as an immunoadjuvant to enhance the immune response to vaccine antigens.134,135 The synthesis is a multistep reaction in which the [NPCl2] unit is substituted with sodium propyl phydroxybenzoate nucleophile then subsequently deprotected under mild alkaline conditions to yield the water-soluble polyelectrolyte.136 Although the free acid is not water-soluble, the sodium salt shows outstanding solubility.137 Importantly, due to the reaction of the free carboxylic acid groups with the polymer backbone (see Section 2.5), direct substitution with the acid groups is not possible. To circumvent this issue, an alternative methodology for incorporation of carboxylic acid functionalities via thiol-ene addition has recently been described.138 Thioglycolic acid is coupled onto an allyl group via thiol-ene photochemical reaction with subsequent deprotection of the acid group with NaHCO3 to yield a water-soluble poly(organo)phosphazene (Fig. 2.28A). Moreover, new approaches have been

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FIGURE 2.28 Possible synthetic routes to water-soluble poly(organo)phosphazenes. (A) Thioglycolic acid addition via thiol-ene reaction. Sulfonated poly(organo)phosphazenes by (B) direct method and (C and D) postsubstitution methods.

developed via noncovalent methods of protection of acid groups.139 In this work, for example, sulfonation of the polyphosphazene is achieved in a single step with the hydroxybenzene sulfonic acid nucleophile, in which the sulfonic acid functionality is noncovalently protected by the hydrophobic dimethyldipalmitylammonium ion (Fig. 2.28B). After complete substitution of all chlorine atoms, the protective group can be easily removed by addition of potassium hydroxide followed by precipitation in methanol. This relatively facile approach has a significant potential compared to the previous synthetic routes in which the sulfonation of polyphosphazenes was accomplished via postsubstitution methods (Fig. 2.28C and D).140142 A large number of polyelectrolytes have been synthesized with some variations, such as fluorinated polyphosphazene polyelectrolytes with 60 mol% trifluoroethoxy groups and 40 mol% ionic carboxylic acid groups.143 The polymers show good solubility in water, even with high content of fluorinated side groups. Moreover, 3-(4-hydroxyphenyl)

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propionate groups can be also incorporated into the polymer backbone to afford poly[di(carboxylatoethylphenoxy)phosphazene] (PCEP),144 which interestingly shows improved immunoadjuvant activity compared to PCPP.145,146 Cationic polymers can be also synthesized. For example, by substitution of [NPCl2]n with 2-dimethylaminoethylamine moieties poly[(2-dimethylaminoethylamino)phosphazene] (pDMAEA-ppz) is synthesized (Fig. 2.29A).147

FIGURE 2.29 Chemical structures of some cationic poly(organo)phosphazenes. (A) Poly[(2-dimethylaminoethylamino)phosphazene] (pDMAEA-ppz), (B) quaternized pDMAEA-ppz with allyl bromide, and (C) quaternized poly[(3-dimethylaminopropylamino)thionylphosphazene].

Although previous studies reported unsuccessful attempts to synthesize pDMAEA-ppz,148 Luten et al. noted the importance of long reaction times (6 days at room temperature). This polymer contains free tertiary amines that are positively charged at physiological pH. Additionally, by quaternization of the tertiary amine with allyl bromide, for example, the cationic polymer is obtained (Fig. 2.29B), which allows further reactions such as cross-linking to obtain different hydrogels (see Section 2.7).149 In another study, cationic polythionylphosphazenes, obtained from the ROP of the cyclic thionylphosphazene followed by substitution reactions with 3(dimethylamino)propylamine, have been synthesized.6 The free dimethylamino groups were quaternized in presence of dimethyl sulfate and diisopropylethylamine in methanol at room temperature (Fig. 2.29C).

2.6.2 Noncharged poly(organo)phosphazenes Poly[bis(2-(2-methoxyethoxy)ethoxy)phosphazene] was one of the first water-soluble and stable polyphosphazenes synthesized by Allcock and coworkers150 and used as a solid polymer electrolyte.150152 Henceforth a

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wide range of water-soluble and stable polyphosphazenes with commercially available poly(ethylene glycols) (PEGs) have been also reported.153 For applications requiring degradability, hydrolytically more sensitive polymers have been synthesized by grafting commercially available Jeffamine M-1000 (Fig. 2.30A).113 As previously mentioned in Section 2.3,

FIGURE 2.30 Chemical structures of some noncharged and water-soluble poly(organo) phosphazenes. (A) Jeffamine M-1000-substituted polyphosphazene. (B) Poly(di[2-(2-oxo-1pyrrolidinyl)ethoxy]phosphazene) (PYRP).

dendritic polyols have been recently synthesized,35 opening the opportunity to prepare readily hydroxyl-functionalized poly(organo)phosphazenes, thus avoiding the tedious protection and deprotection reactions required for polyphosphazenes bearing glyceryl moieties.154 Another important water-soluble polyphosphazene is PYRP (Fig. 2.30B), synthesized by Andrianov and coworkers121 to mimic the well-known and established polyvinylpyrrolidone. In this manner, the properties of the N-ethylpyrrolidone substituent such as water solubility and its suitability in medical applications are combined with the inherent degradability of the polymer backbone. This has been exploited, for example, in the solubilization of pharmaceutical agents.155 Another alternative route to water-soluble poly(organo)phosphazenes is provided by mixed substitution, in which hydrophobic side groups are combined with hydrophilic substituents.127,130,156 For example, by incorporation of hydrophilic sugars and hydrophobic alkanes, amphiphilic poly (organo)phosphazenes can be prepared, in which hydrophobic moieties can agglomerate in a micellar-like structure.157,158 A further example includes substitution of an enzymatically degradable peptide sequence in combination with the hydrophilic Jeffamine M-1000 oligomer, whereby an

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intra- and intermolecular self-assembly of the polymer was observed (Fig. 2.31), as confirmed by DLS measurements.127 Furthermore, upon con-

FIGURE 2.31 Schematic illustration of micellar-like structure formation of amphiphilic poly(organo)phosphazenes. Source: Adapted with permission from Linhardt, A.; Ko¨nig, M.; Scho¨fberger, W.; Bru¨ggemann, O.; Andrianov, A.; Teasdale, I. Biodegradable Polyphosphazene Based Peptide-Polymer Hybrids. Polymers 2016, 8, 161.

jugation of hydrophobic drugs (via covalent bonds), increasing the hydrophobicity of the polymer, the self-assembly of the polymers is enhanced.127,159 Additionally, due to the formation of such micellar structures, hydrophobic drugs such as doxorubicin can be also physically loaded in the core of the micelle.160,161 Another distinguished characteristic of some amphiphilic polymers is their capability to undergo phase transitions upon temperature changes. This variety of polymers is commonly known as thermoresponsive or thermosensitive polymers. As a result of a phase transition above certain temperatures in which the polymer becomes insoluble, these polymers are considered to have a lower critical solution temperature (LCST). Polymers that exhibit an LCST are completely soluble in water at temperatures below the LCST, but their solubility decreases above the LCST, driving the solution to a precipitation or gelation due to a collapse of the polymer chains. Among all synthesized thermoresponsive poly(organo)phosphazenes, mixed substituted polymers are the most studied polyphosphazenes. Polyphosphazenes with hydrophilic methoxy-poly(ethylene glycol) (MPEG) side groups in combination with hydrophobic amino acid ester moieties represent a few of these polymers.156,162164 In these cases, the LCST is affected not only by the different ratio of hydrophilic to hydrophobic substituents, but also the type of salt, the structures of the amino acids, and the pH of the surrounding environment.156 The LCST can be changed sharply in acidic solutions (pH , 4) (Fig. 2.32), in the presence mostly of inorganic salts, and by increasing the amount or composition of the hydrophobic group. Moreover, by addition of organic solvents into the aqueous phase the effect of the LCST can be modified, in which hydrophilic

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FIGURE 2.32 Influence of the pH on the LCST of polymers (a) and (b). Source: Adapted with permission from Lee, S.B.; Song, S.C.; Jin, J.I.; Sohn, Y.S. A New Class of Biodegradable Thermosensitive Polymers. 2. Hydrolytic Properties and Salt Effect on the Lower Critical Solution Temperature of Poly(Organophosphazenes) with Methoxypoly(Ethylene Glycol) and Amino Acid Esters as Side Groups. Macromolecules 1999, 32, 78207827. Copyright (1999) American Chemical Society.

solvents such as alcohols and amines with short chains increase the LCST.165 In a similar manner, thermoresponsive poly(organo)phosphazenes with amino-methoxy-PEG substituents alongside amino acid ester groups have been also synthesized.166,167 Moreover, thermoresponsive poly (organo)phosphazenes grafted with N-isopropylacrylamide and ethyl glycinate as side groups have also been reported with an LCST around 30 C in aqueous solution.168,169 Polymers with an LCST in this region are particularly interesting for biological applications. Interestingly, simple mono-substituted poly(organo)phosphazenes with side groups that present amphiphilic-like character through incorporation of different ratios of propylene oxide (PO) to ethylene oxide (EO) also have an LCST (around 18 C).170 In a similar manner, poly [(alkyl ether)phosphazenes] also shows an LCST (around 80 C),171 while polymers with branched alkyl ether side groups have lower LCST values (in the range of 38 C65 C).153 Here, a trend was observed, in which an LCST decrease was related to both a decrease in the length of the branched alkyl ether side groups and an increase of the ionic strength of the NaCl solutions.

2.7 Soft materials 2.7.1 Hydrogels Hydrogels are cross-linked hydrophilic polymers with the ability to absorb water or other aqueous media.172 One way to achieve this is through physical cross-linking, hence polymers demonstrating an LCST can assemble to physically cross-linked gels.173 Poly(organo)phosphazenes have been thoroughly investigated by the group of Song for their

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gel-forming thermoresponsive behavior, especially in regard to their application as degradable injectable drug delivery systems.162,166,167 Poly(organo)phosphazenes, cosubstituted with amino acid esters and PEG, have been investigated and have shown an increase in LCST, the temperature at which the gel is formed, which is shown to be correlated to an increase in hydrophilicity of the polymer. Slight variations of the side groups, such as increasing the length of the MPEG chain or choosing different amino acids and their corresponding esters, result in different LCST values, and therefore a tunability of the LCST by choice of polymer design, with polymer concentration being insignificant within the range of 3-30 wt.% in aqueous solution.162 A more detailed investigation into this type of polymer, with different chain lengths of aminofunctionalized PEG as the hydrophilic and L-isoleucine ethyl ester as the hydrophobic side group, shows a reversible solgel behavior, with the solution turning into a transparent gel, followed by an opaque gel and finally into a turbid suspension with increasing temperature (Fig. 2.33).167 Introducing carboxylic acid moieties to these polymers as

FIGURE 2.33 Solgel transitions of a thermoresponsive poly(organo)phosphazene featuring PEG and amino acid ester substituents. Source: Reproduced with permission from Lee, B.H.; Song, S.-C. Synthesis and Characterization of Biodegradable Thermosensitive Poly(organophosphazene) Gels. Macromolecules 2004, 37, 45334537. Copyright (2004) American Chemical Society.

a third substituent type gives access to not only an amphiphilic, but also a poly(organo)phosphazene capable of ionic interactions for creating dual-interacting polymer nanoparticles, which can form hydrogels upon increased temperature. These ionic interactions are used to load

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bone morphogenetic protein-2 (BMP-2) onto the nanoparticles and create a sustained release system, which has been evaluated both in vitro and in vivo and has shown a prolonged release of BMP-2 using hydrogels formed with these dual-interacting nanoparticles compared to nonionic charged polymeric nanoparticles.174 In a similar vein, PEG-substituted polyphosphazenes, with glycine ethyl ester as cosubstituent and hydrolysis site, have been synthesized and cross-linked via α-cyclodextrin units creating supramolecularstructured injectable hydrogels, where the cyclodextrin and some PEG chains form physical cross-links, leaving the remaining PEG chains as the hydrophilic segment. Again, chain lengths, ratios of the substituents, and concentration of the polymer play an important role for the gelation time and hydrogel characteristics, with in vitro studies showing improved characteristics, such as stability and release of bioactive compounds, for longer PEG chains.175 Similarly, poly(ethylamino)phosphazenes can be used as thermoresponsive gels by changing the balance of the hydrophobic and hydrophilic characteristics of the polymer via addition of salts of different carboxylic acids in aqueous solution.176 While thermoresponsive gels rely on physical cross-linking, most hydrogels are connected via chemical cross-linking, achieved by either UV or γ-ray irradiation, to improve the mechanical properties of the gels.173 Introducing a photo-cross-linkable moiety, such as methacrylate, as a cosubstituent of the polymer chains of a thermoresponsive hydrogel results in dual cross-linked systems with improved mechanical properties, tunable by the ratio of the substituents (Fig. 2.34).177 Due to technical challenges surrounding UV irradiation of polymers after injection into biological tissue, a new approach was developed. Here, the polymers are pretreated with UV light prior to injection, with chemical cross-links not yet formed at room temperature. When injected into the body, the thermoresponsive hydrophilic/hydrophobic interactions form a gel which, after incubation, exhibits improved properties due to the delayed chemical cross-linking of the UV-activated methacrylate functionalities.178 Thiol-ene chemistry can also be employed for photochemical crosslinking. Here, allyl functionalities can be introduced during macromolecular substitution of the poly(dichloro)phosphazene118 or via modification of the poly(organo)phosphazene.149 For this, poly(2-dimethylaminoethylamine)phosphazenes are reacted with allyl bromide via a quaternization process yielding allyl-functionalized polyphosphazenes. Subsequent UV irradiation with PEG-dithiol gives cross-linked hydrogels with pores, with an increase in cross-linker content resulting in increased mechanical strength, but a decrease in pore size. These ionic polymeric hydrogels have been investigated for their reversible enzyme binding properties.149 Variation of chain length and architecture of the cross-linkers from dithiols

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FIGURE 2.34 Photographic (A) and schematic (B) representation of the formation of dual cross-linked hydrogels. Polymer solution at room temperature (a) forming a hydrogel at body temperature (b) resulting in a compact hydrogel when exposed to UV radiation (c). Source: Reproduced with permission from Potta, T.; Chun, C.; Song, S.-C. Dual Cross-Linking Systems of Functionally Photo-Cross-Linkable and Thermoresponsive Polyphosphazene Hydrogels for Biomedical Applications. Biomacromolecules 2010, 11, 17411753. Copyright (2010) American Chemical Society.

to star-shaped multithiols affect the morphology of the resulting hydrogels, providing tunability of the gel characteristics, such as swelling, mechanical properties, pore size, and even degradation rates.179 Poly[di(carboxylatophenoxy)phosphazene] (PCPP) can be employed as an anionic polymer to give access to gel matrices via the addition of divalent cations rendering encapsulation of cells a possibility.180 These ionic hydrogels have been investigated with Ca21 and Cu21 as well as trivalent cations such as Al31 and exhibit stability under acidic and neutral conditions. The ionic bonds can, however, be cleaved and the

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polymer was shown to dissolve in basic solutions of monovalent cations and, in the case of potassium ions, even at neutral pH.137

2.7.2 Elastomers Elastomeric materials require polymer chains to exhibit a high degree of flexibility, stemming from long chains, flexible backbones, and a lack of crystallinity in order to be capable of reorientation during impact or stress. They also require a low degree of cross-linking to keep the polymer chains organized, and prevent a lasting change of shape. The obvious similarity of polyphosphazenes to traditional polysiloxane-based elastomers (silicone rubber) renders them strong candidates for the preparation of elastomers. Investigations into poly(organo)phosphazenes have been carried out for their use as elastomeric materials, and these materials can be divided into halogen-containing and halogen-free elastomers.25,172 Nonelastomeric poly(trifluoroethoxy)polyphosphazenes have been thoroughly investigated by Allcock and coworkers.172 The change in side group composition to two different fluoroalkoxy moieties yields an overall change in characteristics for the polymeric material, with the loss of crystallinity due to the removal of the molecular symmetry (Fig. 2.35).172,181 The

FIGURE 2.35 Nonelastomeric poly(trifluoroethoxy)polyphosphazene (A), elastomeric poly(fluoroalkoxy)polyphosphazenes (B and C).172

limit of length of the fluoroalkoxy side groups has been investigated with a mixed substitution of trifluoroethoxy groups and substituents with fluoroalkoxy chain lengths of 8 and 10, respectively. Due to the limited solubility and low reactivity of the long-chain fluoroalkoxy substituents, they comprise only 15% of the polymer substituents. This results in amorphous materials with accompanying elasticity at low temperatures, but their elasticity is also hindered by backbone cleavage as a result of an excess of sodium trifluoroethoxide required during synthesis.182 An additional improvement in elastomeric properties is achieved via free-radical crosslinking of a third substituent bearing a small concentration of unsaturated organic moieties. The particular characteristics of these polyphosphazene elastomeric materials include impact dampening, hydrocarbon resistance, and flexibility at low concentrations. These materials are also more durable than most organic elastomers when exposed to radiation from high energy to UV due to the transparency of the inorganic backbone from NIR to

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middle UV wavelengths.172 Cross-linkable substituents, such as dimethacrylate glycol esters, have been used in dental applications as denture liners.183 Here, the poly(fluoroalkoxy)phosphazene is combined with an alkyl methacrylate to increase the hardness of the material as well as the binding strength to other materials needed for these applications. The most advantageous property of this material is the curability below 100 C, and the relative simplicity of the procedure, which also eliminates the need for bonding agents with potential adverse reactions.183 An increase in flexibility of the polyphosphazene material, important for elastomeric behavior, can be achieved by introducing nonfluorinated groups randomly distributed alongside the fluoroalkoxy units.111 Alkylsilyl moieties are introduced via functionalization of a poly(organo)phosphazene bearing phenyl and fluoro substituents (Fig. 2.36).

FIGURE 2.36

Alternative synthetic route to mixed substituted, halogen-containing

elastomers.184

Subsequent partial reaction with trifluoroethanolate yields materials with the ability to cross-link via the alkylsilyl groups at temperatures above 200 C.184 With the introduction of aryloxy groups (here oligo-pphenyleneoxy) as cosubstituents, the mechanical properties and polymer morphology can be drastically altered, particularly if the aryloxy substituents are longer than the trifluoroethoxy groups, such that they protrude from the system and are accessible for aryl cross-coupling, which turns the previously thermoplastic material into an amorphous elastomeric material.185 The incorporation of differently substituted cyclotriphosphazenes186,187 and cyclotetraphosphazenes,188 [NPR2]3 and [NPR2]4, respectively, for noncovalent cross-linking of the polymer chains (so-called interdigitation) also enhances the elastomeric properties of the poly(fluoroalkoxy)phosphazene material (Fig. 2.37). A decrease in elastomeric properties, and a more leathery appearance, can be achieved with chloroalkoxy substituents, preferably cosubstituted with fluoroalkoxy groups. While the size of the chlorinated substituents reduces the mobility of the polymer chains, it increases the resistance of the materials to combustion.172 Nonhalogen-bearing elastomers can be prepared via substitution with nonhalogenated alkoxy side groups, and even poly(organo)phosphazenes containing only a single substituent type are capable of exhibiting elastomeric characteristics due to their lack of tendency toward crystallization.189

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FIGURE 2.37 Schematic representation of the interaction of cyclotriphosphazene groups on a trifluoroethoxy cosubstituted polyphosphazene. Source: Adapted with permission from Modzelewski, T.; Allcock, H.R. An Unusual Polymer Architecture for the Generation of Elastomeric Properties in Fluorinated Polyphosphazenes. Macromolecules 2014, 47, 67766782. Copyright (2014) American Chemical Society.

With increasing lengths of alkoxy chains, these poly(alkoxy)phosphazenes exhibit glass transition temperatures in the range of 2 65 C to 2 105 C, very low for polymers of any type. Cosubstitution of these alkoxy groups with methoxyethoxyethoxy substituents yields gums,189 which can be crosslinked via UV or γ-ray irradiation resulting in elastomers, like their fluoroalkoxy counterparts.172 Poly(aryloxy)phosphazenes have also been investigated as elastomeric materials, but exhibit glass transition temperatures near room temperature.172 Block and graft copolymers also play an important role in preparing elastomeric materials. Specifically, di- or triblock polymers are synthesized utilizing the flexibility of the polyphosphazene chain and combining it with either a flexible polysiloxane, a rather stiff organic polymer, or a second polyphosphazene block containing bulky substituents to increase the stiffness of this block, resulting in stronger and more impact-resistant materials compared to their nonblock copolymer counterparts.172 The synthesis of polyphosphazene-b-polyorganosiloxane block copolymers190 combining two well-studied inorganicorganic elastomers172 is described earlier in Section 2.3. Here, the properties of these materials can be tuned by variation of the molecular weight of the polyphosphazene block, with increasing molecular weight changing the physical character of the products from adhesive gums to crystalline solids.47,190

2.8 Conclusions and outlook The current state-of-the-art of the synthetic chemistry of polyphosphazenes has been detailed, describing the structureproperty relationships of these highly interesting inorganic polymers. Their multifaceted chemistry leads to a host of unique, interesting, and tailorable properties. Although only alluded to in this chapter, this versatile

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bottom-up chemistry clearly results in the capacity for a wide range of contemporary and potential applications, many of which are currently under investigation in academic and industrial laboratories around the world. In order to prepare valuable materials for the modern market, it is essential that the fundamental synthetic chemistry behind their preparation is well understood, reproducible, and scalable. It would appear that polyphosphazenes, after many years of endeavor, are slowly reaching this level of maturity. As shown in this chapter, the basic methods of synthesis are relatively well established, at least on the laboratory scale, facilitating preparation of a range of polyphosphazene-based materials. Furthermore, in recent years, more controlled polymerization routes have been established allowing for the synthesis of the next generation of materials with better defined structures and more complex macromolecular architectures. While there are already some commercial applications of polyphosphazene-based materials, this remains relatively modest in volume considering their rich history and potential. One of the major reasons for this is the continuing need for reproducible and reliable methods of synthesis. The advancements of recent years, as described in this chapter, could prove vital in this regard. While for reasons of cost, mass production in the spirit of vinyl polymers remains implausible, their synthetic versatility makes polyphosphazenes ideally suited for niche markets and for highly demanding applications such as biomedical materials. A particularly attractive feature, especially in the current climate in which the poor degradability of most organic polymers has become a major issue, is the hydrolytic degradability of many polyphosphazenes. Of particular significance is the wide range of degradation rates available in direct combination with the versatile materials properties. Indeed, this wide range of properties cannot be matched by biopolymers or by currently available degradable synthetic polymers, such as polyesters. Overall, this positions polyphosphazenes as not only highly interesting synthetic materials but also potentially extremely useful and valuable commercial commodities.

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157. Chen, C.; Qian, Y.-C.; Sun, C.-b; Huang, X.-J. Self-Assembly and Morphological Transitions of Random Amphiphilic Poly([small beta]-d-glucose-co-1-octyl) phosphazenes. Soft Matter 2015, 11, 62666274. 158. Chen, C.; Huang, X.-J.; Liu, Y.; Qian, Y.-C.; Xu, Z.-K. Synthesis and Self-Assembly of Amphiphilic Polyphosphazene with Controllable Composition via Two Step Thiolene Click Reaction. Polymer 2014, 55, 833839. 159. Aichhorn, S.; Linhardt, A.; Halfmann, A.; Nadlinger, M.; Kirchberger, S.; Stadler, M.; Dillinger, B.; Distel, M.; Dohnal, A.; Teasdale, I.; Scho¨fberger, W. A pH-sensitive Macromolecular Prodrug as TLR7/8 Targeting Immune Response Modifier. Chem. Eur. J. 2017, 23, 1772117726. 160. Qiu, L. Y.; Wu, X. L.; Jin, Y. Doxorubicin-Loaded Polymeric Micelles Based on Amphiphilic Polyphosphazenes with Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) and Ethyl Glycinate as Side Groups: Synthesis, Preparation and In Vitro Evaluation. Pharm. Res. 2009, 26, 946957. 161. Xu, J.; Zhao, Q.; Jin, Y.; Qiu, L. High Loading of Hydrophilic/Hydrophobic Doxorubicin into Polyphosphazene Polymersome for Breast Cancer Therapy. Nanomedicine 2014, 10, 349358. 162. Song, S.-C.; Lee, S. B.; Jin, J.-I.; Sohn, Y. S. A New Class of Biodegradable Thermosensitive Polymers. I. Synthesis and Characterization of Poly(organophosphazenes) with Methoxy-Poly(ethylene glycol) and Amino Acid Esters as Side Groups. Macromolecules 1999, 32, 21882193. 163. Lee, S. B.; Song, S. C.; Jin, J. I.; Sohn, Y. S. Surfactant Effect on the Lower Critical Solution Temperature of Poly(organophosphazenes) with Methoxy-poly(ethylene glycol) and Amino Acid Esters as Side Groups. Colloid Polym. Sci. 2000, 278, 10971102. 164. Lee, B. H.; Lee, Y. M.; Sohn, Y. S.; Song, S. C. Thermosensitive and HydrolysisSensitive Poly(organophosphazenes). Polym. Int. 2002, 51, 658660. 165. Lee, S. B.; Song, S. C.; Jin, J. I.; Sohn, Y. S. Solvent Effect on the Lower Critical Solution Temperature of Biodegradable Thermosensitive Poly(organophosphazenes). Polym. Bull. 2000, 45, 389396. 166. Lee, B. H.; Song, S.-C. Synthesis and Characterization of Biodegradable Thermosensitive Poly(organophosphazene) Gels. Macromolecules 2004, 37, 45334537. 167. Lee, B. H.; Lee, Y. M.; Sohn, Y. S.; Song, S.-C. A Thermosensitive Poly(organophosphazene) Gel. Macromolecules 2002, 35, 38763879. 168. Zhang, J. X.; Qiu, L. Y.; Jin, Y.; Zhu, K. J. Thermally Responsive Polymeric Micelles Self-Assembled by Amphiphilic Polyphosphazene with Poly(N-isopropylacrylamide) and Ethyl Glycinate as Side Groups: Polymer Synthesis, Characterization, and In Vitro Drug Release Study. J. Biomed. Mater. Res. Part A 2006, 76, 773780. 169. Zhang, J. X.; Qiu, L. Y.; Zhu, K. J.; Jin, Y. Thermosensitive Micelles Self-Assembled by Novel N-Isopropylacrylamide Oligomer Grafted Polyphosphazene. Macromol. Rapid Commun. 2004, 25, 15631567. 170. Wilfert, S.; Iturmendi, A.; Henke, H.; Bru¨ggemann, O.; Teasdale, I. Thermoresponsive Polyphosphazene-Based Molecular Brushes by Living Cationic Polymerization. Macromol. Symp. 2014, 337, 116123. 171. Allcock, H. R.; Pucher, S. R.; Turner, M. L.; Fitzpatrick, R. J. Poly(organophosphazenes) with Poly(alkyl ether) Side Groups: A Study of Their Water Solubility and the Swelling Characteristics of Their Hydrogels. Macromolecules 1992, 25, 55735577. 172. Allcock, H. R. Polyphosphazene Elastomers, Gels, and Other Soft Materials. Soft Matter 2012, 8, 75217532. 173 Iturmendi, A.; Teasdale, I. Water Soluble (Bio)degradable Poly(organo)phosphazenes. Polyphosphazenes in Biomedicine, Engineering, and Pioneering Synthesis, Vol. 1298. American Chemical Society: Washington, DC, 2018, 183209.

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174. Seo, B.-B.; Choi, H.; Koh, J.-T.; Song, S.-C. Sustained BMP-2 Delivery and Injectable Bone Regeneration Using Thermosensitive Polymeric Nanoparticle Hydrogel Bearing Dual Interactions with BMP-2. J. Controlled Release 2015, 209, 6776. 175. Tian, Z.; Chen, C.; Allcock, H. R. Injectable and Biodegradable Supramolecular Hydrogels by Inclusion Complexation between Poly(organophosphazenes) and α-Cyclodextrin. Macromolecules 2013, 46, 27152724. 176. Burova, T. V.; Grinberg, V. Y.; Grinberg, N. V.; Dubovik, A. S.; Moskalets, A. P.; Papkov, V. S.; Khokhlov, A. R. Salt-Induced Thermoresponsivity of a Cationic Phosphazene Polymer in Aqueous Solutions. Macromolecules 2018, 51, 79647973. 177. Potta, T.; Chun, C.; Song, S.-C. Dual Cross-Linking Systems of Functionally PhotoCross-Linkable and Thermoresponsive Polyphosphazene Hydrogels for Biomedical Applications. Biomacromolecules 2010, 11, 17411753. 178. Kim, Y.-M.; Potta, T.; Park, K.-H.; Song, S.-C. Temperature Responsive Chemical Crosslinkable UV Pretreated Hydrogel for Application to Injectable Tissue Regeneration System via Differentiations of Encapsulated hMSCs. Biomaterials 2017, 112, 248256. 179. Potta, T.; Chun, C.; Song, S.-C. Design of Polyphosphazene Hydrogels with Improved Structural Properties by Use of Star-Shaped Multithiol Crosslinkers. Macromol. Biosci. 2011, 11, 689699. 180. Cohen, S.; Bano, M. C.; Visscher, K. B.; Chow, M.; Allcock, H. R.; Langer, R. Ionically Crosslinkable Polyphosphazene: A Novel Polymer for Microencapsulation. J. Am. Chem. Soc. 1990, 112, 78327833. 181. Rose, S. H. Synthesis of Phosphonitrilic Fluoroelastomers. J. Polym. Sci., Part B: Polym. Lett. 1968, 6, 837839. 182. Tian, Z.; Liu, X.; Manseri, A.; Ameduri, B.; Allcock, H. R. Limits to Expanding the PN-F Series of Polyphosphazene Elastomers. Polym. Eng. Sci. 2014, 54, 18271832. 183. Gettleman, L.; Farris, C.L.; Rawls, H.R.; LeBouef, R.J., Jr. Soft and Firm Denture Liner for a Composite Denture and Method for Fabricating. US4432730A, 1984. 184. Allcock, H. R.; Coggio, W. D. Synthesis and Properties of High Polymeric Phosphazenes with (Trimethylsilyl)methyl Side Groups. Macromolecules 1993, 26, 764771. 185. Modzelewski, T.; Wonderling, N. M.; Allcock, H. R. Polyphosphazene Elastomers Containing Interdigitated Oligo-p-phenyleneoxy Side Groups: Synthesis, Mechanical Properties, and X-ray Scattering Studies. Macromolecules 2015, 48, 48824890. 186. Modzelewski, T.; Allcock, H. R. An Unusual Polymer Architecture for the Generation of Elastomeric Properties in Fluorinated Polyphosphazenes. Macromolecules 2014, 47, 67766782. 187. Modzelewski, T.; Wilts, E.; Allcock, H. R. Elastomeric Polyphosphazenes with PhenoxyCyclotriphosphazene Side Groups. Macromolecules 2015, 48, 75437549. 188. Li, Z.; Chen, C.; Tian, Z.; Modzelewski, T.; Allcock, H. R. Polyphosphazenes with Cyclotetraphosphazene Side Groups: Synthesis and Elastomeric Properties. J. Inorg. Organomet. Polym. Mater. 2016, 26, 667674. 189. Weikel, A. L.; Lee, D. K.; Krogman, N. R.; Allcock, H. R. Phase Changes of Poly (alkoxyphosphazenes), and Their Behavior in the Presence of Oligoisobutylene. Polym. Eng. Sci. 2011, 51, 16931700. 190. Prange, R.; Allcock, H. R. Telechelic Syntheses of the First Phosphazene Siloxane Block Copolymers. Macromolecules 1999, 32, 63906392.

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S E C T I O N

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Inorganic chemistry in ionic liquids

C H A P T E R

3 Application of ionic liquids in inorganic synthesis Di Li1 and Wenjun Zheng2,3 1

Institute for Energy Research, Jiangsu University, Zhenjiang, P.R. China, Department of Chemistry, Key Laboratory of Advanced Energy Materials Chemistry (MOE), TKL of Metal and Molecule-Based Material Chemistry, College of Chemistry, Nankai University, Tianjin, P.R. China, 3 Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin, P.R. China 2

3.1 Introduction As an important area of synthetic chemistry, inorganic synthesis incorporating new materials fabrication methods has gradually become a crucial branch of inorganic chemistry. In recent years, the rapid expansion of emerging sciences and technologies has presented urgent demands for the development of new inorganic materials, with the result that inorganic synthesis is attracting increasing attention in related disciplines. This development of synthetic inorganic chemistry has led to new synthetic routes involving special techniques, as well as theoretical structural investigations, and has expanded conventional methods of synthesis into a more comprehensive discipline.1 The introduction of new materials, especially new solvents and regulating agents, has been important in realizing the production of high-performance materials for use in energy storage and conversion, catalysis, sensing, water remediation, and biomedicine. As an important category of compounds, ionic liquids (ILs) have found extensive use and show promise in a variety of (physical and mechanistic) roles in inorganic synthesis.2,3

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The first IL, [C2H5NH3][NO3], was prepared by Walden in 1914 via neutralization of ethylamine with concentrated HNO3.4 In comparison with traditional solvents, ILs exhibit many significant advantages in inorganic synthesis: (1) they are good solvents for a great variety of inorganic materials, and can bring unusual combinations of reagents into the same phase; (2) they are easy to prepare and are highly polar owing to their composition of poorly coordinating ions and provide a polar alternative to a two-phase system; and (3) they may be used in high-vacuum reaction processes, since they are not prone to evaporation. In addition, ILs also show good thermal stability and provide high synthetic flexibility for inorganic synthesis.5,6 The main functions of ILs used in inorganic synthesis can be ascribed to three points: template, green solvent, and precursor. 1. Template Long molecular chain ILs show lyotropic and thermotropic liquidcrystalline behavior in different solvents over a wide temperature range. For example, 1-hexadecyl-3-methyl-imidazolium chloride, [C16mim]Cl, a common long molecular chain IL, exhibits liquid-crystalline properties in water. It also displays thermotropic liquid-crystallinity from 50 C to 230 C. On the basis of these advantages, [C16mim]Cl is typically used as the template in synthesis of inorganic materials. Monolithic supermicroporous silica with lamellar order was synthesized by Zhou and coworkers by a nanocasting technique, where [C16mim]Cl was employed as a template. The as-prepared silica walls with an interlayer distance of B2.7 nm, a pore diameter of B1.3 nm, and a wall thickness of B1.4 nm were arranged in a regular parallel orientation. Furthermore, after removing the [C16mim]Cl template, the ordered lamellar nanostructure was well preserved.7 Our group prepared Ni/Ni3C core/shell hierarchical nanospheres using an in situ ILassisted one-step hydrothermal method. The IL 1-butyl-3methylimidazolium acetate, [Bmim]Ac, played crucial roles in the overall formation of the hierarchical structure. Three stages have been proposed as the possible growth mechanism of this product. First, when the [Bmim]Ac was added into the reaction system, Ni21 was transformed into elemental Ni. Then, due to the catalytic activity of small particles of elemental Ni, the [Bmim]Ac underwent partial carbonization to active carbon. Finally, under the structure-directing influence of [Bmim]Ac, the newly formed active carbon atoms migrated into the Ni nanospheres and Ni3C nanosheets were generated.8 2. All-in-one medium ILs have been considered as an “all-in-one” medium for the fabrication of inorganic materials, because they are able to simplify the reaction process and provide greater control over the phase and

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morphology of the final products. This “all-in-one” conception of ILs was first proposed and tested by Taubert and coworkers.9 Thereafter, many studies applied this strategy using various all-in-one ILs. By introducing the IL [C16mim]Cl as the “all-in-one” solvent, our group prepared a series of BiOCl nanostructures by an ionothermal synthetic method, including ultrathin nanoflakes, nanoplate arrays, and curved nanoplates.10 In this synthetic process, [C16mim]Cl acted as the reactant, solvent, soft template, and capping agent. The possible mechanism is as follows: weak interaction between [BiOCl] layers via van der Waals forces leads to loose packing along the c-axis, and the [C16mim]1 cation is therefore easily adsorbed onto the ab plane of BiOCl. Thus crystalline growth along the [001] direction of BiOCl will be inhibited and, as a result, two-dimensional (2D) BiOCl nanostructures are preferentially obtained. Guided by these strategies, we further synthesized three-dimensional (3D) hierarchical CuS microspheres by a low-temperature and facile solvothermal approach, using the copper-containing 1-butyl-3-methylimidazolium salt [Bmim]2Cu2Cl6 as the precursor.11 Due to the covalent bonds generated between the [CuS] tetrahedron layer and the [CuS] triangle layer, and the presence of van der Waals interactions between the SS layers, the crystal growth is propagated in the ab plane but not along the c-axis. Once the intermediate complex decomposed into the [CuS] nucleus, the [Bmim]1 cation is adsorbed on the (001) plane of [CuS] to decrease the surface energy, resulting from the Lewis acidity of the H atoms at the C2 position of the [Bmim]1 rings, thus inhibiting crystal growth in the c direction. In consequence, CuS nanosheets with average thickness of 1015 nm were generated. In addition, due to the influence of the alkyl chains of the ILs, the CuS nanosheets would be further assembled to 3D hierarchical CuS microspheres. 3. Precursor In addition to the above functions, ILs can also be used as the material precursor in inorganic synthesis. Not only can ILs be used as the precursor for nitrides and carbon materials, but also can be employed as the precursor for some metallic compounds or elementary substances containing Cu, Fe, Co, etc. Paraknowitsch and coworkers demonstrated that ILs featuring dicyanamide anions were crucial precursors for the fabrication of the N-doped carbon materials.12 At calcination temperatures of 900 C and 1000 C, the N content of the resulting materials were 10.518.8 wt.% and 8.910.4 wt.%, respectively. These materials exhibited graphite-like structures, with the N and C uniformly distributed throughout the products. Li et al. prepared mesoporous Fe-N-C oxygen reduction electrocatalysts using Fe-IL (ferrocene-based ionic liquid) and N-IL (nitrogen-enriched ionic liquid) as the metal-containing feedstock and

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compatible nitrogen content regulator, respectively.13 Typically, these mesoporous Fe-N-doped ordered mesoporous carbon catalysts (FeX@NOMC) were synthesized from Fe-IL or its homogeneous mixture with N-IL via a hard template route, and the N content of Fe25@NOMC prepared in this manner using pure Fe-IL was 1.4 wt.%. When the Fe-IL and N-IL were combined in 1:1 mass ratio, the N content of the Fe10@NOMC increased to 11.9 wt.%. The FeX@NOMC composites are shown to possess a mesoporous structure with high surface areas (411506 m2 g21), large pore volumes, and highly uniform pore size distribution with iron oxide nanoparticles forming a well-dispersed embedded nanophase. Li and coworkers demonstrated that both regular nanocrystals and mesocrystals can be synthesized by IL precursors.14 In this study, hollow ZnO mesocrystals possessing a high degree of order were formed from ZnO nanoparticles in the strongly hydrated IL tetrabutylammonium hydroxide (TBAH). Ding et al. anchored cobalt single sites on the surface of carbon nanotubes using a functional IL with both sulfates and vinyl groups as the ligand.15 Co species were generated by the reaction of sulfate groups in the IL precursor with CoCO3. Due to the effective adsorption of the imidazolium cation on the surface of nanocarbon, the Co species could also be homogeneously distributed on the carbon nanotubes.

3.2 Advantages and key factors of the structural regulation mechanism of ionic liquids in inorganic synthesis In comparison with conventional solvents, ILs are attractive due to physicochemical properties such as negligible vapor pressures, outstanding thermal/chemical stability, good ionic conductivity, high mobility, nonflammability, and nontoxic characteristics.7 In addition, since these physicochemical properties rely heavily on the constituents of the ILs, thus they can be easily controlled by modulating the cations and anions of the ILs.16 These tunable characteristics allow the ILs to be used in designing the specific reaction systems. Therefore ILs may be substituted for traditional solvents in inorganic synthesis.1720 In the nanomaterials synthesis processes, one of the structuredirecting effects of the ILs is understood to result from geometric matching and adsorption configuration. The geometric matching principle leads to the adsorption selectivity of ILs on the surface of nanomaterials, which is because of the different lattices of specific crystal facets. Effective geometric matching could not only satisfy the space requirement for interionic stacking of ILs, but also maximize

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the interaction between ILs and the nanomaterials. On the other hand, different adsorption configurations show different absorption energies, which determine the absorption stability of ILs on nanomaterials (Fig. 3.1). In our previous study, we found that the IL 1-ethyl-3methylimidazolium bromide, [Emim]Br, was beneficial to formation of the rodlike rutile phase TiO2 because of the π-stacking of imidazole rings. By adopting this strategy, products with different phase compositions could be controlled. Thus we further explored the properties of ILadsorbed TiO2 surface to understand the influence of IL on the shape and exposed facet of TiO2 crystals by theoretical calculations using semiempirical DFT plus dispersion correction (DFT 1 D) methods.21 We first investigated the adsorption energies and geometries of [Emim]Br on TiO2 surface in IL environment to understand the most preferred adsorption facets of TiO2. The results indicated that the rutile (110) and anatase (100) planes were more inclined to adsorb the IL. After the IL adsorption, the surface energy gap increased markedly, especially between the anatase (101) and (001) and between the rutile (110) and (001) planes. This resulted in increase in exposure of the anatase (100) facet, and an increase in the length-to-diameter ratio of the rutile nanocrystal. Therefore the equilibrium shapes of TiO2 were deduced by calculation of the surface energies and application of the Wulff construction. Our work provides a new insight for understanding the effect of

FIGURE 3.1

ILs in synthesis of 0D, 1D, 2D, and 3D inorganic materials based on the principles of geometric matching and adsorption configuration.

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geometric matching and adsorption configuration on decision of the nanomaterials’ morphologies. The interaction between ILs and a Cu substrate was investigated by Qiang et al., and they also studied the adsorption mechanism of ILs on the surface of Cu by molecular dynamics simulations.22 The experimental and calculation results indicated that the ILs could tightly adsorb on the Cu surface in parallel orientation and generate a covalent bond by not only sharing the p electron density of the imidazolium ring with Cu, but also by migration of electrons from Cu dorbitals to vacant orbitals of the imidazolium moiety. This parallel mode of interaction of the IL could effectively minimize the aggressive attack from the corrosive medium. In addition, ILs with longer alkyl chains would show higher inhibition efficiencies on the surface of copper. We also studied the IL effect model on the synthesized NH4-Dw (ammonium aluminum carbonate hydroxide) and γ-AlOOH nanostructures.23 This work confirmed that by adjusting the position of the substituents and the length of the side-chain on the imidazole ring, the interaction intensity between the IL cations and the substrate could be regulated. It also showed the geometric matching and adsorption configuration to be important in determining the morphologies of the products obtained.

3.3 Ionic liquidsassisted synthesis of nanomaterials Under the influence of both geometric matching and adsorption configuration, the ILs can regulate the morphology of the resulting inorganic materials from zero-dimensional [0D; quantum dot (QD), etc.], one-dimensional (1D; nanowire, nanorod, nanotube, etc.), twodimensional (2D; nanosheet, etc.) to three-dimensional (3D; nanosphere, hierarchical structure, etc.) (Fig. 3.2).

3.3.1 Zero-dimensional structures QDs, with discrete energy levels and modulated bandgap, are considered good candidates for use in fluorescence imaging. In previous reports, most of the semiconductor QDs were synthesized from organometallic precursors. As the surfaces of these QDs were usually capped with trioctylphosphine/trioctylphosphine oxide (TOP/TOPO) or other long-chain alkylamines that conferred poor solubility, the compatibility of the QDs should be improved by introduction of other effective preparation methods. Synthesis of QDs using an IL system could permit modulation of the surface hydrophilic or hydrophobic properties by

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FIGURE 3.2 Schematic illustration of inorganic materials with 0D, 1D, 2D, and 3D structures synthesized by solvothermal process.

appropriate selection of different ILs, and this approach has attracted significant interest. Rodrı´guez-Cabo et al. synthesized 37 nm CdS nanoparticles via a simple method.24 Typically, the mixture consisted of bulk CdS and the IL trihexyl(tetradecyl)phosphonium cation ([P66614]1), and was heated with stirring. When the mixture was allowed to cool, it was centrifuged to remove the excess bulk material. During the synthesis process, the IL played two roles, namely those of nanoparticle former and stabilizing agent. Three selenoether-functionalized ILs, including N-[(phenylseleno)methylene]pyridinium, N-(methyl)-, and N-(butyl)-N0 -[(phenylseleno)methylene] imidazolium with the bis(trifluoromethane)sulfonimide ([Tf2N]2) anion, were synthesized by Klauke and coworkers from pyridine, N-methylimidazole and N-butylimidazole with in situ obtained phenylselenomethylene chloride, PhSeCH2Cl, followed by ion exchange.25 Using these as-prepared ILs to react with zinc acetate dihydrate under microwave irradiation, ZnSe nanoparticles with an average diameter of 410 nm were formed, the sizes of the ZnSe nanoparticles being dependent on the reaction conditions. Liu et al. successfully synthesized superparamagnetic Fe3O4 nanoparticles via the hydrothermal method using the assistant IL [C16mim]Cl.26 The average diameter of as-synthesized Fe3O4 nanoparticles was approximately 10 nm

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with good dispersity. The IL was used as the stabilizer by adsorbing on the particle surfaces to prevent the agglomeration of Fe3O4 nanoparticles. This type of Fe3O4 nanoparticles showed a high saturation magnetization. Carbon dots (CDs/CQDs), a new category of QDs, are quasispherical nanoparticles with diameters less than 10 nm, which are widely applied in energy storage and conversion.27 They were first reported in 2004 and possess a number of advantageous properties such as good solubility, low toxicity, simplicity in modification, and so on.28 These advantages potentially open up applications in areas such as sensing and bioimaging, electrocatalysis, light-emitting diodes, photocatalysis, and solar cells. In addition, the CDs also can be prepared using some simpler and faster methods than those used for other carbon materials, making them attractive alternatives to existing carbon materials in a variety of applications.29 Li et al. reported a simple preparation of IL-functionalized CDs by electrochemical exfoliation of graphite rods with an amino-terminated IL added to the reaction system.29 The diameter of the IL-CDs was about 2.6 nm, with a strong photoluminescence and a quantum yield of about 11.3%. Thus this product has the potential to be used for cell imaging. Furthermore, the IL-CDs showed outstanding catalytic activity for O2 and H2O2 reduction reactions with excellent electron transfer properties. More interestingly, these IL-CQDs have promise as matrices for immobilization of enzymes to build biosensors. Li and coworkers were later able to synthesize CDs of varying sizes via a similar method but using an electrolyte consisting of water and two ILs.30 By altering the water content in the mixed electrolyte, the size of the CDs could be tuned. When the water content was 24%, 38%, and 56%, the sizes of the CDs produced were 4.9, 4.1, and 3.1 nm, respectively. The CDs exhibited the typical excitation wavelength-dependent maxima of photoluminescence and a quantum yield of nearly 10%. The strongest emission peak of the CDs was located at 439 nm at an excitation wavelength of 360 nm. Di et al. synthesized CQDs/BiOI by solvothermal strategy assisted by the reactable IL, 1-hexyl-3-methyl-imidazolium iodide, [Hmim]I.31 The IL was beneficial to build the compact junctions between CQDs and BiOI. Therefore the CQDs/BiOI photocatalyst showed enhanced photocatalytic activity in comparison to pristine BiOI. This improved photocatalytic performance might be attributed to the synergistic effect of the tight contact interface between CQDs and BiOI and the effective charge separation boosted by CQDs. A simple and environment-friendly route was reported for fabrication of S- and N-codoped CDs by Zhuo and coworkers using one-step hydrothermal treatment of 1-butyl-3-methylimidazolium 2-amino3-mercaptopropionic acid salt and polyethylene glycol.32 The CDs synthesized by this method were nearly spherical. With increasing the reaction

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time, the size of the CDs became smaller. It was found that the amorphous carbon was gradually transformed into the crystallized CD. In addition, the higher reaction temperature was beneficial to the generation of CDs with higher quantum yields. Very recently, Pham-Truong et al. developed a microwave-assisted method for the preparation of nanometer scaledoped CDs in the presence of bio-based materials and the IL 1-ethyl-3-methylimidazolium ethylsulfate, [Emim][ESO4].33 First, glutamine and glucose in IL were used as C and N sources, then CDs were formed that only used IL as the N source. Both CDs exhibited outstanding electrocatalytic activity toward oxygen reduction, with a prevalent two-electron pathway resulting in the generation of H2O2. More interestingly, the CDs synthesized in the presence of glucose and IL showed a selective two-electron reduction of O2, with H2O2 production in up to 90% efficiency over a potential range of approximately 0.8 V.

3.3.2 One-dimensional structures 1D nanostructures, including nanowires, nanorods, and nanotubes, have recently aroused intensive attention owing to their orientated electronic and ionic transport capability and strong tolerance to stress change via facile stress relaxation processes. These 1D materials have been widely used in the preparation of electronic, electrochemical, optical, and optoelectronic devices. Therefore continued development of 1D nanomaterials with unique structure and performance characteristics is of great importance. Kahimbi et al. recently reported a reagent-free IL-assisted ball milling method in the production of rod-shaped IL/Fe2O3 hybrids with irregular size.34 The as-prepared sample showed high surface area of 202 m2 g21 and narrow pore size distribution, which was beneficial for supercapacitor applications. In the synthesis process, ILs not only acted as structure-directing templates for building rodlike Fe2O3 with porous structure, but also functionalized the surface of the IL/Fe2O3 hybrids, leading to good wettability and improved ion transfer. Electrochemical test results indicated that the IL/Fe2O3 hybrids had high specific capacitance, fast and reversible charge/discharge rates, and outstanding longterm cycle stability, and thus may be outstanding candidates for pseudocapacitive electrode materials. In the field of photocatalysis, ZnO is one of the earliest semiconductors used as a photocatalytic material for degradation of organic pollutants. Due to the good charge migration ability and excellent crystallinity, 1D ZnO nanostructures are also widely used for biosensors and gas sensors. Therefore design and control of ZnO nanomaterials with specific structure

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and morphology are of great interest.35 Pancielejko and coworkers thoroughly investigated the effects of adding IL 1-butylpyridinium chloride, [BPy]Cl, on the morphology, structure, and photocatalytic and photoelectrochemical properties of TiO2 nanotubes.36 IL NTs with well-ordered structures can be generated by electrochemical anodization of titanium foil, using an organic electrolyte with a small content of [BPy]Cl. Such well-ordered TiO2 nanotubes can be obtained even at the low voltage of 10 V. In this system, the [BPy]Cl played a structure-directing effect to promote the formation of the TiO2 nanotubes. Furthermore, the presence of [BPy]Cl was observed to influence the nanotube diameter, while the nanotube length was preserved. Our group developed a method to synthesize mesoporous α-Ga2O3 hierarchical structures by calcining the as-prepared α-GaOOH precursor.37 This precursor was assembled by nanorods using an IL-assisted ([Bmim][OH]) hydrothermal method. The mesoporous α-Ga2O3 exhibited excellent photocatalytic for degradation of Rhodamine B (RhB) in aqueous solution due to its hierarchical and porous structure resulting from the IL. Qiao’s group reported a strategy to prepare N/S-codoped graphene microwires.38 The catalyst precursor, which was generated by the infiltration of graphene framework with the IL N-methyl-2-pyrrolidonium hydrogen sulfate, [Hnmp]HSO4, was crucial for this synthesis process. After carbonization of the precursor, the final products with high heteroatom-doping contents (N 10.8% and S 2.4%), densely packed microstructure, and rich porosity were formed. Owing to these structural properties, the N/S-codoped graphene microwires can be used as an efficient catalyst electrode for oxygen evolution reaction and in a Znair battery system.

3.3.3 Two-dimensional structures Graphene consists of single sheets of 2D sp2-hybridized carbon. Due to long-range π-conjugation, graphene displays superior mechanical, thermal, and electrical properties, which have aroused extensive interest for theoretical and experimental studies.3941 The highest quality graphene is prepared by the top-down method of mechanical exfoliation, but this method is limited by the low throughput and low yield. In order to harvest the monolayer graphene, van der Waals attraction between the layers must be overcome. Recently, some approaches to synthesize monolayer graphene have been explored, such as chemical efforts to exfoliate and stabilize sheets in solution, bottom-up approach to graphene directly from precursors, and attempts to in situ catalyze growth on a substrate.42 However, all of these methods are imperfect and need to be modified. Introduction of ILs into the synthesis of single graphene sheets could

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effectively perfect the existing methods, and may also possess the added advantage of further functionalizing the products. Matsumoto and coworkers found that graphite nanosheets can be formed in 30 min by microwave irradiation of the graphitic layers in presence of oligomeric 1,10 -[1,2-ethanediylbis(oxy-1,2-ethanediyl)]bis (3-butyl-1H-imidazolium-1-yl) di(hexafluorophosphate), IL2PF6, and 1,10 -[1,2-ethanediylbis(oxy-1,2-ethanediyl)]bis(3-(2-(2-(2-(3-butyl-1Himidazolium-1-yl)ethoxy)ethoxy)ethyl)-1H-imidazolium-1-yl) tetra (hexafluorophosphate), IL4PF6, as fluid media.43 This method can lead to a high yield of 93% based on the mass of loaded graphite, with a good selectivity of 95% toward single-layer graphene. In addition, the structural integrity of as-prepared graphene was also as good as the precursor graphite. In this synthesis process, nearly quantitative exfoliation is reached on microwave irradiation without centrifuging. Lu et al. further developed the IL-assisted exfoliation method to prepare fluorescent graphene.44 When the content of ILs was low (.10% water), water-soluble, oxidized carbon nanomaterials were formed, while at higher IL concentrations, IL-functionalized carbon nanomaterials can be obtained. By varying the water/IL ratio in the electrolyte, the chemical composition and surface passivation of the assynthesized graphene can be modulated. As a result, the fluorescence performance of the graphene can be tuned from the ultraviolet to visible regions. Liu et al. reported a mild, one-step electrochemical method to prepare IL-functionalized graphite sheets in presence of a variety of ILs and water.45 These IL-treated graphites could be further exfoliated into functionalized graphene nanosheets. It is very interesting that the as-prepared functionalized graphite sheets can be homogeneously distributed in polar aprotic solvents, and do not need to be further deoxidized. Shang et al. developed an environment-friendly IL-assisted grinding method for direct exfoliation of natural graphite into few-layer graphene of high purity.46 An IL ([Bmim]PF6) was chosen in this work on account of being a green solvent with a surface tension well matching the surface energy of graphite, which could inhibit the restacking of detached graphene sheets. It is worth noting that this procedure was performed under mild conditions and depended on pure shear force to exfoliate the graphene layers from the graphite flakes. Therefore this strategy avoided severe defects in the graphene sheets and chemical reactions derived from cavitation effects induced during sonolysis. Other 2D sheetlike structures have also become research hotspots in recent years. Jin and coworkers developed an IL-assisted, simple and controllable method to synthesize 2D nitrogen-doped microporous carbon sheets.47 In this work, IL-functionalized graphene oxide (GO) sheets acted as a shape-directing agent and a resorcinol/formaldehyde

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polymer was used as the carbon precursor. The thickness of the microporous carbon layer can be adjusted by simply varying the reactants/ GO content ratio. These 2D nitrogen-doped microporous carbon materials exhibited abundant micropores with narrow pores, short diffusion paths, good wettability, and highly electrically conductive networks. Electrochemical performance tests demonstrated that this product showed high rate capability and specific capacitance, and excellent long-term stability when used as a supercapacitor electrode. Kong et al. also synthesized a flake-like carbon material via a direct carbonization route, where poly(vinylidene fluoride-co-hexafluoropropylene) and IL were used as dual templates, and polyacrylonitrile used as the carbon precursor.48 In this route, aggregated IL acts as the pore template. The as-synthesized carbon flakes showed excellent specific capacitance, good energy density, high power density, and outstanding durability. Kaper et al. synthesized a lamellar structure of alternating sheets of V2O5 and cations from an imidazolium-based IL.49 Due to the intercalation of the IL cations, growth along the high charge density perpendicular [100] direction of the shcherbinaite phase is inhibited. After calcination under different conditions, diverse vanadium oxide nanostructures, including V2O5, V2O3, and VO2, were formed from the lamellar IL-V2O5. Alammar and coworkers synthesized SrSnO3 photocatalysts via a microwave preparation route in various ILs followed by a calcination process to optimize the materials’ crystallinity.50 The authors investigated the influence of the ILs containing different cations, including [C4mim]1, [C6(mim)2]21, [C4Py]1, and [P66614]1, with the [Tf2N]2 [bis (trifluoromethane)sulfonimide] anion on the crystallization, structure, and morphology of the products. The morphologies, sizes, and size distributions of the photocatalyst particles were different when the various ILs were used. For example, the products obtained from [P66614][Tf2N] exhibited needlelike particles with a narrow size distribution, and the products synthesized using [C6(mim)2][Tf2N]2 showed larger particles with a broader size distribution. In addition, when n-butylpyridinium bis(trifluoromethane)sulfonimide, [C4Py][Tf2N], was used, nanospheres with a diameter of B50 nm could be prepared. Zhang and coworkers reported a one-step, low-cost, environmentfriendly, and large-scale IL-assisted grinding method to prepare MoS2 nanosheets from bulk MoS2.51 On account of the IL-assisted grinding exfoliation of graphene, nanosheet and nanodot base structures have been successfully realized. Exfoliation by such an IL-assisted grinding strategy was first proposed to synthesize MoS2 nanosheets. This fabrication process simply mixed the reactants and exploited mechanical shear force to exfoliate bulk MoS2 to MoS2 sheets. Generally, during solventassisted exfoliation synthesis of nanosheets, the minimized enthalpy of

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exfoliation and effective exfoliation of layered materials are derived from the well-matched surface energies of solvent and layered material. The surface energy of IL is well matched with the surface energy of MoS2, thus, the inherent van der Waals forces between MoS2 sheets could be effectively conquered by the IL, facilitating the exfoliation of bulk MoS2 to MoS2 sheets, and suppressing the restacking of detached MoS2 layers. Very recently, our group synthesized Cu7Te4 nanosheets with 2.1 nm thickness through an IL-assisted ionothermal method.52 The IL [Bmim] Cl played multiple roles in this process. First, the IL played three important roles in the first stage of forming Cu7Te4 nanoplates, as reaction medium, reaction initiator, and template. In the initial reaction stage, the surface structure of Te nanorods was reduced to Te22 by IL under heating. Meanwhile, Cu plates were corroded by IL to form Cu1 in the presence of the excess Cu in the reaction system. Due to the excess of elemental Cu, any amount of Cu21 present remained low. When the Cu ions contacted the surface of the Te nanorods, the Te was immediately transformed to Cu7Te4, resulting in the growth of a thin Cu7Te4 shell on the Te nanorod cores. On the basis of the earlier discussion, the IL appeared to be the key factor in dictating the formation of Cu7Te4. Furthermore, the as-prepared Cu7Te4 nanosheets exhibited enhanced electrocatalytic activity and long-term stability in comparison to bulk Cu7Te4 for water oxidation. Sundrarajan and coworkers synthesized ZnO nanocrystals by a greener strategy, via extraction from the peel of Punica granatum (pomegranate) in the presence of IL, and the as-fabricated ZnO nanocrystals showed good hexagonal and sheetlike structures. The morphology and structure characterizations indicated that the IL acted as agglomeration inhibitor and to improve clear morphology.53 Our group successfully synthesized aggregated α-Fe2O3 nanoplates by the self-assembly of nanoplatelets in a side-to-side manner in the presence of IL.54 The IL 1propyl-3-methylimidazolium iodide, [Pmim]I, was employed and assisted in the assembly and coalescence of small nanoplatelets into final nanoplates. Beyond the above materials, in recent years IL-assisted synthesis of g-C3N4 has also aroused great attention, which is mainly ascribed to the extensive study of g-C3N4 materials in the field of photocatalysis. Yan et al. developed a simple IL-assisted hydrothermal method to convert bulk g-C3N4 into a stable hydrogel.55 Because of the particular interactions between the IL and the g-C3N4, the gelation occurred through delamination of the layered structure, upon which the amphiphilic foamlike network was formed. In this work, the ππ interactions of the cation in the IL and the hydrogen bonds generated from the side chains of the IL tail were beneficial to break the initial van der Waals

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interactions and stabilized the open gelated structure, thus preventing the stacking of the g-C3N4 nanosheets. Zhao et al. reported a simple method to synthesize Br-doped g-C3N4 with highly porous structure by using the IL 1-butyl-3-vinylimidazolium bromide, [Bvim]Br, as the Br source and soft template.56 This product exhibited superior photocatalytic hydrogen evolution activity under visible-light irradiation, due to the enhanced electron transport capability and improved optical and conductive properties, which might be ascribed to the large surface area derived from the porous structure and the narrower bandgap resulting from the both Br doping and porous structure. Raziq et al. synthesized S-doped porous g-C3N4 using the IL 1-butyl-3-methylimidazolium thiocyanate, [Bmim][SCN], as the S source and simultaneously coupled with TiO2 and Au-TiO2 to improve photocatalytic performance.57 These products exhibited good visible-light photocatalytic activities for CO2 reduction, water splitting, and organic pollutant degradation. The enhanced photocatalytic performance might be ascribed to the extended solar spectrum response upon doping S to create surface states near the conduction band of the porous g-C3N4 material and to the enhancement of charge separation by coupling Au-TiO2.

3.3.4 Three-dimensional structures 3D hierarchical nanostructures, such as self-assembled hollow spheres and sheaflike architectures, with high surface area and synergistic interactions play crucial roles in applications such as water remediation, gas sensing, biosensing, and so on. Some studies have found that the nanomaterials are prone to assembly to the hierarchical structures when the ILs are present in the reaction system. For example, Li et al. reported the fabrication of flowerlike Cu2O architectures via a microwave-assistance method in the presence of the IL [Bmim][BF4].58 By adjusting the amount of IL present, the flowerlike structure of Cu2O consisting of thin nanosheets can be obtained. The bandgap of the asprepared Cu2O was B2.25 eV and the surface area was 65.77 cm2 g21. In addition, the product exhibited excellent visible-light photochemical activity for the reduction of Cr(VI) to Cr(III) and good long-term stability. Kowsari and Faraghi successfully fabricated flowerlike Y2O3 phosphors without metal activators using an IL-assisted method involving calcination.59 The IL played an important role in the generation of various morphologies of Y2O3, and the effects of the IL on the Y2O3 shape were investigated experimentally. The results indicated that the morphologies and photoluminescence spectra of Y2O3 were strongly dependent on the type of cation and anion in the IL employed. By

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reducing the length of the subsidiary chain of the cation in the IL, the thickness of the nanosheet could be increased. Xu et al. prepared α-Fe2O3 hollow spheres in the presence of the IL 1-octyl-3-methylimidazolium tetrachloroferrate(III), [Omim][FeCl4], under solvothermal conditions.60 As a result, during the α-Fe2O3 hollow spheres formation process, the [Omim] [FeCl4] simultaneously served as Fe source, solvent, and template. Moreover, the α-Fe2O3 hollow spheres showed good electrical conductivity, high photocurrent, and outstanding photocatalytic activity toward degradation of Rhodamine B. BiOI flowerlike hollow microspheres with uniform shape were successfully prepared by Xia and coworkers via an ethylene glycol-assisted solvothermal approach in the presence of IL [Bmim]I.61 Interestingly, a hole was found in the surface of BiOI flowerlike hollow microspheres. It was found that [Bmim]I played three roles in fabrication of these BiOI flowerlike hollow microspheres, namely as a source of I, as solvent, and as a template, which was crucial to the formation of the hollow structure. Hierarchical BiOBr microspheres were synthesized by Zhang et al. by an ionothermal route.62 The IL [Bmim]Br was used as soft template for promoting nucleation and in situ growth of 3D hierarchical BiOBr mesocrystals without surfactants. In addition, IL-BiOI with enhanced charge separation rate and photocatalytic activity toward decolorization of aqueous methyl orange has also been synthesized by Huang and coworkers, employing [Emim][PF6] as the IL.63 Our group selected a Se-containing IL, 1-n-butyl-3-methylimidazolium methylselenite ([Bmim][SeO2(OCH3)]), to synthesize ZnSe hollow nanospheres by a facile one-pot hydrothermal method, where N2 gas bubbles acted as the template.64 We found that [Bmim][SeO2(OCH3)] served as both Se source and stabilizer for the formation of ZnSe hollow nanospheres. Then, we further synthesized CdSe dendrites using [Bmim][SeO2(OCH3)] as the precursor.65 These CdSe dendrites were self-assembled by the oriented attachment of nanospheres. In addition, we also prepared flowerlike CdSe dendrites via a Brønsted acidbase IL-assisted solvothermal method. A mechanistic investigation found that the flowerlike dendrites were a result of the interaction between the polar structure of CdSe crystals and the IL [DMFH][HCO2].66 BielickaGiełdo´n et al. first reported the effect of the IL cation type, such as imidazolium, pyridinium, and pyrrolidinium, on the shape, surface properties, and photocatalytic activity of BiOX synthesized via solvothermal method in glycerol.67 The authors systematically investigated the various ILs with regard to cation type, halogen source, and templating agent for the fabrication of the BiOX. In the synthesis process, the ILs played the crucial roles in loosening of the structure and increasing the particle size of products. In addition, it has also been found that ILs increased specific surface area and pore volume of BiOX. Sun and coworkers fabricated composition-tunable

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heterostructured BiOI photocatalysts by a facile IL-assisted precipitation route at room temperature.68 Interestingly, by careful regulation of the reaction conditions, two groups of BiOI hybrids, including BiOI/Bi4O5I2 and Bi4O5I2/Bi5O7I, were successfully prepared. The two groups of hybrid photocatalysts exhibited remarkably enhanced photocatalytic performance toward decomposition of o-phenylphenol (OPP) and 4-tert-butylphenol (PTBP) under visible-light irradiation in comparison to single-phase BiOI, Bi4O5I2, and Bi5O7I photocatalysts. Chen and coworkers synthesized two kinds of self-assembled hierarchical BiOBr microcrystals by a facile microwave-assisted method in the presence of reactable IL [C16mim]Br.69 The as-prepared BiOBr with porous and hollow microsphere structures were obtained via a solvothermal method with or without polyvinyl pyrrolidone (PVP), respectively. It was found that the IL acted as solvent, reactant, and template during the synthetic process. Encouragingly, the BiOBr hollow and porous microspheres showed excellent photocatalytic performance for degradation of organic pollutants (exemplified by Rhodamine B) under visible light. Hollow TiO2 microspheres were synthesized by Nakashima et al. in the presence of [Bmim][PF6].70 In this reaction system, no hard template was added, demonstrating the utility of the IL as an effective all-in-one solvent. Hierarchically patterned macroporous TiO2 architectures were developed by Zhou and coworkers by a spontaneous self-assembly route.71 A mixture composed of 1-octadecene (ODE) and an ODEimmiscible 1-alkyl-3-methylimidazolium-based IL was used as the reaction medium in this work. Wang et al. fabricated single-crystal α-Fe2O3 mesoporous nanospheres by an IL [C12mim][BF4]-assisted hydrothermal synthetic method.72 On the basis of the structure and morphology characterization, it was found that the IL played a crucial role in the control of microstructure and morphology of the α-Fe2O3 nanostructures by regulating the self-assembly of the primary nanoparticles. Zhang et al. synthesized a sheaflike CuO consisting of nanoplates by a hydrothermal method at 100 C from copper salts and NaOH in the presence of the IL [Bmim][BF4].73 The as-prepared structures with lengths of 45 μm, thickness of 6580 nm, and terminal angle of 60 degrees consisted of monoclinic CuO of high crystal quality. In this work, the morphologies of CuO were dependent on the manner in which the IL was fed into the system, with the IL serving both as a cosolvent and a modifier in the reaction system. Furthermore, uniform peachstone-like CuO 3D architectures consisting of singlecrystal nanosheets were fabricated by employing IL 1-octyl-3methylimidazolium trifluoroacetate, [Omim]TA, as capping agent under IL-assisted hydrothermal conditions. These 3D architectures evolved from nanoparticles to 2D nanosheets and 3D peachstone-like

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nanostructures, with the cations of the ILs serving to control the morphology of the crystals. Furthermore, it was found that the concentration of IL and the reaction time directly influenced the morphology of the CuO.74 Marcos Esteban and coworkers prepared Cu2O nanocubes using copper salts as the precursor via microwave irradiation in IL [Bmim][BF4] without addition of extra reducing agent.75 Cubic Cu2O nanocubes of 43 6 15 nm were fabricated using Cu(OAc)2 H2O with [Bmim][BF4]. Furthermore, the size of the Cu2O nanocubes increased on isolation from the neat IL by addition of acetonitrile, which gave Cu2O nanocubes of 100500 nm in size, indicating the ability of the IL to stabilize small nanoparticles. Lu et al. developed an alternative route to synthesize metal nanoparticles/carbon heterostructures by directly sputtering metal into the IL. This is a facile, environment-friendly strategy, requiring no additives or stabilizers, and is free of any by-product.76 By employing the IL-assisted method, Cu2O nanoparticles grafted onto multiwalled carbon nanotubes with small size and high uniformity could be harvested by directly sputtering metallic Cu into the IL [Bmim][BF4]. This Cu2O/MWCNTs nanocomposite delivers outstanding electrochemical properties, such as high specific capacitance and good cycling stability and rate capability. Li et al. reported a new method to synthesize Cu2O crystals with controllable shape by electrodeposition in the presence of IL.77 The 1methyl-3-ethylimidazolium salt containing ethylsulfate anions is a hydrophilic IL, and dramatically affects the morphology of the Cu2O crystals. When small amounts of IL were added in the deposition solutions, the shape of the Cu2O crystals turned from cubic to octahedral and spherical. ZnO hexagonal micropyramids were prepared by Zhou et al. in an analogous IL (a mixture consisting of oleic acid and ethylenediamine). It is interesting that all exposed in this ZnO material  surfaces were composed of polar 6 (0001) and 1011 facets.78 Zhu and coworkers synthesized hierarchical ZnO structures with a diversity of morphologies using metal-containing ILs functioning as both solvents and metal-oxide precursors.79 Lee et al. described a facile and catalyst-free method to prepare Ndoped porous carbon materials with large surface area by an open vessel polymerization and thermolysis of task-specific IL precursors bearing a char-forming nitrile functionality.80 The surface area and porosity of the products were dependent on the character of cation/anion pairing in the IL. This work demonstrates that mesoporous carbon can be prepared by direct carbonization of a task-specific IL precursor, where the IL might serve as a self-porogen. A controllable one-pot route to prepare N-doped ordered mesoporous carbon (NMC) with a high N content was reported by Wei and coworkers, which involved an evaporation-induced



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self-assembly process using dicyandiamide as a nitrogen source.81 The as-obtained NMC exhibited high CO2 capture ability and good performance as a supercapacitor material resulting from its high surface area and high N content. Wang and Dai presented a method to prepare functional porous carbon and carbon-oxide composite materials from conventional ILs by confined carbonization.82 Interestingly, this method utilizes the space confinement inside oxide networks to convert the ILs with no char residue into carbon precursors by carbonization. Moreover, this method allowed a rational tuning of the pore structure of the products from microporous to mesoporous and macroporous architectures. In addition, the elements N and B can be easily doped into carbon frameworks using heteroatom-substituted ILs. Zeolites are crystalline microporous aluminosilicates, consisting of corner-sharing {SiO4} and {AlO4} tetrahedra. Recently, the major application of zeolites is in detergency. The employment of ILs in the synthesis process would effectively increase the diversity of these materials. Ionothermal synthesis of zeolite and zeotype materials was first reported by Cooper and coworkers in 2004.83 In their work, a series of aluminophosphate zeolites were successfully synthesized using IL 1ethyl-3-methylimidazolium bromide, [Emim]Br, and urea/choline chloride deep eutectic solvents. In particular, the aluminophosphates SIZ-1, SIZ-3, SIZ-4, SIZ-5, and SIZ-6 were obtained when [Emim]Br was used, and the novel zeolite architecture SIZ-2 and the nonzeolitic aluminophosphate AlPO-CJ2 were generated by choosing choline chloride/urea eutectic mixtures. Thereafter, ionothermal synthesis was widely used for a variety of zeolites and zeolite analogues. Li et al. reported a method to prepare aluminophosphate molecular sieve membranes on porous alumina disks via an ionothermal synthesis route by substratesurface conversion.84 A variety of molecular sieve membranes (including CHA, AEL, AFI, and LTA types) have been successfully prepared. In addition, this method is simple and environmentally benign, and can be applied to large-scale production. Siliceous zeolites silicalite-1 (MFI) and theta-1 (TON) were successfully fabricated by Wheatley and coworkers by an ionothermal method, using IL 1-butyl-3-methylimidazolium hydroxide, [Bmim]OH, as both the solvent and structure-directing agent.85 Ma et al. reported a straightforward synthetic strategy to fabricate high-silica mordenite (MOR) zeolites without adding seed or fluoride additive.86 The zeolites exhibited well-crystallized MOR phases with wide window of SiO2/Al2O3 ratios, ranging from 11 to 263. This synthetic process was strongly dependent on the gel preparation by acid hydrolysis of the silica precursor in presence of IL [Bmim]Br, which was used as the structure-directing agent, followed by dry-gel conversion. Encouragingly, high-silica ZSM-5 and pure-silica ZSM-22 zeolites could be also fabricated from this method.

