Photochemistry. Volume 46 9781788013598, 178801359X

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Photochemistry Volume 46

A Specialist Periodical Report

Photochemistry Volume 46 Editors Angelo Albini, University of Pavia, Italy Stefano Protti, University of Pavia, Italy Authors Manabu Abe, Hiroshima University, Japan Emilio I. Alarcon, University of Ottawa, Canada Alessandro Aliprandi, University of Strasbourg & CNRS, France Christophe Bour, Paris-Sud University, France Youhei Chitose, Hiroshima University, Japan Luisa De Cola, University of Strasbourg & CNRS, France and Karlsruhe Institute of Technology, Germany Brian N. DiMarco, University of Strasbourg & CNRS, France Bo-Wen Ding, Beijing Normal University, China Filippo Doria, University of Pavia, Italy Pooria Farahani, KTH Royal Institute of Technology, Sweden Antonio France ´ s-Monerris, University of Lorraine & CNRS, France Angelo Giussani, University College London, UK Andreas Herrmann, Firmenich SA, Switzerland M. Consuelo Jime ´ nez, Technical University of Valencia, Spain Irene E. Kochevar, Massachusetts General Hospital and Harvard Medical School, USA Benjamin Lipp, University of Mainz, Germany Ya-Jun Liu, Beijing Normal University, China Ge ´ raldine Masson, Paris-Sud University, France Christopher McTiernan, University of Ottawa, Canada Miguel A. Miranda, Technical University of Valencia, Spain Kazuhiko Mizuno, Nara Institute of Science and Technology, Japan Antonio Monari, University of Lorraine & CNRS, France Miriam Navarrete-Miguel, University of Valencia, Spain Till Opatz, University of Mainz, Germany Loı¨c Pantaine, Paris-Sud University, France Valentina Pirota, University of Pavia, Italy Barbara Procacci, University of York, UK Justina Pupkaite, University of Ottawa, Canada Carlotta Raviola, University of Pavia, Italy Daniel Roca-Sanjua´n, University of Valencia, Spain Javier Segarra-Martı´, Imperial College London, UK

Evan M. Sherbrook, University of Wisconsin–Madison, USA Erik J. Suuronen, University of Ottawa, Canada Takashi Tsuno, Nihon University, Japan Tehshik P. Yoon, University of Wisconsin–Madison, USA Michela Zuffo, University of Pavia, Italy

ISBN: 978-1-78801-336-9 PDF ISBN: 978-1-78801-359-8 EPUB ISBN: 978-1-78801-559-2 ISSN: 0556-3860 DOI: 10.1039/9781788013598 A catalogue record for this book is available from the British Library r The Royal Society of Chemistry 2019 All rights reserved Apart from fair dealing for the purposes of research for non-commercial purposes or for private study, criticism or review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry or the copyright owner, or in the case of reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page. Whilst this material has been produced with all due care, The Royal Society of Chemistry cannot be held responsible or liable for its accuracy and completeness, nor for any consequences arising from any errors or the use of the information contained in this publication. The publication of advertisements does not constitute any endorsement by The Royal Society of Chemistry or Authors of any products advertised. The views and opinions advanced by contributors do not necessarily reflect those of The Royal Society of Chemistry which shall not be liable for any resulting loss or damage arising as a result of reliance upon this material. The Royal Society of Chemistry is a charity, registered in England and Wales, Number 207890, and a company incorporated in England by Royal Charter (Registered No. RC000524), registered office: Burlington House, Piccadilly, London W1J 0BA, UK, Telephone: þ 44 (0) 207 4378 6556. For further information see our web site at www.rsc.org Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon, CR0 4YY, UK

Preface DOI: 10.1039/9781788013598-FP007

Volume 46 follows the pattern of previous titles from Volume 39 onwards, which combines a review on the latest advancements in photochemistry (every other year on a part of this discipline) and highlights some topics. We thank the reviewers, who maintained their thorough work once again, as well as the contributors of highlights. We thank Professor Elisa Fasani, who after several years has left the editorial team. As usual, it has been a tough job to complete all the contributions (almost) within the planned deadlines. However, hard work as it may have been, having the opportunity of seeing such a large wealth of photochemical experience has been a really nice experience. We thank the staff working on Specialist Periodical Reports (Janet, Robin and Katie), the Royal Society of Chemistry, our colleagues of the PhotoGreen Lab at the University of Pavia, and the young researchers in our lab, who make photochemistry such an entertaining experience every day. Finally, we are grateful to Dr Daria Manganaro, who supplied the original artwork for this volume. Angelo Albini and Stefano Protti

Photochemistry, 2019, 46, vii–vii | vii  c

The Royal Society of Chemistry 2019

Author biographies DOI: 10.1039/9781788013598-FP008

Manabu Abe was born in Sakai City, Osaka Prefecture, Japan. He received his PhD from the Kyoto Institute of Technology (KIT), Professor Akira Oku, in 1995, studying the oxidative ring-opening reaction of cyclopropanoneacetals and its application to organic synthesis. In 1995, he became a faculty staff at Osaka University (HANDAI, Prof. Masatomo Nojima’s group). From 1997 to 1998, he was an Alexander-von-Humboldt (AvH) fellow with Professor Dr Waldemar ¨t Wu ¨rzburg in Adam at the Universita Germany. He was also a visiting researcher ¨nchen (Professor Dr Herbert Mayr) in 2007. He moved at the LMU Mu to Hiroshima and became a Full Professor in Organic Chemistry at the Department of Chemistry, Graduate School of Science, Hiroshima University (HIRODAI) in 2007. His research focuses on reactive intermediates chemistry, especially diradicals; organic photochemistry; and unusual molecules.

Emilio I. Alarcon is a principal investigator at the University of Ottawa Heart Institute in Ottawa and an Assistant Professor at the Department of Biochemistry, Microbiology, and Immunology at University of Ottawa. He received his PhD in Chemistry in 2009 from Pontificia Universidad Catolica de Chile and moved to work at the University of Ottawa under the supervision of Professor Scaiano. Dr Alarcon’s research seeks the development of novel biomaterials for treating diverse organs including cornea, skin, and heart tissue. His research has allowed the rational integration of light-triggered photo-bonding mechanism in the fabrication of novel regenerative platforms.

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The Royal Society of Chemistry 2019

Angelo Albini is currently Emeritus Professor of Organic Chemistry at the University of Pavia, Italy. A native of Milan, he completed his studies in Chemistry at Pavia in 1972. After postdoctoral work at the MaxPlank Institute for Radiation Chemistry in Muelheim, Germany (1973–1974), he joined the Faculty at Pavia in 1975 as an assistant and then associate (since 1981) professor. He accepted a Chair of Organic Chemistry at the University of Torino in 1990 and then moved again to Pavia in 1993. He has been Visiting Professor at the Universities of Western Ontario (Canada, 1977–78) and Odense (Denmark, 1983). He is coauthor/ editor of five books (among the others, Heterocyclic N-Oxides, CRC, Orlando, 1990; Drugs: Photochemistry and Photostability, RSC, Cambridge, 1998; Handbook of Preparative Photochemistry, Wiley-VCH, 2009), the senior reporter of the Specialist Periodic Reports on Photochemistry since 2008, as well as coauthor of several reviews and research articles. Alessandro Aliprandi received his PhD in Chemistry from the University of Strasbourg ´nierie at the Institut de Science et d’Inge ´culaires (I.S.I.S.) in 2015 under the Supramole supervision of Prof. Luisa De Cola. His thesis was awarded with the ‘‘Prix de these’’ de la ´ de Strasbourg in 2016. Fondation Universite Then he carried out postodoctoral research in the group of Prof. Paolo Samorı` in the same ´nieur de Reinstitute. From 2018 He is Inge cherche (CNRS) in the group of Prof. Luisa De Cola. His research focuses on self-assembling of (electro)-luminescent transition-metal complexes as well as 2D materials for electronic applications. Christophe Bour received his MSc in organic chemistry from University of Strasbourg where he completed his PhD in 2006 under the supervision of Dr Jean Suffert. He then joined the research group of Prof. Antonio Echavarren in Tarragona (Spain) as a postdoctoral fellow. In early 2009, he moved to the ECPM at the University of Strasbourg to work with Dr G. Hanquet. In September 2010, he was appointed assistant professor at University of Paris-Sud in the group of Prof. V. Gandon. In 2015 he received his HDR diploma and his scientific interests include catalysis, and new synthetic methodologies. Photochemistry, 2019, 46, viii–xxiii | ix

Youhei Chitose received his BA in 2016 and his MA in 2018, both from Hiroshima University. He is a PhD candidate under the supervision of Professor Manabu Abe at the Graduate School of Science, Department of Chemistry, Hiroshima University.

Luisa De Cola is, since September 2013, Professor at the University of Strasbourg (ISIS) and part time scientist at the INT-KIT, Karlsruhe, Germany. She was born in Messina, Italy, where she studied chemistry. After a post-doc in the USA she was appointed Assistant Professor at the University of Bologna (1990). In 1998 she was appointed Full Professor at the University of Amsterdam, The Netherlands. In 2004 she moved to the University of Muenster, Germany. She is the recipient of several awards, the most recent being the IUPAC award (2011), the International Prize for Chemistry ‘‘L. Tartufari’’ and the Catalan – Sabatier prize (2015). She is a member of the German National Academy of Sciences Leopoldina and in 2014 she was Nom´gion d’ Honneur’’ She has published more than inated ‘‘Chevalier de la Le 350 papers and filed 36 patents (H-index ¼ 67).

Brian N. DiMarco was born in Stamford, Connecticut in 1988. He received his BS in Biology and Chemistry at Roger Williams University in 2010, where he began his research career with Prof. Cliff J. Timpson. In 2012, Brian entered Johns Hopkins University under the guidance of Prof. Gerald J. Meyer. Brian subsequently completed his thesis in 2017 at The University of North Carolina – Chapel Hill, where much of his thesis focused on electron transfer reactions relevant to the operation of a dyesensitized solar cell. Brian is currently a postdoctoral researcher in the laboratory of Prof. Luisa De Cola. x | Photochemistry, 2019, 46, viii–xxiii

Bo-Wen Ding received her PhD degree in physical chemistry supervised by Prof. Ya-Jun Liu at the Beijing Normal University (China) in 2017. Her research interests focus on mechanic insight into the bioluminescence of marine organisms using ab initio methods, QM/MM techniques, and nonadiabatic molecular dynamics simulations.

Filippo Doria, born on March 4, 1982, graduated in Chemistry (magna cum laude) at the University of Pavia, June 2006. He obtained his PhD from the same University in 2009, in Chemical Sciences (organic chemistry), completing a thesis entitled ‘‘Molecular recognition and selective alkylation of nucleic acids by photoactivatable alkylating agents’’. During the course of his PhD he spent nine months as a visiting Scientist at the Biomolecular Structure Group, Cancer Research UK, School of Pharmacy, University of London, (UK) with Prof. S. Neidle, working on a project entitled ‘‘Quadruplex nucleic acid structures and their selective recognition by small molecules. Synthesis and chemical biology of novel quadruplextargeted agents’’. During his post-doc, he spent two months as exchange visiting Scientist at the Consejo Superior de Investigaciones Cientı´ficas (CSIC), Instituto di Parasitologia y Biomedicina, Granada, Spain. (i-LINK 0924). In 2015 he started a five years fellowship as Fixed Term Researcher (RTDa) at the Department of Organic Chemistry, University of Pavia, PV, Italy, working on the Synthesis and activation of molecular devices selective for ‘‘G-quadruplexes.’’ (ERC-CG615879). His current research is focused on the synthesis and evaluation of new selective G-quadruplex fluorescent sensor.

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Pooria Farahani received his PhD degree from Uppsala University (Sweden), in 2014, for his theoretical chemistry studies on the chemiluminescence processes of 1,2dioxetane-like systems, under Prof. Roland Lindh and Dr Marcus Lundberg’s supervisions. In 2015, he obtained a grant from ˜o de Amparo ` the Fundaça a Pesquisa do ˜o Paulo (FAPESP) to do a Estado de Sa postdoctoral research at the University of ˜o Paulo (Brazil), within the experimental Sa group of Prof. Wilhelm Josef Baader, at the Departmento de Quı´mica Fundamental, focusing on the application of ‘‘quantum-chemical methods to rationalize efficient electronically excited-state formation in chemical transformation’’. He is now a member of Theoretical Chemistry & Biology Department of the KTH Royal Institute of Technology in Stockholm (Sweden). His recent subject is to study catalytic composites for sustainable synthesis which includes photochemical reactions catalysed by metal–organic frameworks (MOFs).

´s-Monerris graduated in Antonio France pharmacy in 2009 at the University of `ncia (Spain). In 2011, he received an Vale MSc in organic chemistry at the Poly`ncia after a short technical University of Vale stay in a pharmaceutical company. He received his PhD in chemistry in 2017 at the `ncia for his theoretical University of Vale studies on radiation damage to DNA/RNA nucleobases using multiconfigurational and DFT-based methods, a work carried out under the supervision of Dr Daniel Roca´n and Prof. Manuela Mercha ´n. Sanjua Currently, he is a post-doc researcher in the group of Dr Antonio Monari at the University of Lorraine in Nancy (France). His main research interests span the photoinduced phenomena in DNA/RNA nucleobase clusters, the photosensitization of biological systems, the study of the fluorescence and chemiluminescence phenomena and the photophysics of iron-based metal–organic complexes.

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Angelo Giussani graduated in Chemistry in 2008 at the Universita degli Studi di Milano. In 2011 he finalized his European MSc in ‘‘Theoretical Chemistry and Computational Modeling’’ at the Universitat de Valencia. In 2014 he received his PhD at the Universitat de Valencia, where he was working in the QCEXVAL group studying aromatic chromophores performing CASPT2//CASSCF calculations. From 2014 until 2016, he worked at the Universita di Bologna where he was involved in the simulation of 2D spectra and in the study of DNA photoreactions using a QM/MM approach. In 2016 he moved as a Marie Curie Fellow in the group of Dr Graham Worth, were he was performing quantum dynamics simulations using the DD-vMCG method. His main research interest is in the study of photophysical and photochemical phenomena performing both ab initio and quantum dynamics computations.

Andreas Herrmann studied chemistry in Karlsruhe (Germany) and Strasbourg (France). In 1997, he completed his PhD at ¨rich (Switzerland) under the the ETH Zu guidance of Prof. François Diederich and joined Firmenich as a research scientist. He has been working on the development of profragrances for 20 years. In 2016, he received the KGF-SCS Industrial Science Award from the Swiss Chemical Society (SCS) and the Contact Group for Research Matters (KGF) for his work on profragrances. He is author or co-author of almost 70 scientific publications and 25 patents. He has also lectured at the University of Fribourg (Switzerland) for 10 years.

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´nez graduated from the M. Consuelo Jime University of Valencia and obtained her PhD from the Technical University of Valencia (UPV) in 1997 (Organic Photochemistry), under the supervision of Profs. Miguel A. Miranda and Rosa Tormos. She was a ‘‘Marie Curie’’ post-doctoral fellow at Louis Pasteur University (Strasbourg) 1999–2000 with J.-P. Sauvage (Nobel Prize in Chemistry 2016), working on molecular motions, and a visiting professor at CEA (Saclay) in 2011 (femtosecond fluorescence). She is currently Professor of Organic Chemistry at UPV. Her main research activity is focused on organic photochemistry, with particular interest in the study of drug–biomolecule interactions using photophysical techniques. She has published more than 90 scientific contributions in these domains. Irene E. Kochevar is Professor of Dermatology, Harvard Medical School with laboratories in the Wellman Center for Photomedicine of Massachusetts General Hospital. She has applied her background in physical organic chemistry and biochemistry to generating an understanding of fundamental mechanisms by which UV radiation and dye photosensitization generate oxidative stress in cells and the responses of cells to this stress. Dr Kochevar is a co-inventor with Dr Robert Redmond of a light-activated tissue repair technology based on protein photo-crosslinking that, in studies with medical collaborators, has been shown to have multiple applications including sealing wounded skin, cornea, nerves, tendons as well as stiffening cornea and blood vessels. Benjamin Lipp studied biomedicinal chemistry at the Johannes Gutenberg-University in Mainz (Germany), where he joined the group of Prof. Till Opatz for a diploma thesis on the development of photoredox-catalysed Minisci reactions in 2015. Currently, Benjamin is a PhD student in the same group. His research is focused on the development of photoinduced electron transfer reactions and their application to organic synthesis.

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Ya-Jun Liu received his PhD degree in physical chemistry at the University of Science and Technology of China, in 2002. After a postdoctoral period at Uppsala University (Sweden) with Prof. Sten Lunell and at Lund ¨rn O. University (Sweden) with Profs. Bjo Roos and Roland Lindh, he returned to China in 2006 to Beijing Normal University and was promoted to professor in 2012 at the same university where he has remained ever since. Most of his scientific work has been devoted to the theoretical study of photochemistry. In recent years, his research has focused on bioluminescence and chemiluminescence.

´raldine Masson received her PhD in 2003 Ge from the Joseph Fourier University, (France). She then moved to the University of Amsterdam (Holland) as a Marie Curie postdoctoral research fellow with Prof. Jan van Maarseveen and Prof. Henk Hiemstra. At ´ the end of 2005, she was appointed ‘‘Charge de Recherche’’ by the CNRS in the research group of Prof. Jieping Zhu at the Institut de Chimie des Substances Naturelles (ICSN), before initiating her independent career in 2011. She was promoted to Research Director of CNRS in 2014 in the same institute. Her contributions to the field of Organic Chemistry have been recognized with numerous awards including the Diverchim Prize in Synthetic Organic Chemistry from French Organic Chemistry Division (2011), CNRS Bronze Medal (2013), Liebig Lectureship of the German Chemical ´mie des Sciences Society (2016), and Novacap Prize of the French Acade Award (2017). Her group’s research activities are directed toward the development of the design and development of new catalytic methods for the synthesis of optically active molecules displaying biologically activities. The three specific research areas focus on: (1) asymmetric organocatalysis; (2) photoredox-catalysis and (3) asymmetric hypervalent iodine catalysis.

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Christopher D. McTiernan received his BSc in Biochemistry (2008) and MSc in Chemical Sciences (2010) from Laurentian University before obtaining his PhD in Chemistry (2017) from the University of Ottawa. He is currently a postdoctoral fellow in the group of Dr Emilio Alarcon and recipient of a fellowship award from the University of Ottawa Cardiac Endowment Fund. His current research focuses on translating his expertise in materials chemistry and photochemistry in the development of pro-regeneration tissue scaffolds and photoactivated tissue adhesives.

Miguel A. Miranda is Full Professor of Organic Chemistry at the Institute of Chemical Technology (UPV-CSIC) of the Technical University of Valencia. He was post-doctoral researcher at the Universities ¨rzburg and Associate of Saarland and Wu Professor at the University of Valencia, before accepting his present position in 1990. His field of interest is photochemistry, from the fundamentals to the biological, environmental and technological applications (4500 peer-reviewed articles in the field). He has received the Honda–Fujishima Award of the Japanese Photochemistry Association, the Organic Chemistry Award of the Spanish Royal Society of Chemistry, the Theodor ¨rster Award of the German Chemical Society and the Bunsen Society Fo of Physical Chemistry, the Award for Excellence in Photobiological Research of the European Society for Photobiology, and the Award for Recognition to a Distinguished Career of the Spanish Royal Society of Chemistry. He was the President of the European Society for Photobiology from 2009 to 2011.

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Kazuhiko Mizuno was born in Osaka, Japan in 1947 and obtained a PhD in 1976 at Osaka University. He began his academic career at Osaka Prefecture University in 1976 and was promoted to full professor in 1996 and retired in 2012. He became Professor Emeritus. He is now serving as an adjunct professor at Nara Institute of Science and Technology. He was Secretary of the Asian and Oceanian Photochemistry Association (APA) (2004–2008) and President of the Japanese Photochemistry Association (JPA) (2008–2009). He has received the JPA Award (1996) and Award for Distinguished Achievements to APA (2012). His current research interests focus on microflow photochemistry. Antonio Monari is currently a member of the Theoretical Physics and Chemistry Department (LPCT) of the University of Lorraine and CNRS in Nancy, France. After receiving his PhD in Theoretical Chemistry from the University of Bologna, Italy in 2007 and performing a post-doctoral period in Bologna he moved to University Paul Sabatier in Toulouse France in 2009 before securing a tenured associate professor position in Nancy in 2011. His main scientific interests are centred on the study of linear and non-linear spectroscopies as well as photophysical and photochemical processes in complex systems by using hybrid QM/MM methods and non-adiabatic molecular dynamics. He focuses his efforts on the study of the production, evolution and repair of DNA oxidative- and photo-lesions in order to characterize fundamental biological processes and propose alternative phototherapeutic strategies. Miriam Navarrete-Miguel graduated in chemistry at the University of Valencia in 2017. She is currently studying the European Master on Theoretical Chemistry and Computational Modelling at the Institut de `ncia Molecular, Universitat de Vale `ncia Cie (Spain) supervised by Dr Daniel Roca´n. Her research project focuses on Sanjua the application of density functional theory and multiconfigurational wavefunction methods to DNA photochemistry and bioluminescence. Photochemistry, 2019, 46, viii–xxiii | xvii

Till Opatz studied chemistry in Frankfurt/M. (Germany) and received his PhD in 2001 at the University of Mainz (Germany) under the supervision of Prof. Horst Kunz. After postdoctoral research with Prof. Liskamp at Utrecht (Netherlands), he returned to Mainz for his habilitation on the use of imines of normal and reversed reactivity as synthetic building blocks. Till Opatz was appointed Professor of Organic Chemistry at the University of Hamburg (Germany) in 2007. Since 2010, he is full Professor of Organic Chemistry at the University of Mainz and since 2013 adjunct Professor at the University of Alabama (USA). Till Opatz has published more than 180 research articles, reviews and book chapters and was recently selected as highly prolific author of the Journal of Organic Chemistry. His research interests comprise natural product synthesis and structure elucidation, carbohydrate chemistry and, more recently, sustainable chemistry as well as preparative photochemistry.

Loı¨c Pantaine obtained his PhD (2013–2016) in organic chemistry at the Institut Lavoisier de Versailles (University Paris-Saclay), working on asymmetric aminocatalysis under the supervision of Prof. Christine Greck and Dr Vincent Coeffard. In 2017, he joined the ´raldine Masson (ICSN) and Dr teams of Dr Ge Christophe Bour (UPSud) for his first postdoctoral fellowship, during which he worked on photoredox/gold dual catalysis. In 2018 he started his second postdoctoral fellowship in the group of Prof. Gary Molander (UPenn), working on photoredox catalysis and photoredox/nickel dual catalysis.

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Valentina Pirota, born on November 28, 1988, graduated in Chemistry at the University of Pavia in 2012. She received her PhD from the same University in 2015, investigating the reactivity and the toxicity of metal complexed to neuronal peptides involved in neurodegenerative diseases. Her PhD project was supported by the Italian MIUR, through the PRIN. In 2015 she received a post-doctoral fellowship in the frame of an AIRC project at Pavia University, studying selective recognition, covalent modification and stabilization of DNA in the G-quadruplex structures (G4s). In 2016 she started a second postdoctoral project supported by ERC focused on selective compounds targeting the G4s of the Long Terminal Repeat of HIV-1 to offer a novel strategy to be used in combination with current drugs. Her current research interest is focused on gene down-regulation, exploiting DNA and mRNA G4s, as innovative strategy to treat neurodegenerative disease and on metal interaction with neuronal peptides and proteins.

Barbara Procacci graduated from the `degli Studi di Perugia in 2007. She Universita completed her PhD in 2012 at the University of York under the supervision of Professor Robin Perutz, working on photoinduced C–F, C–H, B–H, and Si–H activation by metal complexes focusing on mechanistic investigations. She then took a position in York as a postdoctoral research fellow to work on a project jointly supervised by Professor Simon Duckett and Professor Robin Perutz. Her work is aimed at developing NMR spectroscopy as a time-resolved technique to monitor light-initiated organometallic reactions that happen on a fast time scale.

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Stefano Protti (born in 1979) completed his PhD in Pavia (2007, supervisor: Prof. Maurizio Fagnoni) focusing on photochemical arylations via phenyl cations. He was a postdoctoral fellow at the LASIR laboratory (Lille, France) and at the iBitTec-S Laboratory (CEA Saclay, France). Since 2015 he has been Senior Researcher at the University of Pavia, Italy. Stefano Protti is currently a co-author of more than 80 research articles and reviews, 9 chapters in multi-authored books and the book Paradigms in Green Chemistry and Technology, (2016, Springer IK, with Angelo Albini). The results of his research have been presented at National and International meetings.

Justina Pupkaite received her Bachelor’s degree (2011) and Master’s degree (2013) in Biophysics at Vilnius University (Lithuania). Currently, she is a doctoral candidate in a cotutelle program between the University of Ottawa (Canada) and Linkoping University (Sweden). She works under the supervision of Dr Erik Suuronen at University of Ottawa Heart Institute, co-supervised by Drs Peter Pahlsson and May Griffith. Her research focuses on developing collagen-based biomaterials for regenerative medicine applications, with focus on cardiac repair post myocardial infarction.

Carlotta Raviola (born in 1988) studied chemistry at the University of Pavia where she graduated in 2011. She received her PhD degree from the same university in 2015 (Prof. A. Albini as the supervisor) and spent part of this period at the Tech¨t Mu ¨nchen (Germany) in nische Universita the group of Prof. Thorsten Bach. She is currently a post-doc at the Department of Chemistry of the University of Pavia and her research interests focus on the photoinduced or photocatalytic generation of highly reactive species (aryl cations, (bi)radical intermediates) for synthethic applications.

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´n received his PhD Daniel Roca-Sanjua degree in 2009 for his quantum-chemistry studies on DNA photochemistry carried out at the Quantum Chemistry of the Excited State (QCEXVAL) group of Profs. Manuela ´n and Luis Serrano-Andre ´s, Institut de Mercha ` `ncia Ciencia Molecular, Universitat de Vale (Spain). In 2010, he moved to the group of Prof. Roland Lindh at the Department of ¨m, Uppsala University Chemistry  Ångstro (Sweden), with a Marie Curie postdoctoral grant, where he researched on the development and application of quantum-chemical methods with the MOLCAS program to the bioluminescence and chemiluminescence phenomena. In 2013, he returned to the QCEXVAL group as a postdoctoral ‘‘Juan de la Cierva’’ fellow and since 2017 he is ´n y Cajal’’ fellow (tenure track researcher) on comworking as a ‘‘Ramo putational photochemistry and chemiluminescence.

Javier Segarra-Martı´ received his PhD degree at the Instituto de Ciencia Molecular, Univeristy of Valencia (Spain) in 2014 for his work on photoinduced phenomena in water clusters and DNA/RNA nucleobases ´n under the supervision of Prof. Mercha ´n. He then moved to the and Dr Roca-Sanjua group of Prof. Garavelli at the Dept. of Chemistry, University of Bologna (Italy) to work on multiscale (QM/MM) approaches and non-linear electronic spectroscopies. In 2016 he joined the group of Dr Rivalta at ´cole Normale the Dept. of Chemistry, E `rieure de Lyon (France), to work on DNA photo-sensitisation Supe monitored by employing two-dimensional electronic spectroscopy (2DES). He is currently a Marie Curie Fellow associated to the group of Prof. Bearpark at the Dept. of Chemistry, Imperial College London (UK), where he studies electron dynamics in molecular systems of biological interest.

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Evan Sherbrook received his bachelor’s degree in Chemistry from the University of Vermont in 2013, studying the total synthesis of b-carboline natural products and structural analogues. His graduate work with Tehshik Yoon at the University of Wisconsin-Madison focuses on methods for controlling absolute stereochemistry in electron transfer and energy transfer processes.

Erik Suuronen is a principal investigator at the University of Ottawa Heart Institute in Ottawa, Canada. He is also Associate Professor in the Department of Surgery at the University of Ottawa, with crossappointment to the Department of Cellular & Molecular Medicine. He received his Bachelor’s degree in Biology in 1996 and his PhD in Cellular and Molecular Medicine in 2004, both from the University of Ottawa, followed by a post-doctoral fellowship at the University of Ottawa Heart Institute. His research focuses on tissue engineering and cell-based therapeutic approaches for the treatment of cardiovascular disease.

Takashi Tsuno obtained his PhDs at the University of Shizuoka under the supervision of Prof. Dr M. Sato in 2005 and at the University of Regensburg under the supervision of Prof. Dr H. Brunner in 2007. Currently, he is a Professor at Nihon University and has also been a contributor to SPR Photochemistry since 2009.

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Tehshik Yoon received his MS and PhD from Caltech under the supervision of Erick Carreira and David MacMillan, respectively. This was followed by an NIH postdoctoral fellowship at Harvard with Eric Jacobsen. He has served on the faculty at the University of Wisconsin-Madison since 2005. Prof. Yoon’s research interests largely focus on the use of photochemistry in organic synthesis. His research and scholarship has been recognized with several awards including the Corporation Cottrell Scholar Award, the Beckman Young Investigator Award, the Amgen Young Investigator Award, an Alfred P. Sloan Research Fellowship, an Eli Lilly Grantee Award, and a Friedrich Wilhelm Bessel Award from the Humboldt Foundation.

Michela Zuffo received her BSc and MSc degrees in Chemistry in 2012 and 2014 at the University of Pavia (Italy). She obtained her PhD from the same university in 2018, with a thesis on the selective targeting of specific G-quadruplex structures. She was visiting researcher at the department of Chemistry, University of Cambridge (2013), at the Bioengineering Department, Imperial College – London (2014), and at the IECB of Bordeaux (2017). She is alumna of Ghislieri College and IUSS (Pavia). Since 2018, she holds a postdoctoral position at Institut Curie (Paris). Her research is focussed on the synthesis and evaluation of small molecules targeting non-natural DNA mismatches.

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CONTENTS

Cover A quote from a century ago (back cover) from W. M. Bayliss, Naturwissenschaften, 1918, 101, 295–297. Front cover image courtesy of Dr Daria Manganaro.

Preface

vii

Angelo Albini and Stefano Protti Author biographies

viii

Part 1: Periodical Reports: Organic and Computational aspects (2016–2017) Introduction of the year Stefano Protti and Angelo Albini

3

1 Introduction 2 The sentence of the year, 1918 3 Awards and medals 4 Reviews of the year 5 Highlights in volumes 37 to 46 References

3 4 6 7 23 23

Quantum chemistry of the excited state: recent trends in methods developments and applications Miriam Navarrete-Miguel, Javier Segarra-Martı´, Antonio France´s-Monerris, Angelo Giussani, Pooria Farahani, ´n Bo-Wen Ding, Antonio Monari, Ya-Jun Liu and Daniel Roca-Sanjua 1 Introduction

28

28 Photochemistry, 2019, 46, xxv–xxix | xxv

 c

The Royal Society of Chemistry 2019

2 Developments of methods and theory 3 Conical intersections and their role in photophysics and photochemistry 4 DNA/RNA spectroscopy and photochemistry 5 Photosensitisation of biological structures and photodynamic therapy 6 Chemiexcitation 7 Summary and outlook Acknowledgements References

Organic aspects: photochemistry of alkenes, dienes, polyenes (2016–2017)

30 42 47 52 58 68 70 70

78

Takashi Tsuno 1 Introduction 2 Photoinduced (E)–(Z) isomerization 3 Electrocyclization 4 Photoinduced addition 5 Photocatalysts 6 Photooxygenation and photooxidation 7 Photochemistry of polyenes References

Photochemistry of aromatic compounds

78 78 82 88 92 99 100 101

116

Kazuhiko Mizuno 1 Introduction 2 Isomerization reactions 3 Addition and cycloaddition reactions 4 Substitution reactions 5 Intramolecular cyclization reactions 6 Rearrangements 7 Oxidation References

Organic aspects. Oxygen-containing functions M. Consuelo Jime´nez and Miguel A. Miranda 1 2 3 4

Introduction Norrish type I reactions Hydrogen abstractions `–Bu ¨chi photocycloadditions Paterno

xxvi | Photochemistry, 2019, 46, xxv–xxix

116 116 119 137 145 154 158 163

169 169 169 171 173

5 Photoreactions of multichromoporic systems: dicarbonyl compounds, enones, quinones and quinone methides 6 Photoeliminations: photodecarboxylations, photodecarbonylations and photodenitrogenations 7 Photo-Fries and photo-Claisen rearrangements 8 Photocleavage of cyclic ethers 9 Photoremovable protecting groups 10 Miscellanea References

Function containing a heteroatom different from oxygen (2016–2017)

175 180 183 184 184 186 188

194

Carlotta Raviola, Stefano Protti and Angelo Albini 1 Nitrogen containing functions 2 Functions containing other heteroatoms References

194 208 214

Part 2: Highlights Design and synthesis of two-photon responsive chromophores for application to uncaging reactions Youhei Chitose and Manabu Abe 1 Introduction 2 Examples of photolabile protecting groups (PPGs) and uncaging mechanism 3 Two-photon absorption and excitation 4 Two-photon responsive chromophores 5 Recent developments in TP uncaging reactions 6 Design and synthesis of TP responsive PPGs with stilbene core 7 Perspective for future TP responsive PPGs References

Controlled release of volatile compounds using the Norrish type II reaction Andreas Herrmann 1 Introduction 2 Mechanism of the Norrish type II reaction 3 Light-induced release of volatile compounds by the Norrish type II reaction 4 Conclusions and learnings References

221 221 222 224 225 228 235 238 238

242

242 243 249 261 262

Photochemistry, 2019, 46, xxv–xxix | xxvii

Recent advances in the design of light-activated tissue repair Christopher D. McTiernan, Justina Pupkaite, Irene E. Kochevar, Erik J. Suuronen and Emilio I. Alarcon 1 Overview of light-activated tissue bonding 2 Sutureless tissue bonding: from laser tissue welding to tissue photobonding 3 Photo tissue bonding (PTB) 4 Recent advances in in situ photo-polymerization 5 Conclusion and outlook Acknowledgements References

Photoresponsive molecular devices targeting nucleic acid secondary structures

265

265 266 269 271 276 276 276

281

Michela Zuffo, Valentina Pirota and Filippo Doria 1 Light-up mechanisms 2 Fluorescent sensing of non B-DNA secondary structures 3 Conclusions References

Transition metal complexes in ECL: diagnostics and biosensing

284 292 309 309

319

A. Aliprandi, B. N. DiMarco and L. De Cola 1 Introduction to electrochemiluminescence 2 Ruthenium complexes 3 Iridium complexes 4 Platinum complexes References

Photoinduced bond activation via Ru and Rh dihydrides: principles and selectivity Barbara Procacci 1 Introduction 2 Group 8 metal dihydrides for the reductive elimination step 3 Group 9 metal dihydrides for the oxidative addition step 4 Conclusions and outlook Acknowledgements References xxviii | Photochemistry, 2019, 46, xxv–xxix

319 326 336 342 349

352

352 353 359 365 366 366

Aromatic hydrocarbons as catalysts and mediators in photoinduced electron transfer reactions Benjamin Lipp and Till Opatz 1 Introduction and theoretical background 2 Examples of PET reactions catalysed by aromatic hydrocarbons 3 Examples of PET reactions mediated by aromatic hydrocarbons 4 Conclusion and outlook References

Photo-induced multi-component reactions Loı¨c Pantaine, Christophe Bour and Ge´raldine Masson 1 Introduction 2 Direct photoactivation of reagents 3 Photocatalysis 4 Conclusions References

Asymmetric catalysis of triplet-state photoreactions

370

370 375 384 387 388

395 395 399 408 428 429

432

Evan M. Sherbrook and Tehshik P. Yoon 1 Introduction 2 Arenes and aryl ketones 3 H-bonding xanthones, thioxanthones, and thioureas 4 Lewis acids 5 Transition metal photocatalysts 6 Summary and looking forward References

432 433 436 440 444 446 447

Photochemistry, 2019, 46, xxv–xxix | xxix

Part 1 Periodical Reports: Organic and Computational aspects (2016–2017)

Introduction of the year Stefano Protti and Angelo Albini* DOI: 10.1039/9781788013598-00003

Important advancements in photochemistry in the year 2017 are illustrated by presenting awards, some historical perspectives and some representative examples.

1

Introduction

The present volume, no 46 in the series ‘‘Photochemistry’’ of the Specialist Periodical Reports published by the Royal Society of Chemistry, consists in two different parts. The first section includes a series of reviews on the advancements in computational and organic photochemistry reported in the biennium 2016–2017. The second part of the issue consists of highlights on recent topics, with the aim to provide the reader with a flavour of the advanced research that may be also a pleasant reading for practitioners. In the attempt to better serve our readers, the present introduction chapter includes, along with reviews, thematic issues and papers published in 2017, as well as a section on awards and prizes assigned to researchers operating in the different sectors of photochemistry. A presentation of the quote of the series ‘‘one hundred years ago’’ printed on the back cover has been also included herein. As hinted below, the reviews section is devoted to the recent efforts reported in the field of computational photochemistry and the photoreactivity of organic compounds, including olefins, aromatics and molecules bearing different functional groups. On the other hand, the highlights section includes reports focused on recent advances in different research fields including photomedicine (the design of light-activated tissue bonding and of photoresponsive molecular devices to target nucleic acid secondary structures, as well as of the use of electrochemiluminescent transition metal complexes for biosensing purposes), inorganic (the photoreactivity of metal hydrides), organic (the optimization of photoinduced multicomponent reactions, of the use of polyaromatics as photocatalysts and the development of asymmetric catalyzed triplet-state reactions) and applicative photochemistry (the design of two-photon responsive chromophores for uncaging reactions, the release of volatile compounds via the Norrish-type II reaction and the use of spectroscopy techniques in art). Let’s have a more personal note, before starting the volume. We would like to remember here Professor Ugo Mazzucato. His always strong interest in new ideas, his enthusiasm for research, his patience in listening to anybody, his optimistic and generous contribution to the development of associations and to the growing of individuals will PhotoGreen Lab, Department of Chemistry, University of Pavia, V.Le Taramelli 12, 27100 Pavia, Italy. E-mail: [email protected] Photochemistry, 2019, 46, 1–27 | 3  c

The Royal Society of Chemistry 2019

remain in the heart of anybody that had the fortune to meet him personally.y

2

The sentence of the year, 1918

‘‘An interesting fact comes out from the curve of sensibility of the retina compared with the energy of the light acting. At that particular frequency of vibration corresponding with the yellow–green, the threshold of stimulus coincides with the energy quantum of Plank for that rate of vibration. In other words, the retina is sensitive to as small an incidence of energy as it is possible for it to receive’’ W. M. Bayliss, Light and vision, Nature, 1918, 101, 295–297. Some of the important steps that established the peculiar course of photochemical processes have been portrayed in the last years through important quotations. From the papers printed in 1918, it is appropriate, we think, to take the chose from the photobiological field, since this had consistently grown in those years. In a talk before the members of the Illuminating Society on April 16, 1918 and then printed in Nature1 the authoritative specialist William M. Bayliss, a well known professor of physiology, commented on the present situation of light and vision. He found that the process could be divided in three phases, namely: (1) The registration of light from outside by means of the diotropic system of the eye; (2) The activation and stimulation of some kind that occurred at the nerve terminals;

y

Born in Padua in 1929, Ugo Mazzucato married Gianna Favaro, also a chemist, and had two children: Lucia and Andrea. He received a degree in chemistry from the University of Padua in 1955. He was lecturer in physical chemistry and related subjects at the Universities of Padua, L’Aquila and Perugia. In Perugia, he has been full professor of physical chemistry since 1969 and the Director of the Chemistry Department of the Science Faculty in the 1986–1992. After his retirement in November 2004 he continued to attend the Chemistry Department of the University of Perugia as Emeritus Professor, following some research lines and helping students in the thesis work. He held important positions such as member of the Board of Governors of the University of Perugia. He worked in chemical education as part of commissions of the Italian Chemical Society (SCI) and of the National Research Council (CNR) for reforming the degree programs in the scientific field. He was one of the founding members of the European Photochemistry Association, the Italian Group of Photochemistry, the national divisions of Physical Chemistry and Chemical Education, and the regional section of the Italian Chemical Society. He has authored more than 220 scientific papers on kinetics, spectroscopy, acid-base and charge-transfer equilibria, photographic science, chemical education and, primarily, on photochemistry. His main research interest was focused on the processes of rotation around double bonds (cis-trans photoisomerization) and single bonds (ground-state rotamerism) in stilbene-like compounds and their heteroanalogues and on their bimolecular processes with energy, electron and proton donors or acceptors. His main hobbies were stamp collection, mountain hiking and wine tasting.

4 | Photochemistry, 2019, 46, 1–27

(3) The distribution of the impulses in the brain, while in some mysterious way this generated a conscious impression of light and illuminated objects. These results opened many questions. At first, what happens if the nerve is stimulated in some other way? The answer to this question was that, whatever is the stimulus, the sensation is always one of light (as is the case for other senses, in each connected nerve. On the other hand, illumination of optic nerve did not activate anything, since the nerves per se are not responsive to light. Some form of energy had to be operating at the level of cones and rods, which guaranteed such a high level of sensitization arriving at a single photon level. Cones hat to be photosensitive, because they were the only type of cells present in the highly sensitive fovea centralis, and rods likewise, because of the great similarity of their connections. The only sensible conclusion was that some chemical reaction occurred. A single photoactive pigment was then known and indicated as ‘visual purple’, although the color was rather indicated by most people as a deep red-rose. This made interesting to measure the chemical changes occurring in the presence of the dye. This reaction should lead to photoproducts not disappearing at once, and a temporary bleaching of the dye was observed. In Prof. Bayliss words, ‘‘First the curve gradually falls, the stimulus merely disappears on the advent of darkness. There is no indication of the stimulus of any kind produced by darkness. This is contrary to the well-known theory of Hering, according to which the reaction of restoration, occurring when the light ceases, is associated with the positive sensation of darkness. This point of view had been applied to physiological phenomena in general, but is now practically given up. Secondly, the curve, after it has attained its maximum, remains constant, while the illumination lasts. Thirdly, the reaction does not attain its full intensity suddenly, nor do the products disappear suddenly. In other words, the sensation does not appear at once, nor does it immediately disappear when the stimulus ceases. This is the obvious explanation of the absence of flicker when the alteration of light and darkness are sufficiently rapid. Further, as it would be expected from a chemical reaction, the greater its magnitude, the longer it requires for the products to recombine or otherwise disappear. Incidentally, the form of the curve differs somewhat for different colours. Fourthly, there is a short latent period between the time of incidence of light and the electrical effect, if this is not counterbalanced by a similar period after the illumination ceases; it would result in some deviation from Talbot’s law’’ (that states that when the illumination of a visual field is interrupted with sufficiently high frequency, it appears to the human eye as continuous) ‘‘in its physiological aspect, such as has been described by Parker and Patten. The latent period reminds us of the ‘photochemical induction’ of Bunsen and Roscoe.’’ ‘‘There is reason to believe that the maximum sensibility of the fovea is not when it is the only part of the retina illuminated, but when there is simultaneously a weak illumination of the surrounding parts. This seems to be Photochemistry, 2019, 46, 1–27 | 5

connected with the production and migration of the visual purple. If it is so, its importance in observations with the microscope, the polarimeter, and other optical instruments is obvious. The explanation of positive and negative afterimages is fairly plain – the former by the products of photochemical change not disappearing at once, the latter by temporary exhaustion of the visual purple. Edridge-Green has shown that the situation and shape of the positive afterimage can be altered by jerking the head, showing at the chemical charge is located in the liquid surrounding the rods and cones. Hence, these structures must be affected secondarily. The negative after image is fixed, indicting a situation in the more solid parts of the receptive mechanism.’’ ‘‘The adaptation of the retina to various degrees of illumination. . .is probably due to a change in the position of the pseudo-equilibrium, which results from the fact that the products of a reversible photochemical reaction are continually recombining during the illumination itself. . . .The suggestion that the ratio of brightness of object to which the eye turns should not exceeds 1 : 100 seems a reasonable one. The problem of ‘glare’ is also connected, although the fact of the unpleasant and injurious effect of powerful local stimulation of the retina has also to be taken into account. . . .However, it requires much more investigation, and the cooperation of physiologists, the illuminating engineers, the oculist. . . .The effect of lateral illumination brings up the question of the function of the rods as distinct from that of the cones, as do also vision under weak illumination and that known as ‘night-blindness’. The question of the colour arose according to Ferree’s observations where a yellow or a blue tint is more fatiguing than a white light. . . .An equally important series of questions has been raised by Mr. Gaster, namely the effect on school children with normal and with imperfect vision of working in adequate light.’’ The insight and the clearsight of such article are remarkable, particularly when considering how long has been the research to follow these topics and the complexity of what we now call phototransduction.

3

Awards and medals

Dr Steven Lee of the University of Cambridge received the Marlow Award 2017 (that is annually given to scientists that afforded a ‘‘meritorious contributions to physical chemistry or chemical physics’’) for ‘‘the development of novel single-molecule super-resolution fluorescence techniques’’.2 During the European Society for Photobiology 2017 Congress (Pisa, 4–8 September 2017) Prof. Silvia E. Braslavsky, Prof. Joan E. Roberts and Prof. Miguel A. Miranda received the European Society of Photobiology (ESP) Award for Excellence in Photobiological Research.3 At the same meeting, Prof. Ilaria Testa from Stockholm was awarded with the ESP Young Investigator Award for the contribution of her research group to the field of bioimaging.3,4 Professor Michael Wasielewski (Northwestern University) received the Physical Organic Chemistry Award of the Royal Society of Chemistry in view of his ‘‘pioneering contributions to understanding electron transfer reactions and their dependence on molecular structure and spin dynamics in organic molecules’’.5 Such investigations 6 | Photochemistry, 2019, 46, 1–27

have been exploited in different research fields, including artificial photosynthesis of fuel and energy production.6 Prof. Bern Kohler (Montana State University), received the Inter-American Photochemical Society Award in Photochemistry, for his work in ultrafast laser spectroscopy applied to photobiological processes.7 Prof. David G. Whitten (University of New Mexico Center for Biomedical Engineering) received the prestigious George S. Hammond Award for his outstanding contribution to different photochemical fields, including the investigation of energy and electron transfer reactions and the preparation and application of self organized assemblies.8 The Honda-Fujishima Lectureship Award of The Japanese Photochemistry Association (JPA) went to Prof. Fred Brouwer (Van ’t Hoff Institute for Molecular Sciences, University of Amsterdam) for his efforts in the field of molecular photonics, and, in particular, in the use of organic molecules as luminescent probes.9 The European Academy of Sciences awarded Prof. Vincenzo Balzani (University of Bologna) in recognition for his contribution to the development of major branches of chemistry, such as photochemistry and molecular nanotechnology.10 Professor Nicola Armaroli (CNR, Istituto per la Sintesi Organica e la ` – ISOF, Bologna) was the recipient of the Medal Enzo Fotoreattivita Tiezzi, which is awarded for outstanding contributions to the field of environmental chemistry. Finally, Dr Davide Ravelli (University of Pavia) received the 2017 Ciamician Medal from the Italian Chemical Society as the best young organic chemist of the year and the Vincenzo Caglioti Award (from the National Lincean Academy) for the results obtained in the development of photocatalysts able to promote hydrogen atom transfer reactions.11

4 Reviews of the year 4.1 Handbook and special issues Handbooks. The volume ‘‘Photomechanical Materials, Composites, and Systems: Wireless Transduction of Light into Work’’, (Wiley, 432 pages) has been recently edited by T. J. White and aims to provide the reader with an almost exhaustive overlook of the history, the current state, and the perspectives of light-controlled systems, including photochromic crystals and piezoelectric ceramics.12 The photophysical properties of IrIII complexes make them as the most promising additive for the preparation of materials for optoelectronic applications. The Volume 97 of the series Semiconductors for Photocatalysis, prepared by Zetian Mi Lianzhou and Wang Chennupati Jagadish is focused on the latest advances in the preparation of efficient semiconductor (e.g. metal-oxides and -nitrides and silicon) photocatalysts and electrodes for either water splitting and CO2 reduction.13 The monumental 2-volume set ‘‘Iridium(III) in Optoelectronic and Photonics Applications’’ edited by Eli ZysmanColman offers an exhaustive account of photoactive iridium complexes and their wide applications.14 ‘‘Phototherapy and Photodiagnostic Methods for the Practitioner’’, written and edited by W. S. Chong, J. Y. Pan and S. T. E. Tan, represents the Photochemistry, 2019, 46, 1–27 | 7

first published set of practical guidelines in phototherapy for Asian skin, based on both the many clinical experiences of the Authors at the National Skin Centre in Singapore and the most recent scientific literature data.15 ‘‘Semiconductor Quantum Dots and Rods for In Vivo Imaging and Cancer Phototherapy’’ by M. Chu highlights the multifaceted applications of QDs and QRs (Quantum Rods) as sentinels in lymph node mapping, in vivo tumor target imaging as well as in photodynamic therapy.16 Elsevier recently launched the 4th edition of the volume on Vitamin D, devoted to the multifaceted properties and activities of such biomolecule.17 The 2016 Porter Medal James Barber recently edited, in collaboration with Alexander V. Ruban, the volume ‘‘Photosynthesis and Bioenergetics’’, a collection of papers from leading scientists involved in the investigation of natural photoinduced biological processes, including the Nobel Laureate Rudolph Marcus.18 Flow photochemistry is considered an expanding field in organic synthesis, since in this case the mild conditions involved in photochemical processes add to the ability to merge the mass transfer enhancement of flow chemistry. A convincing approach to that field is offered by the multi-authors handbook ‘‘Photochemical Processes in Continuous-Flow Reactors: From Engineering Principles to Chemical ¨l. The volume (that includes contributions Applications’’ edited by T. Noe of, among the others, professors Yuanhai Su and Thomas Junkers) gives an overview of technological and chemical aspects related with photochemical flow processes.19 The lecture note ‘‘Essentials of Pericyclic and Photochemical Reactions’’ written by B. Dinda represents an introduction to pericyclic and photochemical processes that find application in organic synthesis. The first section of the book focuses on electrocyclic reactions, cycloadditions, sigmatropic rearrangements, and group transfer reactions, while the second parts is devoted to processes exploiting the photoreactivity of different functional groups, including (poly)enes, carbonyls, and aromatics.20 The monograph ‘‘Naphthalenediimide and its Congeners: From Molecules to Materials’’ has been published by the Royal Society of Chemistry, with the editing work of G. Dan Pantos, and consists in ten sections focused on the application of naphthalene- and perylene-diimides in several fields, including organic photovoltaics and DNA binders.21 Special Issues. A celebrated quotation from ‘‘The photochemistry of the future’’ (1912)22 of Giacomo Ciamician introduced the reader to the theme issue of Chemical Society Reviews edited by Sebastiano Campagna and Gary W. Brudvig23 devoted to the recent advances in artificial photosynthesis. Among the different reviews included in the volume (that also included contributions from the research groups of T. J. Meyer, J. J. ´, E. Reisner and G. W Brudvig), we Conception, E. A. Gibson, R. More would like to report the interesting digression of A. Llobet and co-workers on the parameters that should be taken into account when designing a robust and efficient photocatalyst.24 To the same theme was dedicated a special issue of the Compte Rendus de Chimie assembled by Ally Aukauloo and Harry B. Gray.25 Analogously, a theme collection of the Dalton Transations was focused on the Role of Inorganic Materials in Renewable 8 | Photochemistry, 2019, 46, 1–27

Energy Applications. Most of the reviews and research papers published therein are addressed to photocatalytic systems for the selective CO2 conversion to methane,26 improved devices/systems for water splitting,27 and water oxidation.28 A theme issue of the Chemical Society Reviews celebrating the 50th supramolecular chemistry anniversary (guest editors: D. B. Amabilino and P. A. Gale)29 presented, among the other contributions, a biography of Charles Pedersen written by Reed M. Izzat30 and several reviews by, among the others, the 2016 Nobel Prize winners, Ben L. Feringa (with D. Leigh)31 and J. Fraser Stoddart,32 along with a report of Juyoung Yoon et al. on recent advances in the development of crown ethers-containing fluorescent probes.33 Another web issue of the Royal Society of Chemistry consists in 48 papers focused on the advances in the field of chemosensors.34 In particular, the paradigms for the preparation of a fluorescent polymeric thermometer have been discussed by the group of Inada.35 A volume of Chemical Reviews in 2017 was devoted to the light harvesting issue (guest editor: Gregory D. Scholes),36 and also explored the light absorption and energy transfer mechanisms used by the antenna complexes of photosynthetic organisms.37 The volume discussed several aspects of this research field, both from the computational38 and the experimental39 point of view. The development of photosynthetic biohybrid systems (PBSs) able to merge the strengths of inorganic materials and the selectivity of biological catalysts to generate valuable CO2-derived chemicals by using solar light was discussed a theme issue included in Accounts of Chemical Research.40 Tetrahedron published a special issue focused on ‘‘Dynamic Functional Molecular Systems’’ in honour of Ben Feringa, that was awarded with the 2016 Tetrahedron Prize for Creativity in Organic Chemistry.41 The collection includes 30 original papers, most of them focused on the development of photoactivated molecular machines. In particular, Trauner et al. described the design and the behavior of UV (360 nm) photoswitchable azobenzenes (see for instance compound 1 in Scheme 1), which act as antagonist for N-methyl-D-aspartate (NMDA) receptors.42

Scheme 1 Synthesis of a photoswitchable azobenzene able to act as the antagonist for N-methyl-D-aspartate (NMDA) receptors. Photochemistry, 2019, 46, 1–27 | 9

In the same volume, Giuseppone et al. reported in the same issue the multistep, gram scale synthesis of some optically pure Feringa’s motors (2).43

A 2017 issue of Photochemical & Photobiological Sciences was devoted to the health benefits of UV radiation exposure through vitamin D production or non-vitamin D pathways44 and a history of phototherapy was included therein.45 The Journal of Physical Chemistry A recently published a volume dedicated to the memory of Klaus Schulten (1947–2016), who focused his research on solving problems in molecular biophysics, including the investigation of the structure and mechanisms of bioenergetic proteins.46 A computational analysis of molecular dynamics at microsecond scale of Photosystem II (in both monomeric and dimeric forms) embedded in a thylakoid membrane model has been performed by Marrink et al. in order to describe in detail the setup of the protein complexes and the natural cofactors that characterize their mobility.47 The journal Biomedicines published a special issues entitled ‘‘Photodynamic Therapy in Cancer’’ with Carmen Cantisani, Giuseppe Pellacani and Stefano Calvieri as the guest editors.48 In March 2017 The Journal of Photochemistry and Photobiology C: Photochemistry Reviews published a volume devoted to recent advances in bioimaging.49 Among the reports included, we’re pleased to signal the reviews of Kim and co-workers on the synthesis of photoluminescent Quantum Dots (QDs) and their application as optical probes in biosensing.50 A thematic issue on Polymers and Light of Macromolecular Rapid Communications was edited by Cyrille Boyer and Garret Miyake. They assembled 18 contributions, including communications and reviews focused on the recent advances in photopolymerization and in the preparation of polymeric materials.51 A report on the synthesis and surface properties of stimuli-responsive polymeric nanoparticles written by Urban and co-workers is available therein.52 To the theme ‘‘Chirality and Nanophotonics’’ the journal Advanced Photonic Materials dedicated a selection of works selected by the editors Ventsislav Valev, Alexander Govorov, and John Pendry.53 In the contribution by Zanotti et al., the propagation of chiral light in optically induced helical photonic waveguide arrays was explained and investigated in order to demonstrate the selectivity of the system to optical orbital angular momentum.54 10 | Photochemistry, 2019, 46, 1–27

¨nig edited a special issue of the European Journal of Organic Burkhard Ko Chemistry.55 In it, along with a set of concise reviews,56 different scientific contributions, including, among others, the photoredox mediated tandem oxidation/nitroso-Diels–Alder cycloaddition of arylhydroxylamines 3a–d with conjugated dienes 4 described by G. Masson et al.57 for the preparation of variously substituted 3,6-dihydro-1,2-oxazines (5a–d, Scheme 2). Another interesting proposal is the protocol for the photoredox catalyzed cyclopropanation of electron-poor olefins, including Michael acceptors 6a–c, described by Suero and del Hoyo (Scheme 3).58 The partner journal of EurJOC, the Asian Journal of Organic Chemistry, also dedicated a issue on photoredox catalyzed processes, with contributions of Hua Fu,59 Aiwen Lei60 and Ilhyong Ryu.61 Proceedings and research papers. A selection of research papers presented at the 9th European Meeting on Solar Chemistry & Photocatalysis: Environmental Applications (SPEA 9) was recently included in a themed issue of the journal Photochemical & Photobiological Sciences (guest editors: Nicholas Keller and Sixto Malato).62 Most of the original contributions included are devoted to environmental photocatalysis. The group ´ndez-Ramı´rez proposed the modification of of Elizondo and that of Herna TiO2 with RuII polyaza complexes for the solar induced mineralization of the non steroidal anti-inflammatory drug Ibuprofen.63 Similarly, visiblelight absorbing Titania hollow spheres functionalised with tungstophosphoric acid (see a comparison between SEM-micrographs of unmodified and modified TiO2 hollow spheres in Fig. 1) were efficiently employed by Orellana et al. for the photoinduced degradation of 4-chlorophenol.64 Several contributions presented at the 13th Italian Conference on Supramolecular Chemistry (Santa Margherita di Pula (CA), June 2017)

Scheme 2

Scheme 3 Photochemistry, 2019, 46, 1–27 | 11

Fig. 1 SEM micrographs of SiO2 (a), SiO2@TiO2 (b) and @TiO2 (c). Reproduced from ref. 64 with permission from the European Society for Photobiology, the European Photochemistry Association, and The Royal Society of Chemistry.

Fig. 2 Cover-art of the sister issues of Energy Technology and ChemSusChem devoted to the applications of halide-perovskites. Left image reprinted with permission from ref. 67, Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Right image reprinted with permission from ref. 66, Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

have been recently collected in a special issue of Supramolecular Chemistry (Taylor and Francis).65 The multifaceted applications of perovskites (including the preparation of solar cells and bio-imaging) were the topic of two issues of sister journals ChemSusChem66 and Energy Technology,67 following the symposium on ‘‘Halide Perovskites for Optoelectronics Applications’’, a section of the International Conference on Materials for Advanced Technologies (ICMAT 2017) which took place in Singapore (Fig. 2). Several contributions presented at the XXXIII European Congress on Molecular Spectroscopy, (2016, Szeged, Hungary) have been collected in a special issue of the Journal of Molecular Spectroscopy.68 Among the published papers, it should be mentioned the work of T. Sych et al. on the synthesis and the optical properties of albumin-stabilized silver nanodots.69 12 | Photochemistry, 2019, 46, 1–27

4.2 Reviews and original articles ‘‘Considering the extraordinary rate of development of photochemistry, the decision was made to establish a journal to publish not just fundamental studies and the latest developments in more traditional areas of pure and applied photochemistry, but also to provide an appropriate and attractive forum covering the newest burgeoning topics within (and around) the discipline.’’ With such speech of intent, written by Deanne Nolan and Greta Heydenrych, ChemPhotoChem started its activity for Wiley in January 2017.70 The journal (that is co-owned by ChemPubSoc Europe and has Angewandte Chemie as the sister journal) will consists in 12 issues for year, and embraces different research fields, including environmental photocatalysis, photoredox catalytic synthesis and photobiology. The authors wish ChemPhotoChem luck and a considerable success story. The ecosustainable preparation of silver nanoparticles (AgNPs) was achieved by merging biochemistry and photochemistry. Thus, sunlight exposure of a AgNO3 solution in the aqueous extract of Dunaliella salina (playing the dual role of reducing and stabilizing agent) afforded the desired NPs.71 Interestingly, the anticancer potential of such compounds towards MCF-7 cell lines was comparable to that of well known Cisplatin, but was not detrimental to the normal cell line. Analogously, AgNPs were also photochemically synthesized by using Derris trifoliata leaf extract as the reaction medium and tested as larvicidal vectors.72 Recently, inorganic perovskite quantum dots (QDs) have been employed as optoelectronic materials in the preparation of lightharvesting and emitting devices, but their application for photocatalytic purposes remains limited.73 A recent work described the use of colloidal perovskite QDs in the photoreductive conversion of CO2 in carbon based fuels (CH4, CO). The best results were obtained with the CsPbBr3 QDs, where CO2 was reduced with an efficiency of 20.9 mmol g cat1.74 The efficiency was improved by using the CsPbBr3 perovskite QDs/Graphene oxide composite, as schematized in Fig. 3.75 In the field of energy storage, the ‘‘meteoric rise of perovskite singlejunction solar cells’’ and ‘‘perovskite tandem solar cells’’ have been efficiently

Fig. 3 Schematic representation of a CsPbBr3 perovskite quantum dot/graphene oxide composite in the photoreductive conversion of CO2 in carbon based fuels. Reprinted with permission from ref. 75. Copyright 2017 American Chemical Society. Photochemistry, 2019, 46, 1–27 | 13

described in a progress report by Bach and co-workers, with particular attention to the development of increasingly efficient devices.76 On the other hand, A. Walsh focused on the advantages of preparing solar cells based on kesterite mineral structure (such as Cu2ZnSnS4 and Cu2ZnSnSe4), including the fact that they are composed by earth-abundant and nontoxic elements.77 Solar cells able to operate upon indoor illumination can be employed as electric power sources for portable electronics and devices. ¨tzel and co-workers recently described a dye-sensitized solar cell (DSSC) Gra obtained from the combination of sensitizers D35 (8) and XY1 (9, see Fig. 4) with the copper complex CuII/I(tmby) (tmby ¼ 4,4 0 ,6,6 0 -tetramethyl2,2 0 -bipyridine) as the redox shuttle. This exhibited a open-circuit photovoltage of 1.1 V. Notably, the developed DSSC achieved an external quantum efficiency for photocurrent generation that exceeds 90% (when

Fig. 4 Organic dyes recently used in solar cells. 14 | Photochemistry, 2019, 46, 1–27

irradiated in the 400–650 nm domain, and under illumination from a model Osram 930 warm-white fluorescent light tube, the measured powerconversion efficiency was 28.9%.78 Despite the effectiveness of photodynamic therapy (PDT) in the treatment of actinic keratoses and early skin cancers (testified by the fact that PDT is the only FDA approved approach to control field cancerization), the pain related with this procedure often limits a widespread PDT application. The reported interventions on PDT-associated pain were assessed in an impressive review paper by Zeutouni et al. in the aim of identifying the most promising methods to manage and minimize such side-effects.79 Great attention has been given this year to the application of PDT in dentistry; different literature and clinical reviews have been focused to its use as supplementary antimicrobial treatment of deep carious lesions,80 in the disinfection of acrylic denture surfaces,81 as well as in the non surgical cure of chronic periodontitis.82 Among the original papers, Wu et al. prepared photo-cross-linkable semiconductor polymer dots (Pdot) doped with the photosensitizer Chlorin e6 (Ce6) that acts as a nanoparticle platform to perform PDT. The desired Pdots (that are in turn prepared from phototoreactive oxetane derivatives that acted as cross-linkable groups) represent an interpenetrated structure that on one hand prevents Ce6 leaching out from the polymeric matrix and on the other hand leads to an amplified generation of singlet oxygen (F ¼ 0.4 vs. 0.1 of the non Ce6 doped Pdots).83 Folic acid tetrads were used by the research group of Sortino as a template to prepare a mesoporous silica material able to encapsulate meso-tetrakis(4-carboxyphenyl)porphyrin (TCPP) sensitizer in its interior. The thus prepared assembly exhibits a satisfactory singlet oxygen photosensitization efficiency, and enhanced photo-induced mortality in KB cancer cells when compared with the free components (Fig. 5). The development of environment-selective photosensitizers is a challenge in PDT. The aminated-chrysophanol 10 was found to be

Fig. 5 Idealized picture for the targeted PDT with FA (blue)/TCPP(red) assembly released from the mesoporous silica material. Reprinted with permission from ref. 84, Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Photochemistry, 2019, 46, 1–27 | 15

proton-activatable by tumor acidic microenvironment, exhibiting both emission and reactive oxygen species generation. The presence of two tertiary amines ensured an enhanced cellular uptake, while red-shifting at the same time the wavelength of absorption and improving the phototoxicity.85

Nanocomposite particles, consisting in self-assembled porphyrin arrays as the core surrounded by amorphous silica as the shell, have been prepared by Fan and co-workers through a combined surfactant micelle confined self assembly and silicate sol–gel process. Along with the high yield of generated singlet oxygen, the extensive self-assembled network of porphyrins in the core enabled efficient energy transfer and an impressive fluorescence for cell labeling. Furthermore, the silicate shell could be smoothly derivatized to form targeting porphyrin–silica nanocomposites able to destroy selectively tumor cells upon irradiation.86 Photoinitiated living processes, such as radical and cationic polymerizations, received a great attention from both industrial and academic researchers. Fors and co-workers resumed the impact of photoinitiated cationic polymerizations (Fig. 6a) on polymer science and, at the same time, described the state of the art of photocontrolled cationic polymerizations, a rather new approach, where the control over chain growth is actuated by alternating periods of irradiation (activation) and dark (deactivation), while the rate of polymerization depends on the intensity of the light. (Fig. 6b).87 In the same

Fig. 6 Schematic depiction of (a) Photoinitiated cationic polymerizations and (b) photocontrolled cationic polymerizations. Reprinted with permission from ref. 87, Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. 16 | Photochemistry, 2019, 46, 1–27

paper, the authors reported a remarkable strategy for the synthesis of different polymeric structures under identical chemical conditions. The reaction took place with two monomers (an electron-poor and an electron-rich olefin) in the presence of two photocatalysts (having different absorption spectra) able to initiate either a radical or a cationic process. The mechanism of the polymerization and the incorporation of the monomer can be easily tuned via the selection of the wavelength of the light source (Fig. 7). A change in the stoichiometric ratio of the photocatalysts resulted in a further chemical control over the polymerization and allowed for the design of elaborated polymeric structures.88 Selected cases of photoinitiated polymerization taking place in ionic liquids have been described by E. Andrzejewska. This author also resumed most of the applications relying on this strategy, such as the preparation of ion-conductive polymer films.89 Lange et al. reported the gram scale single-crystal-to-single-crystal synthesis of a 2D polymer via photochemical [2 þ 2]-cycloaddition occurring on monomer 11. As illustrated in Fig. 8, the obtained crystals are then wet-exfoliated under mild conditions to afford single and double layer features.90 The photorearrangement occurring in hydrazones has been exploited in the last decade for the development of photochromic materials. A recent feature article described minutely the state of the art of this argument.91 The metal-free, UV-light multicomponent coupling of aryl/alkyl halides and silyl enolates in the presence of DABCO  (SO2)2 as source of sulfur dioxide has been optimized by Wu and co-workers and exploited for the efficient synthesis of b-keto sulfones 13a–c. The process is initiated by the homolysis of a C-halide bond, with the consequent formation of a carbon centered radical, and exhibits a satisfactory functional group tolerance (Scheme 4).92

Fig. 7 Switching the polymerization mechanism and monomer selectivity by changing the wavelength of light irradiation. Reprinted with permission with ref. 88, Copyright 2017 American Chemical Society. Photochemistry, 2019, 46, 1–27 | 17

Fig. 8 The single-crystal-to-single-crystal synthesis of a 2D polymer based on photochemically triggered [2 þ 2]-cycloaddition. The obtained crystals are then wet-exfoliated under mild conditions to afford single and double layer features. Reprinted with permission from ref. 90, copyright 2017 American Chemical Society.

Scheme 4

A self-assembled (glyco)peptide inspired by elastin protein was prepared by taking advantage of combining solid phase peptide synthesis with thiol-ene chemistry. Such biomolecule could be used as biomaterial in the field of tissue engineering and regenerative medicine.93 Single electron transfer (SET) cyclization processes still represents a facile and widely used approach for (macro)cycles building. The preparation of Sansalvamide, on analogue containing two pharmacophores (cyclic peptides and O-phthalimide moiety), has been recently described by Jin et al. The biological activity of the obtained compound was successfully tested in drug-sensitive HeLa, HepG-2 and MCF-7 cell lines in the aim of developing a novel antitumor cyclopeptide drug.94 18 | Photochemistry, 2019, 46, 1–27

As concerning peptido-drugs, the selective, photocatalytic decarboxylative macrocyclization of oligopeptides bearing N-terminal Michael acceptors has been presented by the research group of David MacMillan. The developed approach allows for the preparation of cyclic peptides ranging from 3 to 15 amino acids. The synthetic scope of the procedure was evidenced by synthesizing the somatostatin analogue COR-005 (Scheme 5).95 Photoredox catalysis often involves metal complexes, that frequently rely on high-priced/rare elements such as ruthenium or iridium. However, in recent years, significant efforts have been carried out to exploit complexes containing earth-abundant redox active elements, including the ions CrIII, FeII, CuI, ZnII, and UVI. A review by Christopher Larsen and Oliver Wenger discussed the scope and the mechanism of the reactions developed in this field, providing also the reader with a summary of the electrochemical and photophysical parameters that characterize such innovative photocatalysts.96 The rise of nucleophilic aromatic substitution (SNAr) as a versatile synthetic method is hampered by the low reactivity of arenes. Nicewicz optimized a radical cation accelerated SNAr reaction by using alkoxy groups in compounds 14a–c as nucleofuges and acridinium perchlorate 15 as the visible-light absorbing photocatalyst. The method was extended to the functionalization of guaiacol and veratrole motives that constitute the structure of lignin as well as of polyfunctionalised heterocycles (Scheme 6).97 Interest for processes that merge gold catalysis with photocatalytic/ photochemical processes is currently increasing. One of the most recent

Scheme 5 Photoredox macrocylization to form the bioactive cyclic peptide COR-005. Reprinted with permission from ref. 95, Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Photochemistry, 2019, 46, 1–27 | 19

Scheme 6

Scheme 7

Scheme 8

examples is the catalytic ipsoarylative cyclization of aryl-alkynoates 17a–d or N-arylpropiolamides with phenyl diazonium tetrafluoroborate salts in the presence of catalytic amounts of [(4-OCH3)C6H4]3PAuCl and Ru(bpy)3(PF6)2. This approach was found to afford arylated spirocarbocycles 18a–d in moderate to good yields (Scheme 7).98 Allylarenes can also be efficiently prepared by following the same approach.99 Similar catalytic conditions were employed in the regioselective trifluoromethylthiosulfonylation of alkenes (mainly styrenes) 19a–c (Scheme 8).100 20 | Photochemistry, 2019, 46, 1–27

Scheme 9

Scheme 10

A photocatalyst-free, visible light driven variant of the Suzuki coupling was achieved by using arylazo sulfones as starting photoactivated substrates, and afforded the desired (hetero)biaryls in discrete to good yields (Scheme 9).101 In photoredox catalysis, a single electron transfer (SET) process is the initial step. However, since irradiation allows for the achievement of a series of discrete, yet fundamental, fragment-coupling steps, the viability of excited-state organometallic is possible and the triplet sensitization by energy transfer has long been known as a powerful activation mode. Mac Millan et al. described the formation of the excited-state of a nickel complex via energy transfer from a photoexcited iridium sensitizer upon visible light irradiation. Under these conditions, aryl halides are able to couple with carboxylic acids (an example in Scheme 10).102 Due to its promising multifaceted application, the tautomerization via an excited state intramolecular proton transfer (ESIPT) step is probably one of the most studied processes in photochemistry.103 The critical review of Serdiuk and Roshal104 focused on where double intramolecular proton transfers can occur (for example 23), as well as on the spectral features of these compounds.

The so-called hexadehydro-Diels–Alder (HDDA) reaction, that is the cycloisomerization of substrates containing a 1,3-butadiyne core conjugated to a remote alkyne (24, Scheme 11) to generate an ortho-benzyne Photochemistry, 2019, 46, 1–27 | 21

Scheme 11

Scheme 12

intermediate (25) was described for the first time to occur under photochemical conditions by Hoye and co-workers.105 Notably, whereas the process took place at lower temperatures than those required for the dark reaction, the generated benzynes 25 behave in the same fashion, suggesting that the intermediates obtained under either thermal or photochemical conditions are of the same multiplicity. A tutorial review on the application of time-resolved photoelectron spectroscopy combined with quantum chemistry and dynamics calculations to deepen the electronic relaxation mechanisms of photoexcited molecules was proposed by G. A. Worth and H. H. Fielding.106 A peculiar advantage of this strategy is represented by the different complexity of the examined compounds, that included simple aromatics (benzene, aniline), a pyrrole dimer bound by a weak N–H  p interaction and the green fluorescent protein chromophore. In the last years, a significant attention has been given to the use of laser flash photolysis to elucidate the photochemistry of organic molecules in nanocrystalline suspensions, a in the case of the conversion of a-azidoacetophenone 27 to imine 28 (Scheme 12).107 The same approach has been applied by Garcia Garibay and co-workers to the investigation of the reactivity of diarylmethyl radical pairs photogenerated from crystalline tetraarylacetones,108 as well as to the characterization of transient isocarbazole, playing a key role in the photochemistry of 2-azidobiphenyls.109 22 | Photochemistry, 2019, 46, 1–27

5

Highlights in volumes 37 to 46

Azobenzene photoisomerization, 2016, 44, 294–321 Cultural heritage, and photochemistry, 2010, 39, 256–284 Cyclodextrins, photoresponsive, 2015, 43, 226–269 Exiton fission, 2015, 43, 270–285 Flow photochemistry, 2015, 43, 173–190 Fluorescence Imaging, nanoscale, 2010, 39, 191–210 Global artificial photosynthesis, 2016, 44, 259–282 Industrial applications, of photochemistry 2009, 38, 344–368 Interfacial electronic processes, on the surface of nanostructured semiconductors, 2008, 37, 362–392 History of photochemistry, IAPS, 2012, 41, 269–278 History of photochemistry, EPA, 2011, 40, 197–229 History of photochemistry, APA, 2011, 40, 230–244 Human skin, photoprotection of, 2011, 40, 245–273 Nitric oxide photorelease, 2012, 41, 302–318 Nucleic acids, caged, 2012, 41, 319–341 Organic solid-state luminescence, 2015, 43, 191–225 OLEDs, 2008, 37, 393–406 Photoactivatable protecting groups and carbon monoxide molecules, 2017, 45, 175–190 Photochromic, nanoparticles, 2010, 39, 211–227 Photocatalysis for depollution, 2016, 44, 346–361 Photocatalysis with Donor-Acceptor Polymers, 2017, 45, 191–220 Photolithography materials, 2009, 38, 369–387 Photo-induced water oxidation, 2011, 40, 274–294 Photoluminescence sensors, 2016, 44, 322–345 Photon–molecule coupling fields, 2010, 39, 228–255 Photo-oxygenation, 2009, 38, 307–329 Photoredox systems for building C–C bonds from carbon dioxide, 2017, 45, 165–174 Polymerization, 2014, 42, 215–232 Prebiotic atmosphere, 2012, 41, 342–359 Prebiotic photochemistry, 2009, 38, 330–343 Proton transfer, in flavonols, 2011, 40, 295–322 Reactive oxygen species, 2012, 41, 279–301 Solar energy conversion, 2016, 44, 283–293 Singlet oxygen, in biological media, 2014, 42, 233–278 Solid-state, photoreactions, 2015, 43, 286–320 and 2015, 43, 321–329 TiO2 photoredox catalysis, 2016, 44, 362–381 UV spectra, calculated, 2014, 42, 197–214

References 1 2 3

W. M. Bayliss, Nature, 1918, 101, 295. A. R. Carr, A. Ponjavic, S. Basu, J. McColl, A. M. Santos, S. Davis, E. D. Laue, D. Klenerman and S. F. Lee, Biophys. J., 2017, 112, 1444. http://www.photobiology.eu/esp_awards. Photochemistry, 2019, 46, 1–27 | 23

4 5 6

7 8 9 10 11 12 13 14 15 16 17

18 19

20 21 22 23 24 25 26 27 28 29 30 31 32

I. Testa, E. D’Este, N. T. Urban, F. Balzarotti and S. W. Hell, Nano Lett., 2015, 15, 103. For further information: http://www.rsc.org/ScienceAndTechnology/Awards/ PhysicalOrganicChemistryAward/2017-Winner.asp. A. Timalsina, P. E. Hartnett, F. S. Melkonyan, J. Strzalka, V. S. Reddy, A. Facchetti, M. R. Wasielewski and T. J. Marks, J. Mater. Chem. A, 2017, 5, 5351; R. E. Cook, B. T. Phelan, L. E. Shoer, M. B. Majewski and M. R. Wasielewski, Inorg. Chem., 2016, 55, 12281. J. Chen, A. K. Thazhathveetil, F. D. Lewis and B. Kohler, J. Am. Chem. Soc., 2013, 135, 10290. K. A. Achyuthan, L. Lu, G. P. Lopez and D. G. Whitten, Photochem. Photobiol. Sci., 2006, 5, 859. T. Suhina, S. Amirjalayer, S. Woutersen, D. Bonn and A. M. Brouwer, Phys. Chem. Chem. Phys., 2017, 19, 19998. http://www.eurasc.org/davinci/davinci2017.asp. D. Ravelli, S. Protti and M. Fagnoni, Acc. Chem. Res., 2016, 49, 2232. Photomechanical Materials, Composites, and Systems: Wireless Transduction of Light into Work, ed. T. J. White, Wiley and Sons, 2017, p. 432. Z. Mi and L. Wang, in Semiconductors for Photocatalysis, ed. Jagadish, 2018, vol. 97, p. 492. Iridium(III) in Optoelectronic and Photonics Applications, ed. E. ZysmanColman, Wiley, WCH, 2017, p. 736. S. Chong, J. Y. Pan and S. T. E. Tan, in Phototherapy and Photodiagnostic Methods for the Practitioner, Work Scientific Editions, 2017, p. 136. M. Chu, in Semiconductor Quantum Dots and Rods for In Vivo Imaging and Cancer Phototherapy, Work Scientific Editions, 2017, p. 192. Vitamin D 4th Ed. Volume 1: Biochemistry, Physiology and Diagnostics, ed. D. Feldman, J. W. Pike, R. Bouillon, E. Giovannucci, D. Goltzman and M. Hewison, 2017, 1164 pp. Photosynthesis and Bioenergetics, ed. J. Barber and A. V. Ruban 2017, Work Scientific Editions, p. 368. Photochemical Processes in Continuous-Flow Reactors: From Engineering Principles to Chemical Applications, ed. T. Noel, World Scientific Editions, 2017, p. 284. B. Dinda, Essentials of Pericyclic and Photochemical Reactions, 2017, Springer UK, p. 350. Naphthalenediimide and its Congeners: From Molecules to Materials, ed. G. Dan Pantos, RSC, 2017, p. 343. G. Ciamician, Science, 1912, 385. G. W. Brudvig and S. Campagna, Chem. Soc. Rev., 2017, 46, 6085. ˜ ach, R. Matheu, X. Sala and A. Llobet, P. Garrido-Barros, C. Gimbert-Surin Chem. Soc. Rev., 2017, 46, 6088. A. Aukauloo and H. B. Gray, C. R. Chim., 2017, 20, 207. Y. Zhang, P. Li, L.-Q. Tang, Y.-Q. Li, Y. Zhou, J.-M. Liu and Z.-G. Zou, Dalton Trans., 2017, 46, 10564. T. Takata and K. Domen, Dalton Trans., 2017, 46, 10529. Q. Bu, S. Li, S. Cao, Q. Zhao, Y. Chen, D. Wangad and T. Xie, Dalton Trans., 2017, 46, 10549. D. B. Amabilino and P. A. Gale, Chem. Soc. Rev., 2017, 46, 2376. R. M. Izatt, Chem. Soc. Rev., 2017, 46, 2380. S. Kassem, T. van Leeuwen, A. S. Lubbe, M. R. Wilson, B. L. Feringa and D. A. Leigh, Chem. Soc. Rev., 2017, 46, 2592. Z. Liu, S. K. M. Nalluri and J. F. Stoddart, Chem. Soc. Rev., 2017, 46, 2459.

24 | Photochemistry, 2019, 46, 1–27

33 34

35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

J. Li, D. Yim, W.-D. Jang and J. Yoon, Chem. Soc. Rev., 2017, 46, 2437. The list of contributions for the web issues is available at the link: http:// pubs.rsc.org/en/journals/articlecollectionlanding?sercode=cc&themeid= bd90abd6-cc6b-4523-921f-1bf3baf967d4. S. Uchiyama, C. Gota, T. Tsuji and N. Inada, Chem. Commun., 2017, 53, 10976. G. D. Scholes, Chem. Rev., 2017, 117, 247. T. Mirkovic, E. E. Ostroumov, J. M. Anna, R. van Grondelle, Govindjee and G. D. Scholes, Chem. Rev., 2017, 117, 249. C. Curutchet and B. Mennucci, Chem. Rev., 2017, 117, 294. See for instance: S. Kundu and A. Patra, Chem. Rev., 2017, 117, 712; Y. Jiang and J. McNeill, Chem. Rev., 2017, 117, 838. K. K. Sakimoto, N. Kornienko and P. Yang, Acc. Chem. Res., 2017, 50, 476. L. Ghosez, Tetrahedron, 2017, 73, 4835; A. S. Lubbe, T. van Leeuwen, S. J. Wezenberg and B. L. Feringa, Tetrahedron, 2017, 73, 4837. F. W. W. Hartrampf, D. M. Barber, K. Gottschling, P. Leippe, M. Hollmann and D. Trauner, Tetrahedron, 2017, 73, 4905. Q. Li, J. T. Foy, J.-R. Colard-Itt, A. Goujon, D. Dattler, G. Fuks, E. Moulin and N. Giuseppone, Tetrahedron, 2017, 73, 4874. P. H. Hart, M. Norval and V. E. Reeve, Photochem. Photobiol. Sci., 2017, 16, 281. P. Jarrett and R. Scragg, Photochem. Photobiol. Sci., 2017, 16, 283. E. Tajkhorshid and C. Chipot, J. Phys. Chem. B, 2017, 121, 3203. F. J. van Eerden, T. van den Berg, P. W. J. M. Frederix, D. H. de Jong, X. Periole and S. J. Marrink, J. Phys. Chem. B, 2017, 121, 3237. see the list of contributions at the link http://www.mdpi.com/journal/ biomedicines/special_issues/photodynamic_therapy. T. Hirano and T. Wada, J. Photochem. Photobiol. C, 2017, 30, 1. Y. Parka, S. Jeonga and S. Kim, J. Photochem. Photobiol. C, 2017, 30, 51. C. A. Boyer and G. M. Miyake, Macromol. Rapid Commun., 2017, 38, 1700327. X. Liu, Y. Yang and M. W. Urban, Macromol. Rapid Commun, 2017, 38, 1700030. V. K. Valev, A. O. Govorov and J. Pendry, Adv. Optical Mater., 2017, 5, 1700501. A. Zannotti, F. Diebel, M. Boguslawski and C. Denz, Adv. Optical Mater., 2017, 5, 1600629. ¨nig, Eur. J. Org. Chem., 2017, 1979; S. Crespi, S. Ja ¨ger, See for instance: B. Ko ¨nig and M. Fagnoni, Eur. J. Org. Chem., 2017, 2147. B. Ko See for instance L. Capaldo and D. Ravelli, Eur. J. Org. Chem., 2017, 2056– 2071; J. Z. Bloh and R. Marschall, Eur. J. Org. Chem., 2017, 2085. V. Santacroce, R. Duboc, M. Malacria, G. Maestri and G. Masson, Eur. J. Org. Chem., 2017, 2095. A. M. del Hoyo and M. G. Suero, Eur. J. Org. Chem., 2017, 2122. Y. Jin and H. Fu, Asian J. Org. Chem., 2017, 6, 368. C. Bian, A. K. Singh, L. Niu, H. Yi and A. Lei, Asian J. Org. Chem., 2017, 6, 386. S. Sumino and I. Ryu, Asian J. Org. Chem., 2017, 6, 410. N. Keller and S. Malato, Photochem. Photobiol. Sci., 2017, 16, 8. ´ngora, P. Elizondo and A. Herna ´ndez-Ramı´rez, Photochem. Photobiol. J. F. Go Sci., 2017, 16, 31. ´. Orellana, L. Osiglio, P. M. Arnalb and L. R. Pizzio, Photochem. M. A Photobiol. Sci., 2017, 16, 46. Photochemistry, 2019, 46, 1–27 | 25

65

66 67 68 69 70 71

72 73 74 75 76 77 78

79 80 81

82

83 84 85 86 87 88 89 90 91 92

See for instance: J. Schmitt, V. Heitz, S. Jenni, A. Sour, F. Bolze and B. Ventura, Supramol. Chem., 2017, 29, 769. The complete list of contributions is available at http://www.tandfonline.com/toc/gsch20/29/11?nav= tocList H. J. Bolinkand and S. G. Mhaisalkar, ChemSusChem, 2017, 10, 3680. ´, A. Krishna, S. Tang and D. Fichou, Energy Technol., C. Shen, M. Courte 2017, 5, 1728. `linko, J. Mol. Struct., 2017, 1140, 1. A. J. Barnes and I. Pa T. Sych, A. Polyanichko and A. Kononov, J. Mol. Struct., 2017, 1140, 19. D. Nolan and G. Heydenrych, ChemPhotoChem, 2017, 1, 2. A. K. Singh, R. Tiwari, V. Kumar, P. Singh, S. K. R. Khadima, A. Tiwari, V. Srivastav, S. H. Hasan and R. K. Asthana, J. Photochem. Photobiol. B: Biol., 2017, 166, 202. V. A. Kumar, K. Ammani, R. Jobin, P. Subhaswaraja and B. Siddhardha, J. Photochem. Photobiology B: Biol., 2017, 171, 1. G. Gao, Q. Xi, H. Zhou, Y. Zhao, C. Wu, L. Wang, P. Guo and J. Xu, Nanoscale, 2017, 9, 12032. J. Hou, S. Cao, Y. Wu, Z. Gao, F. Liang, Y. Sun, Z. Lin and L. Sun, Chem. – Eur. J., 2017, 23, 9481. Y.-F. Xu, M.-Z. Yang, B.-X. Chen, X.-D. Wang, H.-Y. Chen, D.-B. Kuang and C.-Y. Su, J. Am. Chem. Soc., 2017, 139, 5660. N. N. Lal, Y. Dkhissi, W. Li, Q. Hou, Y.-B. Cheng and U. Bach, Adv. Energy Mater., 2017, 7, 1602761. A. Walsh, ACS Energy Lett., 2017, 2, 776. M. Freitag, J. Teuscher, Y. Saygili, X. Zhang, F. Giordano, P. Liska, J. Hua, ¨tzel and A. Hagfeldt, Nat. Phot., 2017, S. M. Zakeeruddin, J.-E. Moser, M. Gra 11, 372. J. M. Anga, I. B. Riaz, M. U. Kamal, G. Paragh and N. C. Zeitouni, Photodiagn. Photodyn. Ther., 2017, 19, 308. F. Cieplika, W. Buchalla, E. Hellwig, A. Al-Ahmad, K.-A. Hiller, T. Maisch and L. Karygianni, Photodiagn. Photodyn. Ther., 2017, 18, 54. S. V. Kellesarian, T. Abduljabbar, F. Vohr, H. Malmstrom, M. Yunker, T. V. Kellesarian, G. E. Romanos and F. Javeda, Photodiagn. Photodyn. Ther., 2017, 17, 103. ´s, A. Lo ´pez-Rolda ´n, M. Segarra-Vidal, S. Guerra-Ojeda, L. S. Valle M. D. Mauricio, M. Aldasoro, F. Alpiste-Illueca and J. M. Vila, J. Clin. Periodontol., 2017, 44, 915. Y. Tang, H. Chen, K. Chang, Z. Liu, Y. Wang, S. Qu, H. Xu and C. Wu, ACS Appl. Mater. Interfaces, 2017, 9, 3419. C. Zhou, D. Afonso, S. Valetti, A. Feiler, V. Cardile, A. C. E. Graziano, S. Conoci and S. Sortino, Chem. – Eur. J., 2017, 23, 7672. Y. Bian, M. Li, J. Fan, J. Du, S. Long and X. Peng, Dyes Pigm., 2017, 147, 476. J. Wang, Y. Zhong, X. Wang, W. Yang, F. Bai, B. Zhang, L. Alarid, K. Bian and H. Fan, Nano Lett., 2017, 17, 6916. Q. Michaudel, V. Kottisch and B. P. Fors, Angew. Chem., Int. Ed., 2017, 56, 9670. V. Kottisch, Q. Michaudel and B. P. Fors, J. Am. Chem. Soc., 2017, 139, 10665. E. Andrzejewska, Polym. Int., 2017, 66, 366. ¨ter, J. Am. Chem. Soc. 2017, R. Z. Lange, G. Hofer, T. Weber and A. D. Schlu 139, 2053. I. Aprahamian, Chem. Commun., 2017, 53, 6674. X. Gong, Y. Ding, X. Fan and J. Wu, Adv. Synth. Catal., 2017, 359, 2999.

26 | Photochemistry, 2019, 46, 1–27

93 94 95

96 97 98 99 100 101 102 103

104 105 106 107 108 109

G. Piccirillo, A. Pepe, E. Bedini and B. Bochicchio, Chem. – Eur. J., 2017, 23, 2648. L. Zhao, H. Zhang, G. Tan, Z. Wang and Y. Jin, Tetrahedron Lett., 2017, 58, 1669. S. J. McCarver, J. X. Qiao, J. Carpenter, R. M. Borzilleri, M. A. Poss, M. D. Eastgate, M. M. Miller and D. W. C. MacMillan, Angew. Chem., Int. Ed., 2017, 56, 728. C. B. Larsen and O. S. Wenger, Chem. – Eur. J., 2017, 24, 2039. N. E. S. Tay and D. A. Nicewicz, J. Am. Chem. Soc., 2017, 139, 16100. A. H. Bansode, S. R. Shaikh, R. G. Gonn and N. T. Patil, Chem. Commun., 2017, 53, 9081. O. Manjur, O. Akram, P. S. Mali and N. T. Patil, Org. Lett., 2017, 19, 3075. H. Li, C. Shan, C.-H. Tung and Z. Xu, Chem. Sci., 2017, 8, 2610–2615. C. Sauer, Y. Liu, A. De Nisi, S. Protti, M. Fagnoni and M. Bandini, ChemCatChem, 2017, 9, 4456–4459. E. R. Welin, C. Le, D. M. Arias-Rotondo, J. K. McCusker and D. W. C. MacMillan, Science, 2017, 355, 380. See for recent examples: E. Heyer, J. Massue and G. Ulrich, Dyes Pigm., 2017, 143, 18; Q. Zhu, K. Wen, S. Feng, W. Wu, B. An, H. Yuan, X. Guo and J. Zhang, Dyes Pigm., 2017, 141, 195. I. E. Serdiuk and A. D. Roshal, Dyes Pigm., 2017, 138, 223–244. F. Xu, X. Xiao and T. R. Hoye, J. Am. Chem. Soc., 2017, 139, 8400–8403. H. H. Fielding and G. A. Worth, Chem. Soc. Rev., 2018, 47, 309. S. K. Sarkar, D. V. M. Gatlin, A. Das, B. Loftin, J. A. Krause, M. Abe and A. D. Gudmundsdottir, Org. Biomol. Chem., 2017, 15, 7380. J. H. Park, M. Hughs, T. S. Chung, A. J.-L. Ayitou, V. M. Breslin and M. A. Garcia-Garibay, J. Am. Chem. Soc., 2017, 139, 13312. T. S. Chung, A. J.-L. Ayitou, J. H. Park, V. M. Breslin and M. A. GarciaGaribay, J. Phys. Chem. Lett., 2017, 8, 1845.

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Quantum chemistry of the excited state: recent trends in methods developments and applications Miriam Navarrete-Miguel,a Javier Segarra-Martı´,b c d Antonio France ´ s-Monerris, Angelo Giussani, Pooria Farahani,e Bo-Wen Ding,f Antonio Monari,c Ya-Jun Liu f and Daniel Roca-Sanjua´n*a DOI: 10.1039/9781788013598-00028

Advances (2016–2017) in Quantum Chemistry of the Excited State (QCEX) are presented in this book chapter focusing firstly on developments of methodology and excited-state reaction-path computational strategies and secondly on the applications of QCEX to study light–matter interaction in distinct fields of biology, (nano)-technology, medicine and the environment. We highlight in this contribution developments of static and dynamic electron-correlation methods and methodological approaches to determine dynamical properties, recent examples of the roles of conical intersections, novel DNA spectroscopy and photochemistry findings, photo-sensitisation mechanisms in biological structures and the current knowledge on chemi-excitation mechanisms that give rise to light emission (in the chemiluminescence and bioluminescence phenomena).

1

Introduction

Quantum Chemistry of the (Electronic) Excited State (QCEX) is a field that uses the physical principles of Quantum Mechanics and further concepts particularly developed to efficiently model the chemical processes derived from light–matter interaction or, in general, chemical ¨dinger phenomena involving upper electronic solutions of the Schro equation. QCEX has many applications in biology, (nano)-technology, medicine and the environment, in which the population of the excited electronic states gives rise to chemical phenomena not allowed in ground-state chemistry. E/Z double-bond isomerisations, [2 þ 2] cycloadditions, charge transport, tautomerisations or luminescence are examples of such rich chemistry. Here, multi-radicaloid structures, energy degeneracies between distinct configurations of the electrons, a

Instituto de Ciencia Molecular, Universitat de Vale`ncia, P.O. Box 22085, 46071 Vale`ncia, Spain. E-mail: [email protected] b Department of Chemistry, Imperial College London, London SW7 2AZ, UK c Universite´ de Lorraine & CNRS, Laboratoire de Physique et Chimie The´oriques, Boulevard des Aiguillettes, BP 70239, 54506 Vandoeuvre-le`s-Nancy, France d Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK e Department of Theoretical Chemistry & Biology, School of Engineering sciences in Chemistry, Biotechnology and Health (CBH), KTH Royal Institute of Technology, SE-10691 Stockholm, Sweden f Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China 28 | Photochemistry, 2019, 46, 28–77  c

The Royal Society of Chemistry 2019

intra-molecular or inter-molecular charge transfer (CT) are common features of the excited electronic states which allow the mentioned chemistry. In our previous biannual contributions to the RSC Photochemistry Specialist Reports,1–4 we have reviewed the advances on quantumchemistry computational studies focusing on photo-induced chemical processes and also on the phenomena arisen as the result of a chemical reaction (chemiluminescence (CL), bioluminescence (BL) and dark photochemistry). We have traditionally organised the work in two parts firstly describing methods developments and next analysing the trends observed in the application of QCEX. We shall continue here with such style. For the first part, taking into account the publications in 2016 and 2017, we find convenient this time to split the section into three parts separating static electron-correlated methods, dynamic electroncorrelated methods and methodologies or computational strategies to obtain dynamical properties. QCEX requires multiconfigurational approaches able to describe on the same foot distinct configurations of the electrons around the nuclei (or configuration state functions) which usually appear in excited states with similar energies. The interaction of such energetically-close configurations gives rise to the so-called static (also strong or long-range) electron correlation. A representative method able to compute the static correlation is the complete-active-space self-consistent field (CASSCF), in which a group of chemically-relevant orbitals is chosen and all possible electronic configurations arisen from distributing the active electrons over those active orbitals are allowed to interact in the computational procedure. Such strong-correlated methods provide a correct wavefunction for the excited state, however, the obtained energies are far from accurate. Short-range interaction between electrons (dynamic correlation) is still needed for an accurate energy determination. In this context, a practical and general strategy in the particular case of the CASSCF method is to use second-order perturbation theory for such purpose, giving rise to the complete-active-space second-order perturbation theory (CASPT2) method. CASSCF/CASPT2 and other multiconfigurational methods allow therefore an accurate determination of the excited-state electronic-structure properties, which is a big step although not enough. Excited-state chemistry determinations additionally require computational strategies able to determine the accessible and relevant excited-state chemical paths. Minimum-energy path (MEP) computations are accurate procedures providing a static description based on energy barriers. A further step implies determining excited-state time-dependent properties such as lifetimes or photochemical rates, which is a complex and computationally costly task. Nevertheless, since some years ago, advances in computer hardware, QCEX methods and software have allowed to modestly address such problems. Many scientists in the field are therefore spending efforts to improve and apply such dynamical computational approaches. Regarding applications of QCEX, adiabatic and non-adiabatic chemistry can be distinguished. Whereas the former, similarly to the ground-state Photochemistry, 2019, 46, 28–77 | 29

chemistry, involves only one electronic state (even though this can be formed by many electronic configurations), the latter normally refers to non-radiative changes between two (or more) states. In QCEX, such nonadiabatic chemistry is associated with conical intersections (CIXs) and singlet-triplet crossings (STCs), which are related to internal conversion (IC) and intersystem crossing (ISC) phenomena, respectively. As can be seen in our previous reports, CIXs and STCs are crucial in many phenomena of light-matter interaction of relevance in fields such as DNA damage, organic photovoltaics, luminescence materials or BL. We shall include in this chapter a section dedicated to recent trends on the roles of CIXs and STCs. The other sections shall describe advances on (i) DNA spectroscopy and photochemistry, (ii) photosensitisation mechanisms in biology and medicine and (iii) CL and BL.

2

Developments of methods and theory

Over the last couple of years plenty of novel advances have been made in the field of theoretical chemistry focused on the accurate characterisation of electronic excited states. Most theoretical developments and implementations can be roughly separated in two markedly different research avenues, namely those dealing with an improved description of the so-called static (or strong) correlation and those focusing on efficient ways to include the remaining dynamic correlation. Static correlation manifests itself as a significant deviation of the correlated electron density from the one given by the Hartree–Fock approximation and is often localised in a small portion of the molecule (e.g. metals and nearby ligands in transition metal complexes). This rationale is widely used in CASSCF methods that represent a suitable choice of the mean-field approximation due to its multiconfigurational character and where only dynamic correlation is then missing.5,6 Dynamic correlation, on the other hand, is an extensive quantity with respect to the size of the system, and its evaluation becomes very costly for large molecules. This is mainly due to its slow convergence with respect to the amount of molecular orbitals included, which results in a large increase in the computational demands for quantitative analysis even for small to medium-sized systems when using diffuse and accurate basis sets. These two different kinds of correlation have thus attracted much attention over the last few years and reviewing them will be the focus of the first two sub-sections. It is worth noting, however, that widely used methodologies such as timedependent density functional theory (TD–DFT) have been omitted from this review as we focus on wave function-based ab initio approaches to correlation. The interested reader is pointed towards some recent works that illustrate the state-of-the-art of this particular field.7–9 2.1 Methods: static (strong) correlation A surge in the use of methods accounting for static correlation has been witnessed over the last few years and is mainly due to a range of schemes that has become available for solving the full configuration interaction (FCI) problem in wave function-based multiconfigurational techniques, 30 | Photochemistry, 2019, 46, 28–77

which is the main bottleneck of CASSCF-like methods. These could roughly be separated in a few different strategies, with those based (i) on density matrix renormalisation group-based (DMRG)10–12 techniques, (ii) FCI quantum Monte Carlo (FCIQMC) methods,13–15 and (iii) semistochastic Heat-bath Configuration Interaction (HCI)16,17 being among the most relevant and followed approaches. A schematic view of these different schemes is given in Fig. 1. These different techniques are grounded on quite diverse principles, which will be very briefly summarised next, the reader being referred to the original citations given above for a more detailed account. DMRG focuses on incorporating locality to describe the strong correlation problem as is schematically shown in Fig. 1a top and middle panels, where the sequence of contractions of the auxiliary indices in the DMRG in its matrix product state formalism for the wave function are shown, which induce local correlation and allow for efficient evaluations of expectation values. Fig. 1a lower panel, on the other hand, displays the matrix product form of the states and their overlap, which allows for decomposing the overlap itself as a series of overlaps associated with each localised site and facilitates the computation of expectation values and the application of the variational principle on top of such wave functions.18 DMRG-based algorithms are the oldest and most featured, having been recently implemented within the second-order CASSCF solver19,20 algorithm initially devised by Werner and Knowles21 and also been extended to restricted/complete active space state interaction (RASSI/CASSI)22,23 formulations similar to those previously introduced for standard CASSCF/RASSCF implementations,24,25 which allow obtaining essential magnitudes such as oscillator strengths. FCIQMC relies, on the other hand, on finding a solution to the FCI problem through stochastic means. The key point of FCIQMC is that instead of allocating memory for accommodating the entire FCI vector, as is often done in standard

Fig. 1 Scheme of the different FCI solvers recently developed to tackle the static correlation problem and featuring (a) DMRG, (b) FCIQMC and (c) HCI. Panel (a) is reproduced from ref. 18 with permission from the American Institute of Physics, panel (b) reproduced with permission from ref. 13, Copyright 2016 American Chemical Society and panel (c) reproduced with permission from ref. 17, Copyright 2017 American Chemical Society. Photochemistry, 2019, 46, 28–77 | 31

implementations, only determinants significantly populated along the Monte Carlo sampling (based on a hash algorithm that communicates all walkers or particles used to this purpose, schematically represented in Fig. 1b) are stored so that the many determinants not contributing prominently can be excluded, allowing for much larger active spaces to be feasible. HCI is similar to FCIQMC in that it uses the concept of removing many of the determinants that do not significantly contribute to the wave function, but it does so by following a different path. In this case, the selected configuration interaction method is initially used to pick only the important determinants in the active space (scheme given in Fig. 1c), which is then improved by performing perturbation theory on top of those. HCI brings in a semistochastic implementation that heavily increases the efficiency of the Epstein–Nesbet perturbation theory treatment while also improving the variational stage of the method. In this way, HCI differs from the methods previously outlined in that it also provides estimates of the dynamic correlation energy, neglected in CASSCF-like methods and where dynamic correlation is often included a posteriori with a range of different techniques that will be covered in the next section. One weakness of these methods often mentioned in the literature is the need to define an active space or set of orbitals in which the FCI or similar treatment will be performed given the present inability of running such schemes over the whole molecular orbital space. The choice of the active space is indeed important and requires certain prior knowledge of the system under study and of the method itself,26,27 which can prove to be an insurmountable barrier for non-specialist users. Nevertheless, encouraging recent developments have shown different ways in which active spaces might be automatically selected in a black-box manner,28,29 enabling less experienced researchers to make use of these highly correlated techniques. Fig. 2 shows an example of such an algorithm recently devised by Stein and Reiher29 where a systematic selection procedure is depicted for DMRG, and where a range of initial guesses is shown to yield analogous results thus demonstrating its robustness and thus being suitable for applications in a black-box fashion. Many other developments have been carried out within static correlated methods based on the original implementations that still rely on a Davidson-like solver for the FCI problem. Martı´nez and co-workers have developed a graphical processing unit (GPU)-based algorithm for CASSCF30 including its non-adiabatic coupling framework31 that exploits the massive parallelisation offered by these state-of-the-art technologies. They have also explored efficient approximations to CASSCF such as the floating occupation molecular orbital-complete active space configuration interaction (FOMO-CASCI) within GPU technologies,32,33 which comes at a cost similar to that of TD-DFT while being able to represent states with a sizeable multiconfigurational character. Significant advances have also been made with respect to the more efficient treatment of the two-electron integrals handled by these algorithms via the Cholesky decomposition, which vastly increases the number of basis set functions and hence allows for larger and more precise basis sets to be employed.34–36 32 | Photochemistry, 2019, 46, 28–77

Photochemistry, 2019, 46, 28–77 | 33

Fig. 2 Automatic active space selection algorithm described by Stein and Reiher.29 Figure reproduced with permission from ref. 29, Copyright 2017 American Chemical Society.

These are but a few representative examples that display the overall trends followed in the field, which can be summarised in the following points: (i) alternative and more efficient FCI solvers are being pursued to correlate more orbitals and thus extend the use of statically correlated methods to large scale applications, (ii) methods are being introduced to remove the potential bias of selecting the active space by providing a robust automated active space selection algorithm transitioning these methods to a black-box fashion, and (iii) novel technologies such as GPUs and more sophisticated two-electron integral schemes are being adopted to increase their computational efficiency.

2.2 Methods: dynamic correlation Plenty of advances have been reported over the last couple of years for including more effectively dynamic correlation. Here we will survey recently developed techniques to include dynamic correlation on top of statically/strongly correlated (multiconfigurational) methods. These will be split on those based on (i) CASPT2,37 (ii) N-Electron Valence state perturbation theory (NEVPT2),38 (iii) density functional theory (DFT) on top of multireference wave functions and (iv) coupled-cluster based theories. The first type to be reviewed will be the CASPT2 method,39 which consists on a multiconfigurational variant of second-order Møller–Plesset perturbation theory on top of a CASSCF reference wave function. A revived interest in the CASPT2 method has been witnessed in recent years due to the possibility of overcoming previous limitations associated to its elevated computational scaling. To this end, formulations of the Pair Natural Orbital (PNO)-CASPT240 and the Frozen Natural Orbital (FNO)-CASPT241 have been reported, providing massive speed-ups that enable its use with larger basis sets and larger molecular systems. A novel extrapolation scheme has also been proposed,42 whereby the Shanks extrapolation method can be applied by combining several low-cost FNOCASPT2 (and potentially other similar techniques such as PNO) computations to extrapolate the exact total energy. Shiozaki and co-workers have reported outstanding work on the derivation and implementation of analytical fully internally contracted CASPT2 energy gradients,43,44 and non-adiabatic couplings,45 which enable their long sought use for on-thefly non-adiabatic MD schemes as those that will be discussed over the next section. The CASPT2 method has also been recently extended to work within the Generalised Active Space (GAS) framework leading to the GASPT2 method,46 which is a cost-effective alternative of CASPT2 where only a few selected excitations are allowed within the active space dramatically reducing its cost. DMRG variants of the CASPT2 method47 and its multistate (MS-CASPT2)48 extension have also been recently reported, allowing the accurate determination of electronic excited states with unprecedently large active spaces. NEVPT2 will be reviewed next, being a very similar method to CASPT2 with the exception that it employs a two-electron Dyall Fock operator that drastically reduces some of the known problems of CASPT2 such as 34 | Photochemistry, 2019, 46, 28–77

intruder states and the need to use further corrections for treating openshell systems (IPEA shift).49 Very efficient novel implementations of the NEVPT2 method have been recently reported, featuring its explicitly correlated (F12)50 variant and the domain based localised pair natural orbital (DLPNO)51 among them, which enable the use of NEVPT2 for very large systems and diffuse basis sets. Two different implementations within a DMRG framework have also been recently reported for its partially contracted form,52,53 as well as one within its strongly contracted scheme,54 which refer to different levels of contraction used in the formulation of the zeroth-order Hamiltonian employed. These advances are particularly relevant for transition metal complexes where the double-d shell effect55 forces the inclusion of a large amount of orbitals to the active space in order to provide converged results. A new time-dependent variant has also been introduced for both DMRG-based56 and Matrix Product State (MPS)-based57 wave functions that displays lower scaling than the strongly contracted NEVPT2 method while providing energies analogous to those of the fully uncontracted form, which should greatly improve the applicability of the method for large-scale applications. Finally, two different implementations for the internally contracted NEVPT2 have been devised within the MPS framework,58,59 displaying the huge advances made within N electron valence perturbation theory combined with state-of-the-art DMRG-based methodologies and being favoured in many cases to the more popular CASPT2 method. Another way to include dynamic correlation on top of a statically correlated wave function is to employ DFT, which is known to feature a very favourable scaling and thus provide an efficient and accurate characterisation of the remaining correlation missing combining the advantages of wave function and DFT. To this end, many different approaches have been recently devised and will be surveyed next. The first is the pair-DFT, which is based on a generalisation of Kohn–Sham DFT where the electron kinetic and classical electrostatic energies are computed from a reference wave function and the rest of the energy is obtained from a density functional.60 The main differences with standard Kohn–Sham DFT approaches are the use of a multiconfigurational reference instead of a single Slater determinant and that the density functional is in this case a function of the total density and the on-top pair density instead of being a function of spin-up and down densities. This method has been successfully applied in a number of difficult cases and has been shown to provide reliable results thus making it a promising technique in the field of theoretical photochemistry. The next method is based on the shortrange formulation of DFT (srDFT)61 and uses the same framework previously described making use of a multiconfigurational wave function while exploiting the advantages of DFT for adding the remaining dynamic correlation. In this case, this is done by capitalising on the efficient treatment of the short-range dynamical correlations provided by a number of recent DFT developments and approximations. Another efficient way to include correlation on top of a statically correlated wave function, of multireference configuration interaction (MRCI) nature in this case, is described next thorough the advances in the DFT/MRCI62,63 Photochemistry, 2019, 46, 28–77 | 35

method recently developed by Marian and co-workers. These implementations built on the original work of Grimme and Waletzke64 improves this well-established semi-empirical quantum chemistry method by producing a redesign of the original Hamiltonian which fixes some of its known problems such as the inability to treat bichromophores due to the strong dependence of the parameters used in the Hamiltonian for describing the different excitation classes. Marian and co-workers provide a new parameterisation that is spin-invariant and incorporates a lesser amount of empirical parameters compared to the original formulation,62 which has also been recently extended to treat open-shell systems.63 The last technique combining a multiconfigurational reference and DFT is the ensemble DFT approach.65 The approach is based in considering an ensemble of ground and excited states like in statistical physics, where the ensemble is characterised by the total number of states and their respective weights, and that can be employed in order to simulate electronic excited states in a timeindependent manner while considering a certain degree of strong correlation. The last group of techniques reviewed encompasses coupled cluster and the different advances made to both its use on top of multiconfigurational wave functions as well as the recent improvements made in single determinant formulations to treat potential energy crossing regions. A PNO formulation has been recently presented,66 which allows the characterisation of electronic excited states at a vastly reduced cost by using the back-transformed PNOs within the framework of equation of motion coupled cluster theory and its similarity transformed variant. A derivation for equation of motion coupled cluster analytical non-adiabatic couplings is also to be highlighted,67 as this would in principle allow the use of these extremely accurate techniques for nonadiabatic dynamics simulations. Despite the availability of analytical couplings, the question still remains in whether single Slater determinant-based methods such as these can indeed be reliable for properly representing inherently multiconfigurational regions of the potential energy surface (PEH) such as interstate crossings (CIXs). Koch and co-workers report some encouraging results in this regard by presenting a novel specific formulation of coupled cluster theory that correctly describes conical intersections between electronic excited states of the same symmetry,68,69 which should in principle allow for their use in photo-excited MD. Lastly, a DLPNO formulation of Mukherjee’s statespecific multireference coupled cluster method has also been recently reported,70 providing huge speed-ups for these lengthy simulations and bridging the gap towards their routine use in real applications. The list of recent advances outlined above is by no means exhaustive and represents mostly the different paths taken in order to include dynamic correlation on top of multiconfigurational reference wave functions. These can be summarised as follows: (i) perturbation theorybased methods (CASPT2 and NEVPT2) remain the most popular due to their favourable scaling, (ii) DFT corrections on top of multiconfigurational wave functions appear to be increasing in popularity due 36 | Photochemistry, 2019, 46, 28–77

to being even more efficient computationally than those based on perturbation theory, and (iii) encouraging advances are being made on the coupled cluster front in order to reduce its cost and make it affordable for medium-sized systems as well as to be able to represent crossing regions properly to enable its use in theoretical photochemistry.