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3.4 Summary As described in the earlier examples, it is of great importance to further investigate the utilization of ILs for inorganic synthesis. The chemical inertness, space-filling cations or anions, polar aprotic properties, low vapor pressure, and wide compatibility make ILs uniquely positioned to act as both tailored solvents and templates, and could find use in “all-in-one” synthesis routes. Fortunately, these advantages are already being exploited in syntheses of 0D to 3D nanostructures. Most of these synthetic processes are mature, and can guide the preparation of other materials. Although ILs are widely employed in inorganic synthesis, their practical applications still remain limited. This may be ascribed to two major considerations: first and foremost, the high manufacturing costs and the massive quality loss of ILs during the synthesis and separation processes; second, the selection of a suitable IL for preparation of a specific material requires careful analysis, as ILs with different cations and anions exhibit markedly different properties. But overall, many potential uses of ILs have still not been investigated and the potential of ILs in synthetic inorganic chemistry is still far from fully exploited. On the basis of present research, it is safe to predict that many more achievements in synthesis of inorganic materials using ILs will be made.

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11. Zhang, J.; Feng, H.; Yang, J.; Qin, Q.; Fan, H.; Wei, C.; Zheng, W. Solvothermal Synthesis of Three-Dimensional Hierarchical CuS Microspheres from a Cu-Based Ionic Liquid Precursor for High-Performance Asymmetric Supercapacitors. ACS Appl. Mater. Interfaces 2015, 7, 2173521744. 12. Paraknowitsch, J. P.; Zhang, J.; Su, D.; Thomas, A.; Antonietti, M. Ionic Liquids as Precursors for Nitrogen-Doped Graphitic Carbon. Adv. Mater. 2010, 22, 8792. 13. Li, Z.; Li, G.; Jiang, L.; Li, J.; Sun, G.; Xia, C.; Li, F. Ionic Liquids as Precursors for Efficient Mesoporous Iron-Nitrogen-Doped Oxygen Reduction Electrocatalysts. Angew. Chem. Int. Ed. 2015, 54, 14941498. 14. Li, Z.; Geßner, A.; Richters, J.-P.; Kalden, J.; Voss, T.; Ku¨bel, C.; Taubert, A. Hollow Zinc Oxide Mesocrystals from an Ionic Liquid Precursor (ILP). Adv. Mater. 2008, 20, 12791285. 15. Ding, Y.; Klyushin, A.; Huang, X.; Jones, T.; Teschner, D.; Girgsdies, F.; Rodenas, T.; Schlogl, R.; Heumann, S. Cobalt-Bridged Ionic Liquid Polymer on a Carbon Nanotube for Enhanced Oxygen Evolution Reaction Activity. Angew. Chem. Int. Ed. 2018, 57, 35143518. 16. Moniruzzaman, M.; Nakashima, K.; Kamiya, N.; Goto, M. Recent Advances of Enzymatic Reactions in Ionic Liquids. Biochem. Eng. J. 2010, 48, 295314. 17. Lozano, P.; Garcia-Verdugo, E.; Luis, S. V.; Pucheault, M.; Vaultier, M. (Bio) Catalytic Continuous Flow Processes in scCO2 and/or ILs: Towards Sustainable (Bio) Catalytic Synthetic Platforms. Curr. Org. Synth. 2011, 8, 810823. 18. Greaves, T. L.; Drummond, C. Ionic Liquids as Amphiphile Self-Assembly Media. Chem. Soc. Rev. 2008, 37, 17091726. 19. Jin, W.; Yang, Q.; Zhang, Z.; Bao, Z.; Ren, Q.; Yang, Y.; Xing, H. Self-Assembly Induced Solubilization of Drug-Like Molecules in Nanostructured Ionic Liquids. Chem. Commun. 2015, 51, 1317013173. 20. Soni, S. K.; Ramanathan, R.; Coloe, P. J.; Bansal, V.; Bhargava, S. K. Self-Assembled Histidine Acid Phosphatase (HAP) Nanocapsules in Ionic Liquid [Bmim][BF4] as Functional Template for Hollow Silica Nanoparticles. In Proceedings of Chemeca 2010, Adelaide, Australia, 27-29 September 2010; pp 110. 21 Qi, K.; Li, D.; Fu, J., et al. Elucidating Ionic Liquid Environments that Affect the Morphology of TiO2 Nanocrystals: A DFT 1 D study. J. Phys. Chem. C 2014, 118, 2332023327. 22. Qiang, Y.; Zhang, S.; Guo, L.; Zheng, X.; Xiang, B.; Chen, S. Experimental and Theoretical Studies of Four Allyl Imidazolium-Based Ionic Liquids as Green Inhibitors for Copper Corrosion in Sulfuric Acid. Corros. Sci. 2017, 119, 6878. 23. Duan, X.; Kim, T.; Li, D.; Ma, J.; Zheng, W. Understanding the Effect Models of Ionic Liquids in the Synthesis of NH4-Dw and γ-AlOOH Nanostructures and Their Conversion into Porous γ-Al2O3. Chem. Eur. J. 2013, 19, 59245937. 24. Rodriguez-Cabo, B.; Rodil, E.; Rodriguez, H.; Soto, A.; Arce, A. Direct Preparation of Sulfide Semiconductor Nanoparticles from the Corresponding Bulk Powders in an Ionic Liquid. Angew. Chem. Int. Ed. 2012, 51, 14241427. 25. Klauke, K.; Zaitsau, D. H.; Bu¨low, M.; He, L.; Klopotowski, M.; Knedel, T. O.; Barthel, J.; Held, C.; Verevkin, S. P.; Janiak, C. Thermodynamic Properties of SelenoetherFunctionalized Ionic Liquids and Their Use for the Synthesis of Zinc Selenide Nanoparticles. Dalton Trans. 2018, 47, 50835097. 26. Liu, X.-D.; Chen, H.; Liu, S.-S.; Ye, L.-Q.; Li, Y.-P. Hydrothermal Synthesis of Superparamagnetic Fe3O4 Nanoparticles with Ionic Liquids as Stabilizer. Mater. Res. Bull. 2015, 62, 217221. 27. Choi, H.; Ko, S.-J.; Choi, Y.; Joo, P.; Kim, T.; Lee, B. R.; Jung, J.-W.; Choi, H. J.; Cha, M.; Jeong, J.-R.; Hwang, I.-W.; Song, M. H.; Kim, B.-S.; Kim, J. Y. Versatile Surface Plasmon resonance of Carbon-Dot-Supported Silver Nanoparticles in Polymer Optoelectronic Devices. Nat. Photonics 2013, 7, 732738.

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S E C T I O N

4

Metal-organic frameworks

C H A P T E R

4 Wettability control of metal-organic frameworks Qi Sun1,2 and Shengqian Ma1 1

Department of Chemistry, University of South Florida, Tampa, FL, United States, 2College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, P.R. China

4.1 Introduction Metal-organic frameworks (MOFs) are crystalline materials consisting of inorganic nodes (metal ions or clusters) and multitopic organic linkers, which can be systematically tuned in terms of chemical composition and precise arrangement.15 This fine control over the organic and inorganic components of MOFs offers an extensive set of synthetically accessible and remarkable structures, distinguishing them from other porous materials such as activated carbon, polymers, and zeolites. As a consequence of these properties, MOFs have demonstrated their utility for a variety of applications including,68 but not limited to gas storage/separation,916 chemical separations,17 catalysis,1820 and chemical sensing.2123 However, they have not yet been widely applied in industry, and in many cases the deployment of MOFs is held back by a lack of long-term stability under environmental or application-specific conditions, leading to pore blockages and loss of accessible surface area. Therefore, in order to be applicable, the stability of the materials is of eminent importance.2432 Given the ubiquity of water vapor in the atmosphere, or as a component in applications for which MOFs may find utility, water stability has been a defining topic in determining whether real-world applications are realized using MOFs. It is well accepted that the decomposition of MOFs is typically due to the insertion of a water molecule, which breaks the metalligand

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linkage.33 Therefore, to achieve water stability in MOFs, two main methods have recently been developed, either thermodynamically by using metals and ligands that produce a stronger metal-oxide bond, 3436 or kinetically by designing a framework with steric protection of the MaO bonds from water.3739 Specifically, the use of linkers with enhanced basic properties or metals in higher oxidation states leads to an improvement in the chemical stability as a result of the greatly increased strength of the MaO bond. Based on such design principles, numerous water-stable MOFs have been developed, significantly promoting the expansion of their application.40,41 While efforts are ongoing to prepare new hydrolytically stable materials, there exists an ample library of known MOFs with less stable structures. Kinetically blocking water from reacting with the MOFs can be utilized to enhance the stability of existing MOFs of known topology. Improving the water resistance of these MOFs is equally, if not more, important as finding new stable structures, with the consideration that numerous MOFs have been well studied and have been produced at scale by industry, and these findings can be directly leveraged for a range of current applications.42,43 Considering that a hydrolysis reaction can only progress if the water molecule can approach sufficiently closely to the metal atom to allow interaction between the orbitals on the electrophilic metal atom and the nucleophilic water molecule, preventing the water molecules from attacking the frameworks is clearly expected to enhance their water tolerance. Wetting is an omnipresent phenomenon that can be observed anywhere from high tides on the beach to ion channels in cell membranes. Engineering the wettability of a material presents a rational, yet sophisticated solution to combat failure related to water absorptivity, which has attracted substantial attention in the practical applicability of materials.4457 Imparting the MOF materials with hydrophobicity could not only repel water molecules, thereby protecting MOFs against hydrolysis, but also render them new properties. Given their low adhesion properties and/or the solid/liquid/gas three-phase contact model, chemical behavior on such surfaces is quite different than that on traditional solid/liquid two-phase interfaces. Consequently, in addition to the significant effort being devoted to improving the hydrolytic stability, recent research has focused on applications for these unique interfacial materials such as oil spill cleanup, hydrocarbon storage/ separation, or water purification.5863 In this chapter, we will first introduce the evolution of the study of superwettable materials, mainly focusing on the fundamental rules for building these liquid-repellent materials. In the following sections, we will provide a comprehensive overview of the state of the art in hydrophobic MOF synthesis along with the discussion of the present

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challenges and opportunities. The potential applications of hydrophobic MOFs and related composites in hydrocarbon separation, water purification, oil spill cleanup, and catalysis are then demonstrated. We will attempt to show the mutual benefits offered by the integration of surface chemistry with materials. Finally, we offer perspectives on future directions for this promising field. We believe these findings for the realization of hydrophobic MOFs will offer simple, straightforward approaches for the development of diverse hydrolytically stable MOFs for future applications.

4.2 Wettability of metal-organic framework surfaces Wetting can be defined as the ability of a liquid to maintain contact with a solid surface. Therefore the first rule informed by natural examples of superhydrophobicity is that the chemical compositions of the material surfaces should be hydrophobic. It is generally accepted that solid surfaces with water contact angle (CA) greater than 90 degrees are defined as hydrophobic according to Young’s equation [Eq. (4.1)]. γ sv 5 γ sl 1 γ lv cosθ

(4.1)

Herein, θ is the contact angle and γ sv, γ sl, and γ lv are the surface tensions of solid/vapor, solid/liquid, and liquid/vapor involved in the system, respectively.64 However, this equation cannot be used to describe the contact angle of a sessile drop on a rough surface like MOFs, given that the force balance at the three-phase contact line is affected by surface roughness. To address this concern, more complex approaches taking roughness into account are desired. Volger et al. demonstrated that rather than 90 degrees as in the mathematical concept, a CA of 65 degrees separates solid materials into hydrophobic and hydrophilic, derived from a surface force apparatus supported by ancillary techniques.65,66 Therefore two general rules can be summarized for targeting superhydrophobic materials: generating sufficient roughness on the material surfaces, and tailoring the chemical compositions of material surfaces to be hydrophobic with a water contact angle greater than 65 degrees. The hydrophilicity of a material is typically characterized by performing contact angle measurements, whereby a liquid drop is deposited on the surface, and the drop profiles of static and moving drops are then recorded. In addition to contact angle measurements, roll-off angle experiments are also frequently conducted to determine a substrate’s wettability. To do this, a droplet is deposited on the surface of interest, and the surface is then slowly tilted until the drop rolls off, which will

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FIGURE 4.1 Effect of surface structure on the wetting behaviors of solid substrates in solid/air/water three-phase systems. (A) Diagram of Young’s equation at the condition of a water droplet on a smooth surface with a contact angle θ. (B and C) Same system on a microstructured substrate and micro/nanostructured substrate, respectively. (D) Advancing θAdv and receding contact angle θRec. (E) Tilt angle, that is, the so-called roll-off angle or sliding angle θSA. Source: Reproduced with permission from Wen, L.; Tian, Y.; Jiang, L. Bioinspired Super-Wettability from Fundamental Research to Practical Applications. Angew. Chem. Int. Ed. 2015, 54, 33873399. Copyright 2015, John Wiley and Sons.

occur if the droplet’s adhesion to the substrate is sufficiently low to be overcome by the gravimetric force acting on it. Materials with a higher hydrophobicity show small roll-off angles. In the dynamic case, however, this wettability is characterized by the advancing contact angle (θAdv) and the receding contact angle (θRec). Both of these parameters are dependent on the adhesion of the materials. In general, superhydrophobicity means a high θAdv with a low contact-angle hysteresis, which is characterized by θAdv/θRec or the sliding angle θSA. With respect to porous materials, their performances in water/organic vapor adsorption have proven to be valid, which has the advantage of being more reproducible than contact angle measurements since they do not depend on the sample form and the choice of baseline and require no fitting (Fig. 4.1).67

4.3 Synthesis of hydrophobic metal-organic framework materials Considerable efforts have been devoted to the synthesis of hydrophobic MOFs as well as their related composites. In this section, we summarize the strategies that have been used to impart the MOFs with hydrophobicity (Fig. 4.2). The first approach involves decorating the

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FIGURE 4.2 Strategies for fabricating hydrophobic MOFs and composites. (A) Linkerbased strategy. (B) Postsynthetic modification. (C) External surface corrugation of hydrophobic metal-organic frameworks. (D) Hydrophobic MOF composites by introduction of additional layers, integration with hydrophobic polymers, and formation of hierarchical composites.

ligands of the MOF with low surface energy fluorine-containing or long-chain alkyl substituent linkers to alter the surface properties of the MOF. This strategy promotes stability in liquid water by creating a hydrophobic outer surface that inhibits the diffusion of water molecules into the pores of the MOF. The second approach involves so-called postsynthetic strategies, for example, grafting hydrophobic responsive groups onto preformed MOFs. Although both strategies can effectively exclude water from the MOF’s pores, they may also render the inherent porosity of the resultant MOFs largely inaccessible, because of the steric

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bulk of the groups attached to the ligand/outer surface. An alternative approach that generates highly hydrophobic exterior surfaces but preserves internal porosity involves creating high nano- to micrometer surface roughness. The final method involves the synthesis of hierarchical porous composites based on the hybridization of MOFs intercalated with hydrophobic materials.

4.4 Linker-based hydrophobic metal-organic frameworks Inspired by the low surface energy, extraordinary stability, and numerous applications of fluorous molecules, Omary and coworkers have ignited an effort to explore the synthesis and functional properties of fluorous metal-organic frameworks (FMOFs). They described the synthesis and structural characterization of two new highly fluorinated porous silver azolate MOFs, named FMOF-1 and FMOF-2.68,69 These MOFs were constructed by the association of three or four coordinated silver cations bound to 3,5-bis(trifluoromethyl)-1,2,4-triazolate linkers, yielding porous frameworks (Fig. 4.3A). Considering that the pore channels are densely decorated with low surface energy aCF3 groups, this alignment affords only a weak water-framework interaction and thus repels the water molecules, exhibiting hydrophobicity. The measured contact angle for water on an FMOF-1 pellet is 158 degrees, indicative of superhydrophobicity. To further evaluate the resulting framework hydrophobicity, the authors analyzed the water adsorption isotherms of the resulting FMOF materials and contrasted them with those of a hydrophilic zeolite

FIGURE 4.3 (A) Building Blocks of FMOF-1 (left) and FMOF-2 (right). (B) Water adsorption isotherms collected at room temperature for FMOF-1, zeolite-5A, and BPL carbon. Source: Reproduced with permission from Yang, C.; Kaipa, U.; Mather, Q.Z.; Wang, X.; Nesterov, V.; Venero, A.F.; Omary, M.A. Fluorous Metal-Organic Frameworks with Superior Adsorption and Hydrophobic Properties Toward Oil Spill Cleanup and Hydrocarbon Storage. J. Am. Chem. Soc. 2011, 133, 1809418097. Copyright 2011, American Chemical Society.

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(zeolite-5A) and a hydrophobic activated carbon (BPL carbon). They showed that the hydrophobic character of the MOF materials appeared superior relative to that of the other adsorbents. No adsorption step and thus no water uptake is observed for FMOF-1 even near the saturation pressure (relative pressure of 0.9), whereas under the same conditions, activated carbon is fully saturated with water, and significant water adsorption was observed at a very low P/P0 value (,0.1) for the hydrophilic zeolite (Fig. 4.3B). Impressively, such a hydrophobic character that fully prevents water molecules from entering into the pores means that FMOF-1 does not suffer from degradation even upon long-term exposure to boiling water, as verified by a combination of X-ray powder diffraction and IR spectroscopic analysis. After establishing the framework stability, to demonstrate the potential of these materials, the authors evaluated their performance in the adsorption of hydrocarbons of oil components, showing that the FMOFs exhibit high capacity and affinity to C6aC8 fractions with retained efficiency even in the presence of water.69 Considering that water vapor is a significant component of industrial flue gas (B10%) and cannot be neglected when examining adsorbents for CO2 capture, a material with hydrophobicity is desired. Simulations and adsorption measurements show that FMOF-1 is hydrophobic, and water is not adsorbed in FMOF-1 at room temperature (Fig. 4.3B). CO2 uptake capacity of FMOF-1 is not decreased even in the presence of 80% relative humidity (RH), suggesting that hydrophobic MOFs give promise for CO2 capture from humid gas streams.70 Later, Miljani´c and colleagues reported three perfluorinated Cubased MOFs built from perfluorinated ligands H2OFBPDC (2,20 ,3,30 ,5, 50 ,6,60 -octafluorobiphenyl-4,40 -dicarboxylic acid) and H2PFBPTZ [5,50 (perfluorobiphenyl-4,40 -diyl)bis(1H-tetrazole)]. The most hydrophobic material among these new fluorinated MOFs is obtained by the reaction of H2OFBPDC and Cu(NO3)2 in the presence of a bifunctional pillaring ligand 1,4-diazabicyclo[2.2.2]octane (DABCO). Evidence for the superhydrophobic behavior of the prepared MOFs came from the vapor adsorption studies and contact angle measurements, with a negligible water uptake capacity and a water contact angle of 151 degrees.71 The hydrophobic ligand strategy involves decorating the ligands of the MOF with functional groups that reduce the material’s surface energy, such as perfluorinated aromatics, aCF3 groups, or long alkyl or perfluoroalkyl chains. The use of ligands bearing perfluorinated aromatics in principle makes it possible to tune the hydrophobicity of any MOF whose ligands have one or more CaH bonds. Moreover, the de novo synthetic approach does not reduce the accessible pore space. However, fluorination changes the ligands’ electronic structure and it is often essential to develop new synthetic strategies to access the desired framework

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FIGURE 4.4 Bottom-up approach for the fabrication of a self-cleaning MOF nanostructure by coordination driven self-assembly between ZnII and OPE-C18. Source: Reproduced with permission from Roy, S.; Suresh, V.M.; Maji, T.K. Self-Cleaning MOF: Realization of Extreme Water Repellence in Coordination Driven Self-Assembled Nanostructures. Chem. Sci. 2016, 7, 22512256. Copyright 2016, Royal Society of Chemistry.

topologies. Furthermore, the preparation of complex perfluorinated ligands is, in itself, a challenging synthetic endeavor. New approaches other than using fluorine-containing ligands are desired. Decorating the ligands of the MOF with alkyl substituent linkers has proven effective to alter the MOF’s surface properties. Maji and coworkers reported a superhydrophobic coordination polymer (NMOF-1) assembled by an octadecoxy-functionalized organic linker oligo(p-phenyleneethynylene)dicarboxylate and Zn21 ions (Fig. 4.4).72 Characterization results reveal that the NMOF-1 was assembled by 1D Zn-OPE-C18 chains with octadecyl alkyl chains projecting outward, which reduces the surface free energy and leads to superhydrophobicity in NMOF-1 (CA160 degrees). To further prove the hydrophobic behavior of NMOF-1, benzene and water adsorption isotherms were collected at room temperature. It is worth noting that NMOF-1 has a contact angle of 162 degrees, indicative of superhydrophobicity. This is also supported by advancing and receding contact angle measurements. Impressively, the material’s superhydrophobicity remains intact over a wide pH range of 19 and under high ionic concentrations, thereby advancing a new class of materials capable of water repellent applications. Sun and coworkers report a MOF material (UPC-21) constructed from a pentiptycene-based organic ligand (H4L). Due to the existence of multiaromatic hydrocarbon units in the central pentiptycene core of the ligand, UPC-21 exhibits high hydrophobicity with a water contact angle of 145 degrees and superoleophilicity with an oil contact angle of 0 degree.73 Oil/water separation measurements reveal that this material can efficiently separate oil/water, with a separation efficiency above 99.0% (Fig. 4.5).

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FIGURE 4.5 (A) H4L ligand with dangling hydrophobic groups. (B) Optical images of UPC-21 showing the hydrophobic character. The image of water droplet on the crystals of UPC-21 (top), the inset image in the right-hand corner is the image of the static water droplet (5 mL) and the image of crude oil diluted by hexane dropped on the crystals of UPC-21 (right). (C) Image of UPC-21 that can float on the water (right) and sink in ethyl acetate (left). Source: Reproduced with permission from Zhang, M.; Xin, X.; Xiao, Z.; Wang, R.; Zhang, L.; Sun, D. A Multi-Aromatic Hydrocarbon Unit Induced Hydrophobic Metal-Organic Framework for Efficient C2/C1 Hydrocarbon and Oil/Water Separation. J. Mater. Chem. A 2017, 5, 11681175. Copyright 2017, Royal Society of Chemistry.

FIGURE 4.6 Perspective view of the coordination framework and pore surface structures of MAF-6, chromatograms on the MAF-6-coated capillary for gas chromatography separation of benzene, cyclohexene, and cyclohexane, as well as transient breakthrough calculations for an 85/5/5/5 water/methanol/ethanol/benzene mixture at 100 kPa in a packed bed of MAF-6 at 298K. Source: Reproduced with permission from He, C.-T.; Jiang, L.; Ye, Z.-M.; Krishna, R.; Zhong, Z.-S.; Liao, P.-Q.; Xu, J.; Ouyang, G.; Zhang, J.-P.; Chen, X.-M. Exceptional Hydrophobicity of a Large-Pore Metal 2 Organic Zeolite. J. Am. Chem. Soc. 2015, 137, 72177223. Copyright 2015, American Chemical Society.

Taking advantage of the controllable coordination behavior of imidazolate derivatives, Zhang and coworkers reported that the pore surface hydrophilicity/hydrophobicity of metal azolate frameworks (MAFs) could be readily designed (Fig. 4.6). By varying the template, feeding order, and concentration of reactants during the crystallization of Zn(II)

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2-ethylimidazolate isomers, a MAF material with a hydrophobic external crystal surface and pore channel named MAF-6 was obtained.74 The terminated hydrophilic defects (unsaturated coordination sites) were successfully suppressed by careful control of the synthetic conditions. Gas and vapor adsorption isotherms, gas chromatography, water contact angle measurements, together with transient breakthrough and molecular dynamics simulations show that MAF-6 exhibits high porosity with a Langmuir surface area 1695 m2 g21 and a pore volume of 0.61 cm3 g21. The hydrophobicity and oleophilicity of MAF-6 are evidenced as follows: it can barely absorb water or be wetted by water with a water contact angle of 143 degrees, but readily adsorb large amounts of organic molecules including methanol, ethanol, mesitylene, adamantane, C6aC10 hydrocarbons, xylene isomers, and saturated/unsaturated analogues such as benzene/cyclohexene/cyclohexane or styrene/ethylbenzene. It can also separate these organic molecules from each other as well as from water by preferential adsorption/retention of those having higher hydrophobicity, lipophilicity, or oil/water partition coefficient. With these attributes, MAF-6 distinguishes itself with other porous materials such as SOD-[Zn (mim)2] (Hmim 5 2-methylimidazole, MAF-4/ZIF-8) with a hydrophobic pore surface but a hydrophilic crystal surface.

4.5 Induction of hydrophobicity by postsynthetic modification With suitable attention to linker design by incorporating desired chemical functionality, direct approaches to MOF synthesis are effective for predictively modulating the wettability of the resulting materials. Installing desired functionalities directly, however, is not always possible. To this end, postsynthetic modification (PSM) of MOFs has been instrumental in obtaining frameworks that feature desired functionalities. This approach has the advantage that it can be applied to known MOFs to enhance their hydrolytic stability while retaining some of their intrinsic properties. Two variants of this approach can be distinguished: functionalization with organic substituents and modification with inorganic nodes. The first variant requires a framework with reactive substituents on the ligand that can undergo organic transformations for the introduction of hydrophobic moieties. The second variant necessitates the existence of coordinatively unsaturated metals, allowing for the installation of organic groups. Cohen et al. pioneered the field in imparting hydrophobicity into the otherwise moisture-labile MOFs via PSM as exemplified by IRMOF-3 [Zn4O(NH2-BDC)3; NH2-BDC22 5 2-amino-1,4-benzenedicarboxylate].75 Alkyl chains with different lengths and degrees of branching can be introduced by the reaction of the amino groups with various carboxylic

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FIGURE 4.7 Schematic illustration of the MOFs after postsynthetic modification. One modified organic ligand substituent is shown in each structure. Source: Reproduced with permission from Nguyen, J.G.; Cohen, S.M. Moisture-Resistant and Superhydrophobic Metal-Organic Frameworks Obtained via Postsynthetic Modification. J. Am. Chem. Soc. 2010, 132, 45604561. Copyright 2010, American Chemical Society.

acid anhydrides (Fig. 4.7). To establish the relationship between functional group and the extent of modification of the hydrophobic character of the resulting materials, a set of experiments was conducted showing that longer and branched alkyl chains more efficiently confer the material with hydrophobicity. Contact angle measurements are used to examine the hydrophobic/hydrophilic properties of materials. To assess changes in the moisture stability and hydrophobicity/hydrophilicity of the materials upon PSM, each material was exposed to ambient air or immersed in water and then characterized using powder X-ray diffraction (PXRD) and SEM to investigate the structural integrity. Reacting IRMOF-3 with valeric anhydride yielded the material IRMOF3-AM4, which has a contact angle above 116 degrees and is thus moderately hydrophobic. The hydrolytic stability of these resulting samples was assessed by exposure to ambient air. The addition of hydrophobic substituents stabilizes the bulk crystallinity of the IRMOF structure in air. PXRD patterns of IRMOF-3-AM6 and IRMOF-3-AM15 remain virtually unchanged over 4 days, with no new peaks and little loss in peak intensity, whereas all of the reflections for IRMOF-3 decrease over time, thereby indicating that hydrophobic modifications to the IRMOF lattice can appreciably safeguard the crystallinity of these materials under standard atmospheric conditions. The broader applicability of this methodology was confirmed by transferring it to the MIL-53(Al) structure, giving rise to superhydrophobic materials using the same reaction. The approach shown above can substantially increase moisture resistance; however, a great decrease in the framework’s porosity was observed. To address this issue, Ma and coworkers contributed a general method to impart amphiphobicity on MOF crystals by chemically coating their exterior with a functional surface (Fig. 4.8A).76 The authors rationally designed vinylfunctionalized linkers for construction of MOFs, since vinyl groups can remain intact during the MOF synthesis, yet are sufficiently reactive for further chemical modifications. To controllably introduce fluorinated groups

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FIGURE 4.8 (A) Amphiphobic surface engineering for MOFs. The resultant MOFs exhibit both superhydrophobicity and oleophobicity, while retaining high crystallinity and intact porosity. (B) Schematic illustration to impart amphiphobicity on ZIF-8-V. Synthetic route to create amphiphobic surface via grafting perfluoroalkyl groups on the exterior surface of the ZIF-8-V crystal. Source: Reproduced with permission from Sun, Q.; He, H.; Gao, W.-Y.; Aguila, B.; Wojtas, L.; Dai, Z.; Li, J.; Chen, Y.-S.; Xiao, F.-S.; Ma, S. Imparting Amphiphobicity on Single-Crystalline Porous Materials. Nat. Commun. 2016, 7, 13300. Copyright 2016, Nature Publishing Group.

onto the exterior surface of the resulting MOFs, a relatively bulky fluorinated compound, 1H,1H,2H,2H-perfluorodecanethiol, was employed, which is highly reactive toward the vinyl moiety through a thiol-ene click reaction. After treating the vinyl-functionalized MOFs, isostructural with ZIF-8, named ZIF-8-V, with 1H,1H,2H,2H-perfluorodecanethiol, the resulting MOFs (ZIF-8VF) exhibit both superhydrophobicity and oleophobicity, while retaining high crystallinity and intact porosity, as revealed by contact angle measurements, vapor adsorption, gas adsorption, and PXRD (Fig. 4.8B). Notably, the contact angle of water on ZIF-8-VF sample is as high as 173 degrees, indicative of its extraordinarily superhydrophobic nature; by contrast, the pristine MOF, ZIF-8-V, gives a water contact angle of 89 degrees. Furthermore, ZIF8-VF also shows oleophobicity, as evidenced by the fact that when a series of organic compounds with different surface tensions, including glycerol, 2-hydroxybenzaldehyde, benzonitrile, chlorobenzene, and dodecane, were contacted with the surface of ZIF-8-VF, contact angles of 150, 143, 130, 129, and 92 degrees, respectively, were observed. In contrast, these organic compounds can quickly penetrate the pristine MOF, giving rise to corresponding contact angles of 0 degree. Advantageously, given that the modification only occurs on the external surface of the MOFs, the crystallinity and porosity of the pristine MOFs are fully retained. The chemical shielding effect resulting from the amphiphobicity of the MOFs is illustrated by their performance in water/organic vapor adsorption, as well as by their long-term ultrastability under highly humidified CO2 environments and exceptional chemical stability in acid/base aqueous solutions. More importantly, this strategy is generally applicable, as another vinyl-functionalized MOF (MOF-5-V), isostructural with MOF-5, can be ready conferred with amphiphobic properties, showing extraordinary tolerance to humidified CO2. These results reinforce the utility of these materials in extended applications under harsh environments such as strong acidic and basic conditions.

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Similarly, Huang and coworkers synthesized a superhydrophobic zeolitic imidazolate framework (ZIF-90) through postfunctionalization via an amine condensation reaction between the free aldehyde in ZIF-90 and pentafluorobenzylamine. The resulting material showed high steam stability and has great promise as an effective and durable adsorbent for bio-alcohol recovery.77 The aforementioned examples illustrate that PSM processes avoid the need for (potentially very challenging) synthesis of fluorinated ligands as well as the synthesis of the MOF itself, and many potentially suitable reagents for substitution are commercially available. However, this strategy also has some notable drawbacks: the MOF must be able to withstand the reaction conditions, it is only applicable to MOFs with suitable reactive sites, and the reagents must be able to penetrate into the MOF’s pores. The intrinsic presence of metalaOH groups at metal-oxo nodes of MOFs and their ability to be easily modified provide an alternative route for PSMs, which is advantageous over ligand modification processes that require extra functional groups as an anchor for postmodification steps. Kim and coworkers initiated an attempt to prepare superhydrophobic MOFs by modification of the metal-oxo nodes (Fig. 4.9).78 Given the unique properties of NH2-functionalized MOFs,

FIGURE 4.9 Preparation of superhydrophobic NH2-UiO-66-shp and its versatile applications. Source: Reproduced with permission from Sun, D.; Adiyala, P.R.; Yim, S.-J.; Kim, D.-P. Pore-Surface Engineering by Decorating Metal-Oxo Nodes with Phenylsilane to Give Versatile Super-Hydrophobic Metal-Organic Frameworks (MOFs). Angew. Chem. Int. Ed. 2019, 58, 74837487. Copyright 2019, John Wiley and Sons.

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NH2-UiO-66 was chosen as a model. After treating with phenyl silane, the resulting MOF (NH2-UiO-66-shp) exhibited superhydrophobicity, leading to greatly improved base resistance, whereas the pristine MOF, NH2-UiO-66, quickly decomposes under basic conditions. The superhydrophobicity and high stability of NH2-UiO-66-shp also endow it with great promise for versatile applications, including organic/water separation, self-cleaning, and the formation of liquid marbles for microfluidic devices and sensing. This proof-of-concept study is important, given the wide prevalence of metalaOH groups in MOFs and their facile modification. The precise modification on the metal-oxo nodes of MOFs without blocking the windows of the pores maximizes the preservation of the accessibility of the pores, ensuring their availability in practical applications. This work not only provides a promising material for various functional applications but more importantly, also advances a new and general approach for designing superhydrophobic MOFs for practical uses. In view of the strong interaction between phosphonic acid derivatives and Zr species, Ma and coworkers reported a facile method to modify the external surface of Zr-based MOFs with superhydrophobicity through the incorporation of n-octadecylphosphonic acid (OPA). Such modification has little effect on the inherent porosity and surface area of the pristine MOF while significantly improving the material’s hydrophobicity, thereby rendering it with a high level of resistance to acidic/ basic aqueous solutions and potential in fast removal of organic pollutants from water.79 Han and coworkers developed a universal strategy of constructing superhydrophobic and superoleophilic MOF composites via the reaction between open metal sites on the activated MOFs and octadecylamine. The resulting MOF materials exhibit superhydrophobicity with fully retained porosity and crystallinity. They all demonstrated high adsorption capacities toward organic solvents and exhibited excellent oilwater separation performance (.99.5%) without external pressure.80

4.6 Introduction of external surface corrugation by use of a hydrophobic unit Despite improving the moisture or water stability of MOFs, the approaches described earlier have some crucial drawbacks, such as reduced porosity and complex synthetic procedures. Inspired by the lotus effect, a wide variety of techniques have been employed to fabricate superhydrophobic surfaces by tailoring both surface chemistry and texture. An alternative strategy for providing highly hydrophobic exterior surfaces while retaining the internal porosity would be the

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generation of surface roughness on the nano- to micrometer scale as it is well established that the texturing of a solid surface can significantly increase its hydrophobicity with respect to liquid water.81,82 It is envisioned that in the context of MOFs, ligands featuring an anisotropic crystal morphology with a predominant surface that is both highly corrugated and terminated by aromatic hydrocarbon moieties, which would provide a low-energy surface, are expected to provide a high level of hydrophobicity without the need for any modifications. Kitagawa and coworkers reported such a superhydrophobic MOF material by judicious choice of ligand.83 1,3,5-Tris(3-carboxyphenyl)benzene (H3BTMB) was thus used to coordinate with a Zn species to yield [Zn4(µ3-OH)2(BTMB)2(DMF)3(MeOH)], which possesses an aromatic hydrocarbonterminated surface (Fig. 4.10). To examine the material’s hydrophobic properties, contact angle measurements were performed on as-synthesized and activated powder, single crystals, and pellets, all of which yielded markedly different results, verifying that the nanosurface corrugation has a great impact on the material wettability. Recently, the same group extended such synthetic methods to preparing other MOFs with nanosurface corrugation, named PESD-2 and PESD-3 [Zn2M2(µ3-OH)2(BTMB)2] (MQCo and Ni), with Co21 or Ni21 occupying the octahedrally coordinated Zn21 positions.84 The resulting materials exhibit outstanding superhydrophobic properties with retained performance even under elevated temperature condition. This material also exhibits oil spill cleanup from the water surface in the powder form as well as pellet form up to 385 wt.%. These studies open a new avenue for designing and engineering new composite superhydrophobic porous materials for better water and thermal stability, giving a significant promise for a wide range of applications such as catalysis, separation technology, and addressing environmental problems. Given that multilevel topography could effectively reduce the adhesion and achieve robustness for improving hydrophobicity, Meng and coworkers fabricated a MOF array coating architecture on a copper substrate with a hierarchical micro-/nano-flowerlike architecture by in situ ligand-solvothermal transformations (Fig. 4.11). Benefiting from the unique hierarchical structure, the resulting material exhibits superhydrophobicity, showing a remarkable n-hexane permeate flux as high as 8.3 3 104 L m22 h21 with a separation efficiency above 99.5%.85 Chin and coworkers reported a simple strategy for the synthesis of microstructured surfaces via MOF self-assembly. The developed approach allows for localizing epitaxial growth of MOF at the tips of needle crystals to create mushroom-shaped structures, thus conferring reentrant textures to the MOF-functionalized surfaces. After the needles were subjected to continual growth and the MOF caps had been

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FIGURE 4.10

X-ray single-crystal structures showing (A) 1,3,5-tris(3-carboxyphenyl)benzene [H3BTMB, from “benzene-1,3,5-tris(m-benzoic acid)”], (B) the coordination environment around a single [Zn4(µ3-OH)2]61 cluster, (C) views of a 2D layer consisting of the clusters shown in (B) linked by BMTB32 linkers, (D) the 3D stacking of individual 2D layers, and (E) the structure of the (0k0) surface, which affords a low-energy surface. Hydrogen atoms and solvent molecules have been omitted for clarity in many structures. (F) Schematic representation of PESD-1 in four states, and pictures of a water droplet on corresponding PESD-1 samples. The left two objects are assynthesized forms and the right two objects are degassed forms. Source: Reproduced with permission from Rao, K.P.; Higuchi, M.; Sumida, K.; Furukawa, S.; Duan, J.; Kitagawa, S. Design of Superhydrophobic Porous Coordination Polymers Through the Introduction of External Surface Corrugation by the Use of an Aromatic Hydrocarbon Building Unit. Angew. Chem. Int. Ed. 2014, 53, 82258230. Copyright 2014, John Wiley and Sons.

functionalized with perfluorooctanoyl chloride, the anodized aluminum oxide (AAO)/MOF surfaces were found to be oleophobic, displaying contact angles of up to 100 degrees with n-hexadecane.86

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FIGURE 4.11 (A) Scheme of the preparation process. Typical SEM images of the (B) ZnO array coatings and (C) micro-/nano-MOF array coatings; the insets are the corresponding magnified images. Schematic diagram of the contact state corresponding to the (D) ZnO array state and (E) MOF array state. Source: Reprinted with permission from Zhang, G.; Zhang, J.; Su, P., Xu, Z.; Li, W.; Shen, C.; Meng, Q. Non-Activation MOF Arrays as a Coating Layer to Fabricate a Stable Superhydrophobic Micro/Nano Flower-Like Architecture. Chem. Commun. 2017, 53, 83408343. Copyright 2017, Royal Society of Chemistry.

4.7 Hydrophobic metal-organic framework composites To provide a more general approach applicable to any MOFs, Yu and coworkers developed a facile vapor deposition technique by modifying the surfaces of MOF materials with hydrophobic polydimethylsiloxane (PDMS) to enhance their water and moisture resistance (Fig. 4.12).87 MOF-5, HKUST-1, and ZnBT as representative vulnerable MOFs were successfully coated by PDMS, with well-inherited crystalline nature and pore characteristics. The resulting PDMS-coated MOFs all exhibit highly hydrophobicity with water contact angles of 130 6 2 degrees, while their pristine MOFs show water contact angles close to 0 degree. It is worthy of mention that such coating is stable as evidenced by the hydrophobic behavior of the modified MOFs remaining unchanged, even after prolonged exposure to ambient air. To identify the presence of the PDMS layer on these representative MOFs, a composition line-scan was

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FIGURE 4.12 Illustration of PDMS coating on the surface of MOFs and the improvement of moisture/water resistance of MOFs. Source: Reproduced with permission from Zhang, W.; Hu, Y.; Ge, J.; Jiang, H.-L.; Yu, S.-H. A Facile and General Coating Approach to Moisture/ Water-Resistant Metal-Organic Frameworks with Intact Porosity. J. Am. Chem. Soc. 2014, 136, 1697816981. Copyright 2014, American Chemical Society.

performed, showing the homogeneous distribution of silica throughout the coated MOF, with a Si/Zn atomic ratio of B4.1%. These results inferred that the PDMS had been successfully coated on the MOF surface, which was further proven by high-resolution transmission electron microscopy (HRTEM), clearly showing a B10 nm PDMS coating layer on the MOF surface. The coated PDMS layer significantly promotes the moisture/water resistance of these unstable MOFs, and thereby renders the coated MOFs with well-preserved performance in gas storage and catalysis under practical humid conditions. Later, Zhu and coworkers reported a versatile and straightforward approach to deposit a layer of hydrophobic organosilicone on the MOFs’ external surface with enhanced water stability via a simple solutionimmersion process. The hydrophobic coating is able to protect the encapsulated MOF crystals against water molecules and therefore improves their water stability without significantly decreasing their initial sorption capacity in terms of porosity properties. This strategy is transferable as demonstrated that three representative MOFs (NH2-MIL-125(Ti), ZIF-, and HKUST-1) with different topologies and metal nodes have been successfully imparted with hydrophobicity.88 Moreover, this approach seems very promising as it does not affect the accessibility of the pore space. However, to date the strategies mentioned earlier have only been applied to MOFs with micropores; it will be very interesting to see if this process can be applied to compounds with meso- and macropores without sacrificing porosity. Matzger and coworkers developed another robust route for improving the hydrolytic stability of notoriously water-sensitive MOFs by the incorporation of hydrophobic linear polymer, as exemplified by the

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synthesis of composites of MOF-5 and polystyrene (MOF-5-PS).89 The MOF-5-PS composite is formed by neat heating styrene with MOF-5 at 65 C. The material produced after 24 h of heating (MOF-5-PS-24h) possesses remarkably increased hydrolytic stability over pristine MOF-5, as demonstrated by the fact that the pristine MOF-5 degraded at 53% RH within 4 h, whereas the MOF-5-PS composite was stable for over 3 months under otherwise identical conditions. Maspoch and coworkers presented a rapid and scalable spray-drying (SD) synthesis of MOF@polymer composites with enhanced hydrolytic stabilities.90 As a model study, HKUST-1 and polystyrene (PS) were the MOF and polymer of choice, respectively. The MOF crystals were encapsulated in the PS polymeric matrix by a spray dryer using a mixture of a colloidal HKUST-1 crystals suspension and a PS solution as a feed. This method does not require any purification or filtration steps, since the composites are obtained directly in a dried, pure form. In the resulting composites, the polymer protects the embedded MOF crystals against water molecules, without substantially decreasing their initial sorption capacity, and greatly increases their water resistance in terms of porosity properties (Fig. 4.13). In contrast to forming a random composite of polymer and MOF, Wang et al. partitioned the channels of MOFs into confined, hydrophobic compartments by in situ polymerizations of aromatic acetylenes. Specifically, polynaphthylene was formed via a radical reaction inside the channels of MOF-5 and served as partitions without altering the underlying structure of the framework (Fig. 4.14). With the imparted hydrophobicity, not was only the hydrolytic stability significantly improved but also the competitive adsorption of water versus CO2, which drastically dampens their capacity and selectivity under real humid flue gas conditions, was reduced. Compared with pristine MOF-5, the resulting material (PN@MOF-5) exhibits a doubled CO2 capacity (78 vs 38 cm3 g21 at 273K and 1 bar), 23 times higher CO2/N2 selectivity (212 vs 9), and significantly improved moisture stability, thereby showing great promise for CO2 capture under real humid flue gas conditions.91 In addition to the use of polymer, Fischer and coworkers reported the synthesis of various MOF composites with fluorographene (FG), which allows functional groups to be incorporated into the basal plane of graphene rather than at the edges of the layers. The composites (HFGO@ZIF-8) were achieved by the combination of highly fluorinated graphene oxide (HFGO) with ZIFs. The PXRD of HFGO@ZIF-8 featured all planes corresponding to pristine ZIF8.92 N2 sorption isotherms reveal that the hybrid possesses hierarchical pore structure with a BET surface area of 590 m2 g21. Characterization results indicate that the ZIF-8 nanocrystals act as pillars intercalated between HFGO layers by selective nucleation and controlled growth over oxygen functional groups, producing a hierarchical porous structure. Furthermore, the aCF3

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FIGURE 4.13 (A) Schematic of the spray-drying synthesis of HKUST-1@PS composites. (B) Representative FESEM image of HKUST-1@PS_18% and a discrete composite sphere (inset). Scale bars: 10 and 2 µm (inset). (C) From bottom to the top: PXRD of the simulated patterns for HKUST-1, HKUST-1@PS_18, and the HKUST-1@PS_18 incubated overnight in either water or 10% HCl (v/v) solution. Source: Reproduced with permission from Carne´-Sa´nchez, A.; Stylianou, K.C.; Carbonell, C.; Naderi, M.; Imaz, I.; Maspoch, D. Protecting Metal-Organic Framework Crystals from Hydrolytic Degradation by Spray-Dry Encapsulating Them into Polystyrene Microspheres. Adv. Mater. 2015, 27, 869873. Copyright 2015, John Wiley and Sons.

termination of the HFGO layers gives the composite very low surface energy. These features render the resulting composite with superhydrophobicity. Contact angle measurements showed the composite’s water contact angle (162 degrees) and oil contact angle (0 degree), indicative of superoleophilicity and oleophilicity. The composite material HFGO@ZIF-8 (activated at 160 C) was further exploited for the absorption of oils and various organic solvents. ZIF-8 itself shows an absorption capacity in the range of 10150 wt.%, while HFGO shows negligible uptake, whereas the absorption capacity of HFGO@ZIF-8 is much enhanced and ranges between 20 and 280 wt.%, outperforming those reported for resins and other porous composites (Fig. 4.15). In a continuation of this work, the same group reported an economically viable and readily scalable preparation of hydrophobicoleophilic porous gels by simple mixing of hybrid composites of FGO and metal-organic gel (MOG) composed of Al31 ions and 1,3,5-benzene-tricarboxylate (BTC) linkers and

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FIGURE 4.14 (A) Illustration of competitive adsorption of CO2 against H2O at the surface and edge of PN. (B) Polymerization of DEB in MOFs. (C) Pore size distributions of PN@MOF-5, PN3.2@MOF-5, and MOF-5 based on quenched solid-state density functional theory. (D) CO2 sorption isotherms of PN@MOF-5 and MOF-5 at 273K, 283K, and 298K. (E) Contact angle measurements. (F) Nitrogen sorption profiles of PN@MOF-5 and MOF-5 after exposure to humidity for different times. Source: Reproduced with permission from Ding, N.; Li, H.; Feng, X.; Wang, Q.; Wang, S.; Ma, L., Zhou, J.; Wang, B. Partitioning MOF-5 into Confined and Hydrophobic Compartments for Carbon Capture Under Humid Conditions. J. Am. Chem. Soc. 2016, 138, 1010010103. Copyright 2015, American Chemical Society.

FIGURE 4.15 Illustration showing the concept of the formation and structure of HFGO@ZIF-8. Source: Reproduced with permission from Jayaramulu, K.; Kumara, K.; Datta, R.; Ro¨sler, C.; Petr, M.; Otyepka, M.; Zboril, R.; Fischer, R.A. Biomimetic Superhydrophobic/ Superoleophilic Highly Fluorinated Graphene Oxide and ZIF-8 Composites for Oil-Water Separation. Angew. Chem. Int. Ed. 2016, 55, 11781182. Copyright 2016, John Wiley and Sons.

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FIGURE 4.16 Schematic representations of IRMOF-1 (top) and IRMOF-1 after thermal modification to produce amorphous carbon-coated MOFs (middle) and, at higher temperature, ZnO nanoparticles@amorphous carbon (bottom). The corresponding XRD patterns are shown on the right. Source: Reproduced with permission from Yang, S.J.; Park, C.R. Preparation of Highly Moisture-Resistant Black-Colored Metal-Organic Frameworks. Adv. Mater. 2012, 24, 40104013. Copyright 2012, John Wiley and Sons.

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under solvothermal conditions. The water contact angle of FGO@MOG tablet was 126 6 4 degrees indicating a highly hydrophobic behavior.93 Ghosh and coworkers reported a hydrophobic MOF membrane UHMOF-100/PDMS/PP (UHMOF 5 ultrahydrophobic MOF; PP 5 polypropylene fabric). UHMOF-100 [Cu2(BTFPADB)2] consists of the fluorinated linker 4,4-[3,5-bis(trifluoromethyl)-phenyl]azanediyldibenzoic acid in the presence of copper nitrate. To examine the superhydrophobic behavior of UHMOF-100, contact angle measurements were conducted, with a water contact angle of 177 degrees and an oil contact angle of 0 degree, indicative of superoleophilicity. Vapor sorption isotherms collected at 298 K revealed that only negligible water uptake was recorded, but for hydrophobic organic vapor molecules (benzene, ethylbenzene, toluene, and p-xylene) significant uptake is observed. To utilize the properties of UHMOF-100, it was integrated into a device by spray coating the MOF onto a PDMS/PP membrane. The water contact angle of the prepared membrane was found to be 135 degrees highlighting the hydrophobic nature of the fabricated MOF membrane.94 Willis and coworkers investigated an alternative method for postsynthetically modifying Cu-BTC by a plasma-enhanced chemical vapor deposition of perfluorohexane (PFH), enhancing the stability of Cu-BTC against degradation by water as a result of increased hydrophobicity. The overall crystal structure of Cu-BTC is maintained when submerged in water, and an enhancement of ammonia adsorption capacities gives Cu-BTC plasma broad appeal for many potential applications.95 Through Monte Carlo simulations it was found that PFH sites itself in such a way within Cu-BTC as to prevent the formation of water clusters, hence preventing the decomposition of CuBTC by water. In view of that incorporation of “carbonaceous grease” is helpful to improve the hydrolytic stability of MOFs. Park and coworkers demonstrated that thermal modification of IRMOF-1 remarkably enhanced the stability of the framework against hydrolysis. Specifically, heat treatment of the IRMOF-1 samples led to the formation of an amorphous carbon coating on their surfaces, thus shielding the framework from decomposition under humid conditions. The thermally modified MOFs retained their crystal structure and pore characteristics, even after 14 days of exposure to ambient air.96 This scalable and environment-friendly modification method opens new opportunities for the commercial preparation of water-resistant MOFs (Fig. 4.16). It is well known that the practical applications of zeolitic imidazolate frameworks (ZIFs) have been hampered by their structural instability in humid acidic conditions. Guided by density functional theory calculations, Liang and coworkers demonstrated that the acidic stability of two polymorphic ZIFs (i.e., ZIF-8 and ZIF-L) can be enhanced by the incorporation of functional groups on polypeptides or DNA, which regulates the original Zn-N coordinative environment; concurrently the encapsulated biomolecules are stabilized

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by the ZIF exoskeleton, protecting them from denaturation.97 A range of complementary synchrotron investigations into the local chemical structure and bonding environment suggest that the enhanced acid stability arises from the newly established coordinative interactions between the Zn centers and the inserted carboxylate (for polypeptides) or phosphate (for DNA) groups, both of which have lower pKa’s than the imidazolate ligand. These findings introduce the principle of regulating the bonding environment to stabilize MOFs, paving the way for more sophisticated applications. The integration of MOFs with other materials has been used successfully to prepare composites of MOFs with polymers, carbon materials, or biomolecules. This strategy is very promising because it appears to be universally applicable and the resulting composites couple the beneficial properties of microporous MOFs with the desirable qualities of the other component of the composite. Most reports describing these systems have been based on MOFs that are not inherently sensitive toward water; it would be interesting to see if other more sensitive MOFs could be protected by these hierarchical structures. In general, the combination of two or more of these synthetic concepts to trigger synergistic effects would be very exciting.

4.8 Potential applications of hydrophobic metal-organic frameworks and their composites As discussed in the previous sections, hydrophobic MOF materials and related composites can be synthesized by various routes and have potential industrial applications in various fields. Although the industrial-scale use of hydrophobic MOFs is still distant, they have very attractive properties that make such uses quite plausible in the future. This section presents some key examples that highlight recent advances in the preparation and use of hydrophobic MOFs with potential applications in gas separation/ storage, catalysis, and separation of oil spills from water.

4.9 Gas separation/storage The porosity of MOFs makes them attractive for gas storage applications, where the gaseous density within the framework may be increased relative to bulk gas due to framework 2 guest interactions. In order to achieve separation between two or more components, there must be a differentiation between how the analyte gases interact with the framework, either by size or energetically. There are two primary energetic regimes of gasframework interaction: chemisorption, where the uptake of the gas is dependent on a chemical transformation

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(e.g., bond formation or charge transfer) and physisorption, where the guest molecule interacts with the electric field produced by the framework. Kitagawa and coworkers synthesized a perfluorobutyl-functionalized twodimensional porous coordination polymer (PCP), {[Cu(bpbtp)(L)(DMF)] (DMF)}n (H2bpbtp 5 2,5-bis(perfluorobutyl)terephthalic acid, L 5 2,5-bis(perfluorobutyl)-1,4-bis(4-pyridyl)benzene, DMF 5 N,N-dimethylformamide).98 The pore surface of the PCP is decorated with pendent perfluorobutyl groups that create a densely fluorinated nanospace resulting in unique gas sorption properties. The unique adsorption properties such as preferential adsorption of CO2 and O2, and hysteresis loops in the isotherms for both gases can be attributable to the strong hostguest interactions. Due to the high polarity, fluorophilic character, and low affinity for moisture of fluorinated MOFs, they are a particularly appealing platform for the adsorption of fluorocarbons and chlorofluorocarbons, which are potent greenhouse species. Miljani´c and coworkers reported the synthesis of two mesoporous fluorinated MOFs from extensively fluorinated tritopic carboxylate- and tetrazolate-based ligands (1 and 2, respectively, Fig. 4.17) with Cu(NO3)2 2.5H2O. The resulting tetrazolate-based framework MOFF-5 has an accessible surface area of 2445 m2 g21, the highest thus far achieved among fluorinated MOFs. MOFF-5 crystals exhibit unique affinity toward fluorocarbons and chlorofluorocarbons (CFCs), with weight capacities of up to 225% within seconds of exposure. In addition, this mesoporous material shows unique CO2 sorption isotherms and preference for nonspherical guest molecules, which could tentatively be





FIGURE 4.17

Extensively fluorinated tritopic MOF precursors 1 and 2. Source: Reproduced with permission from Chen, T.-H.; Popov, I.; Kaveevivitchai, W.; Chuang, Y.-C.; Chen, Y.-S.; ˇ Mesoporous Fluorinated Metal-Organic Frameworks with Jacobson, A.J.; Miljani´c, O.S. Exceptional Adsorption of Fluorocarbons and CFCs. Angew. Chem. Int. Ed. 2015, 54, 1390213906. Copyright 2015, John Wiley and Sons.

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rationalized by the low polarities of those guests, mismatched with the highly polarized environment inside fluorinated cavities.99 Given their hydrophobicity and the presence of X 2 F dipoles, fluorinated MOFs have recently emerged as attractive candidates for CO2 removal from fuel gas, whereby hydrophobicity should render the MOF stable toward water vapor, and the presence of CaF dipoles should lead to favorable interactions with the quadrupole of CO2. Farha and coworkers developed a new functionalization technique named solvent-assisted ligand incorporation to incorporate perfluoroalkane carboxylates of various chain lengths (C1aC9) in the Zr-based MOF, NU-1000.100 These fluoroalkanefunctionalized mesoporous MOFs were studied experimentally and theoretically as potential CO2 capture materials. CO2 adsorption studies indicate that perfluoroalkane-functionalized nodes in the resulting system synergistically act as the primary CO2 binding sites, manifesting in systematically higher values for isosteric heat of adsorption (Qst), with increasing chain length. With a synthetic pathway to highly porous fluorinated MOFs, it is expected that exploration and understanding of their adsorption properties will increase. These promise to be distinctive, because of the highly polarized and fluorophilic pore surfaces, electron-deficient nature of aromatic nuclei, and the hydrophobicity of the framework (Fig. 4.18).

FIGURE 4.18 (A) Molecular representations of NU-1000 and schematic representation of solvent-assisted ligand incorporation (SALI). (B) BJH pore size distributions and N2 adsorption isotherms (inset) for NU-1000 and SALI-n samples. (C) Qst of NU-1000, SALI-n, and SALI-n0 samples: (top) calculated from experimental isotherm data and (bottom) comparison of simulated (sim) and experimental Qst values for selected MOFs. (D) Simulated snapshot of CO2 adsorption depicting the primary CO2 binding sites in SALI-7. Source: Reproduced with permission from Deria, P.; Mondloch, J.E.; Tylianakis, E.; Ghosh, P.; Bury, W.; Snurr, R.Q.; Hupp, J.T.; Farha, O.K. Perfluoroalkane Functionalization of NU-1000 via SolventAssisted Ligand Incorporation: Synthesis and CO2 Adsorption Studies. J. Am. Chem. Soc. 2013, 135, 1680116804. Copyright 2013, American Chemical Society.

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4.10 Oil spill cleanup There will be a risk of spillages that may result in significant environmental damage and vast economic loss, as long as oil is prospected, transported, stored, and used. Worldwide, oil spill cleanup costs amount to over $10 billion dollars annually. The adverse impact to ecosystems and the long-term effects of environmental pollution by these and other releases call for an urgent need to develop new materials for cleaning up oil from impacted areas. There are many adsorbents currently in use for oil spill cleanup, including sand, organoclays, and cotton fibers. These adsorbents, however, typically have a strong affinity for water, limiting their effectiveness in cleanup operations. Therefore the development of waterproof sorbents that are effective even at a very low concentration of oil residue remains an urgent challenge. The devastation resulting from the recent Deepwater Horizon oil spill raised awareness and underscored the urgent need for water-stable/-proof sorbents that can effectively remove oil residue in water, on land, and in the air. Hydrophobic MOFs have shown potential for oil cleanup. However, these MOFs were synthesized as microcrystalline powders, and therefore their applications in real-world separation could be affected by poor processability and handling. In addition, the limited pore volume of the MOF material restricts its adsorption capacity. To address these concerns, researchers were motivated to incorporate superhydrophobic MOF coatings onto other substrates to increase applicability. Jiang and coworkers also reported a hydrophobicoleophilic composite by the integration of a hydrophobic MOF with graphene oxide (GO)/sponge composite. The MOF used in this study, USTC6 (Cu2HFPD), is constructed from a tetracarboxylate-based organic linker 4,40 (hexafluoroisopropylidene)diphthalic acid with a Cu2 paddlewheel secondary building unit (SBU). Single-crystal XRD analysis reveals 2D layers in the ac plane with a wavelike surface pendent aCF3 groups between the 2D layers, which decrease the surface energy and induce the high hydrophobicity of USTC-6, giving a water contact angle of 132 degrees. The authors incorporated the obtained hydrophobic MOF on branched sponges functionalized with GO, which facilitate anchoring of USTC-6. The resulting composite retains the hydrophobic/oleophilic nature of USTC-6.101 Remarkably, the sorbent can be further assembled with tubes and a self-priming pump to build a model apparatus that affords consecutive and efficient oil recovery from water. The easy and fast recovery of oils/organic solvents from water based on such an apparatus indicates that it has great potential for future water purification and treatment. Meng and coworkers developed novel superhydrophobic/superoleophilic materials composed of wrinkled microspherical MOF@rGO composites, which possess a unique micro/nanohierarchical architecture consisting of crumpled rGO nanosheets intercalated with well-dispersed MOF nanoparticles.102 Due to the synergistic effects of superwettability and high

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FIGURE 4.19 (A) Digital photographs of pure PU sponge and ZIF-8@rGO@Sponge in water. (B) Silicone oil and water droplets on the ZIF-8@rGO@Sponge with inserted profiles and contact-angle values. (C and D) Digital photographs showing the absorption of dyed silicone oil (C) and chloroform (D) from water by ZIF-8@rGO@Sponge. (E) Oil- and organic-solvent-absorption capacity of the ZIF-8@rGO@Sponge. (F) Separation efficiency of the ZIF-8@rGO@Sponge. (G) Absorption recyclability test of the ZIF-8@rGO@Sponge. The errors are estimated to vary from 2.7% to 6.0% for the absorption capacity and from 0.2% to 0.4% for the separation efficiency. Source: Reproduced with permission from Gu, J.; Fan, H.; Li, C.; Caro, J.; Meng, H. Robust Superhydrophobic/Superoleophilic Wrinkled Microspherical MOF@rGO Composites for Efficient Oil-Water Separation. Angew. Chem. Int. Ed. 2019, 58, 52975301. Copyright 2019, John Wiley and Sons.

meso/microporosity, the formed MOF@rGO composites display a higher absorption capacity and selectivity for the removal of organic solvents and oils from water than the individual constituents. Furthermore, a ZIF8@rGO@Sponge adsorbent made from a commercial polyurethane (PU) sponge showed prominent oilwater separation performance and good recyclability. This study not only provides a promising material for oil spill cleaning and wastewater treatment for organic contaminants, but also a new concept for the structural and multifunctional exploitation of graphene/ MOF-based composite materials (Fig. 4.19).