2.3 Dynamics During the years 2016 and 2017, significant developments in the field of dynamics simulations of photophysical and photochemical processes have been achieved. We shall focus here on achievements on quantum dynamics, and in particular, progresses which have been made regarding on-the-fly quantum dynamics simulations, the possibility of describing states of different spin-multiplicity (as singlet and triplet states), a first non-adiabatic MD method based on the exact factorisation of the electron-nuclear wave function and a promising improvement of the efficient multi-layer multiconfigurational time-dependent Hartree (MLMCTDH) approach based on an adaptively expansion of the number of single-particle-functions during the dynamics. On-the-fly dynamics methods are those that do not require the knowledge of the PEH before the dynamics can be run, but instead, as the name suggested, the required regions of the PEHs are computed only when needed (i.e. on-the-fly) along the dynamics, normally through the interface with an external electronic structure theory program. On-the-fly methods are particularly attractive, since they circumvent one of the main bottlenecks in performing quantum dynamics that is the need of computing beforehand the various PEHs, a task that becomes quickly computationally prohibitive with the increase of the number of degrees of freedom (DOFs). Among on-the-fly dynamics simulations, the direct dynamics variational multiconfigurational method (DD-vMCG) stands out for being a full quantum dynamics method, in which both the basis functions used for expanding the nuclear wave function and the corresponding coefficients evolve according to a variational resolution of the nuclear timedependent Schrodinger equation (TDSE). DD-vMCG is consequently in principle able to correctly describe quantum effects as tunnelling and non-adiabatic processes. Since quantum dynamics are normally run along diabatic states, and since electronic structure theory programs provide instead adiabatic states, a diabatisation procedure is needed in order to run DD-vMCG dynamics. The propagation diabatisation method was previously presented and used in conjunction with DD-vMCG dynamics, and in 2017, the work of Richings and Worth extended its applicability, previously restricted to only two states, to an arbitrary number of states.71 This diabatisation scheme is based on the propagation of the adiabatic/diabatic transformation matrix K, and its relationship with the matrix of non-adiabatic couplings term (NACT) vectors, F, which is: rK ¼  FK. The equation, strictly exact only in the limit of a complete electronic basis set, allows to propagate the K matrix to the subsequent point in the dynamics (R þ DR) from the knowledge of K at Photochemistry, 2019, 46, 28–77 | 37

the initial point (R) and the integration of the F matrix along the path from R to R þ DR. Richings and Worth used the propagation diabatisation scheme for running DD-vMCG dynamics on the butatriene cation and on thymine, including in both cases a variable number of excited states. The results proved the applicability of the propagation diabatisation scheme and showed how the number of states included in a DDvMCG simulation influences the outcomes of the dynamics in terms of population transfer and wavepacket spread. In all on-the-fly dynamics simulations a local approximation of the PEHs based on the actual points computed on-the-fly by the electronic structure theory program must be performed. In 2017, Richings and Habershon presented a method called Gaussian process regression (GPR) for an efficient construction of a global PEH from ab initio electronic structure calculations at selected configurations (see Fig. 3).72,73 According to the GPR method, the PEH is represented by a linear combination of Gaussian functions, centred at a set of M reference points in configuration space. The weights of such an expansion are determined imposing the equality between the approximate PEH and the computed reference points. Initially, a fixed number of reference points are originated by a random uniform sampling for each degree of freedom within the limits of a predefined sampling subspace. New reference points are then added along the dynamics, exploiting the fact that GPR allows the evaluation of the accuracy of the approximated PEH at any point without having to calculate the actual PEH. It is in fact possible to compute the variance at any point, which in turn reflects the accuracy of the PEH based on the expansion derived by the current set of reference points, and can consequently be used in order to decide whether or not compute and add the new geometry to the reference points. A second strength of GPR is that it can provide an approximate PEH having a sumof-products form, which is the form required for MCTDH simulations, consequently making GPR suitable for running MCTDH simulations without the need to precompute the PEH. Richings and Habershon tested the GPR method on the butatriene cation, and on reduced models of malonaldehyde and salicylaldimine. Most of the available quantum dynamics approaches are able to account for non-adiabatic transitions only among states of the same spinmultiplicity, with only semiclassical methods as trajectory surface

Fig. 3 Pictorical representation of the GPR introduced by Richings and Habershon. Reproduced with permission from ref. 72, Copyright 2017 American Chemical Society. 38 | Photochemistry, 2019, 46, 28–77

hopping (TSH) offering the possibility of describing ISC processes. So, despite the recognised importance in many photoinduced processes of the interplay between singlet and triplet states, spin–orbit couplings (SOCs) and the resulting ISC processes were not included in most dynamics simulations. Things have improved since 2016, the year in which two independent publications presented an extension of the ab initio Multiple Spawning (AIMS) method able to describe the interaction between states of different spin-multiplicity.74,75 In both works, the Hamiltonian appearing in the AIMS equation of motion for the wave function amplitudes now includes a SOC part, added to the usual spinfree electronic Hamiltonian and the nuclear kinetic operator. In such a way the off-diagonal elements of the Hamiltonian between two spindiabatic electronic states having different spin multiplicity are equal to the corresponding SOC. The latter can be computed along the dynamics using the first-order saddle-point approximation, which is here particularly justified by the smooth change that the SOC describes with respect to the nuclear position. In line with AIMS philosophy, when an ISC process from state I to J is considered to be likely, the phenomenon is described by creating (spawning) new Gaussian functions on the PEH of state J. The likelihood of an ISC process is evaluated computing an effective coupling parameter, which is proportional to the ratio between the corresponding SOC and electronic energy gap. If the effective coupling parameter is larger than a predefined threshold, and the resulting new spawned basis functions will have an overlap with the parent basis functions larger than a certain value, then ISC is supposed to happen and the spawning process on the J PEH is indeed undertaken. In both papers the new approach has been tested using a Breit–Pauli Hamiltonian in order to account for the SOC. In the first of these two papers,74 resulting from the work of Martinez and co-workers, the new approach, called generalised AIMS (GAIMS, see Fig. 4), has been tested on a model system and for simulating the non-adiabatic dynamics of thioformaldehyde. For the model system GAIMS reproduces the exact results within a maximum

Fig. 4 Pictorical representation of all possible coupling between trajectory basis functions included in the GAIMS method. Reprinted from ref. 74 with permission of AIP Publishing. Photochemistry, 2019, 46, 28–77 | 39

deviation of 7%. In the characterisation of thioformaldehyde, GAIMS describes a small but sizable population of the T2 pp* state in a 200 fs time window after S1 np* excitation. In the second of these two papers,75 resulting from the work of Varganov and co-workers, the approach was tested studying the ISC process between the excited 3B1 and ground 1A1 states of GeH2 and comparing the results with values calculated using statistical non-adiabatic transition state theory. From the comparison a shorter 3B1 lifetime is predicted based on the improved version of AIMS, which is ascribed by the authors to the ability of the implemented method to account for ISC processes at any point along the intersection seam. While Martinez and co-workers used in their tests an interface between AIMS and Molpro in order to compute the needed SOCs, Varganov and co-workers created an interface between AIMS and GAMESS. In 2016 the exact factorisation of the electron-nuclear wave function has been employed for deriving a trajectory-based dynamics method and in 2017 the so derived approach was used for the first time for simulating the photoexcited dynamics of a molecular system.76,77 In the exact factorisation the solution of the TDSE is written as a single product of a time-dependent nuclear function and a time-dependent electronic function, which leads to a decomposition of the original TDSE in coupled equations for the nuclei and the electrons. The nuclear equation is a standard nuclear TDSE, but evolving on a ‘‘time-dependent’’ PEH (TDPEH) and including a time-dependent vector potential, which can be seen as the time-dependent analogous of the non-adiabatic coupling vectors. In the electronic equation, the presence of a so-called ‘‘electron-nuclear coupling operator’’ couples the evolution of the electrons with the nuclear degrees of freedom. Min, Agostini, and co-workers, formulated a coupled-trajectory mixed quantum-classical (CT-MQC) scheme able to solve the two equations.76,77 The approach is based on three main approximations. First, the classical limit of the nuclear equation is derived, and the corresponding Newton equation is instead treated. Second, the time-dependent electronic function is expanded, accordingly to a Born–Huang-like expansion, in the basis of electronic adiabatic states. Third, the term that determines explicit dependence in the electron-nuclear coupling operator on the nuclear wave function is approximated employing information obtained from the trajectories. The resulting CT-MQC equations simply require quantities that can be obtained by standard electronic structure packages, consequently allowing the on-the-fly implementation of the method. In order to test the CT-MQC performances, and in particular its intrinsic ability to correctly account for decoherence effects (which is a well-recognised pitfall of TSH methods), the method has been employed for simulating the photochemistry of oxirane in gas phase, comparing the results with simulations obtained using fewest-switches surface hopping (FSSH) and a corrected version of this algorithm (corr-FSSH) that accounts for quantum decoherence in a phenomenological manner. The results show the ability of CT-MQC to correctly describe quantum decoherence without the need for empirical corrections, as in corr-FSSH, and to have with respect to the latter method a better convergence with the number of 40 | Photochemistry, 2019, 46, 28–77

trajectories. Further work on the use of the exact factorisation for dynamics simulations performed by Curchod and Agostini analysed the topological features of the TD-PEH and of the time-dependent vector potential.78 From their study it emerged that both the TD-PEH and the time-dependent vector potential behave at all times as smooth function of the nuclear coordinates, even in the region of CIX. This latter fact is very promising, since it shows that the EF formalism greatly simplifies the description of non-adiabatic processes, even in the presence of CIXs, which in the adiabatic representation lead to the well-known singularity of the non-adiabatic coupling vectors. In the ML-MCTDH method, the key idea of MCTDH (i.e. an efficient expansion of the N dimensional nuclear wave function in a sum-ofproducts of functions, called single-particle functions (SPFs), with reduced dimensionality) is in turn re-used in order to expand the SPFs. The resulting SPFs can again go through a time-dependent multiconfiguration expansion, and the procedure can be repeated for each new set of SPFs, creating various ‘‘layers’’ in the original expansion, from which the name ‘‘multi-layer’’ MCTDH arises. As in MCTDH, the last expansion will be on the basis of one-dimensional time-independent functions, called primitives. In each layer of MCTDH expansion, SPFs having a certain dimensionality, are expanded in terms of basis functions (either new SPFs or primitives) having a reduced dimensionality. For example, in a three-layer ML-MCTDH approach, the original wave function is described by a first MCTDH expansion (first layer), each of the so-resulting SPFs is in turn expanded accordingly to a new MCTDH expansion (second layer), and finally, the SPFs generated by the second MCTDH expansion are expanded in the basis of the time-independent primitives (third layer). The method is known to be very efficient and able to treat systems of hundreds to thousands of degrees of freedom. For example, in 2017, ML-MCTDH has been used for running dynamics in a high-dimensional model of the LH2 antenna complex of purple bacteria.79 Before starting ML-MCTDH dynamics, a specific multi-layer structure must be chosen, answering the following three questions. How many times the SPFs are expanded accordingly to a new MCTDH expansion? How many SPFs are used in each expansion (which in turn determines the number of configurations in each expansion)? How to combine the degrees of freedom (which in turn determines the reduction in dimensionality undertaken in each layer)? These decisions are key for the efficiency of the method, and are normally taken on the bases of prior experience and a ‘‘trial and error’’ approach. In 2017, MendiveTapia and Gatti proposed a more systematic way for both selecting the number of SPFs and combining the DOFs, implemented in the so-called ML-spawning algorithm.80 The central idea behind their implementation is to start with a reduced number of SPFs, and then automatically increases their number during the dynamics in a ‘‘on-the-fly’’ fashion, using as a criteria the value of the lowest natural orbital population. The natural orbital population of each SPF is in fact related to the importance of the corresponding SPF for the wave function. Normally, in a considered converged dynamics, the value of the lowest natural orbital Photochemistry, 2019, 46, 28–77 | 41

population should not be greater than 103. In the ML-spawning approach when the value of the lowest natural orbital population is above a predefined threshold, more SPFs are created (spawned) into the dynamics. The method consequently follows the philosophy of adding new resources (in this case SPFs) when the dynamics requires them, consequently saving the effort of starting with too many resources (SPFs) than needed, which is particularly true at the beginning of a dynamics where a wave-packet is normally quite localised and fewer SPFs are enough. Regarding the way of combining DOFs, the authors suggested that DOFs in a ML-spawning simulation have grown (i.e. rate at which the associated SPFs are increased) in a similar fashion, should be grouped together. This idea, although successful for the tested cases, implies that test dynamics must be run in order to identify the most efficient way of combining DOFs. The ML-spawning method was tested running simulations on the non-adiabatic dynamics of pyrazine from the S2 excited state and on the quantum dissipative dynamics in a spin boson bath, showing for both cases a significant computational saving using the MLspawning approach with respect to normal ML-MCTDH implementation. Apart from the above reported contributions on quantum dynamics, which provided just a selection by no means meant to be exhaustive, various significant contributions have been presented for semiclassical dynamics. Here we just mention the publication of two thorough reviews on the famous surface hopping method, one presented by Subotnik et al.,81 and the second one published by Wang, Akimov, and Prezhdo.82

3 Conical intersections and their role in photophysics and photochemistry CIXs are quantum-chemical entities that arise from the Born– ¨dinger equation as regions of Oppenheimer approximation of the Schro crossing between at least two PEHs. In case of involving singlet electronic states, they are simply called CIXs, while for crossings between singlet and triplet spin-free states, the term STC is commonly used. As mentioned in the Introduction, they represent the non-adiabatic processes IC and ISC, respectively, and are related to ultrafast excited-state chemistry, in the first case, and spin multiplicity changes, in the second case. In order to properly describe these PEH crossings, special quantumchemistry methods are needed able to describe at the same time at least two electronic configurations (representing each one of the electronic states which cross). For example, the E/Z photo-isomerisation of ethylene is characterised by a CIX that is reached by elongating the double bond, twisting it and pyramidalising one of the carbon atoms. At such crossing structure, two electronic configurations (diradical and zwitterionic) become energetically close to each other. Methods using only one configuration (single-reference methods) cannot deal with the multiconfigurational nature of these crossing regions, with multireference methods being the most appropriate to provide an accurate description. One of the most general and practical methods is CASPT2, which has a good accuracy in photo-chemistry and excited-state 42 | Photochemistry, 2019, 46, 28–77

chemistry for small and medium-size molecules. Such usefulness is evident in the bibliography analysis done in this work (it is the most used method in CIX studies; see Fig. 5a). Other methodological strategies are also already available which were developed to allow approximate solutions in the CIX region. They are motivated by the fact that CASPT2 computations are relatively slower as compared to other types of methods such as TD-DFT and become prohibitive for practical applications in large-size molecular systems or semi-classical dynamics studies with a large ensemble of trajectories. It is however not always possible due to the intrinsic multiconfigurational nature of the CIX. Regarding computational strategies, it is worth noting in Fig. 5b that a significant percentage of articles have addressed the determination of time-dependent properties by using either a quantum or semiclassical approaches. Whereas in the former, a quantum description is provided for both electrons and nuclei, in the latter, nuclei positions and velocities are obtained by integrating Newton’s equations and using electrons gradient computed with quantum methods. As can be seen in Fig. 5, non-adiabatic chemistry or CIXs have been mainly studied in organic p-conjugated molecules (Fig. 5c, CQC) with relevant implications for the design of new materials in nanotechnology or to understand the mechanisms present in nature derived from light–matter interaction (Fig. 5d). Note also the large percentage of studies focused on improvements of methodology to more accurately treat CIX or to decipher new conceptual or mechanistic aspects of the PEH crossings (Fig. 5e). Finally, it is interesting to see that there is a significant number of studies in which CIX characterisations are carried out together with experimental measurements. In this work, in order to illustrate the relevance of CIXs and the synergy of joint experimental-theoretical research approaches, we shall review a

Fig. 5 Statistics calculated on the basis of CIX studies published in 2016 and 2017. Distinct concepts are analysed: the method used to PEHs at or around the crossing region (a), the computational strategy to obtain the excited-state chemistry (energy profiles or semiclassical/quantum dynamics) (b), the chemical nature of the studied molecules (c), the main fields of application (d) and the type of work (e) (201 articles considered).83 Photochemistry, 2019, 46, 28–77 | 43

few works carried out by some of the authors of the present chapter mainly during the period 2016–2017 and focusing on the characterisation of the CIXs and their link to observable data in the experiments. In particular, we shall focus firstly on the CIXs which are reached upon an excited-state double-bond E/Z isomerisation84–86 and secondly, those which imply twisting of bonds in composites of borane clusters and organic rings.87–90 As we shall see, CIXs are useful depending on the case for the design of molecular rotors, organic photovoltaics and better luminescent materials. In 2016, we performed a joint experimental and theoretical study on the photochemical properties of indan-1-ylidene malononitrile (IM) and fluoren-9-ylidene malononitrile (FM).85 They are molecules containing fulvene, which is an interesting chemical structure in the fields of molecular rotors and optoelectronics due to its synthetic versatility, commercial availability and ease of purification for electro-optic studies. Low band-gap materials can be formed when FM is attached to tetrathiafulvene. The experimental study produced ground-state absorption spectra of IM and FM with band maxima at B350 nm and very short excited-state decay lifetimes in the ps scale for IM and in the order of 100 ps for FM. Systematic computations were performed for the IM, FM and their basic chemical unit, the 1,1-dicyanoethylene (DCE) using the CASPT2 method and computational strategies for determining the photochemical decay paths. The main excited-state properties obtained for these systems were the following: – Loss of p-bonding character. The low-lying excited states mainly imply excitations from orbitals with p-bonding character of the non-cyclic double bond to others with p*-anti-bonding nature. Excited states in IM and FM have CT nature from the cyano moiety to the rings. – Elongation, twisting and pyramidalisation. The minimum energy path in DCE is characterised by the elongation and torsion of the non-cyclic double bond and the pyramidalisation of the carbon atom close to the cyano groups. Such distortions bring the ground and excited-state PEHs energetically close (CIX). As for ethylene, the electronic configuration that represents the two states which cross have diradical and zwitterionic nature. – Stabilisation of charge separation upon increasing p-conjugation. The positive charge density in the rings is more stabilised in FM than in IM. This effect is lower at the CIX. Thus, whereas in DCE the CIX energy is clearly lower than the energy of the excited states at the Franck-Condon (FC) region, the relative energy decreases in IM and the CIX becomes much less accessible in FM. The joint experimental and theoretical study85 allows to interpret the experimental observations. Thus, the lower accessibility to the CIX upon excitation to the lowest-lying excited states found for FM as compared to the findings obtained for IM, which can be associated to the higher experimental decay lifetime of the former. Based on the outcomes, one would suggest DCE/IM excited-state properties for the design of 44 | Photochemistry, 2019, 46, 28–77

molecular rotors (accessible E/Z isomerisation CIX), whereas those of FM or larger p-conjugated systems (with less-accessible CIX) would be more important for generating optoelectronic materials in which charge separation is an important target. The elongated-twisted-pyramidalised CIX was also determined in a previous study on indoline, which is the donor moiety of the dye in dyesensitised solar cells (DSSCs).84 In such study, which was already reviewed in our previous contribution,4 the non-radiative decay path via the ethylene-like CIX was associated to the loss of efficiency of the solar cells based on the indoline-dye. We also suggested avoiding flexible double bonds to improve the efficiency. In the same context of E/Z photoisomerisations, we have recently finished another study in collaboration with the experimental group of J. Gierschner in which we have proposed an interpretation for the distinct luminescence properties of dicyanosubstituted p-conjugated materials.86 Two groups of molecules were considered depending on the relative a and b position of the cyano groups in the non-cyclic double bonds with respect to the central ring of the distyrylbenzene skeleton (a- and b-DCS series, respectively). In chloroform solution, a-DCS molecules were found to have much lower experimental fluorescence quantum yields than b-DCS systems. Meanwhile, in highly viscous/solid solutions and in crystalline state, all quantum yields are clearly increasing. A rough approximation of the nonradiative photochemical path by performing TD-DFT and CASSCF computations on representative molecules of the a- and b-DCS series showed that whereas the CIX point appears at similar energies for both type of molecules, the vertical absorption energy is higher for a-DCS than for b-DCS and the energy barrier to reach the CIX point is estimated to be higher for the latter compounds. This implies that in chloroform solution the non-radiative decay path is much less probable in b-DCS than in a-DCS, which directly relates to the higher fluorescence quantum yield of the former. A second interpretation of the experimental data that was provided on the basis of the theoretical results was that the higher yields observed in solid solution and crystalline state (which was called solidstate luminescence enhancement) can be related to the large geometrical distortion that is needed to reach the CIX point. Such distortion is largely hindered when the molecules are packed in the solid state, thus favouring the radiative (fluorescence) decay path. The link between the restricted accessibility to CIX and the luminescence enhancement is also illustrated in a series of studies performed on borane clusters and composites between borane clusters and organic molecules.87–90 As it is commonly known, boron hydrides form clusters such as closo, nido or arachno. Meanwhile, they combine to give rise to macrostructures such as the syn-B18H22 and anti-B18H22 molecules. In 2012, a joint study lead by the theoreticians J. M. Oliva and L. Serrano´s and the experimentalist M. Londesborough explained why the Andre anti-isomer is fluorescent and not syn-B18H22.87 Such explanation was provided based on CASPT2 and photochemical path computations, which showed that the route on the excited state from the FC region to the CIX is barrierless in the syn isomer and has a well-defined minimum Photochemistry, 2019, 46, 28–77 | 45

in the anti-B18H22 molecule. In a subsequent study, the theoretical work predicted that –SH substituents at the 4 and 4 0 positions of the antiisomer would give rise to phosphorescence, which was non-significant in the parent molecule.88 In fact, while triplet population can be only reached in anti-B18H22 at the CIX region, which requires to surmount a relatively high energy barrier, the lowest-lying singlet and triplet states are energetically degenerated along the photochemical decay path of 4,4 0 (SH2)-anti-B18H22 on the singlet manifold. Therefore, radiative decays from both singlet and triplet states were predicted from the theoretical predictions, which were confirmed by performing the pertinent experiments. In the period 2016–2017, some of the authors of the present book chapter have extended the analyses of borane photochemistry to inorganic–organic composites, particularly, the B18H20-(NC5H5)2 molecule, which has pyridine (Py) substituents at the 6 0 and 9 0 positions of the anti-B18H20 system.89 Experiments show that there is a blue shift of the emission band maximum when measurements are carried out in solution with less polar solvents. The blue shifting continues when measuring spectrum in the crystal and especially at low temperatures. Meanwhile, the lowest and highest fluorescence quantum yields were obtained in solution with high-polar solvents and in the crystal at low temperature, respectively. Theoretical analyses of the rotation of the pyridine rings show small effects on the ground and excited states energy profiles. Further photochemical analyses indicated that there are two types of excited-state minima, one in which the two organic rings are coplanar and other minima in which they are twisted. According to the CASPT2 results, the former has larger vertical emission energies than the latter. Therefore, the coplanar geometry was associated with the emissive states in the experimental conditions in which blue shifting was observed. Indeed, twisted structures are hindered in solid state. Twisted structures have also larger dipole moments and accordingly they are expected to be more stabilised in polar solvents. This is in agreement with the band maxima observed in such conditions, which appears red shifted as compared to the other spectra (in solution with less polar solvents or in the crystalline state). Interestingly, the CIX related to the non-radiative decay path in these systems was determined to have a distorted geometry, which implies a rotation and flapping motion of the two pyridine rings. To reach such crossing point, the boron–boron connectivity holding the B(6) atom to the reminder of the boron cluster must be broken. The CIX was found to be energetically above the position of the coplanar and twisted minima and slightly above the position of the bright states at the FC region in the computations in vacuo, which are expected to be a good approximation for the experimental conditions in solution with solvents of low polarity. The high dipole moment obtained for the CIX structure indicates that the non-radiative path should be expected to be more accessible in solution with polar solvents and therefore it was associated to the decrease of the fluorescence quantum yield measured in the experiments in such conditions. Finally, the further increase of the yield in the solid state and especially at low temperature was ascribed to the restricted access to the highly distorted 46 | Photochemistry, 2019, 46, 28–77

structure of the CIX. This is similar to the previous findings for the DCS compounds86 and points to the crucial role of the CIX to interpret the well-known phenomena of solid-state enhanced luminescence (also known in the literature with the less concrete statements J-aggregation, aggregation-induced emission or aggregation-induced enhanced emission). Recently, we have also characterised and interpreted the spectroscopic properties of other inorganic–organic composites which are formed when mixing anti-B18H20 and pyridine, B18H20-8 0 -Py and B16H18-3 0 ,8 0 Py2.90 Both molecules have accessible CIXs on the excited state and accordingly they are not fluorescent. Computations on the former show a STC region along the decay path on the singlet manifold, which could be related to the fact that this system possesses measurable phosphorescence quantum yield of 0.01.

4 DNA/RNA spectroscopy and photochemistry Understanding nucleic acids’ excited states represents a crucial task for modern science since it enhances our comprehension of life evolution and functioning. Processes of utmost relevance, such as the natural selection of the DNA/RNA current chemical structures and the formation of photolesions that may induce serious diseases like skin cancer, have a molecular basis that may be elucidated using the adequate computational tools. However, the inherent difficulties coming from the correct description of the electronic states and their dynamics, the assessment of the influence of the environment and the multi-chromophoric character of DNA/RNA systems, challenge state-of-the-art theoretical methodologies. The development of novel theoretical approaches and the gradual increase in computational power over time allows a tackling of these major issues subsequently yielding remarkable advances in the field of DNA/RNA spectroscopy and photochemistry. The present section covers some of the achievements related to the field reported in 2016 and 2017. It is divided in two subsections. The first one concerns the advances in the comprehension of DNA/RNA spectroscopic features, mainly vertical absorptions and the study of electronic excited-state wave functions, and the second one is devoted to the photochemical pathways that drive the excited-state decay. Photochemical channels of photostability, damage and repair involving pstacked DNA/RNA nucleobases will be emphasised as hot topics of research. 4.1 DNA/RNA light absorption UV light absorption enables populating the excited states of DNA/RNA systems and takes place in nucleobases given its p-conjugated nature. The correct determination of the electronic-state energies and the relative positions of the bright (or optically active) states is fundamental because it determines the initially accessed electronic state upon light absorption and allows direct comparison between theoretical and experimental data. Photochemistry, 2019, 46, 28–77 | 47

Single nucleobases and related structures. Recent efforts have been dedicated to assess the specific impact of the environment in the excited states calculation of DNA/RNA monomeric nucleobases. The absorption spectrum of DNA/RNA nucleobases can be simulated sampling the FC region to obtain a set of nuclear coordinates, which are later on used to compute the vertical absorptions on top of each geometry.91 Pola et al.92 have used a Wigner distribution (quantum harmonic oscillator) on the FC regions of the four DNA nucleobases to assess the impact of the first solvation shell, explicitly included in the system. The authors show nonnegligible solvent effects, demonstrating the well-known destabilisation on the n,p* states due to the explicit hydrogen bonding of water. Another usual approach to include environmental effects is the socalled quantum mechanics/molecular mechanics (QM/MM) hybrid approach, in which the chromophore(s) is(are) described with accurate quantum mechanics (QM) methods whereas the environment is treated as point charges surrounding the QM part. Within this approach, the FC region can be sampled by means of MD or QM/MM MD simulations. ´ndez et al.93 have recently validated this methodology Martı´nez-Ferna to correctly capture the blue shift in the absorption spectrum of 5-methylcytidine due to solvent effects. The authors have employed three different solvation approaches and have contrasted the theoretical results with experimental recordings. Nørby et al.94 have reported averaged embedding parameters for nucleobases inserted in DNA double strands, with the aim to save computational time without a significant accuracy loss when making use of the polarizable embedding model to compute DNA optical properties. The proposed approach was illustrated with 2-aminopurine, a common DNA probe, as a model compound. The authors showed that treating the bulk water around the DNA double strand as a continuum has slight impact in the UV spectra as compared to reference values. Nucleobase clusters. The comprehension of the spectroscopic properties of nucleobase monomers constitutes a first necessary step towards understanding DNA/RNA photochemistry. Nucleic acids are however polymeric chains of chromophores and therefore absorption studies must be expanded to nucleobase multimers in order to describe additional phenomena such as delocalised excitons and charge/energy transport taking place all over the double strands.95 Nevertheless, the complexity for describing the absorption properties of nucleobase clusters, interacting either via Watson–Crick (WC) base pairing and/or p– stacking interactions, increases with the number of atoms considered, requiring larger computational efforts. Nogueira et al.96 have performed a QM/MM study of a solvated polyadenine (dA)20 double strand determining the excited states of eight p-stacked adenine nucleobases making use of a TD-DFT method to describe the electronic states. The quantitative analysis of the delocalisation extent of the excited-state wave functions, shown in Fig. 6, revealed that light absorption takes place mainly over two adjacent nucleobases (47.9%), whereas excitations localised over monomers (22.7%) and trimers (22.8%) also contribute to the spectral intensity. Another important conclusion of the work is that the observed 48 | Photochemistry, 2019, 46, 28–77

Fig. 6 Decomposition of the lowest-energy band of the UV absorption spectrum of (dA)20 computed using the QM/MM approach and the TD-DFT method on top of 100 different geometries. DL stands for delocalisation length, followed by the number of stacked adenine molecules. Reproduced from ref. 96 with permission from the Royal Society of Chemistry.

hypochromism in DNA can be mainly explained by long-range interaction between nucleobases, and not by delocalisation or charge-transfer phenomena. The remarkable delocalisation over the stacked adenine moieties was also reported by other computational studies using coupled-cluster methods.97,98 In particular, Sun et al.98 used ab initio results to parameterise DFT functionals to describe the excited states of a series of DNA tetramers, including alternating and non-alternating AT and GC oligomers. Results also showed vertical delocalisations between p-stacked nucleobases not only for AT but also for GC dimers. By using a different approach, Saha and Quiney99 applied the effective fragment potential method100 to represent the solvent effects in model AT dimers, showing that hydration enhances delocalisation in p-stacked AT clusters whereas showing much less delocalisation in the WC arrangement. The authors interpret this phenomenon in light of the number of hydrogen bonding with the solvent available for each model system. 4.2 DNA/RNA decay pathways The natural photostability of nucleic acids, survivors in a world flooded by UV radiation, has been ascribed to the intrinsic ultrafast decays displayed by natural nucleobases.101 From a theoretical standpoint, this fact has been often explained due to the barrierless decay of the p,p* bright state towards the CI with the ground state in an ultrafast (sub-ps) manner.95,102 Even though this phenomenon is fairly well understood, there are still some open questions without a satisfactory answer, such as the excited-state mechanism of non-canonical nucleobases or the deactivation routes responsible for the long-lived (several to dozens of ps) excited-state components recorded experimentally in double-stranded DNA/RNA.95 Decay pathways of nucleobase monomers and related structures. The advent of new developments as those previously outlined in Section 2 has paved the way for the use of more correlated methods in the characterisation of the photoinduced phenomena triggered in DNA/RNA nucleobases and nucleosides upon UV-light irradiation. Recent studies have Photochemistry, 2019, 46, 28–77 | 49

Fig. 7 Evolution of the different lowest-lying electronic excited states for water-solvated deoxy-thymidine. Panel a displays the ultrafast decay channels, based on 1pp* and 1pHs* excitations, whereas panel b shows the longer-lived channels featuring optically dark 1 nOp* state and two different triplet (3nOp*/3pp*) states. Panel a reproduced from ref. 104, Copyright 2017 American Chemical Society. Panel b reproduced from ref. 105 with permission from the PCCP Owner Societies.

shown the intrinsic differences obtained by mapping the different PEHs of nucleobases103 and nucleosides,104,105 at the CASSCF and CASPT2 levels of theory, illustrating how dynamic correlation is key to faithfully depict photoinduced phenomena in these species (see Fig. 7 for the particular example of deoxy-thymidine). Despite displaying similar PEHs as those reported at the CASSCF level,106 MS-CASPT2 results highlight the role of dynamic correlation in enhancing the ring puckering motion along the main reaction coordinate as shown by the characterised 1pHp* twisted minimum (see Fig. 7a) not featured at CASSCF. Moreover, dynamic correlation also plays a key role in stabilising the 1pHs* state, which under solvation offers an alternative competitive decay channel through a ring-opening CIX with the ground state. Fig. 7b shows the dark states (1/3nOp* and 3pp*), which display a lesser dependence to dynamic correlation and thus resemble more those previously obtained at the CASSCF level.107 The PEHs and associated spectroscopic signals have been shown to be in agreement with the available experimental evidence, not just for canonical nucleobases but also for epigenetic modifications such as 5-methyl-cytosine,108 which display an increased lifetime with respect to its canonical form. Decay pathways of nucleobase clusters. The presence of additional nucleobases in photoexcited DNA/RNA oligonucleotides opens alternative decay routes to the monomeric decays localised in a single nucleobase, due to p–stacking interactions and the WC hydrogen bonding occurring in DNA/RNA double strands. Whereas the former interactions are usually ascribed to long excited-state lifetimes109–113 and the formation of photolesions such as cyclobutane-pyridine dimers (CPDs) or 6-4 photoproduct (64-PP) the inter-strand hydrogen bonding drives photoresponses at the picosecond scale, as shown by recent experimental measurements.114–116 The disentanglement of the excited-state components measured at very different timescales117 represents a challenge for the scientific 50 | Photochemistry, 2019, 46, 28–77

community and needs the use of theoretical methodologies to resolve the riddle. Using TD-DFT in combination with continuum models, it has been recently suggested that the nanosecond fluorescence experimentally registered corresponds to the presence of high-energy long-lived mixed (HELM) states.118,119 These states constitute mixtures of intra-strand Frenkel excitons and CT excitations over alternated AT and GC DNA oligomers. It is proposed that the long-lived fluorescence indeed correspond to the exciplex emission from the excited-state minima of the HELM states. Recently, the decay rate for the electron transfer process from the intra-strand CT state to the ground state in GC stacked dimers has been studied using theoretical methods.120 One of the most common photolesions in DNA is the occurrence of excited-state cycloadditions, which covalently bond the p-stacked nucleobases leading to CPD and 64-PP structures that can induce mutagenesis. Rauer et al.121 have studied the photodimerisation of p-stacked thymine dimers by means of surface-hopping MD using the CASSCF method. In this study, the photoreaction took place in the singlet manifold even though ISC processes with triplet states were allowed to occur. The authors reported that the photo-cycloaddition is mediated by a doubly excited state delocalised over two thymine moieties, placed above the bright state at the FC region. It was suggested that the system needs to overcome an energy barrier in order to populate the reactive state. In a different work, Mendieta-Moreno et al.122 conducted QM/MM nonadiabatic simulations to study the same photoprocess. The authors reported the presence of energy barriers attributable to the motion restrictions imposed by the WC hydrogen bonding and the sugarphosphate backbone. Given the significance of the CPD lesions, even though they are formed in low yield, cells need to repair the photodamage in order to preserve the correct biological function of nucleic acids. Photolyases constitute a family of bacterial enzymes that are able to repair the damage by absorbing blue light. Notwithstanding the relevance of these processes, the molecular basis of the reparation is not completely understood yet. Lee et al.123 have applied QM/MM methodologies to study the photorepair processes, reporting a variety of competing chargetransfer states that could explain the high repair yield of the enzyme. Photodimerisations involving other nucleobases have also been recently studied. The adenine-adenine photoreaction mechanism was tackled by Banyasz et al.124 The authors explained the base-sequence dependence of the experimental quantum yield of the photolesion in terms of molecular–orbital interactions between the two adenine nucleobases. Another study on the adenine–thymine dimerisation also revealed the remarkable influence of the relative syn/anti orientation between the two nucleobases influencing the reactivity of the photocycloaddition.125 Another kind of photolesions consists in the formation of a single C–C bond between two adjacent pyrimidine nucleobases, leading to the socalled 64-PP. Recently, the photoprocess taking place between two stacked thymine molecules was studied by Giussani et al.126 employing the QM/MM approach, describing the QM part with the CASPT2//CASSCF Photochemistry, 2019, 46, 28–77 | 51

protocol.127 The authors found a reactive path along the PEH of a chargetransfer state from the 5-end to the 3-end thymine. From a pro-reactive initial structure, the CT state can decay towards a CIX with the ground state, from which the system, after surmounting an energy barrier on the ground-state PEH, can lead to the formation of an oxetane ring, the known intermediate for 64-PP production. Regarding the photochemical decay channels involving the hydrogen bonding between opposed nucleobases, i.e. WC base pairs, recent efforts have been devoted to understand the electron-driven proton transfer processes in presence of additional p-stacked nucleobases.128 It has been recently shown that not only inter-strand CT states can initiate the pro´ndez et al.130 have cess but also intra-strand CT states.129 Martı´nez-Ferna studied the PEHs associated to these types of mechanisms in alternate GCGC and ATAT tetramers, reporting a barrierless profile for the former and the presence of a significant barrier for the latter, in agreement with the available experimental evidences. Despite recent advances, more sophisticated and better-resolved spectroscopic methods are sought in order to unequivocally assign the different deactivation channels populated in DNA upon UV-exposure. One recent development in that front comes from two-dimensional electronic spectroscopy (2DES), where an enhanced spatial and temporal resolution is obtained with respect to the widely used standard pump–probe set-ups and that has the potential to separate monomeric contributions to those due to excimer/exciplex formation in oligomeric systems. Moreover, this technique is in principle also able to disentangle specific conformations in solvated dimeric and multimeric systems, elucidating the concrete conformations favouring specific channels.131–133 The field is still in its infancy and plenty of work has been dedicated theoretically to the accurate description of the seldom studied high-lying excited state manifold, which characterise the different transitions recorded in these complex experiments.134–136

5 Photosensitisation of biological structures and photodynamic therapy With the notable exception of important chromophores such as retinal embedded in rhodopsin or photosynthetic systems, whose biological significance is obvious, most of the biological polymeric structures, nucleic acids, proteins, and lipid membrane do not absorb visible light, and are instead sensible to ultraviolet UVA and more often UVB and UVC light. This feature can be easily understood in terms of the necessity to protect their integrity in the biological environment, as absorption of light may trigger unwanted photochemical reaction leading to the destruction or modification of the biological structure and hence ultimately to the cell death or to mutation. Actually, given the amount of UVC and UVB light reaching the Earth being filtered by the ozone layer one can recognise a protective strategy of biological organisms to limit the unwanted effects of exposure to the sun as already mentioned in Section 4.2. Direct damage produced by direct exposure, especially in the 52 | Photochemistry, 2019, 46, 28–77

case of nucleic acids, cannot be neglected, being related to skin cancer (cf. Section 4.2). Here, we want to consider the indirect effects produced by relative small chromophores interacting covalently, or most often noncovalently, with biological systems and able to absorb light in the UVA or visible region of the spectrum to subsequently trigger photochemical and photophysical phenomena resulting in the production of damages in the biological structure. The latter is the process known as photosensitisation and from a photophysical and photochemical point of view one can recognise different types of mechanisms. The most common processes involved in sensitisation are related to ISC, i.e. the sensitizers are supposed to populate their triplet manifold with a reasonable efficiency, the triplet states may then evolve to induce electron- or energy-transfer, in a sort of direct mechanisms, or may lead to the production of singlet oxygen (1O2) that will subsequently produce oxidative lesions to the biological systems. However, we will show in the following that such a characterisation is certainly too simplistic and indeed, several different and competitive pathways, including or not triplet population, should be taken into account to provide a comprehensive picture of the phenomena into play. Photosensitizers can be of different nature, but in general are constituted of p-conjugated aromatic moieties, and where the presence of relatively heavy atoms, such as sulphur, may increase the ISC efficiency.137 As an example we remind that polyunsaturated hydrocarbons, produced by fuel combustion and present in the air as a source of pollution may also act as sensitizers, urging to the development of a protective strategy and to the comprehension of the combined pollution plus UV exposome.138 Despite the possible harmful effects related to photosensitisation, the former general process is nowadays gaining a very important popularity as the base of the so-called photodynamic, or light assisted therapeutic strategy.139 The latter are indeed based on the combination of drug administration and exposition to light in order to treat resistant lesions such as surgically untreatable cancers. It is noteworthy that the previous strategy has also been used in antimicrobial and antiviral therapy, as well as in food industry for water and food processing. In many instances, photodynamic therapy requires the use of photosensitizers able to produce 1O2. Furthermore, in order to allow for the non-invasive treatment of deep lesions, sensitizers absorbing in the red or infrared regions of the solar spectrum are strongly envisaged to reach the therapeutic window (650–1350 nm) in which human, and in general biological, tissues are transparent. From those two examples it appears evident how sensitisation may be considered both as a fundamental process necessary to be understood to rationalise the insurgence of harmful diseases and as an opportunity to develop novel therapeutic strategies and drugs. Hence, it is not surprising that a considerable amount of theoretical work has been devoted to such problems in the past two years. From a computational point of view the task is extremely challenging requiring a very well balanced description of different spatial and temporal scales. Indeed, a fully Photochemistry, 2019, 46, 28–77 | 53

description of the photophysical and photochemical pathways experienced by the different chromophores should be accompanied by a good sampling of the conformational space defining the interaction with the biological system and, at the same time, the specific effects and the influence of the environment should be properly taken into account. One of the most paradigmatic photosensitisation processes is certainly DNA photosensitisation and benzophenone as a model system has been the subject of a large number of studies140 elucidating its binding modes141 and their main photophysical pathways, i.e. triplet–triplet energy transfer to thymine.142 However, the interest of benzophenone relies in the fact that its interaction with DNA may open the way to a number of competitive pathways. In particular and due to the increased basicity in the n–p* excited states, benzophenone can act by hydrogen abstraction either from nucleobases or from the backbone sugar of DNA, hence possibly leading to harmful lesions including strand breaks. It has been shown143 that the possible hydrogen-abstraction pathways strongly depend on the interaction modes. Indeed, when benzophenone is interacting in the DNA minor groove, i.e. in the most stable conformation,144 only the backbone sugar hydrogen can be accessed by the carbonyl oxygen. On the contrary, in the case of the double insertion mode, the backbone is not accessible and instead the hydrogen from the nucleobase should be considered as potentially reactive. The free energy profile and the transition state (TS) of the two reactions, i.e. H-abstraction from sugar or from the nucleobase, by the T1 state of benzophenone have been obtained at DFT and wave-function based levels of theory. Results obtained on the isolated model system have unequivocally pointed towards relatively low activation energy of the order of 9–10 kcal mol1, in the same order of some enzymatic reactions. While those results are coherent with the observation that benzophenone may be used as a photocatalyst, these do not explain why the aforementioned pathways and the related photoproduct are observed only marginally. To resolve such an apparent contradiction it is necessary to turn towards the description of the conformational space spanned by benzophenone interacting with DNA as provided by classical MD trajectory. Indeed, if one considers the distribution of the distance between benzophenone carbonyl oxygen and the DNA reactive hydrogens one finds, coherently between minor groove binding and double insertion, that the probability is peaked at around 5–6 Å and only a very marginal population (less than 10%) is found between distances of 2.0–2.5 Å, i.e. only a very minor fraction of benzophenone molecules will be at potentially reactive distances with the DNA components, and hence the energy transfer deactivation channel will be favoured compared to the photochemical hydrogen-abstraction. Hence, in a certain sense this mechanism can be regarded as a sort of self-protection strategy, in which the molecular environment of the macromolecules hampers the reactants encounter and hence strongly diminishes the outcome of the reaction despite the presence of a generally low activation barrier. Apart from its biological significance, this study also provides a clear evidence of the complex interplay and equilibrium between photophysical, electronic and 54 | Photochemistry, 2019, 46, 28–77

structural effects that should be taken into account in the study of the photosensitisation of biological structures. The effects of the molecular environment in tuning and in some instance driving the available photophysical channels when interacting with DNA is also exemplified in the case of two dyes, nile red and nile blue, widely used in biological applications and proposed as sensitizers acting by photoinduced electron transfer to guanines. The optical and photophysical properties of the two isolated and solvated dyes have been fully analysed underlying their absorption in the visible part of the spectrum and characterizing the different excited states.145 More importantly, the reproduction of the absorption and emission spectra has allowed from the one hand to underline the importance of dynamic and vibrational effects in shifting the absorption wavelengths with respect to the one obtained from the ground state equilibrium geometry and on the other hand to validate TD-DFT level of theory against high level CASPT2 results. Furthermore, the reproduction of the absorption spectrum from snapshots obtained from quantum-based Wigner distribution or from classical MD, has also provided an alternative way to refine force field parameters. Subsequently,146 and by using classical MD the interaction modes of the two dyes with self-complementary DNA double strand constituted of guanine and cytosine bases has allowed to pinpoint two stable modes of interaction for both dyes, namely intercalation and minor groove binding. Snapshots issued from the MD trajectories have then been used as starting points to analyse at hybrid QM/ MM level the behaviour of the different excited states. In particular, we have considered local excited states as compared to the states in which the electron is transferred to orbitals localised on the guanine. In the case of the nile red chromophore, it appears that the CT state involving guanine is always higher in energy compared to the local states, whatever the interaction mode considered; hence electron-transfer sensitisation should be excluded for such system. On the other hand, and quite surprisingly, it appears that in the case of nile blue, while intercalation mode always provides energetically inaccessible CT states, in minor binding mode a state inversion operates and the population of the charge-transfer state becomes possible, hence sensitisation should be considered as possible. This occurrence can be rationalised taking into account the fact that in minor groove binding nile blue will be residing close to the negatively charged DNA backbone, hence stabilizing a CT state leaving a hole, i.e. positive charge, on the chromophore. On the other hand, in intercalation the charge separation process will take place in the hydrophobic DNA core, hence destabilizing the CT state. Remarkably enough the effects of nile blue on DNA have been confirmed by experimental results and have also recently led to the latter being officially declared as a potentially genotoxic compound by the European Commission Agencies.147 As evidenced in the case of benzophenone, in addition to the more studied sensitisation phenomena based on electron- or energy-transfer and 1O2 activation, an important consideration has been devoted to the study of alternative photochemical pathways possibly leading to harmful Photochemistry, 2019, 46, 28–77 | 55

photoproduct and therefore to biological structure disruption. As an example, high level molecular modelling has allowed to pinpoint the molecular basis of the induced photo-toxicity of two widely used nonsteroidal anti-inflammatory drugs, ketoprofen and ibuprofen.148 Once again, the combination of TD-DFT and CASSCF/CASPT2 strategy has allowed unravelling an easy accessible pathway resulting in the case of both drug to homolytic dissociation. Hence, the two drugs upon excitation in the UVA region evolve to the production of two highly reactive radical species in the vicinity of the biological structures. Actually, the photodissociation pathway is characterised by very small activation barrier and can be easily accessible upon excitation. In the case of ibuprofen, photodissociation is the only accessible relaxation channel, while in the case of ketoprofen, an analogous of benzophenone, the former is in competition with ISC. However, one should consider that upon triplet population the activation of 1O2 can be triggered contributing to the increase of phototoxicity and oxidative stress. In addition, while classical molecular mechanics (MM) has pointed to the existence of metastable interaction modes with DNA, basically minor groove binding; by using cellular biology assays it has been proved that the combination of exposure to UVA light and to both drugs results in an increase of cell mortality. Given that ibuprofen is used in topic creams to be applied on the skin, its phototoxicity should be taken into account and sun exposure avoided in the case of topic usage. Going from the domain of phototoxicity to the one of phototherapy, efforts have been devoted to take into account two main crucial factors: shifting the absorption maxima to the red portion of the spectrum to cover the therapeutic window, and avoid the activation of singlet oxygen to allow the efficient treatment of solid tumours that produce hypoxic conditions. One efficient way of inducing absorption red-shift is also related to the use of non-linear two-photon absorption (TPA). Indeed, the advantage of TPA is twofold, it allows dividing by two the excitation energy required by the chromophore, hence doubling the absorption wavelength. Furthermore, TPA requires the simultaneous absorption of two photons and its efficiency depends on the square of the light source. Thus, it is significant only at the laser focal point allowing for a much better spatial resolution especially suitable for the treatment of cerebral lesions. The mechanism of action of a TPA active photodrug, bmec, able to significantly decrease viability of cancer cell lines has been fully characterised at molecular level.149 In particular, thanks to QM/MM calculations it has been proved that bmec has an important TPA crosssection reaching hundreds of GM, while it may also interact persistently with DNA strands in both intercalation and minor groove modes as underlined by classical MD simulations. The interaction with DNA does not alter the TPA cross-section and hence the efficiency of the drug activation. Finally, the mechanism of action inducing phototoxicity has been elucidating on both the solvated and DNA interacting bmec and related to the spontaneous production of solvated electrons by the first singlet excited state (S1). Indeed, the energy level of the radical cation plus the solvated electron has been consistently found to be lower than 56 | Photochemistry, 2019, 46, 28–77

that of the S1 state. The interaction with DNA does not modify this feature allowing for the opening of this photochemical channel both for minor groove binding and intercalation. Both the solvated electron and the radical cation can further interact with DNA components inducing either base lesions or strand breaks. In addition to the effects of DNA non-covalent sensitizers, increasing attention has been devoted to the photoinduced effects produced by modified nucleobases, either artificial or derived from DNA lesions.150,151 Resolving the remarkable differences in the spectroscopic features between the canonical nucleobases and their thionated analogues, as well as the elucidation of the excited-state decay molecular mechanisms of the latter, have received an important piece of computational effort.152–154 Substitution of oxygen by sulphur, a heavier element, increases the SOC and therefore increases the efficiency of ISC processes. Thus, the relative positions of STC along the excited-state PEHs play a key role. It has been recently proven that the excitation energies of thiobases are significantly smaller than that of the natural nucleobases, whereas the S0/S1 CIXs are placed at almost the same level.155 The excited-state gets consequently trapped in minima suppressing the intrinsic photostability of natural DNA nucleobases. Finally, and in addition to the DNA sensitisation, computational studies in the period 2016–2017 have been devoted to the elucidation of the sensitisation mechanism acting against biological lipid membranes. In particular, it has been shown156 that the photosensitizer methylene blue is able to interact with a lipid bilayer taken as a model of a biological membrane. Methylene blue mechanism of action being related to an efficient ISC followed by the production of singlet oxygen it is used to generate photo-induced oxidative stress affecting the lipid unsaturations. By classical MD, also using biased methods such as potential of mean force (PMF), it has been shown that methylene blue cannot spontaneously penetrate inside the lipid bilayer, the process requiring to bypass a free energy barrier of around 30 kcal mol1. Further QM/MM CASPT2 calculations on selected MD snapshots have shown that the penetration in the membrane actually decreases the ISC probability, and hence singlet oxygen yield, because it reduces the overlap between singlet and triplet energy levels. Therefore, one should suppose that methylene blue would activate molecular oxygen in the vicinity of the membrane polar heads and the reactive oxygen species would have to diffuse to the centre of the layer to reach the unsaturation. On the contrary, and using a similar protocol combining MD simulations with QM/MM modelling, it has been shown that the naturally occurring hypericin drug157 is able to spontaneously penetrate in the hydrophobic core of lipid bilayers, hence its density nicely overlaps with the one of the lipid double bond. Furthermore, the photophysical key parameters such us singlet triplet gap and SOCs are less affected by the presence of the membrane environment. As a consequence, hypericin ISC probability should remain high, moreover, since its position overlaps almost perfectly with the one of the lipid unsaturation, it could produce singlet oxygen in close proximity to its target increasing thereby the phototoxicity. Photochemistry, 2019, 46, 28–77 | 57

6

Chemiexcitation

Excited-state chemistry arisen from a chemical reaction by a chemiexcitation process has been also the focus of a number of computational works in 2016–2017. We shall firstly describe in this section those works mainly studying the mechanistic aspects of the chemiexcitation which gives rise to light emission (CL) and next the studies with important relevance for the CL phenomena taking place in living organisms (BL). For further reading on the topic, we highlight here a recent extensive work establishing the current knowledge on the molecular basis of the chemi- and bio-luminescence phenomena.158 6.1 Chemiluminescence mechanisms In the CL phenomena, a thermally activated reactant generates a highlyunstable intermediate that undergoes a non-adiabatic transition to an electronically excited-state product. The subsequent transition back from excited- to ground-state product is accompanied by a release of energy in form of cold light. The simplest discovered models for CL transformations consist in unimolecular decomposition of 1,2-dioxetanes and 1,2dioxetanones. The mechanism of these four-membered ring peroxides cleavages has been extensively studied in the last decade by both experimental and theoretical means. On the basis of these studies,159–161 it is known that the unimolecular decomposition of 1,2-dioxetane and 1,2-dioxetanone occurs via a stepwise biradical mechanism. The two-step biradical decomposition implies that once the O–O bond is cleaved, the system enters a biradical region where four singlet and four triplet states are degenerated. After that, the C–C bond rupture begins, leading to dissociation of the molecule into two separated fragments. As we briefly described in the previous contribution to the Photochemistry Specialist Periodical Reports of the Royal Society of Chemistry,4 a very interesting aspect of this proposed mechanism is the presence of a so-called ‘‘entropic trapping’’ region, in which the molecule can split the population among the degenerated manifolds. The entropic trapping region has been shown to play a pivotal role on the dissociation. It basically, regulates the outcome by delaying the ground-state decomposition and giving time to the system to get access to the excited states, e.g., S1 and T1. Based on several experimental studies, the unimolecular decomposition of 1,2-dioxetane and 1,2-dioxetanone has been shown to lead to the formation of triplet excited carbonyl products with the yield of up to 30%. However, the formation of singlet excited state is quite inefficient and can barely reach 1%. Previous theoretical studies on 1,2-dioxetane159,160 and 1,2-dioxetanone162 are in good agreement with this observation. For instance, the computed MS-CASPT2 activation energy for the decomposition of 1,2-dioxetane is of 22 kcal mol1. In 1,2-dioxetanone, the ´s-Monerris et al. by larger triplet population was explained by France means of CASPT2//CASSCF computations.162 The authors found that two triplet excited states, namely T1 and T2, are accessible along the peroxide decomposition path, whereas only one singlet excited state (S1) is available. However, these studies did not clarify how the entropic trapping 58 | Photochemistry, 2019, 46, 28–77

region determines the efficiency of the CL, as well as what its role is in regulating the outcome, or what the lifetime in the biradical region is. In the period of 2016–2017, substantial efforts have been invested to address these fundamental questions in understanding CL phenomenon. Among the whole list, we would like to begin our journey by reviewing some of them wherein simulations of the actual dynamics of the molecular system are reported. In early 2017, Vacher et al.163 revisited the biradical O–O rupture mechanism of the parent 1,2-dioxetane to provide some accurate predictions from molecular basis of the reaction process. By initiating the trajectories at the rate-limiting TS, corresponding to the O–O cleavage, with Wigner distribution, and giving 1 kcal mol1 of kinetic energy, the authors propagated the ‘‘on-the-fly’’ dynamics through the biradical region. The authors used a time-step of 10 au (or 0.24 fs). Moreover, the hopping between the close-lying surfaces along the MEP was allowed throughout the simulations, which was missing in the former report by Farahani et al.160 This indicates transitions among any of the four lowestlying singlet states. The PEHs were probed at the CASSCF level of theory with state-averaging over the four singlet states. On one hand, the results of the ground-state dynamics simulations support a so-called ‘‘frustration’’ before dissociations, postponing the decomposition reaction. They also found a relation between the O–C–C–O dihedral angle and the time spent in the entropic trap. The half lifetime of the biradical region has been reported to be t1/2 ¼ 58 fs. This is indeed shorter than the previous theoretical study in which ground-state dynamics of 1,2-dioxetane was examined (613 fs).160 However, the difference was justified by different initial conditions used in both articles. On the other hand, the results on singlet excited-state dynamics have shown that the longer a trajectory stays in the excited state, the longer it takes to dissociate. Therefore, the singlet excited state even further postpones the dissociation. However, no decomposition was observed along the singlet excited state, supporting the extremely low singlet emission yield (0.0003%) which had been reported by experimentalists. The half lifetime of the biradical region is hence increased to t1/2 ¼ 77 fs. It is noteworthy to mention that the ISCs between the singlet and triplet states are neglected in this contribution and thus further dynamics simulations taking into account the triplet states are required to complement the statements and give an insight into the CL decomposition of 1,2-dioxetane. Later in 2017, Vacher et al.164 performed another theoretical study on substituted 1,2-dioxetanes with various CL quantum yields, which was initially studied experimentally by Baader et al.,165 explaining how the entropic trap determines the efficiency of the CL process. The authors here could successfully rationalise why the excitation yield increases with the degree of methylation wherein four hydrogen atoms of parent 1,2dioxetane were replaced by methyl groups. This methyl substitution enhances the CL yield from 0.3% (parent 1,2-dioxetane) to 35% (tetramethyl-1,2-dioxetane), see Fig. 8. In this contribution, the authors applied the same approach as for the previous study on parent 1,2dioxetane. The results show that the substitution would increase the time Photochemistry, 2019, 46, 28–77 | 59

60 | Photochemistry, 2019, 46, 28–77 Fig. 8 Biradical mechanism has been proposed for the decomposition process of dioxetanes.

spent in the ‘‘trap’’ due to the increase in the number of degrees of freedom which would subsequently increase the population of the excited-state product. Nevertheless, the heavier substituents, simply through their larger mass, slow down the torsional motion around the O–C–C–O dihedral angle which can trap the system for longer time and hence postpones the dissociation. Normally, a dihedral angle of 551 is required to escape the entropic trapping region, thus, longer time to reach large dihedral angle equals to slower dissociation. These results are consequently supported by fitting the calculated dissociation half lifetime to the experimental data. After 1,2-dioxetane, the simplest model for CL and BL transformations is the unimolecular decomposition of 1,2-dioxetanone. To address if there are distinct reaction pathways for the ground and excited state formation in unimolecular four-membered ring peroxide decomposition that possess different activation energies, Farahani et al.166 reported a combined theoretical and experimental mechanistic study on the unimolecular decomposition of spiro-adamantyl-1,2-dioxetanone as a prototype. This system was chosen as a model since it is relatively stable and therefore, can be purified by low-temperature recrystallisation. Based on the intensity measurements at different temperatures, the activation energy of the CL is not the same as the activation energy for the decomposition reaction. This indicates the occurrence of two different pathways for the formation of ground and singlet excited state products. To better understand this difference, multiconfigurational approaches with dynamical corrections have been applied to study the unimolecular decomposition. The decomposition mechanism has been shown to be a two-step biradical pathway in which the stationary points are reported to be optimised at the partial CASPT2 level of theory using constrained numerical gradients and composite gradients167 in conjunction with ANO-L-VDZP basis set. The obtained results confirm the presence of a common TS in the rate-limiting step for ground- and excited-state product formation. However, the TS corresponding to C–C rupture (notrate-limiting) is shown to possess different energies for ground and singlet excited states (see Fig. 9). It is noteworthy to mention that the theoretical activation energy for the rate-limiting step is overestimated as compared to the experiment. The authors however, justified their results by the deviation involved in the CASPT2 excitation energies using the IPEA correction which was reported in a benchmark study by Zobel et al.168 Nonetheless, they claim that the qualitative aspects of the reaction mechanism is in agreement with the experimental findings. In exploring the prototypes in CL reactions, the next generation is 1,2dioxetanedione. Here, the catalysed decomposition (bimolecular decomposition) is proven to occur with very efficient formation of electronically excited state. This is quite different compared to 1,2-dioxetane and 1,2-dioxetanone decompositions for which the reported quantum yields are shown to be low. To rationalise this difference, Farahani and Baader reported a qualitative and quantitative study on the electronically excited formation of unimolecular decomposition on 1,2-dioxetanedione hoping that it could be applied in the study of bimolecular Photochemistry, 2019, 46, 28–77 | 61

Fig. 9 Schematic representation of the PEH for the unimolecular decomposition of spiro-adamantyl-1,2-dioxetanone.

Fig. 10 The 2D-PEH of unimolecular decomposition of 1,2-dioxetanedione.

decomposition of this intermediate.169 By performing MS-CASPT2 geometry optimisations of the stationary points along the PEH as well as MEP searches, the authors analysed mechanistic aspects of the chemiexcitation process. Interestingly, the findings confirm a concerted mechanism for the ground-state dissociation which is contrary to the reported process in 1,2-dioxetane and 1,2-dioxetanone, see Fig. 10. The 62 | Photochemistry, 2019, 46, 28–77

concerted mechanism is a single-step reaction process in which both C–C and O–O ruptures occur simultaneously by overcoming only one TS of 30 kcal mol1. At this TS, the crossings take place which can lead to formation of the excited states. After that, the system enters an extended biradical-like region from which singlet and triplet low-lying manifolds are degenerated. To produce CL, a second TS corresponding to C–C cleavage must be surmounted in the lowest-lying singlet and triplet excited manifolds (37 and 29 kcal mol1 for singlet and triplet manifolds, respectively). Since the activation energy for this second TS is higher in singlet excited state and populating the triplet manifold requires high amount of SOC, there should not be any formation of singlet excited states and/or very low formation of triplet state in the unimolecular decomposition. These findings consequently, support why there is no clear-cut experimental evidence on a direct CL emission from this unimolecular decomposition process. So far, we have only reviewed the studies on unimolecular decomposition of simple models of CL transformation. However, it has been shown that oxidizable fluorescent dyes based on p-conjugated aromatic rings, so-called activators, can promote the decomposition of 1,2dioxetanones. So that the more the activator is oxidizable, the higher intensity the light emission will have. In 2017, Augusto et al.170 studied the interactions between unsubstituted 1,2-dioxetane and 1,2-dioxetanone with model activators (naphthalene and anthracene). The CASPT2//SA-CASSCF potential energy curves along the O–O dissociation show an excited state of CT nature related to the electron-density promotion from the activator to the s* antibonding orbital of the O–O bond. The energy gap between the ground ss* and the intermolecular CT excited state ps* is smaller for the 1,2-dioxetanone complex as compared to the 1,2-dioxetane parent peroxide. This finding supports why activators do not activate the catalysed decomposition of 1,2-dioxetanes and why the efficiency of this process is quite low for 1,2-dioxetanone. The mechanism proposed for the catalysed CL corresponds to two nonadiabatic steps, firstly from the ground ss* state to the excited ps* state of CT nature and secondly from the latter to the emissive excited pp* state of the activator (see Fig. 11).

6.2 Chemiluminescence in biology: bioluminescence BL has been an attractive subject in scientific research for decades due to its broad applications in biotechnology and biomedical fields, such as gene expression, medical imaging and drug screening. In 2016 and 2017, theoretical studies on BL are concentrated on these issues concerning the BL mechanism, the chemical structure or protonated species of light emitter, and the factors modulating the colour and intensity of light emission.171–185 The following paragraphs briefly summarise some impressive contributions to firefly,171,172 firefly squid,177 bacteria,178 and dinoflagellate BL.180,181 Firefly bioluminescence. Among the luminescent organisms, firefly, the paradigmatic BL system, has received the most attention in these Photochemistry, 2019, 46, 28–77 | 63

Fig. 11 CASPT2//SA-CASSCF PEH for the dissociation of a CT complex formed between parent 1,2-dioxetane and anthracene. Reproduced from ref. 170 with permission from the PCCP Owner Societies.

two years.171–176 These contributions mainly focused on the spectra character and the factors affecting firefly BL. Although the absorption or emission energy of firefly luciferin (LH2 shown in Fig. 12) or its oxidative product (oxyluciferin, oxLH2) have been calculated to be compared to the absorption or emission spectra maximum in experiments, the calculated vibronic spectrum was absent. For the first time, the vibrationally resolved absorption and fluorescent spectra of firefly luciferin were simulated using DFT and convoluted by a Gaussian function with displacement, distortion, and Duschinsky effects in the framework of the Frank–Condon approximation.171 The firefly luciferin-luciferase system has been applied in in vivo imaging, hence investigating the factors affecting light colour and intensity is important. A recent theoretical study employed ONIOM approach to investigate the variation of the barrier heights for the decomposition of the high-energy intermediate of LH2 (firefly dioxetanone, DO) and its two analogues in the local electrostatic field (LEF) produced by firefly luciferase.172 The two modified luciferins (BoLH2 and BtLH2) that obviously differ in bioluminescent intensities are shown in Fig. 12. BoLH2 and BtLH2 are modified from LH2 via replacing benzothiazole ring by benzoxazole and benzothiophene 64 | Photochemistry, 2019, 46, 28–77

Fig. 12 Molecular structures of firefly luciferin and its two analogues (BoLH2, BtLH2: replacing the benzothiazole ring in LH2 with benzoxazole and benzothiophene, respectively), oxyluciferin (oxLH2) and their corresponding dioxetanones.

ring, respectively. Those calculated results indicated that positive LEF created by luciferase along the long-axis direction (the x direction, see Fig. 12) could lower the activation energy and serves as an electrostatic catalyst for DO thermolysis. Firefly Squid Bioluminescence. Firefly squid luciferin has a universal core structure, imidazopyrazinone (ImPy, the blue skeleton in Fig. 13), which is common in the luciferins of about eight phyla of luminescent organisms. But this bioluminescent mechanism remains largely unknown, especially for the two key steps: the addition of molecular oxygen to luciferin and the formation of light emitter. In 2017, the detailed mechanism of the two key steps was investigated for the first time by QM calculation with non-adiabatic MD simulation.177 By analyzing the energetics, electronic structures, and CT process, the calculated results indicated that (see Fig. 13): (1) the oxygenation reaction of luciferin is initiated by a single electron transfer (SET) from the luciferin to molecular oxygen, which occurs at the C2 position of the ImPy ring in the luciferin. The high-energy dioxetanone intermediate is formed via a nucleophilic addition reaction followed by biradical annihilation and an Photochemistry, 2019, 46, 28–77 | 65

Fig. 13 The detailed process for the oxygenation of luciferin and the formation of light emitter.

ISC in the vicinity of the singlet/triplet surface intersection. (2) The light emitter is produced from the anionic dioxetanone intermediate via the gradually reversible charge-transfer-induced luminescence (GRCTIL) mechanism with a high quantum yield FS ¼ 43%. Bacteria Bioluminescence. Luminous bacteria emit continuous glow and have been widely used in BL imaging fields, especially as a sensitive and convenient tool for monitoring environmental toxin. But the light emitter of bacteria BL is still a debatable point. An intermediate called 4ahydroxy-5-hydro flavin mononucleotide (HFOH, see Fig. 14) and the final products (flavin mononucleotide, FMN) are assumed as candidates responsible for bacteria BL, because they have similar molecular structures and fluorescence wavelengths. It is worth noting that the similar HFOH and FMN perform opposite fluorescence behaviours in solution and in luciferase. FMN emmits fluorescence in solution but exhibits fluorescence quenching in the bacterial luciferase. What is the exact chemical form of bacterial bioluminophore and why FMN fluorescence quenching occurs in the bacterial luciferase? In 2016, the above problems were solved via high-level QM method, the combined QM and MM method QM/MM, and MD simulation.178 The calculated results revealed that: (1) the S1-state HFOH is the bacterial bioluminophore; (2) FMN fluorescence quenching results from the electron transfer from the quencher (the tyrosine residue 110 in the bacterial luciferase) to FMN with the aid of protein fluctuation. Dinoflagellate Bioluminescence.180,181 Dinoflagellates BL are featured in two aspects: they are the major component of sparkling lights in coastal water; the sparkling luminescence results from fluid shear stress. This luminescence reaction is a luciferin–luciferase one in which the dinoflagellate luciferin is oxidised to the oxyluciferin with the light emission. (see Fig. 15) Generally, the oxyluciferin is the chemical source of light emitter for the luciferin–luciferase systems, such as firefly, Cypridina. But dinoflagellate oxyluciferin is not fluorescent. It is not clear what is the light emitter of dinoflagellate BL and what is the chemical 66 | Photochemistry, 2019, 46, 28–77

Photochemistry, 2019, 46, 28–77 | 67

Fig. 14 Molecular structures of HFOH and FMN, and the fluorescence quenching process of FMN.

Fig. 15 The general process of dinoflagellate BL.

process of light emission. In 2016, dinoflagellate BL was theoretically studied by TD-DFT method for the first time. In this study, the excitedstate E/Z-isomer luciferin or its analogue rather than oxyluciferin is assumed as the bioluminophore and a Dexter energy transfer mechanism for light emission is proposed.180 The excited-state oxyluciferin produced from the oxidation of luciferin acts an energy provider transferring energy to another ground-state luciferin or its analogue that emits radiative transition. The subsequent theoretical study investigated four chemical forms of intermediate in the luciferase catalytic cycle and suggested that the gem-diol(ate) intermediate shown as Fig. 16 is the bioluminophore and E/Z-isomer luciferin proceeds via chemically initiated electron-exchange luminescence (CIEEL)/twisted intramolecular charge transfer (TICT) to produce the bioluminophore.181

7

Summary and outlook

In 2016 and 2017, Quantum Chemistry of the Excited State has continued its rapid growth observed during the last decades within the group of powerful tools to address photochemical and chemiluminescent studies. Method developments carried out in the period reviewed in the present book chapter point towards an even brighter future for QCEX. Thus, we observe relevant advances achieved which overcome the known limitations of the multiconfigurational quantum-chemistry methods related to the amount of strongly correlated electrons or reduce the computational cost needed to obtain the remaining electron correlation (dynamic correlation). We focus in this review on developments carried out in the DMRG, FCIQMC and semi-stochastic HCI methods to provide correct wave functions for determining the static electron correlation, and formulations which largely decrease the cost of computing the short-range or dynamical correlation such as the pair natural orbital or frozen natural orbital within the CASPT2 method. Advances are also observed in the computational strategies for obtaining a dynamical description of excited-state phenomena including lifetimes and population distribution in non-adiabatic processes. We highlight in this work improvements within the quantum dynamics methodologies. 68 | Photochemistry, 2019, 46, 28–77

Photochemistry, 2019, 46, 28–77 | 69

Fig. 16 Proposed mechanism of dinoflagellate luciferase catalytic cycle involving CIEEL for E-isomer luciferin and TICT for Z-isomer of luciferin.

Applications of QCEX methodologies and computational strategies show a progressive trend towards computations on larger-size molecules and systems with a more extended p-conjugation. Illustrative examples are given in the present book chapter in the fields of luminescent materials, molecular rotors, organic optoelectronics, DNA photostability, damage and repair, photosensitisation of biological structures, CL and BL. For instance, works on DNA nucleobases begin to focus more on the competition between distinct excited-state processes in clusters of bases and less on intrinsic properties of the isolated bases which were exhaustively analysed in previous studies. CIXs and STCs remain as relevant targets of many QCEX works and shall remain in future studies. The reason is that such quantum-chemistry entities are crucial to correctly interpret many observable properties measured in spectroscopic, photochemistry and CL experiments. The present book chapter also shows synergic combinations of QM methods with MM static and dynamic approaches to properly deal with the environmental effects. We also observe that analysis of inter-molecular processes are becoming more common in some fields (DNA photochemistry and photosensitisation) and new in others (CL). In chemiluminescence, we find the first attempt to analyse the inter-molecular catalysed CL mechanism by using multiconfigurational quantum chemistry (CASPT2/CASSCF). Accurate determinations of excited-state inter-molecular phenomena are however still a challenge for protocols which are based on a highly-accurate determination of CASPT2 energies on top of CASSCF optimised structures or for semiclassical dynamics studies based on CASSCF gradients. This is due to the fact that CASSCF is not considering dispersion interactions. Approximate TD-DFT structures or computationally-demanding CASPT2 gradients can be used here, although this is not possible in all cases. In this context, DMRG, FCIQMC, HCI or new and practical corrections of the popular CASSCF method shall be of great relevance.

Acknowledgements J.S.-M. acknowledges support from the European Commission through the Marie Curie actions (FP8-MSCA-IF, grant no 747662). D.R.-S. is thankful to the Spanish MINECO/FEDER for financial support through ´n y Cajal fellowship with project CTQ2017-87054-C2-2-P and the Ramo Ref. RYC-2015-19234. A.F.-M. and A.M. are grateful to the French ANR ´ de Lorraine for their support. and the Universite

References 1

2 3

´s, D. Roca-Sanjua ´n and G. Olaso-Gonza ´lez, in PhotoL. Serrano-Andre chemistry, ed. A. Albini, Royal Society of Chemistry, London, 2010, vol. 38, pp. 10–36. ´n and R. Lindh, in Photochemistry, ed. A. Albini, Y.-J. Liu, D. Roca-Sanjua Royal Society of Chemistry, London, 2012, vol. 40, p. 42. ´n, I. Fdez Galva ´n, R. Lindh and Y.-J. Liu, in Photochemistry, D. Roca-Sanjua ed. E. Fasani and A. Albini, Royal Society of Chemistry, London, 2015, vol. 42, p. 11.

70 | Photochemistry, 2019, 46, 28–77

4

5 6 7 8

9

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

´n, A. France ´s-Monerris, I. Fdez Galva ´n, P. Farahani, R. Lindh D. Roca-Sanjua and Y.-J. Liu, in Photochemistry, ed. E. Fasani and A. Albini, Royal Society of Chemistry, London, 2017, vol. 44, p. 16. B. O. Roos, Advances in Chemical Physics, John Wiley & Sons, Inc., 1987, DOI: 10.1002/9780470142943, ch. 7, pp. 399–445. ´s and F. Aquilante, T. B. Pedersen, R. Lindh, B. O. Roos, A. S. d. Mera H. Koch, J. Chem. Phys., 2008, 129, 024113. D. Escudero, A. D. Laurent and D. Jacquemin, in Handbook of Computational Chemistry, ed. J. Leszczynski, Springer, Netherlands, Dordrecht, 2016, pp. 1–35. M. E. Casida and M. Huix-Rotllant, in Density-Functional Methods for Excited ´, M. Filatov and M. Huix-Rotllant, Springer International States, ed. N. Ferre Publishing, Cham, 2016, pp. 1–60. M. Huix-Rotllant, A. Nikiforov, W. Thiel and M. Filatov, in Density-Functional ´, M. Filatov and M. Huix-Rotllant, Methods for Excited States, ed. N. Ferre Springer International Publishing, Cham, 2016, pp. 445–476. ¨ck, Rev. Mod. Phys., 2005, 77, 259. U. Schollwo G. K.-L. Chan and S. Sharma, Ann. Rev. Phys. Chem., 2011, 62, 465. S. R. White, Phys. Rev. Lett., 1992, 69, 2863. G. Li Manni, S. D. Smart and A. Alavi, J. Chem. Theory Comput., 2016, 12, 1245. N. S. Blunt, S. D. Smart, G. H. Booth and A. Alavi, J. Chem. Phys., 2015, 143, 134117. G. H. Booth, A. J. W. Thom and A. Alavi, J. Chem. Phys., 2009, 131, 054106. A. A. Holmes, C. J. Umrigar and S. Sharma, J. Chem. Phys., 2017, 147, 164111. J. E. T. Smith, B. Mussard, A. A. Holmes and S. Sharma, J. Chem. Theory Comput., 2017, 13, 5468. E. Tirrito, S.-J. Ran, A. J. Ferris, I. P. McCulloch and M. Lewenstein, Phys. Rev. B, 2017, 95, 064110. Y. Ma, S. Knecht, S. Keller and M. Reiher, J. Chem. Theory Comput., 2017, 13, 2533. Q. Sun, J. Yang and G. K.-L. Chan, Chem. Phys. Lett., 2017, 683, 291. H. J. Werner and P. J. Knowles, J. Chem. Phys., 1985, 82, 5053. S. Knecht, S. Keller, J. Autschbach and M. Reiher, J. Chem. Theory Comput., 2016, 12, 5881. E. R. Sayfutyarova and G. K.-L. Chan, J. Chem. Phys., 2016, 144, 234301. P.-Å. Malmqvist and B. O. Roos, Chem. Phys. Lett., 1989, 155, 189. P. Å. Malmqvist, B. O. Roos and B. Schimmelpfennig, Chem. Phys. Lett., 2002, 357, 230. S. Keller, K. Boguslawski, T. Janowski, M. Reiher and P. Pulay, J. Chem. Phys., 2015, 142, 244104. V. Veryazov, P. Å. Malmqvist and B. O. Roos, Int. J. Quantum Chem., 2011, 111, 3329. E. R. Sayfutyarova, Q. Sun, G. K.-L. Chan and G. Knizia, J. Chem. Theory Comput., 2017, 13, 4063. C. J. Stein and M. Reiher, J. Chem. Theory Comput., 2016, 12, 1760. E. G. Hohenstein, N. Luehr, I. S. Ufimtsev and T. J. Martı´nez, J. Chem. Phys., 2015, 142, 224103. J. W. Snyder Jr., B. S. Fales, E. G. Hohenstein, B. G. Levine and T. J. Martı´nez, J. Chem. Phys., 2017, 146, 174113. E. G. Hohenstein, J. Chem. Phys., 2016, 145, 174110. B. S. Fales, Y. Shu, B. G. Levine and E. G. Hohenstein, J. Chem. Phys., 2017, 147, 094104. Photochemistry, 2019, 46, 28–77 | 71

34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

66

´n, M. G. Delcey, T. B. Pedersen, F. Aquilante and R. Lindh, I. Fdez Galva J. Chem. Theory Comput., 2016, 12, 3636–3653. M. G. Delcey, T. B. Pedersen, F. Aquilante and R. Lindh, J. Chem. Phys., 2015, 143, 044110. ´n and R. Lindh, Mol. F. Aquilante, M. G. Delcey, T. B. Pedersen, I. Fdez Galva Phys., 2017, 115, 2052. K. Andersson, P.-Å. Malmqvist and B. O. Roos, J. Chem. Phys., 1992, 96, 1218. C. Angeli, R. Cimiraglia, S. Evangelisti, T. Leininger and J.-P. Malrieu, J. Chem. Phys., 2001, 114, 10252. ´n, F. Aquilante and R. Lindh, WIREs Comput. Mol. Sci., 2012, D. Roca-Sanjua 2, 585. F. Menezes, D. Kats and H.-J. Werner, J. Chem. Phys., 2016, 145, 124115. J. Segarra-Martı´, M. Garavelli and F. Aquilante, J. Chem. Theory Comput., 2015, 11, 3772. J. Segarra-Martı´, M. Garavelli and F. Aquilante, J. Chem. Phys., 2018, 148, 034107. B. Vlaisavljevich and T. Shiozaki, J. Chem. Theory Comput., 2016, 12, 3781. M. K. MacLeod and T. Shiozaki, J. Chem. Phys., 2015, 142, 051103. J. W. Park and T. Shiozaki, J. Chem. Theory Comput., 2017, 13, 2561. D. Ma, G. Li Manni, J. Olsen and L. Gagliardi, J. Chem. Theory Comput., 2016, 12, 3208. N. Nakatani and S. Guo, J. Chem. Phys., 2017, 146, 094102. T. Yanai, M. Saitow, X.-G. Xiong, J. Chalupsky´, Y. Kurashige, S. Guo and S. Sharma, J. Chem. Theory Comput., 2017, 13, 4829. G. Ghigo, B. O. Roos and P.-Å. Malmqvist, Chem. Phys. Lett., 2004, 396, 142. Y. Guo, K. Sivalingam, E. F. Valeev and F. Neese, J. Chem. Phys., 2017, 147, 064110. Y. Guo, K. Sivalingam, E. F. Valeev and F. Neese, J. Chem. Phys., 2016, 144, 094111. L. Freitag, S. Knecht, C. Angeli and M. Reiher, J. Chem. Theory Comput., 2017, 13, 451. S. Guo, M. A. Watson, W. Hu, Q. Sun and G. K.-L. Chan, J. Chem. Theory Comput., 2016, 12, 1583. M. Roemelt, S. Guo and G. K.-L. Chan, J. Chem. Phys., 2016, 144, 204113. C. J. Stein, V. von Burg and M. Reiher, J. Chem. Theory Comput., 2016, 12, 3764. A. Y. Sokolov and G. K.-L. Chan, J. Chem. Phys., 2016, 144, 064102. A. Y. Sokolov, S. Guo, E. Ronca and G. K.-L. Chan, J. Chem. Phys., 2017, 146, 244102. S. Sharma, G. Knizia, S. Guo and A. Alavi, J. Chem. Theory Comput., 2017, 13, 488. S. Sharma, G. Jeanmairet and A. Alavi, J. Chem. Phys., 2016, 144, 034103. L. Gagliardi, D. G. Truhlar, G. Li Manni, R. K. Carlson, C. E. Hoyer and J. L. Bao, Acc. Chem. Res., 2017, 50, 66. E. D. Hedegård, Mol. Phys., 2017, 115, 26. I. Lyskov, M. Kleinschmidt and C. M. Marian, J. Chem. Phys., 2016, 144, 034104. A. Heil and C. M. Marian, J. Chem. Phys., 2017, 147, 194104. S. Grimme and M. Waletzke, J. Chem. Phys., 1999, 111, 5645. ´, M. Filatov, in Density-Functional Methods for Excited States, ed. N. Ferre M. Filatov and M. Huix-Rotllant, Springer International Publishing, Cham, 2016, pp. 97–124. ´k, J. Chem. Phys., 2016, 145, 034102. A. K. Dutta, F. Neese and R. Izsa

72 | Photochemistry, 2019, 46, 28–77

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86

87 88

89

90

91 92 93 94 95

S. Faraji, S. Matsika and A. I. Krylov, J. Chem. Phys., 2018, 148, 044103. E. F. Kjønstad and H. Koch, J. Phys. Chem. Lett., 2017, 8, 4801. E. F. Kjønstad, R. H. Myhre, T. J. Martı´nez and H. Koch, J. Chem. Phys., 2017, 147, 164105. J. Brabec, J. Lang, M. Saitow, J. Pittner, F. Neese and O. Demel, J. Chem. Theory Comput., 2018, DOI: 10.1021/acs.jctc.7b01184. G. W. Richings and G. A. Worth, Chem. Phys. Lett., 2017, 683, 606. G. W. Richings and S. Habershon, J. Chem. Theory Comput., 2017, 13, 4012. G. W. Richings and S. Habershon, Chem. Phys. Lett., 2017, 683, 228. ´lez and T. J. Martı´nez, B. F. E. Curchod, C. Rauer, P. Marquetand, L. Gonza J. Chem. Phys., 2016, 144, 101102. D. A. Fedorov, S. R. Pruitt, K. Keipert, M. S. Gordon and S. A. Varganov, J. Phys. Chem. A, 2016, 120, 2911. F. Agostini, S. K. Min, A. Abedi and E. K. U. Gross, J. Chem. Theory Comput., 2016, 12, 2127. S. K. Min, F. Agostini, I. Tavernelli and E. K. U. Gross, J. Phys. Chem. Lett., 2017, 8, 3048. B. F. E. Curchod and F. Agostini, J. Phys. Chem. Lett., 2017, 8, 831. ¨hn, J. Phys. B: At., Mol. Opt. M. F. Shibl, J. Schulze, M. J. Al-Marri and O. Ku Phys., 2017, 50, 184001. D. Mendive-Tapia, T. Firmino, H.-D. Meyer and F. Gatti, Chem. Phys., 2017, 482, 113. J. E. Subotnik, A. Jain, B. Landry, A. Petit, W. Ouyang and N. Bellonzi, Ann. Rev. Phys. Chem., 2016, 67, 387. L. Wang, A. Akimov and O. V. Prezhdo, J. Chem. Phys., 2016, 7, 2100. ISI Web of Knowledge, Thomson Reuters. http://wokinfo.com. ´n and B. Zietz, J. Phys. Chem. C, 2015, A. M. El-Zohry, D. Roca-Sanjua 119, 2249. ´s-Monerris, I. Schapiro, M. Olivucci and L. A. Strada, A. France ´n, Phys. Chem. Chem. Phys., 2016, 18, 32786. D. Roca-Sanjua ¨er, J. Shi, L. E. A. Suarez, S.-J. Yoon, S. Varghese, C. Serpa, S. Y. Park, L. Lu ´n, B. Milia ´n-Medina and J. Gierschner, J. Phys. Chem. C, D. Roca-Sanjua 2017, 121, 23166. ´s, V. Sauri, M. G. S. Londesborough, D. Hnyk, J. Bould, L. Serrano-Andre ´t, T. Polı´vka and K. Lang, Inorg. Chem., 2012, 51, 1471. J. M. Oliva, P. Kuba ´n, P. Kuba ´t, V. Sauri, J. M. Oliva, D. Hnyk, J. Bould, J. Braborec, M. Mercha ´, K. Lang and M. G. S. Londesborough, Inorg. Chem., 2013, I. Cı´sarˇova 52, 9266. ´n, K. Lang, T. Jelı´nek, M. G. S. Londesborough, J. Dolansky´, L. Cerda ´n, A. France ´s-Monerris, J. Martincˇ´k, J. M. Oliva, D. Hnyk, D. Roca-Sanjua ı M. Nikl and J. D. Kennedy, Adv. Opt. Mater., 2017, 5, 1600694. ´, M. G. S. Londesborough, J. Dolansky´, T. Jelı´nek, J. D. Kennedy, I. Cı´sarˇova ´n, A. France ´s-Monerris, K. Langa and R. D. Kennedy, D. Roca-Sanjua W. Clegg, Dalton Trans., 2018, 47, 1709. ´lez, Molecules, P. Marquetand, J. J. Nogueira, S. Mai, F. Plasser and L. Gonza 2017, 22, 49. M. Pola, M. A. Kochman, A. Picchiotti, V. I. Prokhorenko, R. J. D. Miller and M. Thorwart, J. Theory Comput. Chem., 2017, 16, 1750028. ´ndez, A. J. Pepino, J. Segarra-Martı´, A. Banyasz, L. Martı´nez-Ferna M. Garavelli and R. Improta, J. Chem. Theory Comput., 2016, 12, 4430. M. S. Nørby, C. Steinmann, J. M. H. Olsen, H. Li and J. Kongsted, J. Chem. Theory Comput., 2016, 12, 5050. R. Improta, F. Santoro and L. Blancafort, Chem. Rev., 2016, 116, 3540. Photochemistry, 2019, 46, 28–77 | 73

96 97 98 99 100 101

102 103 104 105 106 107 108

109 110 111 112 113 114 115

116 117 118

119 120 121 122 123

J. J. Nogueira, F. Plasser and L. Gonzalez, Chem. Sci., 2017, 8, 5682. Z. Benda and P. G. Szalay, Phys. Chem. Chem. Phys., 2016, 18, 23596. H. Sun, S. Zhang, C. Zhong and Z. Sun, J. Comput. Chem., 2016, 37, 6843. S. Saha and H. M. Quiney, RSC Adv., 2017, 7, 33426. A. DeFusco, N. Minezawa, L. V Slipchenko, F. Zahariev and M. S. Gordon, J. Phys. Chem. Lett., 2011, 2, 2184. M. Pollum, L. Martinez-Fernandez and C. E. Crespo-Hernandez, in Photoinduced Phenomena in Nucleic Acids I: Nucleobases in the Gas Phase and in Solvents, ed. M. Barbatti, A. C. Borin and S. Ullrich, 2015, vol. 355, pp. 245–327. ´n and M. Mercha ´n, Top. Curr. A. Giussani, J. Segarra-Martı´, D. Roca-Sanjua Chem., 2015, 355, 57. ´s-Monerris, D. Roca-Sanjua ´n and M. Mercha ´n, J. Segarra-Martı´, A. France Molecules, 2016, 21, 1666. A. J. Pepino, J. Segarra-Martı´, A. Nenov, R. Improta and M. Garavelli, J. Phys. Chem. Lett., 2017, 8, 1777. A. J. Pepino, J. Segarra-Marti, A. Nenov, I. Rivalta, R. Improta and M. Garavelli, Phys. Chem. Chem. Phys., 2018, 20, 6877. M. Merchan, R. Gonzalez-Luque, T. Climent, L. Serrano-Andres, E. Rodriuguez, M. Reguero and D. Pelaez, J. Phys. Chem. B, 2006, 110, 26471. R. Gonzalez-Luque, T. Climent, I. Gonzalez-Ramirez, M. Merchan and L. Serrano-Andres, J. Chem. Theory Comput., 2010, 6, 2103. ´ndez, A. J. Pepino, J. Segarra-Martı´, J. Jovaisˇaite˙, I. Vaya, L. Martı´nez-Ferna A. Nenov, D. Markovitsi, T. Gustavsson, A. Banyasz, M. Garavelli and R. Improta, J. Am. Chem. Soc., 2017, 139, 7780. D. B. Bucher, B. M. Pilles, T. Carell and W. Zinth, Proc. Natl. Acad. Sci. U. S. A., 2014, 111, 4369. L. M. Nielsen, S. V. Hoffmann and S. B. Nielsen, Photochem. Photobiol. Sci., 2013, 12, 1273. C. Ko and S. Hammes-Schiffer, J. Phys. Chem. Lett., 2013, 4, 2540. D. Roca-Sanjuan, G. Olaso-Gonzalez, I. Gonzalez-Ramirez, L. Serrano-Andres and M. Merchan, J. Am. Chem. Soc., 2008, 130, 10768. L. Blancafort and A. A. Voityuk, J. Chem. Phys., 2014, 140, 95102. Y. Zhang, X.-B. Li, A. M. Fleming, J. Dood, A. A. Beckstead, A. M. Orendt, C. J. Burrows and B. Kohler, J. Am. Chem. Soc., 2016, 138, 7395. K. Rottger, H. J. B. Marroux, M. P. Grubb, P. M. Coulter, H. Bohnke, A. S. Henderson, M. C. Galan, F. Temps, A. J. Orr-Ewing and G. M. Roberts, Angew. Chem., Int. Ed., 2015, 54, 14719. D. B. Bucher, A. Schlueter, T. Carell and W. Zinth, Angew. Chem., Int. Ed., 2014, 53, 11366. ´, J. Phys. Chem. Lett., 2010, 1, 3271. D. Markovitsi, T. Gustavsson and I. Vaya ´, J. Brazard, M. Huix-Rotllant, A. K. Thazhathveetil, F. D. Lewis, I. Vaya T. Gustavsson, I. Burghardt, R. Improta and D. Markovitsi, Chem. – Eur. J., 2016, 22, 4904. M. Huix-Rotllant, J. Brazard, R. Improta, I. Burghardt and D. Markovitsi, J. Phys. Chem. Lett., 2015, 6, 2247. ´ndez, R. Improta and F. Santoro, Theor. Chem. J. Cerezo, L. Martı´nez-Ferna Acc., 2016, 135, 221. ´lez, J. Am. Chem. Soc., C. Rauer, J. J. Nogueira, P. Marquetand and L. Gonza 2016, 138, 15911. J. I. Mendieta-Moreno, D. G. Trabada, J. Mendieta, J. P. Lewis, ´mez-Puertas and J. Ortega, J. Phys. Chem. Lett., 2016, 7, 4391. P. Go W. Lee, G. Kodali, R. J. Stanley and S. Matsika, Chem. – Eur. J., 2016, 22, 11371.

74 | Photochemistry, 2019, 46, 28–77

124

125 126 127 128 129 130 131

132

133

134 135 136 137 138 139 140 141 142 143 144 145 146 147 148

149

˜oz-Losa, A. Banyasz, L. Martinez-Fernandez, T.-M. Ketola, A. Mun L. Esposito, D. Markovitsi and R. Improta, J. Phys. Chem. Lett., 2016, 7, 2020. L. Martinez-Fernandez and R. Improta, Photochem. Photobiol. Sci., 2017, 16, 1277. A. Giussani, I. Conti, A. Nenov and M. Garavelli, Faraday Discuss., 2018, DOI: 10.1039/C7FD00202E. ´rez and L. Serrano-Andre ´s, in Handbook of Computational J. J. Serrano-Pe Chemistry, ed. J. Leszczynski, Springer-Verlag, Berlin, 2012, pp. 483–560. A. Frances-Monerris, J. Segarra-Marti, M. Merchan and D. Roca-Sanjuan, Theor. Chem. Acc., 2016, 135, 31. Y. Zhang, K. de La Harpe, A. A. Beckstead, R. Improta and B. Kohler, J. Am. Chem. Soc., 2015, 137, 7059. L. Martinez-Fernandez and R. Improta, Faraday Discuss., 2018, DOI: 10.1039/C7FD00195A. A. Nenov, J. Segarra-Marti, A. Giussani, I. Conti, I. Rivalta, E. Dumont, V. K. Jaiswal, S. F. Altavilla, S. Mukamel and M. Garavelli, Faraday Discuss., 2015, 177, 345. Q. S. Li, A. Giussani, J. Segarra-Marti, A. Nenov, I. Rivalta, A. A. Voityuk, S. Mukamel, D. Roca-Sanjuan, M. Garavelli and L. Blancafort, Chem. – Eur. J., 2016, 22, 7497. J. Segarra-Marti, V. K. Jaiswal, A. J. Pepino, A. Giussani, A. Nenov, S. Mukamel, M. Garavelli and I. Rivalta, Faraday Discuss., 2018, DOI: 10.1039/C7FD00201G. A. Nenov, A. Giussani, J. Segarra-Marti, V. K. Jaiswal, I. Rivalta, G. Cerullo, S. Mukamel and M. Garavelli, J. Chem. Phys., 2015, 142, 212443. A. Giussani, J. Segarra-Martı´, A. Nenov, I. Rivalta, A. Tolomelli, S. Mukamel and M. Garavelli, Theor. Chem. Acc., 2016, 135, 121. J. Segarra-Martı´, A. J. Pepino, A. Nenov, S. Mukamel, M. Garavelli and I. Rivalta, Theor. Chem. Acc., 2018, 137, 47. B. Epe, Photochem. Photobiol. Sci., 2012, 11, 98. J. Nakamura, E. Mutlu, V. Sharma, L. Collins, W. Bodnar, R. Yu, Y. Lai, B. Moeller, K. Lu and J. Swenberg, DNA Repair, 2014, 19, 3. T. J. Dougherty, C. J. Gomer, B. W. Henderson, G. Jori, D. Kessel, M. Korbelik, J. Moan and Q. Peng, J. Natl. Cancer Inst., 1998, 90, 889. M. C. Cuquerella, V. Lhiaubet-Vallet, J. Cadet and M. A. Miranda, Acc. Chem. Res., 2012, 45, 1558. E. Dumont and A. Monari, J. Phys. Chem. Lett., 2013, 4, 4119. ´n, M. Garavelli, X. Assfeld and E. Dumont, M. Wibowo, D. Roca-Sanjua A. Monari, J. Phys. Chem. Lett., 2015, 6, 576. ´n and M. Marazzi, M. Wibowo, H. Gattuso, E. Dumont, D. Roca-Sanjua A. Monari, Phys. Chem. Chem. Phys., 2016, 18, 7829. H. Gattuso, E. Dumont, C. Chipot, A. Monari and F. Dehez, Phys. Chem. Chem. Phys., 2016, 18, 33180. M. Marazzi, H. Gattuso and A. Monari, Theor. Chem. Acc., 2016, 135, 57. H. Gattuso, V. Besancenot, S. Grandemange, M. Marazzi and A. Monari, Sci. Rep., 2016, 6, 28480. A. Penninks, K. Baert, S. Levorato and M. Binaglia, EFSA J., 2017, 15, 4920. E. Bignon, M. Marazzi, V. Besancenot, H. Gattuso, G. Drouot, C. Morell, L. A. Eriksson, S. Grandemange, E. Dumont and A. Monari, Sci. Rep., 2017, 7, 8885. H. Gattuso, E. Dumont, M. Marazzi and A. Monari, Phys. Chem. Chem. Phys., 2016, 18, 18598. Photochemistry, 2019, 46, 28–77 | 75

150 151 152 153 154

155

156 157 158

159 160 161 162 163 164 165 166 167 168 169 170

171 172 173 174 175 176 177 178 179

˜ iz, M. C. Cuquerella, V. Vendrell-Criado, G. M. Rodrı´guez-Mun V. Lhiaubet-Vallet and M. A. Miranda, Angew. Chem., Int. Ed., 2013, 52, 6476. E. Bignon, H. Gattuso, C. Morell, E. Dumont and A. Monari, Chem. – Eur. J., 2015, 21, 11509. ´lez, Chem. Phys., 2017, S. Mai, M. Richter, P. Marquetand and L. Gonza 482, 9. ´lez, J. Phys. Chem. Lett., 2016, 7, 1978. S. Mai, P. Marquetand and L. Gonza H. Yu, J. A. Sanchez-Rodriguez, M. Pollum, C. E. Crespo-Hernandez, S. Mai, P. Marquetand, L. Gonzalez and S. Ullrich, Phys. Chem. Chem. Phys., 2016, 18, 20168. ´ndez, N. Dunn, P. Marquetand, S. Mai, M. Pollum, L. Martı´nez-Ferna ´ndez and L. Gonza ´lez, Nat. Commun., 2016, I. Corral, C. E. Crespo-Herna 7, 13077. ´lez, ChemPhotoJ. J. Nogueira, M. Meixner, M. Bittermann and L. Gonza Chem, 2017, 1, 178. H. Gattuso, M. Marazzi, F. Dehez and A. Monari, Phys. Chem. Chem. Phys., 2017, 19, 23187. ´n, B.-W. Ding, S. Schramm, R. Berraud-Pache, M. Vacher, I. Fdez Galva ´, Y.-J. Liu, I. Navizet, D. Roca-Sanjua ´n, W. J. Baader and P. Naumov, N. Ferre Roland Lindh, Chem. Rev., 2018, DOI: 10.1021/acs.chemrev.7b00649. L. De Vico, Y.-J. Liu, J. W. Krogh and R. Lindh, J. Phys. Chem. A, 2007, 111, 8013. ´n, F. Zapata and R. Lindh, J. Chem. Theory P. Farahani, D. Roca-Sanjua Comput., 2013, 9, 5404. F. Liu, Y.-J. Liu, L. De Vico and R. Lindh, J. Am. Chem. Soc., 2009, 131, 6181. ´s-Monerris, I. Fdez Galva ´n, R. Lindh and D. Roca-Sanjua ´n, Theor. A. France Chem. Acc., 2017, 136, 70. ´n and R. Lindh, M. Vacher, A. Brakestad, H. O. Karlsson, I. Fdez Galva J. Chem. Theory Comput., 2017, 13, 2448. M. Vacher, P. Farahani, A. Valentini, L. M. Frutos, H. O. Karlsson, I. Fdez ´n and R. Lindh, J. Phys. Chem. Lett., 2017, 8, 3790. Galva W. Adam and W. J. Baader, Angew. Chem., Int. Ed., 1984, 23, 166. ´n and W. J. Baader, RSC Adv., 2017, P. Farahani, M. A. Oliveira, I. Fdez Galva 7, 17462. ´n, J. Comput. Chem., 2015, 36, 1698. M. Stenrup, R. Lindh and I. Fdez Galva ´lez, Chem. Sci., 2017, 8, 1482. J. P. Zobel, J. J. Nogueira and L. Gonza P. Farahani and W. J. Baader, J. Phys. Chem. A, 2017, 121, 1189. ´s-Monerris, I. Fdez Galva ´n, D. Roca-Sanjua ´n, F. A. Augusto, A. France E. L. Bastos, W. J. Baader and R. Lindh, Phys. Chem. Chem. Phys., 2017, 19, 3955. Y.-Y. Cheng and Y.-J. Liu, Photochem. Photobiol., 2016, 92, 552. J.-G. Zhou, S. Yang and Z.-Y. Deng, J. Phys. Chem. B, 2017, 121, 11053. R. Berraud-Pache and I. Navizet, Phys. Chem. Chem. Phys., 2016, 18, 27460. E. Coccia, D. Varsano and L. Guidoni, J. Chem. Theory Comput., 2017, 13, 4357. Y. Noguchi, M. Hiyama, M. Shiga, O. Sugino and H. Akiyama, J. Phys. Chem. B, 2016, 120, 8776. C.-G. Min, Y. Leng, Y.-Q. Zhu, X.-K. Yang, S.-J. Huang and A.-M. Ren, J. Photochem. Photobiol., A, 2017, 336, 115. B.-W. Ding and Y.-L. Liu, J. Am. Chem. Soc., 2017, 139, 1106. Y. Luo and Y.-J. Liu, Chem. – Eur. J., 2016, 22, 16243. ˜es and L. Pinto da Silva, R. F. J. Pereira, C. M. Magalha J. C. G. Esteves da Silva, J. Phys. Chem. B, 2017, 121, 7862.

76 | Photochemistry, 2019, 46, 28–77

180 181 182 183 184 185

M.-Y. Wang and Y.-J. Liu, Photochem. Photobiol., 2017, 93, 511. P. D. Ngo and S. O. Mansoorabadi, ChemPhotoChem, 2017, 1, 383. ˜es and J. C. G. Esteves da Silva, L. Pinto da Silva, C. M. Magalha ChemistrySelect, 2016, 1, 3343. C.-G. Min, P. J. O. Ferreira and L. Pinto da Silva, J. Photochem. Photobiol., B, 2017, 174, 18. C.-G. Min, L. Pinto da Silva, J. C. G. Esteves da Silva, X.-K. Yang, S.-J. Huang, A.-M. Ren and Y.-Q. Zhu, ChemPhysChem, 2017, 18, 117. L. Pinto da Silva, C. M. Magalhaes, D. M. A. Crista and J. C. G. Esteves da Silva, Photochem. Photobiol. Sci., 2017, 16, 897.

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Organic aspects: photochemistry of alkenes, dienes, polyenes (2016–2017) Takashi Tsuno DOI: 10.1039/9781788013598-00078

This review deals with the photochemistry of alkenes, dienes, polyenes, and related compounds through a choice of the literature published during the period January 2016 – December 2017. This chapter also covers the nanotechnology and supramolecular chemistry utilizing isomerization/electrocyclization/cycloaddition reactions of the title compounds.

1

Introduction

The winners of the Nobel prize in chemistry 2016 were Prof. J.-P. Sauvage, Prof. Sir J. F. Stoddart and Prof. B. L. Feringa for the design and synthesis of molecular machines.1–7 Their achievements will be addressed in many parts of this chapter. Especially, the molecular motors, developed by Prof. Feringa and his group, will play a key-role for molecular machines and nanomachines in the future.8 The number of reports regarding addition reactions and functionalization of alkenes and dienes using visible-light photocatalysts9–19 has increased remarkably in recent years. As visible-light sources have been used mainly cheap LED lamps, fluorescent lamps or the sun instead of traditional Hg or Xe lamps. The LED-flow-reactors including photocatalysts have been also developed toward greener synthesis.20–28 In addition, the progress of artificial intelligence (AI)29,30 and internet of things (IoT)31–33 in chemistry and science will be revolutionized during a few decades. What will chemists and scientists do at that time? This review deals with the photochemistry of the title compounds and also covers recent advances in nanotechnology, supramolecular chemistry, and visible-light photocatalysts utilizing isomerization/ electrocyclization/cycloaddition reactions of the title compounds.

2

Photoinduced (E)–(Z) isomerization

2.1 (E)–(Z) Isomerization The photoinduced (E)–(Z) isomerization mechanism and dynamics of stilbene and its derivatives are of great interest as a key-step in photochemistry. Many researchers reported theoretical and spectroscopic studies of the photoinduced (E)–(Z) isomerization mechanism and dynamics of stilbene and its derivatives.34–40

Department of Applied Molecular Chemistry, College of Industrial Technology, Nihon University, Narashino, Chiba 275-8575, Japan. E-mail: [email protected] 78 | Photochemistry, 2019, 46, 78–115  c

The Royal Society of Chemistry 2019

A combination of the Christiansen filter and the photoinduced (E)–(Z) isomerization of stilbene could be used as a phototunable color filter.41 The nanoparticles of the organoboron-bearing stilbene (1) with PS-PEGCOOH were used as a long-term cell tracker with a high fluorescence quantum yield, photostability and low cytotoxicity.42 Photochemistry and photophysics of stilbene-cored dendrimers and their derivatives have been reported by Arai et al.43–46 The photoinduced (E)–(Z) isomerization of stilbene absorbed onto graphene under the exposure to the solar light rendered the energy storage of 0.49 eV.47 Millimeter-size 2D single crystals of (2) were employed as a photo-switchable organic field-effect transistors.48 The (E)-form of (3) under UV-irradiation by the higher absorption ability as compared to the (Z)-isomer enriched the (Z)-isomer.49 The p-cyanostyrylpyridine moiety of the Re complex (4) showed photoswitchable (E)–(Z) isomerization.50 Functionalization of gold particles with supramolecular hosts allowed their plasmon-based photocatalytic activity for (Z)–(E) isomerization of (Z)-4-dimethylaminostilbene to be enhanced.51 ()-Riboflavin acted as a photocatalyst for (Z)-(E) isomerization of 3-phenyl-substituted (Z)-2-alkenenitriles.52

2.2 Stiff-stilbene and molecular motors In 2009, Boulatov et al. reported the photoswitch of a stiff-stilbene bearing a trans-dialkylcyclobutene ring (5).53 Stauch and Dreuw re-investigated the mechanism of the photoswitch using judgement of energy distribution analysis. The analysis suggested that the mechanical Photochemistry, 2019, 46, 78–115 | 79

efficiency of stiff-stilbene and the mechanochemical susceptibility of cyclobutene were much too low to explain the experimentally observed enhancement of the bond dissociation upon the (Z)–(E) photoisomerization of stiff-stilbene.54,55 Boulatov et al. made a quick response to their paper.56 The photoswitch of stiff-stilbene with chiral binaphthyl moieties (6) showed good reversibility under alternative UV irradiation.57 The (Z)-form (7) bearing an urea moiety acted as an anion receptor for anions such as OAc and H2PO4. The (E)–(Z) isomerization of (7) showed a photoswitching system for their anion receptors.58 The (P,Z)and (M,Z)-forms (8) acted as chiral receptors for the recognition of the binol phosphate anion (9).59 The stiff-stilbene (10) bearing alkyl chains on urea substituents exhibited reversible gel–sol photoswitching in aromatic hydrocarbon solvents.60 The photoisomerization of the stiffstilbenes (11)61 and (12)62 as guest molecules with pillar[5]arene as a host molecule could be controlled by host–guest interactions. Feringa et al. isolated separately enantiopure stiff-stilbenes (13) in their (R,R,Z)and (S,S,Z)-forms through supramolecular complex formation with N-benzylcinchonidinium chloride.63 A transfer of chirality from the molecular motor of the chiral dicarboxylic acid (14) to a dynamic helical polymer was found.64 The bis[3.3.3]propellane (15) underwent (E)–(Z) isomerization under UV irradiation in benzene to give an equilibrium mixture of (E) : (Z) ¼ 55 : 45, but under UV irradiation in the presence of I2 and propylene oxide, the oxidative photoinduced electrocyclization of the (Z)-isomer took place to afford the compound (16).65

The motions of the molecular motors extremely fascinate scientists.8,66–69 Computational studies of the molecular motors were reported.70–72 The compound (17) is well-known as the basic molecular motor. The rotation mechanism has been investigated well, but some excited dynamics including the dark state, are still not opened. The dark state has been discussed by using spectroscopic and computational methods.73–76 The rotation speed of (18) coordinated three metal (Zn, Pd and Pt) dichloride were investigated. The rotation speed could be controlled by the metal species.77 The key-step of the molecular motor (19) in 50 different solvents and solvent mixture was discussed.78 Chiral (2S,3S)(20) and (21) were prepared using (S)-1-naphthylethanol and their photochemical and subsequent thermal isomerization was examined.79 Statistical analysis suggested that the solvent parameters govern the isomerization process of the molecular motors. The molecular motor (22) translated light-driven unidirectional rotary motion to controlled movement of a connected biaryl rotor.80 Fluorine-substituted molecular motors including (23) were developed. Due to the fluorine atom the activation 80 | Photochemistry, 2019, 46, 78–115

barrier for the thermal helix inversion was higher than the barrier for backward thermal (E)–(Z) isomerization.81 The SH group of the lightdriven molecular motor (24) picked up an acetyl group from one side of the lower stator, and the acetyl group was transferred to the amino group after the photoinduced (E)–(Z) isomerization (24)-(25)-(26)-(27).82

HS AcO

AcS O

CH2NH2

HO

O

CH2NH2

(25)

(24)

hν

SH O

HO

(27)

SAc CH2NHAc

O

HO

CH2NH2

(26)

Photochemistry, 2019, 46, 78–115 | 81

The molecular motors with the larger volume substituents such as poly(phenylethnylene) groups exhibited the highest photochemical cross sections.83 The sequential occupation of the molecular motor rotation on a quartz surface during a UV and heat-induced cycle was imaged in realtime using defocused wide-field imaging technique.84 A novel unidirectional light-driven molecular motor suitable for a host–guest surface inclusion complex with tris(o-phenylene)cyclo-triphosphazene was prepared. This system could provide a versatile way to 2D surface confinement by precise molecular driven.85 The molecular motor (28) with an extended aromatic core allowed the photoinduced isomerization with visible light up to 490 nm.86 The photoinduced (E)–(Z) isomerization of (29) exhibited dynamic control of the catalytic activity of the Michael addition of 2-cyclopentenone with 3-phenylpropanal.87 The amphiphilic molecular motor (30) underwent responsive aggregation in water by alternate UV and thermal isomerization steps.88 Molecular motors have been applied to some molecular machines. The molecular motors (31) and (32) could act as an engine of a nanocar89 or cell membrane opener.90 Some new molecular switches via the photoinduced (E)–(Z) isomerization were also developed.91–96 The compound (33) bearing an amino group showed weakly photoactivity in the absence of acids, while protonation increased the quantum yields for the isomerization.91

3

Electrocyclization

3.1 Helicenes Martinetti et al. reported a review on the catalytic uses of chiral phosphorus compounds characterized by a helical scaffold as the key stereogenic element of their structures.97 Iodine and ethylene oxide are generally used as oxidants for dihydrophenanthrenes, which are derived from the photoinduced electrocyclization of (Z)-stilbene. Matsushima et al. developed the air-driven KI-mediated oxidative photoinduced electrocyclization of stilbene derivatives as a novel method.98 The fused p-system aromatics have characteristic physical properties. They can be readily prepared by the oxidative photoinduced electrocyclization of diarylethenes. Several diphenanthrylethene derivatives were prepared and their oxidative photoinduced electrocyclization led to fused p-system 82 | Photochemistry, 2019, 46, 78–115

aromatics with seven benzene rings.99 The triene (34) underwent oxidative photoinduced electrocyclization to give a three-bladed propeller-shaped triple [5]helicene.100 The oxidative photoinduced electrocyclization of the corannulene-phenylethene (35) afforded extended corannulene drivatives.101 The oxidative photoinduced electrocyclization of the compound (36) afforded dibenz[a,h]anthracene in 77% yield. Scholl reaction of dibenz[a,h]anthracene with AlCl3 at room temperature gave liquid-crystalline benzo[ghi]perylene diimde.102 The racemic hexahelicene with a nitrile group was prepared by the oxidative photoinduced electrocyclization of (37) in the presence of I2 in THF. The (P)and (M)-enantiomers were isolated separately by HPLC on a chiral stationary phase.103 Sequentially performed Wittig reactions and the oxidative photoinduced electrocyclization by continuous flow reactors was developed by Okamoto et al. Various phenacene derivatives have been readily prepared by the flow reactor method.104 Phenanthrene derivatives, obtained by the oxidative photoinduced electrocyclization of stilbenes, were studied for anticancer properties against human colon and epithelial cancer cell lines. The compound (38) showed potency with good IC50 values.105 The oxidative photoinduced electrocyclization of the biphenyl based tetraenes (39) and (41) led to no-planar oligoarylene macrocycles (40) and (42) in moderate yields.106 Heterohelicenes have been expected to have potential applications.97,107,108 Novel heterohelicene derivatives were prepared by the oxidative photoinduced electrocyclization of heterodiarylethenes.109–122

3.2 Dithienylethene and derivatives The photochromism of dithienylethene and its derivatives leads to extremely fascinating photoswitches, optical memories, and actuators in molecular devices and nanotechnology.123–129 Many researchers reported on the photochromic mechanism of dithienylethene derivatives by DFT and/or spectroscopic techniques.130–142 Although the centre part of Photochemistry, 2019, 46, 78–115 | 83

photochromic dithienylethenes is generally a perfluorocyclopentene ring or cyclopentene ring, photochromism of dithienylethenes and diarylethenes with a new centre part have been recently investigated.143–161 Shirinian et al. prepared novel photochromic dithienylethenes and diarylethenes which possessed a cyclohexene ring, cycloalkenone ring, and furan-2(5H)-one ring as the centre part and reported their photochromism.143–147 An increase in ring size of cycloalkenones showed a hypsochromic shift of the absorption maximum of the closed form. The intramolecular hydrogen bond of (43) increased the quantum yield of the photocyclization.143 Hollow crystals of the diarylethene (44) with a perfluorocyclohexene ring as the centre part showed photosilent phenomena by UV irradiation, i.e., the crystal was bending at the UV-irradiated part.148,149 Such photosilent phenomena of the diarylethenes show a trend in single-crystal-to-single-crystal phase transitions.162–165 The ringclose isomer of the dithienyl p-benzoquinone (45) could be utilized for the visible-light-driven oxidation reaction.150 The acenaphthylene (46) bearing two thienyl groups did not show photochromism. However (46) readily underwent a tandem addition of a nucleophile and an electrophile to afford (47). The resulting (47) showed photochromic behaviour.151

The formyl-substituted dithienylethene (48) acted as a light-active sensitive probe for primary and secondary amines.166 Multi-addressing photoswitches of the diarylethene derivatives by metal ions [Mg(II),167 Ca(II),167 Al(III),168–178 Cr(III),178 Fe(III),178–180 Cu(II),181–189 175–177,190–200 197,198,201–203 187 204 Zn(II), Cd(II), Sn(II), and Hg(II) ], anions [F,186,192,199,205 I,206 CN174,206], pH control,168–170,207–216 amino acid 84 | Photochemistry, 2019, 46, 78–115

[cysteine],180,205 and PhSH217 have been developed. Especially Pu and his group made contributions to this area and also prepared many novel diarylethene derivatives.218–229 Of course, other groups have also prepared new diarylethenes and examined their photochromism.230–238

Photoresponsible switches of diarylethenes bearing organometallic moieties239–248 or coordinated metals249–258 including MOFs123–126,259–261 have been widely studied. The carbene ruthenium complexes (49) and (50) acted as a photoswitchable olefin metathesis catalysts. (Z,Z)-1,4Cyclooctadiene was polymerized by metathesis with the open form of (49), while diethyl diallylmalonate underwent metathesis with the closed form of (50) to afford the ring-closed form.239 The bimetallic complex (51) showed high cytotoxic potential for various cell lines, but did not undergo photoinduced electrocyclization by UV irradiation.248 The dithienylethene derivatives coordinated iron,249,250 manganese,251 or lanthanide ions252 are expected to be magneto-optical molecular devices. For example, the dithienylethene (52), containing bis(pyrazolylpyridyl) ligand parts, reacted with Fe(ClO4)2 to yield the supramolecular helicate [Fe2(52)3](ClO4)4 as orange crystals. The helicate [Fe2(52)3](ClO4)4 showed spin crossover in the solid state and in the solution.250 The dithienylethene (53) reacted with CuX2 (X ¼ OAc or NO3) in pyridine to afford two different one-dimensional polymers, [Cu(53)(py)3]2py and [Cu(53)(py)3]2H2O  0.5Et2O, whose supramolecular organization significantly differed in the crystal lattice. [Cu(53)(py)3]2py showed reversible solid state photochromism, whereas this process was hampered for [Cu(53)(py)3]2H2O  0.5Et2O.256 The reaction of the close-form of (54) with [Pd(NCMe)4]2BF4 yielded a rhombicuboctahedral sphere (6.4 nm) of [Pd24(close-54)48]. The rhombicuboctahedral sphere [Pd24(close-54)48] upon 617 nm irradiation immediately afforded a tentative sphere [Pd24(open-54)48]. The tentative sphere slowly underwent decomposition to give an equilibrium mixture of assemblies of [Pd3(open-54)6] and [Pd4(open-54)8].257 The dithienylethene (55) reacted with Zn(II) to yield a bistable MOF. The pore size of the MOF Photochemistry, 2019, 46, 78–115 | 85

could be changed by photoswitching without structural damage of the framework.258

The photoswitching of dithienylethenes on solid surfaces or metal nanoparticles has been widely applied as optoelectronic devices.262–276 A bifunctional organic thin-film transistor with the dithienylethene (56) resulted in a flexible non-volatile optical memory device with over 256 distinct current levels.262 The photoswitching of dithienylethenes exhibited superwater-repellency.277,278 A double roughness structure with the dithienylethene (57) microcrystalline surface was reversibly controlled by UV and visible irradiation and the photoswitching showed a water-droplet-bouncing phenomenon. This result supported the origin of self-cleaning on a lotus leaf.278 Photoswitches of the dithienylethenes have been widely investigated in life sciences and supramolecular chemistry.279–304 Several dithienylethenes, bearing a tetraphenylethylene moiety, were prepared and showed photoswitchable aggregation-induced emissions.279–281 A supramolecular assembly was constructed with the [Ru(bpy)3]21 complex bearing two crown ethers as the host moieties and the dithienylethene bonding two dialkylammomiun ions as the guest moieties, which could ¨rster resonswitch on/off the luminescence of [Ru(bpy)3]21 by a high Fo ance energy transfer efficiency (FRET) and photoisomerization of the dithienylethene.284 Such FRTE studies using photoswitchable dithienylethenes were also reported.285,286,297,305 Dithienylethene-bonded permethyl-b-cyclodextrins/porphyrins285 or borondipyrromethene287 could be applied to control singlet oxygen generation in aqueous solution. This controllable technique has potential for photodynamic therapy. Ulrich’s group designed a photodynamic therapy using the photoswitching of the dithienylethene (58). Second generation photoswitchable peptidomimetics exhibited the practical possibility of 86 | Photochemistry, 2019, 46, 78–115

cytotoxicity by photoregulation in vitro. The open-form (58) had about 8.0-fold higher cytotoxicity than the close-form.293 The close-form of the dithiazolylethene (59) with 436 nm irradiation showed a good cytotoxicity for Madin-Darby canine kidney cells, while the open-form with 436 nm irradiation or the close-form with 546 nm irradiation was not lethal. The dithiazolylethene (59) intercalated between DNA base pairs. The open-form (59) was released from DNA, but the photocytotoxicity was characterized by a large charge transfer in the DNA to the close-form direction.294 The photoswitching of dithienylethenes was applied for bioimaging of liposomes,290,291 mitochondria,292 or cells.295–297 The PEGylated perylenemonoimide-dithienylethene (60) could be observed under super-resolution fluorescent microscopy with an optical resolution of 30 nm for liposomes.290 The similar photochrom (61), bearing hydrophilic and mitochondria-targeted polymers, acted as superresolution MitoTrakers with sub-30 nm spatial resolution.292 Upon UV irradiation, the dithienylethene (62) incorporated in human serum albumin underwent enantioselective cycloaddition to give the close-form in over 99ee%.296 The photochromism of the dithienylethene, bearing peptide chains, was investigated for the flexibility and rigidity of the structure of lipid membranes. The open- and close-forms could influence the conformation of the adjacent residues when incorporated into the ¨nig et al. reported that the photobackbone of a linear peptide.299 Ko chromism of dithienylethenes and fulgimides was controllable by histone deacetylase inhibitors.302 Fatigue-resistance photoswitches of dithienylethenes, bearing deazaadenosine303 or natural deoxyadenosine,304 were developed. Many photoswitches of diarylethenes bearing polymer chains or of diarylethenes in polymers were synthesized and their photochromic properties were reported.306–318 Polymer micelles including 9,10diphenylanthracene as a fluorescence resonance energy transfer donor and (63) as an acceptor photoswitch showed that the color of the emitted fluorescence was continuously changed from blue to yellow by photoisomerization of (63).306 Dithienylethene/ionic liquid/cellulose paper was developed, which exhibited vivid coloration/decoloration upon UV/visible irradiation.307 The photochromic diarylethene (64) underwent retroDiels–Alder reaction at 130 1C, but not the close-form. Such differences are expected to be applicable to stimuli-regulatable polymer recycling and polymer mechanochemistry.308 The reaction of dithienylethene (65) with amino-functionalized polysilane chains led to photochromic rubbery materials with viscoelasticity. The rubbery materials had reversible self-healing properties by UV/visible irradiation.316 A dithienylethene-graphene composite film acted as photoswitchable micro-supercapacitor.318 The photochromic properties of diarylethenes in single crystals or in the solid state were widely investigated.128,148,162–164,203,205,220,221,223,225,226,233,319–323 The photochromic behavior of (66) in the crystal under application of shear stress was reported. The application of shear stress allowed the non-photochromic crystal (66) to undergo photochromism.319 Because the photocyclization Photochemistry, 2019, 46, 78–115 | 87

of (67) upon UV irradiation generated a large strain in the rigid crystalline phase, the crystal underwent photoinduced explosive fragmentation accompanied by a color change from colorless to blue.320