4.11 Catalysis Control of the wettability of a catalyst surface is widely known to be of great importance in the regulation of interactions between heterogeneous catalysts and reactants, which is directly related to catalytic activity and selectivity. Jiang and coworkers reported that hydrophobic modification can enhance catalytic performance. They performed styrene

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FIGURE 4.20 (A) Preparative route for Pd/UiO-66@PDMS. (B) Catalytic hydrogenation of styrene over UiO-66@PDMS, Pd/UiO-66, and Pd/UiO-66@PDMS (1:150 Pd:styrene molar ratio). Source: Reproduced with permission from Huang, G.; Yang, Q.; Xu, Q.; Yu, S.-H.; Jiang, H.-L. Polydimethylsiloxane Coating for a Palladium/MOF Composite: Highly Improved Catalytic Performance by Surface Hydrophobization. Angew. Chem. Int. Ed. 2016, 55, 73797383. Copyright 2016, John Wiley and Sons.

hydrogenation in a batch reaction over the pristine composite Pd/UiO-66 and a PDMS-modified hydrophobic hybrid, Pd/[email protected] The parent Pd/UiO-66 required 255 min to achieve complete hydrogenation. By contrast, the PDMS-coated hybrid afforded full conversion within 65 min. The enhanced activity of the Pd/UiO-66@PDMS hybrid could thus be primarily ascribed to the hydrophobic responsive PDMS surface modification of the Pd surface, leading to the enhanced affinity for hydrophobic substrates. The composite Pd/UiO-66@PDMS catalyst also showed superior performance in the hydrogenation of other hydrophobic substrates such as nitrobenzene and cinnamaldehyde (Fig. 4.20). Long and coworkers investigated the effects of a local hydrophobic environment on product selectivity and catalyst stability with respect to cyclohexane oxidation in expanded analogues of Fe2(dobdc) (dobdc42 5 2,5-dioxido-1,4-benzenedicarboxylate), a MOF featuring exposed iron(II) sites.104 A threefold enhancement of the alcohol:ketone (A:K) product ratio and an order of magnitude increase in turnover number can be achieved by simply altering the framework pore diameter and installing nonpolar, hydrophobic functional groups near the iron center. Detailed Mo¨ssbauer spectroscopy, kinetic isotope effect, and adsorption studies suggest that the incorporation of simple nonpolar groups remarkably increases both the selectivity and stability of framework-embedded iron sites for cyclohexane oxidation catalysis without directly affecting the structure or reactivity of the iron centers themselves. Outer coordination sphere and pore environment effects may prove to be significant in the context of many other MOF-catalyzed reactions and are well worthy of further investigation (Fig. 4.21). Hu and coworkers reported the effect of hydrophobic modification in the catalytic hydrogenation of cinnamaldehyde using iron(III)

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FIGURE 4.21 Oxidation of cyclohexane to cyclohexanol and cyclohexanone in Fe2(dobdc) and expanded pore derivatives and view of one-dimensional hexagonal pores of Fe2(dobdc), with an inset showing the local coordination environment around each coordinatively unsaturated iron(II) site and the corresponding TON values in oxidation of cyclohexane. Source: Reproduced with permission from Xiao, D.J.; Oktawiec, J.; Milner, P.J.; Long, J.R. Pore Environment Effects on Catalytic Cyclohexane Oxidation in Expanded Fe2(dobdc) Analogues. J. Am. Chem. Soc. 2016, 138, 1437114379. Copyright 2016, American Chemical Society.

porphyrin (FeP-CMP) to modify the surface of MIL-101@Pt and prepare MIL-101@Pt@FeP-CMP. In the same work, the authors proved that MIL-101@Pt@FeP-CMP sponge has a higher turnover frequency (1516.1 h21), with 97.3% selectivity for cinnamyl alcohol in 97.6% yield.105

4.12 Conclusions and perspectives In this chapter, we provide a comprehensive summary of the design concept, preparation, and applications of hydrophobic MOFs and their composites, highlighting state-of-the-art strategies. We discussed the basics of wetting of hydrophobic materials, followed by four strategies for preparing hydrophobic MOFs, namely, (1) the use of hydrophobic ligands, (2) postsynthetic grafting of hydrophobic side chains onto reactive sites (ligand or metal node), (3) the targeted exploitation of surface corrugation to induce hydrophobicity, and (4) the preparation of hydrophobic composites. While ligand functionalization is the most wellstudied approach, it is restricted to structures where nonpolar entities can be incorporated without compromising the structural nature of the framework. Surface modification approaches based on coreshell models hold promise for a number of further systems provided there is

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References

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compatibility in the binding domain for the core and shell entities. Imparting crystal surface hydrophobicity via hydrophobic polymer coating approaches is perhaps one of the simplest and most generalizable approaches for improving MOF water stability, in view of the fully retained specific surface area and crystal textural properties of the resulting composites. Given the low adhesion of water molecules, MOF materials with hydrophobicity could not only repel water molecules, thereby protecting MOFs against hydrolysis, but also render them with new properties. We give examples of intriguing properties of MOFs and related composites with hydrophobicity for various applications. This summary of the wettability control of MOFs and its ability to increase their hydrolytic stability and confer new properties upon them lays important groundwork that will help accelerate their practical application. Building upon these achievements, further insight into how the modification strategy affects the MOF adsorption properties and processibility in the target application still need to be explored.

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S E C T I O N

5

Frustrated Lewis pairs and small molecule activation

C H A P T E R

5 Rivaling transition metal reactivity—an exploration of frustrated Lewis pairs chemistry Meera Mehta1 and Christopher B. Caputo2 1

Department of Chemistry, The University of Manchester, Manchester, United Kingdom, 2Department of Chemistry, York University, Toronto, ON, Canada

5.1 Introduction One of the key functions of a catalyst is the activation of relatively inert nonpolar chemical bonds and the incorporation of these activated species into new molecules, many of which are value-added chemical products. The widespread use of catalysts is highlighted by the fact that B90% of fine chemicals require a catalytic step at some stage of their preparation.1 Traditional catalysts tend to feature the late transition metals, as they can access redox processes to effect bond modification (consider Pd-catalyzed cross-coupling).2 However, such elements are often expensive and have low crustal abundance. By contrast, maingroup elements are less expensive, have high crustal abundance, and in the case of lighter elements are often less toxic.3 These advantages have spurred increasing interest in main-group systems to effect stoichiometric small molecule activation and have led toward catalytic transformations. Perhaps the most successful example in this arena is the study of frustrated Lewis pair (FLP) systems, first introduced by Prof. Douglas Stephan in 2006.4

Synthetic Inorganic Chemistry DOI: https://doi.org/10.1016/B978-0-12-818429-5.00003-X

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5.2 Evidence that unique chemistry was possible with main-group Lewis acids and bases Much of the attributed reactivity of the main group can be understood through the definitions of an acid and base as outlined by Gilbert Lewis nearly 100 years ago.5 A Lewis acid is an electron-pair acceptor, whereas a Lewis base is considered an electron-pair donor. Lewis acids and bases are known to react with one another, resulting in a dative bond, to form a “classical Lewis acidbase adduct” (Scheme 5.1). A quintessential example of this donoracceptor interaction is in ammonia borane, with NH3 acting as the electron-pair donor and BH3 (generated from the dimer B2H6) as the electron-pair acceptor.

SCHEME 5.1 Classical Lewis acid and base reactivity.

Two decades after Lewis’ initial definition, the first anomaly was described. A report by Brown in 1942, entitled “Steric Strains as a Factor in the Relative Stability of Some Coordination Compounds of Boron” describes the observations that steric bulk around a Lewis base or acid can impact the ability to form dative bonds with Lewis acids.6 They used BMe3 as a Lewis acid and found it will form a stable dative bond with pyridine; however, by increasing the steric pressures around the nitrogen center, with 2,6-lutidine, adduct formation was precluded. A smaller Lewis acid, BF3, can, however, form a dative bond with both pyridine and 2,6-lutidine (Fig. 5.1, top). These were the first observations that steric encumbrance can impact the chemistry of Lewis acids and bases. Subsequently, Wittig and Benz described that the Lewis pair Ph3P-BPh3 will still react with highly activated substrates, as they will undergo a 1,2-addition reaction with in situ-generated benzyne forming a 1,2-disubstituted benzene product, indicating that a slight equilibrium exists with the free phosphine and borane.7 Shortly thereafter, Tochtermann investigated the combination of sodium triphenylmethane (NaCPh3) and BPh3 as initiators for butadiene polymerization.8 Instead of the desired polymerization, addition across the butadiene was observed, which was further corroborated through reactions of the same Lewis pairs with acenaphthylene, resulting in an unexpected 1, 6-addition reaction (1, Fig. 5.1, bottom). These unexpected reactivities were considered anomalous and the chemistries were not further probed.

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FIGURE 5.1 Unexpected reactivity between Lewis acids and bases.

FIGURE 5.2 Early examples of frustrated Lewis pair cooperativity.

In what could be considered the first evidence of FLP catalysis, Piers reported that the Lewis acid B(C6F5)3 can catalytically reduce ketones via a hydrosilylation reaction.9 It was noted that a classical Lewis acid/ base adduct can be formed between the carbonyl functionality and the Lewis acid; however, this interaction existed in an equilibrium with the free species, allowing the free Lewis acid and base to cooperatively activate the SisH bond resulting in reduction of the carbonyl species (Fig. 5.2, top). This mechanism was further elucidated by Oestreich and coworkers where they studied this reaction using a chiral silane to confirm that stereochemical inversion occurs at the silicon center.10 One interesting example is the ortho-substituted N/B Lewis pair, 1(NPh2)-2-[B(C6F5)2]C6H4 (2), synthesized by Roesler and Piers (Fig. 5.2, bottom).11 This compound is structurally related to the modern FLP

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systems and indeed was found to react with H2O and HCl to generate the zwitterionic species. They also found that this compound could liberate hydrogen from the corresponding aminoborate with the addition of a strong Brønsted acid (Jutzi’s acid) [H(OEt2)2][B(C6F5)4]. This reactivity is very reminiscent of FLP behavior, and provides a precursor for the initial report by Stephan and coworkers in 2006.4

5.3 The discovery of reversible dihydrogen activation and catalysis The reversible activation of dihydrogen was well studied at transition metal centers; however, it had not been previously possible with lighter main-group elements. The unique zwitterionic phosphonium borohydride, (Mes)2PH(C6F4)BH(C6F5)2 (3-H2), could be synthesized through a nucleophilic aromatic substitution reaction between B(C6F5)3 and Mes2PH, followed by subsequent fluoride/hydride exchange using a sacrificial silane. This compound was found to lose H2 at 100 C, which was to be expected with a protic and hydridic hydrogen atom in the same molecule. The paradigm shift occurred when it was found that the neutral (Mes)2P(C6F4)B (C6F5)2 (3) could activate H2 at room temperature, resulting in the aforementioned phosphonium hydridoborate (Scheme 5.2).4 It was postulated that the steric encumbrance provided by the mesityl rings on the phosphorus and the pentafluorophenyl substituents on boron prevented the Lewis acid and base from forming a classical Lewis acidbase adduct. Thus there was “unquenched” reactivity available, allowing the Lewis base and acid to act in concert with each other (analogous to how oxidative addition occurs at a transition metal), activating H2.

SCHEME 5.2 The first example of metal-free dihydrogen activation.

Shortly thereafter, it was found that simple, nonesoteric phosphines and B(C6F5)3 could cooperatively activate H2 in an intermolecular fashion using bulky phosphines, such as tBu3P or Mes3P.12 This steric requirement was necessary for H2 activation, as smaller phosphines such as Ph3P or Me3P, which form classical Lewis acid/base adducts with B(C6F5)3, do

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not result in any H2 activation. The topic of steric constraints has evolved since this first report and will be discussed throughout this chapter. The true impact of this discovery was subsequently revealed when the original P/B intramolecular system was applied as a metal-free hydrogenation catalyst for the reduction of sterically hindered imines and aziridines.13 The original mechanism was believed to involve initial H2 activation between the P/B intramolecular FLP followed by proton and hydride delivery to the unsaturated substrate, resulting in a weak Lewis acidbase adduct between the amine and Lewis acid. This adduct was found to rapidly dissociate, regenerating the FLP catalyst and producing the hydrogenated product (Fig. 5.3, top). This initial mechanism was revisited shortly thereafter when it was found that the Lewis acid B(C6F5)3 could independently hydrogenate sterically encumbered imines. These systems formally generate an intermolecular B/N FLP and H2 activation could be achieved between the Lewis acid and the substrate, resulting in an activated iminium hydridoborate intermediate (4). This would further undergo reduction forming the desired product and regenerating the catalyst (Fig. 5.3, bottom).14

FIGURE 5.3 Early examples of catalytic hydrogenation of imines with FLPs.

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This result provided the impetus for employing B(C6F5)3 as a hydrogenation catalyst for a comprehensive library of unsaturated substrates and these will be highlighted throughout the chapter. However, FLP chemistry goes beyond hydrogenation catalysis, and they are truly beginning to encroach on reactivity once thought only to exist in the transition metal realm and beyond. With the rate that this field has grown over the last decade, it is impossible to highlight all of the exciting discoveries that have been made; however, we intend this chapter to be a valuable resource for those new to the field and who are interested in learning more about FLPs and their potential.

5.4 Small molecule activation The ability to activate dihydrogen, a nonpolar molecule, opened the door to a myriad of small molecules to be explored by FLP combinations. This subject and scope have been extensively reviewed,1519 however, a few significant examples are highlighted in the following sections, which deal with the activation and chemistry of relatively inert molecules with FLPs.

5.4.1 Carbon dioxide activation Shortly after the initial discovery of dihydrogen splitting, the reactivity of carbon dioxide was investigated. Due to its critical importance as a greenhouse gas, the activation and reduction of CO2 using FLPs became a burgeoning area of research. It was initially found by both Stephan and Erker that inter- and intramolecular FLP combinations could effect CO2 activation, with the nucleophilic phosphine attacking the electrophilic carbon, with concomitant BsO bond formation (products 5, and 6, Fig. 5.4).20 This activation was found to be reversible, where the intermolecular FLPs required 80 C under static vacuum to release the CO2, whereas the intramolecular systems would rapidly lose CO2 under ambient conditions.

FIGURE 5.4 Inter- and intramolecular activation of CO2 using FLPs.

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FIGURE 5.5 Reactivity of phosphine/trihaloalane FLPs with CO2.

The reactivity of related Lewis acids, specifically aluminum halides, AlX3 (X 5 Cl or Br), were explored as components for CO2 activation.21 Combinations of these alanes with Mes3P were subjected to CO2 atmospheres and it was found that these combinations could also activate the gas in a similar fashion. However, unlike their borane congeners, the alanes bound in a 2:1 manner, with each oxygen atom on the CO2 fragment capped with an Al center (7). Excitingly, treatment of these activated compounds with an excess of ammonia borane (NH3BH3) resulted in the stoichiometric reduction of CO2 to methanol (Fig. 5.5, top). Furthermore, when AlI3 was utilized, two equivalents of the activated complex, Mes3P(CO2)(AlI3)2 (8), would decompose to form CO and the by-products Mes3P(CO2)(O(AlI2)2)(AlI3) (9) and [Mes3PI][AlI4] (Fig. 5.5, bottom).22 The mechanism was further elucidated by utilizing strong organoaluminum Lewis acids, such as Al(C6F5)3 and Al(OC (CF3)3)3, in place of the aluminum halides.23 It was found that the 2:1 adduct of CO2 (8) was the kinetic product. Dissociation of one of the Lewis acids occurs, leading to a cascade of reactions, resulting in the CO extrusion and formation of the thermodynamic product 9. The catalytic reduction of CO2 to value-added chemicals is not trivial due to the high thermodynamic stability of the gas. This necessitates an equal thermodynamic driver to push these reductions toward catalytic turnover. Nevertheless, the facile activation of CO2 using FLPs expedited these developments and it was not long until scientists combined these approaches for catalytic reduction of CO2. Piers utilized a clever combination of B(C6F5)3, 2,2,6,6-tetramethylpiperidine (TMP), and Et3SiH to facilitate a tandem activation and hydrosilylation of CO2 to methane.24 CO2 can be activated with a TMP and B(C6F5)3 FLP to form a TMPHboratocarbamate ion pair (10), which in the presence of silane can be converted to the silyl carbamate and the ion pair [TMPH]1 [HB(C6F5)3]2. With an excess of silane and B(C6F5)3, the silyl carbamate can be reduced to methane, producing a siloxane side product (Fig. 5.6, top).

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FIGURE 5.6 Catalytic CO2 reduction using FLPs.

Fontaine and coworkers took a different approach toward CO2 reduction. Instead of utilizing intermolecular FLP combinations, they investigated a simple intramolecular FLP based on an aryl-bridged phosphine/ borane, 1-Bcat-2-PPh2-C6H4 (11, Fig. 5.6, middle).25 This ambiphilic molecule is of interest because unlike the previous examples, the Lewis acid and base components are fairly weak. These ambiphilic molecules tend to

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be more robust and will more easily release substrates to facilitate catalysis. This FLP can act as an effective catalyst for the reduction of CO2 using catechol borane (HBcat) or BH3 SMe2 as the reductant, with a catalyst loading as low 0.1%, selectively producing methanol upon hydrolysis with turnover frequencies up to 973 h21 and turn over numbers (TONs) up to 2950 at 70 C. One final example that builds upon the lessons of the prior two cases is by Cantat and coworkers. In a 2016 study, they explored a series of base-stabilized silylium cations as a novel N/Si1 FLP for the reduction of CO2.26 Utilizing the guanidine derivative, 1,5,7-triazabicyclo[4.4.0] dec-5-ene (TBD), they were able to form base-stabilized silylium cations using chlorosilanes (Fig. 5.6, bottom). These FLPs were found to be effective catalysts for the reduction of CO2, with as low as 2.5 mol% catalyst loading using hydridoboranes as the reducing agent (9-BBN, HBcat or HBpin), again producing methanol upon hydrolysis. Unsurprisingly, 9-BBN was the most effective reducing agent as it has the most hydridic character. Density functional theory (DFT) calculations were undertaken to elucidate the mechanism and they confirmed that the reaction proceeds through an N/Si1 FLP with activation of CO2 as one of the first steps. The catalytic reduction of CO2 is of clear importance due to its availability and greenhouse gas potential. The aforementioned examples used silane or borane reducing agents that produce a stoichiometric amount of by-product. The FLP-mediated hydrogenation of CO2 represents a powerful approach to reducing this greenhouse gas. Ashley and O’Hare reported that the intermolecular FLP, tetramethylpiperidine (TMP) and B(C6F5)3, will react with H2 and CO2, resulting in the hydrogenation of CO2 to methanol at 160 C after 6 days.27 This stoichiometric reaction was found to proceed through a formatoborate salt [TMPH] [HCO2B(C6F5)3], resulting from the insertion of CO2 into the borohydride generated upon H2 activation. Stephan and Fontaine followed this work with an intramolecular FLP in order to facilitate this reaction under ambient conditions.28 The compound 1-BR2-2-NMe2-C6H4 (R 5 2,4,6-Me3C6H2) will activate H2 with concomitant protodeborylation, generating a BH2 functionality. In the presence of H2 and CO2, this FLP will hydrogenate the greenhouse gas producing a mixture of boron bound formates, acetals, and methoxides. Catalytic hydrogenation of CO2 using FLPs had long eluded scientists. Archetypal B/N or B/P FLP combinations have yet to achieve this reduction in a catalytic fashion. However, the unprecedented Lewis pair, B(C6F5)3/K2CO3 was recently reported to react with H2 and CO2 producing formate stoichiometrically, proceeding through a carbonate-bound borate anion.29 Through judicious screening of the base component, it was found that combinations of B(C6F5)3 and Cs2CO3 could catalytically hydrogenate CO2 to formate with TONs approaching 4000. This proof of principle example indicates



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the power that FLPs could have to effect CO2 hydrogenation and that nonconventional combinations of Lewis acids and bases may be required to facilitate this reaction.

5.4.2 Carbon monoxide activation Carbon monoxide is a commonly used ligand for transition metals resulting in very robust complexes. This is owed to the fact that the π* orbitals in CO can accept electron density from the metal, stabilizing the complex through back-bonding. However, examples of interactions of CO with main-group Lewis acids are sparse. It was noted in the 1930s by Schlesinger and Burg that the treatment of B2H6 with CO results in the formation of borane carbonyl (BH3CO); however, reduction does not occur and this adduct dissociates upon warming.30 Brown later reported an efficient way to synthesize alcohols was to react trialkylboranes with CO at high temperatures.31 This reaction proceeds via insertion of the CO into a boroncarbon bond. However, FLPs provide a scaffold more akin to transition metals with the ability to accept and donate electron density. Therefore it is not surprising that FLPs can cooperatively activate and reduce CO. The first example of CO activation by FLPs was reported by Erker et al. In this work, they discovered that CO would form a thermodynamically stable, yet unisolable adduct with Piers borane (12, Fig. 5.7).

FIGURE 5.7 Top - Activation of CO by HB(C6F5)2 and trapping of formylborane by an intramolecular FLP. Bottom - Isolation of a pyridine bound formylborane.

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However, this could be trapped by a suitable intramolecular P/B FLP, [Mes2PC2H4B(C6F5)2], forming an η2-formyl B(C6F5)2 subunit where both the carbon and oxygen atoms of CO are bound to a boron center (14, Fig. 5.7).32 This work represents the first example of CO activation by an FLP. They subsequently followed up this work to better understand the unexpected formylborane intermediate (13). Using an FLP based on a norbornane scaffold, the postulated base-stabilized hydroborated product of CO, (C6F5)2(py)BC(O)H could be isolated (15, Fig. 5.7).33 In the absence of the FLP, only the Lewis acid/base adduct of pyridine and Piers borane was isolable. It should be noted that the pyridine-stabilized formylborane 15 has similar chemical reactivity to a normal aldehyde as it can readily be reduced or can undergo Wittig olefination. Simultaneously, Stephan and coworkers investigated the reactivity of intermolecular FLPs.34 A 2:1 mixture of B(C6F5)3 and tBu3P was found to react with syn-gas (CO and H2) forming a formyl borate salt, [tBu3PH] [(C6F5)3BCHOB(C6F5)3] 16, which could be isolated and fully characterized. The formation of this product occurs via initial FLP activation of H2 followed by CO activation by the second equivalent of B(C6F5)3, which is in turn followed by reduction of the activated CO. The salt 16 would readily lose CO if put under vacuum; however, upon heating at 90 C for 2 h an epoxyborate anion 17 formed, through C6F5 migration (Fig. 5.8). Interestingly, if the original salt was left under an atmosphere of syn-gas overnight, two new products would form in B2:3 ratio. These were identified as the double CO inserted product [tBu3PH][(C6F5)2BCH(C6F5)O2CB(C6F5)3] 18 and the protodeboronated product [tBu3PH] [(C6F5)CH2B(C6F5)OB(C6F5)3] 19 (Fig. 5.8). These experiments demonstrate that metal-free activation of syngas can result in the reduction and cleavage of the CsO bond in carbon monoxide. This reaction is reminiscent of FischerTropsch chemistry, which requires a heterogeneous transition-metal catalyst.

FIGURE 5.8

Syn-gas activation with an intermolecular FLP.

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Building upon this chemistry, FLPs have found the potential to unlock chemistries that were not previously possible. Erker and coworkers utilized their original FLP activated formyl borate (14) to promote the coupling of carbon monoxide with nitrogen monoxide (20, Scheme 5.3).35

SCHEME 5.3 Carbon monoxide coupling with nitrogen monoxide via an intramolecular FLP.

This FLP-mediated reaction proceeds via a radical pathway, whereby the formylborane can dissociate from the FLP, allowing NO to add, resulting in a transient radical intermediate. This intermediate rapidly reacts with the formylborane fragment, forming a CsN bond. Finally, excess NO can abstract a hydrogen atom, forming HNO, which decomposes to N2 and H2O. This mechanism is supported by the fact that if this reaction is performed in the absence of molecular sieves, decomposition products are observed. This report highlights an example of how FLPs can unlock new doors to unprecedented reactivity.

5.4.3 Dinitrogen activation The challenges associated with activating and functionalizing N2 remain at the forefront of chemistry research. The HaberBosch process, which utilizes a heterogeneous iron catalyst, is the benchmark method for the reduction of N2 to NH3. Nevertheless, this process is very energy intensive and finding new alternatives remains a priority. Dinitrogen has long been known to act as a ligand for transition metals, through electron-pair donation from the N2 to an empty d-orbital on the metal with subsequent π-back-donation from the metal to the π* orbitals of N2. Dinitrogen is isoelectronic to CO, yet the FLP chemistries of the two are quite different, owing to the nonpolar nature of N2. Even now, there have been no reports of any archetypal FLP combination being capable of activating N2. Nevertheless, N2 surrogates and transition metal partners have opened the door to FLP systems that could potentially activate N2. The first step to understanding how FLPs could effect N2 activation would be to explore how the Lewis acid interacts with the weakly basic N2 molecule. This understanding could be facilitated by

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investigating the impact that B(C6F5)3 has on low-valent transition metal N2-complexes. In 2017 the groups of Szymczak36 and Simonneau37 showed that B(C6F5)3 can activate the N2 ligand bound to complexes of low-valent Fe, Mo, and W, forming MsNsNsB(C6F5)3 complexes. In these cases, the borane interacts with the electron density in the π* orbitals of N2, increasing the back-bonding from the metal and resulting in a “pushpull” activation motif (21 and 22, Fig. 5.9). Moving toward N2 surrogates, diazomethanes (R2CN2) could be thought of as carbene adducts of N2, and the chemistry of diazomethanes and B(C6F5)3 reflects this description as under ambient conditions they will insert into the BsC bond with liberation of N2.38 Nevertheless, if diphenyldiazomethane is used and the reaction is kept at 78 C, the diazomethane-B(C6F5)3 adduct can be isolated (23, Fig. 5.9).39 This species could be considered a carbene/borane FLP that can activate N2 in a “pushpull” fashion. Unfortunately, upon warming, this product decomposes, liberating N2 and generating Ph2CB(C6F5)3. Additionally, the use of Piers borane (HB(C6F5)2) results in the 1,1-hydroboration of diphenyldiazomethane, forming the product Ph2CNN(H)B(C6F5)2 (24, Fig. 5.9). While not via an FLP, main-group N2 activation was recently achieved by Braunschweig and coworkers utilizing cyclic alkyl(amino) carbene (CAAC) stabilized borylene complexes.40 A borylene (RB:) is isoelectronic with

FIGURE 5.9 Models of FLP-type activation of N2.

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carbene (R2C:), having both a lone pair of electrons and an empty orbital. Reduction of the precursor [(Dur)B(CAAC)Br2] (Dur 5 2,3,4,6-tetramethylbenzene; CAAC 5 1-(2,6-diisopropylphenyl)-3,3,5,5-tetamethylpyrrolidin-2-ylidene) with an excess of KC8 generates a borylene in situ, which rapidly fixates N2 between two [(Dur)B(CAAC)] borylene units (25, Scheme 5.4). This remarkable result shows the potential that highly reduced main-group

SCHEME 5.4 Metal-free dinitrogen activation using a borylene.

species have for activating small molecules. Melen and coworkers provided unique perspective on this finding, stating “the landmark study published by Braunschweig represents a paradigm shift in this field, where boron, an element whose role in N2 activation was thought to be to “pull” through its Lewis acidic nature was able to “push” electron density to N2.”41 These findings represent the first steps to understanding how the main-group elements, and specifically FLPs can be designed to activate and functionalize N2.

5.4.4 Hydrogenation catalysis Hydrogenation reactions are some of the most widely utilized in synthesis, finding applications within the pharmaceutical, electronics, food, and petrochemical industries. These reactions are usually facilitated using heterogeneous or homogeneous transition-metal catalysts. One of the most remarkable facets of FLP chemistry is their ability to catalyze the metal-free hydrogenation of unsaturated substrates. In order to achieve H2 activation, we require both the Lewis acid and base components in the system. Thus initial reports of FLP-catalyzed hydrogenations utilized intramolecular P/B molecules to activate hydrogen and transfer it to the substrates. In addition to the results reported in the introduction, Erker and coworkers reported in 2008 that a weakly intramolecularly interacting ethylene-bridged P/B system could effectively activate hydrogen and could catalyze the hydrogenation of sterically bulky ketimines and enamines.42 Alternatively, these hydrogenations could proceed through an intermolecular mechanism. There are two possible intermolecular routes, the first being by the free Lewis acid interacting with the Lewis basic substrate to cooperatively activate hydrogen and facilitate hydrogenation. The hydrogenation of imines commonly proceeds via this route,14 one interesting

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example being the hydrogenation of anilines to cyclohexylamines. Reported by Stephan, Grimme, and coworkers in 2012, the combination of bulky anilines (such as tBuNHPh) with B(C6F5)3 will cooperatively activate H2 at room temperature; however, heating to 110 C under an atmosphere of H2 surprisingly resulted in the complete reduction of the aromatic ring to the cyclohexylamine.43 Alternatively, an intermolecular mechanism could utilize a combination of the Lewis acid with a very weak Lewis base [such as P(C6F5)Ph2 or Et2O] to activate H2, generating a strong Brønsted acid that can protonate a substrate, followed by borohydride reduction to achieve the hydrogenation. This strategy is commonly used for the hydrogenation of olefins or carbonyl functionalities.4447 In the decade since their first reported use in hydrogenation chemistry, FLP systems have been designed to effectively hydrogenate nearly every type of unsaturated functional group, ranging from olefins and alkynes to N-heterocycles and carbonyls. This area continues to rapidly develop, broadening the scope of this reaction, and has been reviewed extensively elsewhere.4850 However, most of these FLP-catalyzed hydrogenations result in a racemic mixture if the substrate is prochiral, with little to no enantioselectivity. This lack of stereoselectivity is an important distinction from asymmetric transition-metal catalysis. In order to truly compete with these metal-based systems, efforts have been made to develop asymmetric FLP catalysts that can achieve a reasonable level of enantioselectivity. The strategy employed to generate asymmetric FLP catalysts has focused on the development of chiral Lewis acids. To this end several methods are described, the first is through the isolation of a borane Lewis acid directly bound to a chiral motif. The first reports of enantioselective hydrogenation with chiral FLPs came from Klankermayer et al. in 2010, where they described the synthesis of camphor-derived chiral boranes (26, Fig. 5.10)

FIGURE 5.10 Chiral boranes for enantioselective FLP hydrogenation catalysis.

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capable of hydrogenating prochiral ketimines with up to 83% ee.51 In an attempt to improve the enantioselectivity of this transformation, an intramolecular P/B FLP system derived from camphor was developed (27, Fig. 5.10). This catalyst was found to be more robust and recyclable than their first-generation system; however, it could not achieve ee’s .76% for the hydrogenation of prochiral ketimines.52 Another route toward chiral boranes was pioneered by Pa´pai and Repo. Repo had previously reported the use of ansa-amino-boranes as effective FLPs for catalytic hydrogenations; however, the introduction of a chiral amine into this framework only led to moderate enantioselectivities.53 It was hypothesized that the chiral center is too far removed from the active N/B FLP (28, Fig. 5.10). In response, they designed a multistep synthesis to produce a chiral amino-borane by direct substitution onto the 2- and 20 -positions of an asymmetric binaphthyl core, resulting in a chiral B/N molecular tweezer (29, Fig. 5.10).54 Excitingly, this system was found to be an effective hydrogenation catalyst for both prochiral imines and enamines, resulting in ee’s ranging from 32% to 99%. Erker and coworkers utilized the planar-chirality inherent to ferrocene to synthesize a series of asymmetric ferrocenyl P/B FLPs (30, Fig. 5.10). These systems were reasonably active for the hydrogenation of imines; however, the enantioselectivity of these catalysts was limited, achieving a maximum of 69% ee.55,56 Two recent examples of direct substitution onto chiral motifs have been reported by Wang, utilizing C2-symmetric bisboranes. The first is derived from a bicyclic [3.3.0]diene (31) and the second derived from a spriocyclic [4.4] diene (32, Fig. 5.10). Generation of the chiral Lewis acid catalyst is achieved through hydroboration of the dienes with HB(C6F5)2. These systems were found to achieve high yields and excellent ee’s (up to 94%) for the hydrogenation of imines and quinolines.57,58 An alternative approach, which has proven to be remarkably successful, aims to generate a chiral borane in situ rather than isolating the Lewis acid in advance. This work has been pioneered by Du. The initial report in 2013 describes the use of chiral dienes on a sterically encumbered binaphthyl platform as a “ligand” for a borane Lewis acid.59 These olefins can be hydroborated in situ using HB(C6F5)2 to generate a chiral Lewis acid (33, Scheme 5.5). In the first report, they describe how this system is effective for the enantioselective hydrogenation of a large

SCHEME 5.5

Generation of a chiral borane in situ via hydroboration.

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series of imines with ee’s ranging from 74% to 89%. This platform has since been proven to be quite functional, providing facile routes toward enantioselective hydrogenation of silyl enol ethers,60 N-heteroarenes such as 2,3-disubstituted quninoxalines,61 and quinolines,62 to name a few.63 This scaffold has found applications beyond hydrogenation catalysis, toward more classic Lewis acid chemistry. One example from the Wasa group describes the use of these chiral borane catalysts for the enantioselective direct Mannich-type reaction between ketones, esters, or thioesters with imines resulting in the β-aminocarbonyl products.64 Finally, the use of borenium cations (R2BL1) as FLP Lewis acid components has been thoroughly explored.65,66 Generally, these borenium cations have a donor ligand bound to boron (phosphine, carbene, triazole, etc.), which can be used to tune the stereochemistry around the Lewis acidic site. Attempts had previously been made by Melen, Crudden, and Stephan to generate asymmetric borenium cations using chiral carbenes.67 Unfortunately, these systems all resulted in low enantioselectivity in the hydrogenation of imines. This riddle was not solved until 2019 when Ashley and Fuchter reported the use of IBiox-derived N-heterocyclic carbenes (NHCs) (IBiox 5 bioxazolines) in combination with 9-BBN to form chiral borenium Lewis acids. They found throughout the study that the choice of prochiral ketimine was crucial for high enantioselectivity upon hydrogenation.68

5.5 Mechanistic insights into frustrated Lewis pair small molecule activation When a Lewis acid and base are unable to form a formal Lewis adduct the LUMO from the Lewis acid and HOMO from the Lewis base are available for further reactivity. There are two prevailing theories on the mechanism behind FLP bond activation and evidence exists to support both hypotheses. The first is that the Lewis pairs preorganize to cooperatively activate the substrate, via an “encounter complex” (Fig. 5.11). Preorganization of these orbitals can be achieved by both intermolecular and intramolecular FLP systems. In the former case, this organization is mainly driven by secondary interactions in solution (i.e., London dispersion forces). These FLP encounter complexes have been predicted through computational studies,69,70 furthermore some experimental evidence has lent credence to this hypothesis. Although difficult to study in solution due to the fluxional nature of the mixtures, Wiegand et al. nonetheless found that it was possible to distinguish between classical Lewis acidbase adduct formation and FLP formation by solid-state NMR spectroscopy.71 Furthermore, Rocchigiani and Macchioni utilized 19F, 1H HOESY diffusion and VT-NMR studies to

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FIGURE 5.11 Possible mechanisms of action for FLP activation of small molecules.

probe the encounter complex of FLPs in solution. From this work, a barrier of ΔG 5 0.4 kcal mol21 was determined for PMes3/B(C6F5)3 by NOESY experiments.72 Finally, Swadzba-Kwasny and coworkers have identified FLP encounter complexes between tBu3P and B(C6F5)3 in an ionic liquid medium and confirmed this through neutron scattering and NMR experiments.73 Recently, the concept of frustrated radical pairs (FRPs) has provided ancillary support for this mechanism. FRPs are combinations of sterically encumbered Lewis acids and bases, which undergo single electron transfer and are capable of activating bonds in a homolytic fashion.74 In fact, Mu¨ller and coworkers recently showed that certain Lewis acid/base adducts could proceed via a single electron transfer mechanism.75 For single electron transfer to occur, the Lewis base and acid must be in close proximity to one another, thus indirectly providing evidence for the formation of an encounter complex. Alternatively, the Lewis acid could independently activate the substrate, priming it for attack by the Lewis base. For example, an H2 complex could be formed with the Lewis acid, akin to a transition metal, followed by deprotonation of the activated H2 molecule (Fig. 5.11). Again, experimental evidence is sparse, but some notable examples include the work by Piers and Tuononen, where they were able to isolate a boranesilane complex using a highly Lewis acidic perfluorinated borole and Et3SiH (34, Fig. 5.12).76 This complex represents a direct observation of the key intermediate in the aforementioned FLP-mediated hydrosilylation catalysis. Another example was shown by Stephan, with the synthesis of a Lewis acidic borane bearing a pendent olefin (C6F5)2B (CH2CH2CH2CHQCH2) (35, Fig. 5.12).77 At low temperatures, a boraneolefin interaction was observed using 1H{19F} HOESY spectroscopy and upon introduction of a Lewis base, FLP addition to the olefin was

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FIGURE 5.12 Direct evidence of Lewis acid activation of substrates.

observed. These two representative examples imply that FLP reactivity may rely more heavily on the Lewis acid partner, rather than on a cooperative approach between the two components of a sterically encumbered Lewis pair. Understanding the mechanism behind bond activation remains at the forefront of research in the field.

5.6 Frustrated Lewis pairmediated CsH bond activation FLPs have found applications beyond small molecule activation and hydrogenation catalysis. Transition metalcatalyzed functionalization of CsH bonds to form new CsE bonds has provided an efficient way to access value-added products without the need for activated precursors.78 These transformations are of particular importance when generating CsB bonds, as organoboranes are versatile building blocks for creating new bonds via the Suzuki-Miyaura cross-coupling reaction. Although advancements have been made in the activation of arene CsH bonds using base metal complexes, this reaction remains primarily the purview of noble metals. Furthermore, main-group Lewis acids are well known to activate CsH bonds, most famously in FriedelCrafts alkylation and arylation reactions.79 Interest in this activation has recently seen a resurgence through various hydroarylation chemistries,8082 but these all proceed through a similar, FriedelCrafts type electrophilic aromatic substitution mechanism. Introducing the Lewis base partner in an FLP combination opens the door for new CsH to CsX bond formation reactions. An early example of this chemistry was reported by Ingleson and coworkers with investigations into the application of borenium cations toward catalytic borylation of arenes.83 A catalytic amount of a triflate-stabilized borenium cation (36) can facilitate aromatic borylation with a series of arene

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substrates and catechol borane (CatBH). Hydrogen gas could be observed in these reactions and catalysis suppression was observed in the presence of hindered bases, such as 2,6-di-tert-butylpyridine, employed to capture H1. This observation is consistent with protonation of the CatBH borohydride as part of the catalytic cycle. The proposed mechanism for this reaction is shown in Fig. 5.13. It was also found that borylation regioselectivity at low temperatures was directed by arene electronic effects. For instance, borylation of toluene affords the ortho- and para-substituted products rather than the meta-, and no benzylic activation was noted, precluding a radical mechanism. At this time, Ingleson had found that pinacolborane would not give the arene borylation product, but instead ring-opening at the pinacol group was observed. Later, in 2011, a stoichiometric example of direct one-pot arene borylation with pinacolborane was also reported by Ingleson (Fig. 5.14).

FIGURE 5.13 CsH borylation using catalytic borenium cations.

FIGURE 5.14 One-pot arene borylation with pinacolborane.

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FIGURE 5.15 Catalytic CsH borylation of heterocycles with FLPs.

Under ambient conditions, amine-stabilized borenium cations 37 and 38 were allowed to react with electron-rich N-heterocycles and resulted in regioselective borylation of a CsH bond in high conversion.84 These reactions are thought to proceed through a FriedelCrafts type mechanism, the subsequent transesterification was also explored to yield the more synthetically useful and robust pinacolborane-substituted product. Seminal work in this field was reported by Fontaine and coworkers in 2015 where the FLP (1-TMP-2-BH2-C6H4)2 (TMP 5 2,2,6,6-tetramethylpiperidine) (39) was found to activate CsH bonds of heteroarenes in an unprecedented reaction and catalyze the borylation of furans, pyrroles, and electron-rich thiophenes.85 In this Lewis acidbase cooperative CsH bond activation, the basic amine serves to abstract a proton, while the Csp2H electron density is transferred to the Lewis acidic borane. This process differs from a traditional Lewis acid FriedelCrafts type mechanism and is reminiscent of two-electron processes accessed by transition metal complexes. In the presence of equimolar pinacol borane (pinBH) evolution of H2 could be observed, along with functionalization of Bpin at the arene and regeneration of 39 (Fig. 5.15). It was also found that catechol borane and 9-borabicyclo[3.3.1]nonane could be employed in this transformation. This work has subsequently been expanded upon, through catalyst optimization as well as development of bench-stable precursors which can be used on a practical scale for the synthesis of borylated heterocycles.86,87

5.7 Immobilization of frustrated Lewis pairs FLP chemistry is mainly the purview of homogeneous processes—all of the aforementioned chemistry occurs in the solution state. Nevertheless, many important catalytic processes require the use of heterogeneous catalysts. In these reactions the catalyst and reactants are in different phases, often featuring a catalyst immobilized onto a material or

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FIGURE 5.16

MIL-101(Cr) derived FLP for catalytic hydroboration of imines.

surface. Working with homogeneous catalysts offers the advantage of investigating well-defined catalytic sites that can often be manipulated to enhance reactivity or selectivity. However, working with heterogeneous catalysts often allows for easy workup, removal, and recycling of catalysts. Immobilizing well-defined catalysts on a surface offers the best of both worlds and has been a recent area of interest for FLP chemists.88 In 2018 Ma and coworkers employed metal-organic frameworks (MOFs) as a porous crystalline material to immobilize Lewis acidbase interactions, termed a MOF-Lewis pair. In this work, a phase pure sample of MIL-101(Cr) was prepared and postsynthetically functionalized with the Lewis base 1,4-diazabicyclo[2.2.2]octane (DABCO). Subsequent reaction of this functionalized MOF with B(C6F5)3 revealed adduct formation between the Lewis acid and base, as shown in Fig. 5.16 (depicted as cartoon 40).89 This adduct formation was reversible in solution and this MOF-Lewis pair was found to catalytically effect the hydroboration of imines with pinacolborane and the hydrogenation of alkylidene malonates. Furthermore, the Lewis pair grafting was tolerated during the hydroboration reaction conditions and catalyst recycling was successful over seven cycles. Meanwhile, Thomas and coworkers focused their investigations on semi-immobilized FLPs using microporous polymer networks.90 In this work, porous polymers featuring sterically encumbered phosphines were prepared and impregnated with B(C6F5)3 (41, Fig. 5.17). These polymers displayed strong swelling properties and would often form gels in common laboratory solvents. Interaction of the borane Lewis acid and the Lewis bases of the polymer was quantified using fluorescence spectroscopy studies and 31P NMR spectroscopy. Upon reaction of this material with HD, scrambling to H2 and D2 was observed,

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FIGURE 5.17

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Semi-immobilized FLPs in a microporous polymer network.

consistent with reversible H2 activation. However, further application of this system in hydrogenation catalysis has not yet been reported. Finally, Shaver et al. exploited reversible small molecule activation between Lewis acidic and basic sites to form bridges as a route to link polymer strands.91 In this work, polymers functionalized with Lewis acids (42) and Lewis bases (43) were independently prepared. Classical Lewis adduct formation was precluded in these systems due to steric encumbrance; however, diethyl azodicarboxylate could be activated, cross-linking polymer chains and resulting in gel formation (44, Scheme 5.6). Reversible

SCHEME 5.6 Self-healing polymer networks utilizing FLP reactivity.

small molecule activation in these systems gave rise to dynamic self-healing properties. More recently, the rheological characterization of these networks was undertaken and it was determined that these polymer networks behaved like noncovalently linked supramolecular assemblies, and upon small molecule activation the self-healing and gelation occurred extremely rapidly.92

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5.8 Unconventional Lewis acid partners The Lewis acidic component is a critical partner in FLP chemistry and the Lewis acidic character of compounds featuring a group 13 element has been well established, as they possess a low-lying LUMO derived from an empty p-orbital, which is primed to accept electron density. As observed thus far in the chapter, the group 13 Lewis acid B(C6F5)3 is the quintessential exemplar used throughout the field. However, significant research has been undertaken to expand the library of Lewis acids across the p-block to encompass group 14, 15, and 16 examples. These unconventional Lewis acids are described in the following section and are finding applications in FLP chemistry.

5.8.1 Carbon Lewis acids Carbocations are a class of potent yet often neglected Lewis acids. Undergraduate course material often relates that carbocations are commonly formed in organic reaction pathways but are highly reactive and often nonisolable intermediates. This notion is mostly true, but both hyperconjugation and resonance forms can be invoked when discussing triarylmethyl (trityl) cations, [Ar3C]1, examples of isolable carbocations.93 The earliest examples of carbocations in Lewis acid catalysis are trityl perchlorates that were found to mediate Mukaiyama aldol-type reactions, among others.9496 However, further mechanistic investigation of the Mukaiyama aldol reaction by Denmark and Bosnich gave conflicting results, showing that these reactions may be proceeding via in situ-generated silylium catalysis.97,98 Franze´n et al. were able to exclude the silicon-cation pathways by avoiding the use of silicon-containing substrates, focusing their investigations on trityl tetrafluoroborate as a catalyst for DielsAlder reactions.99 Furthermore, in 2016 the Stephan group prepared air-stable trityl cations employing para-methoxy substituents and tested their activity toward Markovnikov hydrothiolation of 1,1-disubstituted and trisubstituted olefins.100 One interesting example of small molecule activation at a carbon center was reported by Bertrand et al. when it was demonstrated that (alkyl)-(amino)carbenes (45) could independently activate H2 and NH3 under mild conditions (46 and 47, Fig. 5.18, top).101 Unlike traditional FLP systems, these compounds possess both the Lewis acidic and basic sites at the same center. Alcarazo and coworkers, on the other hand, explored weakly acidic allenes with NHCs in more conventional FLP chemistry. These all-carbon allene/carbene FLPs were unable to activate H2; however, heterolytic cleavage of disulfide SS bonds was observed at 78 C.102,103 These systems were reported as possessing “kinetic frustration” where low temperatures precluded quenching of the Lewis acidic and basic

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FIGURE 5.18

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Selected examples of carbon-based Lewis acids in FLP-type chemistry.

components by adduct formation. Later, Arduengo and coworkers reported on an all-carbon FLP system capable of activating H2 by pressuring a solution of ItBu carbene (ItBu 5 N,N0 -bis(tertbutylimidazol)-2-ylidene) with trityl cation at 60 C to yield triphenylmethane and the corresponding imidazolium salt.104 An unusual example of a carbon-based Lewis acid in FLP chemistry was reported in 2013, derived from a Ru-ƞ6-arene complex (48) where the metal center is a nonparticipant in H2 activation. Instead H2 is activated between the ortho- or para-position of the activated arene ring and an external phosphine base (Fig. 5.18, bottom).105,106 More recently, Stephan and coworkers explored [Ph3C]1 as the Lewis acid component in FLP chemistry. In this report, it was found that (o-tolyl)3P was a suitable Lewis base, while other phosphines readily underwent arene substitution at the trityl cation. Meanwhile, the (o-tolyl)3P/ [Ph3C][BF4] combination does not react with HD, but will eliminate H2 from 1,4-cyclohexadiene to afford [(o-tolyl)3PH][BF4] and Ph3CH. Terminal alkyne activation was also noted upon reaction with 1-bromo-4-ethynylbenzene and 1-methyl-4-ethynylbenzene to afford an indene derivative via the transient adduct of the alkyne with trityl cation and concomitant formation of the salt by-product, [(o-tolyl)3PH][BF4]. Beside CsH bond activation, SsS bond activation could be observed upon reaction with diphenyl disulfide and NsN bond activation upon reaction with pentafluorophenyl azide.107 Carbon Lewis acids in FLP chemistry were expanded upon by Ingleson to include carbenium ions, specifically N-methylacridinium cations, with investigations into the 1,2-hydrocarbation reaction of alkynes.108

5.8.2 Silicon Lewis acids The pronounced electrophilicity of silicon centers is noted in the presence of bases, where adduct formation is possible even for a tetracoordinate silicon atom, affording a hypervalent species.109 As a consequence

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FIGURE 5.19 Selected examples of silylium Lewis acid generation. (A) Hydride abstraction, (B) Allyl-group elimination, (C) Ring-opening protonolysis, (D) Substituent exchange, (E) Cyclohexadienyl elimination.

of the increase in atomic size when moving down the group, SisC bonds are longer than CsC bonds as the orbital overlap between the atoms is less effective. As such, early investigations into silylium cations were motivated by the desire to better understand heavier carbocation analogues. Known methods for the generation of silicon cations include (Fig. 5.19AE): hydride abstraction,110,111 allyl-group elimination,112 ring-opening protonolysis of strained cyclic silanes,113 substituent exchange,114 and cyclohexadienyl elimination.115 First described by Lambert, hydride abstraction was successfully achieved by allowing triethylsilane to react with triphenylmethyl tetrakis(pentafluorophenyl)borate in toluene to afford the triethylsilylium toluene complex.111 In 1975 Corey and coworkers initially investigated these types of hydride abstraction reactions; however, these efforts were unsuccessful due to the use of incompatible counterions and solvents.116 The Reed group, however, was able to prepare silylium cations with some of the most chemically robust and noncoordinating carborane anions ([HCB9H4Br5]2 and [HCB11H5X6]2; X 5 Cl, Br, I).110 X-ray diffraction studies revealed that both silylium cations prepared by Lambert and Reed were not truly free, with Lambert’s system coordinating one molecule of toluene and Reed’s system coordinating one of the halogen atoms from the carborane anion. In an effort to access the free silylium cation, Lambert increased the steric bulk around the silicon center using the mesityl group. However, it was found that the SisH bond was inaccessible, therefore instead of a

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hydride abstraction pathway an allyl-leaving group pathway was favored.112 The formation of this free silylium cation was confirmed by X-ray crystallography and displayed a remarkable downfield chemical shift in the 29Si NMR spectrum at δ 5 225.5 ppm. An interesting route to silicon cations was reported by Manners et al. where strained sila[1]ferrocenophanes underwent ring-opening protonolysis in the presence of [H(OEt2)2][B(C6F5)4] to afford the ether adduct of the corresponding silylium cation substituted with a ferrocenyl unit.117 Employing Corey’s method of hydride abstraction by [CPh3][B (C6F5)4] in the absence of ethereal solvents, Oestreich et al. were able to prepare a related ferrocenyl-silylium cation.118 Interestingly, Oestreich noted that in the absence of coordinating solvent an interaction between the silicon and iron center could be observed. This compound represents the first example of a silylium Z-type ligand on a transition metal. Furthermore, Mu¨ller found that hydride abstraction of silanes substituted with mixed aryl and alkyl groups would undergo disproportionation reactions to yield triarylsilylium cations.114 Finally, inspired by both the Corey and Schade/Mayr approach to generate the silylium cation, the Oestreich group abstracted a hydride from the cyclohexa-2, 5-dien-1-yl group on a silane using trityl tetrakis(pentafluorophenyl) borate, resulting in the formation of a Wheland complex, which can also be rationalized as an arene-stabilized silylium cation.115 Despite the difficulties associated with the formation of a free tricoordinate silicon cation, the toluene-coordinated [Et3Si(tol)][B(C6F5)4] salt (49) was found to be a very active catalyst for several organic transformations (Fig. 5.20). One of the earliest examples was reported in 2005 by the Ozerov group, with the hydrodefluorination of fluoroalkanes.119 Silicon cations were also found to effect the hydrosilylation of alkenes and ketones, as well as the DielsAlder reactions of unactivated dienes.120122

FIGURE 5.20 Silylium cationmediated catalysis. (A) Hydrodefluorination catalysis, (B) Hydrosilylation catalysis, (C) Hydrodeoxygenation Catalysis, (D) Diels Alder catalysis.

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FIGURE 5.21 Selective CsF bond activation with a Si/P FLP.

With respect to more traditional FLP chemistry, Mu¨ller reported that silylium cations are acceptable Lewis acids for heterolytic activation of H2 gas with phosphines.114,123 However, a limitation with silylium/phosphorus FLP systems is that the SisH bond is not hydridic enough to reversibly activate H2 under ambient conditions, thus impeding subsequent hydrogenation chemistry. Interestingly, Mu¨ller and coworkers utilized silylene Lewis bases in combination with silylium Lewis acids to generate an allsilicon FLP for the activation of dihydrogen.124 Finally, an intramolecular silylium/phosphine FLP (50) was prepared by Stephan and coworkers and found to activate alkylfluoride bonds, namely PhCF3, Ph2CF2, and PhCF2H (Fig. 5.21).125 These reactions represent a rare example of monohydrodefluorination, albeit stepwise, using a main group system.

5.8.3 Nitrogen Lewis acids Nitrogen-based Lewis acids that are isoelectronic with carbenes, nitrenium cations (shown in Scheme 5.7) were first reported by Boche et al. in 1996.126 In line with the work of Arduengo on stable carbenes, it was found that bis(amino) ligands were necessary to form an isolable crystalline ionic species. Seminal work reported by Gandelman in 2011 described the preparation of nitrenium cations featuring pendent phosphine ligands, which

SCHEME 5.7

Nitrenium cation resonance structures.

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FIGURE 5.22

197

Lewis acidic reactivity of a nitrenium cation.

were further explored as ambiphilic ligands on rhodium and ruthenium.127 From these investigations it was found that nitrenium cations are weak σ-donors but considerable π-acceptors. Later, stoichiometric reactions of these ions with neutral and anionic Lewis bases were explored and it was determined that reactivity was focused at the internal nitrogen, consistent with this being the Lewis acidic center (51), as shown in Fig. 5.22.128 With respect to application in traditional FLP reactivity, a cyclic (alkyl)(amino) carbene (CAAC) analogue of the nitrenium cation, known as a cyclic (alkyl)(amino)nitrenium (CAAN) cation, was prepared by Stephan and coworkers. Interestingly, the nitrogen center was found to be reasonably Lewis acidic, as exemplified by formation of Lewis acidbase adducts with phosphines and NHCs. In the presence of a bulky Lewis base (tBu3P), these CAAN would act as a Lewis acid component for the FLP activation of disulfides, indicating the feasibility of nitrogen Lewis acids in FLP chemistry. With this evidence for Lewis acidic behavior, Mehta and Goicoechea reported on a nitrenium cation as a Lewis acid catalyst to effect FriedelCrafts dimerization of 1,1-diphenylethylene, hydrodefluorination of 1-fluoroadamantane, deoxygenation of ketones, transfer hydrogenation of olefins, and dehydrocoupling of alcohols and amines with silanes.129

5.8.4 Phosphorus Lewis acids The Wittig reaction is perhaps the best-known example of a P(V) reagent in organic chemistry, where the electrophilicity at phosphorus is exploited for the conversion of carbonyls to olefins.130 Since the 1960s, pentacoordinate phosphorus has been recognized as exhibiting Lewis

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acidic behavior, noted by the coordination chemistry of these compounds.131 For instance, a Lewis acidbase adduct can be formed between PF5 and N-trimethylsilylimidazole. Upon heating, FSiMe3 is eliminated to give a covalent bond between N and P.132 In 1977 Cavell reported the first example of CO2 insertion into a pentacoordinate amidophosphorane,133 and this work was furthered by Stephan and coworkers by irreversible sequestering of CO2 between a ring-strained amidofluorophosphorane or diamidophosphorane (52 and 53, Scheme 5.8).134 This

SCHEME 5.8 CO2 activation between a P/N FLP in a diamidophosphorane.

reaction can be interpreted as activation of CO2 by a nitrogen/phosphonium FLP. The Lewis acidity of phosphonium cations has also been explored by Gabbaı¨ for fluoride ion binding, where cooperativity between Lewis acidic centers was observed upon the preparation of a bidentate ortho-substituted phosphonium/borane species, which showed higher fluoride ion affinity, as compared to the para-derivative.135 The Lewis acidity of tetracoordinate phosphorus(V) species is derived from a low-lying σ* orbital oriented opposite the most electronwithdrawing substituent. In the 1980s simple tetraalkylphosphonium salts were found to be active Lewis acid catalysts for aldol-type reactions of aldehydes or acetals with nucleophiles, as well as for Michael reactions of α,β-unsaturated ketones with acetals.136 Later, Terada and Kouchi investigated the ability of phosphonium salts derived from phosphine oxides or phosphinates and trifluoromethanesulfonic anhydride to catalyze DielsAlder reactions.137 Of the salts shown in Fig. 5.23, enhanced reactivity was observed with systems that incorporated electron-withdrawing trifluoromethyl substituents.

FIGURE 5.23 Examples of phosphonium Lewis acids explored in catalysis.

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Concurrent with these findings, the Stephan group focused their attention on highly electrophilic phosphonium cations (EPCs).138,139 Initially, derivatives of triarylphosphines functionalized with an increasing number of pentafluorophenyl groups were oxidized with XeF2 to afford the corresponding difluorophosphoranes. Subsequent abstraction of a fluoride anion by [Et3Si(tol)][B(C6F5)4] gave a series of fluorophosphonium cations (Scheme 5.9). From standard Lewis acidity tests and

SCHEME 5.9 Synthesis of highly Lewis acidic fluorophosphonium cations.

the diagnostic 31P NMR spectra it was found that [FP(C6F5)3]1 (54) was the most Lewis acidic of this series and it was further employed to effect the hydrodefluorination of fluoroalkanes and has found applications in other unusual Lewis acidcatalyzed transformations such as the tandem transfer hydrogenation of olefins via dehydrocoupling.140 The highly electrophilic fluorophosphonium cation, [FP(C6F5)3]1, was found to have limited stability in the presence of other phosphines and would readily disproportionate; however, the silylamine Lewis base, p-tol2NSiEt3, was capable of forming an FLP with 54, which would activate H2 and promote the hydrogenation of olefins.141 Later, it was found that the family of EPCs is not limited to phosphines featuring electron-withdrawing groups. EPCs can also be accessed by stabilizing additional cationic charge. Seminal work in this field was reported with the preparation of fluorophosphonium dication 55, which is derived from oxidation of a carbene-stabilized phosphenium cation by XeF2 followed by fluoride abstraction, shown in Scheme 5.10.142 This product displayed remarkable Lewis acidity and readily abstracted fluoride from F2P(C6F5)3 to form [FP(C6F5)3][B(C6F5)4] and [(SIMes)PF2Ph2][B(C6F5)4] (SIMes 5 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene). The

SCHEME 5.10 Synthesis of fluorophosphonium dications.

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FIGURE 5.24 Electrophilic fluorophosphonium cations employed in catalysis.

EPC [(SIMes)PFPh2][B(C6F5)4]2 (55) was found to mediate the hydrodefluorination of fluoroalkanes and hydrosilylation of olefins, along with the reduction of ketones,143 phosphine oxides,144 and amides.145 Furthermore, it was found that the aryl substituents on the phosphorus could be exchanged for alkyl substituents while retaining its high Lewis acidity.143 This library of dicationic EPCs was expanded by the inclusion of systems derived from diphosphines146148 and pyridylphosphines.149 Moreover, the PNP pincer ligand 2,6-bis(diphenylphosphine)methyl pyridine provided a scaffold for both dicationic and tricationic phosphonium salts.150 A number of these examples are shown in Fig. 5.24. Recent developments in this field have been focused on replacing the axial fluorine of these phosphonium cations with alkyl, alkyloxy, or trifluoromethyl groups in an effort to increase oxygen and moisture stability.151153

5.8.5 Antimony Lewis acids In 2010 Yin and coworkers were interested in the preparation of organoantimony FLP system to affect the direct Mannich reaction of aldehydes, amines, and cyclohexanone.154 To this end, they utilized a tetrahydrodibenzo[c,f][1,5]azastibocine cyclic framework to stabilize an antimony triflate salt (56, Fig. 5.25). These complexes displayed superior Lewis acidity, catalytic activity, and air-stability when compared to their halo-antimony counterparts. Later, Gabbaı¨ explored a tetracoordinate antimony Lewis acid in the cooperative fluoride ion capture with a mesityl-substituted borane (57).155 Interesting, this system abstracted fluoride from its phosphonium analogue (shown in Fig. 5.25), indicating the greater Lewis acidity of the stibonium cation. They built upon this discovery by synthesis of a bidentate Lewis acid containing two antimony(V) centers bearing o-chloranil (3,4,5,6-tetra-chlorobenzoquinone) substituents. It was found that this new bidentate Lewis acid was superior for binding fluoride ions from water.156 This structural motif

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201

FIGURE 5.25 Examples of antimony Lewis acid reactivity.

utilizing o-chloranil antimony(V) centers was explored in the preparation of an intermolecular and an intramolecular FLP between the neutral antimony Lewis acid and a phosphine Lewis base. This unique combination was reported to capture formaldehyde from water.157 As mentioned in Section 5.1, Lewis acidcatalyzed hydrosilylation was one of the first examples of FLP-mediated catalysis. This has been extended toward stibonium Lewis acids; however, the mechanism of action appears to be different. An ortho-substituted dicationic stibonium complex, [1,2-(Ph2MeSb)2C6H4]21, was prepared and explored in the activation of aldehydes, and has subsequently been used as a hydrosilylation catalyst for aldehyde reduction. Unlike the hydrosilylation mechanism proposed for B(C6F5)3 by Oestreich and Piers, it is suggested the hydrosilylation with this antimony dication proceeds by activation of the aldehyde rather than the silane. Recently, Gabbaı¨ and coworkers prepared the tetra(pentafluorophenyl)stilbene cation, and it was found to be capable of abstracting fluoride from the [SbF6]2 anion and [BF(C6F5)3]2, evidence of highly Lewis acidic behavior.158 Despite its stability in air, in solution [Sb(C6F5)4]1 mediated the polymerization of THF and hydrodefluorination of fluoroalkanes, presumably through a silylium initiator mechanism.

5.8.6 Sulfur Lewis acids While less prevalent than other main-group Lewis acids, it is possible to generate a sulfur Lewis acid by generating cationic complexes in

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FIGURE 5.26 Examples of dicationic sulfur Lewis acids.

higher oxidation states. Early investigations in dicationic chalcogens were undertaken by Furukawa and coworkers. However, these examples were limited to annulated derivatives with covalent linkages to the maingroup element.159,160 Whereas, Ragogna reported on the preparation of sulfur(II) dications stabilized by diamino ligands (58, Fig. 5.26), the bonding has been best described as that of an N,N-chelated sulfur dication.161 Along with DFT studies, these compounds were found to exhibit Lewis acidic behavior in their coordination of the triflate counterion in the solid state. Next, Ragogna and coworkers found that by moving to a tricoordinate N,N,N-platform they could prepare air-stable chalcogen(II) dications (59, Fig. 5.26).162 Whereas, by using monodentate nitrogen-based ligands highly reactive sulfur(II) dications could be prepared and further exploited in 1,2-addition reactions across olefins and carbodiimides (60, Fig. 5.26).163 Meanwhile, Gabbaı¨ focused his work on the preparation of sulfur cations in cooperative fluoride and cyanide anion capture reactions.164,165 Later, Stephan reported a new avenue to S(IV) Lewis acids via oxidation of aryl sulfoxides with XeF2 followed by fluoride abstraction to afford fluorosulfoxonium cations.166 The acidic nature of these compounds is derived from the SF σ* orbital. Similar to the work reported by Ragogna, the solid-state structure revealed an interaction between the sulfur center and the triflate counterion. Finally, these compounds were explored in the Lewis acidmediated polymerization of THF, hydroamination of 1,1diphenylethylene, and the hydrothiolation of 1,1-diphenylethylene.

5.9 Transition metal frustrated Lewis pair systems Cooperative Lewis pair chemistry incorporating a d-block Lewis acid has been investigated to a much lesser extent. These mixed p- and d-block systems offer the unique advantage of accessing alternative reactions pathways following substrate activation, such as migratory insertion, oxidative addition, reductive elimination, and sigma bond metathesis (all well known within transition metal chemistry). Given the history of transition metal chemistry, there are many examples of reactivity that in retrospect can be identified as FLP chemistry (often predating

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the discovery of main-group FLP systems), and as such this discussion has been limited to developments in the field where the authors have made their inspiration from traditional main-group FLP systems clear.167

5.9.1 Early transition metals Over the past few decades, group 4 complexes have been heavily explored in metallocene and postmetallocene olefin polymerization catalysis, made possible by their electrophilic character.168 As such, exploring them as the Lewis acid component of an FLP system was a natural extension of this known reactivity. The earliest example of FLP reactivity by a Lewis pair featuring a transition metal was reported in 2011 with the capture of N2O by a zirconocene/phosphine ([Cp*2Zr (OMe)][B(C6F5)4]/tBu3P) pair.169 The Wass group, as a leader in this area, focused their studies on the intramolecular FLP reactivity of group 4 metallocene phosphinoaryloxide complexes.170,171 It was found that the reactivity of these complexes is highly dependent on the steric bulk between the phosphine and the metallocene, with increasing “frustration” leading to increasing FLP reactivity. For instance, the solid-state structure of complex 61 revealed ˚ , cona bond distance between zirconium and phosphorus of 2.8826(5) A sistent with a long but persistent interaction (Fig. 5.27). Complex 62, however, displays no such interaction, but instead features a labile halobenzene solvate in the coordination sphere. This difference in frustration has an enormous impact on reactivity; complex 61 is unable to activate H2 while complex 62 is able to activate H2, along with carbon monoxide, carbon dioxide, carbonyls, olefins, ethers, and alkyl halides. Some examples of this reactivity are shown in Fig. 5.27. Along with probing the steric encumbrance and electronic effects at the metal center, at the phosphine, and from the auxiliary ligands, hafnium and titanium derivatives of 62 were prepared in an effort to probe the impact of the metal center on the degree of “frustration.”172 As expected, the MsP bond distance in the isoelectronic structures decreases in the order Hf . ZrcTi. Moreover, in the case titanium, complexes in the 13 and 14 oxidation states could both be prepared, and it was found that the Ti(III) complex has a longer MsP bond. Later, isolobal decamethylscandocinium cation and HB(C6R5)3 (R 5 H/F) anion were explored by Piers and coworkers in the activation of CO and CO2, followed by subsequent hydride transfer.173,174 Meanwhile, Erker accessed a zirconium cation/phosphine intramolecular FLP (63) via migratory insertion of a phosphino alkyne into the [Zr]-CH3 ˚ ), bond of [Cp*2Zr-CH3]1.175 Despite the presence of a ZrsP bond (2.6670(7) A this complex displayed FLP reactivity when allowed to react with t-butyl

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FIGURE 5.27 Reactivity of an intramolecular Zr/P FLP.

FIGURE 5.28 Small molecule activation with an intramolecular Zr/P FLP.

isocyanate, CO2, N2O, and mesityl azide, to yield the products shown in Fig. 5.28. Reaction with H2, however, led to formation of diphenyl(2-phenylprop-1-en-1-yl)phosphane, presumably through an H2 activated intermediate.

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5.9 Transition metal frustrated Lewis pair systems

Recently, the Wass group has focused their efforts on the preparation of intermolecular FLP derived from Lewis acidic cationic zirconium(IV) alkoxide complexes and phosphorus/nitrogen Lewis bases with further applications in small molecule activation (i.e., H2, CO2, THF, PhCCH, and Me2NH BH3) and catalytic imine hydrogenation.176178 Early transition metal FLP chemistry is not limited to metallocene derivatives. For instance Stephan and coworkers prepared a hafnium complex featuring a tridentate NSN ligand with pendent phosphines, which was found to activate CO2 between the Hf center and the pendent phosphines to give a variety of complexes.179



5.9.2 Mid/late transition metals There are fewer examples of mid-to-late transition metals as a counterpart in FLP chemistry; however, some such systems have emerged. Select examples of complexes from DuBois and Bullock are shown in Fig. 5.29, which act as the hydride acceptor in the presence of internal or external Lewis bases upon exposure to H2 gas.180182 Stephan et al. succeeded in preparing a ruthenium tris(aminophosphine) complex with a pendent phosphine arm, which effected the activation and subsequent reduction of carbon dioxide and benzaldehyde using HBpin.183 Conversely, Berke and coworkers focused their investigations on exploiting the Lewis basic properties of rhenium hydride complexes (64) in the presence of an external Lewis acid to access FLP-type pathways, as shown in Fig. 5.30.184 Subsequent addition of silane to 65 results in a mixture of products, including the CO2 reduced product

FIGURE 5.29

Transition metal complexes that activate H2 akin to FLPs.