4 Photoinduced addition Photochemical [2 þ 2] cycloaddition is a very useful organic synthetic tool. In 2016, Chemical Reviews focused on photochemical [2 þ 2] cycloaddition by publishing several reviews.9,324,325 The photochemical [2 þ 2] cycloaddition was applied to the synthesis of natural products such as solanoeclepin A,326 aplydactone,327 8-epi-isoaplydactone,328 phenalinolactone,329 and xylopiana A.330 Mykhailiuk et al. developed a multigram two-step approach to substituted 3-azabicyclo[3.2.0]heptane derivatives from benzaldehyde, allylamine, and cinnamic acid as starting materials. This method is expected to be applicable to drug synthesis.331 In addition, using incandescent floodlights, a gram-scale synthesis for photochemical [2 þ 2] cycloaddition of (E)-cinnamic acid was developed.332

Styrylpyrenes in the context of a DNA duplex upon visible irradiation underwent photochemical [2 þ 2] cycloaddition to yield the cross-linked duplex. This duplex was converted into the uncross-linked single strands 88 | Photochemistry, 2019, 46, 78–115

by UV-irradiation.333 DNA three-way junctions, bearing 4-methoxybenzophenone and 4-methylbenzophenone as C-nucleosides at the hydrophobic binding pocket, acted as aptamers and chiral photoDNAzymes. Upon 369 nm LED irradiation, 4-(3-butenoxy)quinolinone underwent regioselective and enantioselective intramolecular [2 þ 2] cycloaddition.334 Cyanostilbene liquid crystals (68) and (69) in their mesophases provided two different routes for polarization light-driven modulation. The stilbene (68) underwent photoinduced (E)–(Z) isomerization, while slow intermolecular [2 þ 2] cycloaddition of (69) was found. The resulting [2 þ 2] cycloadducts readily underwent retrocycloaddition above 240 1C.335 N

N N

R (72) R = 3-pyridyl (75) R = 4-pyridyl (78) R = C6H4F-o

N

N N

N

N

(73)

N

(74)

N

N

N H

(79)

N

R1

N N

N

N H

R2

Cl(76) R1 = COOH, R2 = H (77) R1 = H, R2 = COOH

(80)

N HN

N

CH2

N O

2

N (82)

(81) R1 N

N

MeO

N

COOEt

N

R2 (83) R1 = Me, R2 = H

X-

Et MeO

N

N Se (86) X = I, I3, or TsO

(85)

(84) R1 = H, R2 = Me O N

F

MeOOC

COOCH2CH2Br

MeOOC

COOMe

NH N H (87)

O

N (88)

(89)

Photochemical [2 þ 2] cycloaddition of supramolecular complexes of (18-crown-6)styryl dyes with alkylammonium chains336,337 and of (15-crown-5)styryl dyes with the Ba21 ion338 was reported. The styryl dye (70) underwent photochemical [2 þ 2] cycloaddition in the crystal and in aqueous solution in the presence of cucurbit[8]uril to give a syn-head-totail adduct. The topochemistry of the photochemical [2 þ 2] cycloaddition of the host–guest complex of the styryl dye (70) with cucurbit[8]urils Photochemistry, 2019, 46, 78–115 | 89

was investigated by fluorescence upconversion techniques.339 The bis(styrylbenzoquinoline) (71) upon UV irradiation resulted in stereospecific intramolecular [2 þ 2] cycloaddition to yield the rctt-cycloadduct.122 Photochemical [2 þ 2] cycloaddition of diarylethenes in the solid state including MOFs128,129 and hydrogen-bonded organic frameworks (HOF) is a high-performance tools for green-sustainable chemistry and for crystal engineering.324 Unsymmetrical dipyridylethene (72) reacted with AgNO3 and 1,4-naphthalenedicarboxylic acid (1,4-H2ndc) to give a onedimensional zigzag coordination polymer, {[Ag(1,4-ndc)(72)2]  2H2O}n, while the reaction with Zn(NO3)2 led to a diamond framework, {[Zn(1,4-ndc)(72)]2  H2O}n. The head-to-head and head-to-tail cyclobutanes (73) and (74) were obtained from the solid state photocycloaddition of {[Ag(1,4-ndc)(72)2]  2H2O}n and {[Zn(1,4-ndc)(72)]2  H2O}n, respectively.340 Three dimension photoresponsible porous magnetic material, {[Co3(75)3  4H2O][Cr(CN)6  2(75)  2EtOH  2H2O]}, was prepared by the reaction of (75), Co(NO3)2 and K3[Cr(CN)6] in a mixture of EtOH/H2O. The guest (75) in the 3D material allowed photoinduced postsynthetic modification of the pore surface via [2 þ 2] cycloaddition. The resulting 3D MOF including [2 þ 2] cycloadducts introduced enhanced CO2 selectively over that of N2.341 Solid state photochemical [2 þ 2] cycloaddition of [{Zn(75)2  3H2O}2(75)]4NO3  3(75)  14H2O was also reported.342 The reaction of the pyridinium chloride (76) with Zn(NO3)2 in DMF afforded a 2D MOF with rare clockwise and anti-clockwise spiral nanotubular channels arranged alternately in the structure. The photochemical [2 þ 2] cycloaddition of the 2D MOF could be triggered to undergo structural transformation from 2D to 3D. This structural transformation could be applicable to separate ethanol and water.343 UV irradiation of the complex, [CdCl2(77)]  3.5H2O, in the solid state induced [2 þ 2] cycloaddition in 100% yield. The cycloadduct underwent isomerization into the unusual rcct-isomer by recrystallization.344 Crystals of the complex, [Zn(NCS)2(78)2]  DMF were photosilent, i.e., the complex underwent photochemical [2 þ 2] cycloaddition, whose crystals were popping under UV irradiation.345 Coordination polymers of (79)–(81) were prepared and their photochemical [2 þ 2] cycloadditions were investigated.346,347 Crystallization of the complex, [Zn{H(82)}Cl3], led to large-size hollow hexagonal tubular crystals. A stereoselective photochemical [2 þ 2] cycloaddition of [Zn{H(82)}Cl3] was found, whereas its methyl blue-coated crystals did not respond to UV irradiation.348 McGillivray et al. reported template effects for the photochemical [2 þ 2] cycloaddition of metal complexes and hydrogen bond-based templates of (83) and (84). The hydrogen bond-based templates of (83) or (84) with resorcinol derivatives were photostable, whereas the Ag complexes underwent stereoselective photochemical [2 þ 2] cycloaddition.349 The hydrogen bond-based templates of (75) with sulfuric acid350 or 1,2,4,5-tetrabromobenzene351 also underwent photochemical [2 þ 2] cycloaddition. In addition, the hydrogen bond-based templates of (75) with sulfuric acid had a 2D-hydrogen bonded network, transformed into a 3D HOF by heating at 50 1C.350 The hydrogen-bonded cocrystals of the diene (85) with 5-methoxyresorsinol led to the intermolecular [2 þ 2] 90 | Photochemistry, 2019, 46, 78–115

cycloadduct upon 313.5 nm irradiation, whereas irradiation without an optical filter afforded the cyclooctadiene dimer.352 The styrylbenzoselenazoles (86) with iodide, triiodine, or the tosylate anion were prepared. Their crystal packing was favorable for photochemical [2 þ 2] cycloaddition.353 5-Fluorouracil (87) is well-known as the anticancer drug. An 1 : 1 mixture of (87) and bis(2,2-pyridylethene) (88) in methanol gave colorless plate-like cocrystals. The cocrystals upon UV irradiation underwent quantitative photochemical [2 þ 2] cross-cycloaddition.354 Unsymmetrical p-quinodimethane (89) underwent topochemical [6 þ 6] photocycloaddition via single-crystal-to-single-crystal to yield a bridgesubstituted [2.2]paracyclophane.355 2D polymer crystals of (90) having a biphenyl core were prepared by crystallization of a saturated solution in methanol/acetonitrile. The 2D polymer upon LED irradiation underwent topochemical [2 þ 2] cycloaddition to give the 2D polymer.356 But O But But N

O But

N (91)

3BF4But O But

(90)

The aggregation state of supramolecular assemblies constructed with calixarene incorporating stilbene moieties could be tuned by heating and photochemical [2 þ 2] cycloaddition.357 The molecular assemblies consisted of different layers of redox-active Ru or Os complexes with redoxinactive spacers, (91) and PdCl2. The photochemical [2 þ 2] cycloaddition of the spacer (91) in the assemblies increased chemical and electron permeability.358 R Mes

COOH Br

N R

N

MeO

N

NH O

(96)

I

I

R

COO-

Cl (97) R = C

O-

O

O

R

I

I

R

N S

Me

(94) R = Bu (95) R = CH2CONH(CH2)3Si(OEt)MCM-41

Br

(93)

N O

O

O

(91) R = Me, X = ClO4(92) R = Ph, X = BF4O

O

O

Br

HO

X-

MeO

2Na+

C Cl N

N S

Cl Cl (98)

Photochemistry, 2019, 46, 78–115 | 91

5

Photocatalysts

5.1 Metal-free photocatalysts Recently, functionalization of alkenes, dienes, and polyenes using visible-light redox photocatalysts aroused much attention in organic chemistry. Some reviews regarding this area were published.9–19 This method can employ greener light sources as LED lamps, fluorescent lamps or the sunlight instead of Hg or Xe lamps. In addition, from the back ground of green and sustainable chemistry, metal-free photoreactions using organic photocatalysts (91)–(103)359–386 have advantages. 9-Mesityl-10-methylacridinium perchlorate (91) which is known as the Fukuzumi catalyst, acted as a good visible-light photocatalyst for hydration (Path I),359 alkylation (Path II),360 decarboxylative Giese-type reaction (Path III),361 oxo-acyloxylation (Path IV),362 trifluoromethylation (Path V),363 and oxidative [4 þ 2] cycloaddition (Path VI).364 Upon blue LED irradiation, p-methoxystyrene in the presence of (92) as a photocatalyst and PhSSPh as a hydrogen transfer catalyst underwent intermolecular [4 þ 2] cycloaddition to give tetrahydronaphthalene in 77% yield (Path VII).365 Eosin Y (93) is also a green light photoredoxcatalyst for cross-coupling of diazonium salts (Path VIII),366 sulfonylation (Path IX),367 oxosulfonylation (Path X),368 decarboxylative alkylation (Path XI),369 and trifluoromethylation (Path XII).370,371 Intramolecular [2 þ 2] cycloaddition of nitrogen- or sulfur-containing dienes mediated by flavin (94) and visible light irradiation was reported (Path XIII).372 In addition, flavin (95) immobilized on mesoporous silica was developed as a heterogeneous visible light photocatalyst for intramolecular [2 þ 2] cycloaddition of dienes (Path XIV).373 The thiothanthone (96) having a chiral building block acted as an enantioselective visible-light photocatalyst for the intermolecular [2 þ 2] cycloaddition of electron-deficient alkenes with 2(1H)-quinolones. Solar irradiation of 1-penten-3-one with 2(1H)-quinolones led to a cyclobutane in 86%ee yield (Path XV).374 The cross-linked poly(benzothiodiazole) network (97) was prepared by Sonogashira–Hagihara cross-coupling, which was a good homogeneous visible-light photocatalysts for regioselective and stereoselective [2 þ 2]

92 | Photochemistry, 2019, 46, 78–115

cycloaddition of styrene derivatives (Path XVI).375 Rose Bengal (98) also acted as a visible-light photocatalysts for the intermolecular [2 þ 2] cycloaddition of 3-ylideneoxindoles (Path XVII).376

Fluoroalkylations using visible-light metal-free photocatalysts have been developed (Paths V, XII, XVIII–XXI). A Hantzsch ester (99) was employed by the photoreductive hydrofluoroacetamidation for alkenes with 2-bromo-2,2-difluoro-N-phenylacetamide (Path XVIII).377 Blue LED irradiation of styrene derivatives in the presence of an S-(difluoromethyl)sulfonium reagent and perylene (100) as a photocatalyst in acetonitrile afforded N-(3,3-difluoro-1-phenylpropyl)acetamide in good yields (Path XIX).378 Trifluoroalkylated alkenes (Path XX) and trifluoromethylated iodoalkanes (Path XXI) were selectively prepared by controlling the reaction conditions of the Niel red (101) visible-light photocatalyst.379 The cyanamide-functionalized carbon–nitride (102) was a good visible-light heterogeneous photocatalyst for sulfonylation of alkenes with sulfinate salts (Path XXII).380 Benzophenone and its derivatives were used as photocatalysts for substitution of vinyl sulfones (Path XXIII)381 and for addition of alkenes (Paths XXV–XXVII).382–385

Photochemistry, 2019, 46, 78–115 | 93

Non-acidic C(sp3)–H bonds of cycloalkanes or heterocycloalkenes in dichloromethane were readily abstracted by 2-chloroanthraquinone (103) upon 365 nm irradiation to give radical species. The resulting radical species reacted with 1,1-bis(phenylsulfonyl)ethene with alkanes to give adducts.386

94 | Photochemistry, 2019, 46, 78–115

N-Halosaccharins (104) acted effectively in the visible-light promoted intermolecular haloamination and haloetherification of alkenes.387

5.2 Visible-light metal photocatalysts Photoreactions of alkenes using visible-light metal photocatalysts are recently making remarkable progress.9–19 It is well known that the Ir and Ru complexes, Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir(ppy)2(dtbbpy)PF6, [Ir(ppy)2(bpy)]PF6, fac-Ir(ppy)3, and [Ru(bpy)3]2X are typical visiblelight metal photocatalysts. In addition, other useful visible-light metal photocatalysts have been developed. Radical conjugated addition of electron deficient alkenes and alkylidenemalonates, upon blue LED irradiation in the presence of a catalytic amount of Ir[dF(CF3)ppy]2(dtbbpy)PF6, led to the adducts in good yields (Paths XXVIII388 and XXIX389). The conjugated addition of a-amino radicals to 2-pyridylstyrenes was achieved by the combination of Brønsted acid and visible-light metal photocatalyst, Ir[dF(CF3)ppy]2(dtbbpy)PF6 (Path XXX).390 Fluoroalkyl substituents have attracted increasing attention due to the specific effects of the fluorine atoms on physical and biological properties. Many fluoro-substituted chemicals were prepared by visible-light metal photocatalytic reaction of alkenes (Paths XXXI– XLIX)391–409 with several fluoroalkyl sources under optimal conditions. Although decarboxylative difluoroacetylation of cinnamic acid with ICF2COOEt was achieved by merging a photocatalyst, Ru(bpy)3Cl2 and a copper catalyst, [Cu(NCMe)4]PF6 (Path XLVI).406 The platinum(II) complex (105) acted as a good visible-light photocatalyst for the difluoroacetylation (Path XLVII).407 Upon blue LED irradiation, a mixture of a-trifluoromethylalkenes with a-keto acids in the presence of Ir[dF(CF3)ppy]2(dtbbpy)PF6 as the photocatalyst and LiOH as a base in DMSO afforded gem-difluoroalkenes in good yields (Path XLVIII).408 When N-Boc-substituted a-amino acids were used as the decarboxylative reagents instead of the a-keto acids, 1,1-difluorohomoallyic amines were obtained.408 a-Trifluoromethylalkenes also underwent visible-light induced [3 þ 3] annulation with tertiary amines using Ir(dmppy)2(dtbbpy)PF6 to yield 3-fluorotetrahydropyridine (Path XLIX).409

Photochemistry, 2019, 46, 78–115 | 95

N-Phenyl-substituted amino acids underwent visible-light photocatalyzed decarboxylative addition with 2-cyclohexenone (Path L).410 Tetrabutylammonium decatungstate acted as a photocatalyst for the decarboxylative addition of electron-deficient alkenes with arylacetic acids, but the irradiation source was a UV-lamp (Path LI).411 Styrene underwent visible-light photocatalyzed hydroacylation with benzoic acid by blue LED irradiation in the presence of tris(trimethylsilyl)silane (Path LII).412 Visible-light metal photocatalytic dual functionalization of alkenes were reported.413,414 Dual functionalization took place in a mixture of methyl acrylate and t-butyldimethyl((1-phenylvinyl)oxysilane) as electron-deficient and electron-rich partners and benzoic acid as the acyl radical precursor in the presence of the fac-Ir(ppy)3 photocatalyst to yield methyl 1,1-dibenzoylacetate in 94% yield (Path LIII).413 White LED irradiation of a mixture of styrene and 2,2,2-trichloroethoxy 96 | Photochemistry, 2019, 46, 78–115

p-cyanobenzoyloxycarbamate in the presence of fac-Ir(ppy)3 in acetonitrile afforded the diamidation product in 67% yield (Path LIV).414 The hydroamination of unactivated alkenes with secondary alkyl amines was developed (Path LV). Several visible-light Ir photocatalysts were examined and a combination of Ir[dF(Me)ppy]2(dtbbpy)PF6 as the photocatalyst and 10 mol% 2,4,5-triisopropylbenzenethiol gave the best result.415

As shown in reaction Paths XXXIX,399 XL,400 XLIX,409 LVI–LXIV,416–424 many heterocyclic compounds were prepared by intermolecular cycloaddition or intramolecular cyclization using visible-light photocatalysts. The dual Au and photoredox-catalyzed difunctionalization mechanism was Photochemistry, 2019, 46, 78–115 | 97

investigated by DFT calculation (Path LXIV). The calculation suggested that the favored Au catalytic cycle was the sequence of radical addition, single electron transfer, coordination, cyclization and reductive elimination.424 Methyl N-phthalimidoyl oxalate generated the methoxycarbonyl radical by visible-light photocatalyst, Ru(bpy)32PF6 and (99). The methoxycarbonyl radical readily trapped with electron-deficient alkenes to give adducts (Path LXV).425 Upon blue LED irradiation, 1-methylstyrene in the presence of fac-Ir(ppy)3 underwent hydroxysulfonylation with p-nitrobenzenesulfonylchloride (Path LXVI),426 while oxidative sulfonylation of alkenes using the Ir(ppy)2(dtbbpy)PF6 photocatalyst was found (Path LXVII).427

A synergistic combination of the gold catalyst, PriAuCl, and the photocatalyst, Ru(bpy)3Cl2, achieved that both the CF3S group and the PhSO2 group were regioselectively introduced into alkenes (Path LXVIII).428 A combination of the selenium catalyst, (PhSe)2, and the photocatalyst (106) under air resulted in oxidative allyic esterification of alkenes (Path LXIX).429 Visible-light mediated photocatalytic reactions using palladium catalysts were also reported (Paths LXX430 and LXXI431). Novel visible-light photocatalyzed cyclopropanations were reported (Paths LXXII432 and LXXIII433). In Path LXXII, the formation of the iodomethyl radical carbenoid ICH2  in the photoredox-catalyzed cycle was suggested.432 Cr(Ph2Phen)33BF4 was a better visible-light photocatalyst for the diazo-based cyclopropanation of electron-rich alkenes than the ruthenium complexes, Ru(bpy)32PF6 and Ru(bpz)32PF6.433 98 | Photochemistry, 2019, 46, 78–115

The visible-light photocatalyzed hydrocarboxylation of alkenes with CO2 was achieved by the combined use of [Rh{P(C6H4CF3-p)3}2Cl]2 and Ru(bpy)32PF6 (Path LXXIV).434 The UV light/3,6-Ph2xanthen-9-one/ Cu(IPr)2Cl system was used for the carboxylation of cyclohexene at the 3-position with CO2 (Path LXXV).435 Green LED irradiation of Nphenylmaleimide with N,N-dimethylaniline in the presence of the visiblelight photocatalyst, Cu(dap)2Cl led to a tetrahydroquinoline in 77% yield (Path LXXVI).436 Co(dmg)2(py)Pri acted as a visible-light photocatalyst for the regioselective coupling reaction of alkenes with an epoxy group (Path LXXVII).437 A combination of Co(dmg)2(py)Cl and (91) upon blue LED irradiation allowed the photocatalytic anti-Markovnikov oxidation of b-alkyl-substituted styrenes with water (Path LXXVIII).438 The visible-light photocatalyzed hydrophosphination of alkenes with diphenylphosphine using [CpFe(CO)2]2 was developed. Although the hydrophoshination of styrene afforded the adduct in a low yield, styrenes with methyl, trifluoromethyl, or methoxy groups as the substituents on the phenyl ring gave the adducts in excellent yields (Path LXXIX).439 The regioselective intramolecular [2 þ 2] cycloaddition of cinnamates to cyclobutanes was achieved by using Ir[dF(CF3)ppy2]2(dtbbpy)PF2 as the visible-light photocatalyst (Path LXXX).440 Yoon et al. reported the visiblelight photocatalyzed intermolecular [2 þ 2] cycloadditions of alkenes (Path LXXXI)441 and of alkenes with butadienes (Path LXXXII).442 When the photocatalyst, chiral ligand and Lewis acid Ru(bpy)32PF6, (S,S)ButPyBox and Sc(OTf)3 were used, excellent enantiomeric excess values were obtained. The intermolecular [2 þ 2] cycloaddition of 3ylideneoxindols in Path XVII also took place using Ru(bpy)321 as the photocatalyst. A computational study was published.443 Yoon et al. developed the Ru(bpz)32B(ArF)4 photocatalyzed Diels–Alder reaction of alkenes with dienes (Path LXXXIII).444 Substituted styrenes in the presence of heterogeneous TiO2 photocatalysts upon 395 nm irradiation under oxygen atmosphere afforded aryltetralones via intermolecular [2 þ 2] cycloaddition, ring expansion and oxygenation (Path LXXXIV).445 Blue LED irradiation of estragol with Pd-decorated TiO2 nanoparticles as a visible-light photocatalyst led to isomerization to anethole in 93% yield.446 A combination of TiO2 as visible-light heterogeneous photocatalyst and the Togni I reagent as a hypervalent iodine(III) co-initiator resulted in the addition reaction of unactivated alkenes with BrCH(COOEt)2, C4F9I, CHCl3 or CCl4.447

6

Photooxygenation and photooxidation

Singlet oxygen which is readily produced by photosensitization, is well known as a very useful oxidant for alkenes, dienes, and polyenes. Hence, the microflow reactors connected with low energy LED lamps have been widely applied in this area. Reviews regrading oxygenation and oxidation of alkenes including LED-microflow-reactors were published.27,448,449 The 1 : 2 complex of meso-tetraphenylporphyrin and 2,3-dichloro-5,6dicyano-1,4-benzoquinone acted as a visible-light photooxygenative catalyst of alkenes.450 Griesbeck et al. reported a synthetic approach to Photochemistry, 2019, 46, 78–115 | 99

mono- and bicyclic perortho-esters with a central 1,2,4-trioxane ring using the singlet oxygen ene-reaction of allylic alcohols.451 In addition, his group discussed the ene-reaction mechanism of allylic alcohols with singlet oxygen by DFT calculation.452 Novel nitrogen-containing endoperoxides were prepared by the [4 þ 2] cycloaddition of dienes with singlet oxygen.453 A vortex reactor for continuous flow thermal and photochemical reactions was developed. The vortex reactor prepared artemisinin (109) in 50% yield by optimal conditions from the starting material dihydroaltemisinic acid (110).454

Several aerobic epoxidations of alkenes using heterogeneous455–459 and homogeneous460 photocatalysts have been reported. Though oxygen is usually used as an oxygen source in the epoxidation, novel photocatalytic epoxidations of alkenes with water as the oxygen source were developed.461–463 Synergetic photocatalytic systems constructed with Ru(bpy)3Cl2, [Co(NH3)5Cl]Cl2 and [(bTAML)FeOH2]NEt4 enabled the epoxidation of alkenes with water to yield epoxides in good yields.461 The manganese(V) complex, [Mn(N)(CN)4]2PPh4, was also applicable to the epoxidation of alkenes.462 In addition, when the chiral manganese complex, [(R,R-BQCN)Mn(OTf)2] was employed as the epoxidation catalyst, asymmetric epoxidation was found.463

7

Photochemistry of polyenes

The effect of different conformations and substitutions on the photoinduced (E)–(Z) isomerization of a retinal protonated Schiff base model (111) was investigated by nonadiabatic molecular dynamics simulations. The simulations indicated that the effect on bond selectivity, the directionality of the isomerization, the excited-state lifetime, and the product distribution of (111) was derived from the ensemble of trajectories.464 The triene (112) which is a donor-acceptor Stenhouse adduct, as a new class photoswitch underwent the photoinduced (E)–(Z) isomerization, followed by the thermal 4p-electrocyclization to afford (113).

The identification of the role of the intermediate during the formation (113) revealed a key step in the photoswitching mechanism.465 Fensterbank 100 | Photochemistry, 2019, 46, 78–115

et al. prepared the polyenes (114) and (115) and tried the synthesis of ladderanes by photoinduced multiple intramolecular [2 þ 2] cycloaddition. The polyene (114) upon 300 nm irradiation led to two stereoisomeric cyclobutane derivatives, sym- and dis-(116) in 45% and 25% yields, respectively. Under similar conditions, the polyene (115) afforded a mixture of sym- and dis-(117) and the macrocycle (118). The macrocycle (118) was derived from multiple Cope rearrangements of dis-(117).466

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

R. van Noorden and D. Castelvecchi, Nature, 2016, 538, 152. R. D. Astumian, Chem. Sci., 2017, 8, 840. D. A. Leigh, Angew. Chem., Int. Ed., 2016, 55, 14506. V. Richards, Nat. Chem., 2016, 8, 1090. C. Toumey, Nat. Nanotechnol., 2017, 12, 1. H. D. Burrows and R. M. Hartshorn, Pure Appl. Chem., 2016, 88, 917. B. Halford, Chem. Eng. News, 2016, 94, 5. B. L. Feringa, Angew. Chem., Int. Ed., 2017, 56, 11060. ¨ster, Y. Zou and T. Bach, Chem. Rev., 2016, 116, 9748. S. Poplata, A. Tro X. Deng, Z. Li and H. Garcı´a, Chem. – Eur. J., 2017, 23, 11189. C. R. Jamison and L. E. Overman, Acc. Chem. Res., 2016, 49, 1578. J. Chen, X. Hu, L. Lu and W. Xiao, Acc. Chem. Res., 2016, 49, 1911. K. A. Margrey and D. A. Nicewicz, Acc. Chem. Res., 2016, 49, 1997. M. N. Hopkinson, A. Tlahuext-Aca and F. Glorius, Acc. Chem. Res., 2016, 49, 2261. L. Zhang and E. Meggers, Acc. Chem. Res., 2017, 50, 320. T. Courant and G. Masson, J. Org. Chem., 2016, 81, 6945. Y. Jin and H. Fu, Asian J. Org. Chem., 2017, 6, 368. D. Menigaux, P. Belmont and E. Brachet, Eur. J. Org. Chem., 2017, 2008. M. Gurry and F. Aldabbagh, Org. Biomol. Chem., 2016, 14, 3849. S. Fuse, Y. Otake and H. Nakamura, Eur. J. Org. Chem., 2017, 6466. P. D. Morse, R. L. Beingessner and T. F. Jamison, Israel J. Chem., 2017, 57, 218. J. J. Douglas, M. J. Sevrin and C. R. J. Stephenson, Org. Process Res. Dev., 2016, 20, 1134. ´, C. Bottecchia, N. J. W. Straathof, V. Hessel and T. Noe ¨l, Chem. D. Cambie Rev., 2016, 116, 10276. A. A. Ghogare and A. Greer, Chem. Rev., 2016, 116, 9994. R. Ciriminna, R. Delisi, Y. Xu and M. Pagliaro, Org. Process Res. Dev., 2016, 20, 403. R. Porta, M. Benaglia and A. Puglisi, Org. Process Res. Dev., 2016, 20, 2. K. Misuno, Y. Nishiyama, T. Ogaki, K. Terao, H. Ikeda and K. Kakiuchi, J. Photochem. Photobiol., C, 2016, 29, 107. J. A. M. Lummiss, P. D. Morse, R. L. Beingessner and T. F. Jamison, Chem. Rec., 2017, 17, 667. P. De Luna, J. Wei, Y. Bengio, A. Aspuru-Guzik and E. Sargent, Nature, 2017, 552, 23. Photochemistry, 2019, 46, 78–115 | 101

30 31 32

33 34

35

36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

M. K. Yadav, New J. Chem., 2017, 41, 1411. M. T. Sebastian, H. Wang and H. Jantunen, Curr. Opin. Solid State Mater. Sci., 2016, 20, 151. Y. H. Kim, J. S. Park, Y. Choi, S. Y. Park, S. Y. Lee, W. Sohn, Y. Shim, J. Lee, C. R. Park, Y. S. Choi, B. H. Hong, J. H. Lee, W. H. Lee, D. Lee and H. W. Jang, J. Mater. Chem. A, 2017, 5, 19116. E. Singh, M. Meyyappan and H. S. Nalwa, ACS Appl. Mater. Interfaces, 2017, 9, 34544. I. N. Ioffe, M. Quick, M. T. Quick, A. L. Dobryakov, C. Richter, A. A. Granovsky, F. Berndt, R. Mahrwald, N. P. Ernsting and S. A. Kovalenko, J. Am. Chem. Soc., 2017, 139, 15265. A. L. Dobryakov, M. Quick, C. Richter, C. Knie, I. N. Ioffe, A. A. Granovsky, R. Mahrwald, N. P. Ernsting and S. A. Kovalenko, J. Chem. Phys., 2017, 146, 044501. M. Quick, A. L. Dobryakov, I. N. Ioffe, A. A. Granovsky, S. A. Kovalenko and N. P. Ernsting, J. Phys. Chem. Lett., 2016, 7, 4047. M. de Wergifosse, A. L. Houk, A. I. Krylov and C. G. Elles, J. Chem. Phys., 2017, 146, 144305. M. Aschi, V. Barone, B. Carlotti, I. Daidone, F. Elisei and A. Amadei, Phys. Chem. Chem. Phys., 2016, 18, 28919. H. Yao, M. Chung, C. Huang, S. M. Lin, C. Chen, T. Luh and I. Chen, J. Phys. Chem. A, 2017, 121, 7079. Y. Harabuchi, R. Yamamoto, S. Maeda, S. Takeuchi, T. Tahara and T. Taketsugu, J. Phys. Chem. A, 2016, 120, 8804. K. Ogawa, M. Hara, S. Nagano, T. Seki and Y. Takeoka, Chem. Lett., 2017, 46, 1386. H. Yuan, L. Wang, S. Li, H. Liang, C. Lu, Y. Wang and C. Zhao, J. Mater. Chem. B, 2016, 4, 5515. M. Taima, Y. Ishida and T. Arai, Can. J. Chem., 2017, 95, 1013. H. Sakurai, T. Maruyama and T. Arai, Photochem. Photobiol. Sci., 2017, 16, 1490. H. Sakurai and T. Arai, Bull. Chem. Soc. Jpn., 2016, 89, 911. T. Kobayashi and T. Arai, Bull. Chem. Soc. Jpn., 2017, 90, 820. J. Zhao and J. Ma, J. Chem. Phys. C., 2016, 120, 25131. M. Cao, Z. Cai, X. Chen, K. Yi and D. Wei, J. Mater. Chem. C, 2017, 5, 9597. F. Bejarano, I. Alcon, N. Crivillers, M. Mas-Torrent, S. T. Bromley, J. Veciana and C. Rovira, RSC Adv., 2017, 7, 15278. K. P. S. Zanoni and N. Y. M. Iha, Dalton Trans., 2017, 46, 9951. M. Padilla, F. Peccati, J. L. Bourdelande, X. Solans-Monfort, G. Guirado, M. Sodupe and J. Hernando, Chem. Commun., 2017, 53, 2126. ¨hne, J. B. Metternich, D. G. Artiukhin, M. C. Holland, M. von Bremen-Ku J. Neugebauer and R. Gilmour, J. Org. Chem., 2017, 82, 9955. Q. Yang, Z. Huang, T. J. Kucharski, D. Khvostichenko, J. Chen and R. Boulatov, Nat. Nanotechnol., 2009, 4, 302. T. Stauch and A. Dreu, Phys. Chem. Chem. Phys., 2016, 18, 15848. T. Stauch and A. Dreu, Phys. Chem. Chem. Phys., 2016, 18, 26994. Y. Tan and R. Boulatov, Phys. Chem. Chem. Phys., 2016, 18, 26990. N. Zhu, X. Li, Y. Wang and X. Ma, Dyes Pigm., 2016, 125, 259. S. J. Wezenberg and B. L. Feringa, Org. Lett., 2017, 19, 324. ´, B. L. Feringa and S. J. Wezenberg, Angew. Chem., Int. Ed., 2016, M. Vlatkovic 55, 1001. S. J. Wezenberg, C. M. Croisetu, M. C. A. Stuart and B. L. Feringa, Chem. Sci., 2016, 7, 4341.

102 | Photochemistry, 2019, 46, 78–115

61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83

84 85 86 87 88 89

H. Zhu, L. Shangguan, D. Xia, J. H. Mondal and B. Shi, Nanoscale, 2017, 9, 8913. Y. Wang, C. Sun, L. Niu, L. Wu, C. Tung, Y. Chen and Q. Yang, Polym. Chem., 2017, 8, 3596. T. van Leeuwen, J. Gan, J. C. M. Kistemaker, S. F. Pizzolato, M. Chang and B. L. Feringa, Chem. – Eur. J., 2016, 22, 7054. T. van Leeuwen, G. H. Heideman, D. Zhao, S. J. Wezenberg and B. L. Feringa, Chem. Commun., 2017, 53, 6393. T. Hackfort, B. Neumann, S.-G. Stammier and D. Kuck, Can. J. Chem., 2017, 95, 390. S. Kassem, T. van Leeuwen, A. S. Lubbe, M. R. Wilson, B. L. Feringa and D. A. Leigh, Chem. Soc. Rev., 2017, 46, 2592. N. Harada, Chirality, 2017, 29, 774. C. Cheng and J. F. Stoddart, ChemPhysChem, 2016, 17, 1780. T. Pan and J. Liu, ChemPhysChem, 2016, 17, 1752. B. Oruganti and B. Durbeej, J. Mol. Model., 2016, 22, 219. B. Oruganti, J. Wang and B. Dorbeej, ChemPhysChem, 2016, 17, 3399. L. Shao, J. Zhao, B. Cui, C. Fang and D. Liu, Chem. Phys. Lett., 2017, 676, 216. R. Beekmeyer, M. A. Parkes, L. Ridgwell, J. W. Riley, J. Chen, B. L. Feringa, A. Kerridge and H. H. Flieding, Chem. Sci., 2017, 8, 6141. C. R. Hall, J. Conyard, I. A. Heisler, G. Jones, J. Frost, W. R. Browne, B. L. Feringa and S. R. Meech, J. Am. Chem. Soc., 2017, 139, 7408. X. Pang, X. Cui, D. Hu, D. Jiang, D. Zhao, Z. Lan and F. Li, J. Phys. Chem. A, 2017, 121, 1240. S. Amirjalayer, A. Cnossen, W. R. Browne, B. L. Feringa, W. J. Buma and S. Woutersen, J. Phys. Chem. A, 2016, 120, 8606. A. Faulkner, T. van Leeuwen, B. L. Feringa and S. J. Wezenberg, J. Am. Chem. Soc., 2016, 138, 13597. A. S. Lubbe, J. C. M. Kistemaker, E. J Smits and B. L. Feringa, Phys. Chem. Chem. Phys., 2016, 18, 26725. T. van Leeuwen, W. Oanowski, E. Otten, S. J. Wezenberg and B. L. Feringa, J. Org. Chem., 2017, 82, 5027. P. ˇ Stacko, J. C. M. Kistemaker, T. van Leeuwen, M. Chang, E. Otten and B. L. Feringa, Science, 2017, 356, 964. P. ˇ Stacko, J. C. M. Kistemaker and B. L. Feringa, Chem. – Eur. J., 2017, 23, 6643. J. Chen, S. J. Wezenberg and B. L. Feringa, Chem. Commun., 2016, 52, 6765. J. Conyard, P. Stacko, J. Chen, S. McDonagh, C. R. Hall, S. P. Laptenok, W. R. Browne, B. L. Feringa and S. R. Meech, J. Phys. Chem. A, 2017, 121, 2138. B. Krajnik, J. Chen, M. A. Watson, S. L. Cockroft, B. L. Feringa and J. Hofkens, J. Am. Chem. Soc., 2017, 139, 7156. J. Kaleta, J. Chen, G. Bastien, M. Dracˇ´nsky ı ´, M. Masˇ´ at, C. T. Rogers, B. L. Feringa and J. Michl, J. Am. Chem. Soc., 2017, 139, 10486. T. van Leeuwen, J. Pol, D. Roke, S. J. Wezenberg and B. L. Feringa, Org. Lett., 2017, 19, 1402. S. F. Pizzolato, B. S. L. Collins, T. van Leeuwen and B. L. Feringa, Chem. – Eur. J., 2017, 23, 6174. D. J. van Dijken, J. Chen, M. C. A. Stuart, L. Hou and B. L. Feringa, J. Am. Chem. Soc., 2016, 138, 660. ´pez, A. Saywell, A. Bakker, J. Mielke, T. Kumagai, M. Wolf, V. Garcı´a-Lo P. Chiang, J. M. Tour and L. Grill, ACS Nano, 2016, 10, 10945. Photochemistry, 2019, 46, 78–115 | 103

90 91 92 93 94 95 96 97 98 99 100 101 102

103 104 105 106 107 108 109

110 111 112 113 114 115 116 117 118

´pez, F. Chen, L. G. Nilewski, G. Duret, A. Aliyan, A. B. Kolomeisky, V. Garcı´a-Lo J. T. Robinson, G. Wang, R. Pal and J. M. Tour, Nature, 2017, 548, 567. U. K. Jayasundara, H. Kim, K. P. Sahteli, J. I. Cline and T. W. Bell, ChemPhysChem, 2017, 18, 59. A. Nikiforov, J. A. Gamez, W. Thiel and M. Filatov, J. Phys. Chem. Lett., 2016, 7, 105. L. Wang, G. Huan, R. Momen, A. Azizi, T. Xu, S. R. Kirk, M. Filatov and S. Jenkins, J. Phys. Chem. A, 2017, 121, 4778. B. Oruganti, J. Wang and B. Durbeej, Org. Lett., 2017, 18, 4818. J. Wang, B. Oruganti and B. Durbeej, Phys. Chem. Chem. Phys., 2017, 19, 6952. C. H. Pollok, T. Riesebeck and C. Merten, Angew. Chem., Int. Ed., 2017, 36, 1925. C. S. Demmer, A. Voituriez and A. Marinetti, C. R. Chim., 2017, 20, 860. T. Matsushima, S. Kobayashi and S. Watanabe, J. Org. Chem., 2016, 81, 7799. S. Fujino, M. Yamaji, H. Okamoto, T. Mutai, I. Yoshikawa, H. Houjou and F. Tani, Photochem. Photobiol. Sci., 2017, 16, 925. H. Saito, A. Uchida and S. Watanabe, J. Org. Chem., 2017, 82, 5663. V. Rajeshkumar and M. C. Stuparu, Chem. Commun., 2016, 52, 9957. M. G. Belarmino Cabral, D. M. Pererira de Oliveira Santos, R. Cristiano, H. Gallardo, A. Bentaleb, E. A. Hillard, F. Durola and H. Bock, ChemPulsChem, 2017, 82, 342. M. Ben Braiek, F. Aloui and B. Ben Hassine, Tetrahedron Lett., 2016, 57, 4273. H. Okamoto, H. Takahashi, T. Takane, Y. Nishimiya, K. Kakiuchi, S. Gohda and M. Yamaji, Synthesis, 2017, 49, 2949. ´douar, F. Aloui, A. Beltifa, H. Ben Mansour and B. Ben Hassine, C. R. H. Gue Chim., 2017, 20, 841. A. Robert, P. Dechambenoit, E. A. Hillard, H. Bock and F. Durola, Chem. Commun., 2017, 53, 11540. A. G. Lvov and V. Z. Shirinyan, Chem. Heterocycl. Compd., 2016, 52, 658. L. Li, C. Zhao and H. Wang, Chem. Rec., 2016, 16, 797. A. Yamamoto, Y. Matsui, E. Ohta, T. Ogaki, H. Sato, T. Furuyama, N. Kobayashi, K. Mizuno and H. Ikeda, J. Photochem. Photobiol., A, 2016, 331, 48. L. Viglianti, N. L. C. Leung, N. Xie, X. Gu, H. H. Y. Sung, Q. Miao, I. D. Williams, E. Licandro and B. Z. Tang, Chem. Sci., 2017, 8, 2629. M. Takeshita, T. Hirowatari and A. Takedomi, Tetrahedron Lett., 2016, 57, 3565. X. Zhao, L. Zhang, J. Song, Y. Kan and H. Wang, J. Org. Chem., 2016, 81, 4856. W. Xu, L. Wu, M. Fang, Z. Ma, Z. Shan, C. Li and H. Wang, J. Org. Chem., 2017, 82, 11192. T. Chen, B. Zhang, Z. Liu, L. Duan, G. Dong, Y. Feng, X. Luo and D. Cui, Tetrahedron Lett., 2017, 58, 531. ˇ. Marinic´, U. Mazzucato, I. ˇ V. Botti, F. Elisei, F. Faraguna, Z Sagud, M. ˇ Sindler-Kulyk and A. Spalletti, J. Photochem. Photobiol., A, 2016, 329, 262. X. Zhang, E. L. Clennan, T. Petek and J. Weber, Tetrahedron, 2017, 73, 508. X. Zhang, E. L. Clennan, N. Arulsamy, R. Weber and J. Weber, J. Org. Chem., 2016, 81, 5474. C. Shen, M. Srebro-Hooper, M. Jean, N. Vanthuyne, L. Toupet, J. A. G. Williams, A. R. Torres, A. J. Riives, G. Muller, J. Autschbach and J. Crassous, Chem. – Eur. J., 2017, 23, 407.

104 | Photochemistry, 2019, 46, 78–115

119 120

121 122 123 124 125 126 127 128 129 130 131 132 133 134

135 136 137 138

139

140 141 142

143 144 145 146 147

T. Murase, T. Suto and H. Suzuki, Chem. – Asian J., 2017, 12, 726. ¨rgi, T. Biet, K. Martin, J. Hankache, N. Hellou, A. Hauser, T. Bu N. Vanthuyne, T. Aharon, M. Caricato, J. Crassous and N. Avarvari, Chem. – Eur. J., 2017, 23, 437. G. M. Upadhyay, H. R. Talele and A. V. Bedekar, J. Org. Chem., 2016, 81, 7751. M. F. Budyka, T. N. Gavrishova and N. I. Potashova, Chem. Select., 2016, 1, 36. A. S. Lubbe, W. Szymanski and B. L. Feringa, Chem. Soc. Rev., 2017, 46, 1052. V. A. Barachevsky, High Energy Chem., 2016, 50, 371. L. Fu, B. Leng, Y. Li and X. Gao, Chin. Chem. Lett., 2016, 27, 1319. D. Kitagawa and S. Kobatake, Chem. Rec., 2016, 16, 2005. H. Isla and J. Crassous, C. R. Chim., 2016, 19, 39. C. L. Jones, A. J. Tansell and T. L. Easun, J. Mater. Chem. A, 2016, 4, 6714. S. Huang, T. S. Andy Hor and G. Jin, Coord. Chem. Rev., 2017, 346, 112. M. Kim, J. Yun and M. Cho, Sci. Rep., 2017, 7, 967. H. Sotome, T. Nagasaka, K. Une, S. Morikawa, T. Katayama, S. Kobatake, M. Irie and H. Miyasaka, J. Am. Chem. Soc., 2017, 139, 17159. ¨tzel, M. Herder, F. Eisenreich, A. Bonasera, A. Grafl, L. Grubert, M. Pa J. Schwarz and S. Hecht, Chem. – Eur. J., 2017, 23, 3743. A. Fihey, R. Russo, L. Cupellini, D. Jacquemin and B. Mennucci, Phys. Chem. Chem. Phys., 2017, 19, 2044. Y. Ishibashi, T. Umesato, M. Fujiwara, K. Une, Y. Yoneda, H. Sotome, T. Katayama, S. Kobatake, T. Asahi, M. Irie and H. Miyasaka, J. Phys. Chem. C, 2016, 120, 1170. H. Sotome, T. Nagasaka, K. Une, C. Okui, Y. Ishibashi, K. Kamada, S. Kobatake, M. Irie and H. Miyasaka, J. Phys. Chem. Lett., 2017, 8, 3272. G. Pariani, M. Quintavalla, L. Colella, L. Oggioni, R. Castagna, F. Ortica, C. Bertarelli and A. Bianco, J. Phys. Chem. C, 2017, 121, 23592. T. Yanai, M. Saitow, X. Xiong, J. Chalupsky´, Y. Kurashige, S. Guo and S. Sharma, J. Chem. Theory Comput., 2017, 13, 4829. I. Hamdi, G. Buntinx, A. Perrier, O. Devos, N. Jaı¨dane, S. Delbaere, A. K. Tiwari, J. Dubois, M. Takeshita, Y. Wada and S. Aloı¨se, Phys. Chem. Chem. Phys., 2016, 18, 28091. K. Khodko, V. Khomenko, Y. Shynkarenko, O. Mamuta, O. Kapitanchuk, D. Sysoiev, N. Kachalova, T. Huhn and S. Snegir, Chem. Phys. Lett., 2017, 669, 156. T. Takeshita, H. Kurata and M. Hara, J. Photochem. Photobiol., A, 2017, 344, 28. X. Li, W. Li, H. Ågren, H. Tian and W. Zhu, Dyes Pigm., 2016, 125, 348. G. T. Vasilyuk, V. F. Askirka, A. V. Lavysh, S. A. Kurguzenkov, V. M. Yasinskii, O. I. Kobeleva, T. M. Valova, A. O. Ayt, V. A. Barachevsky, Y. N. Yarovenko, M. M. Krayushkin and S. A. Maskevich, J. Appl. Spectrosc., 2017, 84, 770. A. G. Lvov, A. M. Kavun, V. V. Kachala, Y. V. Nelyubina, A. V. Metelitsa and V. Z. Shirinian, J. Org. Chem., 2017, 82, 1477. A. G. Lvov, N. A. Milevsky, A. M. Yanina, V. V. Kachala and V. Z. Shirinian, Org. Lett., 2017, 19, 4295. A. V. Zakharov, E. B. Gaeva, A. G. Lvov, A. V. Metelista and V. Z. Shirinian, J. Org. Chem., 2017, 82, 8651. A. G. Lvov, E. Yu. Bulich, A. V. Metelista and V. Z. Shirinian, RSC Adv., 2016, 6, 59016. A. G. Lvov and V. Z. Shirinyan, Chem. Heterocycl. Compds., 2016, 52, 658. Photochemistry, 2019, 46, 78–115 | 105

148

149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183

E. Hatano, M. Morimoto, T. Imai, K. Hyodo, A. Fujimoto, R. Nishimura, A. Sekine, N. Yasuda, S. Yokojima, S. Nakamura and K. Uchida, Angew. Chem., Int. Ed., 2017, 56, 12576. E. Hatano, M. Morimoto, K. Hyodo, N. Yasuda, S. Yokojima, S. Nakamura and K. Uchida, Chem. – Eur. J., 2016, 22, 12680. E. Saito, T. Ako, Y. Kobori and A. Tsuda, RSC Adv., 2017, 7, 2403. C. Lambruschini, L. Banfi and G. Guanti, Chem. – Eur. J., 2016, 22, 13831. O. Galangau, S. Delbare, N. Ratel-Ramond, G. Rapenne, R. Li, J. P. D. C. Calupitan, T. Nakashima and T. Kawai, J. Org. Chem., 2016, 81, 11282. J. P. D. C. Calupitan, O. Galangau, O. Guillermet, R. Coratget, T. Nakashima, G. Rapenne and T. Kawai, Eur. J. Inorg. Chem., 2017, 2451. X. Liu, Z. Zhao, J. Wang, W. Zhang and H. Zhang, J. Photochem. Photobiol., A, 2017, 335, 155. K. P. Schultz, D. W. Spivey, E. K. Loya, J. E. Kellon, L. M. Taylor and M. R. McConville, Tetrahedron Lett., 2016, 57, 1296. N. M. Wu, H. Wong and V. W. Yam, Chem. Sci., 2017, 8, 1309. C. Wong, C. Poon and V. W. Yam, Chem. – Eur. J., 2016, 22, 12931. C. Li and H. Zeng, J. Heterocycl. Chem., 2016, 53, 1706. Y. Li, Q. Lin, S. Wang, R. Tan and S. Xiao, Tetrahedron Lett., 2016, 57, 2647. J. P. D. C. Calupitan, O. Galangau, O. Guilermet, R. Coratger, T. Nakashima, G. Rapenne and T. Kawai, J. Phys. Chem. C, 2017, 121, 25384. A. S. Gertsen, S. T. Olsen, S. L. Broman, M. B. Nielsen and K. V. Mikkelsen, J. Phys. Chem. C, 2017, 121, 195. D. Kitagawa, K. Kawasaki, R. Tanaka and S. Kobatake, Chem. Mater., 2017, 29, 7524. A. Hirano, T. Hashimoto, D. Kitagawa, K. Kono and S. Kobatake, Cryst. Growth Des., 2017, 17, 4819. D. Kitagawa, R. Tanaka and S. Kobatake, CrystEngComm, 2016, 18, 7236. H. Koshima, H. Uchimoto, T. Taniguchi, J. Nakamura, T. Asahi and T. Asahi, CrystEngComm, 2016, 18, 7305. V. Valderry, A. Bonasera, S. Fredrich and S. Hecht, Angew. Chem., Int. Ed., 2017, 56, 1914. S. Cui, Z. Tian, S. Pu and Y. Dai, RSC Adv., 2016, 6, 19957. Y. Xue, R. Wang, C. Zheng, G. Liu and S. Pu, Tetrahedron Lett., 2016, 57, 1877. X. Zhang, R. Wang, G. Liu, C. Fan and S. Pu, Tetrahedron, 2016, 72, 8449. S. Pu, C. Zhang, C. Fan and G. Liu, Dyes Pigm., 2016, 129, 24. E. Feng, R. Lu, C. Fan, C. Zheng and S. Pu, Tetrahedron Lett., 2017, 58, 1390. L. Li, H. Li, G. Liu and S. Pu, J. Photochem. Photobiol., A, 2017, 338, 192. S. Wei, X. Li, C. Fan, G. Liu and S. Pu, Tetrahedron, 2017, 73, 6164. R. Wang, N. Wang, S. Pu, X. Zhang, G. Liu and Y. Dai, Dyes Pigm., 2017, 146, 445. Y. Fu, Y. Tu, C. Fan, C. Zheng, G. Liu and S. Pu, New J. Chem., 2016, 40, 8579. R. Lu, S. Cui, S. Li and S. Pu, Tetrahedron, 2017, 73, 915. L. Ma, G. Liu, S. Pu, C. Zheng and C. Fan, Tetrahedron, 2017, 73, 1691. Y. Tang, S. Cui and S. Pu, Tetrahedron, 2016, 72, 4400. H. Xu, H. Ding, G. Li, C. Fan, G. Liu and S. Pu, RSC Adv., 2017, 7, 29827. G. Liao, C. Zheng, D. Xue, C. Fan, G. Liu and S. Pu, RSC Adv., 2016, 6, 34748. D. Xue, C. Zheng, S. Qu, G. Liao, C. Fan, G. Liu and S. Pu, Luminescence, 2016, 32, 652. L. Ma, G. Liu, S. Pu, H. Ding and G. Li, Tetrahedron, 2016, 72, 985. S. Wang, X. Li, W. Zhao, X. Chen, J. Zhang, H. Agren, Q. Zhu, L. Zhu and W. Chen, J. Mater. Chem. C, 2017, 5, 282.

106 | Photochemistry, 2019, 46, 78–115

184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227

X. Dong, R. Wang, G. Liu, P. Liu and S. Pu, Tetrahedron, 2016, 72, 2935. H. Ding, B. Li, S. Pu, G. Liu, D. Jia and Y. Zhou, Sens. Actuators, B, 2017, 247, 26. Y. Fu, C. Fan, G. Liu and S. Pu, Sens. Actuators, B, 2017, 239, 295. S. Qu, C. Zheng, G. Liao, C. Fan, G. Liu and S. Pu, RSC Adv., 2017, 7, 9833. L. Li, H. Li, G. Liu and S. Pu, Luminescence, 2017, 32, 1473. Q. Ai and K. Ahn, RSC Adv., 2016, 6, 43000. Z. Tian, S. Cui, C. Zheng and S. Pu, Spectrochim. Acta A, 2017, 173, 75. E. Feng, Y. Tu, C. Fan, G. Liu and S. Pu, RSC Adv., 2017, 7, 50188. Z. Tian, S. Cui and S. Pu, Tetrahedron Lett., 2016, 57, 2703. Y. Fu, C. Fan, G. Liu, S. Cui and S. Pu, Dyes Pigm., 2016, 126, 121. X. Zhang, H. Li, G. Liu and S. Pu, Luminescence, 2016, 31, 1488. Z. Tian, S. Cui, G. Liu, R. Wang and S. Pu, J. Phys. Org. Chem., 2016, 29, 421. X. Li, G. Ji, W. Oh and Y. Con, Mol. Cryst. Liq. Cryst., 2016, 636, 1. D. Zhang, S. Li, R. Lu, G. Liu and S. Pu, Dyes Pigm., 2017, 146, 305. G. Li, D. Zhang, G. Liu and S. Pu, Tetrahedron Lett., 2016, 57, 5205. J. Liu, H. Liu and S. Pu, J. Photochem. Photobiol., A, 2016, 324, 14. P. Jin, M. Liu, F. Cao and Q. Luo, Dyes Pigm., 2016, 132, 151. F. Duan, G. Liu, P. Liu, C. Fan and S. Pu, Tetrahedron, 2016, 72, 3213. G. Liao, C. Zheng and S. Pu, J. Photochem. Photobiol., A, 2017, 317, 115. X. Zhang, R. Wang, C. Fan, G. Liu and S. Pu, Dyes Pigm., 2017, 139, 208. Y. Tang, S. Cui and S. Pu, J. Fluoresc., 2016, 26, 1421. J. Wang, L. Ma, G. Liu, H. Ding and S. Pu, Tetrahedron, 2016, 72, 8479. X. G. Tang, H. L. Liu and S. Z. Pu, Photochem. Photobiol. Sci., 2016, 15, 1579. H. Lan, G. Lv, Y. Wen, Y. Mao, C. Huang and T. Yi, Dyes Pigm., 2016, 131, 18. C. Zheng, C. Fan, S. Pu, B. Chen and B. Chen, J. Mol. Struct., 2016, 1123, 355. ´ki, D. Jardel and J.-L. Pozzo, L. Sanguinet, S. Delbaere, J. Berthet, G. Szalo Adv. Opt. Mater., 2016, 4, 1358. C. Yu, B. Hu, Z. Zhao and Z. Chen, Pharm. Chem., 2016, 8, 12. S. Kusumoto, T. Nakagawa and Y. Yokoyama, Adv. Opt. Mater., 2016, 4, 1350. J. Gurke, M. Quick, N. P. Ernsting and S. Hecht, Chem. Commun., 2017, 53, 2150. S. Mahvidi, S. Takeuuchi, S. Kusumoto, H. Sato, T. Nakagawa and Y. Yokoyama, Org. Lett., 2016, 18, 5042. P. Jin, F. Cao and Q. Luo, Tetrahedron, 2016, 72, 5488. ´ki, O. Ale ´ve ˆque, J.-L. Pozzo and S. Delbaere, L. Sanguinet, J. Berthet, G. Szalo Dyes Pigm., 2017, 137, 490. X. Chai, Y. Fu, T. D. James, J. Zhang, X. He and H. Tian, Chem. Commun., 2017, 53, 9494. G. Hu, H. Cheng, J. Niu, Z. Zhang and H. Wu, Dyes Pigm., 2017, 136, 354. S. Fan, Y. Fu and S. Pu, Z. Krystallogr. NCS, 2016, 231, 215. J. Wang, G. Liu, C. Fan and S. Pu, Z. Krystallogr. NCS, 2017, 232, 359. H. Xu, R. Wang, C. Fan, G. Liu and S. Pu, Turk. J. Chem., 2016, 40, 38. G. Liao, D. Xue, C. Zheng, R. Wang and S. Pu, J. Braz. Chem. Soc., 2016, 27, 1989. Y. Wang, Y. Yan, D. Liu, S. Liu, G. Wang and S. Pu, Optik, 2016, 127, 5285. R. Wang, X. Zhang, S. Pu, G. Liu and Y. Dai, Spectrochim. Acta A, 2017, 173, 257. P. Liu, H. Liu, G. Liu, Z. Zhang, F. Xu and S. Pu, J. Phys. Org. Chem., 2017, 30, e3716. C. Zheng, G. Liao, C. Fan, R. Wang and S. Pu, J. Chem. Res., 2017, 41, 423. H. Xu, S. Wei, C. Fan, G. Liu and S. Pu, Tetrahedron, 2017, 73, 6479. C. Zheng, E. Feng, C. Fan and S. Pu, Z. Krystallogr. NCS, 2016, 231, 1159. Photochemistry, 2019, 46, 78–115 | 107

228 229 230

231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246

247 248 249 250 251 252 253 254 255 256 257

D. Zhang, C. Fan, C. Zheng and S. Pu, Dyes Pigm., 2017, 136, 669. F. Duan, G. Liu, C. Fan and S. Pu, Tetrahedron Lett., 2016, 57, 1963. A. R. Tuktarov, A. A. Khuzin, A. R. Akhmetov, L. M. Khalilov, A. R. Tulyabaev, V. A. Barachevskii, O. V. Venedilktova and U. M. Dzhemilev, Mendeleev Commun., 2016, 26, 143. R. Castagna, V. Nardone, G. Pariani, E. Parisini and A. Bianco, J. Potochem. Photobiol. A, 2016, 325, 45. C. Yu, B. Hu, C. Liu and J. Li, J. Phys. Org. Chem., 2017, 30, e3584. T. Hu, Z. Li, T. Wanga and H. Zeng, J. Heteocycl. Chem., 2016, 53, 109. T. Ichikawa, M. Morimoto, H. Sotome, S. Ito, H. Miyasaka and M. Irie, Dyes Pigm., 2016, 126, 186. T. Ichikawa, M. Morimoto and M. Irie, Dyes Pigm., 2017, 137, 214. K. Tanaka, D. Kitagawa and S. Kobatake, Tetrahedron, 2016, 72, 2364. F. Hu, C. Jiang, W. Liu, J. Wang, J. Yin and S. H. Liu, Dyes Pigm., 2017, 135, 161. S. Takeuchi, T. Nakagawa and Y. Yokoyama, Photochem. Photobiol. Sci., 2016, 15, 325. A. J. Teator, H. Shao, G. Lu, P. Liu and C. W. Bielawski, Organometallics, 2017, 36, 490. Y. Cai, Y. Cao, Q. Luo, M. Li, J. Zhang, H. Tian and W. Zhu, Adv. Opt. Mater., 2016, 4, 1410. A. Escribano, T. Steenbock, C. Hermann and J. Heck, ChemPhysChem, 2016, 17, 1881. A. Escribano, T. Steenbock, C. Stork, C. Hermann and J. Heck, ChemPhysChem, 2017, 18, 596. A. Mulas, X. He, Y.-M. Hervault, L. Norel, S. Rigaut and C. Lagrost, Chem. – Eur. J., 2017, 23, 10205. F. Arnaud and J. Denis, J. Phys. Chem. C, 2016, 120, 11140. M. H. Chan, H. Wong and V. W. Yam, Inorg. Chem., 2016, 55, 5570. J. Boixel, Y. Zhu, H. Le Bozec, H. A. Benmensour, A. Boucekkine, K. M. Wong, A. Colombo, D. Roberto, V. Guerchais and D. Jacquemin, Chem. Commun., 2016, 52, 9833. L. Zhang, H. Li, Q. Liu, M. Ye, L. Zheng, X. Fan and W. Liang, J. Organomet. Chem., 2017, 846, 230. ´rio, R. Pe ´rez-Toma ´s, S. J. Teat A. Presa, L. Barrios, J. Cirera, L. Korrodi-Grego and P. Gamez, Inorg. Chem., 2016, 55, 5356. ¨rtel, A. Witt, F. W. Heinemann, S. Bochmann, J. Bachmann and M. Mo M. M. Khusniyarov, Inorg. Chem., 2017, 56, 13174. M. Estrader, J. S. Uber, L. A. Barrios, J. Garcia, P. Lloyd-Williams, O. Roubeau, S. J. Teat and G. Aromı´, Angew. Chem., Int. Ed., 2017, 56, 15622. A. Fetoh, G. Cosquer, M. Morimoto, M. Irie, O. El-Gammal, G. A. El-Reash, B. K. Breedlove and M. Yamashita, Sci. Rep., 2016, 6, 23785. M. A. Yatoo, G. Cosquer, M. Morimoto, M. Irie, B. K. Breedlove and M. Yamashita, Magnetochemistry, 2016, 2, 21. C. P. Sen and S. Valiyaveettil, RSC Adv., 2016, 6, 95137. J. Wang, L. Shi, J. Wang, J. Chen, S. Liu and Z. Chen, Dalton Trans., 2017, 46, 2023. H. Cheng, G. Hu, Z. Zhang, L. Gao, X. Gao and H. Wu, Inorg. Chem., 2016, 55, 7962. `re, R. Cle ´rac, O. Roubeau and G. Aromi, J. S. Uber, M. Estrader, C. Mathonie Cryst. Growth Des., 2016, 16, 4026. ´mez, X. Ribas, A. Jose, P. Peretzki, M. Han, Y. Luo, B. Damaschke, L. Go M. Seibt and G. H. Clever, Angew. Chem., Int. Ed., 2016, 55, 445.

108 | Photochemistry, 2019, 46, 78–115

258 259 260 261 262 263 264 265 266 267 268

269 270 271 272 273 274 275 276 277 278

279 280 281 282 283 284 285 286 287 288

B. J. Funrlong and M. J. Katz, J. Am. Chem. Soc., 2017, 139, 13280. I. M. Walton, J. M. Cox, T. B. Mitchell, N. P. Bizier and J. B. Benedict, CrystEngComm, 2016, 18, 7972. C. B. Fan, Z. Q. Liu, L. L. Gong, A. M. Zheng, L. Zhang, C. S. Yan, H. Q. Wu, X. F. Feng and F. Luo, Chem. Commun., 2017, 53, 763. J. M. Cox, I. M. Walton and J. B. Benedict, J. Mater. Chem. C, 2016, 4, 4028. T. Leydecker, M. Herder, E. Pavlica, G. Bratina, S. Hecht, E. Orgiu and P. Samorı`, Nat. Nanotechnol., 2016, 11, 769. Q. Wang, J. Frisch, M. Herder, S. Hecht and N. Koch, ChemPhysChem, 2017, 18, 722. H. Chen, N. Cheng, W. Ma, M. Li, S. Hu, L. Gu, S. Meng and X. Guo, ACS Nano, 2016, 10, 436. T. Tsuruoka, R. Hayakawa, K. Kobashi, K. Higashiguchi, K. Matsuda and Y. Wakayama, Nano Lett., 2016, 16, 7474. D. Taherinia and C. D. Frisbie, J. Chem. Phys. C, 2016, 120, 6442. ¨rner, D. Wolf, T. Schumacher, P. Bauer, M. Thelakkat and C. Scho M. Lippitz, J. Chem. Phys. C, 2017, 21, 16528. G. T. Vasilyuk, V. F. Askirka, A. E. German, J. F. Sveklo, V. M. Yasinskii, A. A. Yaroshevich, O. I. Kobeleva, T. M. Valova, A. O. Ayt, V. A. Barachevsky, V. N. Yarovenko, M. M. Krayushkin and S. A. Maskevich, J. Appl. Spectrosc., 2017, 84, 588. T. Toyama, K. Higashiguchi, T. Nakamura, H. Ymaguchi, E. Kusaka and K. Matsuda, J. Phys. Chem. Lett., 2016, 7, 2113. K. Higashiguchi, M. Nakazaki and K. Matsuda, Adv. Opt. Mater., 2016, 4, 1385. R. Russo, A. Fihey, B. Mennucci and D. Jacquemin, J. Phys. Chem. C, 2016, 120, 21827. G. Vamvounis, C. R. Glasson, E. J. Bieske and V. Dryza, J. Mater. Chem. C, 2016, 4, 6215. K. Yamamoto and T. Tsujioka, Mater. Lett., 2016, 179, 158. T. Tsujioka and K. Yamamoto, Jpn. J. Appl. Phys., 2016, 55, 061602. T. Tsujioka and M. Okuda, Appl. Surf. Sci., 2017, 426, 169. N. Xin, C. Jia, J. Wang, S. Wang, M. Li, Y. Gong, G. Zhang, D. Zhu and X. Guo, J. Phys. Chem. Lett., 2017, 8, 2849. K. Takase, K. Hyodo, M. Morimoto, Y. Kojima, H. Mayama, S. Yokojima, S. Nakamura and K. Uchida, Chem. Commun., 2016, 52, 6885. R. Nishimura, K. Hyodo, H. Sawaguchi, Y. Yamamoto, Y. Nonomura, H. Mayama, S. Yokojima, S. Nakamura and K. Uchida, J. Am. Chem. Soc., 2016, 138, 10299. R. Singh, H. Wu, A. K. Dwivedi, A. Singh, C. Lin, P. Raghunath, M. Lin, T. Wu, K. Wei and H. Lin, J. Mater. Chem. C, 2017, 5, 9952. H. Dong, M. Luo, S. Wang and X. Ma, Dyes Pigm., 2017, 139, 118. G. Sinawang, J. Wang, B. Wu, X. Wang and Y. He, RSC Adv., 2016, 6, 12647. N. Maeda, T. Hirose, S. Yokoyama and K. Matsuda, J. Chem. Phys. C, 2016, 120, 9317. S. Chen, W. Li, X. Li and W. Zhu, J. Mater. Chem. C, 2017, 5, 2717. H. Wu, Y. Chen and Y. Liu, Adv. Mater., 2017, 29, 1605271. ¨fer, J. Moreno, S. Bobone, S. Chiantia, A. Herrmann, S. Hecht F. Schweigho and J. Wachtveitl, Phys. Chem. Chem. Phys., 2016, 19, 4010. G. Liu, X. Xu, Y. Chen, X. Wu, H. Wu and Y. Liu, Chem. Commun., 2016, 52, 7966. Q. Hu, Y. Lu, C. Yang and X. Yan, Chem. Commun., 2016, 52, 5470. G. Liu, Y. Zhang, C. Wang and Y. Liu, Chem. – Eur. J., 2017, 23, 14425. Photochemistry, 2019, 46, 78–115 | 109

289 290 291 292 293

294 295 296 297 298

299 300 301 302

303 304 305 306 307 308 309 310 311 312 313 314 315

A. Sakaguchi, K. Higashiguchi and K. Matasuda, ChemPhotoChem, 2017, 1, 488. J. Liu, B. Xin, C. Li, N. Xie, W. Gong, Z. Huang and M. Zhu, ACS Appl. Mater. Interfaces, 2017, 9, 10388. H. Cheng, P. Ma, Y. Wang, G. Hu, S. Fang, Y. Fang and Y. Lin, Chem. – Asian J., 2017, 12, 248. J. Liu, B. Xin, C. Li, W. Gong, Z. Huang, B. Tang and M. Zhu, J. Mater. Chem. C, 2017, 5, 9339. O. Babii, S. Afonin, L. V. Garmanchuk, V. V. Nikulina, T. V. Nikolaienko, O. V. Stroozhuk, D. V. Shelest, O. I. Dasyukevich, L. I. Ostapchenko, V. Iurchenko, S. Zozulya, A. S. Ulrich and I. V. Komarov, Angew. Chem., Int. Ed., 2016, 55, 5493. ´n-Carrasco, Dyes Pigm., 2017, 142, 530. J. P. Cero Y. Osakada, T. Fukaminato, Y. Ichinose, M. Fujitsuka, Y. Harada and T. Majima, Chem. – Asian J., 2017, 12, 2660. K. Kawamura, K. Osawa, Y. Watanabe, Y. Saeki, N. Maruyama and Y. Yokoyama, Chem. Commun., 2017, 53, 3181. D. Kim and T. S. Lee, ACS Appl. Mater. Interfaces, 2016, 8, 34770. B. Roubinet, M. L. Bossi, P. Alt, M. Leutenegger, H. Shojaei, S. Schnorrenberg, S. Nizamov, M. Irie, V. N. Belov and S. W. Hell, Angew. Chem., Int. Ed., 2016, 55, 15429. O. Babii, S. Afonin, T. Schober, I. V. Komarov and A. S. Ulrich, BBA Biomembr., 2017, 1859, 2505. L. C. Schmidt, V. C. Edelsztein, C. C. Spagnuolo, P. H. Di Chenna and R. E. Galian, J. Mater. Chem. C, 2016, 4, 7035. H. Yotsuji, K. Higashiguchi, R. Sato, Y. Shigeta and K. Matsuda, Chem. –Eur. J., 2017, 23, 15059. D. Wuts, D. Gluhacevic, A. Chakrabarti, K. Schmidtkunz, D. Robba, ¨nig, Org. Biomol. Chem., F. Erdmann, C. Romier, W. Sippl, M. Jung and B. Ko 2017, 15, 4882. ¨schke, Beilstein J. Org. Chem., 2016, 12, 1103. C. Sarter, M. Heimes and A. Ja H. Wang, D. Xi, M. Xie, H. Wang, G. Qu and H. Guo, ChemBioChem, 2016, 17, 1216. ¨fer, L. Dworak, C. A. Hammer, H. Gustmann, M. Zastrow, F. Schweigho ¨ck-Braun and J. Wachtveitl, Sci. Rep., 2016, 6, 28638. K. Ru ¨lter, S. Li, M. Morimoto, S. Tang, J. Hernando, G. Guirado, M. Irie, M. Ba ´asson, Chem. Sci., 2016, 7, 5867. F. M. Raymo and J. Andre H. Koga, M. Nogi and A. Isogai, ACS Appl. Mater. Interfaces, 2017, 9, 40914. J. Kida, K. Imato, R. Goseki, M. Morimoto and H. Otsuka, Chem. Lett., 2017, 46, 992. L. Kortekaas and W. R. Browne, Adv. Opt. Mater., 2016, 4, 1378. D. Kim, J. E. Kwon and S. Y. Park, Adv. Opt. Mater., 2016, 4, 790. ¨hning, J. Schmidt and A. Thomas, Chem. D. Becker, N. Konnertz, M. Bo Mater., 2016, 28, 8523. S. Matsushita, Y. S. Jeong, Y. Okada, H. Hayasaka and K. Akagi, Adv. Funct. Mater., 2017, 27, 1700929. ¨ll, Angew. Chem., O. Nevskyi, D. Sysoiev, A. Oppermann, T. Huhn and D. Wo Int. Ed., 2016, 55, 12698. C. Ritchie, G. Vamvounis, H. Soleimaninejad, T. A. Smith, E. J. Bieske and V. Dryza, Phys. Chem. Chem. Phys., 2017, 19, 19984. T. Nakahama, D. Kitagawa, H. Sotome, S. Ito, H. Miyasaka and S. Kobatake, J. Phys. Chem. C, 2017, 121, 6272.

110 | Photochemistry, 2019, 46, 78–115

316 317 318 319 320 321 322 323

324 325 326 327 328 329 330 331 332 333 334 335 336

337 338

339

340 341 342 343

M. Kathan, P. Kovarˇ´c ıˇek, C. Jurissek, A. Senf, A. Dallmann, ¨nemann and S. Hecht, Angew. Chem., Int. Ed., 2016, 55, 13882. A. F. Thu Y. Arai, S. Ito, H. Fujita, Y. Yoneda, T. Kaji, S. Takei, R. Kashihara, M. Morimoto, M. Irie and H. Miyasaka, Chem. Commun., 2017, 53, 4066. ¨ui, Z. Liu, H. I. Wang, A. Narita, Q. Chen, Z. Mics, D. Turchinovich, M. Kla ¨llen, J. Am. Chem. Soc., 2017, 139, 9443. M. Bonn and K. Mu T. Inoue and M. Inokuchi, Bull. Chem. Soc. Jpn., 2016, 89, 671. M. Morimoto, R. Kashihara, K. Mutoh, Y. Kobayashi, J. Abe, H. Sotome, S. Ito, H. Miyasaka and M. Irie, CrystEngComm, 2016, 18, 7241. D. Kitagawa, T. Nakahama, K. Mutoh, Y. Kobayashi, J. Abe, H. Sotome, S. Ito, H. Miyasaka and S. Kobatake, Dyes Pigm., 2017, 139, 233. D. Kitagawa, T. Okuyama, R. Tanaka and S. Kobatake, Chem. Mater., 2016, 28, 4889. N. Fujinaga, N. Nishikawa, R. Nishimura, K. Hyodo, S. Yamazoe, Y. Kojima, K. Yamamoto, T. Tsujioka, M. Morimoto, S. Yokojima, S. Nakamura and K. Uchida, CrystEngComm, 2016, 18, 7229. R. Remy and C. G. Bochet, Chem. Rev., 2016, 116, 9816. V. Ramamurthy and J. Sivaguru, Chem. Rev., 2016, 116, 9914. G. Lutteke, R. A. Kleinnijenhuis, R. J. Beuving, R. de Gelder, J. M. M. Smits, J. H. van Maarseveen and H. Hiemstra, Eur. J. Org. Chem., 2016, 5845. R. Meier and D. Trauner, Angew. Chem., Int. Ed., 2016, 55, 11251. ¨lle, D. Trauner, R. de Vivie-Riedle and R. Meier, ACS B. S. Matsuura, P. Ko Cent. Sci., 2017, 3, 39. ¨ckner, Eur. J. Org. Chem., 2017, 2950. T. Hampel and R. Bru Y. Zhang, X. Zhou, X. Wang, L. Wu, M. Yang, J. Luo, Y. Yin, J. Luo and L. Kong, Org. Lett., 2017, 19, 3013. A. V. Denisenko, T. Druzhenko, Y. Skalenko, M. Samoilenko, O. O. Grygorenko, S. Zozulya and P. K. Mykhailiuk, J. Org. Chem., 2017, 82, 9627. K. Randazzo, Z. Wang, Z. D. Wang, J. Butz and Q. R. Chu, ACS Sustainable Chem. Eng., 2016, 4, 5053. T. Doi, H. Kawai, K. Murayama, H. Kashida and H. Asanuma, Chem. – Eur. J., 2016, 22, 10533. N. Gaß, J. Gebhard and H.-A. Wagenknecht, ChemPhotoChem, 2017, 1, 48. ´ndez, M. R. de la Fuente, R. Gime ´nez M. Martı´nez-Abadı´a, B. Robles-Herna and M. B. Ros, Adv. Mater., 2016, 28, 6586. E. N. Ushakov, T. P. Martyanov, A. I. Vedernikov, O. V. Pikalov, A. A. Efremova, L. G. Kuz’mina, J. A. K. Howard, M. V. Alfimov and S. P. Gromov, J. Photochem. Photobiol., A, 2017, 340, 80. S. P. Gromov, A. I. Vedernikov, S. K. Sazonov, L. G. Kuz’mina, N. A. Lobova, Y. A. Strelenko and J. A. K. Howard, New J. Chem., 2016, 40, 7524. D. V. Berdnikova, T. M. Aliyeu, S. Delbaere, Y. V. Fedorov, G. Jonusauskas, V. V. Novikov, A. A. Pavlov, A. S. Peregudov, N. E. Shepel, F. I. Zubkov and O. A. Fedorova, Dyes Pigm., 2017, 139, 397. N. Kh. Petrov, D. A. Ivanov, Yu. A. Shandarov, I. V. Kryukov, A. D. Svirida, V. G. Avakyan, M. V. Alfimov, N. A. Lobova and S. P. Gromov, Chem. Phys. Lett., 2017, 673, 99. J. Chen, Y. Hou, Q. Zhou, H. Zhang and D. Liu, CrystEngChomm, 2017, 19, 2603. A. Hazra, S. Bonakala, K. K. Bejagam, S. Balasubramanian and T. K. Maji, Chem. – Eur. J., 2016, 22, 7792. A. M. P. Peedikakkal, J. Chem. Sci., 2017, 129, 239. Y. Zhang, C. Chen, L. Cai, B. Tan, X. Yang, J. Zhang and M. Ji, Dalton Trans., 2017, 46, 7029. Photochemistry, 2019, 46, 78–115 | 111

344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374

L. Cai, C. Chen, Y. Zhang, X. Yang and J. Zhang, CrystEngComm, 2016, 18, 7347. C. E. Mulijanto, H. S. Quah, G. K. Tan, B. Donnadieu and J. J. Vittal, IUCrJ, 2017, 4, 65. A. Garai, S. Sasmal and K. Biradha, Cryst. Growth Des., 2016, 16, 4457. M. Garai and K. Biradha, Cryst. Growth Des., 2017, 17, 925. Y. Shi, W. Li, H. Chen, D. J. Young, W. Zhang and J. Lang, Chem. Commun., 2017, 53, 5515. E. Elacqua, M. A. Sinnwell, B. P. Loren, P. T. Jurgens, R. H. Groeneman, E. W. Reinheimer and L. R. MacGillivray, ChemPlusChem, 2016, 81, 893. A. S. Singh, R. K. Tiwani, M. M. Lee, J. N. Behera, S. Sun and V. Chandrasekhar, Chem. – Eur. J., 2017, 23, 762. C. M. Santana, E. W. Reinheimer, H. R. Krueger Jr., L. R. MacGillivray and R. H. Groeneman, Cryst. Growth Des., 2017, 17, 2054. F. Meng, J. Min, C. Wang and L. Wang, Eur. J. Org. Chem., 2016, 2220. L. G. Kuz’mina, A. I. Vedernikov, J. A. K. Howard, S. I. Bezzubov, M. V. Alfimov and S. P. Gromov, CrystEngComm, 2016, 18, 7506. ´, S. V. S. Mariappan A. J. E. Duncan, R. L. Dudovitz, S. J. Dudovitz, J. Stojakovic and L. R. MacGillivray, Chem. Commun., 2016, 52, 13109. T. Itoh, F. Kondo, T. Uno, M. Kubo, N. Tohnai and M. Miyata, Cryst. Growth Des., 2017, 17, 3606. ¨ter, J. Am. Chem. Soc., 2017, R. Z. Lange, G. Hofer, T. Weber and A. D. Schlu 139, 2053. J. H. Lee, S. H. Jung, S. S. Lee, K. Kwon, K. Sakurai, J. Jaworski and J. H. Jung, ACS Nano, 2017, 11, 4155. R. Balgley, G. de Ruiter, G. Evmenenko, T. Bendikov, M. Lahav and M. E. van der Boom, J. Am. Chem. Soc., 2016, 138, 16398. X. Hu, G. Zhang, F. Bu and A. Lei, ACS Catal., 2017, 7, 1432. R. Zhou, H. Liu, H. Tao, X. Yu and J. Wu, Chem. Sci., 2017, 8, 4654. N. P. Ramirez and J. C. Gonzalez-Gomez, Eur. J. Org. Chem., 2017, 2154. Q. Zhang, Y. Ban, D. Zhou, P. Zhou, L. Wu and Q. Liu, Org. Lett., 2016, 18, 5256. J. Fang, Z. Wang, S. Wu, W. Shen, G. Ao and F. Liu, Chem. Commun., 2017, 53, 7638. D. Wei, Y. Li and F. Liang, Adv. Synth. Catal., 2016, 358, 3887. L. Wang, F. Wu, J. Chen, D. A. Nicewicz and Y. Huang, Angew. Chem., Int. Ed., 2017, 56, 6896. N. Zhang, Z. Quan, Z. Zhang, Y. Da and X. Wang, Chem. Commun., 2016, 52, 14234. ´, T. Slanina and B. Ko ¨nig, Chem. – Eur. J., 2016, A. U. Meyer, K. Strakova 22, 8694. D. Yang, B. Huang, W. Wei, J. Li, G. Lin, Y. Liu, J. Ding, P. Sun and H. Wang, Green Chem., 2016, 18, 5630. ¨nig, Green Chem., 2016, 18, 4743. J. Schwarz and B. Ko S. P. Midya, J. Rana, T. Abraham, B. Aswin and E. Balaraman, Chem. Commun.,, 2017, 53, 6760. T. Yajima and M. Ikegami, Eur. J. Org. Chem., 2017, 2126. ´sek, K. Strakova ´, T. Nevesely´, E. Svobodova ´, Z. Rottnerova ´ and M. Jira R. Cibulka, Eur. J. Org. Chem., 2017, 2139. ´, E. Svobodova ´, T. Hartman, M. Stibor, J. Kopecka ´, J. Cibulkova ´, J. ˇ Spacˇkova J. Chudoba and R. Cibulka, ChemCatChem, 2017, 9, 1177. ¨ster, R. Alonso, A. Bauer and T. Bach, J. Am. Chem. Soc., 2016, A. Tro 138, 7808.

112 | Photochemistry, 2019, 46, 78–115

375 376 377 378 379 380 381 382 383 384 385 386 387 388

389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407

R. Li, C. Ma, W. Huang, L. Wang, D. Wang, H. Lu, K. Landfester and K. A. I. Zhang, ACS Catal., 2017, 7, 3097. L. Wu, G. H. Yang, Z. Guan and Y. He, Tetrahedron, 2017, 73, 1854. W. Huang, W. Chen, G. Wang, J. Li, X. Cheng and G. Li, ACS Catal., 2016, 6, 7471. N. Noto, T. Koike and M. Akita, Chem. Sci., 2017, 8, 6375. G. Park, Y. Choi, M. G. Choi, S. Chang and E. J. Cho, Asian J. Org. Chem., 2017, 6, 436. ¨nig and B. V. Lotsch, Eur. J. Org. Chem., 2017, A. Meyer, V. W. Lau, B. Ko 2179. S. Paul and J. Guin, Green Chem., 2017, 19, 2530. M. Singh, A. K. Yadav, L. D. S. Yadav and R. K. P. Singh, Tetrahedron Lett., 2017, 58, 2206. ´rigaud, S. Peyrottes, J.-P. Uttaro and P. Geant, B. S. Mohamed, C. Pe ´, New J. Chem., 2016, 40, 5318. C. Mathe ´, Eur. J. Org. Chem., 2017, F.-Y. Geant, J.-P. Uttaro, S. Peyrottes and C. Mathe 3850. Q. Lefebvre, N. Hoffmann and M. Reuping, Chem. Commun., 2016, 52, 2493. S. Kamijo, G. Takao, K. Kamijo, T. Tsuno, K. Ishiguro and T. Murafuji, Org. Lett., 2016, 18, 4912. L. Song, S. Luo and J. Cheng, Org. Chem. Front., 2016, 3, 447. A. Gualandi, D. Mazzarella, A. Ortega-Martı´nez, L. Mengozzi, F. Calcinelli, E. Matteucci, F. Monti, N. Armaroli, L. Sambi and P. G. Cozzi, ACS Catal., 2017, 7, 5357. R. A. Aycock, H. Wang and N. T. Jui, Chem. Sci., 2017, 8, 3121. H. B. Hepburn and P. Melchiorre, Chem. Commun., 2016, 52, 3520. L. Zhu, L. Wang, B. Li, B. Fu, C. Zhang and W. Li, Chem. Commun., 2016, 52, 6371. B. Yang, X. Xu and F. Qing, Org. Lett., 2016, 18, 5956. M. Daniel, G. Dagousset, P. Diter, P.-A. Klein, B. Tuccio, A.-M. Goncalves, G. Masson and E. Magnier, Angew. Chem., Int. Ed., 2017, 56, 3997. K. Miyazawa, T. Koike and M. Akita, Tetrahedron Lett., 2016, 72, 7813. Y. Arai, R. Tomita, G. Ando, T. Koike and M. Akita, Chem. – Eur. J., 2016, 22, 1262. X. Geng, F. Lin, X. Wang and N. Jiao, Org. Lett., 2017, 19, 4738. W. Yu, X. Xu and F. Qing, Org. Lett., 2016, 18, 5130. J. C. K. Chu and T. Rovis, Nature, 2016, 539, 272. M. Zhang, W. Li, Y. Duan, P. Xu, S. Zhang and C. Zhu, Org. Lett., 2016, 18, 3266. W. Fu, X. Han, M. Zhu, C. Xu, Z. Wang, B. Ji, X. Hao and M. Song, Chem. Commun., 2016, 52, 13413. Z. Zhang, H. Martinez and W. R. Dolbier, J. Org. Chem., 2017, 82, 2589. G. Dagousset, C. Simon, E. Anselmi, B. Tuccio, T. Billard and E. Magnier, Chem. – Eur. J., 2017, 23, 4282. J. Li, J. Chen, W. Jiao, G. Wang, Y. Li, X. Cheng and G. Li, J. Org. Chem., 2016, 81, 9992. Y. Xu, Z. Wu, J. Jiang, Z. Ke and C. Zhu, Angew. Chem., Int. Ed., 2017, 56, 4545. S. Sumino, M. Uno, T. Fukuyama, I. Ryu, M. Matsuura, A. Yamamoto and Y. Kishikawa, J. Org. Chem., 2017, 82, 5469. H. Zhang, D. Chen, Y. Han, Y. Qui, D. Jin and X. Liu, Chem. Commun., 2016, 52, 11827. J. Zhong, C. Yang, X. Chang, Z. Zou, W. Lu and C. Che, Chem. Commun., 2017, 53, 8948. Photochemistry, 2019, 46, 78–115 | 113

408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443

T. Xiao, L. Li and L. Zhou, J. Org. Chem., 2016, 81, 7908. L. Li, T. Xiao, H. Chen and L. Zhou, Chem. – Eur. J., 2017, 23, 2249. A. Millet, Q. Lefebvre and M. Rueping, Chem. – Eur. J., 2016, 22, 13464. L. Capaldo, L. Buzzetti, D. Merli, M. Fagnoni and D. Ravelli, J. Org. Chem., 2016, 81, 7102. M. Zhang, R. Ruzi, J. Xi, N. Li, Z. Wu, W. Li, S. Yu and C. Zhu, Org. Lett., 2017, 19, 3430. F. Pettersson, G. Bergonzini, C. Cassani and C. Wallentin, Chem. – Eur. J., 2017, 23, 7444. Q. Qjn, Y. Han, Y. Jiao, Y. He and S. Yu, Org. Lett., 2017, 19, 2909. A. J. Musacchio, B. C. Lainhart, X. Zhang, S. G. Naguib, T. C. Sherwood and R. R. Knowles, Science, 2017, 355, 727. Y. Han, Y. Jiao, D. Ren, Z. Hu, S. Shen and S. Yu, Asian J. Org. Chem., 2017, 6, 414. J. Chen, W. Yu, Y. Wei, T. Li and P. Xu, J. Org. Chem., 2017, 82, 243. X. Yang, L. Li, Y. Li and Y. Zhang, J. Org. Chem., 2016, 81, 12433. D. Rackl, V. Kais, E. Lutsker and O. Reiser, Eur. J. Org. Chem., 2017, 2130. E. Fava, M. Nakajima, A. L. P. Nguyen and M. Rueping, J. Org. Chem., 2016, 81, 6959. R. Lin, H. Sun, C. Yang and W. Xia, Asian J. Org. Chem., 2017, 6, 418. D. Alpers, M. Gallhof, J. Witt, F. Hoffmann and M. Brasholz, Angew. Chem., Int. Ed., 2017, 56, 1402. S. Wang, W. Jia, L. Wang, Q. Liu and L. Wu, Chem. – Eur. J., 2016, 22, 13794. Q. Zhang, Z. Zhang, Y. Fu and H. Yu, ACS Catal., 2016, 6, 798. Y. Slutskyy and L. E. Overman, Org. Lett., 2016, 18, 2564. T. Niu, J. Cheng, C. Zhuo, D. Jiang, X. Shu and B. Ni, Tetrahedron Lett., 2017, 58, 3667. S. K. Pagire, S. Para and O. Reiser, Org. Lett., 2016, 18, 2106. H. Li, C. Shan, C. Tung and Z. Xu, Chem. Sci., 2017, 8, 2610. S. Ortgies, C. Depken and A. Breder, Org. Lett., 2016, 18, 2856. S. Sumino and I. Ryu, Asian J. Org. Chem., 2017, 6, 410. X. Guo, C. Hao, C. Wang, S. Sarina, X. Guo and X. Guo, Catal. Sci. Technol., 2016, 6, 7738. A. M. del Hoyo and M. G. Suero, Eur. J. Org. Chem., 2017, 2122. F. J. Sarabia and E. M. Ferreira, Org. Lett., 2017, 19, 2865. K. Murata, N. Numasawa, K. Shimomaki, J. Takaya and N. Iwasawa, Chem. Commun., 2017, 53, 3098. N. Ishida, Y. Masuda, S. Uemoto and M. Murakami, Chem. – Eur. J., 2016, 22, 6524. T. P. Nicholls, G. E. Constable, J. C. Robertson, M. G. Gardiner and A. C. Bissember, ACS Catal., 2016, 6, 451. G. P. Cerai and B. Morandi, Chem. Commun., 2016, 52, 9769. G. Zhang, X. Hu, C. Chiang, H. Yi, P. Pei, A. K. Singh and A. Lei, J. Am. Chem. Soc., 2016, 138, 12037. J. K. Pagano, C. A. Bange, S. E. Farmiloe and R. Waterman, Organometallics, 2017, 36, 3891. S. K. Pagire, A. Hossain, L. Traub, S. Kerres and O. Reiser, Chem. Commun., 2017, 53, 12072. T. R. Blum, Z. D. Miller, D. M. Bates, I. A. Guzei and T. P. Yoon, Science, 2016, 354, 1391. Z. D. Miller, B. J. Lee and T. P. Yoon, Angew. Chem., Int. Ed., 2017, 56, 11891. M. Jiao, D. Han, B. Zhang, B. Chen and Y. Ju, Comput. Theor. Chem., 2017, 1117, 47.

114 | Photochemistry, 2019, 46, 78–115

444 445 446 447 448 449 450 451 452 453 454

455 456

457 458 459 460 461 462 463 464 465 466

S. Lin, S. D. Lies, C. S. Gravatt and T. P. Yoon, Org. Lett., 2017, 19, 368. Y. Liu, M. Zhang, C. Tung and Y. Wang, ACS Catal., 2016, 6, 8389. A. Elhage, A. E. Lanterna and J. C. Scaiano, ACS Catal., 2017, 7, 250. L. Mao and H. Cong, ChemSusChem, 2017, 10, 4461. A. A. Ghogare and A. Greer, Chem. Rev., 2016, 116, 9994. J. Schachtner, P. Bayer and A. J. von Wangelin, Beilstein J. Org. Chem., 2016, 12, 1798. A. G. Mojarrad and S. Zakavi, RSC Adv., 2016, 6, 100931. ¨utigam, M. Kleczka and A. Raabe, Molecules, 2017, A. G. Giesbeck, M. Bra 22, 119. ¨ger, E. Bru ¨llingen, T. Lippold and A. G. Giesbeck, B. Goldfuss, C. Ja M. Kleczka, ChemPhotoChem, 2017, 1, 213. S. Domeyer, M. Bjerregaard, H. Johansson and D. S. Pedersen, Beilstein J. Org. Chem., 2017, 13, 644. D. S. Lee, Z. Amara, C. A. Clark, Z. Xu, B. Kakimpa, H. P. Morvan, S. J. Pickering, M. Poliakoff and M. W. George, Org. Process Res. Dev., 2017, 21, 1042. M. Jafarpour, H. Kargar and A. Rezaeifard, RAC Adv., 2016, 6, 79085. ´ceres, F. Martı´nez, E. A. Pa ´ez-Mozo, S. Valange, H. Martı´nez, M. F. Ca N. J. Castellanos, D. Molina, J. Barrault and H. Arzoumanian, J. Mol. Catal. A, 2016, 423, 248. Y. Huang, Z. Liu, G. Gao, G. Xiao, A. Du, S. Bottle, S. Sarina and H. Zhu, ACS Catal., 2017, 7, 4975. T. S. Symeonidis, A. Athanasoulis, R. Ishii, Y. Uozumi, Y. M. A. Yamada and I. N. Lykakis, ChemPhotoChem, 2017, 1, 479. A. Kumar, A. K. Gupta, M. Devi, K. E. Gonsalves and C. P. Predeep, Inorg. Chem., 2017, 56, 10325. M. Taguchi, Y. Nagasawa, E. Yamaguchi, N. Tada, T. Miura and A. Itho, Tetrahedron Lett., 2016, 57, 230. B. Chandra, K. K. Singh and S. S. Gupta, Chem. Sci., 2017, 8, 7545. G. Chen, L. Chem, L. Ma, H. Kwong and T. Lau, Chem. Commun., 2016, 52, 9271. D. Shen, C. Saracini, Y. Le, W. Sun, S. Fukuzumi and W. Nam, J. Am. Chem. Soc., 2016, 138, 15857. I. Schapiro, J. Phys. Chem. A, 2016, 120, 3353. M. M. Lerch, S. J. Wezenberg, W. Szymanski and B. L. Feringa, J. Am. Chem. Soc., 2016, 138, 6344. ´len, M. Blazejak, L.-M. Chamoreau, A. Huguet, S. Derenne, S. Gue `s-Mansuy and L. Fensterbank, Org. Biomol. Chem., F. Volatron, V. Mourie 2017, 15, 4180.

Photochemistry, 2019, 46, 78–115 | 115

Photochemistry of aromatic compounds Kazuhiko Mizuno DOI: 10.1039/9781788013598-00116

This chapter deals with the photochemical reactions of aromatic compounds including photoisomerization, photoaddition and cycloaddition, photosubstitution, intramolecular photocyclization, photorearrangement, photo-reduction and oxidation, and related photoreactions.

1

Introduction

The photochemistry of aromatic compounds is classified into the similar categories adopted in the previous reviews in the series.1–3 The photoisomerization of arylalkenes, photorearrangement, and photo-reduction and oxidation reactions have less appeared in the period (2016–2017). The photochromic properties including E–Z photoisomerization of azobenzenes and intramolecular photocyclization and cycloreversion of 1,2-di(hetero)arylethenes both in solution and in solid and crystalline states are interesting subjects, but this chapter does not deal with them. Under mild visible-light irradiation conditions, a variety of photochemical transformation using organic dyes and metal complexes such as Ru(bpy)321 and Ir(ppy)3 was reported in view of green sustainable chemistry.4–6 In addition, convenient methods using flow microreactors have been developed for synthetic organic photochemical reactions.7,8 Synthetic organic transformation using photochemistry was also covered in Chemical Reviews as a special issue including historical photoinduced reactions.5–7,9–15

2

Isomerization reactions

Photoisomerization of E-9,9 0 -bitriptindanylidene (E-1), a sterically crowded stilbene bearing E-oriented triptindane moieties, generated the corresponding Z-stilbene (Z-1) in a photostationary mixture (55 : 45). Photocyclodehydrogenation of (Z-1) in benzene solution afforded 1,2,9,10-tetrahydrocyclopenta[hi]acephenanthrylene (2) merged with two triptindane units in 85% yield16 (Scheme 1). Feringa demonstrated a visible-light driven molecular motor bearing dibenzofluorenyl moiety. Irradiation of ((R)-3) (420 nm light) was isomerized to its isomer17 (Scheme 2). Bell reported the photoisomerization of 2,2,2-triphenylethylidenefluorene derivatives (4) as moleculer rotors. Quantum yields for photoisomerization varied significantly with substitutents (f ¼ 0.26 for 2-nitro

Nara Institute of Science and Technology (NAIST) 8916-5 Takayama, Ikoma, Nara 630-0192, Japan. E-mail: [email protected] 116 | Photochemistry, 2019, 46, 116–168  c

The Royal Society of Chemistry 2019

hν hν

(E-1)

(Z-1) hν

(2) Scheme 1

Meax

hν

((P)-(R)-3)

Meeq

((M)-(R)-3) Scheme 2

Ph

Ph

Ph Ph

Ph Ph

hν X

X (Z-4)

(E-4) 4a; X = H, 4b; X =

tBu,

4c; X = NO2, 4d; X = CN, 4e; X = I

Scheme 3

(4c), f ¼ 0.39 for 2-cyano (4d), f ¼ 0.50 for 2-iodo (4e)). 2-Nitro deriveative (4c) is photochemically robust and has a large quantum yield for photoisomerization in the near-UV, which is useful for drive rotor moiety18 (Scheme 3). The amino-substituted fulvene (5) became aromatic in the photoactive excited state (6). It was found to increase the rotary quantum yields of the photoisomerization for light-driven rotary moleculer motors19 (Scheme 4). Upon visible-light irradiation, photoisomerization of E- and Z-stilbene was sensitized by W(CO)4L complexes (L ¼ 2-(1H-imidazol-2-yl)pyridine Photochemistry, 2019, 46, 116–168 | 117

hν + N

N

(6)

(5) Scheme 4

OC

CO N

OC

W

W OC

N

CO N

NH

OC

CO

NH

N CO 8

7 Scheme 5

200 fs Tws HTf MeO

N Z-9

266 nm

VR ~13.4 ps

N

OMe

E-9

Scheme 6

(7) and 2-(2 0 -pyridyl)benzimidazole (8)), which exhibited enhanced phosphorescence from the metal-to-ligand charge transfer (MLCT) excited state with the quantum yield in the order of 103, almost two orders of magnitude higher than those reported for W(CO)4(diimine) complexes. The latter complex (8) also sensitized the photoisomerization of a-methylstilbene, a-phenylcinnamonitrile, and cinnamyl alcohol20 (Scheme 5). Ultrafast E–Z photoisomerization of N-(2-methoxybenzylidene)aniline (9) around C–N double bond was observed and twisted intermediate states were elucidated21 (Scheme 6). Irradiation with 420 nm visible light of the E,Z-configuration (E,Z-10) of bis-hemithioindigo afforded the planar Z,Z-isomer (Z,Z-10) in a highly selective manner. The E,Z-isomer, which has helical conformation, recognized electron-poor aromatic guest (11) to give a charge-transfer (CT) complex (12), which thermally generated the stable Z,Z-isomer (Z,Z-10)22 (Scheme 7). Photoisomerization of aromatic thiol giving thione and thiyl radical was discussed using time-resolved X-ray absorption spectroscopy.23 118 | Photochemistry, 2019, 46, 116–168

NMe2

O C5H11

Me2N

S

S O

C5H11 Me2N hν (420 nm)

NMe2

(Z,Z)-10 Δ

Δ O

NC

C5H11 S

S

CN

O2N

NO2

O C5H11

hν (420 nm)

(11) Me2N

NMe2 12

NMe2

Me2N

iE,Z-10 - 11Åj CT complex

(E,Z-)10 Scheme 7

3

Addition and cycloaddition reactions

Yang and Cong synthesized oligoparaphenylene-derived nanohoop (16) using photodimerization-cycloreversion of anthracene (15),24 which was prepared from diborylanthracene (13) and/or its photocyclodimer (14) (Scheme 8). The photodimerization and cycloreversion of bis-anthracene cyclophane (18) was discussed from the effect of pressure on the reaction rate by Plotnikov and Martinez. Their model predicts that the barrier reduction is linear in the low-pressure regime (up to 2 GPa), but has a nonlinear at higher pressure.25 (Scheme 9). Upon irradiation at 300 nm, the fluorinated azacyclophane (19) afforded the photodimer (20) of benzene core, which was thermally isomerized to syn-o,o 0 -dibenzene isomer (21). The syn-isomer was photochemically cyclized to the cage diene isomer (20)26 (Scheme 10). Maeda and Mizuno reported the disasterselective photocycloaddition of (l )-menthyl 2-naphthalenecarboxylate (22) with 3-furanmethanol (23) to afford caged products (24), (25) (d.e. ¼ 48%, 40% respectively). In photoreactions of di-8-phenyl-(l)-menthyl 2,3-naphthalenedicarboxylate with (23), maximum 67% d.e. was obtained27 (Scheme 11). The photoreaction of 1-cyano-4-hydroxymethylnaphthalene (26) with ethyl vinyl ether (27a) afforded [2 þ 2] cycloadducts (28) and (29) at room temperature in a highly endo-selective manner (89 : 11) via intermolecular hydrogen bonding. However, in the photoreaction with 2hydroxyethyl vinyl ether (27b), lower stereoselectivity (56 : 44) was Photochemistry, 2019, 46, 116–168 | 119

Scheme 8

hν hν 17

18 Scheme 9

observed at room temperature, but at 40 1C highly endo-selective [2 þ 2] photocycloaddition occurred in an 81 : 19 ratio28 (Scheme 12). The hexadehydro Diels–Alder cycloisomerization to produce reactive benzyne derivative (31) afforded polycyclic benzene derivative (32) upon photo-irradiation of tetrayne compound (30). The photoreaction proceeded at much lower temperature (including even at 70 1C) than the thermal reaction29 (Scheme 13). 120 | Photochemistry, 2019, 46, 116–168

F

F

NR F F F

F RN

F F

F

F F

19

NR

F

hν

F F RN

F

NR F

Δ

F F

F

hν (300 nm)

F

F

F F RN

F 21

R = COtBu

20 Scheme 10

O O

+

CH2OH O hν

22

23 OH

O

O

O

OH O

+

O

O

25

24 Scheme 11

OH

OH

OH

R hν

+ O CN 26

O

R

CN O

CN

27 a; R = H b; R = OH

+

28

endo >8

exo 280 nm)

41

CH3CN NC

CN CN + H

H H

NC

CN H

H

n

H H

CN

H

n

H H 43

42 Scheme 16

NC

NC

hν > 280 nm

NC

dry CH3CN 44

aq. CH3CN

O

O

O

46

45 NC

CN

hν > 280 nm CH3CN n

47

NC

H H

NC

CN

NC H

n 48

n = 1,2 Scheme 17 Photochemistry, 2019, 46, 116–168 | 123

Ar CN

O NC

NC hν

O

O

Ar

49

+

50

51

head-to-head

Ar = Ph, p-MeOC6H4, p-MeC6H4 CN

CN hν

head-to-tail

NC

Ar

Ar

+

O

52

Ar

54

O O

Ar

53

Ar = Ph, p-MeOC6H4, p-MeC6H4 Scheme 18

R1 CN 55

O Ar hν > 280 nm

R2

R1

R1 CN Ar

CN

Ar

+ O H O

R2

56

R2

57

Scheme 19

Although C-9 C-10 [2 þ 2] cycloadducts (59), which underwent cycloreversion under longer irradiation, were initially produced, prolonged irradiation selectively afforded (61). Product distributions were dependent on electron-donating and accepting substituents. In the case of R1 ¼ R4 ¼ CN, R2 ¼ H, R3 ¼ OMe, (61) was exclusively produced from the initial stage in a highly selective manner. Aminobenzocyclobutenes (62) were conveniently synthesized by [2 þ 2] cycloaddition of arynes with ketenes followed by reductive amination. The distonic radical cations of (62) upon photooxidation by an excited iridium complex underwent the annulation with arylalkynes (63) to give a variety of naphthalenes (64)37 (Scheme 21). Copper ([Cu(dap)2]1)-catalyzed visible-light irradiation of maleinimides (65) with N,N-dimethylanilines (66) and N-aryltetrahydroisoquinolines (68) 124 | Photochemistry, 2019, 46, 116–168

R2

R4 R1 O

R3

hν benzene

58

R2 R4

R2

R1

R1

O + R3

O

R3 59 R1 = H, CN R3 = H, OMe

R4

60

R2 = H, CN R4 = H, CN, OMe R2

R1 O

R3 61

R4

Scheme 20

Ar

H N R

+

R = MeO, (MeO)2, BnO

Ar R

toluene visible light

CF3 62

[Ir(ppy)2(dtbbpy)][PF6] (2 mol%), K2HPO4

63

64

ppy; 2-phenylpyridine dtbbpy; di-tbu-2,2’-bipyridine

Ar = Ph, p-BrC6H4, p-MeOC6H4, p-nBuC6H4 etc. Scheme 21

in the presence of Brønsted acid such as trifluoroacetic acid (TFA) afforded tetrahydroquinolines (67) and octahydroisoquinolino[2,1-a]pyrrolo[3,4c]quinolines (69) in good yields38 (Scheme 22). Strained and macrocyclic [k](1,7)naphthalenophanes (m ¼ 1, 2, 4, 12; n ¼ 0, 1, 2; k ¼ 11, 12, 14, 16, 18, 22, 24) (71) were synthesized in moderate to good yields by using the photo-dehydro-Diels–Alder reaction of (70)39 (Scheme 23). A suspension of several solid photoactive trans-cinnamic acid derivatives (72) and (73) in cyclohexane exclusively afforded [2 þ 2] homocycloadducts (74) and (75) with total regio- and stereo-selectivities, and no cross-adducts were obtained40 (Scheme 24). Similarly p-, m-, ohydroxycinnamic acid (76), (77), and (78) gave only homo-cycloadducts (79), (80), and (81), respectively.40 Photochemistry, 2019, 46, 116–168 | 125

O R1

N O

H

2.0 equiv TFA green LED DMF, RT, air

R2

O

65

+

N

67

5% [Cu(dap)2]Cl

N

O 65

R

68

H N

2.0 equiv TFA green LED DMF, RT, air

H O

R = H, F, OMe

N

N

R3 = p-OMeC6H4

N

[Cu(dap)2]+

H

N Ph

R3

R3

O

R1

66

O

R2

H N

R2 = H, Br, i Pr

R1 = Ph, Bn, C6F5

Ph

N

5% [Cu(dap)2]Cl

N

+

R

O 69

Cu N R3

R3 Scheme 22

O O O n

O

m O O 70

n

hν CH2Cl2

O

n

O

O

O m

O

m = 2, 3, 4, 6, 10 12 n = 0, 1, 2 k = m + 2n + 8 = 11, 12, 14, 16, 18, 22, 24

n O

71

Scheme 23

Visible-light induced intermolecular [2 þ 2] photodimerization of chalcones (82) and cinnnamic acid derivatives in the presence of factris(2-phenylpyridinato-C2,N) iridium (Ir(ppy)3) efficiently occurred to give cyclobutanes (83) in a highly regio- and diastereo-selective manner. In a similar manner, Ir-complex-sensitized photoreaction of (82) and related a,b-unsaturated aryl compounds (84) with 1,1-diphenylethene (85) afforded [2 þ 2] cycloadducts (86) in high yields41 (Scheme 25). Yamada reported the [2 þ 2] photocyclodimerization of (E)-4-(2-(2naphthyl)vinyl)pyridine (87) and (E)-4-(2-(1-naphthyl)vinyl)pyridine (88) in acidic solution (HCl) via cation–p interaction in a highly stereoselective manner accompanying Z-isomers (93). Anti-head-to-tail cyclodimer (89) was 126 | Photochemistry, 2019, 46, 116–168

hν Me

Me

365 nm cyclohexane

Me CO2H

suspennsion stirring 48 h

CO2H

72

73 p-Tol

CO2H

4,3 Me2C6H3

HO2C

p-Tol

HO2C

74 HO

CO2H 3,4-Me2C6H3

75

OH 4-HOC6H4 CO2H 76

CO2H 77

HO2C

365 nm cyclohexane

OH

4-HOC6H4

HO2C

79

suspennsion stirring 48 h

CO2H

3-HOC6H4

CO2H

CO2H 3-HOC6H4

80 2-HOC6H4

CO2H 81

78 HO2C

2-HOC6H4

Scheme 24

O O 2

Ar

hν, 1 mol % Ir(ppy)3 Ar’

O

Ar‘

1,4-dioxane, Ar, RT, 24h

82

Ar’ Ar

Ar

83

anti-head-to-head

Ar, Ar’ = Ph, o-, p-MeC6H4, o-, p-FC6H4, o-, p-ClC6H4 etc. O O

Ph +

Ar

R 84

Ph

hν, 1 mol % Ir(ppy)3 ClCH2CH2Cl, Ar, RT

85

Ph Ph Ph

Ph 86

R = Ph, OMe, OBn, OH, NH2 etc. Scheme 25

selectively obtained. This photoreaction proceeded upon visible and/or UV light irradiation42 (Scheme 26). Visible-light induced photocatalytic [4 þ 2] benzannulation in the presence of Ir(ppy)3 and tBuONO as a diazotizing agent afforded polycyclic aromatic compounds such as phenanthrenes (95) in moderate to high yields43 (Scheme 27). An efficient radical addition/elimination reaction occurred in the diarylketone-sensitized photoreaction of alkenyl and alkynyl sulfones (96) Photochemistry, 2019, 46, 116–168 | 127

N

N

87

88 hν(> 300 nm) HCl (3 equiv) MeOH

Py Py

Py Np

+

+ Np

Np

Py

Py Py

89

Np

Py Np +

Np

Np

90

+ Py

Np

91

N

Np

92

93

Scheme 26

R1

R1 blue LEDs (7 W) fac-Ir(ppy)3 t BuONO

R3 NH2

+

R3 R4

R4 R2

R2

94

95 R3 = H, Ph, CO2Et R4 = CO2Et, Ph, p-F-C6H4, p-Cl-C6H4, p-MeO-C6H4, o-CF3-C6H4, p-tBu-C6H4

R1 = H, p-F, p-Me, p-CO2Me R2 = H, m-Cl, p-Cl, p-tBu

Scheme 27

SO2Ph

Ph

4,4’-Cl2Ph2CO (20 mol%) +

36 W CFL

O

Ph

O SO2Ph

Ph

O

97 E : Z = 94 : 6

96

O

4,4’-Cl2Ph2CO (20 mol%)

+

Ph NHCH3

36 W CFL

98

99

N H

Scheme 28

and (98) in the presence of ethers or amides in high yields. The process is based on the catalytic formation of a-alkoxy/a-amidyl radicals via homolytic activation of the C(sp3)–H bond of ethers/amides with a catalytic amount of diarylketones in the presence of fluorescent light44 (Scheme 28). Unsymmetrical 2,3-diaryl substituted indoles (102) were synthesized from arylsulfonyl chlorides (100) and o-azidoarylalkynes (101) in the presence of Na2HPO4 under transition-metal free, visible-light irradiation45 (Scheme 29). 128 | Photochemistry, 2019, 46, 116–168

R Ar 1,4-CHD Eosin Y, MeCN

SO2Cl R

+ 100

Ar N 102 H

Na2HPO4 visible light

N3 101

R = F, Cl, Me, MeO etc.

Ar = Ph, p-FC6H4, p-MeOC6H4 etc. Scheme 29

Br +

R

CBr4

Eosin Y CoI2

CO2H R

CBr3

+ R

DMSO visible light 104

103

105

R = H, o-, m-, p-Me, p-F, p-Cl, p-Br, p-MeO etc.

Scheme 30

+ N 106

NH2

Ar 63

O

5 mol% CuCl CH3CN, RT, 10 h O2 blue LEDs

O Ar

N

N H

- CO O

N 108

N H

Ar

107

Ar = Ph, p-tBuC6H4, p-MeOC6H4, 4-FC6H4, 1-naphthyl, 2-naphthyl etc.

Scheme 31

Photoredox and cobalt-catalyzed carboxylation of styrenes (103) with CBr4 afforded the a,b-unsaturated carboxylic acids (104) via radical addition and Kornblum (DMSO) oxidation accompanied by addition products (105). DMSO serves as the oxidant, oxygen source and solvent under the photocatalytic conditions46 (Scheme 30). Visible-light irradiation of 2-aminopyridine (106) with terminal arylalkynes (63) in the presence of copper(I)-catalysis afforded aerobic oxidative C–N coupling products (108). At room temperature, C–C triple bond cleavage occurred with the elimination of carbon monoxide to give (108)47 (Scheme 31). Visible-light irradiation of aryl halides (109) with arylalkynes (63) in the presence of rhodamine 6G (Rh-6G) and N,N-diisopropylethylamine (DIPEA) gave pyrrolo[1,2-a]quinolines (110) and ullazines in moderate to good yields48 (Scheme 32). Furo[3,2-c]coumarines (112) using visible-light promoted photoredox neutral coupling of 3-bromo-4-hydroxycoumarines (111) with arylalkynes (63) were synthesized in the presence of Ir(ppy)2(dtbbpy)PF6 and NaHCO3 in DMSO49 (Scheme 33). Photochemistry, 2019, 46, 116–168 | 129

R1

R1 Br

Rh-6G

+

N

N

DIPEA, DMSO LED 455 nm R

109

63

R1 = H, CF3, COCH3

R

110 R = H, Me, MeO, F, Cl

Scheme 32

Ar OH

O Br

R

Ir(ppy)2(dtbbpy), NaHCO3 +

O

DMSO, 13 W white LEDs R Ar

O

O

O 63

111

112

R = H, OMe, Br, Cl Ar = H, p-MeC6H4, o-, m-, p-MeOC6H4, p-tBuC6H4 etc. Scheme 33

N+

N

H

Me

Broensted acid

113

+ pseudo iminium ion

R

Me N

R 114 Me

R = H, o-, m-, p-Me, o-, m-, p-F etc. Broensted acid (10 mol%) IrIII photocatalyst

Blue LEDs strip PhMe, 25 oC, 14 h

N

115

N

Ph

R

Scheme 34

The conjugated addition of a-amino radicals to arylalkenylpyridines (113) occurred to give (115) in the presence of Brønsted acid and visiblelight photoredox catalysis Ir[dF(CF3)ppy]2(dtbbpy)PF6 via pseudo iminium cation intermediates (114)50 (Scheme 34). Axially chiral 3,4-bisbenzylidene succinate amide esters (116) and (118) photocyclized to give a formal skeleton of ()-podophyllotoxins (117) and (119) by using continuous flow photochemical reactor51 (Scheme 35). Visible-light irradiation of styrenes (103) with difluoromethyltriphenylphosphonim bromide (120) as difluoromethylating reagent and alcohols/water as the nucleophiles afforded difluoromethyl-containing alcohols and ethers (121) in moderate to excellent yields52 (Scheme 36). 130 | Photochemistry, 2019, 46, 116–168

CH3

O N

R

O

CH3

CH3 N

R

hν

CH3

Ph

O O

Ph

O

R

O

R

117

R = 3,4,5-trimethoxy

116

R2 O R2

N O N

R1

R1

hν

R1

O

R2

O

O R2

118

O

119 R1 = methoxy

R2 = methyl

R1

Scheme 35

Nu visible light +

Ar

[Ph3PCF2H]+Br-

103

CF2H Ar

photocat, NuH

120

Nu = OH, OR’

121

Ar = Ph, p-MeOC6H4, p-ClC6H4, p-PhC6H4 etc.