FIGURE 5.30 Lewis basic rhenium complexes as an FLP component.

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(Et3SiO)2CH2. Similarly, an intramolecular Re complex featuring a pendent Lewis acid was later prepared by Labinger and Bercaw, and this complex was exploited for the stepwise reduction of CO to form new CsH and CsC bonds.185 Finally, Wass and Pringle explored platinum(0) and nickel(0) complexes with B(C6F5)3 as intermolecular systems for the cooperative activation of CO, CO2, ethylene, and H2.186 As one can see from these select examples, FLP-type mechanisms featuring cooperativity are known for a variety of transition metal complexes.

5.10 What are the requirements for frustration? Through the examples presented throughout this chapter, it is clear that the steric requirement to engender “frustration” between a Lewis acid and base has evolved since the initial discovery. Early investigation into FLP chemistry inferred that sterically demanding substituents on the Lewis acid and base were necessary to frustrate adduct formation. The discovery that acidbase combinations that exist in equilibrium as the free species and classical adducts are able to engage in FLP reactivity has broadened the definition of these systems. This observation was first made by Erker and coworkers with the preparation of the aforementioned Mes2PCH2CH2B(C6F5)2, which was found to exist in equilibrium between the closed adduct and open FLP (Fig. 5.31, top). The open FLP system was found to activate hydrogen to yield the zwitterionic phosphonium-hydridoborate species and could catalytically effect the hydrogenation of enamines and bulky imines.42,187

FIGURE 5.31

Early examples of Lewis acid/base adducts that could activate small

molecules.

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207

The dynamic equilibrium between this molecule and related intramolecular systems was investigated by NMR spectroscopy and DFT methods.188 In 2009 Stephan et al. reported reversible adduct formation between B(C6F5)3 and 2,6-lutidene (Fig. 5.31, bottom) and exploited this intermolecular combination in the cleavage of dihydrogen gas and the FLPmediated ring-opening of THF.189 Furthermore, large-scale preparation of B(C6F5)3 recommends its isolation as the diethylether adduct, which can be stored indefinitely. While the free borane can be accessed upon sublimation, the ethereal adduct was found to act as an FLP (due to the rapid on/off equilibrium), which could be utilized in catalysis.44,45,47 Understanding of these examples suggests that FLP reactivity would require either electronic or sterically induced frustration to provide access to the free acid and base. These examples are only intended as representative, as numerous examples are now known, particularly with the use of ethereal Lewis bases, where only a small fraction of the Lewis pairs need to be in the form of the free species to facilitate this chemistry. In many of these cases, this equilibrium exists due to the fact that the Lewis base partner is fairly weak. However, Stephan found that highly Lewis basic proazaphosphatrane P(MeNCH2CH2)3N will form a stable adduct with B(C6F5)3 with no spectroscopic evidence of disassociation (66).190 Yet, FLP-type reactivity could be observed upon reaction with CO2, PhNCO, PhNSO, or PhCH2N3 to yield the corresponding insertion products (Fig. 5.32). This

FIGURE 5.32 Evidence of FLP reactivity from a proazaphosphatrane adduct with B (C6F5)3.

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FIGURE 5.33 FLP reactivity from strained boron amidinates.

implies that while on the spectroscopic timescale there is no evidence of a free FLP, even a minor equilibrium FLP concentration could be sufficient to facilitate small molecule activation. In a similar fashion, the four-membered boron amidinates, obtained from the hydroboration reaction between Piers’ borane (HB(C6F5)2) and carbodiimides, were found to insert small molecules such as benzaldehyde, carbon dioxide, t-butyl isocyanide, acetonitrile, carbodiimide, carbon monoxide, and phenylacetylene into the BsN bond, yielding the heterocycles shown in Fig. 5.33.191 At elevated temperatures (80 C) no spectroscopic evidence for the open-chain version of 67 or 68 could be observed. More recently, Mehta and Goicoechea reported on a masked FLP resulting from the carboboration of isocyanates with B(C6F5)3 to yield the nonplanar six-membered heterocycles shown in Fig. 5.34.192 These heterocycles can be thought of as an imine-borane FLP that has captured a second equivalent of isocyanate. It was found that when heterocycles 69 or 70 were heated in the presence of a different isocyanate, exchange

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209

FIGURE 5.34 Isocyanate exchange within a B/N heterocycle via an FLP mechanism.

occurred. Both electron-donating and electron-withdrawing groups were tolerated in this reaction. Furthermore, kinetic and DFT investigations were consistent with a dissociative mechanism featuring a four-membered heterocyclic intermediate, rather than an associative mechanism and a bicyclic transition state. This proposed four-membered heterocyclic intermediate could not be isolated or spectroscopically observed, unlike the boron amidinate heterocycles discussed earlier. These reports demonstrate that FLP reactivity can be observed across a wide range of acidbase pair equilibria, including those where electronic and/or steric contributions do not result in an experimentally observable dissociation. This ever-broadening definition of FLP has been expanded to encompass activation of small molecules between ionic interactions. In 2018 it was found that alkali metal phosphides could reversibly activate dihydrogen.193 In this work it was found that the alkali metal plays an instrumental role in scavenging the hydride, while a secondary phosphine could be observed by 31P NMR spectroscopy. This reversible activation allowed Stephan and coworkers to employ KPtBu2 as a catalyst to mediate hydrogenation of 1,1-diphenylethylene and N-benzyl-tertbutylimine. Later, KPtBu2 was also reported for the activation of carbon monoxide in an FLP-type fashion.194

5.11 Outlook The study of FLPs was pioneered by Stephan and Erker, and this work has since served as inspiration for hundreds of scientists around the world. Contributions from this family of researchers have allowed for the field to evolve from one of fundamental discovery to the direct applications in synthetic chemistry that we see today. Several challenging barriers have been broached in the decade since the discovery of FLPs, including functional group tolerance and substrate scopes for hydrogenation catalysis as well as approaches for larger scale catalysis. Although progress in the field has been exceptional, FLPs are still not commonly

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found in the typical synthetic organic chemist’s toolkit. The question becomes, how do researchers make this jump and where else can FLPs make a significant impact? In order to become a ubiquitous tool for organic synthesis, FLP chemistry must become more accessible—meaning that more air- and moisture-stable catalysts are required. While some progress has been made in this direction, it still remains somewhat limited in the field. Furthermore, a larger library of enantioselective reactions must be developed beyond mere hydrogenation. Encouragingly, this is a field of great interest and researchers such as Du and Wasa, for example, are leading the way to make this a reality. Finally, the scope of FLP-mediated reactions must continue to grow, with a view to identifying unique reactions which existing reagents/catalysts cannot currently accomplish. This will require close collaboration between chemists from the synthetic organic and inorganic fields to address this issue. The application of FLPs has thus far mainly focused on synthesis; however, we may only have scratched the surface of what can be learned from this field. The definition of what constitutes an FLP has evolved significantly since its inception in 2006. Originally, sterically large Lewis acids and bases were required, where no adduct formation was possible. However, the equilibrium that exists between the free species and the Lewis acidbase adduct can be exploited to activate small molecules in an FLP fashion. Even if the equilibrium strongly favors the adduct, only a small proportion of free Lewis acid and base may be needed to achieve reactivity [as highlighted by the ability of Et2O and B(C6F5)3 to act as a competent hydrogenation catalyst system]. Furthermore, recent advancements in frontier orbital engineering with respect to maingroup systems open door to FLP reactivity from a single site [i.e., cyclic (alkyl)(amino)carbenes prepared by the Bertrand group], which may in turn lead to more complex bond activation/formation chemistries. Further investigation into fundamental questions such as “what can be considered an FLP?” and “by what mechanisms do they act?” could prove to be highly impactful and may lead to a more general definition of FLPs beyond their nascence in the main group. With over 1800 reports in the literature according to SciFinder since 2006, the field of FLP chemistry is robust and continues to grow. As new discoveries raise the profile and influence of the field, it will be exciting to see what the next decade of discovery has in store.

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104. Runyon, J. W.; Steinhof, O.; Dias, H. V. R.; Calabrese, J. C.; Marshall, W. J.; Arduengo, A. J. Carbene-Based Lewis Pairs for Hydrogen Activation. Aust. J. Chem. 2011, 64, 1165. 105. Boone, M. P.; Stephan, D. W. A Ru-H6-Arene Complex as a C-Based Lewis Acid in the Activation of Hydrogen and Hydrogenation Catalysis. J. Am. Chem. Soc. 2013, 135, 85088511. 106. Boone, M. P.; Stephan, D. W. Ru-η6-Arene Cations [{(Ph2PC6H4)2B(η6-Ph)}RuX]1 (X 5 Cl, H) as Lewis Acids. Chem. Eur. J. 2014, 20, 33333341. 107. Zhou, J.; Cao, L. L.; Liu, L.; Stephan, D. W. FLP Reactivity of [Ph3C]1 and (o-tolyl)3P and the Capture of a Staudinger Reaction Intermediate. Dalton Trans. 2017, 46, 93349338. 108. Fasano, V.; Curless, L. D.; Radcliffe, J. E.; Ingleson, M. J. Frustrated Lewis Pair Mediated 1,2-Hydrocarbation of Alkynes. Angew. Chem. Int. Ed. 2017, 56, 92029206. 109. Klare, H. F. T.; Oestreich, M. Silylium Ions in Catalysis. Dalton Trans. 2010, 39, 91769184. 110. Reed, C. A.; Xie, Z.; Bau, R.; Benesi, A. Closely Approaching the Silylium Ion (R3Si1). Science 1993, 262, 402404. 111. Lambert, J. B.; Zhang, S.; Stern, C. L.; Huffman, J. C. Crystal Structure of a Silyl Cation with No Coordination to Anion and Distant Coordination to Solvent. Science 1993, 260, 19171918. 112. Lambert, J. B.; Zhao, Y.; Wu, H.; Tse, W. C.; Kuhlmann, B. The Allyl Leaving Group Approach to Tricoordinate Silyl, Germyl, and Stannyl Cations. J. Am. Chem. Soc. 1999, 121, 50015008. 113. MacLachlan, M. J.; Bourke, S. C.; Lough, A. J.; Manners, I. Ring-Opening Protonolysis of Strained Silicon-Containing Rings: A New Approach to Ions with Silylium Character. J. Am. Chem. Soc. 2000, 122, 21262127. 114. Scha¨fer, A.; Reißmann, M.; Scha¨fer, A.; Saak, W.; Haase, D.; Mu¨ller, T. A New Synthesis of Triarylsilylium Ions and Their Application in Dihydrogen Activation. Angew. Chem. Int. Ed. 2011, 50, 1263612638. 115. Simonneau, A.; Biberger, T.; Oestreich, M. The Cyclohexadienyl-Leaving-Group Approach Toward Donor-Stabilized Silylium Ions. Organometallics 2015, 34, 39273929. 116. Corey, J. Y. Generation of a Silicenium Ion in Solution. J. Am. Chem. Soc. 1975, 97, 32373238. 117. Bourke, S. C.; MacLachlan, M. J.; Lough, A. J.; Manners, I. Ring-Opening Protonolysis of Sila[1]Ferrocenophanes as a Route to Stabilized Silylium Ions. Chem. Eur. J. 2005, 11, 19892000. 118. Klare, H. F. T.; Bergander, K.; Oestreich, M. Taming the Silylium Ion for LowTemperature Diels-Alder Reactions. Angew. Chem. Int. Ed. 2009, 48, 90779079. 119. Scott, V. J.; C ¸ elenligil-C ¸ etin, R.; Ozerov, O. V. Room-Temperature Catalytic Hydrodefluorination of C(Sp3)-F Bonds. J. Am. Chem. Soc. 2005, 127, 28522853. 120. Mu¨ther, K.; Oestreich, M. Self-Regeneration of a Silylium Ion Catalyst in Carbonyl Reduction. Chem. Commun. 2011, 47, 334336. 121. Schmidt, R. K.; Mu¨ther, K.; Mu¨ck-Lichtenfeld, C.; Grimme, S.; Oestreich, M. Silylium Ion-Catalyzed Challenging DielsAlder Reactions: The Danger of Hidden Proton Catalysis with Strong Lewis Acids. J. Am. Chem. Soc. 2012, 134, 44214428. 122. Schulz, A.; Villinger, A. “Tamed” Silylium Ions: Versatile in Catalysis. Angew. Chem. Int. Ed. 2012, 51, 45264528. 123. Reißmann, M.; Scha¨fer, A.; Jung, S.; Mu¨ller, T. Silylium Ion/Phosphane Lewis Pairs. Organometallics 2013, 32, 67366744. 124. Scha¨ fer, A.; Reißmann, M.; Scha¨ fer, A.; Schmidtmann, M.; Mu¨ ller, T. Dihydrogen Activation by a Silylium Silylene Frustrated Lewis Pair and the

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143. Mehta, M.; Holthausen, M. H.; Mallov, I.; Pe´rez, M.; Qu, Z.-W.; Grimme, S.; Stephan, D. W. Catalytic Ketone Hydrodeoxygenation Mediated by Highly Electrophilic Phosphonium Cations. Angew. Chem. Int. Ed. 2015, 54, 82508254. 144. Mehta, M.; Garcia De La Arada, I.; Perez, M.; Porwal, D.; Oestreich, M.; Stephan, D. W. Metal-Free Phosphine Oxide Reductions Catalyzed by B(C6F5)3 and Electrophilic Fluorophosphonium Cations. Organometallics 2016, 35, 10301035. 145. Augurusa, A.; Mehta, M.; Perez, M.; Zhu, J.; Stephan, D. W. Catalytic Reduction of Amides to Amines by Electrophilic Phosphonium Cations via FLP Hydrosilylation. Chem. Commun. 2016, 52, 1219512198. 146. Holthausen, M. H.; Bayne, J. M.; Mallov, I.; Dobrovetsky, R.; Stephan, D. W. 1,2Diphosphonium Dication: A Strong P-Based Lewis Acid in Frustrated Lewis Pair (FLP)-Activations of BsH, SisH, CsH, and HsH Bonds. J. Am. Chem. Soc. 2015, 137, 72987301. 147. Mallov, I.; Stephan, D. W. Ferrocenyl-Derived Electrophilic Phosphonium Cations (EPCs) as Lewis Acid Catalysts. Dalton Trans. 2016, 45, 55685574. 148. Holthausen, M. H.; Hiranandani, R. R.; Stephan, D. W. Electrophilic BisFluorophosphonium Dications: Lewis Acid Catalysts from Diphosphines. Chem. Sci. 2015, 6, 20162021. 149. Bayne, J. M.; Holthausen, M. H.; Stephan, D. W. Pyridinium-Phosphonium Dications: Highly Electrophilic Phosphorus-Based Lewis Acid Catalysts. Dalton Trans. 2016, 45, 59495957. 150. Szkop, K. M.; Stephan, D. W. Metal-Free Pincer Ligand Chemistry Polycationic Phosphonium Lewis Acids. Dalton Trans. 2017, 46, 39213928. 151. LaFortune, J. H. W.; Johnstone, T. C.; Pe´rez, M.; Winkelhaus, D.; Podgorny, V.; Stephan, D. W. Electrophilic Phenoxy-Substituted Phosphonium Cations. Dalton Trans. 2016, 45, 1815618162. 152. Fasano, V.; LaFortune, J. H. W.; Bayne, J. M.; Ingleson, M. J.; Stephan, D. W. Air- and Water-Stable Lewis Acids: Synthesis and Reactivity of P-Trifluoromethyl Electrophilic Phosphonium Cations. Chem. Commun. 2018, 54, 662665. 153. Bayne, J. M.; Fasano, V.; Szkop, K. M.; Ingleson, M. J.; Stephan, D. W. Phosphorus(V) Lewis Acids: Water/Base Tolerant P3-Trimethylated Trications. Chem. Commun. 2018, 54, 1246712470. 154. Xia, J.; Qiu, R.; Yin, S.; Zhang, X.; Luo, S.; Au, C. T.; Xia, K.; Wong, W. Y. Synthesis and Structure of an Air-Stable Organoantimony Complex and Its Use as a Catalyst for Direct Diastereoselective Mannich Reactions in Water. J. Organomet. Chem. 2010, 695, 14871492. 155. Wade, C. R.; Gabbaı¨, F. P. Fluoride Anion Chelation by a Bidentate StiboniumBorane Lewis Acid. Organometallics 2011, 30, 44794481. 156. Hirai, M.; Gabbaı¨, F. P. Squeezing Fluoride out of Water with a Neutral Bidentate Antimony(V) Lewis Acid. Angew. Chem. Int. Ed. 2015, 54, 12051209. 157. Tofan, D.; Gabbaı¨, F. P. Fluorinated Antimony(V) Derivatives: Strong Lewis Acidic Properties and Application to the Complexation of Formaldehyde in Aqueous Solutions. Chem. Sci. 2016, 7, 67686778. 158. Pan, B.; Gabbaı¨, F. P. [Sb(C6F5)4][B(C6F5)4]: An Air Stable, Lewis Acidic Stibonium Salt That Activates Strong Element-Fluorine Bonds. J. Am. Chem. Soc. 2014, 136, 95649567. 159. Sato, S.; Ameta, H.; Horn, E.; Takahashi, O.; Furukawa, N. First Isolation and Molecular Structure of Bis(2,2’-Biphenylylene)Sulfuranyl Bis(Tetrafluoroborate) [82S24(C4)]21. J. Am. Chem. Soc. 1997, 119, 1237412375. 160. Kobayashi, K.; Sato, S.; Horn, E.; Furukawa, N. Synthesis of Dicationic Telluranes by Remote Oxidation through a π-Conjugated System. Angew. Chem. Int. Ed. 2000, 39, 13181320.

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180. Rakowski Dubois, M.; Dubois, D. L. The Roles of the First and Second Coordination Spheres in the Design of Molecular Catalysts for H2 Production and Oxidation. Chem. Soc. Rev. 2009, 38, 6272. 181. Liu, T.; Chen, S.; O’Hagan, M. J.; Rakowski Dubois, M.; Bullock, R. M.; Dubois, D. L. Synthesis, Characterization, and Reactivity of Fe Complexes Containing Cyclic Diazadiphosphine Ligands: The Role of the Pendant Base in Heterolytic Cleavage of H2. J. Am. Chem. Soc. 2012, 134, 62576272. 182. Liu, T.; Dubois, D. L.; Bullock, R. M. An Iron Complex with Pendent Amines as a Molecular Electrocatalyst for Oxidation of Hydrogen. Nat. Chem. 2013, 5, 228233. 183. Sgro, M. J.; Stephan, D. W. Frustrated Lewis Pair Inspired Carbon Dioxide Reduction by a Ruthenium Tris(Aminophosphine) Complex. Angew. Chem. Int. Ed. 2012, 51, 1134311345. 184. Jiang, Y.; Blacque, O.; Fox, T.; Berke, H. Catalytic CO2 Activation Assisted by Rhenium Hydride/B(C6F5)3 Frustrated Lewis Pairs - Metal Hydrides Functioning as FLP Bases. J. Am. Chem. Soc. 2013, 135, 77517760. 185. Miller, A. J. M.; Labinger, J. A.; Bercaw, J. E. Reductive Coupling of Carbon Monoxide in a Rhenium Carbonyl Complex with Pendant Lewis Acids. J. Am. Chem. Soc. 2008, 130, 1187411875. 186. Forrest, S. J. K.; Clifton, J.; Fey, N.; Pringle, P. G.; Sparkes, H. A.; Wass, D. F. Cooperative Lewis Pairs Based on Late Transition Metals: Activation of Small Molecules by Platinum(0) and B(C6F5)3. Angew. Chem. Int. Ed. 2015, 54, 22232227. 187. Spies, P.; Erker, G.; Kehr, G.; Bergander, K.; Fro¨hlich, R.; Grimme, S.; Stephan, D. W. Rapid Intramolecular Heterolytic Dihydrogen Activation by a Four-Membered Heterocyclic Phosphane-Borane Adduct. Chem. Commun. 2007, 50725074. 188. Spies, P.; Kehr, G.; Bergander, K.; Wibbeling, B.; Fro¨hlich, R.; Erker, G. Metal-Free Dihydrogen Activation Chemistry: Structural and Dynamic Features of Intramolecular P/B Pairs. Dalton Trans. 2009, 15341541. 189. Geier, S. J.; Stephan, D. W. Lutidine/B(C6F5)3: At the Boundary of Classical and Frustrated Lewis Pair Reactivity. J. Am. Chem. Soc. 2009, 131, 34763477. 190. Johnstone, T. C.; Wee, G. N. J. H.; Stephan, D. W. Accessing Frustrated Lewis Pair Chemistry from a Spectroscopically Stable and Classical Lewis Acid-Base Adduct. Angew. Chem. Int. Ed. 2018, 57, 58815884. 191. Dureen, M. A.; Stephan, D. W. Reactions of Boron Amidinates with CO2 and CO and Other Small Molecules. J. Am. Chem. Soc. 2010, 132, 1355913568. 192. Mehta, M.; Goicoechea, J. M. Carboboration of Isocyanates with Tris (Pentafluorophenyl)Borane and Evidence for Dissociative FLP Chemistry of an AcidBase Pair. Chem. Commun. 2019, 55, 69186921. 193. Xu, M.; Jupp, A. R.; Qu, Z.-W.; Stephan, D. W. Alkali Metal Species in the Reversible Activation of H2. Angew. Chem. Int. Ed. 2018, 57, 1105011054. 194. Xu, M.; Jupp, A. R.; Stephan, D. W. Acyl-Phosphide Anions via an Intermediate with Carbene Character: Reactions of K[PtBu2] and CO. Angew. Chem. Int. Ed. 2019, 58, 35483552.

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S E C T I O N

6

New inorganic therapeutics, I

C H A P T E R

6 Ruthenium and iron metallodrugs: new inorganic and organometallic complexes as prospective anticancer agents Andreia Valente1, Taˆnia S. Morais1, Ricardo G. Teixeira1, Cristina P. Matos2, Ana Isabel Tomaz1 and M. Helena Garcia1 1

Centro de Quı´mica Estrutural and Departamento de Quı´mica e Bioquı´mica, Faculdade de Cieˆncias, Universidade de Lisboa, Campo Grande, Portugal, 2 Centro de Cieˆncias e Tecnologias Nucleares (C2TN), Instituto Superior Te´cnico, Universidade de Lisboa, Bobadela LRS, Portugal

6.1 Introduction Cancer is today a global health problem with a worldwide impact. Statistics indicate that 3 in every 10 people born today will develop a cancer condition during their lifetime, and 1 in 5 will die from it.1 Breast, prostate, lung, and colorectal cancers are the four most incident prevalent cancer conditions for people under 70 years old, with lung and breast cancers presenting the highest mortality rates.2 The deadliest feature of cancer is the development of metastases in which malignant cells invade and spread throughout the body to establish secondary tumors. Current treatment options include surgery, radiation therapy, and chemotherapy. Other options emerging as auspicious are immunotherapy3 and oncolytic virotherapy,4,5 though these modern approaches are

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of limited suitability for most cancer conditions. Chemotherapy still stands out for its high efficacy and is the most frequently used. Three platinum-based compounds are approved worldwide for cancer treatment: cisplatin, carboplatin, and oxaliplatin6,7 (Fig. 6.1).

FIGURE 6.1 Worldwide commercially available platinum drugs (top) and ruthenium prospective drugs that progressed into clinical trials (bottom).

Cisplatin was the first metallodrug available in the market and was a major turning point in chemotherapy, until then limited to the use of organic molecules, thus opening a whole new field of metallodrug development. Its wide acceptance resided in its great efficacy in treating a wide range of cancer conditions.6 However, high toxicity leading to highly debilitating side effects8 and resistance to treatment (either intrinsic or developed after some cycles of therapy) are major drawbacks involved with the use of cisplatin. Much effort has been devoted to the quest for alternatives that combine efficacy with a more tolerable pharmacological profile. Initial efforts focused on addressing the systemic toxicity of cisplatin, which was traced (in part) to the great lability of its chloride ligands leading to a too high reactivity in physiological media.7 In carboplatin, both chlorides were replaced by a chelating dicarboxylate ligand (1,2-cyclobutanedicarboxylate), which resulted in a more stable compound that was much better tolerated despite being slightly less effective.9 Nevertheless, like cisplatin, the primary mode of action was the formation of crosslinks in cellular DNA.6 In oxaliplatin, the two monodentate ammine ligands were replaced by a chelating diamine moiety, (1R,2R)-diaminocyclohexane (or dach), which results in a different biological profile.6,7 Oxaliplatin is used as a frontline treatment for colorectal cancer in combination therapy.6,7,9 Given their efficacy, platinum drugs still stand out as the most often prescribed chemotherapeutics, incorporating about 50% of all oncologic treatments9 despite the toxicity inherent to their use. Still, some tumor conditions are not responsive to these therapies and the lack of effective

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approaches for treating metastases and aggressive metastatic cancers sets an urge for new solutions. Research on Pt-based compounds is at present very active. Current trends that include strategies to design cisplatin-like complexes to target specific receptors in tumor cells9,10 and incorporation of approved drugs as coligands or the use of the Pt(IV) ion (designed to release the Pt(II) active species) were recently reviewed.6,7,9,1113 The quest for metalbased cancer chemotherapeutics that combine high efficiency, low toxicity, and different mechanisms of action has extended to nonplatinum compounds.14,15 Among these, ruthenium- and iron-based compounds are some of the most prominent and have demonstrated great potential.

6.1.1 Ruthenium-based compounds as chemotherapeutic candidates Ruthenium-based compounds have consistently been found to have a lower systemic toxicity, showing some inherent selectivity for cancer cells, and a broader spectrum of action, being active toward cisplatinresistant cell lines. Ruthenium has three biologically accessible oxidation states (II, III, and eventually IV) that can be advantageous for its unique properties. In addition, ruthenium compounds can exert their effect through multiple targets (including but not limited to DNA) that results in different mechanisms of action and different biological response. To date, three complexes have progressed into Phase I/II clinical trials, namely NAMI-A,16,17 KP1019 now replaced in the clinical trials by its more soluble sodium salt NKP133918,19 and, much more recently, TLD1433 (in Phase Ib), which was designed for photodynamic therapy (PDT)20,21 (see Fig. 6.1). Ru(III) complexes NAMI-A (developed by Sava, Mestroni, and Alessio) and KP1019 (disclosed by Keppler and coworkers) are iconic compounds in ruthenium-based anticancer agents. Curiously, both compounds were tested in vivo before in vitro screening. Despite their structural resemblance, these two agents have completely different biological effects.18,19 NAMI-A was remarkably able to prevent the development and growth of metastases in several solid tumor models, while exerting no significant effect on the growth of the primary tumor. In contrast, KP1019/NKP1339 was highly effective in reducing the tumor volume in a platinum-resistant colorectal carcinoma with no relevant antimetastatic effect.19 Despite the effort to understand the way that these ruthenium-based compounds act, the mode of action of NAMI-A and KP1019 is still not fully understood, in part because several parallel mechanisms seem to be triggered. Both NAMI-A and KP1019/NKP1339 are highly prone to hydrolysis under physiological conditions due to

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the presence of weak-binding monodentate ligands, and this high reactivity has surely hindered their progress.19,22 The approach of using a robust chelating ligand structure to stabilize the metal ion was followed very recently in the development of TLD1433 (by McFarland and coworkers), an example of successful drug design.21 TLD1433 is an octahedral complex where the Ru(II) ion is stabilized by a (NN)-polypyridyl ligand set that is combined with a bidentate phenanthroline derivatized to include an α-oligothiophene moiety optimized so as to afford a photosensitizer with improved properties for PDT.21 The initial findings on the exciting properties of the two iconic Ru (III) complexes triggered intense research in this field. It was initially believed that Ru(III) complexes would undergo an “activation-by-reduction” process with the Ru(III) species being reduced to the more active Ru(II) species in the low-oxygen acidic environment of the tumor tissue.19 In this sense, Ru(III) complexes were thought to act as prodrugs and to undergo biotransformations to release the true Ru(II) active species, and most Ru(III) complexes investigated for their anticancer properties were similar to NAMI or KP1019.14,2224 In the design of a successful metallodrug, it is important to stabilize the central metal ion against extensive hydrolysis in aqueous media, and when lower oxidation states are involved, this extends to defending the central metal ion against undesired aerial oxidation. Still, the reactivity of the metal complex is markedly determined by the entire ligand set involved, which can be used to fine-tune the performance of the overall unit and, ultimately, the cellular targets and mechanism of action involved. Over the years, several families of ruthenium compounds with promising properties for cancer therapy have been reported and a myriad of complexes have been developed and studied, predominantly based on the Ru (II) cation.14,20,2529 Recently, two families of octahedral Ru(III)-based compounds stabilized by robust chelating structures were reported. The set of results gathered for these complexes shows the huge potential of these Ru (III) coordination complexes as prospective chemotherapeutics, and is addressed in Section 6.2. In the most intensively studied complexes to date, two major classes of ruthenium compounds emerged: (1) classical octahedral coordination complexes, in which the Ru(II) cation is stabilized by one (or two bidentate) ligand(s) most often with N-heteroaromatic donors [typically derivatives based on 2,20 -bipyridine (bipy), 1,10-phenantroline (phen), and the dipyridophenazine (dppz) structure with more or less extended π-aromatic systems] leaving four (or two) free coordination binding sites for additional coligands30 and (2) half-sandwich organometallic complexes [Ru(arene)(X)(Y)(Z)], characterized by a neutral arene (or mononegative cyclopentadienyl) π-ligand bound to Ru(II) in a pianostool structure where the arene moiety occupies the top of the stool, and

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the three legs (X, Y, and Z) correspond to three remaining coordination sites left to bind mono- or bidentate coligands. Several recent reviews have addressed the extensive class of octahedral Ru(II)polypyridyl complexes reported, focusing on their activity, properties, and mechanism of action.25,30 A variety of organometallic cycloruthenated complexes, that is, complexes with at least one covalent carbon-metal atom, have also displayed interesting potential for cancer therapy and include both octahedral and piano-stool structures. This class has been recently reviewed by Gaiddon and Pfeffer.29 In the class of organometallic ruthenium(II)-arene compounds, two subfamilies have been extensively studied: the RAED [Ru(η6-arene)(en) Cl]1 family (en 5 ethylenediamine) that was proposed by Sadler and coworkers31 and the RAPTA ([Ru(η6-arene)(PTA)X2]) (PTA 5 1,3,5-triaza-7-phosphaadamantane; X 5 Cl2 in the prototype compounds) by Dyson and coworkers.27 The PTA ligand endows the complex with aqueous solubility. The hydrolysis profile for these complexes is like that of cisplatin, with labile chlorides being replaced by water (or OH2) to yield the more reactive aqua form in a process that is supposedly inhibited in the blood plasma (with its high Cl2 content) and activated in the cell cytoplasm after uptake (low Cl2 content). In vivo studies with RAPTA-B (with benzene as the arene cap), RAPTA-C (with paracymene), and RAPTA-T (with toluene) showed in different mouse models bearing mammary carcinoma that, although these complexes lacked activity in the primary tumor, they were effective in reducing the number and weight of lung metastases that originated, revealing their potential as antimetastatic agents.27 In general, the cytotoxicity shown in vitro by this class of compounds is quite low although variations can be introduced, for example, to tether a planar aromatic DNA-interacting moiety to the arene ligand (such as pyrene, anthracene, or naphthalimide) to improve their activity. A comprehensive review of this group of compounds was recently published27 and also includes subclasses of PTA complexes with other face-capping groups in place of the arene such as cyclopentadienyl in, for example, [Ru(η5-C5H5)Cl(PTA)2] or 1,4,7-trithiacyclononane ([9]aneS3) in [Ru([9]aneS3)Cl2(PTA)]. Much work on the [Ru(η5-C5H5)(X)(L)] family (where X is a monodentate and L is a bidentate ligand) for application in cancer chemotherapy has been reported by our group, using the piano-stool {Ru(η5C5H5)}1 scaffold and the three ancillary binding sites to design ruthenium-based drug candidates.3235 In this class, the usual labile ligand (Cl2 or other) is absent, and the compound is designed to act as a whole unit and not as a “pro-drug” requiring activation. The work that led to the development of a structural prototype, exciting recent progress, and the huge potential of this family of compounds is addressed in Section 6.3.

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6.1.2 Iron-based compounds as chemotherapeutic candidates Iron is an essential nutrient to almost all living organisms. Human health is highly sensitive to the cellular levels of iron, with an excess or a deficiency resulting in—or being associated with—disease. Iron is involved in many important biological processes such as oxygen transport, DNA synthesis, or cell cycle progression.36,37 These processes, essential to life and health, are also implicated in carcinogenesis.3739 Cancer has also been related to the excessive accumulation of iron in tissues in several types of human tumors.37,38,40 In physiological media, iron cycles between two oxidation states, namely Fe(II) and Fe(III). Many of the biological functions of iron are based on the interplay of these two oxidation states by one-electron donation or acceptance.39,41 This is a crucial property for electron transport and is also behind the production of reactive oxygen species (ROS), which can be a double-edged sword for iron in the therapeutic context.39,40 On the other hand, given the fact that it is a bioessential metal, iron is anticipated to have a lower metal-induced cellular toxicity in comparison to other metal-based complexes. Another advantage is its abundance and its price, which would endow a huge commercial advantage to iron-based drugs in terms of manufacturing cost. All of these considerations make iron a very interesting transition metal with which to pursue the development of cancer therapeutic drugs. The successful application of bleomycin (BLM), together with the in vivo antiproliferative effect reported for ferrocenium salts (see below, Fig. 6.2), first disclosed the potential of iron complexes in cancer therapy.

FIGURE 6.2 Structures of ferrocerone (left), ferroquine (center), and hydroxyferrocifen (right; n 5 25, 8—see text for details and references).

These laid two paths for the development of iron chemotherapeutics using different approaches: research on very efficient ligands for iron binding (aiming at iron depletion) and the search for iron compounds designed to be cytotoxic, selective, and well tolerated, evolving from the path first sketched by platinum metallodrugs. BLM is a glycopeptide antibiotic that acts as an excellent iron chelator inducing DNA strand breaks via an “activated bleomycin” species formed by its binding to Fe(II), followed by oxygen binding and reduction.42 Iron

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chelators had been commonly used in the clinic for the treatment of iron overload diseases, and the discovery of their antiprolific effect toward aggressive tumors disclosed a new approach in cancer chemotherapeutics focused on efficient binders for iron depletion. Iron chelators targeting the intracellular metabolism of iron for cancer treatment have been the focus of several excellent recent reviews41,4348 and will not be further addressed here. The development of iron-based drugs that are active per se is an intense area of research in anticancer iron-drug candidates. For these, iron is properly bound to one or more different ligands and the therapeutic response is expected to arise from this whole entity. The possibility of designing the structure of the complex by selection of a suitable chelating ligand skeleton to control overall reactivity for optimal performance is both an attractive feature and a big challenge, ultimately defining the classes of compounds that have been investigated in this regard. Currently, several distinct types of iron complexes have been reported with encouraging results. The first iron complexes reported to have excellent antineoplastic properties in vivo were the water-soluble salt complexes ferricenium picrate and ferricenium trichloroacetate, with the formula [Fe (Cp)2]1[X]2 (Cp 5 cyclopentadienyl or η5-C5H5; X 5 picrate or trichloroacetate anions). These were reported to result in cure rates of 100% in female CF1 mice with Ehrlich ascites carcinoma.49,50 This finding drew attention to the potential of ferrocene derivatives as drug candidates, ultimately leading to three compounds that have been studied extensively (Fig. 6.2): (1) ferrocerone, the only one used in the clinic for the treatment of anemia (although no longer available);51,52 (2) ferroquine, the chloroquine derivative of ferrocene and active in chloroquineresistant strains of Plasmodium falciparum (the deadliest malaria strain); it is in Phase II clinical trials for malaria treatment and was reported to exhibit antitumor activity as well;46 and (3) ferrocifen and hydroxyferrocifen, the ferrocene derivatives of the drugs tamoxifen and hydroxytamoxifen, its active metabolite; tamoxifen is an antiestrogen chemotherapeutic currently used in the treatment of hormonedependent (ERα1) breast cancer, while the two ferrocene derivatives in preclinical evaluation are active against both ERα1 and ERα2 breast cancer types.46,51 Given the favorable properties of ferrocene in the context of medicinal chemistry—robustness and stability in biological media, reversible redox activity, low toxicity, suitable lipophilicity and the possibility of derivatization of the cyclopentadienyl ring—ferrocene derivatives have attracted much interest and have mostly dominated research in the area of organometallic iron prospective metallodrugs until quite recently. The library of ferrocene compounds is wide, encompassing several classes of which the ferrocifen family is undoubtedly the most extensive.46

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These compounds incorporating Fe(II) have been the focus of several excellent recent reviews that systematically address their particularities, advances in the knowledge of their mode of action, as well as the several paths followed and challenges to their progress.41,46,51,52 Recently, a new class of organometallic iron(II) metallodrugs based on the Fe(η5-C5H5) scaffold emerged as quite promising for chemotherapy, and is addressed in greater detail in Section 6.3.34 Coordination complexes of iron(II) and iron(III) designed as anticancer drugs have also been reviewed recently.39,41 These complexes exhibit an octahedral geometry where iron is stabilized by one (or more) chelating structure(s) with carefully chosen donor atoms for appropriate Fe(II) or Fe(III) binding, with electron-rich oxygen donors such as Ophenolate being commonly used in Fe(III) complexes and N-heteroaromatic donors such as Npyridine in bidentate 2,20 -bipyridine or 1,10-phenantroline (and derivatives thereof) being preferred Fe(II) binders. Nevertheless, this is not a general rule given the fact that the ease of iron to cycle between 12 and 13 oxidation states (i.e., the Fe(III)/Fe(II) reduction potential) is markedly changed upon coordination and results as a global effect of all ligands involved. The way BLM coordinates iron as a multidentate ligand in the active iron-bleomycin species (namely the donor atoms involved) inspired research on pentadentate polypyridyl ligands to design antitumor iron complexes.39,41,46 Che and coworkers reported the ligands Py5-OH (2,6bis[hydroxybis(2-pyridyl)methyl]pyridine) and qpy (2,20 :60 ,2v:6v,2w:6w,2vvquinquepyridine) that yield, respectively, six- and seven-coordinate Fe(II) complexes53 (Fig. 6.3A). These two complexes exhibited similar and high cytotoxic activity (IC50 values of 0.63.4 μM) against a panel of cancer cell lines. Their activity was traced to DNA damage caused by the formation of ROS that induced apoptosis and cell cycle arrest, although following different mechanisms. These differences were ultimately related to how the penta-N-donor chelator stabilized Fe(II) and modulated its reactivity: Py5-OH was the most efficient Fe(II) “stabilizer” yielding a complex more selective to cancer cells while the activity of Fe(II)-qpy was rather unspecific.53 In the class of multidentate bleomycin-inspired N-donor systems, N4Py (N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)-methylamine) has become one of the most prominent chelators. The Fe(II)-N4Py complex was reported to be an excellent functional and structural mimic of Fe (II)-BLM, able to efficiently cleave plasmid DNA in cell-free media.54,55 In two human cancer cell lines (ovarian SKOV3 and metastatic breast MDA-MB-231 lines), Fe(II)-N4Py was about one-third more active than BLM (or activated Fe(II)-BLM), and was more selective toward the noncancerous cells used (epithelium kidney HK2 line), its action being related to the induction of extensive formation of ROS in the cells.55

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FIGURE 6.3 Structures of iron complexes with reported high anticancer activity and promising profile bearing multidentate ligands inspired by bleomycin (A), with bidentate NN-diimines (B), with cathecolate and derivatives (C), and with tetradentate salen-like ligands (D) (see text for details and references).

Octahedral coordination complexes of Fe(II) with diimines have also been proposed as prospective metallodrugs.41,46 In fact, bipy, phen, and derivatives thereof are privileged scaffolds in drug design. These are bidentate N-hereroaromatic donors (both σ-donating and π-accepting) that combine an excellent metal chelating ability with biological effects in the context of several disease conditions.56,57 A series of tris(diimine) iron(II) complexes with interesting anticancer potential was reported by Palaniandavar and coworkers (Fig. 6.3B).58 All complexes were at least 2.5 times more cytotoxic than cisplatin in the set of cancer cells tested, with IC50 values in the range 1729 μM. The best candidate was the complex with disubstituted 5,6-dimethyl-1,10-phenanthroline [Fe(II) (5,6-dmp)3]21 that interacted with DNA through groove binding, while partial insertion between DNA base pairs occurred with the unsubstituted phen complex [Fe(II)(phen)3]21. Furthermore, [Fe(II)(5,6-dmp)3]21 exhibited better DNA cleavage efficiency and much higher cytotoxic activity toward a human breast cancer cell line (MCF7) (IC50 0.6 μM, 100 times better than cisplatin tested under the same conditions). This behavior was partially ascribed to the higher lipophilicity of the complex conferred by the 5,6-dmp ligand and expected to facilitate its transport through the cell membrane, although factors such as the mode and extent of the interaction with DNA and an adequate redox potential of the core Fe(III)/Fe(II) were also accountable.

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Chen and coworkers59 synthetized a series of iron(II) tris(diimine) complexes with different lipophilicity and planarity, using bipy, phen, and ip (imidazole[4,5-f][1,10]phenanthroline) as the bidentate N-donor bases (Fig. 6.3B). All complexes were cytotoxic toward a panel of different human cancer cells (MCF-7 breast adenocarcinoma, A375 melanoma, HeLa cervical carcinoma, HepG2 hepatocarcinoma, A549 pulmonary carcinoma, PC-12 neuroblastoma, and RHepG2 drug-resistant hepatoma). Although IC50 values for [Fe(II)(bipy)3]21 (the more hydrophilic and less active) were in the range B1635 μM (and higher than those found for cisplatin), the selectivity index (SI, the ratio IC50/(noncancer)/IC50/(cancer)) was much more favorable. All other iron complexes (more hydrophobic, NN-donor more planar) exhibited IC50 values in the low micromolar range and were more active than cisplatin, with [Fe(II)(ip)3]21 presenting the best SI. These differences in the biological response extended to the cell uptake, cellular localization, and the mechanism of action, although the transferrin receptor was involved in the uptake of all complexes. [Fe(II)(bipy)3]21 accumulated in the cell nucleus, induced cycle arrest in the S phase by triggering DNA damage, and activated the p53 signaling pathway; in contrast, iron complexes with planar/hydrophobic NN ligands were localized in cell cytoplasm, and induced apoptosis and G0/G1 arrest in the cycle of MCF-7 cells through regulation of AKT pathway.59 A structureactivity study on phenyl-substituted derivatives [Fe(II)(pip-R)3]21 disclosed the 4-methoxyphenyl derivative as the best agent, specifically inhibiting thioredoxin reductase (an enzyme involved in intracellular oxidative balance regulation and overexpressed in several human tumor cells) and inducing apoptosis, inhibiting cell migration and invasion, and exhibiting antiangiogenic activity while showing negligible toxicity.60 Much of the work on iron-based compounds for cancer therapy has been devoted to complexes designed for PDT, and the library of iron complexes reported was reviewed recently.39,41,46 One of the most promising families included catechol (or derivatives) as the stabilizing unit for iron and a coligand linked to a moiety effective in generating photoinduced DNA cleavage (Fig. 6.3C).61 The two Ophenolate donors in catechol are excellent to chelate iron(III) in a bidentate fashion and additionally provide a low-energy intense charge-transfer absorption band suitable to photoactivate these complexes with red light (within the therapeutic window). The coordination sphere was completed with a tridentate N-donor dipicolylamine ligand derivatized to include anthracene or pyrene as the photoactivated DNA-targeting moiety. These complexes were cytotoxic only when irradiated and were active against HeLa cells even when red light (620850 nm) was used.39,41 Another promising family of iron complexes developed with the same rationale combines tetradentate tripodal phenolatebased ligands as the

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stabilizing unit for iron(III) with a bioactive moiety (such as DNA-binding phenanthroline-like derivatives). We will address this family of complexes in greater detail in Section 6.2. A very auspicious class of anticancer candidates is based on iron salen-like complexes, or iron complexes bearing an N,N0 -disalicylidene1,2-diaminoethane scaffold. Although metallosalens (i.e., salen metal ion complexes) were initially developed primarily for their catalytic properties, the recognition of their potential as artificial DNA nucleases attracted attention to their biological application. The collection of iron complexes bearing salen-type ligands reported as promising anticancer agents is wide, and this family was reviewed recently.39,62 The complex [Fe(III)(salophene)Cl] (Fig. 6.3D) was identified as a promising lead structure, highly cytotoxic and with a wide therapeutic spectrum (leukemia, lymphoma, neuroblastoma, breast, and colon), and quite active against drug-resistant leukemia cells as well as cisplatinresistant ovarian cancer cells.6365 Several structureactivity studies led to complexes active in the low nanomolar range and some were quite selective to cancer cells.39,63,66 It was recently reported that iron(III) salophene complexes induce ferroptosis (a controlled form of cell death that is prompted by iron-dependent generation of ROS causing lipid peroxidation) and/or necroptosis (a type of regulated necrotic cell death) depending on the substituents at the phenylenediamine moiety.63,66 In the following sections of this chapter, we will mainly address properties and features of iron and ruthenium complexes developed as anticancer metallodrugs, focusing on the contribution of our group in this field. These include two main classes: M(II) complexes (M 5 Fe, Ru) stabilized by the ligand Cp and exhibiting a piano-stool geometry and M(III) complexes with an octahedral geometry bearing a tetradentate scaffold to accommodate the metal ion.

6.2 Novel octahedral Ru(III)/Fe(III)-based prospective drug candidates In this section, we focus on Fe(III) and Ru(III) octahedral complexes with a very interesting potential as anticancer chemotherapeutics, namely iron(aminobisphenolates), iron(cyclam), and ruthenium(salen/ salan), which are still emergent and may become new classes of prospective drug candidates with high value.

6.2.1 Iron(aminobisphenolate) tripodal complexes Tripodal aminophenolate ligands offer an immense versatility in the design of coordination complexes. In their simpler form these are

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tridentate ligands with an ONO binding motif. The donor set [Ophenolate, Namine,Ophenolate] is highly suitable to chelate the iron(III) cation (with the “hard” nature of Ophenol donor matching the “hard” character of trivalent iron). The possibility of including an additional donor atom in the Namine arm further highlights the versatility of these molecules in ligand design. Iron(III) complexes of tripodal tetradentate aminophenolate ligands were proposed as functional mimics for catechol 1,2-dioxygenase.6770 In these complexes, with an octahedral (or distorted octahedral) geometry, the two positions remaining after coordination of the tripodal ligand are adjacent cis-coordination sites,67 suitable for the coordination of a bidentate coligand. Ternary complexes of this kind, still quite uncommon, are certainly useful in the design of iron metallodrugs, especially with coligands of therapeutic relevance. In this regard N-heteroaromatic chelators such as 8-hydroxyquinoline (8HQ), 2,20 -bipyridine (bipy), and 1,10-phenanthroline (phen) (and derivatives thereof) are common ligands in coordination chemistry with therapeutic interest in several contexts.56,57,71,72 Chakravarty and coworkers reported a group of ternary iron(III) complexes of a tetradentate phenolatebased ligand inspired by the nonheme enzymes motif [FeL(B)], where L is 2-bis-[3,5-di(tert-butyl)-2-hydroxybenzyl]aminoacetic acid and B is a phenanthroline-like coligand, and evaluated these complexes as prospective photocytotoxic anticancer agents7375 (Fig. 6.4).

FIGURE 6.4 Iron(III) complexes of trianionic tripodal aminophenolate ligands with reported antitumor activity. dpq, dipyridoquinoxaline; dppz, dipyridophenazine; phen, 1,10-phenanthroline.

These complexes cause photoinduced DNA cleavage under visible light via a mechanism involving the formation of hydroxyl radicals, while being cleavage-inactive in the dark. The most active toward DNA cleaving activity was the complex containing dipyridophenazine (dppz), and it was evaluated in vitro on cervical (HeLa) cancer cell lines and healthy keratinocyte (HaCaT) cell lines. It was noncytotoxic in the dark and became very active toward both cell lines upon irradiation with visible light with IC50 values of 36 μM (or lower, if UV light was used). Cells showed nuclear morphological changes consistent with early apoptosis within as little as 2 h of irradiation, which was linked to intracellular extensive ROS generation, possibly inducing apoptosis by direct DNA damage.7375

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In a subsequent structure 2 activity study focused on modified dipyridophenazine ligands, increasing the aromatic surface was proven highly beneficial for the activity of these complexes.75 Although cell uptake was roughly similar for complexes containing the different modified dipyridophenazine ligands, the dppn derivative (dppn is benzo-[i] dipyrido[3,2-a:20,30-c]phenazine) showed an increased DNA binding affinity (and an intercalative mode of binding) and a much lower IC50 value (0.77 μM) in HeLa cells when activated with visible light, being devoid of cytotoxicity (IC50 . 150 μM) in the dark. In comparison, all other complexes of the set were also inactive in the dark, but were much less active upon irradiation (with IC50 values ranging from 61.1 to 5.3 μM) depending on the choice of dipyridophenazine derivative. In an effort to improve the ability of these photocytotoxic iron(III) complexes to specifically target the tumor, the dipyridophenazine ligand was conjugated with biotin (Fig. 6.4),76,77 since biotin receptors are known to be overexpressed in various cancer cell types.76 The biotin-appended iron (III) complexes showed a decreased ability to interact with DNA, but caused selective photocytotoxicity in hepatocellular carcinoma cells over normal cells. A series of new ternary iron(III) complexes envisaged to be stable entities with cytotoxic ability was recently reported by our group.78,79 The aminobisphenolate ligand N,N-bis(2-hydroxy-3,5dimethylbenzyl)-N-(2-pyridylmethyl)amine was used as the stabilizing core for Fe(III) and different bidentate coligands were used (Fig. 6.5), namely neutral NN-heteroaromatic diamine bases (where NN 5 bipy, phen, and phen derivatives) or mononegative NO-heteroaromatic donors (NO 5 8-hydroxyquinoline or its 5-chloro-derivative), to obtain

FIGURE 6.5 Structure of ternary aminobisphenolate iron(III) complexes with bidentate coligands: neutral NN-heteroaromatic diamine bases (bipy and phen derivatives; X 5 CF3SO32) or mononegative heteroaromatic NO-donors (8HQ and its 5-chloro derivative).

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complexes of general formula [Fe(L)(NN)]1 or [Fe(L)(NO)]. The set included the “bare” cationic iron complex (Fe(L), compound 6 in Fig. 6.5) lacking the chelating coligand and permitted evaluation of the advantage of its incorporation in the coordination sphere.78,79 The antiproliferative activity of all iron complexes and free ligands (the tetradentate aminobisphenolate and coligands) was assessed in human cancer cell lines, namely cervical carcinoma (HeLa), non-smallcell lung carcinoma (H1299), and breast adenocarcinoma [MDA-MB-231, used as a model for triple-negative breast cancer (TNBC)—vide infra, Section 6.3.1.5].78,79 As a general trend, HeLa and H1299 cells were more sensitive to the iron complexes than were TNBC cells. The inclusion of the bidentate NN-diimine was beneficial for the antitumor potential, resulting in compounds that were active for all cancer cells in the low micromolar range: IC50 2.27.4 μM.78 Complexes 25 (with phen or a phen derivative, Fig. 6.5) exhibited higher activity than 1 (with bipy). At 72-h incubation, all ternary iron(III) complexes were up to seven times more potent than either of their ligands tested alone. This was particularly clear in the case of phen in lung H1299 cells, with the IC50 value decreasing from 25.6 μM (phen alone) or 19.3 μM (tetradentate L) to 10.8 μM (“bare” complex Fe(L)) and to 3.1 μM for the ternary complex 2 [Fe(L)(phen)] that indicated a positive synergistic effect in combining Fe(III), L, and the coligand in the same entity. Complex 3 (the amino-phen derivative) was the best of the set, with an IC50 around 2 μM for lung and cervix, and 4 μM for TNBC cells. The intrinsic selectivity of complexes 24 for cancer cells was evaluated in noncancerous fibroblast (HFF) and epithelial (RPE) cells. Although at 24-h incubation fibroblasts were more sensitive to these complexes than epithelial cells, no real difference between the two lines was observed at 72-h incubation, with IC50 values (4.37.0 μM) being too similar to those measured for cancer cells. This attested to their lack of selectivity and the need of a means to target them in further developments. The use of NO-hydroxyquinoline donors as coligands in the iron(III)-aminobisphenolate core also resulted advantageous, although to a lesser extent. In general, 7 and 8 (Fig. 6.5) were more cytotoxic than the free coligands or Fe(L) tested alone, with exception of 5-chloro derivative in MDA-MB-231 cells: a lower IC50 value was obtained for free coligand compared to that of complex 8.79 The two ternary complexes showed similar IC50 values at 72 h, and while 7 was the more active of the two (IC50 3.5 μM for HeLa, 6.3 μM for MDA-MB-132), it was nevertheless still slightly less active than the amino-phenanthroline derivative 3 (IC50 2.2 and 4.1 μM, respectively).78,79 The mechanism of action of ternary complexes 24 was studied and DNA was a likely target given their design. Moderate binding

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constants to ctDNA (a mammalian DNA with a right-handed helical “B-like” structure) were obtained for these complexes (B104 M21 cm21), and for 2 and 4 a groove binding mode able to disrupt the normal DNA base-stacking was proposed. Interestingly, complex 3 induced an inversion in the ctDNA helicity with a B - Z (or right-handed - left-handed) conformational change, an effect that could be assigned to the amino-phen coligand.78 An increase in intracellular ROS levels was detected in HeLa, H1299, and MDA-MB-231 cells treated with complexes 24, causing intracellular DNA double-strand breaks and genomic DNA fragmentation that led to ROS-mediated oxidative damage, and apoptosis involving the activation of caspases 3/7 was proposed as the primary mode of cell death for complexes 24. Similar results were found for iron(III) ternary complexes bearing hydroxyquinoline coligands, indicating that apoptosis (as the mode of cell death) results from genomic DNA damage mediated by ROS generated by complexes 7 and 8. These results suggest that the effect of the different coligands in the overall in vitro behavior is marginal, with the exception of complex 3 for which an inversion of the B-DNA helicity was observed. Overall, these iron(III) complexes with a robust tetradentate aminobisphenolate core (offering a mixed binding motif combining two Ophenolate donors with Namine and Npyridine atoms) presented high activity and interesting features that make them worthwhile exploring as potential new anticancer metallodrugs. Although the lack of selectivity to cancer cells of these iron(III)-aminobisphenolates was somewhat expected, this drawback can be circumvented with suitable tumor-targeting approaches, either through derivatizations on the ligand/coligand scaffolds or using appropriate drug delivery systems, which should be pursued in subsequent work.

6.2.2 Iron(III)(cyclam) complexes Cyclams are robust tetradentate scaffolds with N-amine donors offering a [5 1 5 1 5 1 5] chelate ring system for the effective binding of several transition metal ions including iron. Recently, new Fe(III)(cyclam) complexes were explored as anticancer agents for the first time.80 The choice of cyclams was influenced not only by the stability that this polyamine ligand could impart to the complexes, but also by their known biological relevance.81 Indeed, due to the versatility achieved by the N-functionalization of the cyclam backbone, metal complexes of zinc, nickel, copper, cobalt, palladium, and iron have been reported in the medicinal field, in particular as antibacterial agents.8286 In the frame of anticancer applications, this was, as far as we are aware, the first reported example of Fe(III)(cyclam) complexes. The two

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FIGURE 6.6 Structure of the compounds [Fe{(HOCH2CH2CH2)2(R)2Cyclam}Cl2][Cl] (R 5 PhCH2; Fe(III)(cyclam)-1 and 42CF3PhCH2; Fe(III)(cyclam)-2).

new compounds differ in the phenyl substituent of the cyclam (Fig. 6.6) and were found to be stable in DMSO and in cell culture medium. Their cytotoxicity, together with the cyclam ligands, was evaluated on human cervical cancer cells (HeLa) at 24 and 72 h. The cyclams and iron compounds presented similar time-dependent cytotoxicity. The substituent on the cyclam was also shown to have an important role on the overall cytotoxicity since the CF3 group led to a much higher activity (e.g., 30.9 vs 2.4 μM for Fe(III)(cyclam)-1 and Fe(III)(cyclam)-2, respectively, at 72-h incubation). All compounds induced cancer cell death by apoptosis. However, it seems that the mechanism of action behind cell death is different for the cyclam ligands and for the iron complexes. Contrary to the cyclams, both iron complexes induced the production of ROS, especially in the case of Fe(III)(cyclam)-1. This initial set of results indicates that this family of compounds is worth exploring for their therapeutic relevance in cancer treatment.

6.2.3 Ru(III)(salen/salan) complexes Most ruthenium(III) compounds reported as prospective anticancer metallodrugs are complexes bearing monodentate ligands bound to the central metal core, in close resemblance to NAMI and KP1019/NKP1339. These agents are designed to behave as pro-drugs and to be activated in the physiological medium through the release of labile chloride ligands in a manner dependent upon the Cl2 content of the biological compartments as mentioned previously. However, this feature also makes them prone to excessive hydrolytic instability which in turn leads to a difficulty in addressing their real cell targets. Multidentate salen- and salan-type ligands are attractive robust scaffolds, known for their ability to bind a variety of metal ions. Salen is an acronym for N,N0 -bis(salicylidene)-1,2-ethylenediamine (the simplest member of the class), a Schiff base system obtained by the condensation of two equivalents of salicylaldehyde and ethylenediamine (or 1,2diaminoethane). Innumerable variations can be introduced on this

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structure by simply replacing the ethylenediamine by any other diamine, and/or salicylaldehyde by any o-hydroxyaldehyde to obtain a tetradentate scaffold combining two Nimine and two Ophenolate donors in a [6 1 5 1 6] membered chelate ring structure with very good chelating ability toward several metal ions.62 Salan is salen-reduced derivative of the former, also offering an N2O2 binding mode (see below). The library of metalsalen complexes that have been investigated is extensive. Metallosalens are well-known catalysts and popular mimetic bioinorganic models for functional enzymes (among other uses such as artificial DNA base pairs or DNA nucleases),87 and several exhibit antimicrobial and anticancer activity.62,87 Metal complexes of these ligands were shown to have outstanding antitumor properties when the scaffold incorporates 1,2diaminocyclohexane (saldach) or 1,2-phenylenediamine (salophen) as the diamine bridge.66 A leading example is [Fe(III)(salophene)Cl] shown to overcome multiple drug resistance in lymphoma and leukemia cells88 along with other interesting features (as mentioned earlier, see Section 6.1).66 Reports on ruthenium-salen complexes are mostly related to their interest as catalysts8994 despite first reports on the activity of Ru(salen) compounds in DNA cleavage.95 Exception is made for the report of Zhu, Lau, and coworkers on two novel series of Ru(III)(saldach) complexes bearing different monodentate guanidine and amidine as axial ligands.96 The best candidates of each set were selected in accordance with the cytotoxicity shown for a panel of human carcinoma lines HeLa (cervical), A549 (lung), MCF-7 (breast), HepG2 (liver) and are depicted in Fig. 6.7. The bis (amidine)ruthenium(III) complex was the more active of the two, with IC50 values in the sub-micromolar range (0.1 μM, HeLa; 0.5 μM, MCF-7) and much more active than cisplatin (56-fold in HeLa, 24-fold in MCF-7) while being 6-fold less active for noncancer fibroblast cells. The bis(guanidine) ruthenium(III) complex was also very active with an IC50 value of 3.3 μM (MCF-7) and was not cytotoxic for noncancer cells (IC50 . 100 μM for MRC-5 fibroblasts). In addition, both compounds showed similar cytotoxic activity toward sensitive and resistant human ovarian cells indicating a mechanism of action different from that of cisplatin. The axial coligands directed the extent of cell uptake, the preferred subcell localization and mechanism of cell death, markedly changing the mode of action of these Ru(III)(saldach) complexes in MCF-7 cells as well. The guanidine derivative bound weakly to DNA and induced DNA damage, cell cycle arrest at the G2/M phase, and apoptosis. In contrast, the amidine derivative did not interact with DNA, did not exert cell cycle arrest, and was found to induce cell death by a different mechanism (also cell regulated, namely paraptosis). These findings highlight the potential of Ru(III) (salen) complexes as anticancer agents with mechanisms of action distinct from that of cisplatin, and the delicate role that carefully chosen axial ligands may exert on directing their specific biological response.

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FIGURE 6.7 Structures of Ru(III)salen and Ru(II)salan complexes: (A) [Ru(III)(saldach)

X2]1 with axial X 5 amidine (left), guanine (right) as depicted and (B) [Ru(III)(methoxy-salan-dach)Cl(PPh3)] complexes (PPh3 is triphenylphosphine, methoxysalan-dach is the salan ligand derived from dach and 4-methoxy-substituted or 5-methoxy-substituted salicylaldehyde) (RuSalan-1, right or RuSalan-2, respectively) reported to have promising anticancer properties—see text for more details.

Reduction of the imine function to amine in the salen scaffold results in a tetrahydrosalen-reduced derivative, also known as Salan. This change affords a more flexible ligand and circumvents some propensity for hydrolysis in water-containing solvents that some salen structures present.87 These compounds are in fact bis(amino)bisphenolates affording the same N2O2 binding mode as before, now containing two Namine donors that are more basic than Nimine, thus enhancing their coordinating ability. Like metallosalens, most metallosalan complexes reported find application in metal-based catalysis, although these are also useful as molecular sensors and some as prospective metallodrugs. Several salan complexes directed at therapeutic applications have been prepared using different metals, namely copper, nickel, zinc, vanadium, and titanium (this possibly being the most numerous family).87 In the case of ruthenium, two new Ru(III)salan complexes were prepared and studied for their potential as prospective chemotherapeutics.97,98 To the best of our knowledge, these are the only reports on Rusalan compounds as prospective metallodrugs for cancer therapy. The two complexes used 1,2-diaminocyclohexane (dach; R,R isomer) as the diamine bridge (following the report of Zingaro and Gao disclosing

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the salan structure based on dach as a suitable scaffold to convey cytotoxic activity99) and included a methoxy substituent on the salicyl ring at position 4 (RuSalan-1) or position 5 (RuSalan-2) (see Fig. 6.7). For both complexes, spectroscopic characterization was consistent with a distorted octahedral structure and a [Oax,Neq,Neq,Oax] binding motif for the salan ligand with the monodentate coligands phosphine and chloride occupying the remaining equatorial positions.98 Both complexes were found stable in DMSO and in aqueous buffered medium (pH 7.4). The cytotoxic activity of both Ru(III) complexes and corresponding salan ligands was evaluated in human cancer cells, specifically ovarian A2780 and breast MCF-7 and MDA-MB-231 lines. While salan ligands were quite ineffective for the TNBC breast model (MDA-MB-231, IC50B50 μM), activity for these cells was enhanced by coordination to the Ru(III) cation (IC50 27.413.6 μM). Similar trends were observed for ovarian A2780 and breast MCF7 cells, that is, both salan ligands were active (particularly 5-methoxy salan-dach ligand L2, IC50 , 10 μM), yet the coordination of either salan-dach ligand to the Ru metal center resulted in an enhancement of activity (2- to 3.5-fold). RuSalan-2 (bearing the 5-methoxy substituent) was the most active in this set of Ru(III) complexes and ligands (with IC50B4 μM, in the low micromolar range).98 The effect of human serum proteins albumin and transferrin on the cellular viability was also addressed. Since human serum albumin (HSA) and transferrin (hTF) play key roles in the distribution and transport of various compounds, they must be considered when evaluating the interactions of potential metallodrugs (vide infra, Section 6.3.1.2).100 Both Ru(III) complexes were found to bind strongly to HSA that impacted their cytotoxic activity for A2780 cells. While complex RuSalan-1 retained its efficacy when preincubated with albumin, RuSalan-2 was slightly deactivated (in accordance with the binding strength to the protein).98 Cytotoxicity was less affected in the presence of transferrin although the same trend held. Both complexes induced apoptosis, with RuSalan-2 being more efficient in line with cytotoxicity results.97 The interaction of both Ru(III) complexes with DNA is moderately strong (slightly stronger for RuSalan-1 than for RuSalan-2) indicating that although it is a possible molecular target for their action, other targets are most likely involved since RuSalan-2 was more active than RuSalan-1 in all cancer cell lines tested. This hypothesis was supported by results on cell morphology and cycle progression. In fact, complex RuSalan-1 seemed to induce cell cycle arrest at the G2/M phase while RuSalan-2 induced apoptosis without a relevant effect on cell cycle arrest. Despite their structural resemblance, cell morphology was differently affected in each case suggesting that several (and different) targets were likely involved in their biological action. Ultrastructural analysis of cells treated with these complexes showed

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clear changes in the intracellular organization that were consistent with the apoptotic process for RuSalan-1, while profound cellular damage and features suggesting an autophagic process were observed for RuSalan-2. The first results obtained for these Ru(III)salan complexes emphasize the striking impact that small differences in the chelating ligand structure may have on the biological response of the overall complex, ultimately changing the mode of action of the overall compound, and identify this class as a new family of Ru(III) compounds worth exploring as promising chemotherapeutics.

6.3 Designing metallodrugs with the {M(II)(Cp)} scaffold This section is devoted to the class of metallodrug candidates bearing cyclopentadienyl (Cp) as the stabilizing ligand for ruthenium(II) and for iron(II) metal ions. In this approach, our strategy has been the development of new M(II)Cp complexes (M(II) 5 Ru, Fe) with alternative modes of action and able to overcome the limitations presented by the platinum drugs currently in clinical use. As in the most successful approaches in metallodrug design, the whole complex is intended to act as an undissociated cytotoxic unit, and these organometallic complexes are designed to lack intentionally labile ligands in the coordination sphere. Our work on Ru(Cp) complexes encompasses a wider set of compounds compared to the panel of Fe(Cp) candidates that emerged more recently, and in fact were inspired by the former.