Scheme 36

O R’ R

HO

hν (350 nm)

O

TI(Oi Pr)4, BF3•Et2O

X

O

123

122

X = CH2, OCH2, CH2CH2

R’

X

R = H, o-, m-, p-Me, 2,4,6-Me3 R’ = H, Me, Ph

Scheme 37

Griesbeck et al. reported the hydroxyalkylation of aromatic aldehydes and ketones (122) with cyclic ethers giving (123) in the presence of a mixture of Ti(OiPr)4 and BF3  Et2O53 (Scheme 37). Upon metal-free visible-light irradiation, hydroxyazidation of amethylstyrene (124) efficiently occurred to give (126) via (125) in the presence of trimethylsilyl azide (TMSN3), oxygen, and 9-mesityl-10methylacridinium perchlorate (Acr1Mes ClO4) as a photocatalyst54 (Scheme 38). Photochemistry, 2019, 46, 116–168 | 131

Acr+Mes ClO4- (3 mol%) toluene (0.05 M) TMSN3

N3

O2 balloon, 4 Ä MS rt, 12 h, 8 W blue LEDs

124

N3

O OR

OH

R = TMS, H 125

126

Scheme 38

Me O O

Ru(bpy)3Cl2 HE, additive solvent, rt, Ar 40 W CFL

O

O O +

O N

S Ph O

O

127

Me

129

98 H H

EtO2C

CO2Et

HE : Hantzsch ester Me

N H

128 Me

Scheme 39

NH2 HO CHO

+

CN CN

O2 N

130

CN

O

visible light (22 W)

+ O

RT

O

131

O

O

NO2

132

Scheme 40

Internal alkynes (129) from 1-(2-(phenylsulfonyl)ethynyl)benzene (98) with N-phthalimidoyl oxalate (127) were efficiently synthesized by using visible-light in the presence of Ru(bpy)3Cl2 and Hantzsch ester (128)55 (Scheme 39). Highly functionalized dihydropyrano[2,3-c]chromenes (132) using visible-light irradiation of p-nitrobenzaldehyde (130), malononitrile, and 4-hydroxycoumarine (131) via a multicomponent-tandem strategy were efficiently synthesized under solvent and catalyst free mild conditions56 (Scheme 40). Visible-light irradiation of N-aryl glycines (133) with diazo compounds in the presence of rose bengal afforded N-arylaziridines (135) via decarboxylative cyclization (aza-Darzens reaction)57 (Scheme 41). A visible-light induced regio- and stereo-selective addition of alkyl bromide (136) to arylacetylenes (63) gave alkenyl bromides (137) in high efficiency under ambient and metal-free reaction conditions58 (Scheme 42). The photoredox-induced intra- and inter-molecular radical [4 þ 2] annulations of indole derivatives (138) and (142) in the presence of 132 | Photochemistry, 2019, 46, 116–168

-

visible light CO2H Rose Bengal

H N Ar

H

N

+

-H

Ar

N+

O2

Ar

133

+

N2

134

H

R = Et,

etc.

H

CO2R

3-exo-tet cyclization

Ar = Ph, o-, m-, p-MeC6H4, p-F-, p-Cl-, p-Br-C6H4 etc. i Pr, nBu, tBu

CO2R

N2

Ar N

135

CO2R

Scheme 41

Ar O NC

CN

photocatalyst (5 mol %)

Br

+ Ar

N Ph O

O NC

H

63

light source solvent. 48 h

Br

CN H

N Ph O

137

136 Ar = Ph, p-F-, p-Cl-, p-Me-, p-MeO-, p-NO2-C6H4 etc. Scheme 42

Scheme 43

Ru(bpy)321 or Ir(ppy)2(dtbbpy)1 complex as photocatalyst (PC*) afforded tricyclic tetrahydropyridoindoles (139, 140, 143, and 144) via 3-indolyl radicals59 (Scheme 43). Dual gold/photoredox-catalyzed C(sp)–H arylation of terminal arylalkynes (63) using aryl diazonium salts (145) afforded functionalized arylalkynes (146) under mild, redox-neutral conditions60 (Scheme 44). Photochemistry, 2019, 46, 116–168 | 133

AuI complex (10 mol%) Ru(bpy)3 (2.5 mol%)

N2+BF4-

+

DMF (0.1 M) 23 W CFL, rt. 2h

R ’R

63

145

R

R’

146

Au complex ; (p-MeOC6H4)3PAuCl R’ = H, p-CN, p-CO2Et etc.

R = H, p-CN, m-, p-CF3 etc.

Scheme 44

O S Ar

Br

+

O

R

O

R

DMSO, hν

O

147

N

Ir(ppy)3, Li2CO3

N

148

149

CH2SO2Ar

Ar = Ph, p-MeC6H4, p-NO2C6H4, p-MeOC6H4 R = Ph, p-NO2C6H4, p-MeOC6H4 Scheme 45

+ R

O O S F

F F 150

103

+ 152

F

visible light CO2Me fac-Ir(ppy)3 (3.5 mol%)

O O S F F F

NMP, N2, rt, 20 h

CO2Me R

151

t

R = H, p- Bu

visible light CO2Me fac-Ir(ppy)3 (3.5 mol%) 150

F

NMP, N2, rt, 20 h

F 153

F CO2Me

Scheme 46

Visible-light induced radical (phenylsulfonyl)methylation reaction of N-arylacrylamides (148) using bromomethyl phenyl sulfone derivatives (147) in the presence of Ir(ppy)3 and Li2CO3 occurred to give cyclized (arylsulfonyl)methylated compounds (149) under a mild and efficient processs61 (Scheme 45). The visible-light-induced reaction of FO2SCF2CO2Me (Chen’s Reagent) (150) with styrenes (103), indene (152), unactivated alkenes, and heteroarenes using fac-Ir(ppy)3 afforded a variety of carbomethoxydifluoromethylated products such as (151) and (153) in good to excellent yields62 (Scheme 46). Han et al. found the regio- and stereo-selective photoredox-catalyzed chlorotrifluoromethylation of internal arylalkynes (154) to give functionalized alkenes (156) in the presence of CF3SO2Cl (155) under mild conditions using visible light63 (Scheme 47). Photoinduced tandem cyclization of 3-iodoflavones (157) with electronrich five-membered heteroarenes in acetonitrile without any additives 134 | Photochemistry, 2019, 46, 116–168

blue LED Ir(ppy)3(2 mol%)

O R1

R2

+

154

Cl 155

S CF3

CF3 R

Ar

THF, Ar, 30 oC

O

Cl 156

R1 = MeO, CN, CO2Me, TfO, NHAc, NHTs etc R2 = Me, n-Bu, t-Bu, cyclopentyl, cyclohexyl, CO2Et etc. Scheme 47

OMe

OMe Me O

O

N

hν, Ar

+

MeCN

I O

158

157

O

N Me OMe

O hν, Ar MeCN O 159

N Me

Scheme 48

O Ar

Alkyl 63

O 160

O

Alkyl O

Ru(dtbbpy)3Cl2•6H2O NiCl2, Salen, base Ar white LED 161

Alkyl

Ar = Ph, m-, p-MeC6H4, p-FC6H4, p-ClC6H4 etc. Alkyl = C5H11, C7H15, C11H23, etc. Scheme 49

such as transition metals, ligands, and oxidants, afforded (159) via (158) under mild conditions64 (Scheme 48). A photo- and nickel co-catalyzed hydroalkylation of terminal arylalkynes (63) by alkyl diacyl peroxides (160) occurred to give Z-preferred alkenes (161) in moderate to good yields under visible-light irradiation conditions65 (Scheme 49). Polysubstituted furans from a-chloro-alkyl ketones (162) and styrenes (103) via domino radical addition/oxidation sequence were efficiently synthesized to give 2,3,5-trisubstituted furans (163) under visible-light irradiation conditions using photocatalyst fac-Ir(ppy)3, oxidant K2S2O8 and base Cs2CO366 (Scheme 50). An intermolecular radical-radical cross-coupling reaction of secondary and tertiary amines (164) with diaryl ketones (165) and aldehydes occurred to give 1,2-amino alcohols (166) using visible light photoredox Photochemistry, 2019, 46, 116–168 | 135

R

O

visible light fac-Ir(ppy)3, DMSO

+ Cl

103

162

O

Na2S2O8, Cs2CO3, rt

163

R

Scheme 50

H N Me

CO2Et +

164

O Ar

H N

fac-Ir(ppy)3 (2 mol%) Ar

DMAP, LiBF4, RT 3 W blue LEDs

165

Ar OH

CO2Et

Me

Ar = Ph, p-MeO-C6H4, p-F-C6H4

Ar

166

Scheme 51

R1

O R2

H N

Br N

R1

hν, Ir(ppy)3 (2 mol%)

+

Na2CO3, CH3CN, rt

168

167

N

Ph

N R2

169

R1 = Ph, o-, m-, p-MeC6H4, p-MeOC6H4, p-FC6H4, p-ClC6H4, p-BrC6H4, etc. R2 = Ph, m-, p-MeC6H4, p-MeOC6H4, p-FC6H4, p-BrC6H4, Me, tBu Scheme 52

Ir(ppy)2(bpy)+ (10 mol%) Fe(OTf)2 (2 equiv)

Me O N

Ar +

170 Ar =

3,5-di-tBuC6H3

R

O N

O

171

O R

O N

O

CH2Cl2 10 oC, 18 h visible light

172 NMeAr

R = Pr, PhCH2CH2 etc. Scheme 53

catalyst fac-Ir(ppy)3 in moderate to good yields under mild conditions67 (Scheme 51). 1,3,5-Trisubstituted pyrazoles (169) under visible-light irradiation conditions using Ir(ppy)3 were synthesized via radical addition of hydrazones (167) by a-bromo ketones (168)68 (Scheme 52). Miyake et al. reported visible light mediated a-arylation of a,bunsaturated imides (171) via aminium radicals from diarylalkylamines (170) to produce (172) using a photoredox catalyst69 (Scheme 53). Aromatic amides (175) via radical arylation of tert-butyl isonitrile (174) using arylazo sulfones (173) in aqueous acetonitrile were prepared under metal-free visible-light irradiation conditions70 (Scheme 54). 136 | Photochemistry, 2019, 46, 116–168

SO2CH3 N N Ar 173

+

O

LEDs R-NC 174

C

CH3CN/H2O 9/1

Ar 175

N H

R

R = tBu, cyclohexyl

Ar = p-COCH3, m-, p-NO2, m-, p-CN etc. Scheme 54

4 Substitution reactions The visible light catalyzed photosubstitution of aryl diazonium salts (145) have been investigated by several groups. Upon blue LED irradiation, aryl methyl sulfoxides (176) were efficiently synthesized using (141) and DMSO in the presence of Ru(bpy)3Cl2 as a photosensitizer under mild conditions. Diaryl sulfides (178) were efficiently obtained via organocatalytic visiblelight-mediated process from aryl thiols (177) with (145) in the presence of eosin Y under air. Diaryl disulfides (179) were efficiently produced via visible-light-promoted coupling of (145) and CS271–73 (Scheme 55). Direct photoarylation of heteroarenes such as furan, thiophene, and N-methylpyrrole and coumarines with (145) smoothly occurred in the presence of porphyrins as photosensitizers. One-electron transfer from excited porphyrin to (145) causes the formation of aryl radical as a key intermediate74 (Scheme 56). Similar C–H arylation of heteroarenes with (145) using TiO2 was efficiently achieved by use of continuous flow microreactor.75 The cross-coupling of nitroalkenes (181) with (145) under transitionmetal-free conditions efficiently afforded trans-stilbene derivatives (182) under visible light irradiation. This photoreaction proceeded via a radical pathway, with (181) serving as the radical acceptor76 (Scheme 57). Protti and Fagnoni reported the formation of aryl-carbon bonds via photogenerated phenyl cations. A variety of arylated products including biaryls, allylarenes, and 2-arylacetals were smoothly synthesized using flow system under metal-free mild conditions.77 UV irradiation of aryl chloride (183) and (186) in the presence of inert arenes (185), (189), and (190) caused C–C coupling to give biaryls as a facile, efficient, and catalyst-free method78 (Scheme 58). The aryl radical via homolytic cleavage of C–Cl bond is a key intermediate for the formation of biaryls (185, 189, and 190). 5-Phenylpirimidine (192) from 5-bromopyrimidine (191) in the presence of benzene was obtained under UVA irradiation conditions79 (Scheme 59). A variety of hetero-biaryl derivatives were synthesized under mild conditions. Rossi et al. reported the mechanistic insight of a photoinduced basepromoted homolytic aromatic substitution (photo-BHAS). Dimsyl anion, from a strong base such as KOtBu and DMSO, is responsible for inducing the initiation by a photo-BHAS process on alkyl halide. 1-Phenyladamantane (194) via photo-BHAS in the presence of KOtBu and DMSO was efficiently obtained from 1-iodoadamantane (193) and benzene (187)80 (Scheme 60). They also found the direct arylation of benzene to afford 194 using KOtBu and DMSO at room temperature in the absence of Photochemistry, 2019, 46, 116–168 | 137

O O

N2+BF4-

+

R

[Ru(bpy)3]Cl2 (2 mol%)

S Me

Me

blue light, N2, 25

S Me

R

oC

145

176

R = H, 4-MeO, 3,4-diMeO, 4-Me, 3,4-diMe, 4-isopropyl, 4-nitro, 4-Cl, 4-F etc. SH N2+BF4-

S

Green LEDs

+

R

cat., Air, 23 oC OMe 145

178

177

R

N2+BF4-

Ru(bpy)3 (PF6)2 (1 mol%)

+ CS2

R

visible light, DMSO, rt

S S

R

145

179 Scheme 55

N2+BF4 hν

+

Porphyrin or TiO2

O R

145

R = p-F, p-Cl, p-Br, p-NO2, m-CF3

O

R 180

Scheme 56

N2BF4 NO2

Eosin-Y (5 mol%) +

181

R1

DMF, rt LED (530 nm)

145

R1 182

R1 = H, o-, p-Me, o-, m-, p-OMe, o-, m-, p-Cl, p-NEt2,1-naphthyl etc. Scheme 57

any additive. The same methodology was applied to the photoarylation of alkenes to give 196 and 197 using only KOtBu and/or 18-crown-6-ether without any solvent. The visible-light-mediated C–C and C–O cross-coupling of electron-rich phenols (198) and arenes (199) were reported by using [Ru(bpz)3](PF6)2] as photosensitizer and ammonium persulfate as terminal oxidant81 (Scheme 61). 138 | Photochemistry, 2019, 46, 116–168

MeO

OMe hν

+ Cl

+

flow reactor MeCN–H2O (5 : 1)

184

185

183

D Cl +

186

D

D

+ D

D

D

hν

D +

254 nm

D

D

187

C6H5OMe

D

189

188

D

190

70% yield KH /KD = 0.92

Scheme 58

Ar

Br

UVA, K2CO3 (1.1 equiv) + ArH N

MeCN, rt, 24 h

N

N

ArH: C6H6, C6H5Cl

191

N

192

Scheme 59

I

KOtBu, hν

+

Ph

DMSO 187

193

95%

194

R1

Ph R1

Ph

X ArH KOtBu, hν

t

KO Bu, hν R 196 30-87% R1 = H, Me, Ph

18-crown-6 ether

Ar 197

DMSO R ArH = benzene, X = I, Br, Cl thiophene 44-97% R = Me, OMe, CN CO2Et, CF3, Ph, etc. R

195

Scheme 60

Irradiation of primary alkyl bis-catecholato silicates (203) with aryl and heteroaryl bromides 204 in the presence of photoredox and nickel catalysis afforded aryl- and heteroaryl-alkyl cross coupling products (205, Scheme 62).82 Photochemistry, 2019, 46, 116–168 | 139

OMe OH

OMe + MeO

198

OMe Ru(bpz)3(PF6)2 (NH4)2S2O8 blue LEDs 23 oC

199

OMe MeO

OMe OMe

OH +

O

O

202

+

OMe 200

OMe

OMe

OMe

OMe

OMe MeO

OMe

201

OMe

MeO

OMe

Scheme 61

[Ir] (2 mol%) Ni(COD)2 (3 mol%) dtbbpy (3 mol%)

R +

O K O [18-C-6] Si O O

AcO

+

OAc

DMF, Blue LEDs 24 h, rt

Br

203

R

204

205

R = p-CH3CO, m-CH3CO, Me3Si, F, Cl, Br, Me etc. Scheme 62

CN

O

N +

UV-bulb or sunlight

207

R

N 210

phenanthrene

OH 206

R

NC

EWG

R

208 209

R = PhCH2-, Me2CHNHBoc,

etc. O

EWG 211

EWG = CN, CO2Me

Scheme 63

Opatz et al. reported the transition-metal-free decarboxylative photoredox coupling of carboxylic acids 206 with aromatic and heteroaromatic nitriles (207, 208) in the presence of phenanthrene (209). This C–C bond formation upon inexpensive UV sources or sunlight proceeded through a free radical mechanism83 (Scheme 63). 140 | Photochemistry, 2019, 46, 116–168

Irradiation of 2-methylquinoline (212) with hydrogen donors (213) in the presence of tetrabutylammonium decatungstate photocatalysis (TBADT) afforded cross-dehydrogenative coupling products (214) under mild conditions84 (Scheme 64). Cross-coupling reaction of 4-iodobiphenyl (215) with 4-benzyl-1,4dihydropyridine derivative (216) was promoted by a combination of nickel and photoredox catalysts85 (Scheme 65). In the absence of NaOAc or 4,4 0 di-tert-butyl-2,2 0 -bipyridyl (dtbbpy), the yield of (217) was decreased. Balaraman reported the metal-free radical trifluoromethylation of b-nitroalkenes (181) with CF3SO2Cl (218) as a CF3-source using visiblelight photoredox catalysis86 (Scheme 66). A large scale perfluoroalkylation of arenes and heteroarenes using pyridine N-oxide derivatives was achieved under visible-light irradiation conditions. Irradiation of 1,3,5-trimethylbenzene (184) in the presence of trifluoroacetic anhydride as inexpensive CF3 source and 4-phenylpyridine N-oxide efficiently afforded 1-trifluoromethyl-2,4,6-trimethylbenzene (220) and 1,3-bis(trifluoromethyl)-2,4,6-trimethylbenzene (221)87 (Scheme 67). Photoinduced aromatic trifluoromethylation of unactivated arenes (222) and heteroarenes was achieved under a simple, metal- and oxidant-free

+

R-H

N

TBADT (4 mol%) K2S2O8 (4.0 mmol) Solarbox (500 W/m2, 40 oC)

R

MeCN/CH2Cl2 5:1 (20 mL)

N (214)

(213)

(212)

O

O

TBADT ; (Bu4N)4[W10O32]

R-H = n n = 1, 2, 3

O

Scheme 64

Ph Ph

EtO2C + I (215)

CO2Et

fac-[Ir(ppy)3] (1 mol%) NiCl2 (10 mol%) dtbbpy (15 mol%) NaOAc (1.5 equiv)

Ph

oC,

DMI, 25 40 h visible light

N H (216)

Ph

DMI; 1,3-dimethyl-2-imidazolidinone

(217)

Scheme 65

NO2 + MeO 181

CF3SO2Cl 218

Eosin-Y (5 mol%) K2HPO4 MeCN visible light

CF3 MeO

219

Scheme 66 Photochemistry, 2019, 46, 116–168 | 141

Me

Me

Ru(bpy)3Cl2 (1 mol %) TFAA, N-oxide

Me

Me CF3 +

13.2 W blue LEDs Me Me MeCN, 35 oC 220 TFAA: (CF3CO)2O N-oxide ; 4-phenylpyridine N-oxide

Me 184

CF3

F3C Me

Me 221

Scheme 67

+

R

NaSO2CF3

acetone 222

CF3

hν, Ar R

223

224

R = H, 4-t-Bu ,2,4,6-(MeO)3, 2,4,6-Me3 etc. Scheme 68

R

NaH

[Ph3P-CF2H]+Br-

+

HS

R

hν (365 nm)

HF2CS

225

177

226

R = 4-Me, 2-Me, 4-t-Bu, 4-CO2Me, 4-NH2, 4-OH etc. Scheme 69

O S O 147

Ir(ppy)3

H N

Br +

CO2Et

Li2CO3

O S

DMSO, hν

O

227

H N

CO2Et

228 Scheme 70

conditions. CF3 radicals from NaSO2CF3 (223) were generated in the photoexcited aliphatic ketones such as acetone and diacetyl as low cost radical initiators88 (Scheme 68). Studer reported the radical difluoromethylation of arylthiols (177) with (difluoromethyl)triphenylphosphonium bromide (225) through radical pathway under mild reaction conditions. This difluoromethylation chemoselectively occurred via a SRN1 mechanism89 (Scheme 69). Visible-light-promoted (phenylsulfonyl)methylation of electron-rich heteroarenes (227) and N-arylacrylamides in the presence of Li2CO3 was developed using Ir(ppy)3 as a photocatalyst under mild reaction conditions90 (Scheme 70). Both sulfoxidation and sulfenylation of diphenyl iodonium with common sulfurating reagents such as RSSO3Na (R ¼ alkyl, aryl) (229) were achieved via a facile variation of the atmosphere under photocatalyzed conditions91 (Scheme 71). A simple and efficient method for the synthesis of a-arylthioethers (233) via a visible-light-induced direct thiolation with diaryl disulfides 142 | Photochemistry, 2019, 46, 116–168

BF4I+

O-

hν, Eosin Y

S+ Ph 230

Ph

air

nPent

Ph

nPent

Ph

N2

NaO3S2+-nPent

Sulfoxidation

S

hν, Eosin Y

+

231

Sulfidation

229 Scheme 71

S R

R S

O

acridine red (2.0 mol%) TBHP (4 equiv), 4A MS

S

+

3 W green LED rt, 12 h TBHP; tert-butylhydroperoxide R = H, m-,p-Me, p-MeO-, p-CN-, o-, m-, p-F- etc.

232

O

R

233

Scheme 72

O Br

R 204

P

Rh-6G

OR

OR

P(OR’)3, DMSO, DIPEA,25 oC 455 nm Blue LED

R 234

R = H, m-, p-MeO, o-, p-CN, p-CF3 etc. R’ = Me, Et Rh-6G

DIPEA : (i Pr)2EtN

N H

COOEt

O

N•HCl

Scheme 73

(232) was developed usind acridine red as a photosensitizer under mild conditions92 (Scheme 72). ¨nig et al. reported visible-light photo-Arbuzov reaction of aryl Ko bromides (204) with trialkyl phosphites giving aryl phosphonates (234) under mild reaction conditions. Rhodamine 6G (Rh-6G) is used as the photocatalyst, generating aryl radicals under blue light93 (Scheme 73). Benzene (187), naphthalene (236) and several polycyclic aromatic hydrocarbons underwent metal-free photochemical (hydro)silylation and transfer-hydrogenations at mild conditions, with the highest yield for naphthalene (photosilylation; 21%)94 (Scheme 74). The waterborne hyperbranched polyurethane/CD nanocomposite (CD@WPU) in the presence of H2O2 catalyzed para-selective hydroxylation of substituted benzene derivatives (239) under UV light95 (Scheme 75). Photochemistry, 2019, 46, 116–168 | 143

hν (254 nm)

Et3SiH

+

+

+

polymers

24 h SiEt3

187

SiEt3

SiEt3 235

SiEt3

hν (254 nm)

SiEt3 +

236

237

238

Scheme 74

R

R

CD@WPU H2O2 UV light

HO

239

240

R = CO2H, NO2, CHO, CH3, CN Scheme 75

4CzIPN (2 mol%) NiCl2 dme (10 mol%) pyridine (2 equiv)

Br R1SH

rt, Blue LED

CN

R2

tr = 30 min (433 μL/min)

242

N

NC

MeCN/DMF (23:1)(0.05 M)

R2 241

SR1

+

N

N N

243

flow microreactor R1 = p-ClC6H4CH2, p-MeOC6H4CH2 etc. R2 = Ph, p-MeOC6H4, p-MeC6H4, p-BrC6H4 etc.

244

Scheme 76

O

O R

CH3

+

hν

CO2

R = Ph, CH3

245

R CH2CO2H 246

Scheme 77

The cross-coupling of thiols (241) and bromoarylalkynes (242) was promoted by a soluble organic carbazole-based photocatalyst (244) using continuous flow techniques96 (Scheme 76). Mechanism of the photochemical carboxylation of o-alkylphenyl ketones (245) with carbon dioxide giving the corresponding carboxylic acid (246) was theoretically studied. This photoreaction occurs on the S0 surface, rather than on the excited T1 state97 (Scheme 77). 144 | Photochemistry, 2019, 46, 116–168

5

Intramolecular cyclization reactions

A variety of phenanthrenes (248) substituted with phenylethynyl and trimethylsilylethynyl groups were synthesized by use of Mallory photocyclization using (247) and their photophysical properties were investigated. Introducing ethynyl groups into the phenanthrene skeleton caused an increase in the fluorescence quantum yields compared to phenanthrene. The quantum yields and rates of fluorescence were dependent on the substituting position(s) and the terminating group for the C–C triple bond98 (Scheme 78). Okamoto et al. prepared many phenacenes possessing chrysene (252), picene, and fulminene frameworks using a continuous-flow microreactor without isolation of the intermediary diarylethenes (251). They also synthesized [9]phenacenes (254) and applied to field-effect transistors (FETs)99,100 (Scheme 79). Tetracarboxy-functionalized [8]-, [10]-, [12]-, [14]-phenacenes (255) and (257) including esters and imides were synthesized by Durola et al.101,102 (Scheme 80). The imide derivatives were significantly stronger electron acceptor than the corresponding esters. Stuparu et al. developed the synthesis of the coannulene nucleus (260) and (262) by using Mallory-like photocyclization of (259) and (261)103,104 (Scheme 81). Three-bladed propeller-shaped triple [5]helicene (264) was synthesized by use of eliminative and oxidative photocyclization of (263) in moderate

hν O2, I2 247

R

R = Ph, trimethylsilyl

R

248

1-, 3-substituted phenanthrenes 1,6-, 1,8-, 2,7-, 3,6-, 9,10-disubstituted phenanthrenes Scheme 78

PPh3X

CHO

hν, I2, air

KOH

+

CH2Cl2/ H2O 249

250

flow photolysis 251

252

hν, I2

253

bromobenzene 130-140 oC 254

Scheme 79 Photochemistry, 2019, 46, 116–168 | 145

EtO2C

CO2Et

CO2Et

EtO2C

hν, I2, O2 ethyl acetate

EtO2C

EtO2C

CO2Et 255

CO2Et

256 HxO2C

CO2Hx

CO2Hx

HxO2C hν, I2, O2 ethyl acetate

HxO2C

CO2Hx

HxO2C Hx : hexyl

257

CO2Hx 258

Scheme 80

R1

R2

R1

R3

R2 hν, I2, propylene oxide toluene

259 R1 = H, Me

R3

260 R2 = H, CF3

R3 = H, Me, F, CN, MeO, NMe2 etc.

hν, I2, propylene oxide toluene 261

262 Scheme 81

R hν

R

R

R = H, OMe 263

264 Scheme 82

yields105 (Scheme 82). Diastereoisomers, PPM and PMM, were isolated by chromatographic purifications, which were converted to the thermodynamically more stable PPP and MMM isomers. 146 | Photochemistry, 2019, 46, 116–168

O

Ar

S

N

Ar1

O

S

F

265

Ar Ar1CHO

F

LHMDS

266

F

hν

F

267

268

F

F

270

269

271 F

Scheme 83 R

R X

X

hν solvent

X

X R

273

272

R

Cl hν solvent Cl 274

275 Cl

Cl

C12H25 277

C12H25 Cl

Cl 276

hν

C12H25

solvent C12H25

Scheme 84

Several fluorinated polycyclic aromatic hydrocarbons (267)–(271) via Julia-Kocienski olefination from (265) and oxidative photocyclization of (266) were synthesized in a regiospecific manner106 (Scheme 83). Morin et al. prepared nanographenes (273), (275), and (277) by photochemical cyclodehydrochlorination of (272), (274), and (276)107 (Scheme 84). Photochemistry, 2019, 46, 116–168 | 147

Hayashi et al. synthesized tetra- and octa-fluorinated bianthracene derivatives (280) for investigating the effect of electronegative fluorine substitution on their structure and physical property108 (Scheme 85). A triisopropylsilylethynyl(TIPS)-substituted octafluoro compound (280) exhibited strong fluorescence at 657 nm with high fluorescence quantum yield (F ¼ 0.84). Alabugin et al. reported the synthesis of fused helicene (286) using alkynyl precursors (281) under mild conditions109 (Scheme 86). Rapenne and Kawai reported dual photocleavage for 1,2-diarylethene isomers (287) and (288) based phototrigger depending on polarity of solvents110 (Scheme 87). In polar solvents, methanol was selectively eliminated to afford (289), but elimination of acetic acid occurred in apolar solvents to give (290). Phenanthridines (292) were obtained through visible light induced isocyanides (291) insertion promoted the combination of an amide and a TIPS O

O F

F

F

F

F

F

F

F

F

F

F F

F

F

F

F

F

F

F

F F

F

F

hν

O

O

(278)

(279)

F

(280)

TIPS

Scheme 85

I

(281)

ICI DCM - 78 oC

(286)

(283)

I

- HI

hν benzene

I

I

(284)

(282)

Scheme 86 148 | Photochemistry, 2019, 46, 116–168

(285)

H

Ph S

N

AcO S

Ph

UV polar AcO solvent

S

MeOH

OMe S

N

Ph Ph

289

287

S

MeO

N

S

UV apolar MeO solvent

N

S

OAc S

AcOH

290

288 Scheme 87

R2

R2 rt, white LED R1

R1

photocatalyst CF3-BHA

NC

N

N

291

C O

292 CF3-BHA = O-(4-CF3-benzoyl)-hydroxylamine

R1 = H, 5-Cl, 4-Me, 4-MeO etc.

R2 = H, 4-Ph, 4-tBu etc.

Scheme 88

R2

R2 NO2

R1

NO R3

NO2

visible light, N2 Eosin Y, i Pr2NEt

N R3

293 R1 = H, F, Me, MeO

R1

294 R2 = H, F, Me, MeO, R3 = H, Me Scheme 89

photoredox system under mild and eco-friendly reaction conditions111 (Scheme 88). Metal-free photoredox catalyzed cyclizetion of O-(2,4-dinitrophenyl)oximes (293) in the presence of eosin Y and iPr2NEt efficiently afforded phenanthridines (294) in moderate to good yields112 (Scheme 89). Xia et al. found the tunable synthetic route to phenanthrenes (296) and (297) from 3-aryl-N-(arylsulfonyl)propionamides (295) including aryl migration, C–C coupling, 1,3-hydrogen shift, desulfonylation and elimination process113 (Scheme 90). Dihydropyrazole-fused benzosultams (299) and (300) under visible-light irradiation in the presence of co-catalyst (303) and electron accepting additives such as 1,3-dinitrobenzene (301) and tetracyanobenzoquinone (302) were prepared via N-radical 5-exo cyclization/addition/aromatization cascade of b,g-unsaturated hydrazines (298)114 (Scheme 91). Photochemistry, 2019, 46, 116–168 | 149

R1 R1

O S O

O

O hν, morpholine

N

toluene R2

R3

295

R1

+ R3 N O 296

R2

S O 297

R2

R1 = H, Me, OMe, F, Cl, Br, Ph, t-Bu, CN etc. R2 = H, Me, OMe R3 = Me, Bn, allyl, propagyl etc. Scheme 90

PC (2 mol%) Additives K2CO3 (1.5 equiv)

Ts HN

N

3 W blue LEDs, Ar CH3CN, rt, 24 h

Ph 298

O O S N N Ph

+

O O S N N

Ph 299

300

Additives:

H O

O O2N

NO2 NC

CN

NC

CN

N

N

Co N

Py

O

O

301

O Cl

302

N O

H

303 Scheme 91

O +

R 304

Ru(bpy)3Cl2 H2N

NH2

TsOH, CH3CN 82 oC, 23 W CFL, 48 h

N

R

305 R = o-, p-Me, o-, p-F, o-, p-Cl, o-, p-Br, p-MeO, etc.

306

Scheme 92

Arylpyridines (306) and arylquinolines via visible-light induced aerobic C–N bond activation using Ru(bpy)321 were efficiently synthesized in the presence of acetophenones (304) and easily available 1,3-diaminopropane (305)115 (Scheme 92). Indole derivatives (308) were obtained via photoinduced nitrene C–H insertion from arylazide compounds (307)116 (Scheme 93). Yoshmi et al. found the one-step synthesis of spiro dihydroisoquinolinone derivatives (311) from alicyclic amino acids (309) bearing N-(2-phenyl)benzoyl groups via photoinduced electron transfer–promoted decarboxylation using (209) and p-dicyanobenzene (p-DCB)117 (Scheme 94). 150 | Photochemistry, 2019, 46, 116–168

R

R

hν (365 nm) MeCN

N3

N H

307

308

R = t-BuOOC-CH(OH)-, (EtOOC)2CH, PhthNScheme 93

N

CO2H

O

• N

hν (209)-p-DCB

N

O

- CO2

309

O

p-DCB : p-dicyanobenzene

ipso-position 310

311

Scheme 94

CO2H

O

hν (> 350 nm), TiO2

O

CH3CN, H2O, O2

+ CO2, H2O

HO2C 312 CO2H

313 hν

CO2H CO2H

CO2H

(Z)-314

(E)-314

hν (> 350 nm), TiO2 CH3CN, H2O, O2

O

O

+

CO2, H2O

315 Scheme 95

Upon TiO2-catalyzed UV irradiation, aromatic lactones (313) and (315) from diphenic acid (312) and (E)-2-(2-carboxyvinyl)benzoic acid (E-314) were obtained with high selectivity via decarboxylation118 (Scheme 95). A highly regionselective [2 þ 2 þ 2] cyclization of two arylalkynes (63) with nitriles using pyrilium salts (T(p-Cl)PPT) as photoredox catalysts was reported under visible-light irradiation giving 2,3,6-trisubstituted pyridine derivatives (316)119 (Scheme 96). Visible-light induced and oxygen-promoted oxidative cyclization from aromatic enamines (317) intramolecularly afforded quinoline derivatives (318) in good to moderate yields120 (Scheme 97). Similar compounds (321) were obtained in the intermolecular photocycloaddition of (319) with dimethyl acetylene dicarboxylate (320). Photochemistry, 2019, 46, 116–168 | 151

Ar’ T(p-Cl)PPT (30 mol%)

N

2

Ar

+ Ar

blue LED, rt, 12 h

Me

N

Me

O+

Ar‘

Ar

316

63

Ar’

BF4Ar’ = p-ClC6H4

Ar’ = Ph, p-MeC6H4, p-FC6H4 etc.

T(p-Cl)PPT

Scheme 96

O OEt

5% Mes-Acr-Me* 20% CuCl2 20% Phen

Ph NH R1

N

CO2Et

TBHP (3.0 equiv)

CO2Me

5% Ru(bpy)3Cl2

+

N R1

CO2Me CO2Me

20% CuCl O2 (1 atm), r.t. blue LED, DMF (3 mL)

CO2Me

R2 319

R2

318

R1 = H, 4-F, 4-Cl, 4-CF3 etc. R2 = H, 2-F, 3-F, 4-F, 4-Cl, etc.

NH2 R1

O

O2 (1 atm), DMF (3 mL) blue LED, r.t.

R2 317

Ph

O

320

R2

321

R1 = H, 4-Me, 4-Cl, etc. R2 = H, 4-Me 4-MeO, 4-Cl, 4-NO2, etc. Scheme 97

CO2H

O 254 nm, 25 oC O

N3

R

EtOH, NaOAc

N H

R

322

CO2H +

O NH

R

323

324

CO2H

+ NH2

R 325

H2O CO2H

CO2H

CO2H •

R

N

R

R

N

N

Scheme 98

Irradiation of 2-azidobenzoic acids (322) in the presence of NaOAc in ethanol selectively gave 2,1-benzisooxazole-3(1H)-ones (323) via formation of nitrene121 (Scheme 98). Here, in some cases, small amounts of 2-oxo-3-carboxy-3H-azepine (324) and (325) were produced. 152 | Photochemistry, 2019, 46, 116–168

O N N C

R1

fac-Ir(ppy)3

+ BrCH2R2

O

Na2CO3, DMSO visible light R1 = H, Et, tBu, MeO, PhO etc.

N 326

R2 = CN, CO2Et, COPh

N

R2

327

R1

hν

N

N

6-exo-dig

O

O C N

N

R2 R1

R1

R2

iminyl radical

Scheme 99

R3 R2

N2+BF4-

+

R1 N3

R3 145

328

1,4-CHD hν, MeCN Eosin Y K2HPO4

R2

R1 N H 329

R1 = H, 4-F, 4-Cl, 4-MeO etc. R2 = Ph, 4-MeOC6H4, 4-FC6H4, tBu etc. R3 = H, F, Cl, CN, Me, MeO etc. Scheme 100

CO2Et

CO2Et Br N

Ph

[Ir(ppy)2(dtb-bpy)]PF6

Ph

DIPEA, MeCN visible light

N CO2Me

CO2Me 331

330 Scheme 101

Phenanthridine derivatives (327) from N-arylacrylamide (326) using cyano group as a bridge under photoredox catalysis were synthesized via radical addition/insertion/cyclization cascade reaction in moderate to good yields122 (Scheme 99). Transition-metal-free and visible-light-mediated photocyclization of oazidoarylalkynes (328) with diazonium salts (145) giving 2,3-disubstituted indoles (329) was reported123 (Scheme 100). Photochemistry, 2019, 46, 116–168 | 153

Rf -I

+

TEEDA (1.5 equiv) CFL (25 W) THF, Ar, 30 oC, 36 h TEEDA ; Et2NCH2CH2NEt2

NC 332

333

N

Rf

334 Scheme 102

R

R NH2

X

R

DMSO

335

R = H, CN X = Cl, Br

NH2

NH +

t-BuOK, hν

+ X-

336

337

Scheme 103

2,3-Disubstituted indolines (331) utilizing visible-light photoredox catalysis were obtained through tandem cyclization of vinyl radicals in good yields124 (Scheme 101). Perfluoroalkylation of phenanthridines (334), alkenes, alkynes, and electron-rich arenes and hetero arenes using isonitrile (332) and perfluoroalkyl iodides (333) was reported by Chen et al. under compact fluorescent lamp (CFL), low-intensity UV lamp, or sunlight irradiation125 (Scheme 102). Irradiation of 2 0 -halo-[1,1 0 -biphenyl]-2-amines (335) in basic medium caused N-arylation reaction. In general, biphenylamines with electron donating groups such as Me and OMe gave cyclized and reduced products (336) and (337). On the other hand, biphenylamines containing electron withdrawing groups such as CN, CO2Et, and CF3 afforded only the corresponding carbazoles (336)126 (Scheme 103).

6

Rearrangements

Lvov and Shirinyan reviewed a new type of diarylethene photoreactions. Photorearrangement of diarylethenes (338) or (341) via cascade processs of photocyclization/[1,n]-H shift/cycloreversion under inert atmosphere occurred to give benzofurans and benzothiophenes (340) or naphthalene derivatives (344). The quantum yields of the photorearrangement are rather high (0.34–0.49) although the processs includes multi-steps127,128 (Scheme 104). Photodeprotection of 2-nitrobenzyl esters (345) efficiently released the acid (347) with the formation of the corresponding 2nitrosoketones (346), which underwent a photorearrangement to afford bicyclic oxazoles (348) via 1,2-shift of alkyl group (R ¼ iPr). However, methyl group rearranged slowly and phenyl group did not rearrange to give the corresponding bicyclic isoxazolones. In the case of tBu group, 154 | Photochemistry, 2019, 46, 116–168

R

X

UV

UV

O2

anaerobic conditions CH2Cl2

X

R 339

338 X = O, S

O

O

X H2C 340

R = alkyl, halogen

Yield 52-96%

O

O

ortho-substituent UV

H R

O

φ = 0.34-0.49

UV O

R

Ph Me O 342 yield 74-92% (meta/para-R) 31-59% (ortho-R)

Me

O

O

[1,n]-H shift / cycloreversion

H

N

Vis / Δ

Ph

341

O

R

N

Me

NH

N O

R

Ph

Me

R

343

Ph O

344 Scheme 104

R MeO MeO

hν

O NO2 345

O

R

O

Br

MeO

O

MeO

HO + 347

NO

Br

346

R = Me, i Pr. tBu, Ph

hν

MeO

R O O

MeO

N 348 R = i Pr, tBu

Scheme 105

many products including bicyclic isoxazolones (348) were produced129 (Scheme 105). Bonesi et al. reported the formation of 2,2-dimethylchroman-4-ones (350) via photo-Fries rearrangement of aryl 3-methyl-2butenoate esters (349) followed by thermal 6p-electrocyclic reactions and/or thermal (intramolecular oxa-Michael addition) cyclization of the ortho-regioisomers. They also found the regioselective photo-Fries Photochemistry, 2019, 46, 116–168 | 155

rearrangement of acetoanilides (354) under the aqueous micellar green environment. The photoreaction involves homolytic cleavage of a C–N bond to yield a singlet radical pair130,131 (Scheme 106). Maeda reported photo-Fries rearrangement of 1-pyrenyl benzoate derivatives (358) in benzene to give 1-hydroxy-2-pyrenyl aryl ketones (359) along with 1-pyrenol (360)132 (Scheme 107). The exceptionally down field 1 H NMR chemical shift of OH proton in the photoproducts (359) indicates OH

OH O

OH +

Solvent Ar, 25 oC

O

R

O

hν R

+

+

R O

349

O

350

R

351

O

352

R = H, CH3, OPh, Cl, NO2 353 O HN

R’ hν Solvent 25 oC

R

NH2

NH2 O R’

+

R

354

NH2 +

R O

’R

355

R

356

357

R = H, Me, MeO, PhO, Cl, CN, COCH3, NO2 etc. Surfactants Cationic Surfactants N+

BrN+

Cl-

Anionic Surfactant O-

O S

Na+

O O Non-ionic Surfactants

O O

O 22

OH

O 8-9

OH

Scheme 106

R O

O

R O

OH

OH hν (> 280 nm) +

358

359

360

R = Ph, p-NO2C6H4, p-CF3C6H4, p-ClC6H4, p-MeC6H4, p-MeOC6H4 etc. Scheme 107 156 | Photochemistry, 2019, 46, 116–168

Scheme 108

the existence of intramolecular hydrogen bonding. However, 1-pyrenyl aliphatic esters did not rearrange to give the corresponding ketones. Oxidative [1,2]-Brook rearrangement of (361) via hypervalent silicon intermediates (364) induced by photoredox-catalyzed one-electron transfer afforded alkylation and arylation products (363). The formation of reactive radical species (362) have been postulated133 (Scheme 108). Irradiation of ethyl 3-azido-4,6-difluorobenzoate (365) in the presence of oxygen gave ethyl 5,7-difluoro-4-azaspiro[2.4]-hepta-1,4,6-triene-1carboxylate (370) via seven-membered keteneimine intermediate (367). The structure of spiro compound was assigned by NMR spectroscopy134 (Scheme 109). Irradiation of vinyl tosylates (371) in the presence of photoinitiator such as eosin B afforded the rearranged products b-ketosulfones (372) via a sulfinyl radical135 (Scheme 110). Photolysis of 1-cyclopentylidene- and 1-cyclobutylidene-1a,9b-dihydro1H-cyclopropa[l]phenanthrenes (373) produced the strained cyclohexyne and cyclopentyne (375) respectively via the putative cycloalkylidenecarbenes (374). These cycloalkynes (375) were intercepted as Diels–Alder adducts (377) and (379)136 (Scheme 111). Irradiation of a-chlorinated propiophenones (381) gave 2-arylpropanoic acids (382) as rearranged products accompanied by unexpected benzoic acids (383). The formation of benzoic acids as byproducts could be explained by the oxygenation of a-chlorinated propiophenones via their triplet states137 (Scheme 112). Photochemistry, 2019, 46, 116–168 | 157

N3 F

hν, O2 CO2Et F 365 - N2

F

N

F

CO2Et F

TFE-d3 TFE ; CF3CH2OH

370

hν

N

F

+ +

N

CO2Et

F

CO2Et

F 369

366

hν N

F

F

hν CO2Et

F

N F

367

CO2Et

368 Scheme 109

OTs photoinitiator (1 mol%) 5 W white LED solvent, 12 h, rt. F3C

F3C

371

O Ts 372

Scheme 110

7

Oxidation

Irradiation of ethyl 2-(anthracen-9-yl)acetates (384) with a household fluorescent light bulb in the presence of oxygen and a photosensitizer such as methylene blue or tetraphenylporphyrin afforded endoperoxide intermediates (385) in the absence of base. The peroxide was converted to anthrone derivatives (386) and anthraquinones (387) by use of base such as K2CO3 at the elevated temperature. Anthrones (386) thermally converted to anthraquinones (387) at 90 1C in the presence of K2CO3 in good to high yields138 (Scheme 113). Upon irradiation in the presence of oxygen, the endoperoxides (389) of bis(triisopropylsilyl)ethynyl)bistetracene and bis(2-(n-octyldiisopropylsilyl)ethynyl)bistetracene (388) were formed in an extremely slow rate. From computational results, it was explained not on the ring with least aromaticity, but on the ring with smallest distortion energy. Substituted bistetracenes displayed the increased stability toward oxidation compared to pentacene and rubrene139 (Scheme 114). Zhu reported the visible-light induced conversion of styrenes (101) to ketones (391) by use of phenylhydrazines (390), which generated phenyl 158 | Photochemistry, 2019, 46, 116–168

n hν n

- phenanthrene 374

n = 1,2

373

n 375

Ph O

Ph

O

Ph

376

n Ph 377

O

Ph

Ph

Ph

Ph

Ph

- CO

Ph

n

Ph

Ph 380

O Ph

n

Ph

Ph 379

Ph

378 Scheme 111

CH3

O

CO2H +

aq. acetone Cl

Cl Cl

Cl

382

381

383 T*

O

O CH3

CH3

hν Cl

Cl Cl

CO2H

hν

CH3

aq. acetone

Cl

O

O

•

O

O

O• CH3

O2 Cl Cl

381

Cl

O

O•

H•

O O

Cl

OH

hν H•

OH

Cl 383

Scheme 112

and substituted phenyl radicals, in the presence of methylene blue (MB1) under metal-free conditions. This photoxidation included broad substrate scope, readily available reagents and amenability to gram-scale synthesis140 (Scheme 115). Visible light irradiation of methyl aromatics (392) in the presence of Acr1Mes ClO4 and oxygen in methanol afforded the corresponding methyl esters (393) under mild catalytic conditions141 (Scheme 116). Photochemistry, 2019, 46, 116–168 | 159

CO2Et

R1

methylene blue (5.0 mol%) K2CO3 (1.0 equiv) R2

t

AmylOH, O2 (1 atm)

30 W CFL, 90 oC, 48 h

384 CO2Et

O O

R1

HO R2

O

CO2Et

R2

R 2 + R1

+ R1

O

O 385

386

387

K2CO3 (1 equiv)

R1, R2 = Me, MeO, tBu, F, Cl, SiMe3 etc.

tAmylOH

90 oC, 1.5 h Scheme 113

O R

R

O

hν/O2 CDCl3 R 388

R R= 389 Si

R=

Si

,

C8H17

Scheme 114

MB+ {2 mol%) DABCO (1 equiv)

NHNH2 + R1 (390)

air, 7 W blue LEDs, rt MeCN

R2

O R2 R1

(101)

(391)

R1 = H, p-Me, o-Me, p-Cl, p-MeO, p-Br, p-F, p-CH=CH2 etc. R2 = H, p-Cl, o-Cl, p-F, p-MeO, p-CF3 etc. Scheme 115

Meyer et al. reported the photoxidation of aromatic hydrocarbons by a phosphate-bearing flavin mononucleotide (FMN) photocatalyst on high surface area metal-oxide films142 (Scheme 117). Photocatalytic oxygenation of thioanisole (394) and styrene (103) in the presence of trinuclear Ru complexes (396) and Co complex ([CoCl(NH3)5]Cl2) as visible-light sensitizers afforded phenyl methyl 160 | Photochemistry, 2019, 46, 116–168

Me

Acr+-Mes ClO4- (7 mol%) HCl (0.2 equiv)

O

R (392)

OMe

R

MeOH (3 mL), O2 blue LEDs, 30 h

(393)

R = 2-Me, 3-Me, 4-Me, 4-Ph, 4-tBu, 4-MeO, 3,5-Me2 Scheme 116

hν FMN

1

440 nm

3

FMN*

ISC 2e /2H+

PhCH2OH

+

O2

FMNH2

3

FMN*

FMN

+

FMN*

FMNH2 +

PhCHO

H2O2

Scheme 117

O S

S

hν (435 nm)

Ru3 complexes 394

O

395

[CoCl(NH3)5]Cl2 H2O

H

103

396 N N

N

N

N

N

Ru N

N Ru N

N

R

N N

N

N

R

N

R = CH3, H, Br

Ru

N

N

397 Scheme 118

sulfoxide (395) and benzaldehyde (396)143 (Scheme 118). The catalytic activity of 5,5 0 -dibromo-2,2 0 -bipyrimidine ligand was much higher than that of 5,5 0 dimethyl derivative and nonsubstituted one. The photoxidation of ortho-substituted aromatic azides (398) gave nitrile oxide derivatives (400) and (403). In the case of (398b), (400b) and (403b) were intramolecularly cyclized to (401b) and (404b)144 (Scheme 119). Inter- and intra-molecular oxidative photocycloaddition of styrene derivateives (103) and (406) afforded 1-tetralones (405) and (407) in the presence of molecular oxygen and TiO2145 (Scheme 120). Photochemistry, 2019, 46, 116–168 | 161

Upon visible-light irradiation, a-chloro or a-alkoky ketones (408) were synthesized by use of aryl diazonium salts (145), which produced aryl radicals, in the presence of NaCl and ROH with aryl alkyne (63) under mild oxygen atmosphere146 (Scheme 121).

Scheme 119

Scheme 120

N2+BF4+

R1

Ar

blue LED, O2

145

Nu

NuX (2.2 equiv) Eosin Y (3 mol%)

63

Ar R1

O

408

R1 = 4-MeO, 2-, 3-, 4-NO2, 4-CN, 4-Ph etc. Ar = Ph, 4-ClC6H4, 4-BrC6H4, 4-CNC6H4, 4-PhC6H4 etc. NuX : NaCl, MeOH, iPr Scheme 121 162 | Photochemistry, 2019, 46, 116–168

Ru(bpy)3Cl2, copper CH2NH2 Blue LED, DMSO, O 2 R 409

CN R 410

R = H, Me, MeO, F, CF3 etc. Scheme 122

The oxidative transformation of amines (409) to nitriles (410) in the presence of photoredox and copper catalysis such as Ru(bpy)3Cl26H2O and CuBr was achieved upon visible-light irradiation147 (Scheme 122).

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

19 20

K. Mizuno, Photochemistry, ed. A. Albini, Royal Society Chemistry, 2012, vol. 40, pp. 106–145. K. Mizuno, Photochemistry, ed. E. Fasani and A. Albini, Royal Society Chemistry, 2014, vol. 42, pp. 89–141. K. Mizuno, Photochemistry, ed. A. Albini and E. Fasani, Royal Society Chemistry, 2017, vol. 44, pp. 132–187. K. Nakajima, Y. Miyake and Y. Nishibayashi, Acc. Chem. Res., 2016, 49, 1946–1956. K. L. Skubi, T. R. Blum and T. P. Yoon, Chem. Rev., 2016, 116, 10035– 10074. N. A. Romero and D. A. Nicewicz, Chem. Rev., 2016, 116, 10075–10166. ´, C. Bottecchia, N. J. W. Straathof, V. Hessel and T. Noe ¨l, Chem. D. Cambie Rev., 2016, 116, 10276–10341. K. Mizuno, Y. Nishiyama, T. Ogaki, K. Terao, H. Ikeda and K. Kakiuchi, J. Photochem. Photobiol., C, 2016, 29, 107–147. ¨rka ¨s, J. A. Porco Jr. and C. R. J. Stephenson, Chem. Rev., 2016, 116, M. D. Ka 9683–9747. ¨ster, Y.-Q. Zou and T. Bach, Chem. Rev., 2016, 116, S. Poplata, A. Tro 9748–9815. R. Remy and C. G. Bochet, Chem. Rev., 2016, 116, 9816–9849. D. Ravelli, S. Protti and M. Fagnoni, Chem. Rev., 2016, 116, 9850–9913. V. Ramamurthy and J. Sivaguru, Chem. Rev., 2016, 116, 9914–9993. A. A. Ghogare and A. Greer, Chem. Rev., 2016, 116, 9994–10034. S. Dadashi-Silab, S. Doran and Y. Yagci, Chem. Rev., 2016, 116, 10212– 10275. T. Hackfort, B. Neumann, H.-G. Stammlet and D. Kuck, Can. J. Chem., 2017, 95, 390–398. T. van Leeuwen, J. Pol, D. Roke, S. J. Wezenberg and B. L. Feringa, Org. Lett., 2017, 19, 1402–1405. S. C. Everhart, U. K. Jayasundara, H.-J. Kim, R. Procupez-Schtirbu, W. A. Stanbery, C. H. Mishler, B. J. Frost, J. I. Cline and T. W. Bell, Chem. – Eur. J., 2016, 22, 11291–11302. B. Oruganti, J. Wang and B. Durbeej, Org. Lett., 2017, 19, 4818–4821. J. J. Lee, C. P. Yap, T. S. Chwee and W. Y. Fan, Dalton Trans., 2017, 46, 11008–11012. Photochemistry, 2019, 46, 116–168 | 163

21 22 23

24 25 26 27 28 29 30 31

32 33 34 35 36 37 38 39 40 41

42 43 44 45 46 47 48 49 50

B. Debus, M. Orio, J. Rehault, G. Burdzinski, C. Ruckebusch and M. Sliwa, J. Phys. Chem. Lett., 2017, 8, 3530–3535. M. Guentner, E. Uhl, P. Mayer and H. Dube, Chem. – Eur. J., 2016, 22, 16433–16436. M. Ochmann, I. von Ahnen, A. A. Cordones, A. Hussain, J. H. Lee, K. Hong, K. Adamczyk, O. Vendrell, T. K. kim, R. W. Schoenlein and N. Huse, J. Am. Chem. Soc., 2017, 139, 4797–4804. Z.-A. Huang, C. Chen, X.-D. Yang, X.-B. Fan, W. Zhou, C.-H. Tung, L.-Z. Wu and H. Cong, J. Am. Chem. Soc., 2016, 138, 11144–11147. N. V. Plotnikov and T. J. Martinez, J. Phys. Chem. C, 2016, 120, 17898–17908. H. Okamoto, T. Kozai, Z. Okabayashi, T. Shinmyozu, H. Ota, K. Amimoto and K. Satake, J. Phys. Org. Chem., 2017, e3726. H. Maeda, N. Koshio, Y. Tachibana, K. Chiyonobu, G. Konishi and K. Mizuno, J. Photochem. Photobiol., A, 2017, 349, 7–17. H. Maeda, H. Takenaka and K. Mizuno, Photochem. Photobiol. Sci., 2016, 15, 1385–1392. F. Xu, X. Xiao and T. R. Hoye, J. Am. Chem. Soc., 2017, 139, 8400–8403. Q. Liu, J. Wang, D. Li, G.-L. Gao, C. Yang, Y. Gao and W. Xia, J. Org. Chem., 2017, 82, 7856–7868. P. Qin, S. K. Cope, H. Steger, K. M. Veccharelli, R. L. Holland, D. M. Hitt, C. E. Moore, K. K. Baldridge and J. M. O’Connor, Organometallics, 2017, 36, 3967–3973. H. Maeda, T. Uesugi, Y. Fujimoto, H. Mukae and K. Mizuno, J. Photochem. Photobiol., A, 2017, 337, 198–206. H. Maeda, H. Wada, H. Mukae and K. Mizuno, J. Photochem. Photobiol., A, 2016, 331, 29–41. H. Maeda, S. Matsuda and K. Mizuno, J. Org. Chem., 2016, 81, 8544–8551. H. Maeda, H. Sakurai and M. Segi, ACS Omega, 2017, 2, 8697–8708. H. Maeda, R. Nakashima, A. Sugimoto and K. Mizuno, J. Photochem. Photobiol., A, 2016, 329, 232–237. Q. Wang and N. Zheng, ACS Catal., 2017, 7, 4197–4201. T. P. Nicholls, G. E. Constable, J. C. Robertson, M. G. Gardiner and A. C. Bissember, ACS Catal., 2016, 6, 451–457. P. Wessig, M. Czarnecki, D. Badetko, U. Schilde and A. Kelling, J. Org. Chem., 2016, 81, 9147–9157. T. B. Nguyen and A. Al-Mourabit, Photochem. Photobiol. Sci., 2016, 15, 1115–1119. T. Lei, C. Zhou, M.-Y. Huang, L.-M. Zhao, B. Yang, C. Ye, H. Xiao, Q.-Y. Meng, V. Ramamurthy, C.-H. Tung and L.-Z. Wu, Angew. Chem., Int. Ed., 2017, 56, 15407–15410. S. Yamada and Y. Nojiri, Molecules, 2017, 22, 491. T. Chatterjee, D. S. Lee and E. J. Cho, J. Org. Chem., 2017, 82, 4369–4378. S. Paul and J. Guin, Green Chem., 2017, 19, 2530–2534. L. Gu, C. Jin, W. Wang, Y. He, G. Yang and G. Li, Chem. Commun., 2017, 53, 4203–4206. C.-X. Song, P. Chen and Y. Tang, RSC Adv., 2017, 7, 11233–11243. A. Ragupathi, A. Sagadevan, C.-C. Lin, J.-R. Hwu and K. C. Hwang, Chem. Commun., 2016, 52, 11756–11759. ¨nig, Chem. Commun., 2016, 52, 8695–8698. A. Das, I. Ghosh and B. Ko H. Zhou, X. Deng, Z. Ma, A. Zhang, Q. Qin, R. X. Tan and S. Yu, Org. Biomol. Chem., 2016, 14, 6065–6070. H. B. Hepburna and P. Melchiorre, Chem. Commun., 2016, 52, 3520–3523.