6.3.1 Ruthenium: Ru(II)(Cp)-based compounds The Ru(η5-C5H5) (or RuCp) organometallic fragment presents several properties that make it a good scaffold for building new molecules. The cyclopentadienyl ring occupies three coordination sites with η5-hapticity and the three remaining positions in the octahedral coordination sphere of ruthenium can be occupied in various ways, including three monodentate ligands, one bidentate and one monodentate, a tridentate ligand, and even a situation with one η5-ligand together with one ligand of η6-hapticity. The nature of these ligands will influence whether neutral or charged compounds are obtained. Also, the cyclopentadienyl ring is amenable to functionalization, allowing incorporation of a variety of substituents. Thus the piano-stool structure allows multiple possibilities to introduce diverse coligands leading to a large structural diversity.34,101 Furthermore, the π-bonded cyclopentadienyl ring can act both as a donor and as an acceptor group, and can thus modify the acceptor/donor character and reactivity of other coligands.102 The Cp ligand, monoanionic and η5-coordinated to the ruthenium center,

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stabilizes Ru(II) very efficiently, forming an extremely robust [Ru(η5C5H5)]1 unit that remains undissociated even at very high values of energy by ESI-MS (Electrospray Ionization Mass Spectrometry).103 Ru (η5-C5H5) systems have amphiphilic properties, resulting from the conjugation of the hydrophobic cyclopentadienyl ring with the hydrophilic ruthenium center which confers interesting physical and chemical properties to RuCp complexes that are especially relevant for their use as metallodrugs. 6.3.1.1 Establishing a suitable lead structure In 2009 we began exploring the potential of RuCp complexes for cancer therapy by studying the activity of two complexes with phosphines and mono-coordinated N-heteroaromatic ligands against human MiaPaca (pancreatic carcinoma) and LoVo (colon adenocarcinoma) cancer cells (Fig. 6.8A).104 Both compounds exhibited high antiproliferative activity (in nanomolar range) and were within the lowest ever observed for three-legged piano-stool ruthenium complexes until that time. These results led us to further explore this family and to understand how changes in the coligands affected the activity in vitro in a set of human cancer cells of different types, including cisplatin-sensitive and -resistant cells. The panel included leukemia (promyelocytic HL60), ovarian carcinoma (A2780 cisplatin-sensitive and A2780CisR cisplatin-resistant cells), cervical carcinoma (HeLa), breast adenocarcinoma (MCF-7 cells estrogen-dependent ERα 1 , and hormone-independent MDA-MB-231 cells to model TNBC), colon carcinoma (HT29), and prostate carcinoma (PC3 cells from metastasis of grade IV), among others. The cancer cell lines were selected to include the most often diagnosed types of cancer

FIGURE 6.8 Piano-stool Ru(Cp) complexes with different substituents with cytotoxic properties in human cancer cells—see text for details.

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in women (breast) and men (prostate), and cancer conditions with poor prognoses and lacking appropriate clinical treatments. Taking advantage of the versatility of the RuCp unit, a vast number of compounds was developed (Fig. 6.8B depicts some examples). Phosphorus is a good donor for Ru(II) and triphenylphosphine (PPh3) was therefore chosen as a coligand. Compounds bearing three monodentate coligands of general formula [Ru(η5-C5H5)(PPh3)2(L)][X], where L is an N-heteroaromatic or a nitrile ligand (X 5 CF3SO32, PF62), were prepared and evaluated in vitro against HL60, A2780, and MCF7 human cancer cells. All complexes showed high cytotoxicity for all lines investigated, with IC50 values below 6 μM, this being 2- to 41-times more cytotoxic than cisplatin tested under the same conditions.104106 For HL60 cells, we found that compounds with L being a heteroaromatic ligand were more active than those employing nitriles. A family comprising mixed sandwich complexes [Ru(η5-C5H5) 6 (η -derived benzene)][PF6] was also prepared (an example is depicted in Fig. 6.8B).101 However, only two of the compounds of this series (with 2-naphthaldehyde and 9-anthracene carboxaldehyde η6-coordinated) were moderately cytotoxic under the conditions tested. It is likely that the aldehyde group present in both compounds afforded an advantage for intermolecular interactions with biological targets, which resulted in their enhanced (although still mild) activity compared to the rest of the set. Despite the high activity observed for the RuCp complexes with monodentate coligands, these compounds were highly insoluble in aqueous environments, with a high tendency to hydrolyze and/or decompose. Stability in aqueous and physiological media is an important factor to consider prior to any assessment of biological activity. The pursuit of a better profile led to compounds bearing one bidentate coligand to provide greater chemical stability compared to monocoordinated species. Two sets of compounds were prepared with the general formula [Ru(η5-C5H5)(N)(PP)]1 with PP 5 1,2-bis(diphenylphosphino) ethane (DPPE), N 5 monodentate heteroaromatic ligand (Fig. 6.8) and [Ru(η5-C5H5)(N,X)(L)]1 where (N,X) is a bidentate heteroaromatic coligand bound to the Ru(II) center by an Npyridine and an Oketone donor (namely 2-pyridylketone and derivatives—see Fig. 6.9A) or by two Npyridine donors (namely bipy—Fig. 6.9), and L is a monodentate phosphine (PPh3), DMSO, or CO (as in Fig. 6.9B) or an N-imidazole-based coligand. Most of these complexes proved to be stable over a 24-h period in DMSO (a strongly coordinating solvent) and in buffered aqueous media, with the exception of the set [Ru(η5-C5H5)(bipy)(L)]1 where the imidazole derivative L was found to quickly dissociate from the Ru (η5-C5H5)(bipy) core, hampering further studies. The great majority of the compounds displayed high cytotoxicity (again in the micro- and nanomolar range) against the human cancer cells tested, most being

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FIGURE 6.9 Piano-stool “RuCp” complexes: (A) [Ru(Cp)(PPh3)L][CF3SO3] complexes with L as different NO-bidentate coligands derived from 2-pyridylketone and (B) [Ru(Cp) (bipy)B]1 complexes with different monodentate coligands B isolated as triflate or hexafluorophosphate salts as indicated (IC50 values at 72-h incubation are indicated for different cell lines).

more cytotoxic than cisplatin.105,107111 Moreover, most of these compounds were also cytotoxic against cisplatin-resistant ovarian (A2780CisR) and highly aggressive (MDA-MB-231, PC3, HT29) cell lines for which cisplatin shows little or no activity. One of the leads of this family, TM34 (Fig. 6.9B), is remarkably active (in the sub-micromolar range) in the wide range of cell lines in which it was evaluated, including in the most aggressive ones. Interestingly, TM34 also showed a lower cytotoxicity for the nontumorigenic cell line V79 (Chinese hamster lung fibroblasts), with IC50 values 7- to 60-times higher than those found for cancer cells, suggesting some intrinsic selectivity for cancer cells.111 The replacement of the triphenylphosphine in the cation of TM34 by carbonyl (CO) or dimethyl sulfoxide (DMSO) (Fig. 6.9B) substantially affected the cytotoxicity of the complexes. Indeed, the substitution by DMSO led to a noncytotoxic compound, while the complex with CO as coligand was only moderately cytotoxic solely against A2780 cells.107 Both uncoordinated triphenylphosphine and 2,20 -bipyridine are only slightly cytotoxic (IC50 5 155 and 79.4 μM in A2780 cells, respectively), suggesting that the strong cytotoxicity of RuCp complexes results from a synergy between all the fragments of the compound. The counterion also seems noninnocent regarding the overall activity of the complex. The replacement of CF3SO32 by PF62 in the TM34 complex led to a decrease of an order of magnitude in the

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cytotoxicity.107 It is noteworthy that the corresponding salts of these counterions are themselves noncytotoxic. 6.3.1.2 TM34 as a lead compound: binding to human serum blood proteins Once in the body, a drug must be delivered by the bloodstream to its targets. It is well known that many drugs bind to proteins when they enter the bloodstream, and the extent and nature of this interaction is crucial for their distribution and transport in the human body. It can determine their residence time, often increasing the solubility of hydrophobic drugs in the plasma112 and strongly influencing their bioavailability, elimination—and thus their eventual toxic effects.100,113,114 HSA is the most abundant protein in the circulatory system, and the interaction between HSA and metal ions or metallodrugs has awakened considerable interest regarding several metal complexes (Ru, Rh, and Cu among others).100,113120 Indeed, serum blood protein binding was proposed to play a key role in the biological action of KP1019 and NAMI-A complexes, partially accounting for differences in their behavior.100,120 Binding to transferrin (hTF), a specific iron-binding blood plasma glycoprotein, can be exploited for the more selective delivery of a drug to cancer cells, due to the higher amount of transferrin receptors expressed in these cells to support their enhanced iron needs compared to healthy cells.100 In a first approach to understand the pharmacokinetics of TM34, its interaction with albumin and transferrin was evaluated. The binding of this complex to HSA is a fast process (the reaction being completed in less than 30 min) with the formation of a stable adduct of 1:1 stoichiometry between TM34 and the protein, and a conditional stability constant that is comparable to that of KP1019 (proven to be bound by albumin in the blood of treated human patients)100,111 and similar to those found for other rutheniumarene complexes.112,121 These results strongly support that TM34 could be transported in the blood to its targets by HSA.111 The cytotoxic properties in the presence of HSA and hTF were also examined to evaluate the extent to which they might eventually be changed. Cell viability assays with TM34 preincubated with these proteins showed that upon binding to HSA the cytotoxicity of the complex is maintained,111 while binding to transferrin even facilitates the entry of the complexes into cells.109 There is an accumulation ca. 50% higher for transferrin-bound TM34 compared to that observed for the free TM34.109 In fact, serum protein binding seems to be beneficial in the case of these Ru(Cp) complexes. For the complex [Ru(η5-C5H5)(bipy) (DMSO)]1 (noncytotoxic when tested alone - see Fig. 6.9) an increase of ca. 40% in its cytotoxicity was observed when it is preincubated with

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albumin, an effect that is probably due to an improved cellular uptake of the albumin-bound complex by the cells.107 6.3.1.3 Cellular uptake The knowledge of the mechanisms involved in the cellular uptake of a drug is important for evaluating its therapeutic potential and its toxicity. For that, to understand the mechanism of entry into the cells and to know how a drug distributes and accumulates in the cellular compartments is of utmost importance.122 Cell entry mechanisms include endocytosis, passive diffusion, and active transport by proteins. Endocytosis and active transport by proteins are energy-dependent processes that can be modulated, unlike passive diffusion that does not require energy (and is also less likely to be modulated). The uptake mechanism of TM34 on A2780 and MDAMB-231 cancer cells was studied by analytical (ICP-MS, inductively coupled plasma mass spectrometry) and pharmacological methods (using specific endocytosis inhibitors). Thus the temperature dependence and the effect of several endocytosis modulators on the activity of TM34 were evaluated toward these cells. The cytotoxicity of TM34 decreased both in the presence of endocytosis inhibitors and at low temperature (4 C) suggesting a lesser uptake, and thus an energy-dependent process is involved in its cellular uptake mechanism consistent with endocytosis (although a passive/active transport could not be completely ruled out).110 Subcellular localization studies by ICP-MS showed that in A2780 and MDA-MB-231 cells ca. 80% of the Ru content is retained at the cell membrane,109 suggesting that cell targets of TM34 are mainly present at the cellular membrane. Nevertheless, a small percentage was found in the cytosol, cytoskeleton, and nucleus of these cells.109 The Ru content located at the membrane and cytosol fractions represented about 90% of the total Ru taken up by the cancer cells, in striking contrast with cisplatin that accumulates preferentially in the cytosol and nucleus. The different activity profile and the distinct pattern of subcellular localization indicated different cell targets and thus different mechanisms of action for TM34 and cisplatin. 6.3.1.4 Disclosing cellular targets and mechanism of cell death for TM34 Ultrastructural analysis of cells using TEM (transmission electron microscopy) is useful to probe changes in cell morphology induced by a drug candidate and can provide hints on the underlying mechanisms of action as well. This technique was extremely useful to locate cellular targets for TM34. In our first studies the main mechanism of cell death observed in HL-60 cells after treatment with TM34 was apoptosis.105 This was

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confirmed by TEM in MDA-MB-231 cells: after treatment with the complex, cells showed surface blebs suggestive of apoptotic phenomena.110 New pathways involving the endosomal/lysosomal system of the cell have been pointed out as potential targets for drug therapy.123 Lysosomes contain several hydrolases that help degrade intracellular and extracellular material. After their release into the cytosol, they possibly degrade apoptotic proteins, triggering the mitochondrial pathway of apoptosis. Acid phosphatases (AcPs) are a class of nonspecific hydrolases that catalyze the hydrolysis of phosphomonoesters at acidic pH. The effect of TM34 toward AcP was evaluated in MDA-MB-231 cells. Using a cerium-based method and TEM, evidence was obtained that TM34 inhibits this lysosomal enzyme in a dose-dependent manner. In addition, disruption and vesiculation of the Golgi apparatus was observed in cells treated with the complex, which suggested the endosomal/lysosomal system as a possible target, and elongation in mitochondria was detected as well. Altogether, these data suggest that the endomembrane system (and possibly mitochondria) are molecular targets for TM34, involved in the mechanism of cell death.110 The amount of lactic acid produced by cancer cells is known to be proportional to the aggressiveness of the tumor type, since the glycolytic metabolism is modified and enhanced in cancer cells leading to their faster cellular proliferation. Aggressive cancers obtain much of their energy (ATP) by metabolizing glucose directly to lactic acid even in the presence of oxygen (the “Warburg effect”).124 Hence the metabolism in healthy and cancer cells is markedly different, tumor glycolysis offers an opportunity for the development of anticancer drugs. Since both glycolytic enzymes and glucose transporters are overexpressed at the membrane in tumor cells compared with normal cells, together with the fact that TM34 is preferentially retained at the membranes and its strong activity toward highly glycolytic MDA-MB-231 cells pointed it as possibly being operating through these processes. This prompted the study on whether it could target the glycolytic metabolism in cancer cells, namely whether redox enzyme modulation could be involved in its action. The way by which glycolytic cells consume oxygen at the cell surface involves trans-plasma membrane electron transport (tPMET) systems, using intracellular NADH in a process that supports glycolytic ATP production and can be artificially modulated.125 Our studies in three tumor cells of different aggressiveness (A2780, MCF7, and MDAMB-231) indicated that TM34 can inhibit lactate production and tPMET activity in a manner depending on the glycolytic phenotype of the cancer cell and the concentration of the complex.109 Small structural changes introducing substituents in the phosphine (as in TM85) or in the bipy ligand (as in TM102, see below) result in inhibition of the

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reductase enzyme to an extent apparently related to the antiproliferative potential of each complex.109 6.3.1.5 TM90 as another lead compound In what concerned the subfamily of compounds with NO-bidentate ligands (Fig. 6.9A) [Ru(η5-C5H5)(NO)(PPh3)]1 complexes also proved to be highly cytotoxic against several cancer cell lines (A2780, A2780CisR, MCF7, MDA-MB-231, HT29, and PC3), with IC50 values in the same range found for complexes containing NN-bidentate ligands.108 A very interesting aspect found for this subfamily is the exceptional cytotoxic activity for both MCF7 and MDA-MB-231 breast cancer cells, with IC50 values in the nanomolar range, approximately one order of magnitude more active than for other cancer cell lines tested (ovarian, colon, and prostate)—see Fig. 6.9A. These results suggest some intrinsic specificity toward breast cancer, and attracted attention since it is the most prevalent type of cancer diagnosed among women. TNBC in particular (characterized by the absence of ERα, HER2, and PR receptors and modeled with MDA-MB-231 cells) is extremely aggressive and highly metastatic, presenting limited treatment options and very poor prognosis.126,127 Among these compounds TM90 was selected as a lead compound to pursue further studies and assess its potential as a prospective metallodrug for TNBC. TM90 has considerable stability in conditions that mimic in vitro studies in cancer cells, with a half-life of 3 days at room temperature and ca. 17 h at 37 C.128 In contrast with TM34, this compound induces cell death mainly by necrosis. TM90 forms an adduct with HSA with a binding strength comparable to that of TM34 and KP1019. 129 Furthermore, this binding interaction does not affect its cytotoxicity toward MDA-MB-231 cells. 128 These results indicated that albumin might be involved in the distribution and delivery of TM90 to cancer cells. The therapeutic effect of TM90 was evaluated in vivo on female mice bearing TNBC orthotopic tumors. These studies revealed the ability of this compound to suppress in vivo tumor growth by about 50%, without the visible side effects observed for cisplatin, used as a control in this study. Importantly, autopsy revealed the absence of metastases in the main organs in all animals treated with TM90, while metastases were present in the lungs of all control mice. No signs of injury were found in lungs, kidney, liver, and spleen of treated animals.128 This dual effect found for TM90, that is, efficacy against primary tumor together with the ability to suppress the development of metastases, takes TM90 to the front stage in the search of new anticancer drugs.

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6.3.1.6 TM34: structural changes for structureactivity studies As stated earlier, TM34 showed promising in vitro biological behavior, being a lead of the first generation of RuCp-based compounds. Moreover, it revealed an outstanding stability (much better than that of TM90) even under harsh conditions,109111 thus being the perfect scaffold for structureactivity studies. In that frame, several modifications on the phosphine, bipyridine, and cyclopentadienyl ligands were carried out, generating new compounds based on the TM34 scaffold. The rationale behind the structural modifications took into consideration several aspects such as (1) the tuning of the electronic features of the complex, (2) modulation of the hydrophilicity/lipophilicity balance, and (3) the introduction of chemical groups able to target cancer cells selectively. Thus in an initial approach different substituents were introduced at the para-position of the phosphine rings in order to study the influence of different donating groups such as alkoxy and fluoro on the activity, and a sulfonated group was chosen in order to increase the hydrophilicity of TM34 (Fig. 6.10). The presence of the 2 OCH3 (LCR226) or 2 F (LCR203) groups resulted in compounds with IC50 values very close to those of TM34 (Fig. 6.10).130 In contrast, the presence of the sulfonated phosphine in TM85 led to a significant decrease in the cytotoxicity, in particular for the most aggressive cancer cell lines namely MDA-MB231, PC3, and HT29.131 Yet, this compound is much more water soluble than TM34. Solubility is one of the most important parameters needed to achieve concentrations in the circulatory system sufficient to reach the necessary pharmacological response. Hence, this compound was selected for further studies. Subcellular localization assays on A2780 cells treated with TM85 revealed that the introduction of the sulfonated phosphine led to a substantial decrease in the total cellular uptake (down to 0.143 nmol(Ru)

FIGURE 6.10

Structures of complexes TM34, TM85, LCR203, LCR226, TM102, and pmc79 and IC50 values (μM) found at 24-h incubation for MCF-7 and MDA-MB-231 human breast cancer cells.

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mg21 protein vs 3.78 nmol(Ru) mg21 for TM34) that can explain the lower cytotoxicity of TM85. Yet, both compounds present a similar cell distribution profile, that is, more than 90% of total Ru taken up by the cells is localized at the membrane and cytoskeleton fractions.109 Like TM34, TM85 also binds to HSA (although the interaction is weaker than for TM34), and adduct formation with either albumin or transferrin does not affect its activity in A2780 cells; like TM34, binding to transferrin was found to facilitate the entry of TM85 into the cells.109,131 In general, results gathered for TM85 show that the introduction of a sulfonated group in the phosphine ligand does not change the cell uptake mechanism, nor the possible targets previously identified for TM34:109,110,131 TM85 appears to enter the cells by endocytosis (an energy-dependent mechanism) and causes the vesiculation of the Golgi apparatus, again suggesting the endomembrane system as a target for its action. Regarding the glycolytic metabolism, TM85 also inhibited the production of lactate (although at a much higher concentration than TM34) and its cytotoxic activity for MDA-MB-231 cells was found to be much enhanced in the presence of glycolytic inhibitors especially 2deoxyglucose.109 The increased solubility of TM85 allowed its study in vivo in a mouse model. Thus the toxicity and the antitumor effect of TM85 were evaluated in a xenografted prostate cancer (PC3 with high metastatic potential) mouse model. The relevant anticancer activity of TM85 observed in vitro did not fully translate in vivo. In fact, the Ru uptake by the tumor was low, leading to a tumor reduction of ca. 20%. Instead, TM85 accumulated in excreting organs, mainly in the liver. However, no apparent signs of toxicity or nephrotoxicity were observed, and the renal excretion was not reduced.132 Further changes focused on the bipyridine ligand and included a methylated (TM102)133 or an hydroxymethylated group (pmc79)—see Fig. 6.10.134136 As expected, the introduction of the lipophilic 2 CH3 in TM102 led to a compound with a similar (at 24 h) or better (at 72 h)109 cytotoxicity compared to TM34, without significantly affecting its mode of action. The only difference worth mentioning is that, when the compounds are conjugated to transferrin, there is a facilitated uptake into cells for TM34 (Ru quantification by ICP-MS) while for TM102 there is a small decrease, without affecting the overall activity. On the contrary, the introduction of the hydroxymethylated group leads to a decrease in the cytotoxicity for MCF-7 and MDA-MB-231 cells by an order of magnitude. Yet, considering the data obtained so far for each of these compounds, it seems that they still share several features in their mechanism of action, specifically membrane targets and significant morphological alterations of the mitochondria leading to apoptosis. In addition, pmc79-treated cancer cells present different geometry, actin

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depolymerization, and cell-to-cell cytoskeleton extensions are highly decreased compared to control cells. pmc79 also revealed the ability to inhibit the formation of colonies of cancer cells, and to downregulate the proteins involved in cell adhesion and migration, namely the proteins that regulate the actin dynamics (proteomic study), triggering apoptosis.136 In addition, it is well tolerated by zebrafish (LC50 5 7.8 μM).135 Taking into consideration reports from the literature that relates a high Ru localization at the cell membrane with compounds having membrane proteins as targets and antimetastatic activity,137,138 one can postulate that compounds derived from the TM34 family may also present such potential. The reason for the lower cytotoxicity of pmc79 might be related to the fact that this compound was found to be a substrate for some of the most important ABC efflux pumpsa (P-gp, MRP1, and BCRP)134 and showed a reduced uptake in A2780cisR cells (vs A2780).136 This drawback evidenced for pmc79 could be overcome by a combinatory therapy with ABC transporter inhibitors. Unfortunately, data for the other TM34-derived compounds has not yet been gathered, preventing the establishment of a relationship between the substituent at the bipyridine and the activity of the compounds. Structural changes on the Cp ligand consisted of the insertion of a methyl group (R in Fig. 6.11).139,140 A total of four compounds were syn-

FIGURE 6.11 Structures of complexes TM34, LCR136, RT11, and RT12 and IC50 values (μM) at 24-h incubation for cisplatin-sensitive A2780 and cisplatin-resistant A2780cisR human ovarian cancer cell lines. ND, Not determined in these cell lines—see text for details.

thesized by introducing additional modifications at the bipyridyl group (R0 in Fig. 6.11). The results gathered on A2780 cells show that the introduction of the methyl substituent at the Cp ring (LCR136) leads to a decrease in the activity (vs TM34). However, the concomitant introduction of substituents at the Cp and at the bipyridyl led to an increase in the a

One major limitation in chemotherapy is the acquired resistance that cancer cells can develop due to the action of multidrug resistance ABC efflux transporters.

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activity by B7- and B2-fold for 2 CH3 (RT11) and 2 CH2OH (RT12) substituents, respectively (vs 2 H, LCR136; Fig. 6.11). These differences are even more pronounced in the resistant cell line A2780cisR, for which the activity of RT11 is 12- and 2-fold higher than that of LCR136 and RT12, respectively. These results also reveal that these two compounds (LCR136 and RT12 with lower activity for the resistant line) can possibly be subjected to the same mechanisms of cell resistance as cisplatin that, according to the literature, are related to a decreased cellular uptake, high glutathione levels, and increased DNA damage repair.141 Additional flow cytometry studies in the presence of known substrates of each MDR pump (P-gp, MRP1, MRP2 and BCRP) revealed that, while RT11 is not a substrate of P-gp or BCRP and is an inhibitor of MRP1 and MRP2, both LCR136 and RT12 are substrates for P-gp, especially LCR136, thus being easily transported out of the cell by this membrane pump. Finally, the fourth compound of this series, a ruthenium methylcyclopentadienyl complex bearing a perfluorinated bipyridine ligand (RT21, Fig. 6.11), showed promising activity for colorectal cancer cell lines with KRAS (SW480) and BRAF (RKO) mutations [IC50(SW480) 5 1.5 6 0.3 μM; IC50(RKO) 5 2.0 6 0.2 μM] with some intrinsic selectivity [IC50(normal colon epithelial cells) 5 8.7 6 0.9 μM].139 The compound induces cell death by apoptosis and is able to inhibit the formation of RKO colonies,b but not of SW480, indicating that the genetic background of these cells probably affects its mode of action. Overall, structural changes at the phosphine, bipyridine, and η5cyclopentadienyl ligands originated cytotoxic compounds, more active than cisplatin in the cell lines tested. The main differences between these compounds are observed when they were tested in aggressive or resistant cells, such as MDA-MB-231 and A2780cisR, respectively. In that frame, attempts to increase TM34 solubility by the introduction of a sulfonated (TM85) or an hydroxymethyl (pmc79) group were successful, however, at the expense of the activity, which seemed to be related to the decreased cellular uptake (for TM85) or multidrug resistance (MDR) mechanisms (for pmc79). This effect was also observed for other ruthenium compounds, such as KP1019 and NKP1339,142 highlighting how subtle changes in the structure of the compound can severely change its biological performance. However, the inclusion of methyl groups simultaneously at the Cp and the bipyridine produced a complex (RT11) that is able to inhibit two of the most important ABC transporters involved in MDR mechanisms, namely MRP1 and MRP2. b The ability to form colonies is related to the ability of the cancer cell to detach from the primary solid tumor site and form a new tumor mass at a different location, thus being related to the ability of the cancer cell to form metastases. As such, inhibition of colony formation upon exposure to a drug candidate is related to a possible antimetastatic effect.

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6.3.1.7 TM34: the chosen scaffold for cancer targeting strategies One of the major challenges in chemotherapy encompasses the design of drugs that mainly target cancer cells, leaving healthy cells undamaged. In that frame, the TM34 scaffold revealed to be easily modified and two targeting strategies have been adopted, with a view to passive and/or active targeting. Passive targeting was first described by Matsumura and Maeda,143 and states that macromolecules can effectively accumulate in solid tumors due to a phenomenon known as Enhanced Permeability and Retention (EPR) effect that results from gaps in the deficient vasculature of a solid tumor. Active targeting, on the other hand, describes specific interactions between the drug and the cancer cells, usually through specific ligandreceptor interactions. The main mechanism behind active targeting, proposed by Paul Ehrlich more than a century ago,144 is the recognition of a ligand or biomolecule by its specific target/receptor and consequent cell uptake through receptor-mediated endocytosis. Cancer cells require significant amounts of vitamins for their rapid growth leading to the overexpression of several vitamin receptors on their surface (as compared to healthy cells). Thus, to enhance the selectivity of the lead TM34, one approach was to incorporate biotin, vitamin B7, into the bipyridine ligand (LCR134, Fig. 6.12).134

FIGURE 6.12 Targeting strategies used on TM34 complex by derivatization on the bipyridine ligand: active targeting using biotin (top, blue: LCR134); passive targeting using polylactide (bottom: pmc78, n 5 36); combined approach using passive and active targeting with polylactide and a glucose derivative (center: PMC1, n 5 41)—see text for details.

The first step was to confirm that biotin retains its bioactivity after conjugation to the ruthenium center, which it does since it is still recognized by avidin.c Regarding activity, even though LCR134 was found to 3

Avidin is a glycoprotein that can bind up to four biotin molecules with remarkably high affinity. This interaction is considered one of the most specific and stable noncovalent interactions.145

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be less cytotoxic than TM34, it showed a different cytotoxic profile by being twofold more cytotoxic for the triple-negative cancer cell line MDA-MB-231 than for the hormone-responsive MCF-7.130 Intracellular distribution assays revealed that ruthenium is mainly found at the membrane of the cancer cells, being higher for the MDA-MB-231 cell line (90% vs 75%). The compound also leads to cell death by apoptosis and inhibits the formation of cancer cell colonies to a great extent. Thus, as observed for pmc79, this compound also shows antimetastatic potential. Yet, the most important feature disclosed for LCR134 is its ability to significantly inhibit P-gp (more effectively than the reference inhibitor, verapamil). Thus this quite simple compound presents a dual effect rarely found in cytotoxic agents. If one considers the few examples in the literature of ruthenium compounds aimed at active targeted cancer therapy, LCR134 seems to be the one presenting the best overall cytotoxic profile. In terms of in vivo selectivity, a preliminary toxicity assessment in a zebrafish model established that both LCR134 and pmc79 are the best tolerated compounds with LC50 of 5.73 and 6.21 mg L21 at 120-h postfertilization, respectively, showing the absence of severe toxic effects such as necrosis or hemorrhage.135 On the contrary, the compounds LCR203 and LCR226 (Fig. 6.10) without functionalization at the bipyridine caused severe damage to the embryos. In a second approach, in order to concomitantly benefit from the EPR effect (passive targeting) and active targeting (selectivity), a D-glucose end-capped polylactide was attached to the bipyridine (PMC1) (see Fig. 6.12).146 This is the first example in the literature of a polymerruthenium conjugate designed to benefit from both targeting strategies.146,147 This compound revealed a very good cytotoxicity for A2780, MCF-7, and MDA-MB-231 cancer cells (with IC50 values at 72 h of 1.6, 3.9, and 3.8 μM, respectively). The inclusion of the macromolecular ligand led to a different mechanism of action from that of TM34 as one can infer from the different cell internalization distribution: while TM34 mainly accumulated at the cell membrane, PMC1 was preferably localized at the nucleus. Nevertheless, DNA (often proposed as the major target for complexes that accumulate in the cell nucleus) does not seem to be the main molecular target for either, since they did not induce conformational changes on supercoiled plasmid DNA.33 Preliminary studies on PMC1’s mechanism of action indicated that mitochondria and oxidative stress are involved.33,136 In subsequent studies, in order to increase the functionalization of the bipyridine with polylactide an innovative synthetic strategy was employed: the use of 4,40 -diyldimethanol-2,20 -bipyridine as initiator in a DMAPcatalyzed polymerization afforded full bipyridine functionalization.136,148 Curiously, the resulting cytotoxic compound (pmc78) presented a cellular

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distribution not yet observed for the other RuCp compounds—there is a significant Ru content at the cells cytoskeleton, identifying this organelle as a possible target. Indeed, a complete set of biological studies (F-actin immunofluorescence assays, TEM, colony formation assay and proteomics) point out that proteins responsible for the regulation of the microtubule dynamics are the target of pmc78.136 Such a mechanism seems similar to that observed for the drug paclitaxel that suppresses microtubule dynamics, causing the blocking of mitotic activity leading to apoptosis. In addition, mass cytometry coupled to cytometry studies revealed that pmc78 is able to overcome cisplatin mechanisms of cell resistance, placing this compound as a lead. Overall, data obtained so far for the compounds endowed with active and/or passive targeting by derivatization of the bipyridine moiety indicates that these have been successful strategies to obtain complexes with interesting features as cancer drug candidates. In fact: (1) the introduction of biotin led to a decrease in in vivo toxicity for zebrafish (LCR134 vs LCR203/LCR226) and (2) the introduction of a long leg at the bipyridine seems important in endowing the compounds with ability to overcome MDR (LCR134 and pmc78 vs pmc79). Furthermore, several of the RuCp compounds presented here seem to have targets involved in cell adhesion and migration (features that are critical for the antimetastatic effect), placing these compounds within a new class of drugs149 known as “migrastatic agents.” In vivo studies in a rodent model are now ongoing to afford the final proof-of-concept for these drug candidates. Still in the context of active targeting, we recently followed another approach to improve the selectivity of TM34 tethering specific targeting peptides, namely fibroblast growth factor receptor (FGFR)targeting peptides, to the cyclopentadienyl ring.150 FGFR receptors that are overexpressed in several TNBC cells compared to healthy cells enable the preferential binding and accumulation of the targeting peptide into these tumor cells. The choice of the Cp ring for the derivatization was grounded on molecular dynamics. Since the main targets of TM34 are located at cellular membranes, molecular dynamics simulations in a model phospholipid membrane were carried out to investigate how TM34 is oriented in it, identify which coligands would be more water accessible, and hence those that could be functionalized without perturbing the TM34/ membrane interaction. Results showed that Cp and bipy are always more accessible to the water phase, indicating that derivatizations on these ligands would be favorable and would not perturb the ability of TM34 to interact with the membrane.150 Three FGFR-targeting peptides specific for each FGFR1, FGFR2, and FGFR3 receptor subtypes were selected for the conjugation on the Cp ring with a PEG polymer as spacer group (Fig. 6.13). Thus three rutheniumpeptide conjugates (RuPCs) using the TM34 complex as the cytotoxic active

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FIGURE 6.13 Active targeting used on TM34 complex by derivatization on the Cp ring: schematic structure of Rupeptide conjugates depicting three FGFR-targeting peptides (amino acid residues indicated as one letter code).

moiety were prepared. These are the first half-sandwich ruthenium(II) cyclopentadienyl peptide conjugates reported in the literature.150 Peptide conjugation to TM34 was achieved via the functionalization of the Cp ring with a carboxyl substituent that was also evaluated for its activity.150 Although the presence of the COOH group in the Cp ring led to a significant decrease in the cytotoxicity of TM34, these RuPCs proved to be more cytotoxic for SKBR3 breast cancer cells that overexpress FGFR receptors (i.e., FGFR 1 ) than for MDA-MB-231 that do not (i.e., FGFR 2 ). Thus selectivity was enhanced although at the expense of activity. These results indicate that although some modifications on the group used to functionalize the Cp ring are required in order to maintain the cytotoxicity of TM34, this constitutes a promising approach for selectively targeting FGFR(1) breast cancer cells.150

6.3.2 Iron: the potential of Fe(II)(Cp)-based compounds Until recently the chemistry of organometallic iron anticancer chemotherapeutics has been largely dominated by ferrocene derivatives and ferrocifens. Based on results obtained in our group with half-sandwichstructured compounds featuring the RuCp fragment and inspired by the success that ferrocenes had as a framework for the preparation of new potential anticancer agents, we decided to explore the potential of the FeCp moiety as a scaffold for new iron-based anticancer drugs, and have so far reported two different families bearing phosphine and imidazole or nitrile coligands (Fig. 6.14).151154 6.3.2.1 FeCp-containing imidazole ligands We pioneered reports on the synthesis and antiproliferative activity of a new family of compounds of general formula [Fe(η5-C5H5)(DPPE)

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FIGURE 6.14 Structures of “FeCp” compounds with cytotoxic activity: (A) [Fe(Cp)(DPPE) (N)] with DPPE 5 1,2-bis(diphenylphosphino)ethane and N, an imidazole derivative; (B) [Fe (Cp)(DPPE)(NRCR)] with NRCR a nitrile donor bearing an N-heteroaromatic moiety (quinoline/pyrazine derivatives); (C) [Fe(Cp)(CO)I(PR3)] and [Fe(Cp)(CO)(PR3)L] with varying phosphine ligands and L 5 4-aminobenzonitrile, and (D) [Fe(Cp)(CO)(NRCR)(PPh3)] with PPh3 5 triphenylphosphine and NRCR varying 4-substituted benzonitrile coligands.

(L)]1 where L is an imidazole-based ligand (Fig. 6.14A).151 These compounds containing a bidentate phosphine and imidazole coligands were tested in vitro against three human cancer cell lines, namely A2780, MCF7, and HeLa. All compounds exhibited high cytotoxicity for all cell lines tested with IC50 values below 10 μM, and the effect of the substituent depended on the cell line.151 Although almost all compounds were more cytotoxic than cisplatin, it was for the MCF7 line that the most relevant results were found, with IC50 values 729 times lower than those of cisplatin.151 6.3.2.2 FeCp-containing nitrile ligands The set of FeCp compounds containing nitrile ligands (Fig. 6.14B) proved to be highly cytotoxic in human leukemia cancer cells (HL60) with IC50 values lower than those observed for cisplatin for most compounds.152 It was possible to relate the differences in the structure of these complexes with their activity. The compound with the 2-quinolinecarbonitrile coligand (complex 5 in Fig. 6.14B) proved to be the most cytotoxic; however, the change of nitrile group from ortho to

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meta position (complexes 5 and 6) led to a fourfold decrease in cytotoxicity. On the other hand, the replacement of the counterion PF62 by CF3SO32 (complexes 6 and 7) resulted not only in an improvement in cytotoxicity but also in a change in the main mechanism of cell death from necrosis to apoptosis.152 These results showed (once again) how the biological activity is sensitive to small changes in the various components of the global complex. The combined effect of a monodentate phosphine (σ donor) with a carbonyl coligand (π acceptor) was also explored.154 This family of complexes (Fig. 6.14C) presented very curious results in the HeLa cancer cell line, since the neutral compounds (compounds 1012 in which the third coligand was iodide) showed no cytotoxicity for this cell line. Among the cationic compounds, with aminobenzonitrile as the third coligand, we could infer about the effect of the phosphine on the overall cytotoxicity. Complex 14, bearing 4-(diphenylphosphino)benzoic acid, was noncytotoxic, while compounds 13 and 15 (with triphenylphosphine and tris(4fluorophenyl)phosphine, respectively) were quite cytotoxic against HeLa cells, with IC50 values in the same range to those found for [FeCp(DPPE) (NRCR)]1 complexes (Fig. 6.14B). Nevertheless, the complex containing PPh3 was the best of the set with regard to cytotoxic activity.154 A series of structureactivity studies was conducted, focused on varying the nitrile coligand in a set of complexes [Fe(Cp)(CO)(NRCR) (PPh3)]1 where NRCR included 4-substituted benzonitriles and 4-chlorocinnamonitrile as coligands (Fig. 6.14D).153 In this set, all compounds were highly cytotoxic for TNBC breast MDA-MB-231 and colorectal SW480 cancer cells with IC50 in the low micromolar range, and exhibited some inherent selectivity for colorectal cancer cells versus normal colon-derived cells (being 1.83.9 times more active toward the former). The substituents at the nitrile ligands induced other differences in their behavior in addition to slight changes in the cytotoxicity: most compounds induced apoptosis and affected the actin cytoskeleton of cells with exception of the -OH and CH2OH derivatives (complexes 18 and 19 in Fig. 6.14D), suggesting that a different mode of action might be active for these species.153 Overall, the results already obtained for these new families of FeCp compounds highlight their great potential as very active antiproliferative agents that certainly warrant further exploration.

6.4 General synthetic procedures for ruthenium and iron prospective metallodrugs In this section, we cover the synthesis of ruthenium and iron prospective anticancer metallodrugs, mainly focusing on the compounds

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mentioned in the previous sections of this chapter. Nevertheless, the procedures described herein reflect some of the synthetic approaches most common in the preparation of Fe(III)/Ru(III) “inorganic” coordination complexes and Fe(II)/Ru(II) organometallic complexes and are also effective at a more general level. The synthesis of classical coordination complexes is in general achieved from an inorganic salt of the metal ion of interest (commercially available) that is used to prepare the desired complex directly or to prepare a precursor compound that is further modified (usually by ligand substitution) to obtain the target complex. The common procedure for the synthesis of transition metal organometallic complexes involves the use of an inert atmosphere and therefore the manipulation by standard Schlenk techniques is required. In general, all solvents are dried and freshly distilled before use to maximally eliminate any vestiges of water, following the standard methods appropriate for each solvent. Although most of the compounds prepared for medicinal purposes are stable to air, humidity, and water, this is a routine precautionary procedure to optimize yields since the formation of any unstable intermediates may occur during different steps of the reactions. Purification and full characterization of the compounds is mandatory, bearing in mind their use as future drugs. Common purification techniques used in this type of synthesis are mainly recrystallization and/or column chromatography with the purity of the final compounds being certified by elemental analysis that is routinely performed relative to carbon, nitrogen, hydrogen, and sulfur. The structural formula of the compounds are confirmed by several techniques, namely nuclear magnetic resonance (1H, 31P, and 13C NMR), electron paramagnetic resonance and Fourier transform infrared spectroscopies, mass spectrometry, and, whenever possible, single-crystal X-ray diffraction. Studies in solution monitoring the optical spectra of the compounds in the ultraviolet and visible range and electrochemical studies using cyclic voltammetry are very often valuable tools for better understanding the stability of the compounds and the role of the metal in the electronic flow through the overall structure.

6.4.1 Synthesis of octahedral Ru(III) and Fe(III) inorganic complexes The most common starting material in ruthenium chemistry is the hydrated salt of ruthenium(III) chloride, RuCl3 xH2O (where x is approximately 3).122 Very soluble in water and in a wide range of polar organic solvents, this salt is on the basis for the preparation of several Ru(III) and Ru(II) complexes, whether inorganic or organometallic, that are generally used as precursors.155158 Reacting a methanolic solution



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of ruthenium(III) chloride trihydrate RuCl3 3H2O with excess triphenylphosphine affords [RuCl2(PPh3)3], dichlorotris(triphenylphosphine) ruthenium(II).158 This compound is a common starting material for inorganic Ru(II) complexes and is commercially available as well. The convenience of its use is the inherent reactivity due to the unsaturated coordination sphere (16 electrons) internally stabilized by a long ˚ ) weak RuH agostic interaction with one hydrogen atom of a (2.59 A phenyl ring from a phosphine occupying a vacant (axial) coordination site on the Ru(II) ion. Thus it is a five-coordinate ruthenium complex that can be considered as octahedral.156 [RuCl2(PPh3)3] can undergo nucleophilic substitution of the chlorides, addition of two-electron donor ligands, substitution of the triphenylphosphine ligands, and/or a combination of all of these,156 making it one of the most frequently chosen and versatile precursors.

6.4.2 Ru(III)-salan complexes Using [RuCl2(PPh3)3] as the metal precursor, West and coworkers92 reported the synthesis of ruthenium complexes bearing the tetradentate N,N0 -ethylenebis(salicylaldimine) salen ligand. Salen ligands are a specific type of Schiff-base molecule, typically prepared from the condensation of a diamine (e.g., ethylenediamine) with an aldehyde (e.g., salicylaldehyde) in ethanol in a 1:2 stoichiometry.62,99,157 In refluxing benzene (with an excess of triethylamine), [Ru(II)(salen)(PPh3)2] was isolated as a brick-red solid stable to air in the solid state, although readily oxidizing to the Ru(III) analogue in solution, with the formula [Ru(III)(salen)Cl(PPh3)]. This Ru(III) analogue could also be directly synthesized from the same precursor in alcohol (methanol/ethanol).92 During this procedure ruthenium(II) easily undergoes a one-electron oxidation, probably by the oxygen in the air,62,99 a process that can be rationalized by the ease of this dianionic molecule (bearing two Ophenolate and two Nimine as the donor set) to preferably stabilize the Ru (III) cation.92,159,160 Ruthenium(III)(salen) complexes can be prepared by several methods,92,93,159161 one of the most frequent being the reaction of RuCl3 with the desired tetradentate ligand in alkaline ethanol.92,93 Salan (or tetrahydrosalen) ligands are easily obtained from the reduction of imine bonds in the corresponding salen molecule. These can also be prepared by a single-step Mannich condensation using an amine (primary/secondary), formaldehyde, and substituted phenols.87,162 Ru (salan) complexes can be synthesized by the procedure first reported by West and coworkers. Using the ligand salan-dach (obtained from the condensation of cyclohexane diamine and methoxy-substituted salicylaldehyde derivatives) in benzene under reflux and [RuCl2(PPh3)3] as the

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metal precursor, Ru(III) complexes of formula [Ru(III)(salan-dach)Cl (PPh3)] were obtained after recrystallization.98 The reaction is promoted by the presence of triethylamine (NEt3) used in a 10-fold excess to enable the deprotonation of the free salan ligand. This synthetic route yielded a cleaner product and higher yield than an earlier procedure starting from RuCl3.

6.4.3 Iron(III)-aminobisphenolate and cyclam complexes Complexes containing an iron(III) center can be prepared from the salts of this metal, such as Fe(NO3)3 and FeCl3, which are commonly found in their hydrated forms, Fe(NO3)3 9H2O and FeCl3 6H2O. The hexahydrate form of iron(III) chloride, FeCl3 6H2O, has the octahedral structural formula trans-[FeCl2(H2O)4]Cl 2H2O that, with its quite labile ligands, was found adequate for the synthesis of complexes with hindered tetradentate ligands such as cyclams together with one or two additional monodentate ligands.80 The hydrated iron(III) nitrate salt is used as the source of Fe31 ions in the synthesis of octahedral ternary complexes with tetradentate aminobisphenolates and bidentate coligands (such as hydroxyquinoline, pyridines, and phenanthrolines).78,79 The presence of a base is essential to deprotonate the aminobisphenolate at the phenolic function and the reaction can be carried out in the presence of, for example, triethylamine, or a solution of the ligand in, for example, basic methanol can be added to a solution of the iron salt, followed by the addition of the coligand. The synthesis of tetraamine macrocycle cyclams is somewhat less straightforward. The cyclam scaffold can be obtained via a template synthesis of the nickel complex of N,N0 -bis(3-aminopropyl) ethylenediamine involving the condensation of the diamine with glyoxal.163 Tetraand mono-N-functionalized cyclams are easier to obtain (despite the challenges involved) and are the most widely described.163 The preparation of trans-disubstituted cyclams can be accomplished by a convenient procedure developed by Guilard and coworkers by reaction of cyclam with formaldehyde providing exclusively the trans-disubstituted isomer.164,165









6.4.4 Synthesis of ruthenium(II) and iron(II) organometallic complexes 6.4.4.1 Ru(II)Cp piano-stool complexes Complexes containing the scaffold {Ru(II)(η5-C5H5)}, or RuCp, can be prepared using [Ru(η5-C5H5)Cl(PPh3)2] as starting material. The most expedient process of synthesis of this precursor is based on the one-pot high-yield reaction from RuCl3 xH2O and excess triphenylphosphine



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that plays the simultaneous role of ligand and reducing agent to promote the conversion of Ru(III) to Ru(II).166 The general process is based on a successive addition of ethanolic ruthenium(III) chloride and freshly distilled cyclopentadiene solution to a vigorously stirred solution of triphenylphosphine in ethanol. The mechanism of this reaction was suggested to involve the possible unsaturated 16 electron intermediate [RuCl2(PPh3)3] mentioned earlier, with the η5-cyclopentadienyl complex being formed by oxidative addition of the diene to give a ruthenium(IV) hydrido chloride, followed by reductive elimination of hydrogen chloride. This latter step would be facilitated by the presence of excess of the tertiary phosphine, again acting as a reducing agent.166 For typical yield of 85%90%, a 4:1 triphenylphosphine-to-ruthenium excess was found to be sufficient. An alternative method for the preparation of [Ru (η5-C5H5)Cl(PPh3)2] is the direct reaction between [RuCl2(PPh3)3] and cyclopentadiene at room temperature, but this reaction takes 2 days and the yield is inferior to the one-pot reaction described earlier.155 The monodentate chloride and phosphine ligands in [Ru(η5-C5H5)Cl (PPh3)2] are susceptible to substitution by a bidentate ligand in mild reaction conditions, making this compound an excellent precursor for the preparation of different families of RuCp complexes. [Ru(η5-C5H5)Cl(PPh3)2] can be refluxed in acetone with a slight excess of a bidentate phosphine ligand, such as 1,2-bis(diphenylphosphino)ethane (DPPE), to give [Ru(η5-C5H5)Cl(DPPE)] in very good yield,167,168 both compounds being used as starting materials for a variety of new families with anticancer properties. Indeed, halide abstraction from [Ru (η5-C5H5)Cl(PPh3)2] and [Ru(η5-C5H5)Cl(DPPE)] can afford cationic complexes of the type [Ru(η5-C5H5)(PPh3)2L]1 and [Ru(η5-C5H5)(DPPE) L]1 where L is an N-heteroaromatic monodentate ligand, or [Ru(η5C5H5)(PPh3)LL]1 where LL is an NN/NO/NS-bidentate heteroaromatic ligand. This latter type of structure presenting a bidentate heteroaromatic ligand together with one PPh3 coligand was found to be an excellent combination for production of RuCp structures with relevant anticancer properties. Numerous examples of these species are fully presented in Section 6.3. [Ru(η5-C5H5)Cl(PPh3)2] can also be used as a precursor for the synthesis of a water-soluble analogue, [Ru(η5-C5H5)Cl(mTPPMS)2] by the substitution of the two phosphine ligands by the corresponding monosulfonated triphenylphosphines (mTPPMS 5 sodium diphenylphosphine-benzene-3sulfonate or triphenylphosphine-3-sulfonic acid sodium salt).169 This procedure is more straightforward and affords the complex in a much better yield compared to the synthetic route using RuCl3 3H2O, freshly distilled cyclopentadiene, and mTPPMS in refluxing ethanol.169 With monodentate chloride and phosphines, [Ru(η5-C5H5)Cl(mTPPMS)2] then becomes a suitable precursor for a new family of water-soluble RuCp complexes,



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combining chloride abstraction with the use of appropriate bidentate ligands.131 6.4.4.2 Fe(II)Cp piano-stool complexes For the preparation of complexes containing the Fe(Cp) core, the following complexes are commercially available as convenient precursors: cyclopentadienyl iron(II) dicarbonyl dimer168 and dicarbonyl cyclopentadienyliodoiron(II) or [Fe(η5-C5H5)I(CO)2]. Piper, Cotton, and Wilkinson reported the synthesis of the cyclopentadienyl iron(II) dicarbonyl dimer [Fe(η5-C5H5)(CO)2]2 by direct reaction of the metal carbonyl with excess of dicyclopentadiene under a nitrogen atmosphere.170,171 Oxidation of this compound by air in acid alcoholic medium (or by other oxidizing agents under various conditions) yielded the compound [Fe(η5-C5H5)(CO)2Cl] almost quantitatively. Removal of chloride from this complex is quite straightforward with the use of a halide abstractor (e.g., a silver salt) yielding the cyclopentadienyl-dicarbonyl-iron(II) cation that can be isolated from solution using large anions such as the tetraphenylborate ion.170 Using iodine, the oxidation of [Fe(η5-C5H5)(CO)2]2 occurs without release of the carbon monoxide ligands to form a polyiodide from which the compound [Fe(η5-C5H5)I (CO)2I] could be obtained after extraction of the excess of I2 with aqueous sodium thiosulfate solution.170172 [Fe(η5-C5H5)(CO)2I] is a suitable precursor for different families of complexes bearing the “Fe(η5-C5H5)” scaffold by exchange of the CO or I2 ligands.80,155,167 The release of CO requires the irradiation of the reaction mixture with UV light, while the iodide can be replaced in the coordination sphere by reaction with a suitable ligand following halide abstraction with a silver salt. Phosphine or bisphosphine derivatives can be prepared by reaction of [Fe(η5-C5H5)I(CO)2] with the desired ligand upon ultraviolet irradiation of the reaction mixture. In these reactions the coordinating ability of the solvent plays a role in assisting the conversion of the dicarbonyl to the monocarbonyl complex, and so does the nature of the entering ligand with a high π-acceptor character being an essential feature.173 In dry degassed acetone [Fe(η5-C5H5)(CO)I(PR3)] or [Fe(η5-C5H5)I(PP)] complexes can be prepared by reaction with the desired PR3 ligand (PR3 being an aryl phosphine such as triphenylphosphine) or PP (where PP is a chelating diphosphine such as DPPE or 1,2-bis(diphenylphosphino)ethane), upon irradiation of the reaction mixture with UV light. In both of these compounds and following halide abstraction (with e.g., AgPF6 or AgCF3SO3) the iodide can be further exchanged by a suitable monodentate ligand such as a carbonitrile derivative NRCR0 to yield [Fe(η5-C5H5)(CO) (NRCR0 )(PR3)] complexes80 or N-heteroaromatic ligands (N) such as imidazole derivatives to prepare [Fe(η5-C5H5)(CO)(N)(PR3)].155

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6.5 Conclusions and final comments Cancer ranks first as the cause of premature death (at age under 70) in many countries including Canada, the United States, Argentina, Chile, Uruguay, all of Europe, Australia, New Zealand, and Japan, a trend that is also becoming apparent in middle- and low-income countries.1 Available therapies fail to address several cancer conditions efficiently and an appropriate treatment to prevent the development of metastases, the deadliest cancer feature, remains unavailable. Recent advances in the research on ruthenium- and iron-based compounds undoubtedly show that these compounds hold great potential as cancer chemotherapeutic drug candidates. In this chapter an overview of this field is provided regarding Ru- and Fe-based metallodrugs, and particular attention is given to some emergent families of compounds developed by our research group, such as Fe(III)aminobisphenolates, Fe(III)cyclams, and Ru(III)salan complexes. All these families of compounds were found to be active against human cancer cells, some surpassing the activity of cisplatin, and also being active against cisplatin-resistant cell lines. All of these compounds incorporate a tetradentate ligand as a scaffold to strongly chelate the metal ion that can be derivatized to further optimize the overall behavior of the complex and improve their therapeutic potential. Concerning Ru(II) and Fe(II), we focused on the organometallic complexes incorporating the cyclopentadienyl ligand as the stabilizing scaffold. Although the group of Fe(Cp) complexes includes fewer compounds, results gathered so far disclose their therapeutic potential and certainly set them in a prominent position as prospective anticancer drugs. The potential of this class of metallodrugs has also been recently pursued by other research groups.174,175 The work done on Ru(Cp) complexes as cytotoxic active candidates has placed this class of compounds at the very front stage of ruthenium-based anticancer agents. Indeed, these compounds undoubtedly offer alternative modes of action, as proven for, for example, TM90 in vivo with the dual effect of inhibiting the tumor growth and preventing the development of metastases. Importantly, our structureactivity studies allowed to understand how the fine-tuning of compounds modulated their solubility, stability, and inhibitory properties against ABC pumps that are a major cause of MDR in cancer treatments. In addition, in vitro and in vivo selectivity can be modulated by means of passive or active targeting strategies, incorporating polymers or biomolecules (such as biotin) and drug delivery systems targeting specific receptors in cancer cells (such as suitable peptides) into the TM34 lead. This reveals that a new structural approach based on TM34 by derivatization of the N-heteroaromatic ligand (bipy) or alternatively of the

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Cp ring may also be a very promising route in the context of targeted therapy. Among all of the compounds studied so far, LCR134 and pmc78, designed for active or passive targeting, respectively, are those we consider as the second-generation leads. LCR134 stands out as the best metallodrug ever reported with multiple functionalities as cytotoxic agent, strong P-gp inhibitor, and possessing antimetastatic potential. On the other hand, the patented pmc78 complex148 shows similar trends, with the added benefit that its mode of action has already been clarified, positioning it as an antimetastatic and antiinvasion compound. Ongoing in vivo studies will be of utmost importance to validate their potential. Overall, the immense potential of both iron- and ruthenium-based metallodrugs as chemotherapeutics cannot be overstated, and the future holds a promise for new drug classes offering serious advantages over the established therapeutic regimens.

Acknowledgments Centro de Quı´mica Estrutural acknowledges Fundac¸a˜o para a Cieˆncia e Tecnologia (FCT) for financial support through the Project UIDB/00100/2020. Valente acknowledges FCT for the project PTDC/QUI-QIN/28662/2017 and the COST Action STRATAGEM (CA17104, European Cooperation in Science and Technology). Valente and Morais acknowledge the CEECIND 2017 Initiative (CEECIND/01974/2017 and CEECIND/00630/2017, respectively, acknowledging FCT, as well as POPH and FSE-European Social Fund). Teixeira thanks FCT for his PhD Grant (SFRH/BD/135830/2018). Matos thanks FCT for projects UID/Multi/04349/2019 and PTDC/QUI-NUC/30147/2017. Tomaz acknowledges the COST Action NECTAR (CA18202, European Cooperation in Science and Technology).

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New inorganic therapeutics, II

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7 Functional nanocomposites: promising candidates for cancer diagnosis and treatment Okan Icten Hacettepe University, Ankara, Turkey

This chapter is dedicated to my father, Ferit Icten, who passed away from cancer.

7.1 Introduction Cancer is the general name for a collection of related diseases involving uncontrolled division and growth of cells in live bodies and has recently begun to occur very commonly in humans worldwide.1 New cases were estimated at 18.1 million in 2018, with 9.6 million cancer deaths globally in the same year, according to the World Health Organization (WHO). Additionally, it has been estimated that these numbers will continue to rise in the next two decades.2 In order to decrease mortality caused by cancer, the prevailing thought is that early diagnosis and effective therapy are required.3 Common conventional cancer treatment methods can be categorized as surgery, radiotherapy, and chemotherapy.4 Although radiotherapy and chemotherapy are promising approaches for destruction of cancer cells, they suffer from side effects such as drug resistance, systematic toxicity, and damage to healthy tissues.5,6 From this perspective, scientists have focused on the design of novel therapeutics, based on multifunctional nanocomposites to overcome these challenges. Additionally, developing therapeutic methods such as targeted drug delivery,7 immunotherapy,8

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hormone therapy, photodynamic therapy,6 hyperthermia,9 and gene therapy10 and the combination of these methods via a single composite material have received great recent interest for the treatment of cancer.11,12 Another major step for cancer treatment is early diagnosis of cancer cells using imaging techniques such as computed tomography (CT),6 magnetic resonance imaging (MRI), fluorescence imaging (FI),13 and positron emission tomography (PET),14 which utilize contrast agents to enhance the image resolution. Sometimes, a single imaging method is insufficient to make accurate diagnoses in cancer cases. Therefore dual or multimodal imaging techniques should be employed to achieve more accurate and precise information from images and determine the most appropriate treatment method. For this purpose, scientists have begun to investigate the development of new contrast agents that consist of nanocomposites for multiple goals, enabling diagnosis with single, dual, or multiimaging and simultaneous therapy.15,16 Nanocomposites are generally defined as structures possessing various characteristics and functions coming from a combination of diverse materials in a single nanoplatform for a broad range of multiple applications. As seen in the exponential growth of publications on nanocomposites in Fig. 7.1 courtesy of the Web of Science database, the use of nanocomposites in a wide range of applications such as material science, physics, electrochemistry, nanoscience and technology, energy fuels, and polymer science has attracted significant attention over the last 15 years.

FIGURE 7.1 The increase in the number of publications on nanocomposites since 1996. Source: Produced from Web of Science, webofscience.com, 2020. Web of Science - Clarivate [online]. https://apps.webofknowledge.com. (accessed 29 February 2020).17

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Nanocomposites are currently receiving a tremendous amount of scientific interest with a view to biomedical applications, in particular in cancer treatment and diagnosis. Specifically, magnetic nanoparticles are the main components of the nanocomposite materials to be applied in cancer treatment and diagnosis owing to various features, such as simple synthesis and surface modification, biocompatibility, and easy control by using an external magnet.18 Among magnetic nanoparticles, iron oxide forms such as magnetite (Fe3O4) and maghemite (γ-Fe2O3) are widely used in nanocomposites because of their high saturation magnetization and low toxicity19 and these iron oxide forms have been approved by the FDA for use as MRI agents and in other clinical studies.20 Before reviewing the literature on functional nanocomposites, Fig. 7.2 will be useful in providing a conceptual overview of the chapter. Improvement of methods for

FIGURE 7.2 Preparation, modification, and applications of functional nanocomposites in cancer diagnosis and treatment.

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synthesis and modification, especially with a view to cancer treatment and diagnosis, will contribute to the development of more effective therapeutic approaches.

7.2 Synthesis techniques for preparation of nanocomposites The most commonly used methods of synthesis of nanocomposites for cancer therapies will be discussed in this section. Depending on the specific application and desired features such as morphology, crystal structure, size, and surface structure, nanocomposites have been prepared using a diverse array of techniques including hydrothermal/solvothermal, solgel, coprecipitation, thermal decomposition, solid-state, and ball milling synthesis.20 As nanocomposites consist of the combination of more than one structure in a single platform, it may be necessary to utilize two or more synthesis methods simultaneously for their preparation.21 The various synthesis techniques for preparing nanocomposites that have usage potential or have already been used in cancer therapy are outlined in Table 7.1.

7.2.1 Hydro/solvothermal method Hydro/solvothermal synthesis is a process carried out by using pressure-resistant sealed vessels such as an autoclave or reactor at high ambient pressure and temperature (T . 100 C, P . 1 atm) in the presence of water or organic solvent. The method is termed either a hydrothermal or a solvothermal technique if the solvent used is water or an organic solvent, respectively.50,51 The applied temperature and pressure allow the dissolution of precursor chemicals (metal chlorides, nitrates) in the reaction medium and the crystallization of desired products. These techniques represent a single-step route to prepare metal oxide nanoparticles generally. Autoclaves, which are commonly used as the reaction vessel in hydro/solvothermal synthesis, are shown in Fig. 7.3. These vessels are produced from high pressureresistant materials such as stainless steel or titanium and feature a polytetrafluoroethylene (PTFE) cap on the inside to prevent corrosion.52 The hydro/solvothermal method is a convenient technique for nanocomposite production owing to the control it affords over many reaction parameters such as solvent type, reaction time, stirring, pressure, and temperature, which affect the features of the resulting nanocomposites.18 For instance, Icten et al.54 fabricated soft ferromagnetic magnetitegadolinium borate nanocomposites (Fe3O4@GdBO3) for potential MRI and neutron capture therapy (NCT) applications via hydrothermal

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TABLE 7.1

The various synthesis techniques for preparing nanocomposites.

Synthesis techniques

Nanocomposites

Two-step procedures (solvothermal method and chemical reaction in solution)

31

Applications

References

Ag@NaYF4:Yb ,Tm

Photothermal therapy

[22]

Hydrothermal method

HA/alumina HA/MgO

Candidate for biomedical applications

[23]

Two-step procedures (Hummer’s method and hydrothermal method)

MHAp/RGO (magnetite hydroxyapatite nanorods on reduced graphene oxide)

Candidate for drug nanocarrier

[24]

Two-step procedures (Hummer’s method and hydrothermal method)

HAp/GO (hydroxyapatitegraphene oxide)

Drug delivery

[25]

Hydrothermal method

Fe3O4@Gd2O3:Eu31

Candidate for drug targeting and diagnostic analysis

[26]

Solgel method

Mg2SiO4CuFe2O4

Hyperthermia treatment

[27]

Solgel method

ZnPc-TiO2

Photodynamic therapy

[28]

Two-step procedures (solgel method and surface modification)

YPMS@PpIX@FA protoporphyrin IX and folic acidfunctionalized, and mesoporous silicacoated Y2.99Pr0.01Al5O12

Photodynamic therapy

[29]

Two-step procedures (solgel method and surface modification)

2SiO2-B2O3-FA (folic acidfunctionalized borosilicate)

Candidate for BNCT application

[30]

Coprecipitation method

Doxorubicin-loaded CoFe2O4@Albumen

Drug delivery

[31]

Coprecipitation method

Manganese-doped cerium oxide

Photodynamic therapy

[32]

Coprecipitation method

Fe3O4/polymer

Hyperthermia treatment

[33]

31

(Continued)

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TABLE 7.1 (Continued) Synthesis techniques

Nanocomposites

Applications

References

Two-step procedures (coprecipitation method and layer to layer method)

CoFe2O4NPs@Mn-organic framework

Drug delivery

[34]

Three-step procedures (coprecipitation method, surface modification, and chemical reduction method)

Au/TMC/Fe3O4

Candidate for therapeutic agent drug delivery

[19]

Three-step procedures (coprecipitation method, surface modification, and chemical reaction in solution method)

Fe3O4/CdTe

Fluorescent imaging

[35]

Two-step procedures (coprecipitation method, and hydrothermal method)

TiONts-USPIO (titanate nanotubes coated with ultra-small superparamagnetic iron oxide)

MRI agent

[36]

Three-step procedures (coprecipitation method, microemulsion method, and surface functionalization)

Fe3O4@SiO2(FITC)-FA/ CMCD (CM-β-CD conjugated fluoresceindoped magnetic silica)

Simultaneous fluorescence imaging, cancer cell targeting, and drug delivery

[37]

Two-step (coprecipitation method and condensation reaction)

NaBA@PEG-Fe3O4 and NaBA2@PEG-Fe3O4 (mono and bis(ascorbatoborate) complexes functionalized magnetite)

Candidate for BNCT application

[38]

Three-step procedures (combustion synthesis method, coprecipitation method, and solgel method)

Fe10BO3/Fe3O4/SiO2 and GdFeO3/Fe3O4/SiO2

Candidate for BNCT and GdNCT application

[39]

Thermal decomposition method

PEG-covered Gd2O3

Candidate for carrier, targeting, and contrast agent

[40]

Thermal decomposition method

MnCo2O4/Co2Mn3O8

Chemotherapeutic agent

[41] (Continued)

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TABLE 7.1

(Continued)

Synthesis techniques

Nanocomposites

Applications

References

Thermal decomposition method

Multifunctional clustered nano-Fe3O4 chitosan

Hyperthermia treatment

[42]

Thermal decomposition method with sonochemical assistant

CuCo2O4/CuO

Chemotherapeutic agent

[43]

Two-step (thermal decomposition method and surface modification)

Phospholipid-PEG-coated and doxorubicin-loaded superparamagnetic iron oxide

Chemotherapy and hyperthermia treatment

[44]

Two-step (thermal decomposition method and surface modification)

Chitosan-coated MnFe2O4

Hyperthermia treatment

[45]

Ball milling method

Chitosan-coated zinc sulfide nanocomposites

Fluorescence imaging of cancer cells

[46]

Two-step procedures (ball milling method and surface functionalization)

PEGylated Fe3O4@SiO2

A potential candidate for theranostic application

[47]

Two-step procedures (ball milling method and surface functionalization)

Surface-functionalized magnetic boron

Potential candidate in BNCT, magnetic implants, and MRI applications

[48]

Two-step procedures (Hummer’s method and ball milling method)

Graphene oxide-Fe3O4

Hyperthermia treatment

[49]

HA, hydroxyapatite; PEG, polyethylene glycol; TMC, N-trimethylchitosan; ZnPc, Zinc phthalocyanine

synthesis using magnetite or polyethylene glycolcoated magnetite, boric acid or borax, and gadolinium nitrate as precursors. The analysis results in this study indicated that the type of precursors used, their variable concentrations, and the ambient pH affected the formation of gadolinium borate. For example, when borax was employed as a boron source in the hydrothermal synthesis, the triclinic-GdBO3 structure formed over the magnetite. However, vaterite-type orthoborate (GdBO3 [Gd3(B3O9)]) was obtained when boric acid was used as the boron source in an analogous experiment. The Gd/B molar ratio was 1/1 for

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FIGURE 7.3 (A) A vessel from Parr Instrument Company (Series 4760 general-purpose pressure vessel, 100600 mL) and (B) general-purpose acid digestion vessel from Parr Instrument Company.53

both gadolinium borate phases, as seen in the chemical formula of these structures. Additionally, polyethylene glycolcoated magnetite seemed to more favorably support the materials than plain magnetite due to the stabilization of the borate structures by a polyethylene shell via hydrogen bonding. The authors showed that the variation of ambient pH had no significant effect on the gadolinium borate structures produced (Fig. 7.4). In another study, Bharath et al.25 reported an eco-friendly hydrothermal method to fabricate hydroxyapatite/graphene oxide nanocomposites as a powerful drug delivery system. First, the authors synthesized twodimensional graphene oxide sheets by using Hummer’s method. As seen in Fig. 7.5, one-dimensional hydroxyapatite (20 nm diameter and 6080 nm length) nanorods were homogeneously deposited over the graphene oxide sheets by hydrothermal method (180 C,12 h) using creatine phosphate as an organic phosphate source. In addition to possessing a high protein absorption value (Qo), which was 350 mg g21 at neutral

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FIGURE 7.4 The synthesis procedure of magnetite-gadolinium borate nanocomposites. Source: Reproduced with permission from Icten, O.; Kose, D.A.; Zumreoglu-Karan, B., Fabrication and Characterization of Magnetite-Gadolinium Borate Nanocomposites. J. Alloys Compd. 2017, 726, 437444. Copyright 2017, Elsevier.

FIGURE 7.5 Schematic illustration for the preparation of hydroxyapatite/graphene

oxide nanocomposite by the hydrothermal technique (180 C, 12 h). Source: Reproduced with permission from Bharath, G.; Latha, B.S.; Alsharaeh, E.H.; Prakash, P.; Ponpandian, N. Enhanced Hydroxyapatite Nanorods Formation on Graphene Oxide Nanocomposite as a Potential Candidate for Protein Adsorption, pH Controlled Release and an Effective Drug Delivery Platform for Cancer Therapy. Anal. Methods 2017, 9, 240252. Copyright 2017, RSC.

pH, this nanocomposite was shown to be nontoxic to a normal cell line (HaCaT). However, nanocomposite-loaded andrographolide used as a model anticancer drug displayed cytotoxic effects to a cancer cell line (A431), depending on applied doses. Another comprehensive study, including a simple synthesis procedure for a multifunctional Ag nanocube@NaYF4:Yb31,Tm31 nanocomposite via the combination of solvothermal and hydrothermal processes was reported by Chen et al.22 First, Ag nanocubes were prepared in poly(vinylpyrrolidone) and ethylene glycol by adding AgNO3 and NaCl, and this mixture

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was transferred to the autoclave for solvothermal synthesis at 160 C for 4 h. At the same time, NaYF4:Yb31,Tm31 nanoparticles were fabricated under hydrothermal conditions using aqueous solutions of precursor metal nitrates and NaF at 180 C for 24 h. Then, the surface of the Ag nanocubes was coated with NaYF4:Yb31,Tm31 nanoparticles to obtain nanocomposites suitable for photothermal treatment of cancer cells and possessing antibacterial properties. As revealed by SEM and TEM analyses (Fig. 7.6), the size

FIGURE 7.6 (A) SEM image and the particle size distribution of NaYF4:Yb31,Tm31 nanoparticles, (B) SEM image of Ag nanocubes, (C) enlarged image of Ag nanocubes, (D) TEM image of Ag nanocube@NaYF4:Yb31,Tm31 nanocomposites, (E) EDS spectra of Ag nanocube@NaYF4:Yb31,Tm31, and (F) EDS spectra of the surface of Ag nanocubes. Source: Reproduced with permission from Chen, Z.; Liu, G.; Cui, Z.; Liu, Q.; Hong, F.; Yu, W.; Dong, X.; Song, C. Fabrication of NaYF4: Yb31, Tm31-Modified Ag Nanocubes with Upconversion Luminescence and Photothermal Conversion Properties. RSC Adv. 2019, 9, 2077820785 Copyright 2019, RSC.

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and morphology of the NaYF4:Yb31, Tm31, and Ag nanoparticles were 45 nm diameter spherical structures and cubic structures of 245 nm edge length, respectively. The SEM and TEM images of the final product (Ag nanocube@NaYF4:Yb31) showed that NaYF4:Yb31,Tm31 were appended to the surface of the Ag nanocubes and the nanocomposites had an average diameter of 288 nm and rough surfaces. Additionally, all elements in the nanocomposites were detected by energydispersive X-ray spectroscopy (EDS).

7.2.2 Solgel method The solgel method is also one of the promising techniques for the production of various nanocomposites because of the mild reaction conditions involved. In this method, the features of the obtained product such as dimensions, shape, and morphology are based on reaction conditions.20,55 The solgel method includes the hydrolysis and condensation reaction of precursors (often alkoxides), which lead first to the formation of a liquid sol phase which is then converted into the gel phase, resulting in the creation of final metal oxide products after posttreatment. The steps and general chemical reactions of the solgel method are shown in Fig. 7.7.5658 Compared with conventional synthesis methods, the solgel process permits favorable possibilities such as low temperature for the production of structure and high purity and uniform morphology of the products. Additionally, this method allows not only the synthesis of nanocomposites but also the capping of the particles with the desired ligands to confer further functionalization59 and stabilization.60 Bigham et al.27 utilized the solgel method to synthesize multifunctional magnetic Mg2SiO4CuFe2O4 nanocomposite for simultaneous bone cancer therapy and regeneration. CuFe2O4 was fabricated via the solgel combustion technique, in which nitrate salts of copper(II) and iron(III) and citric acid were dissolved in distilled water, and the pH of the mixture was adjusted to 7 at 120 C. The solid product was heated to 700 C in a furnace to obtain CuFe2O4 nanoparticles. Then, these nanoparticles were capped with Mg2SiO4 by using a surfactant-assisted solgel method, using ethylene glycol, cetyltrimethylammonium bromide, and distilled water. The XRD pattern (Fig. 7.8A) indicated that each phase of the nanocomposite was successfully synthesized, and no impurity or new phase was observed. The coreshell structure of the nanocomposite was verified via TEM images (Fig. 7.8B) displaying particle size ,100 nm, and featuring a CuFe2O4 core and Mg2SiO4 shell. Grandi et al.30 prepared borosilicate particles (2SiO2B2O3) via the solgel method and modified them with the addition of folic acid to decrease boron

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FIGURE 7.7 (A) The steps and (B) chemical reactions of the solgel method.

loss and provide overexpression on the cancer cells for BNCT application. Another study related to the solgel synthesis method was performed by Lopez et al.28 for photodynamic therapy applications in cancer treatment. In this study, zinc phthalocyanine-TiO2 nanocomposites (ZnPc-TiO2) were prepared by a single-step solgel method in two different media, depending on the acid source used. Titanium n-butoxide was added into an acid solution (acetic or oxalic acid) of zinc phthalocyanine, and the mixture was stirred until gel formation occurred. Drying for several days gave solid particles. Zinc phthalocyanine was utilized as a photosensitizer agent required for the absorption of photons and the creation of therapeutic effect in photodynamic therapy. Titanium dioxide is also used for the photoactive destruction of cancer cells owing to its strong oxidizing power. In 2018 Sengar et al.29 developed YPMS@PpIX@FA (protoporphyrin IX and folic acidfunctionalized and mesoporous silica-coated Y2.99Pr0.01Al5O12) nanocomposites for application in potential photodynamic therapy.

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FIGURE 7.8 (A) XRD pattern and (B) different magnification TEM images of Mg2SiO4CuFe2O4 nanocomposite. Source: Reproduced with permission from Bigham, A.; Aghajanian, A.H.; Allahdaneh, S.; Hassanzadeh-Tabrizi, S. Multifunctional Mesoporous Magnetic Mg2SiO4CuFe2O4 Core-Shell Nanocomposite for Simultaneous Bone Cancer Therapy and Regeneration. Ceram. Int. 2019, 45, 1948119488. Copyright 2019, Elsevier.

Y2.99Pr0.01Al5O12, protoporphyrin (PpIX), and folic acid (FA) in the designed nanocomposite function as an X-ray energy transducer, converting X-rays into UVvisible photons to increase the therapeutic efficiency, photosensitization, and targeting of cancer cells. YPMS (mesoporous silica-coated Y2.99Pr0.01Al5O12) nanocomposites were synthesized by two-step procedures using a tartaric acidassisted solgel method for preparation of Y2.99Pr0.01Al5O12 and Sto¨ber solgel approach for the mesoporous silica coating. The optimum concentration of tetraethyl orthosilicate (TEOS) for silica coating was determined as 0.04% (v/v) to produce a thick homogeneous layer (14 6 4 nm), which was the critical distance for effective energy transfer. TEM images (Fig. 7.9A) confirmed a coreshell structure with an average particle diameter of more than 100 nm. Surface areas were

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FIGURE 7.9

(A) TEM images of Y2.99Pr0.01Al5O12 and silica-coated Y2.99Pr0.01Al5O12 and (B) overlay of silica-coated Y2.99Pr0.01Al5O12 (i) photoluminescence spectrum, (ii) cathodoluminescence spectrum, and (iii) absorption spectrum of PpIX.29

calculated by the Brunauer, Emmett and Teller (BET) model, confirming the formation of a mesoporous silica structure. While the surface area of silicacoated Y2.99Pr0.01Al5O12 nanocomposites was 70 m2 g21, bare Y2.99Pr0.01Al5O12 nanoparticles possessed a surface area of 7 m2 g21, which verified the formation of a silica layer. Furthermore, luminescence analysis of these nanocomposites (Fig. 7.9B) showed an excellent emission and absorption overlap at 300450 nm between Y2.99Pr0.01Al5O12 and PpIX, leading to an improved photodynamic response. Lastly, the surface of the nanocomposites was functionalized with PpIX, and FA through 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide & N-Hydroxysuccinimide (EDCNHS) coupling and in vitro studies were performed on breast and prostate cancer cells, leading to cell death upon irradiation with UVA.

7.2.3 Chemical coprecipitation The chemical coprecipitation method has been the most commonly used technique to fabricate most of the metal oxide or mixed metal or metal-ceramic nanocomposites described in the literature. This method is based on the dissolution of precursors such as inorganic salts in an appropriate solvent, the precipitation of these salts by adding a base solution at room or moderate temperature, and separation of product from the solution medium, resulting in material production.18,55 The reaction temperature, type and concentration of inorganic salts, use of a surface-active agent, and mixing speed are the primary factors influencing the size distribution and shape of the product obtained by this method. The advantages of the coprecipitation technique are (1) facile sample production and size control, (2) possibility for surface modification in the reaction medium, (3) low synthesis temperature, and (4) eco-friendliness and low cost.21,61

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Chemical coprecipitation is increasingly used to fabricate magnetic nanoparticles (iron oxide or metal ferrite) in nanocomposites for biomedical applications as the use of hazardous solvents and reagents is phased out.31,33,34,38 The general synthesis of metal ferrite nanoparticles is represented by the following equation, where M21 represents a d-block transition metal ion.    M21 aq 1 2 Fe31 aq 1 8 OH aq -MFe2 O4 ðsÞ 1 4 H2 OðlÞ Recently, many studies have reported the preparation and application of nanocomposites, including iron oxide, ferrite metal oxide, and metal oxide using the coprecipitation method. For instance, Qasim et al.31 synthesized the doxorubicin-loaded CoFe2O4@Albumen nanocomposites by utilizing the coprecipitation method with a range of reaction parameters, surface modifications, and drug loading reactions. In this study, CoFe2O4 nanoparticles were fabricated from cobalt(II) and iron(III) salts, sodium hydroxide, oleic acid as a stabilizing agent, and sodium borohydride and hydrazine hydrate to obtain well-ordered crystalline structure without the need for heat treatment. Depending on the relative amount of sodium borohydride used, nanoparticle sizes were found from TEM images of 11 and 15 nm using 0.5 or 1 mg sodium boron hydride, respectively. Additionally, it was observed that CoFe2O4 nanoparticles, with a saturation magnetization of 88 emu g21, prepared using lower levels of sodium borohydride had uniform particle dimensions. As another example of the preparation of nanocomposites via the coprecipitation method, Icten et al. synthesized mono and bis(ascorbatoborate) complexfunctionalized Fe3O4 nanocomposites for targeted delivery/therapy applications (seen in Fig. 7.10).38 Nanocomposites with a particle size of 1015 nm contained 1015 boron atoms μg21 of sample and showed a superparamagnetic behavior at room temperature, and could, therefore, be appropriate for targeted boron neutron capture therapy (BNCT) applications. Ebrahimi et al.34 designed CoFe2O4NPs@Mn-Organic Framework coreshell nanocomposites for drug delivery applications. CoFe2O4 particles with a size of 20 nm were prepared by a typical coprecipitation method. Then, the surface of the particles was covered with an MnOrganic Framework by layer to layer method, and finally, anticancer drug daunorubicin was loaded into the nanocomposite. Characterization and in vitro release studies indicated that the CoFe2O4NPs@Mn-Organic Framework could be a potential candidate for cancer treatment via targeted drug delivery. In another study performed by Atif et al.,32 manganese-doped cerium oxide nanocomposites were successfully synthesized through a simple coprecipitation method for application in photodynamic cancer therapy. A total of 9% Mn-doped cerium oxide

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FIGURE 7.10 Synthetic route and proposed structures or mono and bis(ascorbatoborate) complexfunctionalized Fe3O4 nanocomposites. Source: Reproduced with permission from Icten, O.; Hosmane, N.S.; Kose, D.A.; Zumreoglu-Karan, B. Magnetic Nanocomposites of Boron and Vitamin C. New J. Chem. 2017, 41, 36463652. Copyright 2017, RSC.

nanocomposites exhibited higher cytotoxicities over cancer cell line (MCF7) compared with undoped nanocomposites because of greater levels of reactive oxygen generation, proportional to the level of Mn doping. In addition, Fe10BO3/Fe3O4/SiO2 and GdFeO3/Fe3O4/SiO2 nanocomposites were synthesized by Gao et al.39 as novel agents for boron and gadolinium NCT. Fe10BO3 and GdFeO3 nanoparticles prepared by the combustion method had spherical morphology with an approximate particle size of 60 nm. Then Fe3O4 particles were deposited over the Fe10BO3 and GdFeO3, causing the formation of aggregate structures resulting from strong magnetic forces of attraction. Lastly, the Fe10BO3/Fe3O4 and GdFeO3/Fe3O4 nanocomposites were coated with a thin silica layer to provide a high surface area to the nanocomposite. The saturation

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magnetization values of Fe10BO3/Fe3O4/SiO2 and GdFeO3/Fe3O4/SiO2 at room temperature were measured as 22.6 and 48.7 emu g21, respectively, enabling magnetic separation with an external magnet. Further plans for this study focus on the biological evaluation of the nanocomposites with a view to boron and gadolinium NCT applications.

7.2.4 Thermal decomposition The thermal decomposition technique is one of the synthetic steps used to produce nanocomposites containing magnetic nanoparticles or metal oxide nanoparticles similar to the coprecipitation method. The general procedure consists of the heating of an organometallic complex in high-boiling organic solvents in the presence of stabilizing surfactants at high temperature (150 C350 C) with the subsequent growth of metal oxide particles.62,63 Use of metal acetylacetonates, metal cupferronates, and metal carbonyls as the organometallic complexes and hexadecylamine, fatty acids, and oleic acid as surfactants is typical in this synthesis method.64 The dimension and morphology of structures fabricated by the thermal decomposition method depend on the type and ratio of starting materials, reaction temperature, reaction time, and aging period. The most important advantage of the thermal decomposition method is the production of particles with a narrow size distribution. However, surface modification is necessary for biological applications because the as-obtained particles are generally soluble in apolar solvents.65,66 For instance, chitosan-coated MnFe2O4 nanocomposites were designed by Oh et al.45 as hyperthermia agents in cancer therapy. First, the synthesis of oleate-coated MnFe2O4 nanoparticles was carried out with a thermal decomposition method using manganese(II) and iron(III) acetylacetonate complexes. Subsequently, since the oleatecoated MnFe2O4 nanoparticles had a hydrophobic surface (and were insoluble in an aqueous medium), 2,3-dimercaptosuccinic acid replaced oleate on the surface by a ligand exchange reaction and the nanocomposites were modified with chitosan to enhance their biocompatibility and stability. The analysis results indicated that chitosan-coated MnFe2O4 nanocomposites possessed a monodisperse cubic structure with a particle size of nearly 18 nm and exhibited a positive surface charge (110.02 mV), resulting in the formation of water-dispersible nanocomposites suitable for hyperthermia treatment. Another example of the thermal decomposition method for nanocomposite synthesis was performed by Ahab et al.40 In this study, PEG (polyethylene glycol) covered Gd2O3 nanocomposites were synthesized by a single-step thermal decomposition method at various reaction temperatures (260 C, 280 C, and 300 C) in the absence of any surfactants or solvents. SEM images indicated that

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FIGURE 7.11 SEM images of PEG-covered Gd2O3 nanocomposite at (A) 260 C, (B) 280 C, (C) 300 C, (D) synthesis route of PEG-covered Gd2O3 nanocomposite, and (E) SEM images of dispersed PEG-covered Gd2O3 nanocomposites in water. Source: Reproduced with permission from Ahab, A.; Rohman, F.; Iskandar, F.; Haryanto, F.; Arif, I. A Simple Straightforward Thermal Decomposition Synthesis of PEG-Covered Gd2O3 (Gd2O3@ PEG) Nanoparticles. Adv. Powder Technol. 2016, 27, 18001805. Copyright 2016, Elsevier.

the nanocomposites prepared at 260 C had monodisperse morphology with an average particle size of 178 nm, and elevation of the temperature caused the formation of aggregates (Fig. 7.11). Nevertheless, all nanocomposites were dispersible in an aqueous medium owing to hydrophilic PEG functionalization. In another study, MnCo2O4/Co2Mn3O8 ceramic nanocomposites were synthesized through the thermal decomposition method for application in breast cancer treatment.41 In an eco-friendly approach, a nanocomposite was formed via the reaction between Mn(II), Co(II), and the natural product cochineal in distilled water at 70 C, then the complex was transformed to the final product (MnCo2O4/Co2Mn3O8) by thermal treatment. The ceramic nanocomposites could find use in chemotherapeutic agents due to their ability to provide oxidative stress to breast cancer cell lines (the murine mammary carcinoma 4T1). Quinto et al.44 also developed phospholipid-PEG-coated and doxorubicin-loaded superparamagnetic Fe3O4 nanocomposites for the use in combination therapy of chemotherapy and hyperthermia. Superparamagnetic Fe3O4 nanoparticles, with

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14 nm core diameter and magnetic saturation of 84.6 emu g21, stabilized by oleic acid and oleylamine surfactants were synthesized by the thermal decomposition method, after which phospholipid-PEG molecules were attached to the surface of these particles by the dual-solvent exchange coating method. The model chemotherapeutic drug doxorubicin was successfully loaded into the phospholipid-PEG-modified Fe3O4 nanocomposite.

7.2.5 Ball milling synthesis method Ball milling synthesis has attracted considerable attention as a promising technique for the preparation of composite materials because of its low cost and eco-friendliness.67,68 The ball milling process has two main aims, namely particle size reduction and the mixing of particles to produce new phases.69 Various types of ball milling can be employed for product synthesis, but the planetary and vibratory ball mills have commonly been utilized in the research studies. The fundamental principles of the ball milling technique based on solid-phase reactions are related to balls and mill chamber consisting of the same materials such as hardened steel, ceramic, tungsten carbide, and zirconia.70 In this method, kinetic energy originating from the motion of balls in the chamber is transferred to the milled particles, causing the rupture of chemical bonds and the formation of small particles. Nanometer-sized particles can be produced by high-energy collisions between the balls. As such, the energy transferred and features of the product obtained can be controlled by variable factors such as milling speed and duration, ball size, the weight ratio of balls to powder, and the choice of dry or wet milling type.69,71 Furthermore, ball milling synthesis can also be carried out under argon, hydrogen, or nitrogen atmospheres to provide appropriate conditions for a specific material or phase formation.70 Surfaceactive agents can also be added into the reaction medium to enhance desired product properties such as prevention of aggregation and decrease of particle size.71,72 Icten et al.48 produced surface-functionalized magnetic boron nanocomposites as candidates for BNCT, magnetic implants, and MRI applications. By using a planetary ball mill, undecylenic acid and elemental boron were milled in hexane for 7 h at 400 RPM (80 balls/powder ratio). The acid residues on the surface of the nanocomposites were replaced by dopamine in a ligand exchange process. The magnetic behavior of the nanocomposites (saturation magnetization: 57 emu g21) was due to amorphous Fe-B alloy particles formed during the milling process via leaching of iron from the stainless steel materials. Another study related to the ball milling method for nanocomposite synthesis was published by Arayanaswamy et al.49 Graphene oxide-Fe3O4

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FIGURE 7.12 XRD patterns of nanocomposite milled (A) different graphene oxide/ iron weight ratio, (B) different milling durations, (C) magnetic hysteresis curves of nanocomposites milled different milling durations, and (D) SAR values versus milling duration.49

nanocomposites were synthesized using the planetary ball mill under variable reaction conditions (milling time and graphene oxide/iron weight ratio) for application in in vitro magnetic hyperthermia treatment. As seen in Fig. 7.12, the Fe3O4 phase was solely obtained from the 50:50 composition ratio of graphene oxide:iron powder (Fig. 7.12A), with a milling duration of 40 h required for all of the iron to be oxidized to the Fe3O4 phase (Fig. 7.12B). Furthermore, the highest saturation magnetization value of 78 emu g21 was observed in the sample milled for 25 h related to iron content (Fig. 7.12C). Lastly, a plot of specific absorption rate (SAR) values versus milling duration (Fig. 7.12D) indicated that 25 h milling time at all concentrations had the highest SAR value based on iron content, but a milling time of 40 h was chosen for biological studies due to the formation of the pure Fe3O4 phase and a higher SAR value than that obtained after 45 h. Pilloni et al.47 developed a practical and economical route to nanometer-sized PEGylated Fe3O4@SiO2 nanocomposites through a high-energy ball milling method for use in theranostic applications.

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Following the equation: 6 α  Fe2 O3 1 Si-4 Fe3 O4 1 SiO2 ; Fe3 O4 @SiO2 nanocomposites, with an average particle size distribution between 100 and 200 nm and containing 6 wt.% SiO2, were milled using a Spex 8000 vibratory ball mill for 4 h. Then, surface modification of the Fe3O4@SiO2 nanocomposites was performed using 3-aminopropyl triethoxysilane, followed by methoxypoly(ethylene glycol) N-succinimidyl ester (PEGylation) to enhance biocompatibility and stability in an aqueous medium. In ˇ ´ kova´ et al.46, zinc sulfide coated with another study published by Bujna chitosan nanocomposites were fabricated by a wet ultrafine milling process in the presence of powdered chitosan (310375 kDa) and water. The asobtained nanocomposites demonstrated high positive zeta potential (157 mV), stability in suspension without aggregation, and highly intense visible color in the various cancer cell lines in fluorescence microscopy.

7.3 Surface modification Generally, nanocomposites for biomedical applications should feature some crucial properties, which are desired particle size, appropriate coating, the potential for surface modification, nontoxicity, stability in a biological medium, biodegradability, biocompatibility, and desired magnetic properties.7375 However, all of these features cannot be supplied by simply bare nanocomposites. In particular, magnetic nanocomposites and hydrophobic surfaces on the nanocomposite tend to form aggregate structures due to magnetic attractions and high surface area to volume ratio, causing occlusion of the arteries and thereby dysfunction of mechanisms necessary to biological applications.76 In order to overcome these challenges, and to provide desired features necessary for further functionalization, the surface of nanocomposites should be coated with organic or inorganic structures such as chitosan, dextran, polyethylene glycol (PEG), polyethyleneimine (PEI), polyvinyl alcohol (PVA), oleic acid, oleylamine, folic acid, citric acid, vitamin C, silica, and gold. As seen in Fig. 7.13, these coating agents can be linked to the surface of nanocomposites in different physical forms such as a secondary phase layer, long-chain structure, sparse organic polymer structure, and by encapsulation,77 connected to the surface of the nanocomposite via a variety of ionic and electrostatic interactions, covalent interaction, and secondary interactions. Covalent interaction and encapsulation are the most appropriate modes for surface coating strategies because both enable minimum coating loss and related cytotoxicity.73 Various types of surface modification

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FIGURE 7.13 Surface modification of nanocomposites as (A) secondary phase layer, (B) long-chain structure, (C) sparse organic polymer structure, and (D) by encapsulation.

used in preparing nanocomposites are shown in Table 7.2, and some literature examples are briefly discussed. Chitosan is a natural polymer, which is hydrophilic, biodegradable, nonantigenic, and biocompatible; chitosan and its derivatives have been widely used in biomedical applications due to their abundant natural occurrence and their possession of functional groups. Chitosan features repeating functions such as amine and (two) hydroxyl groups that can lead to the strong attachment of chitosan to particle surfaces.74,75,77 Sun et al.78 reported the synthesis of pH-sensitive ZnO/carboxymethyl cellulose/chitosan nanocomposites for 5-fluorouracil delivery to colonic cancer. Since carboxymethyl cellulose can disintegrate in intestinal fluid and cause burst drug release, ZnO particles in carboxymethyl cellulose beads were coated with chitosan via a self-assembly method. The electrostatic interactions between the negative charge of carboxymethyl cellulose and a positive charge of the chitosan produce a pHsensitive structure as a drug delivery vehicle. Another study related to chitosan modification was performed by Guo et al.79 for application in binary photothermal and immunocancer therapy. CuS particles were coated with thiolated chitosan, followed by conjugation with oligodeoxynucleotides containing cytosineguanine (CpG) motifs. In these “hollow CuS-chitosan-CpG” nanocomposites, chitosan enabled the bonding of the CpG to hollow CuS particles via a disulfide bond. Another example of a natural polymer is dextran, which consists of α-1,6-glycosides with small α (1,3) branches with molecular weights ranging between 10,000 and 40,000 Da.99 Dextran and its derivatives are commonly used as coating agents for both magnetic particles100,101 and nonmagnetic particles102,103 as they are biocompatible, nontoxic, highly hydrophilic, biodegradable polymers.104 As an example of dextran modification, Kumar et al.86 reported the preparation of fluorescein isothiocyanate (FITC)-dextran entrapped and silica-coated gadolinium oxide nanocomposites synthesized via microemulsion method for application in fluorescence and MRI. Dextran acted as a bridge or intermediate bonding

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TABLE 7.2

Modification

The various surface modifications used in preparing nanocomposites. Functional nanocomposite

Application

Benefits of surface modification

References

Chitosan

pH-sensitive ZnO/ carboxymethyl cellulose/chitosan

Drug delivery

To prevent burst drug release and disintegration of the drug in the intestinal fluid

[78]

Chitosan

Hollow CuS-chitosancytosineguanine (CpG)

Combinatorial photothermal and immunocancer therapy

To provide bonding of CpG to hollow CuS particles

[79]

Chitosan

Chitosan-coated layered clay montmorillonite

Drug delivery

To control drug release and improve therapeutic efficacy

[80]

Chitosan

Chitosan-loaded GdDTPA

GdNCT

To provide high accumulation around cancer cells

[81]

PEG and folic acid

PEG-folic acidmodified and doxorubicin-loaded MnFe2O4

Chemohyperthermia therapy

To prevent particle aggregation and increase the cellular uptake (PEG) To provide overexpression on the cancer cells (folic acid)

[82]

PEG and Au

Graphene oxide-iron oxide-Au-PEG

Bioimaging and photothermal therapy

To provide high stability in the physiological medium and negligible in vitro toxicity (PEG), and photothermal therapy agent (Au)

[83]

(Continued)

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TABLE 7.2 (Continued) Benefits of surface modification

Functional nanocomposite

Application

PEG

PEG-coated mesoporous ZnO@Fe2O3

Targeted chemophototherapy

To increase colloidal stability and cytocompatibility

[84]

Poly(ethylene glycol)-blockpoly(2-(N,Ndiethylamino) ethyl methacrylate) (PEG-bPAMA)

PEG-b-PAMA/ Gd@C82

GdNCT

To enable the dissolution of nanocomposite in water

[85]

Dextran

FITC-dextran entrapped and SiO2coated Gd2O3

Fluorescence imaging and MRI

A bridge or intermediate bonding agent to entrap FITC in nanocomposite

[86]

Dextran and folic acid

DOX/Fe3O4/BSADEX-FA (folic aciddextran-coated, doxorubicin, and Fe3O4-loaded albumin)

Drug delivery and MRI

For high circulation time in blood and excellent dispersibility (dextran) To provide overexpression on the cancer cells (folic acid)

[87]

Dextran

Aminodextrancoated Fe3O4graphene oxide

MRI

To form amide bonds on the surface of graphene oxide, and to enhance biocompatibility and biodegradability

[88]

PEI and folic acid

Pal-PEI-FI-FA (fluorescent and polyethyleneiminefolic acid-modified palygorskite)

Cancer drug targeting and fluorescent imaging

A bridge for bonding other molecules on the particle surface (PEI) To provide accurate cancer cell targeting and detection (folic acid)

[89]

Modification

References

(Continued)

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TABLE 7.2

Modification

(Continued) Functional nanocomposite

Application

Benefits of surface modification

References

PEI

Polyethyleniminebased iron oxide

MRI

To prevent aggregation and to prepare highly soluble composite

[90]

PEI

SiO2/Gd-DTPAPolyethylenimine (polyethyleniminegadopentetate dimeglumine-coated silica)

MRI

To bind gadopentetate dimeglumine on the silica surface

[91]

PEI, BSA, and folic acid

PMOs-DOX@MoS2PEI-BSA-FA (doxorubicin-loaded and bovine serum albumin-folic acidMoS2-modified periodic mesoporous organosilica)

Chemophotothermal therapy

To bind MoS2 on the particle surface (PEI) To attach folic acid on the particle (BSA) To specifically target tumor cells (folic acid)

[92]

PVA

Doxorubicinencapsulated and PVA-coated hydroxyapatite

Drug delivery

To control doxorubicin release, enhance the mechanical properties of hydroxyapatite particles, and encourage scaffold formation

[93]

Silica

Fe3O4/SiO2/Gd2O (CO3)2

MRI

To prevent the magnetic coupling between Fe3O4 and Gd2O(CO3)2

[94]

(Continued)

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TABLE 7.2 (Continued)

Modification

Functional nanocomposite

Application

Benefits of surface modification

References

Au, PEG, and folic acid

Au-coated, and PEG and folic acidmodified single-walled carbon nanotubes

Cancer imaging and photothermal therapy

A photothermal therapy agent (Au) To ensure stabilization in various physiological environments (PEG) and selective cancer cell labeling (folic acid)

[95]

Au, dopamine, and hyaluronate

Au and doxorubicinloaded and dopamine and hyaluronatemodified hollow silica

Drug delivery and photothermal therapy

To enhance the photothermal effect (Au and dopamine) To enhance active tumor targeting ability (hyaluronate)

[96]

Folic acid

Folic acid-BPO4

BNCT

To improve treatment effectiveness

[97]

Folic acid

Folate-functionalized boron nitride nanotubes

BNCT

To enhance selective targeting

[98]

FITC, Fluoroscein isothiocyanate

agent to entrap FITC in the nanocomposite. In vitro cell viability studies indicated that these nanocomposites were biocompatible and nontoxic over normal and cancer cell lines. Chen et al.88 developed a synthesis method for amino dextran-coated Fe3O4-graphene oxide nanocomposites for MRI application. In this study, oleic acidfunctionalized Fe3O4 nanoparticles with uniform spherical morphology and particle size of 5 nm were first prepared by the thermal decomposition method, followed by ligand exchange, where oleic acid residues on the surface were exchanged with amino dextran. Aminodextran-coated Fe3O4 particles were conjugated to the graphene oxide via the coupling reaction between amine groups of amino dextran and carboxylic acid groups of the graphene oxide. Amino dextran was selected as it not only enables the formation of amide bonds to the surface of graphene oxide but also features high biocompatibility and biodegradability.

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PEG is the other polymer generally utilized in surface modification, and it is a synthetic, hydrophilic, biocompatible polymer suitable for bonding different types of molecules to the particle surface.74,105,106 PEG-coated particles can circulate for a long time in the blood compared to uncoated particles.73 Shah et al.82 prepared PEG-folic acid-modified and doxorubicin-loaded MnFe2O4 nanocomposites with an approximate diameter of 22 nm for targeted chemo-hyperthermia in cancer treatment. After MnFe2O4 particles were prepared via the coprecipitation technique, their surface was coated with PEG to prevent particle aggregation and promote cellular uptake, followed by attachment of folic acid to provide overexpression on the cancer cells. A magnetic fluid containing the nanocomposites in phosphate buffer saline (PBS) displayed a temperature increase from 25 C to 45 C in about 22 min under an alternating magnetic field, an appropriate temperature for localized hyperthermia treatment of cancer. In another study, graphene oxide-iron oxide-Au-PEG nanocomposites were fabricated via the formation of iron oxide on the surface of graphene oxide with subsequent attachment of gold seeds using polyethyleneimine (PEI) and final conjugation of lipoic acidmodified PEG to the graphene oxide-iron oxide-Au nanocomposite.83 The rationale for the use of the PEG coating in this study was to provide high stability in the physiological medium and for its negligible in vitro toxicity. PEI is another synthetic polymer, which has been used as a coating agent due to its possessing a positive charge and its available variety of linear or branched forms. Compared to other polymers, PEI is relatively toxic and nonbiodegradable, but it can be utilized to deliver DNA and RNA owing to binding ability.73,77 An example study related to PEI modification was reported by Han et al., who fabricated fluorescent palygorskite polyethyleneimine nanocomposites for cancer cells. Palygorskite, a hydrated magnesium aluminum silicate, was grafted with PEI through the coupling grafting method to enable further modification like fluorescein isothiocyanate and folic acid through amine groups. It was observed that the obtained nanocomposites with specific surface area of 237.7 m2 g21 showed no toxic effects up to 300 μg mL21 concentration over HeLa cells and folic acidconjugated nanocomposites had two times higher HeLa cell uptake than nonconjugated nanocomposites, which verified overexpression via folate receptors.89 PVA, or poly(vinyl alcohol), is another example of a synthetic polymer used in biomedical applications due to its biocompatibility and water solubility, and it allows the formation of monodispersed particles and prevents aggregated particle aggregation.74,77 As an illustrative example, Ghosh et al.93 synthesized doxorubicin-encapsulated and PVA-coated hydroxyapatite nanocomposites to treat osteosarcoma-affected bone tissues. Hydroxyapatite particles having a width of 1012 nm, a length of 2535 nm, and Ca/P molar ratio of 1.67 were prepared by an in situ precipitation method. Doxorubicin was then loaded onto the hydroxyapatite particles. In order to control the release

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of doxorubicin, to enhance the mechanical properties of the hydroxyapatite particles, and to encourage scaffold formation, the drug-loaded particles were coated with PVA by a solution-based chemical method. Cytotoxicity studies demonstrated that doxorubicin-encapsulated and PVA-coated hydroxyapatite nanocomposites had higher cytotoxicity toward osteosarcoma cells (MG 63) than doxorubicin-encapsulated hydroxyapatite nanocomposites after 48 h, which was proposed to be a result of the mechanism of cellular uptake. Silica (SiO2) has been widely utilized as an inorganic shell coating material due to its ability to provide excellent biocompatibility, dispersibility, colloidal stability, and chemical stability. Besides, silica-coated particles can easily be modified for diagnosis and treatment applications with functional groups such as folic acid,107 fluorescent molecules,59,108 and Au containing molecules109,110 owing to their surface silanol moieties.74,76,111 In 2015 Yang et al.94 reported the fabrication of Fe3O4/SiO2/Gd2O(CO3)2 nanocomposites for use as T1 and T2 dual-mode agents in MRI applications. First, Fe3O4 nanoparticles having particles size of nearly 12 nm and saturation magnetization value of 56 emu g21 were prepared by thermal decomposition and then coated with various thicknesses (8, 16, and 20 nm) of silica shell, thus preventing magnetic coupling between Fe3O4 as T2 agent and Gd2O(CO3)2 as T1 agent (Fig. 7.14A and B). The second shell layer (Gd2O(CO3)2) of 1.5 nm thickness was grown on the surface of Fe3O4/SiO2. As seen in Fig. 7.14C and D, the magnetic coupling between the T1 layer and T2 layer could be regulated, and appropriate T1 and T2 signals were observed when the thickness of the silica layer was increased from 8 to 20 nm. Another study related to silica modification carried out by Jain et al.112 describes the development of cerium-doped gadolinium aluminum garnet (Gd2.98Ce0.02Al5O12) nanocomposites for simultaneous imaging and photodynamic therapy of cancer cells. Gd2.98Ce0.02Al5O12 particles with an average size of 74 nm were synthesized via the solgel method, coated with a silica layer with a thickness of 18 nm, then modified with rose bengal (4,5,6,7-tetrachloro-20 ,40 ,50 ,70 -tetraiodofluorescein) as a photosensitizer. In order to effectively load rose bengal on the surface of cerium-doped gadolinium aluminum garnet particles, the surface of these particles was coated with a mesoporous silica layer. Under low X-ray energy (55 kV), the developed nanocomposites generated higher singlet oxygen levels than rose bengal alone, which indicated the nanocomposite could be a promising candidate for photodynamic therapy application. Additionally, the nanocomposite could be utilized as a T1 contrast agent because of the paramagnetism of gadolinium(III). As one of the most commonly used inorganic modification materials, gold (Au) has attracted significant attention for having an unusual property known as surface plasmon resonance (SPR) absorption113 as well as high stability, biocompatibility, and ease of binding to various

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FIGURE 7.14 (A) Schematic and TEM image of Fe3O4/SiO2/Gd2O(CO3)2 nanocomposite, (B) TEM images of different silica thickness on the nanocomposites, (C) T1- and (D) T2-weighted MR images and their color-coded images of Fe3O4/SiO2/Gd2O(CO3)2 nanocomposite with varying SiO2 thickness by using 3T MRI. Source: Reproduced with permission from Yang, M.; Gao, L.; Liu, K.; Luo, C.; Wang, Y.; Yu, L.; Peng, H.; Zhang, W. Characterization of Fe3O4/SiO2/Gd2O(CO3)2 Core/Shell/Shell Nanoparticles as T1 and T2 Dual Mode MRI Contrast Agent. Talanta 2015, 131, 661665. Copyright 2015, Elsevier.

functional groups.74,77 Plasmonic properties of Au have been utilized in diagnosis, detection, and cancer photothermal therapy.110 As an example, Wang et al.95 developed Au-coated, PEG, and folic acidmodified single-walled carbon nanotubes (SWNTs) for cancer imaging and treatment. SWNTs functionalized with single-strand DNA and cationic polymer to facilitate the Au bonding on the surface were decorated with small (4050 nm) gold seeds by in situ solution-phase synthesis. Then PEG and folic acid were attached to the nanocomposite surface in order to confer stability in various physiological environments and selective cancer cell labeling, respectively. PEG and folic acidmodified SWNT-Au nanocomposites displayed the photothermal effect to destroy cancer cells due to sufficient SPR of the decorated gold seeds. As an additional example, the facile synthesis of Au and doxorubicin-loaded and dopamine- and hyaluronate-modified hollow silica nanocomposites for tumor targeting and photothermal therapy applications were reported by Seo et al.96 In this study, the nanocomposite increased the temperature up to 48 C and Auhyaluronate and Au-dopamine indicated nearly the same temperature

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value (30 C) within 100 s under NIR laser irradiation. The combination of Au and dopamine in the nanocomposite resulted in a synergistic effect, which contributed to the enhancement of the photothermal properties. Furthermore, the nanocomposite exhibited superior endocytosis with cancer cells without any cytotoxicity.

7.4 Cancer diagnosis and treatment applications of functional nanocomposites Ongoing research has led to significant advances in early cancer detection and treatment, as evidenced by high 5-year survival rates (nearly 90%). As part of this, functional nanocomposites have recently garnered tremendous scientific interest for biomedical applications, in particular cancer treatment and diagnosis.114 In this section, we discuss the potential applications of functional nanocomposites in cancer diagnoses such as MRI, FI, and cancer treatments such as NCT, hyperthermia, photodynamic therapy, and drug delivery.

7.4.1 Magnetic resonance imaging MRI is one of the most effective diagnostic techniques, relying on the precession of protons in an applied magnetic field. MRI offers the advantages of high 3D resolution and atomic contrast, noninvasiveness, and the use of nonionizing radiation compared to other imaging techniques such as CT, PET, single-photon emission computed tomography, and ultrasonography.115,116 MRI has been used in hospitals around the world since the FDA (Food and Drug Administration) permitted its clinical use in 1985, and the Nobel Prize in Medicine (2003) was awarded to Paul Lauterbur and Sir Peter Mansfield for their studies on MRI.117 In order to produce MR imaging of the human body, protons are the nuclei employed due to their particular magnetic properties and to their abundance in water and fat molecules. The basic mechanism of MRI involves the alignment of unpaired magnetic spins in a strong external magnetic field, returning to the original state by a relaxation process divided into T1 (longitudinal) and T2 (transverse) relaxation of spins after application of radio frequency (excitation) and the formation of images depending on the relaxation time contrast of different tissues.18,76 The contrast difference is insufficient owing to the very small structural differences between healthy and diseased tissues, and therefore, it is difficult to discern the differences in tissues using MRI. Contrast agents, which increase the signal contrast between healthy and diseased tissues, have been used in order to overcome this problem.118 Commercially, superparamagnetic iron oxide as a

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negative T2 agent and chelates of Mn21 and Gd31 as positive T1 agents have been widely used in clinical applications.118 In recent years, various inorganic-based nanocomposites possessing single-mode or dual-mode properties have been developed to provide more accurate diagnostic imaging.119124 For instance, in 2019, Pinho et al.125 reported on Gd- and Eucomplex-loaded γ-Fe2O3@SiO2 nanocomposites as promising candidates for T1 and T2 agents in MRI and optical imaging agents. These nanocomposites were highly dispersed in water for at least 24 h owing to their negative zeta potential. Gd-complex-loaded γ-Fe2O3@SiO2 nanocomposites (r1: 27.2 mM21 s21 vs [Gd]) and Gd-Eu-complexes-loaded γ-Fe2O3@SiO2 nanocomposites (r1: 38.8 mM21 s21 vs [Gd 1 Eu]) exhibited high r1 values compared to Gd complex (r1: 6.5 mM21 s21 vs [Gd]) because of the facile interaction of the Gd complex in the silica shell with water molecules and the slow tumbling rate of nanocomposites. As T2 contrast agents, r2 values of Gd-complex-loaded γ-Fe2O3@SiO2 and Gd-Eu-complex-loaded γ-Fe2O3@SiO2 decreased from 89 to 77.8 and 44.6 mM21 s21 (vs [Fe]), respectively, but they still showed high r2/r1 values. Besides, Gd-Eucomplexes-loaded γ-Fe2O3@SiO2 nanocomposite showed no cytotoxicity toward HeLa cells up to 62.5 μg mL21 concentrations. Another exciting study including the design of manganese oxidebased multifunctionalized (PEGylated and FITC grafted) hollow silica nanocomposites for pHsensitive T1 contrast agent and drug delivery platform use was carried out by Chen et al.126 Since the manganese oxide particles were soluble at weakly acidic pH, these multifunctional nanocomposites exhibited a relaxation rate r1 of 8.81 mM21 s21, 11 times greater than that observed at neutral pH. In another study published by Lu et al.,127 clustering nanocomposites formed by encapsulation of manganese-doped superparamagnetic iron oxide particles with amphiphilic diblock copolymer methoxy poly(ethylene glycol)-b-poly(3-caprolactone) (mPEG-b-PCL) was utilized as a contrast agent in MRI. Superparamagnetic iron oxide particles were not used as T1 agents, but they contributed to the enhancement of proton relaxation by shortening MR T2 relaxation times. As seen in Fig. 7.15A and B, the clustered nanocomposites possessed a particle size of approximately 80 6 30 nm and a saturation magnetization of 65 emu g21. These nanocomposites supported the growth of mouse macrophage cells (Raw 264.7) and human hepatocarcinoma cells (HepG2) without any cytotoxicity (Fig. 7.15C). Besides, in vivo MRI studies demonstrated that these nanocomposites inside micelles caused significant contrast increases 5 min after intravenous application, and these contrast changes could still be observed after approximately 36 h (Fig. 7.15D and E). As another example of an MRI application, Lu et al.128 reported the development of novel multifunctional NaGdF4:Dy@PDA-PEG-FA nanocomposites (PDA: polydopamine) for MRI agent and CT imaging-guided photothermal therapy. Respectively, longitudinal relaxivity (r1) and transverse

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FIGURE 7.15 (A) TEM image, (B) the hysteresis loop measured at 300K of Mn-doped superparamagnetic iron oxide particleloaded micelles, (C) cytotoxicity test of Mn-doped superparamagnetic iron oxide particleloaded micelles with different cell lines, (D) mouse liver T2-weighted TSE images after application of Mn-SPIO micelles, and (E) average values of relative signal intensity. Source: Reproduced with permission from Lu, J.; Ma, S.; Sun, J.; Xia, C.; Liu, C.; Wang, Z.; Zhao, X.; Gao, F.; Gong, Q.; Song, B. Manganese Ferrite Nanoparticle Micellar Nanocomposites as MRI Contrast Agent for liver imaging. Biomaterials 2009, 30, 29192928. Copyright 2009, Elsevier.

relaxivity (r2) values of this nanocomposite were 1.27 mM21 s21 (which was lower than the values for CTX-NaGdF4:Ho31 and Gd-DTPA owing to the presence of PDA shell) and 126.0 mM21 s21, which was comparable with values for superparamagnetic iron oxide particles. Furthermore, NaGdF4: Dy@PDA-PEG-FA nanocomposites demonstrated significant cytotoxicity against 4T1 (mouse breast cancer) cells thanks to the photothermal effect under 808 nm irradiation.

7.4.2 Fluorescence imaging FI has become a powerful tool for early stage cancer cell screening. It provides a noninvasive, selective, real-time, and more cost-effective way to diagnose cancerous or precancerous lesions in many locations.129,130 The basic principle of FI is based on the absorption of light by

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fluorescent agents at a specific wavelength, then the emission of light at lower energy within a short time period (0.520 ns) and detection of these emitted photons by charge-coupled devices or photomultiplier tubes, resulting in the formation of the image. In recent years, the combination of nanoparticles with various fluorescent agents such as fluorescent dyes131 (the most common are coumarin, fluorescein, Alexa Fluor, and cyanine),132136 quantum dots,137 metallic nanoparticles,138 and fluorescent proteins139 has increased the scope of the FI technique.140142 FI can also be employed in real-time to guide treatments such as hyperthermia, photodynamic therapy, or chemotherapy to improve the accuracy of location for in vitro and in vivo situations.143145 As one example of FI of cancer cells, fluorescein isothiocyanatedoped silica and folic acidmodified gadolinium borate and iron oxide nanocomposites (FA/FITC-SiO2/GdBX/Fe3O4) were prepared by Icten et al.59 for multifunctional applications involving FI, MRI, and NCT. Fluorescence microscopy images of a control sample, FA/FITC-SiO2/GdBX/Fe3O4, FA/FITC-SiO2/GdBX/PEG1500/Fe3O4, and FA/FITC-SiO2/GdBX PEG400/Fe3O4 showed that after MIA-PaCa-2 cells were incubated with these samples at 10 μg mL21 concentration for 24 h, green emission from FITC in nanocomposites was clearly observed in contrast to the control sample, as seen in Fig. 7.16A. Dotplot analysis of samples related to fluorescence intensity (Fig. 7.16B) also provided information about cell-size using side forward scatter measurement (FSC) and cell-granularity related to side scatter (SSC) measurement of cells after incubation. In the dot-plot analysis, while FSC height along the x-axis remained essentially constant, SSC height increased for MIA-Pa-Ca-2 cells incubated with the test samples, indicating the uptake of the samples into the cells. Zhou et al.146 prepared silica-coated Gd2O3:Yb31,Er31 nanocomposites for MRI and FI in in vivo and in vitro studies. HeLa cells labeled with silica-coated Gd2O3:Yb31,Er31 nanocomposites exhibited high NIR to visible upconversion fluorescence intensity under an inverted fluorescence microscope after incubation for 2 h. The nanocomposites showed red upconversion fluorescence at all applied positions, and the fluorescence was still observed at the injection depth of 5 mm. Additionally, these nanocomposites could be utilized as T1 contrast agents to enhance the r1 relaxivity of water protons by gadolinium. Another critical study performed by Jiang et al.147 illustrates multiple applications for Au@mesoporous SiO2/rhodamine B isothiocyanate nanocomposites, such as FI, photocontrolled drug release, and photothermal therapy. In the cell imaging study, HepG2 cells (human hepatocellular carcinoma) incubated with nanocomposite at 150 μg mL21 for 12 h displayed bright fluorescence intensity from rhodamine B isothiocyanate under 488 nm laser excitation as a result of the penetration of the nanocomposite into

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FIGURE 7.16 (A) Fluorescence microscopy images and (B) dot-plot analysis of MIAPa-Ca-2 cells incubated with 10 μg mL21 concentration samples (Sample 1: FA/FITC-SiO2/ GdBX/Fe3O4; Sample 2: FA/FITC-SiO2/GdBX/PEG1500/Fe3O4; Sample 3: FA/FITC-SiO2/ GdBA/PEG400/Fe3O4). Source: Reproduced with permission from Icten, O.; Kose, D.A.; Matissek, S.J.; Misurelli, J.A.; Elsawa, S.F.; Hosmane, N.S.; Zumreoglu-Karan, B., Gadolinium Borate and Iron Oxide Bioconjugates: Nanocomposites of Next Generation with Multifunctional Applications. Mater. Sci. Eng. C 2018, 92, 317328. Copyright 2018, Elsevier.

the cell membrane. Besides, these nanocomposites possessed low cytotoxicity toward HepG2 cells even at high concentrations (0.2 mg mL21) after incubation for 24 h. In this study, confocal laser scanning microscopy coupled with an 808 nm laser was used for the first time to simultaneously monitor photothermal therapy, drug release, and cell position and viability. Likewise, Sun et al.148 demonstrated the preparation and applications in immunolabeling and fluorescent imaging of antiCEACAM8-conjugated Fe3O4/CdTe magnetic/fluorescent nanocomposites. The anti-CEACAM8 antibody was bound on the Fe3O4/CdTe surface to enable specific coupling with the CEACAM8 receptor on the HeLa cell membrane. While single HeLa cells displayed no fluorescence intensity under 488 nm excitation, the same cells treated with antiCEACAM8-conjugated nanocomposites showed fluorescence, indicating that the cells had been successfully labeled with the antibodyfunctionalized nanocomposites.

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TABLE 7.3 Nucleus

Neutron capture cross-section values of selected nuclei. Neutron capture cross-section values (barn: 10224 cm2)

16

0.00019

12

0.0035

1

0.333

O C

H

14

1.83

10

3840

N B

157

Gd

313

254,000

7.4.3 Neutron capture therapy NCT is a potential cancer therapy utilizing neutron radiation and neutron capture agent components. In NCT, an external neutron beam of relatively low energy (thermal neutron: less than 0.4 eV or epidermal neutron: between 0.4 and 10 keV) is applied to the tumor then the highenergy particles generated by a neutron capture reaction kill the cancer cells while sparing healthy cells. Neutron capture cross-section values of significant elements are given in Table 7.3. As seen in this table, O, C, H, and N in healthy tissues have low cross-section values, while 10B and 157Gd isotopes have high cross-section values. For this reason, 10B (for BNCT) and 157Gd (for gadolinium neutron capture therapy, GdNCT) are the isotopes commonly used as NCT agents.149,150 BNCT is a binary cancer treatment method associated with the nuclear reaction between the 10B isotope and thermal neutrons, as seen in the following reaction: 10

B 1 nthermal ð0:025 eVÞ-11 BT-4 He21 ð1:78 MeVÞ1 7 Li31 ð1:01 MeVÞ 1 2:79 MeV ð6%Þ -4 He21 ð1:47 MeVÞ1 7 Li31 ð0:84 MeVÞ 1 2:31 MeV ð94%Þ

In this reaction, the 10B isotope is irradiated with thermal neutrons to initially form an unstable, excited state 11B nucleus that decays to produce a high-energy 4He21 (α-particle) and a 7Li31 ion. These particles have high linear energy transfer (LET) properties, approximately 49 μm in tissues, which is smaller than the cell diameter.151,152 Therefore the α-particles and lithium ions destroy the surrounding cancer cells. The effective 10B dose is approximately 35 μg of 10B per gram of tissue or 1019 10B atoms per cell.153,154 The actual BNCT agents used in clinical studies are boronophenylalanine (BPA) and sodium borocaptate (BSH), but even these agents have a low 10B tumor/blood, and tumor/tissue

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ratio.154 Recent research has focused on increasing the numbers of clinically applicable nanocomposite agents, with high 10B content and which can be effectively transported to the tumor cells for BNCT applications.97,98,154157 GdNCT is the other type of NCT, in which 157Gd is used as an agent instead of 10B as it possesses an even higher neutron capture cross-section, approximately 65 times greater than the boron-10 isotope. The GdNCT reaction is more complex than that for BNCT, as shown in the following reaction151: Gd 1 nthermal -158 GdT-158 Gd 1 γ 1 7:94 MeV ð1Internal conversion electrons 1 Auger-Coster-Kronig ðACKÞ electronsÞ 157

In this process, after 157Gd is irradiated with thermal neutrons, the excited 158Gd nucleus emits internal conversion (IC) electrons and Auger-Coster-Kronig (ACK) electrons, together with X-ray and photon emissions.158 Auger and IC electrons are the most biologically effective among these particles for killing cancer cells because of their high LET, averaging 0.3 MeV m21.159 According to the results of the published studies, the optimal dose of 157Gd in tumors for GdNCT should be 50200 μg 157Gd g21 tumor tissue since neutron fluence rapidly decreases in the depth of tumors because of the high absorption of neutrons by Gd atoms.160 The well-known Gd(III) MRI contrast agents such as Gd-DTPA (gadolinium diethylenetriamine penta-acetic acid) and Gd-DOTA (gadolinium tetraazacyclododecane tetraacetic acid) have also been used for GdNCT applications.151,161 GdBNCT, using a combination of 157Gd and 10B, provides some advantages for potential applications in NCT. For example, boron can form stable bonds with C, H, and N atoms enabling easy attachment to an NCT agent. On the other hand, GdNCT may more extensively affect tumors than BNCT owing to its high thermal neutron capture capability. 157Gd also offers the possibility to perform simultaneous therapy during neutron irradiation because it has been used as an MRI diagnostic agent.149 However, it should be administered with at least an optimal ratio of 3 (157Gd to 10B) for simultaneous GdNCT and BNCT applications.162 Agents including both 157Gd and 10B, such as a tethered closocarborane cage bonded to Gd-DTPA or Gd-DOTA-monoamide chelates, have been developed for combined BNCT and GdNCT.163 In a study related to BNCT, Zhu et al.154 designed ortho-carboranemodified and starch-coated magnetic nanocomposites using a click reaction. The results indicated that in an external magnetic field (1.14 T), nanocomposites accumulated in cancer cells by providing 51.4 μg boron g21 tumor ratio, and the tumor/normal cell boron content ratio of almost 10/1. In another study, Ciofani et al.98 reported the application of quantum dot (Qdot 605 ITK) and folate-functionalized boron nitride

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nanotube composites. In vitro biological studies performed using glioblastoma and fibroblast cell lines showed that there was effective uptake of the functionalized boron nitride nanotubes by glioblastoma cells, but not by fibroblast cells, suggesting that these functionalized nanotubes may be potential candidates for boron delivery in BNCT. Self-assembled carborane derivativemodified gold nanocomposites were used by Wang et al.155 for bioimaging of boron delivery to cancer cells to enhance the BNCT effect. After various cancer cells such as HeLa and U87, as well as L02 normal cell lines were incubated with these nanocomposites at different concentrations between 1.5 and 15 μg mL21 for 48 h, these cells showed greater than 85% survival rates. Furthermore, SEMEDS analysis was performed to determine the content of boron in the cancer cells (HeLa). While HeLa cells incubated with the carborane derivate alone contained 1.96% boron, those incubated with carborane derivativemodified gold nanocomposite had a 6.98% boron content, an effective dose for BNCT application, and verified the high accumulation of boron in the cancer cells achievable via passive tumor targeting. In another study, Achilli et al.97 reported folic acid-BPO4 nanocomposites as a novel boron delivery agent for BNCT. Bare BPO4 particles led to a decrease in cell viability of up to 15% at 20 μg mL21 concentration after 18-h incubation, but no toxicity was seen for the folic acidfunctionalized particles. Additionally, folic acidfunctionalized BPO4 had a favorable effect on cell viability at low concentrations. The development of new gadolinium-bearing agents has also attracted significant attention by researchers owing to its high neutron capture cross-section.81,85,164168 For instance, Mi et al.165 reported the use of calcium phosphate-Gd-diethylenetriaminepentaacetic acid nanocomposites (Gd-DTPA/CaP) for MRI and GdNCT. Gd-DTPA/CaP preferentially accumulated in the cancer cells after intravenous application, and the quantity of Gd-DTPA/CaP in the cancer cells rose from 2.2% to 3.9% over a 7-h period (from 3 to 10 h), with this accumulated level being retained after 24 h. After intravenous injection of samples in C26 tumor-bearing mice and thermal neutron irradiation, tumor volume for those treated with Gd-DTPA/CaP showed no change until day 12, but tumor volume for those treated with Gd-DTPA increased over 10-fold compared to the control group, indicating that CaP was central to the effective delivery of Gd-DTPA to tumor tissues and high uptake by cancer cells. Similarly, tumor size effectively decreased after Gd-DTPA/ CaP injection and irradiation compared with other groups. A similar study related to the use of Gd-DTPA with chitosan carrier for GdNCT was carried out by Fujimoto et al.81 The results obtained from comparison experiments indicated that chitosan-loaded Gd-DTPA resulted in higher accumulation than commercial Gd-DTPA in the tumor cell pellets (malignant fibrosis histiocytoma cells), and the gadolinium levels

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FIGURE 7.17 (A) Size distribution of gadolinium oxide core and polysiloxane shell nanocomposite, (B) confocal microscopy image and T1-weighted images of EL4 cells after incubation with/without nanocomposites, the temporal evolution of bioluminescence intensity ratios of cells (I/I0) after thermal neutron irradiation at (C) 1 Gy, (D) 2 Gy, and (E) 3 Gy (Gd concentrations, mM; 0 5 ’, 0.01 5 K, 0.05 5 ▲,0.1 5 ▼and 0.3 5 V). Source: Reproduced with permission from Bridot, J.-L.; Dayde, D.; Rivie`re, C.; Mandon, C.; Billotey, C.; Lerondel, S.; Sabattier, R.; Cartron, G.; Le Pape, A.; Blondiaux, G. Hybrid Gadolinium Oxide Nanoparticles Combining Imaging and Therapy. J. Mater. Chem. 2009, 19, 23282335. Copyright 2018, RSC.

were 30.5 and 9.5 μg, respectively. However, commercial Gd-DTPA showed a greatly reduced T1 value (327 ms) in comparison to the control (630 ms), while the higher accumulation of the chitosan-loaded GdDTPA apparently had a negative effect on MRI enhancement, with a T1 value of 400 ms. Bridot et al.164 also reported that multifunctional encapsulated gadolinium oxide nanocomposites (polysiloxane shell containing rhodamine B isothiocyanate and PEG layer) could be a potential candidate for an MRI and GdNCT agent. Uptake of the nanocomposites by EL4 (mouse T cell leukemia) cells was verified via fluorescence microscopy showing the characteristic red emission of rhodamine B isothiocyanate (Fig. 7.17A and B) and T1-weighted picture of EL4 cells incubated in the presence of the nanocomposite displayed a brighter image compared to those incubated in the absence of nanocomposite (Fig. 7.17C). The temporal evolution of bioluminescence intensity ratios of cells (I/I0) after thermal neutron irradiation at various doses such as 1, 2, and 3 Gy, where 1 Gy 5 1 J kg21 (Fig. 7.17DF) showed that this ratio remained constant until 36 h at 1 Gy and later slowly rose as a

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result of the formation of metabolic disorder affecting the proliferation, but inhibition of the cell proliferation occurred, and the cells were effectively destroyed after the irradiation at higher doses. Few studies covering the combination of boron and gadolinium NCT have thus far appeared in the literature owing to the difficulty of preparing nanocomposites containing both 10B and 157Gd isotopes. Generally, there are studies involving complex structures of Gd-DTPA or Gd-DOTA with carboranes.163,169 Icten et al.59 describe an example of a nanocomposite material designed for this purpose. In this study, a 10 μg sample of the magnetite-gadolinium borate nanocomposites containing 1015 atoms of 10B and 157Gd in the cell incubation (0.125 3 106 cancer cells), giving a calculated ratio of applied atoms/cell of approximately 1010 atoms per cell, which was 10-fold greater than required concentrations for the combination of both therapies. Furthermore, it was determined that the Gd/10B molar ratios were above 4 for all samples, which was sufficient for the simultaneous application of both NCT methods.

7.4.4 Hyperthermia The term hyperthermia is derived from the Greek “hyper” (to excess) and “therme” (heat). Hyperthermia is a promising cancer treatment method based on increasing the temperature around cancer cells.170 The appropriate temperature window is 41 C45 C, which is higher than normal body temperature, to destroy cancer cells without excessively affecting normal cells.171 Depending on the applied locality, hyperthermia can be divided into three classes, which are local (tumor only), regional (all affected tissue/organ), and whole-body (metastatic cancer cells) hyperthermia.9 The temperature increase can be supplied by various external sources such as ultrasound, radio frequency, laser, and magnetic (these methods are named ultrasound hyperthermia, radio-frequency ablation, photothermal therapy, and magnetic hyperthermia, respectively).76 Two significant parameters affecting hyperthermia therapy are the intensity of heat and the proper targeting of the heat toward the targeted region. Although promising results were obtained in early studies, it was observed that normal tissues were also damaged because of improper control of heat between normal and abnormal tissues.18 In recent years, photothermal treatment and magnetic hyperthermia have attracted more attention due to the ability to remotely control the temperature increase around cancer cells, compared to other methods utilizing, for example, laser or microwave radiation where insufficient heat is generated. In comparison with photothermal treatment that uses near-infrared radiation, magnetic

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hyperthermia can be applied to all tissues or organs thanks to the deep penetration of the external magnetic field.172175 Nevertheless, many researchers are working on the preparation of novel materials for magnetic hyperthermia76,176181 and photothermal therapy.182187 In magnetic hyperthermia, the term “specific loss power (SLP)” can be used to compare the effectiveness of different materials for hyperthermia therapy, and the term corresponds to the heat generated per particle volume. For this reason, high SLP is required to effectively destroy cancer cells at low particle concentrations. The commonly used expression of SLP is “SAR, W kg21” formulated as follows:   SAR 5 C 3 ΔT=Δt 3 1=mnp In this equation, C is the specific heat of the nanofluid, ΔT/Δt is the initial slope of the timetemperature curve, and mnp is mass of nanoparticles.76,188 It is typically necessary to apply at least 2040 W kg21 power density to create temperatures sufficiently high for hyperthermia treatment, approximately 42 C.189 In photothermal therapy, SAR (W m23) is related to the absorption cross-section and laser fluency. SAR 5 N 3 Qnano 5 N 3 Cabs 3 I where N is the number of nanoparticles per cubic meter, Qnano is the heat generated by the nanoparticle, Cabs is the absorption cross-section area of the nanoparticle (m2), and I is the laser fluency (W m22). In addition to gold nanoparticles, carbon nanotubes, fullerene, and graphenebased materials have been applied to photothermal therapy due to their sensitivity to laser light.190 Hatamie et al.191 synthesized graphene/cobalt nanocomposites, with cobalt content of 80% for hyperthermia therapy and MRI diagnosis. MTT ((3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide)) cell viability studies were carried out using L929 mouse fibroblast cells incubated at different concentrations for 24, 48, and 100 h (Fig. 7.18A). While the nanocomposites caused no significant toxicity to the L929 cells at all concentrations (between 10 and 100 μg mL21) after 24-h incubation, they started to induce toxicity after 48-h incubation (80% cell viability at 100 μg mL21 concentration) and 100-h incubation (50% cell viability at 100 μg mL21 concentration). In the hyperthermia experiments, high heat transfers were found at 350 kHz magnetic field for 0.01 and 0.005 g mL21 nanocomposite concentrations (Fig. 7.18B and C), and high SLP values were observed at lower concentration of the nanocomposite (Fig. 7.18D). Additionally, the graphene/cobalt nanocomposite may also be an appropriate candidate for use as a T1 MRI agent.

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FIGURE 7.18 (A) MTT cell viability results of L929 mouse fibroblast cells incubated with graphene/cobalt nanocomposites at different concentrations for 24, 48, and 100 h; temperaturetime curves of graphene/cobalt nanocomposites in solution under changing magnetic field at (B) 0.01 g mL21, (C) 0.005 g mL21, and (D) SLP values versus frequency at 0.01 and 0.005 g mL21 concentrations. Source: Reproduced with permission from Hatamie, S.; Ahadian, M.M.; Ghiass, M.A.; Saber, R.; Parseh, B.; Oghabian, M.A.; Shanehsazzadeh, S. Graphene/Cobalt Nanocarrier for Hyperthermia Therapy and MRI Diagnosis. Colloids Surf. B 2016, 146, 271279. Copyright 2016, Elsevier.

In another study performed by Shlapa et al.,176 (La, Sr) MnO3/SiO2 core/shell composites with a particle size of 4045 nm were developed and used in magnetic hyperthermia as an inducer. The prepared core/ shell nanocomposites increased the temperature up to 43 C45 C, sufficient for therapeutic effect in hyperthermia under a 300 kHz frequency magnetic field. The temperature level reached saturation after a defined time, which may be advantageous in preventing damage to normal cells due to overheating. These nanocomposites may, therefore, be a viable candidate as an inducer for magnetic hyperthermia applications. Daboin et al.177 described the production of silica-coated and Au@Fe3O4-modified Mn12xCoxFe2O4 nanoparticles and their use in hyperthermia investigations. When compared to SiO2-Mn12xCoxFe2O4, Au@Fe3O4-SiO2Mn12xCoxFe2O4 exhibited a high SAR value related to depending on the increase of system magnetization of Au@Fe3O4. The

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SAR values of Au@Fe3O4-SiO2-Mn12xCoxFe2O4 nanocomposites versus Mn21 content in water and hydrogel showed an increase in SAR values for x 5 00.5 ratio nanocomposites in a hydrogel and x 5 0.250.501 ratio nanocomposites in water. As a result, the highest influence on hyperthermia (SAR: 360 W g21) was observed with Au@Fe3O4-SiO2CoxFe2O4 using the hydrogel, as altering the fluid viscosity was seen to contribute to the heating efficiency. Zhou et al.183 reported the application of folic acidfunctionalized SWNT nanocomposite structures in photothermal therapy. After murine mammary EMT6 tumor cells were cultured with this nanocomposite for 12 h, no cytotoxic effect was seen toward cell viability. Furthermore, normal (FR1 ) and knockdown (FR2 ) folate receptor cells were incubated with the nanocomposites for 2 h, then irritated by a 980-nm laser for 2 min. As a result, greater cell death was observed in the FR1 cells owing to the overexpression of the folate receptor. For in vivo experiments performed using mouse tumors, the tumor area with nanocomposite (1 mg kg21) was irritated by laser for 5 min, and the surface temperature was measured as 63 C. However, when the same test was performed without nanocomposite, the surface temperature measured only 54 C. These results proved that folic acidfunctionalized SWNT nanocomposite structure could improve the efficiency of photothermal therapy. In another study, a FeWO4@Polypyrrole nanocomposite synthesized by Xiao et al.182 was used as a novel photothermal agent and displayed significant photothermal toxicity over cancer cells (HeLa). It could also be used in MRI, X-ray CT, and infrared thermal imaging as a multimodal agent.

7.4.5 Photodynamic therapy Photodynamic therapy is one of the noninvasive methods for cancer treatment. This technique possesses no significant side effects such as low selectivity, drug resistance, or normal tissue damage compared to radiotherapy or chemotherapy.192 Photodynamic therapy requires three components: (1) excitation light to supply energy, (2) photosensitizers that initiate the photodynamic therapy reaction, and (3) oxygen molecules that generate reactive oxygen species such as superoxide anions, hydrogen peroxide, and hydroxyl radicals.193 The fundamental principle of photodynamic therapy depends on the excitation of photosensitizers at a specific wavelength and the subsequent reaction of excited photosensitizers with biomolecules around related cells to form radical and radical anions (type I) or the energy transfer to singlet oxygen for the generation of triplet oxygen (type II).194,195 Singlet oxygen and free radicals have a photocytotoxic effect, leading to the destruction of cancer cells via necrosis or apoptosis (Fig. 7.19).196

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FIGURE 7.19 Jablonski diagram of photodynamic therapy. Source: Reproduced with permission from Majumdar, P.; Nomula, R.; Zhao, J. Activatable Triplet Photosensitizers: Magic Bullets for Targeted Photodynamic Therapy. J. Mater. Chem. C 2014, 2, 59825997. Copyright 2016, RSC.

Several recent studies have described the design of nanomaterials for this purpose, including useful photosensitizers such as organic species (bacteriochlorins, chlorins, phthalocyanines, xanthenes, porphyrins, anthraquinones, and cyanines)197199 and inorganic materials (quantum dots, TiO2, gold, carbon nanomaterials, and tungsten oxide).194,200202 For example, Cheng et al.199 designed the composite platform of Pd-porphyrin-modified silica particles for cancer cell treatment for photodynamic therapy. The morphology of human caucasian breast adenocarcinoma cells treated without nanocomposite showed no major change, but significant changes in the morphology were observed upon irradiation with 532 nm laser when treated with 25 μg mL21 nanocomposite for 2 h. Furthermore, cytotoxicity studies showed that the nanocomposites had a low cytotoxic effect at concentrations of 25 μg mL21 or below without irradiation, but the cell viability significantly decreased to 10% with incubation at 25 μg mL21 nanocomposite concentration for 2 h and 532 nm laser irradiation (energy dose 2.4 J cm22). As mentioned earlier in Section 7.3, Jain et al.112 developed the rose bengalloaded Gd2.98Ce0.02Al5O12@mSiO2 nanocomposite for simultaneous T1-weighted MRI and X-ray photodynamic therapy. The combination of rose bengal (as a photosensitizer) with Gd2.98Ce0.02Al5O12 particles (as a donor) in the same structure permitted high-energy fluorescence resonance energy transfer (energy transfer from donor to photosensitizer due to spectral overlap) for treatment of deep tumors using photodynamic therapy. Compared to rose bengal alone, these mSiO2 nanocomposites produced four times higher levels of singlet oxygen under 55 kV X-ray irradiation and it was observed that the viability of cancer cells incubated with the nanocomposites decreased upon

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irradiation of blue light. Moreover, these nanocomposites could be used as a T1-weighted contrast agent due to the presence of gadolinium. One of the most important factors affecting the efficacy of photothermal therapy is hypoxia (low oxygen level) in solid tumors. Hydrogen peroxide can form as an undesired metabolite under prolonged conditions of hypoxia, which can cause cancer cell mutagenesis and metastasis and the resistance of cancer cells to photodynamic therapy. The use of catalysts to form oxygen in situ inside tumors has been commonly utilized to combat solid tumor hypoxia and improve therapy efficiency. For instance, chlorin e6-linked Pd@Pt-PEG nanocomposites (Pd@PtPEG-Ce6) were produced to improve photothermal therapy by affecting the hypoxic surroundings of solid tumors. In this study performed by Wei et al.,203 Pd@Pt particles were used as catalase-like nanomaterials to react with hydrogen peroxide to produce oxygen, resulting in enhancement of the photothermal effect, as measured by levels of free Ce6 in the inert environment. As seen in Fig. 7.20A, while laser irradiation or nanocomposite alone caused no prevention of tumor growth of mice, free Ce6 irradiated with 660-nm laser and nanocomposite irradiated with 808-nm laser blocked the tumor growth in mice for up to 6 days. However, the nanocomposite inhibited the tumor growth for 12 days when irradiated with 808-nm laser owing to the effective oxygen production and accurate targeting of the nanocomposite. The nanocomposite irradiated at 660 and 808 nm led to the most effective tumor growth prevention in all groups because the photothermal influence of Pd@Pt under 808 nm laser irradiation increased cellular uptake of the nanocomposite and facilitated oxygen production inside the tumors via decomposition of hydrogen peroxide. These results were supported by the tumor images, with the most effective treatment of mice tumors being seen in the 12thday image (Fig. 7.20B). Moreover, the bodyweight of all mice in the study remained essentially constant (Fig. 7.20C). Consequently, the designed nanocomposite can be considered an appropriate candidate for improved cancer PDT. Chang et al.204 successfully prepared N-TiO2/SiO2/Fe3O4 nanocomposites for use as a photosensitizer in photodynamic therapy. The in vitro photodynamic studies demonstrated that the N-TiO2/SiO2/Fe3O4 nanocomposites provided effective photodynamic inhibition over HeLa cells when compared to TiO2 alone. This inhibition of proliferation of HeLa cells was 67.97% at 500 μg mL21 when irritated with xenon lamp with an intensity of 10 mW cm22 for 125 min.

7.4.6 Drug delivery Although conventional chemotherapy has been commonly applied to treat cancer patients, the drugs used in these treatments are nonselective,

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FIGURE 7.20 (A) Tumor volumes, and (B) body weights of mice treated under different conditions, and (C) images of tumor changes before and after treatment. Source: Reproduced with permission from Wei, J.; Li, J.; Sun, D.; Li, Q.; Ma, J.; Chen, X.; Zhu, X.; Zheng, N. A Novel Theranostic Nanoplatform Based on Pd@ Pt-PEG-Ce6 for Enhanced Photodynamic Therapy by Modulating Tumor Hypoxia Microenvironment. Adv. Funct. Mater. 2018, 28, 1706310. Copyright 2018, John Wiley and Sons.

damage healthy cells, and cause serious undesired side effects such as hair loss, loss of appetite, weight loss, and nausea and vomiting. The main reasons for these side effects are due to nonspecific drug delivery, low solubility, high-dose administration, and multiple drug resistance.18,205 Therefore novel chemotherapeutic delivery systems must be developed using various materials including inorganic particles, polymers, lipids, dendrimers, liposomes, and nanotubes in order to overcome these issues and enhance drug efficiency.205210 Notably, improved control over material features such as particle size, shape, desired chemical and physical behaviors, surface structure, and type of targeting has recently given rise to a new horizon for clinical therapeutics resulting from the advent of nanotechnology.211 As shown schematically in Fig. 7.21, drug carriers designed by a nanotechnological approach can effectively destroy cancer cells without toxic effects to healthy cells

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FIGURE 7.21 Comparison of traditional and nanotechnological drug delivery methods. Source: Reproduced with permission from Dadwal, A.; Baldi, A.; Kumar Narang, R. Nanoparticles as Carriers for Drug Delivery in Cancer. Artif. Cells Nanomed. Biotechnol. 2018, 46 (Suppl. 2), 295305. Copyright 2018, Taylor & Francis.

because of high selective accumulation in tumor cells and active cellular uptake compared with traditional chemotherapeutic agents. Two strategies are utilized for specific delivery of drugs to desired locations: active targeting and passive targeting.212 Passive targeting is based on the abnormal pore size in tumor vessels and the accumulation of drugs in the cancer cells. Nanocarriers with the appropriate size and surface features can circulate in the blood for a long time and quickly reach the tumor region.213 Cancer cells require the formation of new vessels or the orientation of existing vessels around cancer tissues for oxygen and nutrient supply, and their irregular nature leads to leaky blood vessels with numerous pores surrounding tumor cells, called the enhanced permeability and retention (EPR) effect.212 This property facilitates drug accumulation at the cancer site. Passive targeting is limited for a few reasons, such as the dependence of the EPR effect on the tumor location and close blood vasculature networks and the high interstitial pressure of the vessels.213,214 In active targeting, however, nanocarriers are modified with specific moieties such as antibodies, antibody fragments, and peptides to overcome the limitations of passive transport.212 This targeting concept is based on the interaction of surface features of the nanocarriers with receptors or antigens on the surface of cancer cells, resulting in the enhancement of uptake of the nanocarriers and their high accumulation in the cancer cells.212,215

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Qasim et al.31 loaded doxorubicin (as the anticancer drug) in albumencoated cobalt ferrite (CoFe2O4@Albumen) nanocomposite for targeted drug delivery. The doxorubicin loading efficiency and capacity of CoFe2O4@Albumen nanocomposite, possessing particle size between 80 and 130 nm, were calculated as 93.3% and 4.45%, respectively. The high loading efficiency was due to the strong interaction between albumen (the negative charge from the carboxylate group) on the surface of CoFe2O4 and doxorubicin (the positive charge from the amine group). Moreover, the nanocomposite demonstrated pH-dependent drug release behavior in in vitro tests and even after high dose (800 μg mL21) incubation of THP-1 cells with the CoFe2O4@Albumen nanocomposite for 24 h, cell viability of 77% was retained, which showed that the nanocomposite was highly biocompatible and could be a suitable carrier for targeted drug delivery. Chitosan-modified and hyaluronic acidconjugated graphene oxide nanocomposites were developed by Liu et al.216 to be used in the controlled and targeted delivery of the anticancer drug SNX-2112 to inhibit the crucial heat shock protein 90 in the tumor cells. The rationale for the use of hyaluronic acid as a targeting ligand was to enhance cellular uptake of the drug by cancer cells due to specific recognition by glycoprotein CD44 on the surfaces of some cancer cells. The release of SNX-2112 was related to pH in phosphate-buffered saline (PBS), and the amount of drug released from the nanocomposite was higher at pH 5.5 than at pH 7.4 owing to the easier release of the drug from inside the nanocomposite with greater solubility of chitosan in the more acidic environment. The SNX-2112-loaded nanocomposite exhibited a slight toxic effect to normal cells (human bronchial epithelial cells) but caused effective destruction of A549 cancer cells at different concentrations ranging from 5 to 320 μg mL21 (70% of cells destroyed at 320 μg mL21). Furthermore, in vivo studies showed the SNX-2112-loaded nanocomposite led to no serious long-term injury. In another study, Matai et al.217 developed 5-fluorouracil (an anticancer drug)-loaded and poly(amidoamine) dendrimerstabilized Ag nanocomposites (5-FU@DsAgNCs). The use of 5-fluorouracil with silver nanoparticles in this study aimed to create a synergistic anticancer effect since silver nanoparticles cause apoptosis, which is defined as programmed cell death, similar to that caused by selenium and cisplatin. Delivery of 5-fluorouracil in the nanocomposite exhibited a continuous release profile, while free 5-fluorouracil had a faster release profile within 6 h (nearly 90%). These release profiles verified that 5-fluorouracil displayed controlled diffusion from poly(amidoamine) dendrimerstabilized silver nanocomposites in the PBS environment. As can be seen in Fig. 7.22A and B, compared to only 5-fluorouracil-loaded dendrimer, and dendrimer-stabilized silver nanocomposite, 5-FU@DsAgNCs synergistically destroyed A549 and MCF-7 cancer cells depending on the applied dose, with calculated IC50 values

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FIGURE 7.22 (A) A549 cell viability, (B) MCF-7 cell viability (cells were incubated with D: dendrimer, 5-FU-D: 5-fluorouracil-loaded dendrimer, DsAgNC: dendrimer-stabilized silver nanocomposite, 5-FU@DsAgNC: 5-fluorouracil-loaded and dendrimer-stabilized Ag nanocomposites), (C) FE-SEM images of A549 and MCF-7 cells treated and untreated with IC50 5-FU@DsAgNC. Source: Reproduced with permission from Matai, I.; Sachdev, A.; Gopinath, P. Multicomponent 5-Fluorouracil Loaded PAMAM Stabilized-Silver Nanocomposites Synergistically Induce Apoptosis in Human Cancer Cells. Biomater. Sci. 2015, 3, 457468. Copyright 2015, RSC.

for 5-FU@DsAgNCs over A549 and MCF-7 cells of 5 and 1.5 μg mL21, respectively, since the two cell lines possess different gene expression behaviors and intracellular signaling pathways. FE-SEM images (Fig. 7.22C) showed that A549 and MCF-7 cells turned into spherical structures with different sizes, and the breakup of cell membranes and the formation of apoptotic bodies occurred when both cells were treated with IC50 5-FU@DsAgNCs. This indicates that 5-FU@DsAgNC was effective in killing both types of cancer cells.

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Han et al.218 prepared a lipid bilayercoated mesoporous silica nanocomposite as a drug carrier. The lipid bilayer coating served to enhance uptake of the nanocomposites by cells because of the affinity of the lipid layer to the cell membrane while reducing the cytotoxicity and hemolysis percentage. The loading efficiency of the model anticancer drug doxorubicin into the lipid bilayercoated mesoporous silica nanocomposite was estimated at 16%, with the release behavior of the drug again being pH dependent. A high release ratio (68%) was obtained at pH 5 within 24 h. Furthermore, the IC50 value of doxorubicin-loaded nanocomposite (0.306 mg mL21) over MCF-7 cells was lower than that of doxorubicin solution alone (0.686 mg mL21), indicating that the nanocomposite plays an important role in improving the efficiency of drug delivery into the cells. Consequently, the prepared nanocomposite could be a more widely applicable candidate for effective drug delivery because of its excellent biocompatibility and ability to enhance cellular uptake.

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216. Liu, X.; Cheng, X.; Wang, F.; Feng, L.; Wang, Y.; Zheng, Y.; Guo, R. Targeted Delivery of SNX-2112 by Polysaccharide-Modified Graphene Oxide Nanocomposites for Treatment of Lung Cancer. Carbohydr. Polym. 2018, 185, 8595. 217. Matai, I.; Sachdev, A.; Gopinath, P. Multicomponent 5-Fluorouracil Loaded PAMAM Stabilized-Silver Nanocomposites Synergistically Induce Apoptosis in Human Cancer Cells. Biomater. Sci. 2015, 3, 457468. 218. Han, N.; Wang, Y.; Bai, J.; Liu, J.; Wang, Y.; Gao, Y.; Jiang, T.; Kang, W.; Wang, S. Facile Synthesis of the Lipid Bilayer Coated Mesoporous Silica Nanocomposites and Their Application in Drug Delivery. Microporous Mesoporous Mater. 2016, 219, 209218.

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8 Recent advances in the selective functionalization of anionic icosahedral boranes and carboranes Mustapha Hamdaoui, Rajesh Varkhedkar, Jizeng Sun, Fan Liu and Simon Duttwyler Department of Chemistry, Zhejiang University, Hangzhou, P.R. China

8.1 Introduction Polyhedral clusters based on the frameworks closo-dodecaborate ([B12H12]22, often referred to as “dodecaborate”) and monocarba-closododecaborate ([CB11H12]2, often referred to as “monocarborane”) are a fascinating class of boron-rich main group compounds featuring icosahedral geometry and delocalization of electron density.19 The purpose of this chapter is to provide an account of recent advances in the selective derivatization of these molecular cages, with an emphasis on metal-mediated transformations. As an introduction, some background information and selected properties of the clusters are presented. This is then followed by an outline of the concept of BsH activation and a brief history of the organometallic chemistry of boron clusters. Finally, two main sections comprise their transition metal (TM)mediated functionalization featuring BsH activation as a key step. The nomenclature for dodecaborates and monocarboranes includes both the number of vertices and the three-dimensional arrangement of the boron and carbon centers; “dodeca” refers to 12 corners, and the prefix closo indicates that the compounds exhibit a structure akin to a

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closed cage with only triangular faces (Fig. 8.1). The numbering system for the vertices has been defined by IUPAC rules and follows an apex/ upper-belt/lower-belt/bottom-vertex pattern.10 In this chapter, gray

FIGURE 8.1 Structure and vertex numbering of the icosahedral boron clusters [B12H12]22 and [CB11H12]2.

spheres in the structures of cluster compounds depict a BsH unit or, if a specific substituent is attached, a boron atom. The three-dimensional electron distribution of closo cage compounds has been deduced from X-ray diffraction data and computational studies. It can be considered analogous to the π aromaticity of classical organic arenes such as benzene and is often referred to as σ aromaticity.1116 Theoretical analyses suggest that in [B12H12]22 the highly delocalized bonding in the boron framework comprises 26 skeletal electrons, that is, 12 3 3e2 from the boron centers plus 2e2 from the overall charge, disregarding electrons from the exoskeletal (2 center2 electron) BsH bonds. These 26 electrons occupy 13 bonding molecular orbitals, rendering the dodecaborate anion exceptionally thermodynamically stable. Similar calculations have been performed on the monocarborane anion. It is important to note that a bond line (or connectivity) drawn between two cage atoms in a boron cluster does not represent a conventional two-electron bond. Technically, each line represents 26/20 5 1.3 electrons, thus the 20 connectivities rather show the three-dimensional icosahedral arrangement of the vertices. The σ aromaticity of the anions [B12H12]22 and [CB11H12]2 results in exceptional chemical and thermal stability, which sets them apart from common organic or inorganic substituents. For example, the cesium salt Cs2[B12H12] withstands temperatures of up to 800 C without showing

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decomposition. Also, it is inert in strongly Brønsted-acidic or -basic solutions. Even when treated with elemental fluorine in liquid hydrogen fluoride, the icosahedral B12 core remains unchanged, although vertex fluorination occurs. The monocarborane cage features similar properties. In terms of size, the volume of the unfunctionalized clusters, including ˚ 3 (Fig. 8.2).17 This hydrogen atoms, has been calculated to be c. 150 A value can be compared to those of benzene and adamantane, which are ˚ 3. approximately 100 and 135 A

FIGURE 8.2 Approximate van der Waals volumes of benzene, adamantane, and [B12H12]22.

Halogenation renders the boron clusters even more inert, and to a broader audience polyhalogenated anionic boranes may be best known as weakly coordinating anions.1823 They have made it possible to isolate and crystallize highly reactive cationic species such as silylium ions, borinium ions, chloronium ions, and protonated arenes (Fig. 8.3).2427 For this reason,

FIGURE 8.3

[CB11H12]2.

Main group cations isolated as salts of halogenated derivatives of

weakly coordinating halogenated derivatives of [B12H12]22 and [CB11H12]2 have also proved to be ideal counterions for highly active cationic catalysts. The unique steric and electronic properties of icosahedral boron clusters has led to a large number of applications over the past decades; in addition to taking advantage of their weakly coordinating nature, researchers have used them in various other fields, such as ligand design, supramolecular chemistry, fluorescence/phosphorescence studies, and materials science.2832 With regard to medicinal chemistry, the

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high boron content of such cages has made them ideal building blocks for boron neutron capture therapy but also as pharmacophores that can interact specifically with biological targets, for example, causing enzyme inhibition, while generally exhibiting low toxicity.3340 Primary tools for the analysis of boron clusters are NMR spectroscopy and mass spectrometry. Both methods have several general advantages, which make them highly convenient for rapid characterization: (1) reliable detection of microgram-to-milligram quantities; (2) data can be collected within minutes; (3) the required instrumentation is available in any typical chemistry or chemical engineering department; and (4) they allow for detailed studies of isolated single compounds but can also be applied in reaction monitoring. Since the early days of investigations into polyhedral boranes, boron NMR spectroscopy has been the most versatile method for structure determination.4143 The two isotopes 10B and 11B occur in 19.6% and 80.4% natural abundance, respectively, and both are NMR-active (Table 8.1). Of the two nuclei, 11B is more suitable for NMR measurements. In addition to its higher natural abundance, it has a smaller nuclear spin and quadrupolar moment than 10B. Also, its sensitivity is about 0.113 relative to 1H versus 0.0039 for 10B, and the resonance frequency is about three times that of 10B. The T1 relaxation times of 11B are often in the range of 10500 ms and therefore allow rapid pulsing. Thus milligram quantities of substance can be analyzed within minutes, providing spectra with very good signal-to-noise ratio. Calibration is usually done versus external BF3 Et2O, which is set to 0 ppm; the chemical shift range for icosahedral boron clusters typically runs from approximately 40 to 110 ppm. Depending on the structure and symmetry of the compound, the line widths are between 20 and 200 Hz. These values result from the inherent quadrupolar moment and 11Bs1H, 11Bs11B as well as 11 Bs10B coupling. One-bond scalar coupling to 1H is observed in the range



TABLE 8.1 NMR properties of the boron nuclei

10

B and

11

B.

10

11

Natural abundance

19.6%

80.4%

Nuclear spin I

3

3/2

Sensitivity relative to 1H

0.0039

0.133

22.1

754

NMR frequency ( H 5 500 MHz)

53.7 MHz

160.4 MHz

Calibration standard (0 ppm)

BF3 Et2O

B

Sensitivity relative to

13

C

1

B



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of 100150 Hz and can be eliminated by decoupling, similar to 13C{1H} NMR spectroscopy. As a specific example, the 11B and 11B{1H} NMR spectra of [Cs][CB11H12] are depicted in Fig. 8.4. The C5v symmetry of the anion leads to three reso-

FIGURE 8.4 11B and 11B{1H} NMR spectra of [Cs][CB11H12] (128 MHz for for 1H, acetone-d6, 23 C, referenced to external BF3 Et2O 5 0 ppm).



11

B, 400 MHz

nances, namely, from vertices B(26), B(711), and B(12). They are observed at 16.2, 13.2, and 6.7 ppm and are split into doublets in the 11 B spectrum due to 11B1H coupling. Decoupling from 1H leads to the simplified 11B{1H} NMR spectrum, in which the resonances appear without any overlap. The short relaxation times of all boron vertices (,500 ms) enable quite accurate integration, which clearly indicates a 1:5:5 ratio of chemically inequivalent nuclei. The ultimate assignment of B(26) versus B(711) was made on the basis of a 11Bs11B COSY NMR experiment. While compounds of high symmetry and simple substitution patterns afford spectra that can be easily interpreted, the 11B NMR spectra of multiply and unsymmetrically substituted clusters can be complicated and exhibit overlapping signals. In these cases, 11Bs11B COSY NMR spectroscopy and 11Bs1H 2D techniques can be used to rationalize the spectra, but complete and unequivocal assignment is not always

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possible.44,45 One-dimensional 1H NMR spectroscopy can also be performed but requires decoupling from 11B for sharpening of the resonances of the protons directly attached to boron. Such spectra still exhibit 1 Hs1H and 1Hs10B coupling, which leads to relatively broad signals and inaccurate integration. Despite these complicating factors, combined 11 B and 1H NMR spectroscopy remains an indispensable tool for the analysis of boron cage compounds. It should also be mentioned that 11 B NMR spectra can be recorded in nondeuterated solvents, thus making the method highly economical especially as applied to reaction monitoring. Mass spectrometry is another extremely useful method to characterize compounds based on the dodecaborate and monocarborane scaffolds. Because they are already negatively charged (unless the substitution pattern leads to zwitterionic character), ionization is not an issue, and the clusters can conveniently be detected by ()-ESI mass spectrometry. Microgram quantities are sufficient for clear signals, and their high thermal stability results in little fragmentation so that relatively simple mass spectra can be obtained. The mass-spectrometric analysis of the [CB11H12]2 ion is shown in Fig. 8.5. The two isotopes 10B and 11B, occurring in 19.6% and 80.4%

FIGURE 8.5 Calculated and experimental mass spectra of [CB11H12]2.

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abundance, permit the prediction of the expected spectrum. The calculated spectrum contains six major peaks in the range of m/z 140145, of which the most intense appears at m/z 143. The experimental and calculated spectra are very similar, thus confirming the presence of 11 boron atoms and an overall molecular mass of 143 g/mol. The isotopic distribution also allows one to distinguish boron clusters from other ions with coincidentally similar masses, as such species would most likely feature a markedly different isotope pattern. In reaction monitoring, mass spectrometry not only offers the advantage of showing consumption of starting material and increasing concentration of product(s), but it also clearly indicates the degree of substitution when multiple BsH vertices are functionalized. This is especially useful for BsH activation reactions in which one or more BsC bonds can be formed. The degree of substitution is in many cases relatively difficult to determine by NMR spectroscopy unless specific reference spectra are available. This limitation underscores the complementarity of the two methods, NMR and MS, comprising a powerful couple for the development of synthetic methodologies for novel boron cluster derivatives.

8.2 BsH activation for the functionalization of anionic boron clusters The practical versatility of boron clusters has inspired researchers to develop a number of methods for their derivatization. Traditional approaches to introduce new substituents at BsH vertices rely on direct electrophilic substitution or a combination of halogenation and subsequent cross-coupling, for example, by palladium catalysis.46,47 However, the challenges associated with these strategies are those of vertex selectivity and of control over the degree of substitution because of the high symmetry of the clusters. In this regard, the monocarborane anion offers a certain advantage. On the one hand, the C(1) carbon vertex can in many cases be functionalized by deprotonation with butyllithium and subsequent reaction with electrophiles; on the other hand, the carbon atom causes a dipole moment in the cluster, leading to slightly different reactivities of the upper-belt B(26), lower-belt B(711), and B(12) positions toward electrophiles.6 This difference can be used in halogenation and alkylation procedures, but the regioselectivity is still far from ideal in many of these reactions. In organic chemistry, the activation and functionalization of CsH bonds have become one of the most powerful synthetic concepts of the past two decades.4855 In particular, the controlled introduction of new substituents to aromatic starting materials bearing a directing group has

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enabled the preparation of compounds that would otherwise be impossible to access or that would require a much more involved synthetic route. A general outline of CsH activation/functionalization is shown in Scheme 8.1. The directing group DG is a functionality that contains a

SCHEME 8.1 Directing group-controlled, transition metalmediated CH activation of benzene derivatives. DG, Directing group; FG, functional group; TM, transition metal.

Lewis-basic site, which can coordinate a TM. Commonly used directing groups are carboxylic acids and their derivatives or heterocycles such as pyridine. Complexation of the metal by the organic starting material leads to a first intermediate in which the metal center is held in close proximity to the ortho hydrogen atom. This CsH position is then activated, most often by a cyclometalationdeprotonation process. The resulting species contains a direct carbonmetal bond, which can be subsequently functionalized with a suitable coupling partner. Upon substitution of the ortho carbon atom, the metal fragment is released and can bring about modification of another aromatic starting molecule and thus act as a true catalyst. As discussed in the introduction, boron clusters exhibit essentially spherical delocalization of electron density. Based on the analogy between 2D-aromatic benzene derivatives and 3D-aromatic boranes, the positional descriptors ortho, meta, and para can be used for monosubstituted icosahedral clusters (Fig. 8.6). Thus in a directing group-carrying dodecaborate or monocarborane, B(26) 5 ortho, B(711) 5 meta, and B(12) 5 para.

FIGURE 8.6 ortho, meta, and para relationship in aromatic compounds and its analogy in anionic boron clusters.

One can then, at least in principle, envision TM-mediated BsH activation as an attractive alternative to address the general synthetic obstacles in the preparation of novel boron cluster derivatives. In a sequence similar to involved in CsH activation, ortho BsH activation would

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afford desired products with a reduced number of steps and with high regioselectivity (Scheme 8.2): (1) the directing group is capable of coordinating to a TM fragment; (2) in the complex formed, proximity

SCHEME 8.2 Directing group-controlled, transition metalmediated BH activation of anionic boron clusters. DG, Directing group; FG, functional group; TM, transition metal.

between the metal center and one of the cage vertices leads to activation of the BsH bond by BsTM bond formation; and (3) treatment with a suitable coupling partner furnishes the selectively functionalized product and releases the TM that enters a new catalytic cycle. Early studies on the cyclometalation of neutral boron cages date back to the 1970s. In two closely related publications that appeared in 1973 and 1975, Hawthorne and coworkers reported on the chemistry of 1,2-dicarbadodecaboranes (or carboranes), whose parent structure is 1,2-C2B10H12. They investigated the effect of a phosphine group attached to C(1) on the reactivity of the cluster and showed that combination with iridium(I) complexes can induce formation of BsIr(III) species by oxidative addition to BsH bonds.56,57 After the pioneering days of BsH activation, neutral dicarbaboranes have remained the main focus of the organometallic chemistry of closo cages. Catalytic protocols for their modification have mainly been developed by Xie and coworkers over the past 10 years. Their work as well as results from other laboratories have been summarized in several review articles.5861 On the other hand, the metal-mediated functionalization of anionic icosahedral clusters is a young research area. Results in this field have so far only been surveyed as part of two recent reviews.62,63 Before the first reports of TM-mediated BsH activation of anionic icosahedral boron clusters under directing group control, Weller and coworkers described vertex functionalization of the unsubstituted parent monocarborane [CB11H12]2.64,65 Their studies are summarized later because they represent a landmark in monocarborane chemistry. Also, they included the first example of a fully structurally characterized species featuring a direct boronmetal bond between an anionic closo cage and a TM. Specifically, poly-ethylation by a sequence of ethenylation hydrogenation events starting from overall neutral (PPh3)2Rh(I) [CB11H12] was reported. This starting complex was obtained as a

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crystalline material in high yield by metathesis between [(PPh3)2RhCl]2 and [Ag][CB11H12]. Reaction of (PPh3)2Rh(I)[CB11H12] with excess ethene in dichloromethane at room temperature, followed by treatment with hydrogen gas, gave the B(7)- and B(12)-ethyl intermediates as an inseparable mixture (Scheme 8.3). After a total of six similar

SCHEME 8.3 Exhaustive ethenylationhydrogenation of the complex (PPh3)2Rh(I) [CB11H12] affording the penta-substituted monocarborane.

ethenylationhydrogenation cycles, the penta-substituted product with two ethyl groups on the upper belt, two ethyl groups on the lower belt, and a B(12)-ethyl group was obtained in 75% yield. This final substitution pattern after exhaustive ethylation indicated that formation of more BsC bonds was precluded by steric hindrance arising from the five ethyl groups covering the cage. In terms of the mechanism, a Rh(I)/Rh(III) pathway was proposed, and a detailed sequence of steps for the first ethenylation is outlined in Scheme 8.4, shown only for the B(12)-isomer. Initial oxidative addition

SCHEME 8.4 Proposed mechanism for the B(12)-ethenylation of the complex (PPh3)2Rh(I)[CB11H12].

in the presence of ethene leads to a B(12)sRh(III) species, which then undergoes insertion to give the second intermediate. β-Hydride elimination affords the B(12)-vinyl monocarborane coordinated to the formal Rh(III)-dihydride fragment, which then loses hydrogen to afford the vinyl carboraneRh(I) complex. The latter complex and also the free B (12)-vinyl monocarborane (along with the B(7) isomer) were characterized unambiguously. Rhodium-mediated reduction of the double bond by excess hydrogen then furnishes the mono-ethylated cage. From there

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on, a series of similar steps ultimately afford the penta-substituted monocarborane. Installing a methyl or silyl group at the C(1) vertex in the starting material provided access to products with a lower degree of substitution. For example, starting from (PPh3)2Rh(I)[1-(iPr3Si)-CB11H11], three cycles of ethenylation/hydrogenation afforded the B(7,9,12)-tri-ethylated monocarborane in 63% yield. Interestingly, all of the above reactions required a full equivalent of rhodium, and the authors stated, “Attempts to make any of these transformations catalytic,. . ., did not lead to appreciable turnover, even though a variety of anion/metal fragment/solvent combinations were tried.” This observation was attributed to relatively strong interactions between the variety of cage anions in the reaction mixture and the rhodium phosphine fragments. Weller and coworkers also observed that Rh(III) complexes in which [CB11H12]2 was coordinated to a (PR3)RhH2 (R 5 iPr, cyclohexyl, cyclopentyl) moiety lost molecular hydrogen when placed in a vacuum (Scheme 8.5).66

SCHEME 8.5 Formation of a dimeric Rh(III)/Rh(I) monocarborane complex featuring one direct BRh(III) and five BHRh(I) agostic-like interactions.

This loss resulted in the formation of a dimeric Rh(I)/Rh(III) species that featured one direct BsRh(III) and five BsHsRh(I) agostic-like interactions. In solution, the dimer underwent a fast internal isomerization on the NMR time scale at room temperature. X-ray diffraction of the cyclohexyl derivative revealed a structure in which the isomerization was frozen out and the different environments of the metal centers could be clearly distinguished. Approximate coordination geometries were square pyramidal for Rh(I) ˚ and and octahedral for Rh(III), with key distances BsRh(III) 2.061(3) A ˚ . Interestingly, the loss of hydrogen was reversible Rh(I)sRh(III) 2.7962(2) A for all three derivatives (R 5 iPr, cyclohexyl, cyclopentyl), and exposing the dimers to H2 in CD2Cl2 regenerated the starting materials quantitatively. This publication was of high importance to the field of monocarborane BsH activation since it was the first report of the isolation and full characterization of a species containing a direct boronTM bond.

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8.3 Directing group-controlled formation of organometallic complexes of the monocarborane anion After Weller’s initial work on nondirected BsH activation of [CB11H11]a, investigations into the organometallic chemistry of monocarborane anions resumed in 2013 with a report by Lavallo, Maron, and coworkers.67 The authors began their study by incorporating a phosphine group at the carbon vertex of the cluster to form [1-(iPr2P)-CB11H11]a via reaction of the in situ-generated C(1)-lithiate with iPr2PCl. Their motivation was to probe the properties of the carborane phosphine as a ligand toward iridium. Would this compound coordinate to metal fragments primarily via the phosphorous center or via the B(712) positions as in the complexes studied by Weller? How strong would it be as an electron donor toward the metal? And if interaction through phosphorus occurred, would this allow for directed, selective BsH activation? To address these questions, the authors dissolved the monocarborane phosphine [1-(iPr2P)-CB11H11]a in C6D6 in the presence of the dimeric Ir(I) complex [Ir(cod)Cl]2 (cod 5 cyclooctadiene), which resulted in the formation of the zwitterionic complex [1-(PiPr2)-CB11H11-Ir(cod)] (Scheme 8.6); evidence for its composition was obtained by multinuclear

SCHEME 8.6 Formation of a zwitterionic iridium complex by reaction of the monocarborane phosphine [1-(iPr2P)-CB11H11]a with Ir(I).

(1H/31P/11B) solution NMR analysis and by single-crystal X-ray diffraction. At room temperature, NMR resonances attributable to BsH bonds interacting with Ir or to the potential product of oxidative addition, containing a BsIr(III)sH moiety, could not be detected. On the other hand, upon cooling the sample to 280 C, the authors observed a signal at 21.42 ppm in the 1H NMR spectrum, which was assigned to (BsH)2sIr, shifted upfield in comparison to the free phosphine carboranyl ligand (1HsB(26) 5 0.93 ppm). Reversible BsH activation and IrsB cyclometalation was ruled out for this complex based on further experimental data derived from infrared spectroscopy, which showed no

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evidence for absorptions that could be assigned to an IrsH vibration. Variable temperature 11B{1H} NMR experiments were conducted and suggested that a dynamic process involving rotation of the metal fragment with respect to the upper belt took place. At room temperature, three 11B{1H} resonances in a 5:5:1 ratio were observed, consistent with effective fivefold symmetry of the complex at room temperature, and therefore indicating fast rotation on the NMR time scale. Upon cooling to a90 C, the 11B{1H} NMR spectra became more complicated, consistent with a static structure of lower symmetry. A coalescence temperature of a75 C was determined, corresponding to ΔG‡ 5 c. 8 kcal mol21 as the activation barrier to rotation. X-ray diffraction of a single crystal of [1-(iPr2P)-CB11H11-Ir(cod)] showed that it was indeed best described as an Ir(cod) fragment coordinated by the phosphorus center and two upper-belt BsH units, that is, the phosphine carborane acted as a chelating ligand without undergoing BsH activation. A notable geometrical feature charac˚ for the coorterizing this structure was the elongated distance of 1.451(4) A dinated cyclooctadiene CsC double bond trans to the (BsH)2Ir motif. In comparison, the distance of the double bond trans to phosphorus was 1.362 ˚ , a value typical of a CsC double bond in organic compounds. (4) A Furthermore, the IrsC distances trans to the BsHsIr interactions were shorter than those found for the IrsC bonds opposite to the phosphorus center. Based on these findings, the authors proposed that the [Ir(η2-CC)] moiety trans to BsH can alternatively be viewed as an iridacyclopropane, the compound as a whole being an Ir(III) complex with d6 electronic configuration (Scheme 8.6, right resonance structure). This idea was somewhat supported by data inferred from density functional theory (DFT) calculations carried out at the M06L level of theory. First, a natural bond orbital (NBO) analysis, a method that studies intra- and intermolecular bonding interactions including charge transfer and conjugative interactions, indicated a natural electron population of 1.785 electrons for the two BsH bonds interacting with the iridium atom, suggesting little disruption upon coordination and limited electron density transfer to the metal (NBO analysis for unperturbed BsH carborane bonds gave a value of 1.972 electrons). Second, a Mayer bond order analysis, a method to quantify bond orders, not only suggested that the BsH bonds remain mostly undisrupted upon interaction with the iridium center but also provided support of the iridacyclopropane model, the resonance contribution taken into account given X-ray geometrical parameters discussed earlier. In fact, an MBO value of 1.06 was obtained for the cyclooctadiene CsC bond trans to BsH, consistent with a significant trans influence and hence almost full reduction of the double bond to a single bond. The study of [1-(iPr2P)-CB11H11]a thus revealed that tethering a phosphine substituent to the C(1) position of [CB11H12]a rendered metal coordination by upper-belt BsH vertices

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favorable, different from the interaction between [CB11H12]a and rhodium in the complex [(CB11H12)Rh(PPh3)2] used by Weller. In 2015 Lavallo and coworkers noticed just how close they had been to BsH activation when using the strategy of installing a phosphine group at the C(1) monocarborane position. In a comparative study, they examined the 1,2-dicarbaborane phosphine [1-P(iPr2)-1,2-C2B10H11], a starting material very closely related to [1-(iPr2P)-CB11H11]a from their 2013 publication.68 Upon mixing with 0.5 equivalents of [(ClIr(cod)]2 in hexane at room temperature, the 1,2-dicarbaborane analogue underwent clean BsH activation to afford cyclometalated Ir(III) complexes (Scheme 8.7). The two diastereomers

SCHEME 8.7 Formation of iridium(III) BH activation complexes by reaction of the monocarborane phosphine [1-(iPr2P)-1,2-C2B10H11]a and iridium(I).

were formed in a 4:1 ratio based on spectroscopic data. This result was in marked contrast to the findings involving the monocarborane phosphine. 1 H NMR spectroscopic analysis of the isolated mixture in C6D6 at room temperature showed a doublet resonance at 16.42 ppm (2JPaH 5 13.1 Hz) attributed to the iridium-bound hydride ligand; the hydride signals were overlapping for the two diastereomers. This resonance indicated that BsH bond cleavage had occurred by oxidative addition at the iridium center, resulting in the four-membered iridacycle. Also, the same spectrum exhibited two broad signals at 5.87 and 5.75 ppm in a 4:1 ratio, attributed to the CsH carborane resonances of the major and minor diastereomer, respectively. The 11 B NMR spectrum of the product mixture could not be interpreted in detail because of the large number of broad and overlapping resonances. A value of 18.0 ppm was given for the BsIr vertex; however, the actual spectrum was not shown, and no explanation was provided as to how this assignment was made. An IR absorbance at 2223 cm21, in addition to the strong BsH stretches around 2500 cm21, was interpreted as an IrsH stretching mode. An X-ray diffraction analysis of one of the diastereomers was in agreement with the conclusions drawn from spectroscopic data. The crystal structure confirmed the occurrence of a BsH activation event eventually resulting in B-cyclometalation. A distorted octahedral geometry around the iridium center was found, with the hydride positioned

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cis to the phosphine ligand. Important distances were found to be as fol˚ , IrsB 2.094(2) A ˚ and IrsCl 2.498(5) A ˚ . Distances lows: IrsP 2.320(5) A for the CsC double bonds of the cod ligand coordinated to iridium (trans to the Ir-bound phosphorus and boron atoms) fell in the typical range generally described for olefins interacting with iridium ˚ ). This finding was in contrast with the unusually large dis(1.35a1.44 A tances described for the CsC bonds coordinated trans to the interacting boron atoms in the X-ray structure obtained for the zwitterionic, agostic-like complex studied by Lavallo in 2013 (discussed earlier). In order to round off their investigation, the authors treated the zwitterionic complex [1-(iPr2P)-CB11H11-Ir(cod)] from their 2013 publication with the chloride salt [Me4N][Cl] in benzene (Scheme 8.8). Again no BsH

SCHEME 8.8 Formation of the phosphine/chloride iridium(cod) product starting from the zwitterionic, agostic-like phosphine/(BH)2 iridium(cod) precursor.

activation was observed. Instead, chloride acted as a nucleophile and replaced the (BsH)2 motif, and the product [(carborane-PiPr2)Ir(cod)Cl] was obtained. Characterization by multinuclear NMR spectroscopy, IR spectroscopy, and X-ray diffraction revealed that the monocarborane was now interacting with the iridium center only through phosphorus. Lavallo’s findings were followed by a computational study in 2016 by Zhang’s group. They performed DFT calculations on a series of mono- and dicarbaboranes identical and closely related to Lavallo’s clusters.69 Structures and relative energies of these starting materials and their corresponding Ir(III)(cod) iridacycle complexes, including transition states for BsH activation/oxidative addition, were considered. On the one hand, the calculations were in agreement with Lavallo’s experimental observations. They started from precomplexes carboraneIr(I)(cod) and confirmed that cyclometalation was thermodynamically favorable for the dicarbaborane phosphine [1-P(iPr2)-1,2-C2B10H11] (ΔG 5 0.93 kcal mol21) but endergonic for the anionic [1-(iPr2P)-CB11H11]a (ΔG 5 15.22 kcal mol21). On the other hand, the authors predicted that a slight change in monocarborane phosphine structure would render iridacycle formation favorable; starting from [1-(R2P)-CB11H11]a with R~CH(CF3)2, the resulting Gibbs free energy was

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predicted to be ΔG 5 11.18 kcal mol21 (Fig. 8.7). This change was primarily attributed to steric considerations. A comparison of the optimized geometries of the precomplexes showed that increased steric bulk of the

FIGURE 8.7 Cyclometalated iridium complexes predicted to be thermodynamically stable.

substituents at phosphorus decreased the C(cage)-P-Ir bond angle, thus leading to a shorter distance between the BsH bond and Ir. As a consequence, cyclometalation occurred with smaller values for ΔG‡ and ΔG. Furthermore, incorporation of CH2, NH, or O units between the cage C atom and phosphorus was also shown to make BsH activation/oxidative addition more favorable. The Ir(III) iridacycles formed from [1-(Me2P)X-CB11H11]a (X~CH2, NH, O) and Ir(I)(cod) were thermodynamically stable (Fig. 8.7), likely because of more relaxed internal bond angles within the five-membered ring. In 2016 Lavallo’s group reported an interesting reaction between the dianionic two-coordinate carborane Pd(0) complex [(1-(iPr2P)-CB11H11)2Pd]22 and chlorobenzene (Scheme 8.9); the Pd(0) complex had been obtained by

SCHEME 8.9 Palladium(II) complexes formed from the bis(monocarborane phosphine) palladium(0) precursor.

reaction of [1-(iPr2P)-CB11H11]a with (Me3SiCH2)2Pd(cod).70 The main product, obtained in neat chlorobenzene at room temperature, was the formal Pd(II) species [(1-(iPr2P)-CB11H11)2Pd(Ph)]2. Its formation most likely proceeded through oxidative addition of chlorobenzene and subsequent elimination of LiCl. In addition, however, a minor fraction of a second product was also obtained, which was identified as a B-cyclometalated Pd(II) complex featuring a four-membered palladacycle.

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This special kind of BsH activation was interpreted as initial oxidative addition of chlorobenzene immediately followed by σ bond metathesis involving loss of one BsH hydrogen atom and the Ph ligand, that is, overall elimination of LiCl as well as benzene. The structure of the palladacycle was confirmed by multinuclear NMR spectroscopy and single-crystal X-ray diffraction analysis. Several groups of overlapping resonances were observed in the 11B{1H} NMR spectrum in tetrahydrofuran (THF) at 25 C, with a resonance at a21.6 ppm most likely stemming from the palladiumbound boron vertex. Furthermore, the authors presented theoretical calculations to shed light on the mechanistic manifold, and they also performed a series of Kumada cross-coupling reactions between aryl Grignard reagents and substituted chlorobenzenes highlighting the catalytic activity of the two-coordinate carborane Pd(0) complex. The findings by Weller, Lavallo, and Zhang, but also by researchers in the field of neutral dicarbaboranes made it clear that a more thorough investigation of selective BsH activation processes in anionic boron cages necessitated the careful design of the cluster starting material. This would be crucial for fundamental studies of organometallic species with a boronmetal interaction and, subsequently, potential catalytic processes for vertex functionalization. In order to explore the intermediates of BsH bond activation, the Duttwyler group set out to address these challenges by a directing group approach akin to CsH activation chemistry. To this end, three criteria regarding the directing group were identified: (1) facile introduction to the cage, (2) ability to coordinate to the metal and enable BsH activation beyond agostic interactions, and (3) lack of competitively activated CsH bonds. After an evaluation of several functional groups installed at the C(1) vertex of the monocarborane ion, the sulfonamide functionality turned out to fulfill these criteria, and the results were reported in 2017.71,72 The tosyl amide of the monocarborane cage was synthesized from the C(1)-carboxylic acid by treatment with oxalyl chloride, followed by reaction with tosyl amine (Scheme 8.10). The observed distances in the

SCHEME 8.10 Synthesis of the C(1)-tosyl amide of the parent monocarborane.

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˚ ) CsC 1.505(3), C~O 1.206(2), CsN 1.378 X-ray crystal structure were (A (3), and NsS 1.657(2); the sum of angles around C~O was 360.01, and the torsion angle CsCsNsS was 176.61, indicating coplanarity of the entire sulfonamido moiety. These geometric parameters indicated that upon NsH deprotonation and N coordination to a TM, energetically favorable BsH activation and eventual formation of a five-membered metallacycle (MsBsCsCsN) featuring a direct boronmetal bond would occur. Using the tosyl amide directing group, three monocarbaborane metal complexes were prepared selectively and fully characterized, involving iridium, rhodium, and palladium. The reaction between the tosyl amide and a stoichiometric amount of IrCp*(OAc)2 in acetonitrile leads to a yellow precipitate, which was identified as the corresponding anionic iridacycle (Scheme 8.11). Its structure was elucidated by X-ray

SCHEME 8.11 Preparation of the monocarborane tosyl amide iridium complex; overall negative charge highlighted by brackets only for the product.

diffraction and multinuclear NMR spectroscopy. The crystal structure showed that the iridacycle consisted of the carborane amide coordinated as a bidentate B,N ligand to the IrCp*(MeCN) fragment. Key distances ˚ and NsIr 2.147(4) A ˚ . Both values were consiswere B(2)sIr 2.123(7) A tent with direct B/NsIr interactions, given that as a general observation, the bond length between a main group element and TM is on the ˚ . There was no indication of a residual H atom order of 2.12.2 A attached to B(2) or Ir. The five-membered metallacycle exhibited only slight puckering, with internal angles of B(2)sIrsN 79.51 degrees, B(2)CsC 113.31 degrees, CsCsN 112.01 degrees, and a torsion angle of B(2)sCsCsN 12.41 degrees. A theoretical investigation into the reaction pathway for iridacycle formation was carried out on the basis of DFT calculations

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(Scheme 8.12). They were carried out starting from a precomplex exhibiting NsIr/acetateIr coordination, giving the acetic acidcoordinated product. According to computations at the B97-D/LanL2dz level of theory in acetonitrile continuum, product formation is exothermic by 7.86 kcal mol21,

SCHEME 8.12 Energy profile for the cyclometalation process calculated at the B97-D/ LanL2dz level of theory in acetonitrile continuum.

with a calculated barrier of 8.25 kcal mol21. The reaction mechanism proceeds through a six-membered ring transition state, where a hydrogen atom is transferred from B(2) to the carbonyl O atom of the acetate ligand. This hypothesis is consistent with proposed pathways for the activation of dicarbaboranes and studies on CsH activation reactions proceeding through a deprotonationcyclometalation mechanism. HOMO/LUMO calculations suggested that the HOMO of the iridacycle is primarily localized around the iridium fragment as well as N and B(2), while the LUMO is associated with the tolylSO2 moiety and the Cp* π-system. They indicated B(2) and Ir as the centers with the highest probability of attack by an electrophile, while attack by a nucleophile was predicted to occur at C(ipso) of the tolyl ring. Electrophilic chlorination was used as a model reaction to test the reactivity of the iridacycle. Based on the frontier density plots, attack was expected to take place around the BsIr moiety. Treatment with N-chlorosuccinimide indeed afforded the B(2)-chlorinated product selectively in

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68% isolated yield (Scheme 8.13); no other regioisomers were detected in this transformation. As for the rhodium complex, treatment of the tosyl amide with one equivalent of Cp*Rh(OAc)2, following a similar procedure as for

SCHEME 8.13

Selective B(2)-monochlorination of the monocarborane tosyl amide irid-

ium complex.

iridium, afforded a new deeply red-brown product, which was identified as the corresponding rhodacycle (Scheme 8.14).72 X-ray analysis revealed that the anionic complex consisted of the carborane moiety act-

SCHEME 8.14 Preparation of the monocarborane tosyl amide rhodium complex; overall negative charge highlighted by brackets only for the product.

ing as a chelating B,N ligand toward a RhCp*(MeCN) fragment, analogously to the iridium case. Observed key distances were RhsB(2) 2.111 ˚ and RhsN 2.141(4) A ˚ . These were similar to those found for the (6) A iridacycle and consistent with a direct B(2)sRh interaction. The fivemembered rhodacycle was relatively flat with an internal angle of B(2) RhsN 79.38 degrees and a torsion angle of B(2)sCsCsN 9.54 degrees.

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Applying similar cyclometalation conditions starting from the tosyl amide and Pd(OAc)2 resulted in the formation of the palladacycle, which was also isolated in 80% yield as a colorless solid (Scheme 8.15).

SCHEME 8.15 Preparation of the monocarborane tosyl amide palladium complex; overall double negative charge highlighted by brackets only for the product.

X-ray diffraction revealed a dimeric dianionic structure; the dianionic complex showed B,N chelation to one Pd(II) center and S~OsPd coordination ˚, to the second Pd center. Observed distances were B(2)Pd 1.999(6) A ˚ , and PdsO 2.435(3) A ˚ . The ligand geometry around PdsN 2.059(4) A palladium was square-planar with a sum of angles around Pd of 360.07 degrees and a distance between the best-fit plane through the ligated ˚. atoms BsNsOsN and Pd of 0.126 A A detailed multinuclear NMR analysis of all three cyclometalated products was consistent with the structures found by X-ray crystallography, although the palladacycle was likely to exist as a solventcoordinated monomer in acetonitrile solution. A summary of the 11B NMR spectroscopic data is provided in Fig. 8.8. In the 11B{1H} NMR spectrum of the tosyl amide starting material, B(26) appeared at 14 ppm, B(711) at 13 ppm, and B(12) at 6 ppm. The spectra of the iridacycle showed resonances around 7.6, 10.2 to 14.7, and 14.7 to 17.2 ppm in a ratio of 1:8:2, consistent with 11 boron vertices including B(2)Ir. Based on 11B11B COSY NMR experiments, the signal at 7.6 ppm was assigned to B12, while B(2)Ir and B(9) gave rise to overlapping signals centered at 16.2 and 15.7 ppm. The rhodacycle and the palladacycle showed comparable 11B resonances for vertices B(12), B(38/10,11), and B(9), which appeared around 7.5, 10 to 15, and 16.5 ppm, respectively. On the other hand, B(2) with a direct B[TM] bond was observed at 6.4 ppm for the rhodacycle and at 19.6 ppm for the palladacycle. Thus there seemed to be no general rule as to

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FIGURE 8.8 11B NMR spectroscopic data for the monocarborane tosyl amide and its transition metal complexes (CD3CN solution, 23 C).

whether the B(2) signal would experience shielding or deshielding upon cyclometalation. All complexes showed remarkable inertness. Solutions of the iridacycle in acetonitrile under a nitrogen atmosphere remained unchanged over weeks; heating to 70 C in a sealed NMR tube for 2 days did not lead to any decomposition. In the solid state, either as a powder or in crystalline form, samples remained unchanged in air for 2 weeks. Similarly, the rhodacycle and palladacycle were inert over weeks at room temperature and over days at 50 C.

8.4 Transition metal-catalyzed functionalization of anionic boron clusters The first example of selective catalytic derivatization of the monocarborane anion was reported shortly after the isolation of the tosyl amide metallacycles.73 In this case, the pyrrolidine amide moiety served as the directing group. Using a similar synthetic approach as for the tosyl amide, pyrrolidine amides with B(12) 5 H, Br, and I were prepared in yields of 88%, 76%, and 87%, respectively. In order to establish conditions for TM-catalyzed boron vertex modification, coupling with ethyl acrylate was chosen as a model reaction to give functionalized product(s) with potential multiple degrees of substitution. Using [RhCp*Cl2]2 in

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combination with AgSbF6 and Cu(II) successfully led to BsC bond formation. Carrying out this transformation in dimethylacetamide at 100 C selectively afforded tetrasubstitution across positions B(25) (Scheme 8.16).

SCHEME 8.16 Synthesis of monocarboranes functionalized at the B(25) positions.

The product contained three reductively coupled ester moieties and one ethyl acrylyl substituent with a remaining double bond. The reaction also worked with the B(12)sBr starting material without competitive side reactions at any of the vertices. Under similar reaction conditions, the monocarborane cage could be coupled with activated alkenes such as phenyl acrylate, styrene, and 4-fluorostyrene to give tetrasubstituted clusters in 57%74% yields after purification by chromatography. For these transformations, as well as

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for all other products, the experiments were conveniently performed on the bench and did not require air-free conditions. 4-Methoxystyrene as an electron-rich alkene was also tested; however, this substrate afforded only trace amounts of product. Using acetonitrile provides access to products exhibiting a lower degree of functionalization. The B(2/4) disubstituted fluorophenyl compound could thus be obtained in 44% yield by monitoring the reaction by ESI-MS and stopping it at the point of di-substitution. Reaction with diphenylacetylene in dimethylacetamide resulted in tetra-alkenylation, demonstrating that alkynes are viable coupling partners for the BsH functionalization. Ir(III) also brought about BH activation, generally leading to a reduced degree of substitution. Using [IrCp*Cl2]2/AgSbF6 in 1,2-dichloroethane, coupling with diphenylacetylene afforded mono-alkenylated product in 55% yield. Under the same conditions, formation of BsN bonds was also successful. Reaction with tosyl azide caused sulfonamidation at the B(2/4) positions. Characterization of the products was achieved by multinuclear NMR spectroscopy, X-ray crystallography, and mass spectrometry; furthermore, several compounds were prepared on a gram scale. Selective monochlorination was accomplished using Rh(III) and N-chlorosuccinimide as the chlorinating agent. Starting from pyrrolidine amides carrying H, Br, or I at the B(12) position, treatment with three equivalents of N-chlorosuccinimide in the presence of [RhCp*Cl2]2/Ag (I)/Cu(II) in 1,2-dichloroethane cleanly led to B(2)-substituted products in isolated yields of 68%82% (Scheme 8.17). Notably, no positional

SCHEME 8.17

Regioselective B(2) monochlorination of monocarboranes.

isomers were obtained. This finding was remarkable because electrophilic halogenation of monocarboranes generally favors substitution at the B(12) vertex, followed by reaction at B(711). In the absence of Rh(III), chlorination indeed took place at the B(12) position. Prior to this study, no protocols had been described for the selective halogenation of upper-belt boron vertices when BsH bonds in positions 712 were available, so this

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methodology thus offered a useful strategy to prepare otherwise inaccessible halogenated derivatives of the monocarborane anion. For a better understanding of the reaction mechanism, a stoichiometric experiment with Ir(III) was performed. Treatment of the pyrrolidine starting material with one equivalent of IrCp*(OAc)2 in acetonitrile at room temperature afforded the neutral cyclometalated complex in 82% isolated yield (Scheme 8.18). X-ray crystallographic analysis

SCHEME 8.18 Formation of the neutral monocarborane pyrrolidine amide iridacycle.

unambiguously revealed a direct BsIr interaction. The BsIr distance ˚ was comparable to the BsIr distance of the tosyl amide iridaof 2.128 A cycle discussed earlier. Combining this complex with diphenylacetylene in acetonitrile afforded the mono-alkenylated product, suggesting that the complex was a key intermediate in the catalytic cycle. Isocoumarins are fused lactonic heterocycles that have attracted much attention in the field of medicinal chemistry (Fig. 8.9A). They exist

FIGURE 8.9 (A) Core structure of isocoumarins and (B) isocoumarin analogues obtained by fusing the monocarborane cage with unsaturated lactones.

ubiquitously in nature and can be isolated from bacteria, fungi, plants, and insects.74,75 As secondary metabolites featuring a broad range of biological properties, they have been studied with regard to their antiviral, antibacterial, antiinflammatory, and antitumor activities. Significant progress has been made in the synthesis of isocoumarins involving classical organic transformations and also CsH bond activation processes. Formal replacement of one or more carbon atoms by boron allows for the investigation of boracoumarins, a novel class of compounds. In 2018

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Duttwyler and coworkers reported an approach to produce a series of isocoumarins in which the benzene ring is replaced by a monocarborane (Fig. 8.9B).76 The resulting analogues are heterocyclic products with fused 2D/3D aromatic systems. Their strategy was based on TM-induced BsH activation, coupling with an alkyne and subsequent cyclization (Scheme 8.19). In this procedure, the

SCHEME 8.19 Synthesis of isocoumarin analogues by oxidative annulation between monocarboranes and diaryl alkynes.

carboxylic acid group at the C(1) position of the cage first serves as a directing group and then becomes an integral part of the lactonic moiety by OsC bond formation. One-pot oxidative annulation occurred starting from carborane carboxylic acids and diaryl alkynes in the presence of an Ir (III)Ag(I)/Cu(II) catalytic system. The products were isolated upon purification by silica gel chromatography. The established reaction conditions were applied to the generation of an array of derivatives, a selection of which is displayed in Scheme 8.19. Variation of the diaryl alkyne included electrondonating and electron-withdrawing groups, furnishing the products

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in yields of 50%66%; phenyl, methoxyphenyl, and fluorophenyl substituents serve as examples. Remarkably, protecting group-free ketone and thiophene moieties could be used as well. Although the yields were reduced in these cases, the methodology demonstrated the possibility of step-efficient preparation of boraheterocycles, which had not been accessible by traditional cluster chemistry. Furthermore, monocarborane starting materials with substituents such as bromo, ethyl, and phenyl at the B(12) position led to the isocoumarin analogues in yields of 34%66%. Starting from the fused boraheterocycles, the feasibility of subsequent BsH functionalization was probed. In this transformation, the lactone moiety was anticipated to act as the directing group and gives rise to a second BsC bond formation. Under Ir(III) catalysis using slightly modified reaction conditions, alkenylation at the B(4) position occurred with complete regioselectivity (Scheme 8.20). This

SCHEME 8.20 Alkenylation of the isocoumarin analogues by BH activation/BC bond formation at the B(4) position.

concept was applied to the synthesis of symmetrically and unsymmetrically substituted butterfly-shaped products in moderate to high yields. This study showed that the carboxylic acid moiety can serve as a simple yet highly versatile directing group by enabling initial BsH activation, participating in OsC bond formation and finally inducing a second BsC coupling event. Shortly after, Uchiyama, Takita, and coworkers reported on a one-pot process to access fused clusterbiaryl products from the parent monocarborane [CB11H12]2.77 Their strategy involved copper-mediated coupling of the C(1) vertex with cyclic diaryliodonium salts to afford

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2,20 -carborane-iodobiaryl intermediates (Scheme 8.21). This step was immediately followed by palladium-catalyzed BsH bond activation/ BsC bond formation. The use of Cu(I) in the first coupling was crucial; reaction between the C(1) lithiate and diaryliodonium species only

SCHEME 8.21 1

Synthesis of fused monocarboranebiaryl products (yields are based on

H NMR spectra).

caused reduction of the latter without CsC bond formation. The authors also tested conditions under which the palladium catalyst was present from the beginning, but this resulted in significantly reduced yields. The substrate scope for this annulation was examined using a series of disubstituted diaryliodonium triflates. Yields for electron-deficient to moderately electron-rich substrates were in the range of 13%61%, including fluoro, chloro, cyano, ester, and methyl substituents. It must be noted, however, that most products were not isolated in pure form, and NMR yields were given instead. Diaryliodonium salts whose structure could give rise to regioisomers furnished inseparable mixtures of products except for the 5,50 -dichloro starting material. The most remarkable feature of this methodology was that no prefunctionalization of the parent monocarborane cage was necessary. It was, in a way, a directing

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group-free, yet directed annulation with complete regioselectivity with regard to cage vertex substitution. X-ray diffraction studies of Uchiyama’s fused products and the isocoumarin analogues revealed small but characteristic changes in interatomic cluster distances upon cyclization. A slight contraction of the C(1)sB(2) bond was observed, while the other bond lengths were not affected (Fig. 8.10). This finding was in agreement with a certain delocalization of electron density within the newly formed ring.

FIGURE 8.10 Interatomic distances (A˚) in Uchiyama’s cyclization products and the isocoumarin analogues as determined by X-ray crystallography.

The C5v symmetry of the [CB11H12]2 anion prompts the question: Can direct functionalization of the entire upper or lower boron belt, that is, the B(26) or B(711) positions, be achieved? The BsH vertices within each belt feature equal reactivity, and in principle this allows for fivefold substitution, leading to products in which the C5 rotational axis is retained. One the one hand, such a transformation poses an interesting fundamental challenge, but beyond that the resulting compounds constitute intriguing building blocks for applications in areas such as ligand design and supramolecular chemistry. Early studies on the derivatization of monocarboranes showed that under harsh conditions, [CB11H12]2 can be hexahalogenated at the B(712) positions. These reactions afford multiply substituted C5-symmetrical products in a single preparatory step, and this has been an important method to access extremely weakly coordinating and redox-inert anions. On the other hand, direct construction of five or six BsC bonds had not been achieved until recently. The first demonstration of regioselective catalytic fivefold BsH functionalization of the monocarborane cluster, and boron clusters generally speaking, was reported in 2018.78 In this case, the synthetic strategy relied on the carboxylic acid functionality at the C(1) position as the directing group and iodoarenes for coupling with the upper-belt BsH vertices. The anion [1-COOH-CB11H11]2 has the advantage that it is an easily accessible starting material and that the sCOOH group can be used as a functional group handle for, for example, ester or amide

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formation. Successful one-pot, fivefold BsH activation was achieved using a catalytic system that involved Pd(OAc)2, AgOAc, and HOAc plus six equivalents of the iodoarene (Scheme 8.22). The reactions could

SCHEME 8.22 Synthesis of penta-arylated carboranes by Pd-catalyzed coupling with iodoarenes.

conveniently be set up under ambient conditions (air) and required either no or only slight heating. The products were purified by silica gel column chromatography and isolated in generally high yields. Simple phenyl, alkylphenyl, and halophenyl coupling partners were tolerated well. Oxygen- and nitrogen-containing substituents were also compatible with this procedure, among them even a free alcohol. A reduced yield of 59% was observed for coupling with 2-iodonaphthalene. All transformations proceeded with complete regioselectivity at the B(26) positions, thus affording novel C5-symmetrical derivatives of the [CB11H12]2 anion. It was further found that a one-pot, fivefold coupling/decarboxylation cascade took place with 1,3-bromoiodobenzene and a series of other electron-deficient iodoarenes for coupling at a reaction temperature of 60 C. This was the first demonstration of the use of a

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traceless directing group in monocarborane chemistry. Yields were in the range from 82% to 99%, and the method proved particularly efficient in the case of 4-COOR substitution. In addition, directing group removal of more electron-rich products shown in Scheme 8.23 in a separate step, using dimethyl formamide as solvent at 100 C, afforded C(1)sH products in very high yields of 91%99%.

SCHEME 8.23 Synthesis of penta-arylated carboranes by one-pot Pd-catalyzed coupling with iodoarenes and directing group removal.

The reaction mechanism of this fivefold BsH activation was studied in detail by DFT calculations. As a major finding, the computational results strongly indicated that the couplings take place in a merry-goround fashion, that is, the first coupling is followed by arylation at an adjacent B position, and this process continues until the entire upper belt is functionalized. Also, the efficient one-pot penta-arylation/directing group removal could be rationalized; electron-poor aryl substituents make the formation of the dianion [:CB11Ar5H6]22 more favorable, a species that, at least transiently, is generated during decarboxylation. Based on the previous work that had demonstrated the feasibility of direct penta-substitution of monocarborane anions, Duttwyler and coworkers reported a transformation involving oxidative BsH/CsH crosscoupling with alkenes. They introduced five boroncarbon bonds at the B(26) positions, enabling for the first time the preparation of selectively penta-alkenylated boron clusters.79 The procedure started from monocarborane carboxylic acids and aromatic or aliphatic alkenes to furnish the penta-functionalized products

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(Scheme 8.24). A combination of Pd(II) and Ag(I) served as the catalytic system. Notably, the reactions proceeded with high selectivity. Only dehydrogenative coupling was observed, and it occurred with complete regio- and stereoselectivity at the alkene; vinyl-type substitution

SCHEME 8.24

Pd(II)-catalyzed penta-alkenylation of monocarborane carboxylic acids.

products with E configuration were obtained exclusively. The presence of oxygen did not disturb the transformations, thus allowing for a facile set-up in a fume hood under ambient conditions. A series of terminal alkenes were used as starting materials in combination with the parent monocarborane carboxylic acid [1-COOH-CB11H11]2 in order to investigate the substrate scope. Electron-neutral and -deficient styrenes, among them fluorine- and cyano-containing derivatives, gave yields of 53%86%. Electron-rich styrenes were tested as well; however, these substrates afforded only small amounts of penta-substituted product, and analysis of the reaction mixtures showed that compounds with a lower degree of substitution were also present. On the other hand, the reaction proceeded in good to high isolated yields with various steric aliphatic alkenes. Simple hydrocarbons and also substrates containing ester and ether functionalities were well tolerated. Furthermore, the protocol was shown to be reproducible on a gram scale with similar yields. Subsequently, monocarborane starting materials with B(12) substituents such as chloro, bromo, methyl, phenyl, and cyano were probed with styrene and 4-fluorostyrene as coupling partners. A series of pentaalkenylated carboranes was prepared in yields ranging from 69% to 82%. 8. Advances in fundamental main group chemistry, I

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Additional synthetic utility of this BsH functionalization was demonstrated by catalytic reduction of the double bonds with hydrogen on Pd/C in a second step while retaining the directing group, but also by removal of the directing group without affecting the alkenyl substituents. The latter transformation is relevant because it allows for the installation of new groups at the C(1) position. Decarboxylation was accomplished under basic conditions in dimethylacetamide, which provided access to a series of solely B(26)-alkenylated monocarboranes in high yields (Scheme 8.25).

SCHEME 8.25

Base-induced decarboxylation of the penta-alkenylated carboranes.

Per-functionalization of the upper or lower belt of monocarboranes results in clusters featuring a fivefold rotational axis. As a stereochemically intriguing extension, if all the five positions at B(26) or B(711) are substituted by homochiral moieties, a chiral unidirectional cone with C5 symmetry can be designed. Such compounds are interesting from a fundamental stereochemical perspective as well as in the context of recognition of chiral guests and building blocks for chiral supramolecular structures. An optically pure chiral ether was chosen as the coupling partner for penta-alkenylation, and the desired product was obtained in 73% yield (Scheme 8.26). Subsequent experiments, such as using the enantiomer of

SCHEME 8.26

Formation of homochiral, penta-alkenylated carborane carboxylic acids.

the ether and chiroptical measurements, showed that the transformation occurred with the stereogenic centers remaining entirely intact. In order to account for the formation of only vinyl-type (E)-pentaalkenylated products, the authors proposed a selective β-hydride 8. Advances in fundamental main group chemistry, I

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elimination as a key step. In this model, a BsCsCsPd intermediate is formed along the catalytic cycle after BsH activation/BsPd bond formation and insertion of the alkene (Scheme 8.27). Hydride elimination

SCHEME 8.27 Proposed selective β-hydride elimination to account for the observed regio- and stereochemistry.

then takes place selectively at one of the saturated carbon centers to furnish the B-vinyl-type alkenePd complex, which is likely to exhibit greater stability than the alternative allyl-type intermediate. Ag(I)-mediated removal of the formal hydride ligand and similar continuation of the substitution process eventually affords the observed products. Until 2016, the selective catalytic BH activation of dodecaborate clusters had remained unexplored due to the stability of the [B12H12]22 dianion and the challenge of forming Bmetal bonds under mild conditions. Traditional methods to access functionalized dodecaborates primarily rely on reactions with electrophiles or cross-coupling. Reactions using electrophiles under harsh conditions often afford several products from multiple degrees of substitution or from formation of regioisomers.46 Palladium-mediated crosscoupling is possible but requires the presence of a Bhalogen bond in the starting material, introduced by an electrophilic halogen source such as I2.80,81 The exhaustive hydroxylation of [B12H12]22 was reported by Hawthorne and coworkers using H2SO4/SO3 in the presence of a catalyst such as [Pt(bpym)]Cl2, [Pt((NH3)2]Cl2, or [PdCl2] for the one-pot synthesis of [B12(OH)12)]22.82 A reaction mechanism involving an HsMsB (M~Pd, Pt) intermediate for the BsH activation was suggested, but no mechanistic study was carried out. In 2016 Schleid and coworkers reported the first structural evidence of a Bmetal intermediate for BsH bond activation of the [B12H12]22 anion.83 Upon heating, an aqueous mixture of Bi31 cations and [B12H12]22 furnished charge-neutral solvated BisB12H11 complexes by formal metalationdeprotonation. The complexes were characterized by X-ray diffraction and NMR spectroscopy. Schleid’s results made it clear that, under the right conditions, BsH bonds in dodecaborate clusters can be activated in a manner similar to organic aromatic compounds. However, further functionalization of the BsBi bond or transformations using substoichiometric amounts of Bi(III) were not explored. In 2016 Duttwyler and coworkers for the first time demonstrated TMcatalyzed regioselective BsH activation of the dodecaborate cage to synthesize various 1,2,3-trisubstituted derivatives.84 The dimethylureido 8. Advances in fundamental main group chemistry, I

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functionality (sNHC(O)NMe2) was attached to the parent [B12H12]22 to serve as a directing group for metal coordination and subsequent BsH activation. Various reaction conditions were screened to optimize selective coupling of the ureido precursor with internal alkynes in the presence of a Rh(III) catalyst. Using 2.5 mol% [RhCp*Cl2]2 and Cu(OAc)2 as a stoichiometric oxidant afforded the product with regioselective ortho-monoalkenylation and subsequent BsO cyclization to provide 1,2,3-trisubstituted clusters (Scheme 8.28). This process comprising double BsH activation in

SCHEME 8.28 Rh(III)-catalyzed alkenylationannulation of dimethylureido-substituted dodecaborate. 8. Advances in fundamental main group chemistry, I

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acetonitrile did not require oxygen-free or moisture-free reaction conditions and occurred at room temperature within 24 h to afford efficient coupling and cyclization. Minor side products from dialkenylation and direct annulation were observed but could be separated by chromatography. Under the optimized reaction conditions, the methodology was compatible with various electron-rich and electron-deficient aryl substituents moderate to high yields. Notably, unprotected ketones and thiophene rings were tolerated without competing side reactions with Rh(III). Unsymmetrical aryl alkyl alkynes such as MeCRCPh and dialkyl alkynes such as EtCRCEt also afforded the corresponding products with high regioselectivity but in reduced yields. The reaction mechanism of this twofold coupling was studied by isolation of an early key intermediate of the catalytic cycle, a rhodium complex featuring agostic-like BsH interactions (Fig. 8.11). Single-crystal

FIGURE 8.11 Lewis structure and X-ray crystal structure of the early key intermediate of the alkenylationannulation reaction; only BH hydrogen atoms are shown in the ORTEP plot.

X-ray diffraction as well as detailed NMR studies indicated coordination of the Rh(III)Cp* fragment by the ureido oxygen atom and two BsH vertices. Additional control experiments suggested a catalytic manifold comprising BsC coupling followed by BsO coupling and release of the final product. Furthermore, varying the directing group to sNHC(O)NEt2 resulted in a substantial decrease in the yield of the reaction, a finding that underscored the importance of the exact structure of the directing group for BsH activation. The strategy to use N-acyl directing groups for selective BsH activation of the dodecaborate cluster was extended by the same group in 2018.85 Specifically, the starting materials were amides of the type {B12}sNH(CO)Ar. Aryl amides are crucial motifs in organic chemistry as, for example, easily accessible and modifiable pharmacophores in drug discovery, and more recently also as directing groups for CsH activation. The important question at the outset of this study was whether the aromatic CsH bonds or the cluster BsH vertices would be activated preferentially by TMs.

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The aryl amide motif is highly versatile directing group, allowing for various substitution patterns. Rh(III)-catalyzed coupling of electron-rich and electron-poor as well as naphthyl and thiophenyl amides worked well in combination with diphenylacetylene as the alkyne (Scheme 8.29).

SCHEME 8.29 Rh(III)-catalyzed alkenylation/cyclization of dodecaborate amides.

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The transformations were carried out in acetonitrile under ambient conditions. Notably, all dodecaborate starting materials underwent exclusive BsH activation with moderate to high isolated yields of the alkenylated/cyclized products; no competitive aryl CsH activation was observed. Furthermore, the diarylalkyne coupling partner could be varied with very good functional group tolerance. In addition, the utility of the methodology was underscored by subsequent transformations. The alkenylated/cyclized product from the reaction of the 4-iodophenyl amide with diphenylacetylene was cleanly alkynylated by Sonogashira coupling, followed by N-methylation (Scheme 8.30). This sequence occurred in excellent yields, which

SCHEME 8.30 Sonogashira coupling and N-methylation of alkenylated/cyclized dodecaborate.

demonstrated that the C(aryl)I serves as a convenient functional group handle, and, more generally, illustrates that late-stage modification of dodecaborate clusters is possible. Until 2018, the selective B-alkylation of boron clusters under mild conditions had remained an unsolved challenge; methylation and ethylation using strongly electrophilic alkylation agents are possible but are associated with poor control over the degree of substitution and regioselectivity. To overcome this synthetic limitation, the alkylation of the benzamide {B12}sNH(CO)Ph by reductive coupling with different alkenes was probed in the same 2018 study. The reaction with different olefins under Rh(III) catalysis turned out to afford the desired 1,2,3trisubstituted alkylated/cyclized clusters (Scheme 8.31). Electron-rich and electron-deficient styrenes as well as 2-vinylnaphthalene afforded the corresponding products in moderate to good yields. The reaction also tolerated nonaromatic alkenes, notably including unprotected alcohols. Additionally, different aryl amide directing groups were tested in combination with styrene as the coupling partner, furnishing phenethylated

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SCHEME 8.31

381

Rh(III)-catalyzed alkylation/cyclization of the dodecaborate benzamide

{B12}NH(CO)Ph.

products in yields of 54%70% ({B12}sNH(CO)Ar, Ar 5 e.g., p-tolyl, 4-fluorophenyl, 1-naphthyl, 2-naphthyl, 2-thiophenyl). Based on their studies of dodecaborate BsH activation using N-acyl directing groups, Duttwyler and coworkers proposed a mechanistic pathway for the functionalizationcyclization cascade. The dodecaborate amide and RhCp*Ln (L 5 solvent, Cl2 or AcO2) first form a complex with

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agostic-like BsH interactions, as shown in Scheme 8.32. In a formal metalationdeprotonation process, acetate-mediated BsH activation leads to a six-membered rhodacycle with a direct BsRh bond. Subsequent coordina-

SCHEME 8.32 Proposed mechanism for the Rh(III)-catalyzed functionalization/cyclization of N-acyl-substituted dodecaborates (L 5 solvent, Cl2 or AcO2).

tion/insertion of the alkyne/alkene affords an intermediate with BsCsCsRh connectivity. Subsequent alkenyl/alkyl ligand protonation followed by a Rh shift leads to a second agostic-like complex, which undergoes another BsH activation/cyclization step to form the BsO bond. Upon this reductive elimination, decomplexation releases the final product and Rh(I). Cu(II) reoxidizes Rh(I) to Rh(III), which enters a new catalytic cycle. In 2018 Duttwyler and coworkers reported a metal-free reaction for the facile synthesis of fused dodecaborate-diboraoxazoles by BsO bond formation.86 Clean mono-acylation of [B12H11(NH3)]2 with several acyl chlorides was accomplished at room temperature under mild conditions

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(Scheme 8.33). This protocol involved deprotonation of the NH3 functionality by NaH and required only 1.1 equivalent of acylation agent in dry THF solvent. The reaction tolerated various acylating reagents with

SCHEME 8.33 Synthesis of dodecaborate amide and cyclization to give fused diboraoxazoles.

different steric and electronic properties to afford corresponding N-acylation products in high yields. These products were subsequently utilized for the formation of the fused dodecaborate-diboraoxazoles. Cyclization of the acylation products was explored using different reaction conditions involving [RhCp*Cl2]2 along with various oxidants such as AgI or CuII and also metal-free oxidants such as iodine(III) reagents. Remarkably, using the reagent PhI(OAc)2 in MeOH, cyclization occurred smoothly to afford the desired fused diboraoxazoles in high yields within 10 min. Notably, the reaction required only one equivalent of PhI(OAc)2 for complete conversion that included BsH to BsO bond transformation. The reaction proceeded efficiently with all N-acyl substrates to afford the corresponding cyclized products.

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The hybrid 3D-/2D-fused diboraoxazoles resemble benzoxazoles, which are flat aromatic organic N,O-heterocycles. Benzoxazoles are constituents of many synthetic pharmaceutical and agrochemical compounds as well as natural products. They also feature a wide range of bioactivities, such as antiinflammatory, antiproliferative, and antimicrobial properties. Thus the dodecaborate-diboraoxazoles can be viewed as 3D analogues of classical benzoxazoles. In order to probe their bioactive features, the antimicrobial activity of the diboraoxazole compounds was studied against Neisseria gonorrhoeae, Staphylococcus aureus, and Enterococcus faecalis. Some of the synthesized compounds displayed minimal inhibitory concentrations of 416 μg mL21 against N. gonorrhoeae, which was found to be more efficient than some of the marketed antibiotics such as azithromycin and ciprofloxacin. Interestingly, control compounds involving only benzoxazoles without the boron cluster moiety displayed lower activity, which highlighted the importance of the cage for the antibacterial activity. Thus these boraneheterocycle hybrid compounds are promising candidates for further assays in which diverse biological targets are probed. In addition, they are novel examples of the concept “escape from the flatland,” which is based on the organic synthetic strategy to start from a flat aromatic molecule and modify a part of it in such a way that it becomes more threedimensional, for example, by introducing saturated carbon centers.

8.5 Outlook The results summarized in this chapter demonstrate the rapid progress that has been made in terms of derivatization of anionic boron cages over the last few years. BsH activation is a fascinating field to explore for inorganic and synthetic organic chemists alike. The catalytic protocols allow for product preparation in a small number of steps, and they also provide routes to compounds hitherto inaccessible by electrophilic substitution or halogenationcross-coupling methods. Notable features of the new methodologies are very good control over regioselectivity and degree of substitution as well as a broader variety of substituents that can be introduced at the boron vertices. Compared to the impressive findings and rich literature from the field of CsH activation, TM-mediated BsH functionalization is a research area where efforts in several directions are still highly desirable. In terms of fundamental studies, details of the mechanistic manifolds must be more fully investigated, and to this end, state-of-the-art calculations will require to be involved. An improved understanding of certain steps or entire catalytic cycles will likely allow the synthetic community to more easily optimize reaction conditions and use new coupling partners to form BsX bonds. Also, the development of protocols based on earth-abundant metals such as manganese, iron, cobalt, and nickel is an important goal.

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Such an extension of the synthetic toolbox will have a significant impact on the preparation of specifically designed boron clusters and their future applications.

Acknowledgements Financial support by the National Natural Science Foundation of China (No. 21871231 and 21850410451) and the Special Funds for Basic Scientific Research of Zhejiang University (No. 2019QNA3010 and 2018QNA3011) is gratefully acknowledged.

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64. Molinos, E.; Kociok-Ko¨hn, G.; Weller, A. S. Polyethyl Substituted Weakly Coordinating Carborane Anions: A Sequential Dehydrogenative BorylationHydrogenation Route. Chem. Commun. 2005, 36093611. 65. Molinos, E.; Brayshaw, S. K.; Kociok-Ko¨hn, G.; Weller, A. S. Sequential Dehydrogenative Borylation/Hydrogenation Route to Polyethyl-Substituted, Weakly Coordinating Carborane Anions. Organometallics 2007, 26, 23702382. 66. Molinos, E.; Brayshaw, S. K.; Kociok-Ko¨hn, G.; Weller, A. S. Cationic Rhodium MonoPhosphine Fragments Partnered with Carborane Monoanions [closo-CB11H6X6]2 (X~H, Br). Synthesis, Structures and Reactivity with Alkenes. Dalton Trans. 2007, 48294844. 67. El-Hellani, A.; Kefalidis, C. E.; Tham, F. S.; Maron, L.; Lavallo, V. Structure and Bonding of a Zwitterionic Iridium Complex Supported by a Phosphine with the Parent Carba-closo-dodecaborate CB11H112 Ligand Substituent. Organometallics 2013, 32, 68876890. 68. Estrada, J.; Lee, S. E.; McArthur, S. G.; El-Hellani, A.; Tham, F. S.; Lavallo, V. Resisting BH Oxidative Addition: The Divergent Reactivity of the o-Carborane and Carbacloso-Dodecaborate Ligand Substituents. J. Organomet. Chem. 2015, 798, 214217. 69. Zhang, C.; Ma, D. Activation of BH Bonds in Ir(I) Complexes Supported by Phosphine with Carba-closo-Dodecaborate and o-Carborane Ligand Substituents: A DFT Investigation. J. Organomet. Chem. 2016, 819, 242247. 70. Chan, A. L.; Estrada, J.; Kefalidis, C. E.; Lavallo, V. Changing the Charge: Electrostatic Effects in Pd-Catalyzed Cross-Coupling. Organometallics 2016, 35, 32573260. 71. Shen, Y.; Pan, Y.; Liu, J.; Sattasathuchana, T.; Baldridge, K. K.; Duttwyler, S. Synthesis and Full Characterization of an Iridium BsH Activation Intermediate of the Monocarba-closo-Dodecaborate Anion. Chem. Commun. 2017, 53, 176179. 72. Shen, Y.; Pan, Y.; Liu, J.; Sattasathuchana, T.; Baldridge, K. K.; Duttwyler, S. Transition Metal Complexes of a Monocarba-closo-Dodecaborate Ligand via BsH Activation. Eur. J. Inorg. Chem. 2017, 44204424. 73. Shen, Y.; Pan, Y.; Zhang, K.; Liang, X.; Liu, J.; Spingler, B.; Duttwyler, S. BsH Functionalization of the Monocarba-closo-Dodecaborate Anion by Rhodium and Iridium Catalysis. Dalton Trans. 2017, 46, 31353140. 74. Saeed, A. Isocoumarins, Miraculous Natural Products Blessed with Diverse Pharmacological Activities. Eur. J. Med. Chem. 2016, 116, 290317. 75. Saddiqa, A.; Usman, M.; Cakmak, O. Isocoumarins and 3,4-Dihydroisocoumarins, Amazing Natural Products: A Review. Turk. J. Chem. 2017, 41, 153178. 76. Lin, F.; Shen, Y.; Zhang, Y.; Sun, Y.; Liu, J.; Duttwyler, S. Fusing Carborane Carboxylic Acids with Alkynes: 3D Analogues of Isocoumarins via Regioselective BsH Activation. Chem. Eur. J. 2018, 24, 551555. 77. Akimoto, G.; Otsuka, M.; Miyamoto, K.; Muranaka, A.; Hashizume, D.; Takita, R.; Uchiyama, M. One-Pot Annulation for Biaryl-fused Monocarba-closo-Dodecaborate Through Aromatic BsH Bond Disconnection. Chem. Asian J. 2018, 13, 913917. 78. Lin, F.; Yu, J.-L.; Shen, Y.; Zhang, S.-Q.; Spingler, B.; Liu, J.; Hong, X.; Duttwyler, S. Palladium-Catalyzed Selective Five-Fold Cascade Arylation of the 12-Vertex Monocarborane Anion by BsH Activation. J. Am. Chem. Soc. 2018, 140, 1379813807. 79. Shen, Y.; Zhang, K.; Liang, X.; Dontha, R.; Duttwyler, S. Highly Selective PalladiumCatalyzed One-Pot, Five-Fold BsH/CsH Cross Coupling of Monocarboranes with Alkenes. Chem. Sci. 2019, 10, 41774184. 80. Himmelspach, A.; Finze, M.; Vo¨ge, A.; Gabel, D. Cesium and Tetrabutylammonium Salt of the Ethynyl-closo-Dodecaborate Dianion. Z. Anorg. Allg. Chem. 2012, 638, 512519. 81. Peymann, T.; Knobler, C. B.; Hawthorne, M. F. Synthesis of Alkyl and Aryl Derivatives of closo-[B12H12]22 by the Palladium-Catalyzed Coupling of closo[B12H12]22 with Grignard Reagents. Inorg. Chem. 1998, 37, 15441548.

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82. Bondarev, O.; Hawthorne, M. F. Catalytic Hydroxylation of [closo-B12H12]22  Adaptation of the Periana Reaction to a Polyhedral Borane. Chem. Commun. 2011, 47, 69786980. 83. Zimmermann, L. W.; Van, N.-D.; Gudat, D.; Schleid, T. Bismuth Undecahydro-closoDodecaborane: A Retainable Intermediate of BsH Bond Activation by Bismuth(III) Cations. Angew. Chem. Int. Ed. 2016, 55, 19091911. 84. Zhang, Y.; Sun, Y.; Lin, F.; Liu, J.; Duttwyler, S. Rhodium(III)-Catalyzed AlkenylationAnnulation of closo-Dodecaborate Anions Through Double BsH Activation at Room Temperature. Angew. Chem. Int. Ed. 2016, 55, 1560915614. 85. Zhang, Y.; Wang, T.; Wang, L.; Sun, Y.; Lin, F.; Liu, J.; Duttwyler, S. Rh(III)-Catalyzed Functionalization of closo-Dodecaborates by Selective BsH Activation: Bypassing Competitive CsH Activation. Chem. Eur. J. 2018, 24, 1581215817. 86. Sun, Y.; Zhang, J.; Zhang, Y.; Liu, J.; van der Veen, S.; Duttwyler, S. The closoDodecaborate Dianion Fused with Oxazoles Provides 3D Diboraheterocycles with Selective Antimicrobial Activity. Chem. Eur. J. 2018, 24, 1036410371.

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S E C T I O N

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C H A P T E R

9 Coordination of N-heterocyclic carbene to SiSi and PP multiple bonded compounds Anukul Jana Tata Institute of Fundamental Research Hyderabad, Hyderabad, India

9.1 Introduction Elements of the second-row such as carbon, nitrogen, or oxygen readily form multiple bonds among themselves resulting in a vast number of chemical compounds. In contrast, isolable compounds having multiple bonds between heavier main-group elements such as silicon or phosphorus have remained elusive for a very long time.1 This has resulted in a formalized classical double bond rule which states that “elements having a principal quantum number greater than 2 should not be able to form (p-p)-π bonds with themselves or with other elements.”2 Subsequently, in 1976, Lappert et al. reported the molecular structure of the first distannene compound, [Sn{CH(SiMe3)2}2]2, 2, a compound that can be considered as possessing a tintin double bond (Scheme 9.1).3 The synthesis of 2 involves a metathesis reaction of either SnCl24 or Sn[N(SiMe3)2]2, 1 with 2 equivalents of the bulky alkyl lithium

SCHEME 9.1 Synthesis of distannene 2.

Synthetic Inorganic Chemistry DOI: https://doi.org/10.1016/B978-0-12-818429-5.00005-3

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© 2021 Elsevier Inc. All rights reserved.

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(Me3Si)2CHLi (Scheme 9.1). The X-ray single-crystal analysis reveals a ˚ , with both tin centers possessing a nontintin bond distance of 2.764 A planar geometry. Finally in 1981, landmark reports appeared of the isolation of siliconsilicon double bonded compound (disilene) by West et al.5 and phosphorusphosphorus double bonded compound (diphosphene) by Yoshifuji et al.6 For the synthesis of the first isolable disilene 5, West et al. considered 2,2-bis(2,4,6-trimethylphenyl)hexamethyltrisilane 3 as a precursor (Scheme 9.2). Photolysis of 3 with 254 nm ultraviolet light in hydrocarbon solution leads to the formation of tetramesityldisilene 5 as a bright orange-yellow crystalline solid. The formation of tetramesityldisilene 5 is via the initially formed divalent silicon intermediate, dimesitylsilylene 4. Compound 5 exhibits a singlet resonance at δ 5 63.6 ppm ˚ with a in its 29Si NMR spectrum. The SiSi bond distance is 2.160 A 7 trans-bent geometry around the disilene motif.

SCHEME 9.2

Synthesis of disilene 5.

In the case of the first isolable diphosphene 8 Yoshifuji et al. considered super-mesityl as a substituent at the phosphorus center and the corresponding dichloro derivative 6 has been considered as a synthon (Scheme 9.3). Accordingly the reaction of 6 with Mg leads to 8 under reductive coupling in a 54% yield. Compound 8 is thermally stable and can be handled in air. In the first report the 31P NMR resonance for compound 8 was reported at δ 5 259.0 ppm. Later, however, Cowley et al. investigated compound 8 and

SCHEME 9.3

Synthesis of diphosphene 8.

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395

found its 31P resonance to be δ 5 494.0 ppm. Moreover, they also looked into the source of the resonance reported at δ 5 259.0 ppm (actually it was 264.0 ppm). It was revealed to result from diphosphane, which can be regarded as the product of the oxidative addition of dihydrogen to the phosphorusphosphorus double bond of 8.8 Solid-state molecular structure anal˚ with ysis reveals the phosphorusphosphorus bond distance to be 2.034 A 7 the two aryl groups in a trans-orientation. In all of these examples, steric encumbrance around the heavy maingroup elements allowed kinetic stabilization of the multiply bonded compounds (Schemes 9.19.3). These reports opened the flood gates and since then several homo- and heteroatomic multiple bonded compounds involving heavier main-group elements have been reported.9 In the case of siliconsilicon triple bonded compounds, in 2002 Wiberg et al. first reported the formation of disilyne as an oxygensensitive orange-red solution by the reduction of a 2,3-dichlorodisilene 9 with lithium naphthalenide (LiC10H8) in tetrahydrofuran (THF) at 278 C (Scheme 9.4).10 The 29Si NMR spectrum of 10 exhibits a signal at δ 5 91.5 ppm for the silicon nuclei of the disilyne moiety along with other signals at higher fields. The investigators were unable to grow suitable single crystals for X-ray structural analysis.

SCHEME 9.4 Synthesis of disilyne 10.

In 2004 the formation of disilyne was verified by a formal [2 1 2]cycloaddition reaction between the siliconsilicon triple bond and ethene (Scheme 9.5).11

SCHEME 9.5 Formal [2 1 2]-cycloaddition reaction of 10 with ethylene.

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In 2004 Sekiguchi et al. reported the first crystalline siliconsilicon triple bonded compounds by the reduction of 2,2,3,3-tetrabromo-1,1,4,4-tetrakis[bis (trimethylsilyl)methyl]-1,4-diisopropyltetrasilane with 4 equivalents of KC8 in THF (Scheme 9.6).12 It produces 1,1,4,4-tetrakis[bis(trimethylsilyl)methyl]1,4-diisopropyl-2-tetrasilyne, a stable compound with a siliconsilicon triple bond as an emerald green crystalline solid. The 29Si NMR spectrum exhibits a signal at δ 5 89.9 ppm for the silicon nuclei of the disilyne moiety along with other signals at higher fields, similar to that of Wiberg’s disilyne 10 (δ 5 91.5 ppm).10 The solid-state structural analysis shows that the ˚ . The substituents at the silicon siliconsilicon triple bond length is 2.062 A centers of the disilyne moiety are arranged in a trans-bent orientation.12 Subsequently, disilynes with aryl and alkyl substituents have been reported.13

SCHEME 9.6

Synthesis of disilyne 13.

In the meantime in 1991 Arduengo III et al. first reported the stable crystalline N-heterocyclic carbene (NHC) 15 (Scheme 9.7).14 Since the first isolation of NHC by Arduengo III et al., there have been continuous reports of various isolable carbenes15 and, moreover, NHCs have found application in transition metal catalysis16 as well as in organocatalysis.17

SCHEME 9.7

Synthesis of N-heterocyclic carbene 15.

In this chapter, the chemistry of NHC coordination to siliconsilicon and phosphorusphosphorus multiple bonded compounds will be discussed.

9.2 NHC coordination to a SiSi triple bonded compound In 2010 Sekiguchi et al. first demonstrated that disilyne 13 with 1,3,4,5-tetramethylimidazol-2-ylidene, an N-heterocyclic carbene, NHC

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16 can coordinate to the siliconsilicon triple bonded functionality (Scheme 9.8).18 As a result it produced the disilyneNHC complex 17. Upon NHC coordination, the two silicon nuclei of the disilyne moiety became magnetically nonequivalent. Therefore the 29Si NMR spectrum exhibits resonances at δ 5 28.7 (NHC-Si-Si) and 276.3 (NHC-Si-Si) ppm. In the solid state, the SiSi double bonded motif adopts a trans-geometry. The disilyne 13 does not form a 1:2 complex with NHC, 16 even in the presence of an excess of 16.

SCHEME 9.8 Reaction of disilyne 13 with NHC 16.

In compound 17 the lone pair electrons residing on two-coordinated Si atoms have been utilized in complexation with ZnCl2 (Scheme 9.9).18 Upon complexation of 17 with ZnCl2, the disilyne-NHC-ZnCl2 complex 18 was produced, in which the central siliconsilicon bond adopted the cis-geometry. The 29Si NMR spectrum exhibits resonances at δ 5 66.9 (NHC-Si-Si) and 190.8 (NHC-Si-Si-ZnCl2) ppm for the two silicon nuclei of the disilyne motif. In the solid state, the SiSi double bonded motif adopts a trans-geometry.

SCHEME 9.9 Reaction of NHC-coordinated disilyne 17 with ZnCl2.

Compound 17 can also react with MeOTf under the formation of 19, which is the first example of a base-stabilized heavy group 14 element analogue with vinyl cation character (Scheme 9.10).19 The molecular structure indicates that there are significant contributions from the NHC-stabilized cationic resonance structure, the disilene-like structure, and even some contribution from the silylene-like structure.

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SCHEME 9.10

Reaction of NHC-coordinated disilyne 17 with MeOTf.

9.3 Reversible NHC coordination to SiSi double bonded compounds NHC coordination to a cyclotrisilene, a molecule containing the siliconsilicon double bonded functionality, is known. In 2012 Scheschkewitz et al. reported the coordination of 1,3-diisopropyl-4,5dimethylimidazol-2-ylidene an N-heterocyclic carbene, NHC 21 to a cyclotrisilene 20 (Scheme 9.11).20 The reaction of 20 with 21 in hexane at 220 C resulted in the formation of an adduct 22 with an immediate color change to deep red. Red crystals of 22 were obtained in a 48% yield. The coordination of the NHC to the cyclotrisilene 20 causes an upfield shift for all of the 29Si signals of 22 that were unambiguously assigned by 1 H/29Si 2D NMR spectroscopy. The 13C chemical shift of the carbene center of 22 at δ 5 161.4 ppm is shifted by Δδ 5 44.5 ppm with respect to the free NHC 21 (δ 13C 5 205.7 ppm).21 A similar upfield 13C shift had been observed when upon NHC coordination to disilyne.18

SCHEME 9.11

Reversible NHC 21 coordination to cyclotrisilene 20.

Unlike in the case of 13, however, complex formation is reversible, as variable temperature NMR studies show that 22 dissociates in solution (Scheme 9.11). Although 20 and 22 thus coexist at room temperature in comparable concentrations, only signals for the adduct 22 are observed at 223K. The Gibbs free energy change of the dissociation process at 298K is estimated at ΔG 5 9 kJ mol21.

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SCHEME 9.12 Reversible NHC 21 coordination to cyclotrisilene 23.

Subsequently, Scheschkewitz et al. considered the fully arylsubstituted cyclotrisilene 23 for the coordination of 1,3-diisopropyl-4,5dimethylimidazol-2-ylidene 21 (Scheme 9.12).22 The 1:1 reaction of 23 and 21 at room temperature led to an immediate color change to dark green. The 29Si NMR shows the three new resonances at δ 5 101.99, 53.89, and 260.54 ppm in an equal ratio along with resonances for 23, indicating a partial conversion into a new species. The two low-field signals are diagnostic of a siliconsilicon double bond unperturbed by coordination of a Lewis base and/or incorporation into a small ring system. Indeed, the 29Si NMR signal at δ 5 260.54 ppm is consistent with an NHC-coordinated silylene moiety. The 13C signal of the carbenic carbon atom at δ 5 173.42 ppm was shifted upfield by Δδ 5 32 ppm compared to that of free NHC 21, which indicates involvement in a donoracceptor interaction. Disilenyl silylene 25 was isolated as darkgreen crystals in 23% yield by crystallization from cyclohexane. Moreover, in case of fully aryl-substituted cyclotrisilene 23 the NHCcoordinated complex also formed at very low temperatures. Combination of 23 and 21 at 183K afforded a dark-red solution as opposed to the dark-green color of 25. The 29Si NMR spectrum at 210K displays three high-field resonances at δ 5 245.57, 295.27, and 2126.76 ppm, which are assigned to the cyclic cyclotrisileneNHC adduct 24 on the basis of their similarity to those of 22. As expected, the cyclotrisileneNHC adduct 24 was thermally unstable and slowly rearranged to give the disilenyl silylene adduct 25, even at 210K

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(approximately 30% conversion after 2.5 h at 210K). On warming tions of 24 to room temperature, only 25 and free 23 and 21 observed by NMR spectroscopy. However, shock freezing of such tions to liquid nitrogen temperatures followed by warming to resulted in the formation of mixtures of 25 and 24.

soluwere solu210K

9.4 Reversible NHC coordination to PsP double bonded compounds In 2017 Matsuo et al. reported cleavage of a PQP double bond mediated by NHC (Scheme 9.13).23 They considered bulky aryl-substituted diphosphene24 based on a fused-ring octa-R-substituted s-hydrindacene skeleton (Rind groups) for this study.25 In case of Eind-substituted diphosphene, it required 11 days at room temperature and for EMindsubstituted diphosphene 2 h were needed to complete the reaction (Scheme 9.13). They did not observe any intermediates during this conversion; however, they proposed the NHC-coordinated highly polarized diphosphene as an intermediate.

Rind P P

+

Rind

N

N

N

Rind P

N

N

N P

P Rind

Rind

26a (Eind) 26b (EMind)

Rind

SCHEME 9.13

27a 27b

16 R1 R1

R2 R2

R1 R1

R2 R2

=

28a 28b

Eind: R1 = R2 = Et EMind: R1 = Et, R2 = Me

Reversible NHC coordination to diphosphene 26.

To address the possible formation of phosphinidene as an intermediate, they performed the crossover experiment between the Eind- and EMind-substituted diphosphenes 26a and 26b at 110 C in toluene-d8. No 31P resonances due to an unsymmetrical diphosphene 29 were observed (Scheme 9.14).23

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SCHEME 9.14 Reaction of two diphosphenes 26a and 26b.

Subsequently, in 2019 our group studied NHC coordination to a terphenyl-substituted diphosphene.26 The 1:1 reaction of diphosphene 30 with NHC 16 leads to the isolation of the NHC-coordinated diphosphene 31 (Scheme 9.15).

SCHEME 9.15 Reversible NHC coordination to a diphosphene 30.

The 31P{1H} NMR spectrum of the 1:1 reaction mixture of 30 and 16 at room temperature showed two upfield doublets of equal intensity at δ 5 295.36 and 20.78 ppm (1JPP 5 423 Hz) along with the signal of the free diphosphene 30 at δ 5 492 ppm in an approximate 70:30 ratio. As this ratio remained unaltered even after 2 h, we suspected that the coordination of NHC might indeed be reversible. The remarkable difference in the chemical shifts accompanied by a large coupling constant proves the presence of two nonequivalent phosphorus nuclei in different electronic environments, consistent with the formation of the NHCdiphosphene adduct 31 (Scheme 9.15). In order to quantify the thermodynamic parameters (ΔG, ΔH, and ΔS) and equilibrium constants of the binding of 16 with 30, we recorded the variable temperature 31P NMR spectra of the 1:1 mixture in toluene-d8 solution. The value of the Gibbs free energy change thus obtained was ΔG298 5 211.2 6 1.1 kJ mol21.

9.4.1 Thermodynamic data of equilibrium between 30 and 31 A 0.0805 M solution (0.4 mL Tol-d8) of 30 and 16 was prepared in an NMR tube and the 31P and 1H spectra were measured at 10K

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TABLE 9.1 Concentrations for 30, 16, and 31 determined via spectroscopy at a range of temperatures.

31

P NMR

SI. No.

T (K)

30 (mM)

16 (mM)

31 (mM)

K (M)

ΔG (kJ mol21)

1

253

4.83

4.83

75.67

3243.62

217.01

2

263

7.24

7.24

73.25

1397.43

215.84

3

273

10.46

10.46

70.03

640.06

214.67

4

283

16.1

16.1

64.4

248.44

212.97

5

293

21.73

21.73

58.76

124.44

211.75

temperature intervals between 253K and 293K. The integration of the 31 P resonances for 30 and 31 allowed the concentration of both components to be determined (Table 9.1). Equilibrium constants for each temperature were calculated from the corresponding free energy changes. The entropy (ΔS) and enthalpy (ΔH) changes were calculated using the van’t Hoff equation ln K 5 2ΔH/ RT 1 ΔS/R. The linear regression of 1/T versus ln K led to the values of ΔH298 5 250.74 6 1.09 kJ mol21, ΔG298 5 211.15 6 1.07 kJ mol21, and ΔS298 5 2132.85 6 2.56 J mol21 K21 (Fig. 9.1). In order to further substantiate the reversibility of NHC coordination, we monitored the changes in the absorption of 30 (in THF) with increasing concentrations of 16 by UV/vis spectroscopy (Fig. 9.2). A THF solution of

FIGURE 9.1 Plot of ln K (as y) versus 1/T (as x) for the equilibrium between 30 1 16 and 31.

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FIGURE 9.2 UV/vis spectra of 30 with increasing concentrations of 16.

free diphosphene 30 absorbs at λmax 5 448, 372, and 317 nm. Upon gradual addition of 16, the absorbance at 448 nm increases while the absorbance at 372 nm decreases in intensity as the equilibrium is shifted toward 31. The absorbance at λ 5 317 nm is shifted to λ 5 324 nm when the concentration of 16 exceeds 1.11 equivalents (1.33, 2.22, and 4.44 equivalents). A clear isosbestic point is revealed at λ 5 392 nm (Fig. 9.2). From the UV/vis studies, the Gibbs free energy of formation of 31 is estimated as ΔG298 5 213.30 kJ mol21, which is close to the value obtained from the variable temperature NMR study (ΔG298 5 211.2 6 1.1 kJ mol21).

9.4.2 Calculation of thermodynamic parameters using UV/vis spectra A series of solutions with varying concentrations of 30 and 16 were prepared, as shown in Table 9.2. Spectra were recorded in THF at 298K and the absorption maxima at 372 and 448 nm were noted (Table 9.2). Absorbance versus relative concentration of added 16 was plotted following the equation Lb 5 1/2{1/K 1 St 1 Lt 2 O( 〖(1/K 1 Lt 1 St)〗 ^24StLt)} (Fig. 9.3),27 where Lb is equivalent to total absorbance (A), St is total concentration of diphosphene, and Lt is the concentration of carbene added. The single-crystal X-ray diffraction analysis of 31 reveals that 16 is coordinated to one of the P-centers of the former diphosphene moiety (Fig. 9.4). ˚ , longer than that observed in The PaP bond length in 31 is 2.134(2) A 28 ˚ 30 (2.029(1) A). The calculated Wiberg bond order (30: 1.812; 31: 1.116) and the partial natural bond orbital charges (30: P1 5 0.280, P2 5 0.326; 31: P1 5 0.494, P2 5 20.116) at the B3LYP/6-311 G(d,p) level of theory clearly

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TABLE 9.2 Concentrations and absorbance for the UV/vis titration of 30 with 16. Equivalents 16

A at 448 nm

A at 372 nm

SI. No.

30 (mM)

16 (mM)

1

1.0885

0

0.00

0.07986

1.27887

2

1.0885

0.1208

0.11

0.09496

1.23762

3

1.0885

0.2416

0.22

0.11675

1.21381

4

1.0885

0.3624

0.33

0.14963

1.21213

5

1.0885

0.6039

0.55

0.17802

1.13718

6

1.0885

1.2079

1.11

0.24104

1.03872

7

1.0885

1.4495

1.33

0.28081

1.06244

8

1.0885

1.9327

1.77

0.2989

1.06942

9

1.0885

2.4158

2.22

0.36518

1.03378

10

1.0885

2.8990

2.66

0.40283

1.05193

11

1.0885

3.3822

3.10

0.45361

1.04477

12

1.0885

3.8653

3.55

0.44189

1.04033

13

1.0885

4.8317

4.44

0.45351

0.99947

FIGURE 9.3 Curve fitting for determination of the equilibrium constant K for the equilibrium between 30 1 16 and 31 by UV/vis spectroscopy.

indicate elongation and polarization of the PQP bond upon coordination of NHC. The carbenic carbon C1 is connected to the P1 center with an angle of 113.26(18) degrees with respect to P1aP2 bond vector. The two terphenyl ligands adopt a trans-arrangement with a torsion angle of C8 2 P1 2 P2 2 C32 5 166.8(2) degrees. The bond distance between ˚ and hence carbenic carbon and coordinated phosphorus in 31 is 1.876(2) A 9. Advances in fundamental main group chemistry, II

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FIGURE 9.4 Molecular structure of 31 (thermal ellipsoids at 50% probability; hydrogen atoms omitted for clarity).

FIGURE 9.5 HOMO and HOMO-1 orbitals of compound 31 at 0.04 atomic units.

slightly greater than the corresponding distance in NHCMe4-coordinated ˚ ).29 phosphaalkene, MesP 5 CPh2 (1.8512 A The two nonbonding electron pairs at P2 implied by the ylidic nature of 31 correspond to the HOMO and HOMO-1 (Fig. 9.5). While the HOMO almost exclusively consists of a p-orbital centered on the formally negatively charged P center, the HOMO-1 is delocalized across the PaP unit. Subsequently, to address the complete cleavage of the PaP bond in 31, we monitored the 1:2 reaction between 30 and 16 (Scheme 9.16).

SCHEME 9.16

Synthesis of NHC-coordinated phosphinidene 32 from diphosphene 30.

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FIGURE 9.6 Molecular structure of 32 showing thermal ellipsoids at 50% probability level; all hydrogen atoms are omitted for clarity.

After 4 days, a color change from deep red to yellow occurred and the appearance of a new 31P resonance at δ 5 277 ppm was observed, in the range for a carbene-stabilized phosphinidene.30 Subsequently, the reaction mixture was heated at 105 C for 30 h to ensure complete dissociation resulting in the formation of 32 (Scheme 9.16). The formation of 32 from 30 provides strong experimental corroboration for the mechanism proposed by Matsuo and coworkers for the NHC-mediated cleavage of a PQP bond in a diphosphene (Scheme 9.13).23 The distance between phosphorus and the carbenic carbon in 32 is ˚ (Fig. 9.6), which is comparable with that reported for an 1.786(2) A NHC-stabilized phosphinidene.31 However, it is shorter than that ˚ ). between phosphorus and the carbenic carbon in 31 (1.8306(19) A Subsequently, in a wider systematic study of NHC coordination of diphosphene we have considered other NHCs with different electronic and steric natures (Scheme 9.17).21,32

SCHEME 9.17

Chemical structures of NHCs considered for the coordination study to

diphosphene 30.

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Room temperature solution state 31P NMR studies revealed that 33 binds with 30 to form approximately 20% of 39 (Scheme 9.18).33 On the other hand, with 16 70% adduct formation is observed under similar conditions (Scheme 9.15).34 This observation suggests that 16 is more nucleophilic than 33, which is in accordance with the calculated Tolman electronic parameters (TEP) [ʋ (cm21) 5 2051.7 for 16 and 2054.1 for NHCMe2].35 The other NHCs that we employed did not show any adduct formation at room temperature, presumably because of their lower nucleophilicity arising from increased steric bulk. As entropy should favor adduct formation at lower temperature, variable temperature 31P NMR of the corresponding mixtures of NHCs with 30 expectedly revealed first indications of 40 at 273K, whereas the observation of 41 required a temperature as low as 233K (Scheme 9.18). Conversely, 21, 36, 37, and 38 do not appear to indulge in adduct formation even at 193K.

SCHEME 9.18 Reversible NHC coordination to a diphosphene 30.

From the 31P NMR spectra, the formation of 39 and 41 is indicated by the presence of two doublets with the same coupling constant. In the case of 40, the differing N-substitution in concert with hindered rotation about the PaC bond between the carbenic carbon and phosphorus leads to the formation of diastereomers. Therefore the 31P NMR spectrum of 40 shows two sets of doublets centered at 19.1 and 287.6 ppm (1JPP 5 405 Hz) and 1.1 and 292.6 ppm (1JPP 5 430 Hz), the latter being attributable to the major isomer. In order to quantify the thermodynamic parameters (ΔG, ΔH, and ΔS) and equilibrium constants for the binding of 33, 34, and 35 with 30, variable temperature 31P NMR spectra of the corresponding 1:1 mixtures were recorded in toluene-d8 solutions. The resulting ΔG298 for 33 is 23.6 6 1.3 kJ mol21, which is less negative than that for 16 (ΔG298 5 211.2 6 1.1 kJ mol21).34 This clearly indicates that 33 is a weaker donor than 16. On the other hand, the ΔG298 for 34 and 35 was 15.8 6 3.51 and 120.9 6 7.81 kJ mol21, respectively. Bright red single crystals of 39 were obtained from a saturated toluene solution at 235 C along with 30. Due to the pronounced polarization of the PQP moiety of 30 upon coordination of 16, an enhanced reactivity was anticipated. We probed the

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addition reactions of water in the presence of 16 as NHC-free diphosphene 30 is inert toward hydrolysis (Scheme 9.19). Thus far, only the hydrolysis of Lewis acidcoordinated diphosphene and heteroleptic diphosphenes has been reported.36 Addition of 1 equivalent of H2O to a THF solution of 31 (1:1 mixture of 30 and 16) at room temperature led to an immediate color change from red to yellow (Scheme 9.19). The observation of four new multiplets in the 31P NMR spectrum comprised of two pairs of multiplets of equal intensity at δ 5 9.55 and 277.36 ppm and δ 5 28.50 and 246.76 ppm indicate complete conversion to two new species.

SCHEME 9.19

Stoichiometric reaction of H2O with mixture of 30 and 16.

Indeed, the molecular structure determination reveals the formation of phosphino-substituted phosphine oxide 43 (Fig. 9.7) and phosphido phosphine oxide 44 (Fig. 9.8) in the course of reaction (Scheme 9.19). The solid-state structures of these two compounds match well with the ˚ solution state NMR data. The PaP distances involved are 2.1946(8) A ˚ for 43 and 2.1099(11) A for 44. These distances are longer than those in ˚ , 31: 2.134 A ˚ ). The PaO bond length found in 43 30 or 31 (30: 1.985(2) A

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FIGURE 9.7 Molecular structure of 43 showing thermal ellipsoids at the 50% probability level; all the hydrogen atoms are omitted for clarity except PaH.

FIGURE 9.8 Molecular structure of 44 showing thermal ellipsoids at the 50% probability level; all the hydrogen atoms are omitted for clarity except PaH and imidazolium CaH.

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˚ , shorter compared with that in 44 (1.492(2) A ˚ ) presumably is 1.478(2) A because of a H-bonding interaction with an imidazolium cation.37 The ˚ ) is slightly longer than that observed in PaP distance in 43 (2.1946(8) A metal carbonyl (Lewis acid)free phospha-Wittig-Horner reagent ˚ ).38 (Mes*PHaP(O)(OEt)2) (2.1854 A Lewis acidfree phospha-Wittig-Horner reagent (Mes*PHaP(O) (OEt)2) is known to be readily deprotonated to the lithiated phosphaWittig-Horner reagent, Mes*P 5 P(OLi)(OEt)2.38 Similarly, the phosphinosubstituted phosphine oxide 43 is transformed to the corresponding ion pair 44 through deprotonation by 16 (Scheme 9.19). The complete formation of 44 from 43 is observed when 2 equivalents of 16 are added. The 31 P NMR spectrum of the phosphino-substituted phosphine oxide 43 exhibits two doublets at δ 5 9.55 and 277.36 ppm with a 1JPP of 230 Hz. In 44 the corresponding resonances are observed at δ 5 28.50 and 246.76 ppm with a 1JPP of 464 Hz. These trends are similar to those observed in Mes*PHaP(O)(OEt)2 (1JPP 5 222 Hz) and Mes*P 5 P(OLi)(OEt)2 1 38 ( JPP 5 615 Hz). Despite, the imidazolium character of NHC moiety in 44, the addition of BPh3 as NHC scavenger results in the liberation of 43 as previously observed for NHC-coordinated main group species.39 The exclusive formation of 43 has also been achieved by the addition of Et3N HCl to the reaction mixture. In order to gain some insight into the reaction mechanism, we studied the reaction mixture of 30 and 16 in the presence of a stoichiometric amount of water at low temperature by measuring the 31P NMR spectra. As the temperatures are increased from 193K to 263273K, two resonances are observed in the 31P NMR spectrum at 111.0 (d) and a34.2 (dd) ppm with 1JPP 5 338 Hz and 1JPH 5 209 Hz. We attribute these signals to the 1,2-addition of water to the diphosphene with formation of 42 containing a PaH moiety (Scheme 9.19). The formation of a 1,1-addition product can be safely ruled out as it is predicted to be 102.9 kJ mol21 less stable (on the basis of electronic energy as given by density functional theory (DFT) calculations) than the 1,2-addition product. Clearly, such an initial water addition product, 42, is unlikely to be stable at room temperature (or even at 273K) and thus it leads to the formation of 43 and 44. To obtain a doubly hydrolyzed product as previously observed in the case of a heteroleptic diphosphene,36 we performed the reaction of 30 with 2 equivalents of H2O and 2 equivalents of 16 in THF. However, this reaction also led to the same results as obtained with 1 equivalent of H2O and 16. In view of the apparent equilibrium, we expected the hydrolysis of 30 to be catalytic in 16. In addition, the calculated relative free energy for the formation of 43 from 31 (31 1 H2O-43 1 16) is determined to be ΔG298 5 212.1 kcal mol21 at the B3LYP-D3/6311-G(d,p) level of theory. Indeed, treatment of 30 with 1 equivalent of H2O in the presence of 10 mol% of 16 at 278 C leads to .90% of 43 (TON 5 9) (Scheme 9.20).



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SCHEME 9.20 Catalytic reaction of H2O with 30 in the presence of 10 mol% of 16.

At higher temperatures, the hydrolysis of 16 becomes competitive, significantly reducing the yield of 43 and thus the TON. Since the NHCs, 33, 34, and 35 were found to bind with 30, as shown earlier, we investigated the reaction of 30 with water after stoichiometric addition of these NHCs (Scheme 9.21). These reactions resulted in the formation of 43 along with the corresponding zwitterionic compounds 45, 46, and 47, respectively. Instead of stoichiometric amounts of the NHCs, we then attempted the catalytic hydrolysis of 30 in the presence of 10 mol% of 33, 34, and 35 (Scheme 9.22). Under these conditions, 43 is predominantly formed and found alongside unreacted diphosphene, 30. In order to improve the yield, the addition of water must be carried out in portions to avoid hydrolysis of the corresponding NHC that arrests the catalytic turnover. Despite the observations that 21, 36, 37, and 38 do not form adducts with 30, we nevertheless studied their role in assisting its hydrolysis. We hypothesized that while actual adduct formation might not occur, these NHCs in proximity to the PQP function might polarize it toward further reactivity. Indeed, the reaction of 30 and H2O in the presence of a stoichiometric amount of 21 in THF seems to go to completion; the 31P NMR shows complete consumption of the starting diphosphene and formation of a new compound 48 (90%) as the major product, alongside 43 and 49 (Scheme 9.23). Efforts to isolate 48 resulted invariably in the

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SCHEME 9.21

Stoichiometric reaction of H2O with 1:1 mixture of 30 and 33 or 34 or 35.

isolation of 49 (90%) along with 7% of 43 and only 3% of 48. To further probe this reaction, we investigated the low-temperature 31P NMR of the reaction mixture. At 203K two doublets of doublets at 123.1 (1JPP 5 308 Hz, 2JPH 5 18 Hz) and 247.8 (1JPP 5 308 Hz, 1JPH 5 222 Hz) ppm are observed, which are indicative of the formation of the water addition product 48. After 2 days, we see the conversion to 43 and 49 with only a small amount of 48 remaining. The 1H NMR spectrum confirms the incorporation of 21 into 48. The pattern and trends of 31P chemical shifts as well as the coupling constants of the initial addition product 48 are similar to those of 42 (Scheme 9.19). The structural assignment is further supported by the addition of 16 to a solution of 48, which immediately results in its conversion to 43 and 44. Treatment of 48 with the Lewis acid BPh3 as an NHC scavenger40 results in the immediate formation of 50, which slowly rearranges to compound 43 in 24 h. Due to the hindered rotation about the PsP bond, 50 occurs as two conformational isomers in a 7:10 ratio with one set of doublet of doublets in the 31P NMR spectrum. Compound 50 formally constitutes a

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SCHEME 9.22 Catalytic reaction of H2O with 30 in the presence of 10 mol% of 33 or 34 or 35.

1,2-addition product of water to a diphosphene, analogous to the tautomerization of phosphinous acids, R2POH, to the corresponding phosphorus oxide, R2P(O)H.40 The isomeric 1,1-addition product of water to diphosphene, 30 is calculated to be 38.9 kJ mol21 thermodynamically higher than the 1,2-addition product, 50. Despite the comparatively high stability of the proposed intermediate 48, we considered the use of catalytic amounts of 21 (10 mol%) in THF for the hydrolysis of 30. At low temperature (278 C), indeed no catalytic activity is seen (Scheme 9.24). At room temperature, however, the reaction affords 43 almost quantitatively (95%) alongside about 2.5% of 49. Although we do not observe 48 in the catalytic reaction, it is proposed that it must be involved as an intermediate that quickly releases 43 to regenerate 21 (Scheme 9.24). With 36 in THF, we observe the direct formation of 43, in almost 90% spectroscopic yield, along with 5% of 51 and 5% of 52 (Scheme 9.25). Catalytic use of 36 also leads quantitatively to the formation of 43 (Scheme 9.26). On the other hand with 37, we observe the formation of 43 (20%) along with unreacted diphosphene, 30 (80%), even after a reaction time of 2 days (Scheme 9.27). With 38, 30 remains unchanged in reaction with 1 equivalent of water even after 5 days (Scheme 9.28).

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SCHEME 9.23

Stoichiometric reaction of H2O with mixture of 30 and 21.

SCHEME 9.24

Catalytic reaction of H2O with 30 in the presence of 10 mol% of 21.

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Ter +

P P

tBu N

Ter

30

No adduct formation

N tBu

36 H2O N tBu N

tBu

H O

Ter P

P

Ter

H

51

tBu N Ter H O + P P N tBu H Ter

t Bu N

N tBu H

H

O Ter P P

Ter

36

43

52

SCHEME 9.25 Stoichiometric reaction of H2O with a mixture of 30 and 36.

SCHEME 9.26 Catalytic reaction of H2O with 30 in presence of 10 mol% of 36.

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SCHEME 9.27

Stoichiometric reaction of H2O with a mixture of 30 and 37.

SCHEME 9.28

Stoichiometric reaction of H2O with mixture of 30 and 38.

The reaction of 31 with H2 does not proceed under ambient conditions. On the other hand, 31 does react instantaneously with NH3 BH3 as dihydrogen source affording two diastereomers (d/l-53 and meso-53) of dihydrodiphosphane (Scheme 9.29). The parent diphosphene 30 only



SCHEME 9.29



Reaction of 30 with NH3 BH3 in presence of 16.

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FIGURE 9.9 Comparison between the experimental (top) and simulated (bottom) 31P NMR spectra of (A) meso-53 and (B) d/l-53 compounds. The scalar couplings used for the simulations are shown at the lower right.



reacts sluggishly with NH3 BH3, taking more than 7 days to afford the product in modest yields. The 31P NMR spectra of d/l-53 and meso-53 exhibit an AA0 XX0 pattern with the peaks centered at δ 5 2109.9 and 2101.4 ppm, respectively (Fig. 9.9). To determine the magnitudes of the coupling constants of the AA0 XX0 spin system, a simulation of the 1H and 31P NMR spectra was performed (Fig. 9.9). Previously, Erickson et al. reported the formation of one of the diastereomers of compound 53 by the tin-catalyzed dehydrocoupling of TerPH2.41 Based on the current study it can be concluded that the previously reported diastereomer had the mesoconfiguration. The initially formed racemic mixture of d/l-53 is slowly converted to the meso-isomer, meso-53, reaching equilibrium within 12 h at room temperature. This has been confirmed by performing the reaction and measuring the 31P{1H} NMR spectrum at 250 C. DFT calculations at the B3LYP-D3/6-311 G(d,p) level of theory indeed show that meso-53 isomer is lower in free energy than d/l-53, by 2.3 kcal mol21. Single-crystal X-ray diffraction analysis of crystalline samples of 53 exclusively resulted in a structural model consistent with meso-53 (Fig. 9.10). As this model depends on the somewhat ambiguous determination of the hydrogen positions H1P and H1P*, we cannot exclude the presence of a mixture of isomers in the solid state. Indeed, the CP-MAS 31P{1H} NMR of a crystalline sample shows the presence of both diastereomers. Subsequently, we have considered the NHC-coordinated diphosphene 31 as a ligand for coordination to transition metal complexes. To demonstrate this first, we reported the use of 31 as a ligand for Au(I) complexes. The reaction of AuCl SMe2 with a 1:1 solution of 16 and



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FIGURE 9.10

Molecular structure of meso-53 (thermal ellipsoids shown at the 50% probability level; hydrogen atoms except H1P and H1P* are omitted for clarity).

diphosphene 30 in THF at 278 C leads to the NHC/diphosphene-coordinated Au(I)-chloride 54 (Scheme 9.30).42 Formation of 54 reveals the ability of the diphosphene motif to act simultaneously as both a Lewis acid and a Lewis base, analogous to disilyne 13 (Scheme 9.9).18 The 31P

SCHEME 9.30 Synthesis of NHC-coordinated diphosphene stabilized Au(I)Cl complex, 54.

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NMR spectrum of 54 displays two doublets at δ 5 1.34 and 231.46 ppm with 1JPP 5 462 Hz, which is between the values observed for 31 (1JPP 5 423 Hz) and the monoaurated adduct, Mes*(AuCl)P 5 PMes* (1JPP 5 539 Hz).43 Interestingly, in solution, the coordinated NHC 16 does not dissociate unlike 31 that exists in equilibrium with 30 and 16 (Scheme 9.15). The stability of 54 is probably due to the coordination of the diphosphene moiety to AuCl, which enhances the electrophilicity of the second P center, resulting in stronger binding to NHC 16. This is also supported by DFT calculations on the highly endergonic dissociation of 16 from 54 (21.8 vs 6.7 kcal mol21 from 31) in THF. The molecular structure of 54 was confirmed by single-crystal X-ray ˚ ) in diffraction analysis (Fig. 9.11). The PaAu bond distance (2.2540(8) A 44 ˚ 54 is longer than those in Ph3P AuCl (AuaP 2.235 A) and in the corresponding diaurated adduct of Mes*-substituted diphosphene, Mes*(AuCl) ˚ ).43 The P1aP2 bond distance is 2.219(1) A ˚ and P 5 P(AuCl)Mes* (2.201 A ˚ is thus considerably longer than in the free diphosphene 30 (2.029 A) or in ˚ ). 31 (2.134 A With the NHC/diphosphene-coordinated Au(I)-chloride 54 in hand, we considered the preparation of the analogous Au(I) hydride. Consequently, the 1:1 reaction of 54 with N-selectride at 278 C affords



FIGURE 9.11 Molecular structure of 54 with thermal ellipsoids shown at the 50% probability level. All hydrogen atoms and one molecule of cocrystallized toluene are omitted for clarity.

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SCHEME 9.31

Synthesis of NHC-coordinated diphosphene stabilized Au(I)-hydride, 55.

the NHC/diphosphene-stabilized Au(I) hydride, 55 in 90% yield as light yellow crystals (Scheme 9.31). The 31P NMR spectrum of 55 exhibits two resonances at δ 5 1.6 ppm as a doublet (1JPP 5 470 Hz) and at δ 5 214.5 ppm as a doublet of doublets (1JPP 5 470 Hz, 2JPH 5 138 Hz). In the 1H NMR spectrum, the doublet at δ 5 4.60 ppm (2JPH 5 138 Hz) can be unambiguously assigned to the AuaH resonance that is upfield shifted in comparison to that of NHCDip-stabilized Au(I)-hydride (5.11 ppm).45 The IR spectrum of 55 shows a strong sharp band at 1893 cm21 for the AuH motif, in good agreement with the calculated value (1880.2 cm21). The molecular structure of 55 (Fig. 9.12) reveals a PaP bond distance ˚ that is slightly shorter than the PaP bond distance in 54 of 2.197(1) A

FIGURE 9.12 Molecular structure of 55 with thermal ellipsoids shown at the 50% probability level. All H atoms except AuH and one cocrystallized molecule of benzene are omitted for clarity.

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due to less pronounced π-back-donation. Indeed, the PaAu bond dis˚ is larger than the 2.2540(8) A ˚ observed in 54 tance in 55 of 2.3297(9) A suggesting a stronger trans influence of the hydride compared to the chloride ligand. The Au(I) hydride 55 is stable in the presence of degassed water in toluene overnight; a solid crystalline sample even persists in open air at least for 2 days. In solution, however, 55 slowly undergoes concurrent 1,3-shifts of hydrogen from the Au-center and NHC from the phosphorus center (thus exchanging their positions) resulting in the Au(I)-phosphinophosphide 56 (Scheme 9.32) as shown by the appearance of a doublet of doublets in the 1 H NMR spectrum at δ 5 4.19 ppm (dd, 1JPH 5 214 Hz, 2JPH 5 9 Hz). H N

P

N Ter P

P

Δ

Ter

Ter P Au

Au

Ter

N

N H

55

56

SCHEME 9.32 Rearrangement of 55 to 56.

The concomitant migration of the NHC ligand from the phosphorus to the gold center is evident from the significantly smaller coupling of the 13C{1H} signal at δ 5 193.6 ppm of the carbenic carbon atom to the nearest 31P nucleus (2JCP 5 53 Hz for 56 vs 1JCP 5 99 Hz for 54). Conversion is completed by heating to 65 C for 1 h. According to our DFT results, the rearrangement of 55 to 56 is exergonic by 26.1 kcal mol21. The structure of the NHC-stabilized Au(I)-phosphinophosphide 56 was finally confirmed by X-ray diffraction on single crys˚ and thus tals (Fig. 9.13). The PaP bond distance in 56 is 2.218(1) A slightly longer than that in the reported cyclic-diaminoboryl-substituted ˚ ).46 diphosphene derived lithium phosphinophosphide (2.1775 A In order to address the hydridic character of the AuH moiety in 55, we considered the hydroauration reaction with CO2. The hydrometallation of carbonyl compounds, in particular of CO2, is a key step in catalytic conversions to access C1-feedstock materials.47 In fact, the formation of 57 from 55 and CO2 is computed to be exergonic by 11.6 kcal mol21. Upon passing CO2 gas into a toluene solution of 55 at room temperature, the quantitative formation of Au(I) formate 57 was observed based on 31P NMR of the reaction mixture (Scheme 9.33). The 1H NMR spectrum of 57 exhibits a doublet centered at δ 5 9.50 ppm (4JHP 5 7 Hz), consistent with the proposed formate as a prominent IR band at 1884 cm21 for the CQO stretching frequency. The molecular structure of 57 was confirmed by X-ray crystallography

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FIGURE 9.13 Molecular structure of 56 with thermal ellipsoids shown at the 50% probability level. All hydrogen atoms and one molecule of cocrystallized hexane are omitted for clarity.

SCHEME 9.33

Synthesis of NHC-coordinated diphosphene stabilized Au(I) formate, 5.

˚ (Fig. 9.14). The AuaO bond distance in the Au(I) formate 57 of 2.140(4) A 48 ˚ is slightly longer than that of a reported Au(III) formate (2.102 A). To the best of our knowledge, the formation of 57 represents the first example of any gold formate obtained by direct hydroauration of CO2. We had noted that the 31P NMR spectrum of the residue after removal of the solvent shows the presence of about 5% of the starting Au(I) hydride, 55. This observation prompted us to further investigate a possible spontaneous release of CO2 from 57. The release of CO2/HCO22 from transition metal formates is well known49 and the reductive elimination of CO2 from a binuclear Au(III)/CO2 complex has been reported.50 Indeed, the application of 0.12 mbar vacuum for 15 h

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FIGURE 9.14 Molecular structure of 57 with thermal ellipsoids shown at the 50% probability level. All hydrogen atoms and one molecule of toluene are omitted for clarity.

results in the original Au(I)-hydride 55 in about 50%. Decarboxylation of 57 above 65 C proceeds to complete conversion, but also affords 56, the thermal isomerization product of 55 as side product. To facilitate the release of CO2, we added NHC 21 in the anticipation that it might induce the required 1,3-H shift (β-hydride elimination)51 by coordination to the carbonyl group and removal of CO2 from equilibrium as NHCCO2 adduct 58.52 Addition of 1 equivalent of 21 to a solution of 57 at room temperature indeed resulted in the immediate formation of 55 (Scheme 9.34). In order to verify the CO2 release at lower temperatures and to check for intermediates, we carried out a variable temperature NMR study of a 1:1 toluene-d8 solution of 21 and 57. At 278 C, the 31P NMR spectrum does not show any indication for the release of CO2. At 210 C, we observed one new set of peaks at δ 5 235.2 and 0.9 ppm (1JPP 5 465 Hz). These resonances disappear while approaching room temperature with the concomitant appearance of the resonances diagnostic of 55. The occurrence of an intermediate suggests that the reaction may indeed proceed through the initial coordination of 21 to the carbonyl carbon center of 57 to give the thermally unstable adduct 59, analogous to the nucleophilic coordination of NHC to aldehydes.53 Subsequent hydride migration (β-hydride

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SCHEME 9.34

NHC 22-mediated release of CO2 from Au(I)-formate, 57.

elimination) would lead to the 21 adduct of CO2 58 and Au(I) hydride 55 (Scheme 9.34). The calculated Gibbs free energy values confirm that the reaction 57 1 21-55 1 58 is endergonic by 7.4 kcal mol21. Finally, we contemplated the use of the NHC/diphosphene-coordinated Au(I)-hydride 55 for the dehydrogenation of formic acid HCO2H. The stoichiometric reaction of 55 and HCO2H indeed results in the Au(I)-formate 57 with elimination of H2 (Scheme 9.35). Computationally, the formation of 57 from 55 and HCO2H is thermodynamically favorable by 13.5 kcal mol21.

SCHEME 9.35 Au(I) hydride, 55 mediated release of H2 and CO2 from HCO2H (inset: reaction of HCO2H to CO2 and H2).

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References

9.5 Conclusions In summary, we have discussed the coordination of an NHC to siliconsilicon and phosphorusphosphorus multiple bond functionalities. In case of disilyne the NHC-coordinated disilyne act as a Lewis base to bind with ZnCl2 and MeOTf. The NHC coordination to the disilene motif of cyclotrisilenes results in the formation of the NHC adduct in a reversible manner. Depending on the substituents at the silicon centers of the cyclotrisilene, NHC can reversibly open the Si3-scaffold with the formation of NHC-stabilized disilenyl silylene. In the case of diphosphenes, depending on the substituents at the P-centers, reaction with NHC can directly lead to the cleavage of the PQP double bond, giving NHC-coordinated phosphinidene or produce reversibly NHC-coordinated diphosphene. The reversible coordination of the NHC to a diphosphene significantly enhances the reaction rate for hydrolysis and hydrogenation by NH3 BH3. Moreover, NHC-coordinated diphosphene acts as a ligand toward the Au(I)-chloride moiety, and also further stabilized monomeric Au(I)-hydride. The NHCdiphosphene-coordinated Au(I) hydride exhibits pronounced hydridic character and thus reacts reversibly with CO2 to produce the corresponding Au(I)-formate species.



References 1. (a) Conlin, R. T.; Gaspar, P. P. Evidence for the Dimerization of Dimethylsilylene to Tetramethyldisilene. J. Am. Chem. Soc. 1976, 98, 868870. (b) Sakurai, H.; Nakadaira, Y.; Kobayashi, T. trans- and cis-1,2-Dimethyl-1,2-diphenyldisilene. Is Si~Si a True Double Bond? J. Am. Chem. Soc. 1979, 101, 487488. (c) Daly, J. J.; Maier, L. Molecular Structure of Phosphobenzene. Nature 1964, 203, 11671168. (d) Daly, J. J.; Maier, L. Structure of Phosphobenzene. Nature 1965, 208, 383384. 2. Jutzi, P. New Element-Carbon (p-p)π Bonds. Angew. Chem. Int. Ed. Engl. 1975, 14, 232245. 3. Goldberg, D. E.; Harris, D. H.; Lappert, M. F.; Thomas, K. M. A New Synthesis of Divalent Group 4B Alkyls M[CH(SiMe3)2]2 (M~Ge or Sn), and the Crystal and Molecular Structure of the Tin Compound. J. Chem. Soc., Chem. Commun. 1976, 261262. 4. Davidson, P. J.; Lappert, M. F. Stabilisation of Metals in a Low Co-ordinative Environment using the Bis(trimethylsi1yl)methyl Ligand; Coloured SnII and PbII Alkyls, M[CH(SiMe3)2]2. J. Chem. Soc., Chem. Commun. 1973, 317. 5. West, R.; Fink, M. J.; Michl, J. Tetramesityldisilene, a Stable Compound Containing a Silicon-Silicon Double Bond. Science 1981, 214, 13431344. 6. Yoshifuji, M.; Shima, I.; Inamoto, N. Synthesis and Structure of Bis(2,4,6-tri-fert-butylphenyl)diphosphene: Isolation of a True “Phosphobenzene”. J. Am. Chem. Soc. 1981, 103, 45874589. 7. West, R. Isolable Compounds Containing a Silicon-Silicon Double Bond. Science 1984, 225, 11091114. 8. Cowley, A. H.; Kilduff, J. E.; Newman, T. H.; Pakulski, M. Diphosphenes (RP~PR). Synthesis and NMR Characterization. J. Am. Chem. Soc. 1982, 104, 58205821.

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