164 | Photochemistry, 2019, 46, 116–168

51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82

K. Lisiecki, K. K. Krawczyk, P. Roszkowski, J. K. Maurinb and Z. Czarnocki, Org. Biomol. Chem., 2016, 14, 460–469. Y. Ran, Q.-Y. Lin, X.-H. Xu and F.-L. Qing, J. Org. Chem., 2016, 81, 7001– 7007. ¨ler, J.-M. Neudo ¨rfl, E. Zorlu and A. G. Griesbeck, J. Org. Chem., M. Reckentha 2016, 81, 7211–7216. B. Yang and Z. Lu, ACS Catal., 2017, 7, 8362–8365. C. Gao, J. Li, J. Yu, H. Yanga and H. Fu, Chem. Commun., 2016, 52, 7292–7294. J. Tiwari, M. Saquib, S. Singh, F. Tufail, M. Singh, J. Singh and J. Singh, Green Chem., 2016, 18, 3221–3231. Y. Liu, X. Dong, G. Deng and L. Zhou, Sci. China Chem., 2016, 59, 199–202. K. Wang, L.-G. Meng and L. Wang, J. Org. Chem., 2016, 81, 7080–7087. D. Alpers, M. Brasholz and J. Rehbein, Eur. J. Org. Chem., 2017, 2186–2193. A. Tlahuext-Aca, M. N. Hopkinson, B. Sahooab and F. Glorius, Chem. Sci., 2016, 7, 89–93. F. Liu and P. Li, J. Org. Chem., 2016, 81, 6972–6979. W. Yu, X.-H. Xu and F.-L. Qing, Org. Lett., 2016, 18, 5130–5133. H. S. Han, Y. J. Lee, Y.-S. Jung and S. B. Han, Org. Lett., 2017, 19, 1962–1965. Q. Yang, R. Wang, J. Han, C. Li, T. Wang, Y. Liang and Z. Zhang, RSC Adv., 2017, 7, 43206–43211. Y. Li, L. Ge, B. Qian, K. R. Babu and H. Bao, Tetrahedron Lett., 2016, 57, 5677–5680. S. Wang, W.-L. Jia, L. Wang, Q. Liu and L.-Z. Wu, Chem. – Eur. J., 2016, 22, 13794–13798. W. Ding, L.-Q. Lu, J. Liu, D. Liu, H.-T. Song and W.-J. Xiao, J. Org. Chem., 2016, 81, 7237–7243. X.-W. Fan, T. Lei, C. O. Zhou, Q.-Y. Meng, B. Chen, C.-H. Tung and L.-Z. Wu, J. Org. Chem., 2016, 81, 7127–7133. Y. Ando, T. Kamatsuka, H. Shinokubo and Y. Miyake, Chem. Commun., 2017, 53, 9136–9138. M. Malacarne, S. Protti and M. Fagnoni, Adv. Synth. Catal., 2017, 359, 3826– 3830. M. M. D. Pramanikab and N. Rastogi, Chem. Commun., 2016, 52, 8557–8560. B. Hong, J. Lee and A. Lee, Tetrahedron Lett., 2017, 58, 2809–2812. J. Leng, S.-M. Wang and H.-L. Qin, Beilstein J. Org. Chem., 2017, 13, 903–909. ´ska, B. Ko ¨nig and D. Gryko, Eur. J. Org. Chem., 2017, 2104– K. Rybicka-Jasin 2107. ¨fer, M. Rueping and D. C. Fabry, Y. A. Ho, R. Zapf, W. Tremel, M. Pantho T. H. Rehm, Green Chem., 2017, 19, 1911–1918. N. Zhang, Z.-J. Quan, Z. Zhang, Y.-X. Da and X.-C. Wang, Chem. Commun., 2016, 52, 14234–14237. M. Bergami, S. Protti, D. Ravelli and M. Fagnonia, Adv. Synth. Catal., 2016, 358, 1164–1172. L. Wang, W. Qiu, H. Shao and R. Yuan, Int. J. Photoenergy, 2016, 5632613. J. Ruch, A. Aubin, G. Erbland, A. Fortunato and J.-P. Goddard, Chem. Commun., 2016, 52, 2326–2329. ´n, J. I. Bardagı´, M. Puiatti and R. A. Rossi, J. Org. Chem., 2017, 82, M. E. Bude 8325–8333. ¨nig, Eur. J. Org. Chem., A. Eisenhofer, J. Hioe, R. M. Gschwind and B. Ko 2017, 2194–2204. ´ve ˆque, L. Chenneberg, V. Corce ´, J.-P. Goddard, C. Ollivier and C. Le L. Fensterbank, Org. Chem. Front., 2016, 3, 462–465. Photochemistry, 2019, 46, 116–168 | 165

83 84 85 86 87 88 89 90 91 92 93 94

95 96 97 98 99 100 101

102 103 104 105 106 107 108 109

110

111

B. Lipp, A. M. Nauth and T. Opatz, J. Org. Chem., 2016, 81, 6875–6882. M. C. Quattrini, S. Fujii, K. Yamada, T. Fukuyama, D. Ravelli, M. Fagnonia and I. Ryu, Chem. Commun., 2017, 53, 2335–2338. K. Nakajima, S. Nojima and Y. Nishibayashi, Angew. Chem., Int. Ed., 2016, 55, 14106–14110. S. P. Midya, J. Rana, T. Abraham, B. Aswin and E. Balaraman, Chem. Commun., 2017, 53, 6760–6763. J. W. Beatty, J. J. Douglas, R. Miller, R. C. McAtee, K. P. Cole and C. R. J. Stephenson, Chemistry, 2016, 1, 456–472. L. Li, X. Mu, W. Liu, Y. Wang, Z. Mi and C.-J. Li, J. Am. Chem. Soc., 2016, 138, 5809–5812. N. B. Hein and A. Studer, Org. Lett., 2017, 19, 4150–4153. F. Liu and P. Li, J. Org. Chem., 2016, 81, 6972–6979. Y. Li, M. Wang and X. Jiang, ACS Catal., 2017, 7, 7587–7592. X. Zhu, X. Xie, P. Li, Jianqi Guo and L. Wang, Org. Lett., 2016, 18, 1546–1549. ¨nig, ACS Catal., 2016, 6, 8410–8414. ¨sel and B. Ko R. S. Shaikh, S. J. S. Du R. Papadakis, H. Li, J. Bergman, A. Lundstedt, K. Jorner, R. Ayub, S. Haldar, B. O. Jahn, A. Denisova, B. Zietz, R. Lindh, B. Sanyal, H. Grennberg, K. Leifer and H. Ottosson, Nat. Commun., 2016, 12962. V. Kumar Das, S. Gogoi, B. M. Choudary and N. Karak, Green Chem., 2017, 19, 4278–4283. J. Santandrea, C. Minozzi, C. Cruche and S. K. Collins, Angew. Chem., Int. Ed., 2017, 56, 12255–12259. S.-H. Sua and M.-D. Su, RSC Adv., 2016, 6, 50825–50832. Y. Hakoda, M. Aoyagi, K. Irisawa, S. Kato, Y. Nakamura and M. Yamaji, Photochem. Photobiol. Sci., 2016, 15, 1586–1593. H. Okamoto, H. Takahashi, T. Takane, Y. Nishiyama, K. Kakiuchi, S. Gohda and M. Yamaji, Synthesis, 2017, 49, 2949–2957. Y. Shimo, T. Mikami, S. Hamao, H. Goto, H. Okamoto, R. Eguchi, S. Gohda, Y. Hayashi and Y. Kubozono, Sci. Rep., 2016, 6, 21008. T. S. Moreira, M. Ferreira, A. Dall’armellina, R. Cristiano, H. Gallardo, E. Hillard, A. Elizabeth, H. Bock and F. Durola, Eur. J. Org. Chem., 2017, 4548–4551. T. S. Moreira, M. Ferreira, A. Dall’armellina, R. Cristiano, H. Gallardo, E. A. Hillard, H. Bock and F. Durola, Eur. J. Org. Chem., 2017, 4548–4551. V. Rajeshkumar and M. C. Stuparu, Chem. Commun., 2016, 52, 9957–9960. V. Rajeshkumar, M. Court, D. Fichou and M. C. Stuparu, Eur. J. Org. Chem., 2016, 6010–6014. H. Saito, A. Uchida and S. Watanabe, J. Org. Chem., 2017, 82, 5663–5668. S. Banerjee, S. Sinha, P. Pradhan, A. Caruso, D. Liebowitz, D. Parrish, M. Rossi and B. Zajc, J. Org. Chem., 2016, 81, 3983–3993. M. Daigle, A. Picard-Lafond, E. Soligo and J.-F. Morin, Angew. Chem., Int. Ed., 2016, 55, 2042–2047. H. Hayashi, N. Aratani and H. Yamada, Chem. Eur. J., 2017, 23, 7000–7008. R. K. Mohamed, S. Mondal, J. V. Guerrera, T. M. Eaton, T. E. Albrecht-Schmitt, M. Shatruk and I. V. Alabugin, Angew. Chem., Int. Ed., 2016, 55, 12054–12058. O. Galangau, S. Delbaere, N. Ratel-Ramond, G. Rapenne, R. Li, J. P. D. C. Calupitan, T. Nakashima and T. Kawai, J. Org. Chem., 2016, 81, 11282–11290. H. Zhou, X. Z. Deng, A. H. Zhang and R. X. Tan, Org. Biomol. Chem., 2016, 14, 10407–10410.

166 | Photochemistry, 2019, 46, 116–168

112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129

130 131 132 133 134 135 136 137 138 139 140 141 142 143

X. Liu, Z. Qing, P. Cheng, X. Zheng, J. Zeng and H. Xie, Molecules, 2016, 21, 1690. M. Chen, X. Zhao, C. Yang, Y. Wang and W. Xia, RSC Adv., 2017, 7, 12022– 12026. Q.-Q. Zhao, X.-Q. Hu, M.-N. Yang, J.-R. Chen and W.-J. Xiao, Chem. Commun., 2016, 52, 12749–12752. B. Hu, Y. Li, W. Dong, X. Xie, J. Wan and Z. Zhang, RSC Adv., 2016, 6, 48315– 48318. L. Junk and U. Kazmaier, Org. Biomol. Chem., 2016, 14, 2916–2923. T. Yamada, Y. Ozaki, M. Yamawaki, Y. Sugiura, K. Nishino, T. Morita and Y. Yoshimi, Tetrahedron Lett., 2017, 58, 835–838. R. Oketani, T. Miyake, S. Jinnai, T. Fukui, H. Tsujimoto, M. Matsumura and S. Higashida, Chem. Lett., 2016, 45, 801–803. K. Wang, L.-G. Meng and L. Wang, Org. Lett., 2017, 19, 1958–1961. X.-F. Xia, G.-W. Zhang, D. Wang and S.-L. Zhu, J. Org. Chem., 2017, 82, 8455–8463. D. Yu. Dzhons and A. V. Budruev, Beilstein J. Org. Chem., 2016, 12, 874–881. Y. Yu, Z. Cai, W. Yuan, P. Liu and P. Sun, J. Org. Chem., 2017, 82, 8148–8156. C. Jin, L. Su, D. Ma and M. Cheng, New J. Chem., 2017, 41, 14053–14056. S. K. Pagire and O. Reiser, Green Chem., 2017, 19, 1721–1725. Y. Wang, J. Wang, G.-X. Li, G. He and G. Chen, Org. Lett., 2017, 19, 1442–1445. W. D. Guerra, M. E. Buden, S. M. Barolo, R. A. Rossi and A. B. Pierini, Tetrahedron, 2016, 72, 7796–7804. A. G. Lvov and V. Z. Shirinyan, Chem. Heterocycl. Compd., 2016, 52, 658–665. V. Zakharov, E. B. Gaeva, A. G. Lvov, A. V. Metelitsa and V. Z. Shirinian, J. Org. Chem., 2017, 82, 8651–8661. N. Chikaraishi Kasuga, Y. Saito, N. Okamura, T. Miyazaki, H. Satou, K. Watanabe, T. Ohta, S. Morimoto and K. Yamaguchi, J. Photochem. Photobiol., A, 2016, 321, 41–47. D. Iguchi, R. Erra-Balsells and S. M. Bonesi, Tetrahedron, 2016, 72, 1903– 1910. D. Iguchi, R. Erra-Balsells and S. M. Bonesi, Photochem. Photobiol. Sci., 2016, 15, 105–116. H. Maeda, T. Akai and M. Segi, Tetrahedron Lett., 2017, 58, 4377–4380. Y. Deng, Q. Liu and A. B. Smith, J. Am. Chem. Soc., 2017, 139, 9487–9490. H. Andersson, G. Hanna, J. Graefenstein, M. Isobe, M. Erdelyi and M. O. Sydnes, J. Org. Chem., 2017, 82, 1812–1816. L. Xie, X. Zhen, S. Huang, X. Su, M. Lin and Y. Li, Green Chem., 2017, 19, 3530–3534. D. P. Maurer, R. Fan and D. M. Thamattoor, Angew. Chem., Int. Ed., 2017, 56, 4499–4501. K. R. More and R. S. Mali, Heterocycl. Lett., 2017, 7, 341–345. K. Kim, M. Min and S. Hong, Adv. Synth. Catal., 2017, 359, 848–852. S. Thomas, J. Ly, L. Zhang, A. L. Briseno and J.-L. Bredas, Chem. Mater., 2016, 28, 8504–8512. Y. Ding, W. Zhang, H. Li, Y. Meng, T. Zhang, Q.-Y. Chen and C. Zhu, Green Chem., 2017, 19, 2941–2944. L. Zhang, H. Yi, J. Wang and A. Lei, Green Chem., 2016, 18, 5122–5126. P. Dongare, I. MacKenzie, D. Wang, D. A. Nicewicz and T. J. Meyer, Proc Natl. Acad. Sci., 2017, 114, 9279–9283. S. Phungsripheng, M. Akita and A. Inagaki, Inorg. Chem., 2017, 56, 12996– 13006. Photochemistry, 2019, 46, 116–168 | 167

144

145 146 147

E. M. Chainikova, A. R. Yusupova, S. L. Khursan, A. N. Teregulova, A. N. Lobov, M. F. Abdullin, L. V. Enikeeva, I. M. Gubaydullin and R. L. Safiullin, J. Org. Chem., 2017, 82, 7750–7763. Y. Liu, M. Zhang, C.-H. Tung and Y. Wang, ACS Catal., 2016, 6, 8389–8394. T.-F. Niu, D.-Y. Jiang, S.-Y. Li, B.-Q. Ni and L. Wang, Chem. Commun., 2016, 52, 13105–13108. C. Tao, B. Wang, L. Sun, Z. Liu, Y. Zhai, X. Zhang and Jian Wang, Org. Biomol. Chem., 2017, 15, 328–332.

168 | Photochemistry, 2019, 46, 116–168

Organic aspects. Oxygen-containing functions M. Consuelo Jime ´ nez* and Miguel A. Miranda* DOI: 10.1039/9781788013598-00169

In this chapter, most of the reported work deals with photochemistry of the carbonyl group; however, the photoreactions of other oxygen-containing functions are included as well. The coverage period is 2016–2017, and as a general rule, only original research articles reporting new experimental results are discussed; reviews or purely theoretical calculations are not quoted.

1

Introduction

As in the previous volumes of these periodical reports, the chapter is `mainly organised according to reaction types (e.g., Norrish I/II, Paterno ¨chi, photo-Fries/photo-Claisen, etc.). After each heading, the basic Bu photochemical results are presented first, and then more specific aspects are mentioned (synthetic applications, stereoselectivity, biological, technological or environmental applications, etc.). This is followed by photoreactions in microheterogeneous systems, in solid matrixes or in the crystalline state. When available, mechanistic studies based on time-resolved spectroscopies, including ultrafast detection, are included. Only photoreactions where the oxygen containing compounds are the light absorbing species are considered, so the fast-growing field of visible-light reactions using different types of photocatalysts is beyond the scope of the present chapter.

2

Norrish type I reactions

Fundamental aspects of the reaction in structurally simple carbonyl compounds still deserve some attention. Thus, photolysis of cyclohexanone in the vapour phase has been performed using 311 nm UV light. The main primary photoproducts, detected by FTIR spectroscopy, are 5-hexenal and butylketene. The obtained results agree with theoretical calculations at DFT/B3LYP/6-311þþG** level.1 Likewise, a theoretical study on the photochemistry of Irgacure 907 (1) has been performed by DFT methodologies. The photocleavage reaction orginates from a np* triplet excited state, generating two radical species, as expected for a typical type-I photoinitiator.2 Several synthetic applications of the Norrish type I reaction have been reported. They include the diastereoselective synthesis of (Z)-3-(alkoxymethylene)isobenzofuran-1-ones by photolysis of benzamides (2),3 the total synthesis of protoilludanes involving photocleavage of the bicyclic Departamento de Quı´mica/Instituto de Tecnologı´a Quı´mica UPV-CSIC, Universitat Polite`cnica de Vale`ncia, Camino de Vera s/n, 46022 Valencia, Spain. E-mail: [email protected]; [email protected] Photochemistry, 2019, 46, 169–193 | 169  c

The Royal Society of Chemistry 2019

ketone (3) with intramolecular 1,3-acyl migration to indenone 44 and the synthesis of 12,12 0 -azo-13,13 0 -diepi-ritterazine N using Norrish type I cleavage of polycyclic ketone (5) as key step.5 Photocleavage of appropriate ketone precursors has been used as a tool to generate site-specific radicals in nucleic acids. For instance, photolysis of ketone (6) leads to formation of 2 0 -deoxyadenosin-N6-yl radical with release of acetone.

The formation of such an intermediate is followed by laser flash photolysis, as the growth of a transient with lmaxE340 nm within ca. 5 ms.6 The independent generation of 5,6-dihydropyrimidin-5-yl radicals in organic solvents has been achieved by Norrish type I cleavage of the lipophilic tert-butyl ketone precursors (7). The formation of the purported intermediates has been confirmed by trapping with a nitroxide-derived profluorescent probe. Further evidence has been furnished by nanosecond laser flash photolysis through detection of long-lived transients, with absorption maxima in the range 350–420 nm, depending on the substitution. The experimental results are supported by multiconfigurational ab initio CASPT2//CASSCF methodology.7 Following a similar approach, Norrish type I photocleavage of the benzyl substituted nucleotide (8) leads to generation of a C2 0 -uridine radical and subsequently produces strand breaks via cleavage of the b-phosphate. This is relevant in connection with RNA strand scission by the hydroxyl radical, particularly under anaerobic conditions.8 The Norrish type I reaction appears to be involved in the photodegradation of polymers, such as polyvinyl acetate,9 lignin10 and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate).11 This is accompanied by changes in colour, morphology, crystallinity index, fluorescence intensity, etc. The photodegradation process has been followed by UV–Vis, FTIR-ATR, FT-Raman or SEM measurements. Addition of UV absorbers such as phydroxybenzophenone or 5-benzoyl-2-hydroxy-4-methoxybenzenesulphonic acid may result in an enhanced photostability.9 The Norrish type I photofragmentation is involved not only in polymer photodegradation, 170 | Photochemistry, 2019, 46, 169–193

but also in photopolymerisation. Thus, covalent attachement of TEMSI2BAPO (9) onto silica particles leads to inmobilised photoactive moieties that promote photocuring of thyol-ene systems. The reaction kinetics is followed by FT-IR, photo-DSC and thermogravimetric analysis.12

Manipulation of the excited state behaviour of selected guests is achieved within two new cavitands derived from octa acid in aqueous medium. The presence of a benzoate anion at the top periphery is associated with a triplet sensitiser behaviour of the host. Interestingly, the Norrish type I cleavage of 1-phenyl-3-(p-tolyl)propan-2-one whitin the confined space of the cavitands leads exclusively to cage products.13

3

Hydrogen abstractions

3.1 Norrish type II and related intramolecular hydrogen abstractions Visible light irradiation of pyreneacyl sulphides (10) gives rise to intramolecular g-hydrogen abstraction by the ketone group, followed by b-cleavage of the intermediate 1,4-biradical. This Norrish type II elimination yields thioaldehydes that can be trapped by nucleophiles or dienophiles, providing a versatile ligation platform.14 Intramolecular hydrogen abstraction occurring in o-alkylsustituted phenyl ketones leads to photoenols (o-quinodimethanes), which are trapped by electrophiles. Using the Togni reagent, trifluoromethylation at the o-benzylic position is observed,15 whereas in the presence of enones and chiral amino acid esters as catalysts, asymmetric Michael addition occurs,16 to give saturated ketones (11). Likewise, the photoenolisation of o-methylbenzophenones leads to the corresponding hydroxy-oquinodimethanes, which serve as nucleophiles in an intermolecular aldol desymmetrisation of achiral 2-fluoro-substituted cyclopentane-1,3diketones.17 In the case of o-alkylbenzoylphosphonates, the electron withdrawing nature of the phosphonate substituent facilitates ring closure of the o-quinodimethane intermediate and results in formation of strained benzocyclobutenols (12).18 The intramolecular hydrogen abstraction by carbonyl compounds can also be used with synthetic purposes. For example, irradiation of diketone (13) at ca. 405 nm leads to Norrish–Yang cyclisation. This transformation is used as a key step in the total synthesis of zaragozic acid C (14).19 When the hydrogen atom is abstracted from remote positions, larger rings are Photochemistry, 2019, 46, 169–193 | 171

formed in a Yang-like reaction. Thus, cyclopropyl ketones (15) undergo a stereospecific photocyclisation to afford dihydrobenzopyranols.20 Intramolecular hydrogen abstraction has found application in the field of polymers. In this context, photoactive benzoxazines containing a carbonyl chromophore and a hydrogen donating site, such as (16), are effective in the photomodification of polybutadiene under 300–350 nm light. The resulting benzoxazine-functionalised polybutadienes undergo thermally activated curing without any catalyst.21 Related dyes (17) containing N,N-dialkylamino and ketone groups are efficient one-component visible light photoinitiators for the polymerisation of methyl methacrylate. The process can be followed by absorption and emission spectra, combined with ESR and CV analysis.22 The Norrish–Yang photocyclisation of ketones (18)–(20) has been investigated in the solid state and monitored by single crystal XRD experiments. The external stimuli, such as pressure, temperature, radiation energy as well as the crystal parameters, have different degrees of influence on the course of the reaction.23–26

Suspensions of nanocrystals are appropriate media for transient absortion spectroscopic studies. In this context, laser flash photolysis of crystalline a-(o-tolyl)acetophenone and a-(o-tolyl)-p-methylacetophenone shows rate limiting d-hydrogen atom transfer in the triplet excited state (2.7107 s1 and 1.5106 s1, respectively) leading to very short-lived biradicals that do not accumulate. The markedly slower rate for the p-methylsubstituted derivative is assigned to an increased contribution of the p,p* excited state.27 Likewise, laser flash photolysis has been employed to monitor the photoenolisation of ketoester (21). Intramolecular benzylic hydrogen abstraction leads to a 1,4 biradical (lmaxB340 nm) that evolves to the Z- and E- photoenols, after intersystem crossing. Steady-state photolysis of (21) under anaerobic conditions does not give any product, whereas in the presence of oxygen peroxide (22) is obtained.28 Steady-state irradiation of a-cholesterol conjugated with (R)- or (S)suprofen results in intramolecular hydrogen abstraction from the allylic C7 position, to give biradicals that collapse to coupling products such as (23). The conjugate of (R)-suprofen reacts significantly faster, indicating a stereodifferentiation in the photobehaviour.29 172 | Photochemistry, 2019, 46, 169–193

3.2 Intermolecular hydrogen abstraction reactions The rate of formal hydrogen abstraction can be markedly increased by proton-coupled electron transfer. As an example, the triplet excited state of o-benzoylbenzoic acid is quenched by toluene with kQ ¼ 8.0105 M1 s1, whereas in the absence of the intramolecular Lewis acid, the reaction does not occur.30 Solar photolysis of amphiphilic 2-oxoalkanoic acids in aqueous media, under environmentally relevant conditions, leads to oligomeric amphiphiles, arising from intermolecular hydrogen abstraction and subsequent radical coupling processes. These photoproducts are multitailed lipids, which exhibit interesting properties, including spontaneous self-assembly into aggregates. In addition, monomeric products result from Norrish type II to generate pyruvic acid.31 Glyoxilic acid, another 2-oxoalkanoic acid, undergoes a-cleavage or participates in hydrogen abstraction, generating reactive species under solar irradiation; UV–Visible and fluorescence spectroscopies reveal that the photoproducts undergo dark thermal aging.32

The triplet excited state of benzophenone abstracts hydrogen atoms from positions 3 and/or 7 of sodium cholate, giving radical pairs which eventually end up with formation of the oxo analogues of the bile salts with concomitant reduction of the benzophenone chromophore. This radical-mediated dehydrogenation is reminiscent of the enzymic action of hydroxysteroid dehydrogenases.33 A related hydrogen abstraction by photoexcited benzophenone from DNA substructures (thymine nucleobase and backbone sugar) has been analysed by means of theoretical calculations, using high level multiconfigurational perturbation and density functional theory. In DNA, simulations have made use of molecular dynamics and hybrid quantum mechanics methods. A strong dependence of the H-abstraction with the interaction mode is evidenced.34 Solvent effects, especially intermolecular hydrogen bonding, on the structure and behaviour of the triplet excited state of xanthone have been investigated by a combination of time-resolved resonance Raman and UV–Vis transient absorption spectroscopies, together with timedependent DFT calculations. As a result of these studies, it is proposed that the different hydrogen bonding modes operating in the two lowest triplet states of xanthone lead to a lower contribution of the np* triplet state, being thus responsible for the reduced photoreactivity of this ketone towards hydrogen abstraction in protic solvents.35,36

4 Paterno ` –Bu ¨ chi photocycloadditions Among the fundamental aspects of this reaction, it has been recently found that a complementary strategy based on pp* excited alkenes Photochemistry, 2019, 46, 169–193 | 173

(rather than np* excited carbonyls) is effective in the formation of oxetanes. In the case of enamides (24), this is achieved by changing the R substituent from phenyl to methyl or hydrogen. In both cases, oxetanes `–Bu ¨chi photoreaction efficiency has been (25) are obtained.37 The Paterno remarkably improved in a flow microreactor (under slug flow conditions) in water. The method has been optimised for the photocycloaddtion between ethyl benzoylformate and 2,3-dimethyl-2-butene.38 Flow photochemistry has been employed to scale-up the photoreaction between enol ether (26) and benzaldehyde, yielding oxetane (27) in multigram amounts. The latter has been used as synthetic precursor of the cytotoxic lactone (þ)-goniofufurone.39 The oxetane core of oxetin and epi-oxetin (28) has been constructed by `–Buchi photoreaction between a N-formyl enamine and a glyoxPaterno ilate ester. Further steps, including final resolution protocols, afford the enantiomerically pure compounds on gram scale.40

The known directing effect of hydroxyl groups on the regiochemistry of `–Bu ¨chi reaction has been extended to 5-oxazoylmethanol the Paterno derivatives (29). When aromatic aldehydes are used, an unsual endo stereoselectivity is observed.41 The photoreaction between benzaldehydes and 2,3-dihydrofuran has been achieved inside the cavities of NaY zeolite, with enhanced stereoselectivity.42 In both cases, the stereoselectivity is explained by the interaction between HSOMO and LSOMO in the biradical intermediates. `–Bu ¨chi reaction with tamdem mass Coupling of the Paterno spectrometry has been exploited for localisation of the C–C double bonds in a variety of lipids, including unsaturated fatty acids,43 cholesteryl esters44 and glycerophospholypids.45–47 This approach is based on the production of characteristic fragment ions, which are diagnostic for CQC location and isomer quantitation and has revealed itself as a useful tool in uncovering structural diversity of lipids due to unsaturation. Steady-state irradiation of thymine derivatives (30) in the presence of benzophenone results in the formation of the two regioisomeric oxetanes with a new C–O bond between C5 or C6 of the pyrimidine and the carbonyl oxygen. The observed photoreactivity is markedly higher for the methyl than for the t-butyl derivative, due to steric hindrance. By contrast, direct irradiation in the absence of sensitiser gives rise to a Norrish–Yang photoreaction (30, R ¼ C(CH3)3) or to cyclobutane dimers (30, R ¼ CH3). The mechanistic insights obtained by laser flash photolysis are in accordance with the observed photoreactivity.48 174 | Photochemistry, 2019, 46, 169–193

5 Photoreactions of multichromoporic systems: dicarbonyl compounds, enones, quinones and quinone methides 5.1 Dicarbonyl compounds The photophysical and photochemical properties of 1,3-diketones have been examined by means of theoretical calculations. These relatively simple systems may undergo a variety of processes, including excited state proton transfer or charge transfer, keto-enol tautomerization, Z–E isomerization, rotation about single bonds and a-cleavage.49,50 In the case of avobenzone, widely used as UV-filter in sunscreens, torsion around the C2–C3 bond of photoexcited chelated enol leads to internal conversion to the ground state and formation of the E-rotamer. The solvent dependent photolability is connected with the relative order of the lowest triplet pp* and np* states of the keto tautomer.50 Oxidative photocyclisation of 1,3-diketones (31) affords the highly functionalised polycyclic products (32) via 6p electrocyclisation of the enol form, without addition of transition metals or any other oxidant.51 Spiropyran derivatives (33) are synthesised by one-pot three-component visible light irradiation of indantrione, active methylene compounds and 1,3-diketones.52 Although the reaction mechanism is unclear, cyanoolefin intermediates (34) have been isolated.

Diketone (35) is a two photon dye, wich displays favourable photophysical properties and a remarkable polarity sensitivity, based on the keto-enol tautomerism. In addition, it also possesses red-light emission, sufficient photostability, and low pH sensitivity. Hence, this dye has been used for living cells imaging to visualize the small changes of intracellular polarity in apoptotic cells.53 Several p-expanded a,b-unsaturated 1,3-diketones, for instance (36), with excellent solubility in most organic solvents, exhibit very broad absorption spectra and negligible fluorescence. Interestingly, these dyes Photochemistry, 2019, 46, 169–193 | 175

have two-photon absorption cross-sections at polymerisation wavelengths that make them suitable photoinitiators with broad fabrication windows.54 The keto-enol tautomerisation of 2-alkyl-1,3-diketones (37) in solution has been investigated by means of steady-state and laser flash photolysis. The diketo tautomers are photoconverted into the keto-enol forms mainly through the triplet excited state. The enols can be considered as temporal UVA sunscreens, as the back reaction occurs thermally within a few days.55 5.2 Enones Blue-light irradiation of o-aminoaryl substituted a,b-unsaturated ketones such as (38) results in double bond isomerisation; subsequent thermal cyclodehydration affords the corresponding quinolines in good yields.56 Photochemical electrocyclisation of aryl b-halovinyl ketones (39) leds to tetrahydrofluorenones and related structures. The method has been applied to the synthesis of natural products containing the tetrahydrofluorenone moiety.57 In a related reaction, photocyclisation of acrylanilides has been achieved using a microfluidic flow photoreactor, to obtain tetrahydroquinolines. This approach has been used for the synthesis of ()-t-vabicaserin (40).58 The UVA induced oxa-6p electrocyclisation of dienone systems has been used to achieve a biomimetic synthesis of briareolate ester B (41) from briareolate ester L (42). The process is reversed by UVC irradiation, which allows establishing a photochromic switch.59 Photorearrangement of chromones such as (43) to diarylketones (44) also involves a 6p electrocyclisation, which is followed by hydrogen shift and final ring opening with rearomatisation.60

Sensitised irradiation of the tricyclic b,g-enones (45) follows a oxa di-pmethane rearrangement, to give triquinanes (46) along with 1,3-acyl shift, affording cyclobutanones (47). Direct irradiation leads only to the latter products.61 176 | Photochemistry, 2019, 46, 169–193

Site-selective photochemical fluorination of steroidal enones can be achieved at allylic and homoallylic positions through a reaction pathway that includes intramolecular hydrogen abstraction, radical fluorination and restoration of the enone. This has been applied to the synthesis of complex molecules, such as the triterpenoid saponin derivative (48).62 Intramolecular [2 þ 2] photocycloaddition of enones (49) to afford tricyclic products (50) occurs from the excited triplet state with a remarkable regioselectivity, favouring straight- over cross cycloaddition A susbstitution-dependent atropselectivity is also observed.63 Direct irradiation of aryloxycyclohexenones (51) at 366 nm leads to racemic tetrahydrodibenzofuranones (52) in moderate to good yields. In the presence of a chiral copper–bisoxazoline complex or upon photosensitisation by thioxantone, significant enantioselectivities are observed.64 Stereoselective photosantonin rearrangement of crossconjugated cyclohexadienone (53) affords the corresponding cyclopentenone (54). This transformation constitutes the key step in a scalable synthesis of ()-thapsigargin.65 A related photorearrangement leads from dienone (55) to valuable intermediates in the synthesis of cubebane-, spiroaxane-, and guaiane-type sesquiterpenes.66 Furyl substituted enones (56) udergo photoisomerisation to unsaturated aldehydes (57). The reaction mechanism has not been proven, although a carbene is proposed as intermediate. The nitro-substituted photoproduct shows polarity-dependent fluorescent properties and has potential application in optical data storage.67

Solar simulated photolysis of dienogest (58), an oral contraceptive containing a dienone moiety, gives rise to complex mixtures in aqueous media at different pH values. The major process is a reversible photohydration that increases its environmental persistence. In addition, several minor photoproducts are obtained with enhanced strogenic properties. This information is important regarding environmental risk assessment of this synthetic drug.68 Photochemistry, 2019, 46, 169–193 | 177

Solid-state irradiation of 2-allyl, 2,4-dimethoxy and 5-bromo-2-methoxy substituted cis-cinnamic acid results in the head-to-head cyclobutane dimers as the almost exclusive products. This process competes with geometric isomerisation as a minor reaction pathway. By contrast, the corresponding trans-cinnamic acids give rise to the head-to-tail dimers, except in the case of an unreactive bromo derivative.69 The [2 þ 2] photodimerization of 2,6-difluorocinnamic acid in the crystal state has been investigated at different pressures. The main observation is that the rate of the reaction increases with increasing pressure due to the decrease in the volume of free space columns and the decrease in the distance between the reactive carbon atoms in adjacent monomer molecules.70 Topochemical photocycloaddition of tetrasubstituted p-quinodimethane (59) affords the [2.2]paracyclophane (60) via a single crystal-to-single crystal [6 þ 6] photocycloaddition. In solution, under aerobic conditions, a peroxide resulting from formal oxygen trapping of a biradical intermediate is obtained.71 While irradiation of achiral enone carboxamides (61, R1QH) results in 6p electrocyclisation to 3,4-dihydroquinolin-2-ones (62), o-phenyl-substitued enone carboxamides (61, R1 ¼ t-Bu) undergo intramolecular hydrogen abstraction, leading to spiro-b-lactams (63). This dual reactivity and selectivity pattern is supported by photophysical measurements (including detection of the triplet excited states and zwitterionic intermediates by transient absorption spectroscopy) and theoretical calculations.72

5.3 Quinones Photoinduced intramolecular hydrogen abstraction in naphthoquinones (64) leads to 1,4-biradical intermediates, which ultimately afford naphthols (65). This can be regarded as an intramolecular redox reaction.73 Photolysis of (þ)-komaroviquinone (66) gives rise to ()-cyclocoulterone (67) and komarovispirone (68). Both natural products contain the methylendioxy group, whose photolytic formation provides an evidence for the possible involvement of a non enzymatic route in the biogenesis of this unit.74

Photochemical migration of a phenyl group in 1-phenoxy anthraquinone conjugates with tetraethylene glycol (69) gives rise to isomeric compounds (70). This photochromic transformation has a strong 178 | Photochemistry, 2019, 46, 169–193

influence on the complexation with sodium or calcium cations, so (69) and (70) can be regarded as photocontrolled ionophores.75 Photoreduction of the 3,6-di-tert-butyl-o-benzoquinone (71), in the presence of N,N-dimethylanilines, leads to the corresponding hydroquinones both in the acrylate monomer and in poly(quinone methacrylate) or on the surface of polymer matrix pores. The kinetics of the reaction depends on the electron-donating ability of the amine and on the monomeric or polymeric nature of the quinone.76 The donor/acceptor nature of the solvent has a significant influence on the photoreduction kinetics of 3,6-di-tert-butyl-1,2-benzoquinone in the presence of N,Ndimethylanilines.77 Quinone photoredox chemistry appears to be involved in the daytime/nighttime conversion of NO2 into HONO on soils. This is supported by experiments performed on mineral surfaces coated with juglone as a model quinone.78 Theoretical calculations are in agreement with experimental results obtained for antrhaquinone (72) in neutral aqueous solution by means of transient UV–Vis absorption and time-resolved resonance Raman spectroscopy in the nanosecond timescale, which indicate that protoncoupled electron transfer is the initial step for the intramolecular photoredox process leading to (73).79 The nature of the solvent and the substitution pattern have a marked influence on the properties, relative energies and chemical reactivities of the np* and pp* triplet excited states within a family of related compounds.80 Proton coupled electron transfer has been investigated by means of CIDNP in the photoreaction between 2,6-disubstituted benzoquinones and DABCO as a model system of the primay electron transfer during photosynthesis.81 5.4

Quinone methides

Conjugated quinone methides (74) are obtained from appropriate precursors (75) upon UV–Vis light activation. Laser flash photolysis allows detection of 74, along with the triplet excited states of (75). The reactivity of (75) towards photohydration and trapping by thiols has been studied to evaluate the capability of these compounds to act as alkylating agents and singlet oxygen sensitisers.82 Photochemistry, 2019, 46, 169–193 | 179

Visible light irradiation of anthrols (76) affords the corresponding quinone methides (77). These intermediates have been detected by LFP, and their reactivity towards nucleophiles investigated in connection with the light enchanced antiproliferative effect of 76 on human cancer cell lines.83,84 Quinone methide precursors have been prepared from tyrosine and used as building blocks in the synthesis of peptides, which can be modified afterwards by photoactivation. In this context quinone methides from dipeptides have been detected by laser flash photolysis (lmaxE400 nm, t ¼ 100 ms-20 ms) and their reactivity with nucleophiles has been studied in connection with their possible applications in organic synthesis, materials science, biology and medicine.85 Photoexcitation of the binol derivative (78) in aqueous solution affords the corresponding quinone methide (79). Fluorescence quenching of the precursor by water suggests the involvement of an excited state intramolecular proton transfer. Femtosecond and nanosecond transient absorption spectra prove that water molecules participate in the process and in the subsequent release of the leaving group to afford the quinone methide.86

6 Photoeliminations: photodecarboxylations, photodecarbonylations and photodenitrogenations Photolysis of phthaloyl peroxide at l ¼ 266 nm in acetonitrile at room temperature gives rise to decarboxylation, affording o-benzyne. A minor product is ketene (80). Trapping of o-benzyne with methyl 1-methylpyrrole-2-carboxylate leads to the Diels–Alder cycloadduct (81).87 Photodecarboxylation of cyclic carbonate esters occurs with formation of 1,3-biradical intermediates, which ultimately yield oxiranes and several other radical-derived products. By contrast, photolysis of the corresponding cyclic sulphite esters follows ionic pathways that afford products resulting form nucleophilic trapping by the solvent, without generation of oxiranes.88 Solar photolysis of aqueous pyruvic acid under aerobic conditions produces acetyl and ketyl radicals, which react further to afford 2,3dimethyltartaric acid, 2-(1-carboxy-1-hydroxyethoxy)-2-methyl-3-oxobutanoic acid, and 2-hydroxy-2-((3-oxobutan-2-yl)oxy)propanoic acid. The results from kinetic isotope effect studies are in agreement with an initial proton coupled electron transfer.89

The acyl radicals generated upon photodecarboxylation of a-oxocarboxylic acids react with phenyl propiolates to give coumarins (82). The reaction is catalysed by hypervalent iodine reagents through formation 180 | Photochemistry, 2019, 46, 169–193

of esters, which are the actual light absorbing species.90 The reaction also works with acrylamides, but in this case five-membered ring products such as (83) are formed.91 Likewise, when the substrates are vinylcyclobutanols, decarboxylative acylation is concomitant with ring expansion, and 1,4dicarbonyl compounds (84) are obtained.92 Photodecarboxylative addition of phenylacetates to N-(bromoalkyl)phthalimides gives hydroxyphthalimidines, which are readily converted into isoindolinones (85).93 Phthalimide activated adamantane carboxylic acids such as (86) undergo photodecarboxylation. In the case of the b-substituted analogues (87, 88), this process is acompanied by cyclisation, to afford complex product mixtures.94 By contrast, phthalimidoadamantane-tyrosine conjugates do not exhibit the usual photodecarboxylation reactivity, which is attributed to quenching of the excited phthalimide by intramolecular electron transfer from the tyrosine moiety.95 Selected photodecarboxylations involving intra- or inter-molecular activation by phthalimides have been successfully achieved in a meso-scale continuousflow photoreactor, with improved efficiency and productivity.96 Not only phthalimides, but also maleimides connected to C-terminal cysteines (89) mediate photodecarboxylation, releasing the corresponding vinylamino derivatives.97 The photoreactivity of ketoprofen is enhanced upon complexation with b-cyclodextrin. This is attributed to conformational changes of the drug in the inclusion complex, associated with variations in the dihedral angle between the two aromatic rings and with a reduced mobility of the carbonyl group.98 The photobehaviour of a ketoprofen/ibuprofen dyad (90) has been investigated by femtosecond transient absorption spectroscopy. Decarboxylation takes place from the triplet state in the picosecond timescale (time constant ca. 550 ps), to give a carbanionic species with lmax ¼ 610 nm.99 The photoreactivity of fenofibric acid is characterised by decarboxylation from the triplet excited state. This process has been investigated in the presence of human serum albumin by steady-state irradiation, fluorescence, and laser flash photolysis. Covalent photobinding to the protein is detected, resulting in the covalent attachement to he Tyr-476 residue.100

Photochemistry, 2019, 46, 169–193 | 181

Steady-state and time-resolved photolytic studies have shown that cyclopropenones (91) release the corresponding alkynes upon photodecarbonylation within 5 nanoseconds. These photoproducts are used for click chemistry in [3 þ 2] or [4 þ 2] cycloaddition reactions with benzyl azide and 1,2,4,5-tetrazines, respectively.101 Two- or three-photo excitation of cyclopropenones (92) with femtosecond near-IR pulses leads to photodecarbonylation with formation of the corresponding dibenzocyclooctynes. The latter are traped by azides, affording the corresponding triazoles. This process enables high resolution 3D photoclick derivatisation of hydrogels and tissues.102 Photolysis of carbonyl diisocyanate OC(NCO)2 with an ArF laser (lexc ¼ 193 nm) in solid argon matrixes at 16 K leads to photodecarbonylation, yielding a novel carbonyl nitrene OCNC(O)N. Subsequent visible light ((lexc4395 nm) irradiation results in a Curtius-rearrangement affording OCNNCO.103 Aqueous nanocrystaline suspensions of tetraarylacetones in the presence of submicellar CTAB undergo an eficcient photodecarbonylation reaction, giving rise to intermediate diarylmethyl radical pairs within the laser pulse duration (8 ns). The transient absorption spectra under these conditions exhibit maxima at lmax ¼ 330–360 nm, according to expectations from measurements in homogeneous solutions. The triplet radical pair has a relatively long lifetime, in the range of 40–90 ms, depending on the substitution pattern.104 Gas-phase photolysis of 5-diazo Meldrum’s acid (93) yields three photoproducts within less than 1 ps: a carbene formed after denitrogenation, a ketene resulting from Wolf rearrangement and a second carbene involving both denitrogenation and decarbonylation. This has been explained by theoretical calculations at the MS-CASPT2//CASSCF level.105 Enantioselective Sharpless dihydroxylation of a,b-unsaturated diazoketones, followed by Wolff photorearrangement have been used as key steps in the synthesis of enantiopure 4,5-disubstituted 2-furanones.106 Whereas direct irradiation of diazoketones (94) leads mainly to the Wolf rearrangement products, benzophenone photosensitisation in the presence of hydrogen-donating solvents (RH) gives rise to hydrazones (95), without elimination of nitrogen.107 Photolysis of 3-azido-2,2-dimethyl-1,3-diphenylpropan-1-one in the solid state leads to isobutyrophenone and benzonitrile. Laser flash photolysis of nanocrystals allows detection of the triplet excited azidoketone at lmax ca. 475 nm. The triplet energy, calculated by timedependent density functional theory, is 79 kcal mol1, which is sufficient for cleavage of the Cb-Cg bond.108

182 | Photochemistry, 2019, 46, 169–193

7

Photo-Fries and photo-Claisen rearrangements

Multiconfigurational theoretical calculations on the photo-Fries rearrangement of phenyl acetate have proposed a three state model for the reaction: an aromatic 1pp*, generated immediately after light absorption, a pre-dissociative 1np*, where the energy is transferred to the dissociative region and a 1ps*, where bond cleavage occurs. The conversion of 1pp* to 1np* involves pyramidalisation of the carbonyl carbon, while transformation of 1np* to 1ps* occurs through stretching of the CO group.109 It is generally assumed that the photo-Fries rearrangement of aryl esters takes place from the singlet excited state of the aryloxy chromophore. Interestingly, in the case of 1-pyrenyl benzoates, the reaction takes place from the singlet excited state of the benzoyl chromophore, because the energy of the pyrenyl singlet is insufficient to cleave the CO–O bond. Accordingly, 1-pyrenyl alkanoates do not undergo the photorearrangement.110 The known formation of 2,2-dimethylchroman-4-ones during the photo-Fries rearrangement of aryl 3-methyl-2-butenoate esters in nonprotic solvents has been attributed to excited state intramolecular proton transfer in the primary acylphenols, followed by thermal cyclisation.111 The photo-Fries rearrangement continues to attract attention in the field of polymer curing and stability. Photogeneration of radical pairs in the photo-Fries rearrangement triggers polymerisation of 4,4 0 dimethacryloyloxy biphenyl and 3,3 0 -dimethacryloyloxy biphenyl in liquid crystals.112 Likewise, photo-Fries rearrangement of the aryl ester groups and photoinitiated crosslinking of methacryloyl moieties are observed under UV irradiation of polyhydroxystyrene with azofragments containing free methacrylic double bonds.113 Chemical structure changes during aging of poly(acrylonitrile-butadiene-styrene)/polycarbonate (ABS/PC) blend under UV irradiation have been investigated by FTIR analysis. Due to photo-Fries rearrangement of the PC component, the ABS/PC blends display enhanced photostability.114 Photodecomposition of block copolymers synthesised from polyurethane and poly(methyl methacrylate) occurs both by photo-Fries rearrangement of the urethane linkages and photodeprotection of end-functionalised o-nitro benzyl groups.115 Photo-Fries rearrangement of aryl acetamides has been investigated in micellar (ionic and non-ionic) media. Control of the primary radical pair mobility in these microheterogeneous systems results in a remarkable photoproduct selectivity, with enhanced yields of the o-rearranged products.116 Photolysis of 1,4-bis(phenylsulphonyloxy)benzene produces S–O cleavage, with generation of a phenylsulphonyl/phenylsulphonyloxyphenoxy radical pair. Further steps end with formation of photo-Fries rearrangement products, together with a large amount of acidic species.117 Likewise, N-arylsulphonimides have been found to be efficient nonionic photoacid generators. This is because, in addition to the photo-Fries products, photolysis of the sulphonimides releases sulphinic Photochemistry, 2019, 46, 169–193 | 183

and sulphonic respectively.118

acids

under

anaerobic

or

aerobic

conditions,

Irradiation of coumarin-caged 4-hydroxy tamoxifen (96) does not only lead to uncaging, but also to a significant amount of the photo-Claisen rearrangement product (97). The use of an extended, self-immolative linker, allows circumventing this undesired side reaction.119

8 Photocleavage of cyclic ethers Direct photolysis of styrene oxide yields phenylacetaldehyde, toluene and bibenzyl as primary photoproducts. Styrene glycol carbonate gives rise to a similar mixture of photoproducts. This is consistent with initial cleavage of the benzylic C–O bond, to give a singlet 1,3-biradical; this intermediate affords directly the aldehyde or, after intersystem crossing to the triplet biradical, the other two photoproducts.120 Epoxide (98) is successfully reduced upon irradiation with white light in the presence of sodium carbonate, sodium hydrosulphite and a pyridinium salt to give alcohol (99). This is a key step in the synthesis of juglocombins A and B.121

9

Photoremovable protecting groups

Coumarin-caged ceramide analogues (100), useful for cell studies, photorelease the parent ceramides upon direct exposure to 350 nm UV light.122 The dicyano derivatives (101) are appropriate photocages for carboxylic acids and amines, which can be released upon irradiation with green light.123 This principle has been applied to the photocontrolled delivery of cyclic RGD peptides.124 Related photoremovable protecting groups containing a coumarin chromophore with extended p conjugation display suitable two-photon absorption properties in the near-IR region. Thus, benzoates (102) are efficiently uncaged by two-photon irradiation above 700 nm, with optimal wavelength depending on the substitution pattern.125 Quinone trimethyl locks, such as (103), are appropriate longwavelength photoremovable protecting groups for alcohols and amines. 184 | Photochemistry, 2019, 46, 169–193

Intramolecular photoreduction using visible light generates reactive phenols, whose fast lactonisation to (104) is accompanied by uncaging in quantitative yields.126 Product analysis, kinetic isotope effects, stereochemical labeling, radical clock and transient absorption studies support an electron transfer mechanism.127

Thiochromone S,S-dioxides are efficient photolabile protecting groups for phosphates, amino acids and sulphonic acids. The uncaging of (105) proceeds straightforward, with formation of a condensed furan derivative (106) along with the released substrates.128 Carboxylic acids, including amino acids, can be photoreleased from the corresponding bimane caged compounds (107) by means of visible light. Both single and dual release can be achieved from the same bimane unit.129 Photolysis of o-nitrobenzyl esters (108) releases the deprotected carboxylic acids along with the corresponding o-nitrosoketones. Substitution at the a position by a bulky alkyl group increases the rate of the reaction. Further photorearrangement of the nitrosoketones affords bicyclic oxazoles (109).130 Thiocarbamates (110), which contain a photoremovable protecting group of the same family, undergo a photoactivated release of carbonyl sulphide, which is readily hydrolysed to hydrogen sulphide by carbonic anhydrase.131 A photocleavable o-nitrobenzyl-caged antitumour prodrug of 5-fluorouracil has been reported (111). It shows a decreased toxicity, but retains the antitumor activity against cancer cells after exposure to UV radiation.132 An alternative approach for the photocontrolled release of 5-fluorouracil makes use of a pyrene substituted oligonucleotide trimer (112). The process is triggered by electron injection from the excited pyrene unit.133 Coumarin fused oxazoles (113) have been employed as photocages for carboxylic acids, using butanoic acid as model compound.134 Likewise, fused coumarin esters (114) have been reported to photorelease 5aminolevulinic acid, which is an established prodrug in photodynamic therapy.135 Photochemistry, 2019, 46, 169–193 | 185

Sunscreen-based photocages are not only useful for the photocontrolled release of bioactive compounds, but also to prevent photodegradation. The concept has been proven linking avobenzone, a widely used UVA filter, to the photosensitive nonsteroidal anti-inflammatory drug ketoprofen (115).136 Photoremovable protecting groups based on bis-acetyl carbazole (116) are appropriate systems for the dual release of carboxylic acids, alcohols, thiols, and amines in a sequential mode. These systems are appropriate for drug delivery, cellular uptake and biocompatibility, as shown by in vitro studies.137 The concept of photoremovable protecting groups has also found application in the field of polymers. Thus, attachement of the photocleavable o-nitrobenzyl moiety to polymeric micelles based on amphiphilic polyaspartamides loaded with paclitaxel provides a photo-responsive system for the controlled release of this anticancer drug.138 Epoxy monomers containing photolabile o-nitrobenzyl esters are cured via photoinduced cationic ring opening. The resulting crosslinked networks are photodegraded upon excitation of the nitrobenzyl chromophore, which allows obtaining patterned films for applications in photolithography.139 Poly(carbonate)s with pendent o-nitrobenzyl esters self-assemble in aqueous solution to spherical micelles. Upon controlled exposure to UV light, cleavage of the photolabile group leaads to disassembling of the micelles. This assembling/disassembling strategy provides a potential entry to smart polycarbonates nanocarriers for controlled drug release.140 Random methacrylic copolymers based on photocleavable 6-bromo-7hydroxycoumarinyl esters and N,N-dimethylaminoethyl methacrylate (117) undergo photochemical deprotection leading to film dissolution. The process can be trigerred by exposure to either UV or near-IR light, due to the substantial two-photon cross section of the photolabile chromophore.141

10

Miscellanea

Irradiation of a-bromo carbonyl compounds in the presence of alkynes in aqueous media yields b,g-alkynoates (118), which can be readily converted into the corresponding allenoates.142 186 | Photochemistry, 2019, 46, 169–193

Irradiation of (119) in toluene leads mainly to the tricyclic butyrolactone (120), together with a minor regioisomer. Control experiments indicate that ring contraction with release of the amine fragment is a UV–Vis photochemical process, which is independent from the UV-driven 6p electrocyclisation.143 Photocyclisation of a related chiral 1,2-bisbenzylidene succinate amide ester (121) in methanol is the key step in the synthesis of ()-podophyllotoxin. The reaction can be performed in a multigram scale, using a flow photoreactor.144 Photochemical splitting of the b-lactam ring in the antihyperlipidemic drug ezetimibe (122) follows a formal retro- Staudinger reaction, giving a highly reactive ketene intermediate that is intramolecularly trapped by the benzylic alcohol, to give lactone (123). When complexed to human serum albumin, the ketene is trapped by the neighbouring Lys414 and Lys525 residues, leading to covalent amide adducts.

Docking and molecular dynamics simulation studies explain the selectivity of (122) for these amino acid residues and the covalent modification mechanism.145 Oxime ester derivatives are typical photoinitiating systems in photopolymerisation. In the case of (124) and (125), photocleavage of the N–O bond leads to radicals capable of triggering polymerisation of methyl methacrylate. The highest efficiency is observed at lexc ca. 400 nm, even if the molar absorption coefficient of the photoinitiators is higher at shorter wavelengths.146 Three ketones containing benzoyl and phenylthiylmethyl groups (126)– (128) have been studied by laser flash photolysis in acetonitrile. Whereas (127) and (128) show exclusively the transient absorption spectra of their triplet states, (126) gives rise to the phenylthiyl radical, indicative of C–S Photochemistry, 2019, 46, 169–193 | 187

bond breaking. Xanthone photosensitisation leads to similar results in the case of (126) and (127); by contrast, under these conditions (128) gives rise to the phenylthiyl radical. The latter result is explained by the involvement of an upper triplet state in the photosensitisation of (128) by xanthone.147 The photobehaviour of m-substituted benzophenones (129) and (130) in acidic aqueous medium has been examined by time-resolved spectroscopy and density functional theory calculations. The hydroxymethyl derivative (129) undergoes an intramolecular photoredox reaction, to give (131). Converserly, the only process observed for (130) is excited-state deprotonation to the benzylic carbanion.148 Through-bond triplet exciplex formation in donor–acceptor systems linked through a rigid bile acid scaffold has been demonstrated in (132) and (133) using laser flash photolysis, upon population of the triplet acceptors (naphthalene, or biphenyl) by through-bond triplet–triplet energy transfer from a benzophenone donor.149 Femtosecond stimulated Raman spectroscopy has been used to study the hydrogen bonding dynamics of a photoexcited coumarin (134) in ethanolic solution. Following 400 nm excitation, cleavage of the hydrogen bond is observed in the singlet photoexcited fluorophore with less than 140 fs time constant. The subsequent dynamics are attributed to solvation of the nascent free (134), hydrogen bond reformation and radiative emission from the relaxed excited state (13 ps, 37 ps and more than 1ns decay time constants, respectively). These studies on hydrogen bond making and breaking dynamics are important because this type of interactions play a key role in numerous chemical reactions and biological processes.150

References 1

A. Chattopadhyay, K. Mondal, M. Samanta and T. Chakraborty, Chem. Phys. Lett., 2017, 675, 104. 2 E. G. Leggesse, W.-R. Tong, S. Nachimuthu, T.-Y. Chen and J.-C. Jiang, J. Photochem. Photobiol., A, 2017, 347, 78. 3 S. Mor and S. N. Dhawan, Chem. Biol. Interface, 2016, 6, 243. 4 E. L. Chang, B. Bolte, P. Lan, A. C. Willis and M. G. Banwell, J. Org. Chem., 2016, 81, 2078. 5 Y. Shi, X.-L. Jiang, W.-S. Tian and Wei-Sheng, J. Org. Chem., 2017, 82, 269. 6 L. Zheng, M. Griesser, D. A. Pratt and M. M. Clinton, J. Org. Chem., 2017, 82, 3571. ´s-Monerris, G. M. Rodrı´guez-Mun ˜iz, D. Roca7 I. Aparici-Espert, A. France ´n, V. Lhiaubet-Vallet and M. A. Miranda, J. Org. Chem., 2016, Sanjua 81, 4031. 8 R. Paul and M. M. Greenberg, J. Org. Chem., 2016, 81, 9199. 9 E. Bubev, A. Georgiev and M. Machkova, J. Mol. Struct., 2016, 1118, 184. 10 A. Cogulet, P. Blanchet and V. Landry, J. Photochem. Photobiol., B, 2016, 158, 184. 11 J. Lim, Jungseop and J. Kim, Macromol. Res., 2016, 24, 9. 12 M. Sahin, S. Schloegl, S. Kaiser, W. Kern, J. Jieping and H. Gruetzmacher, J. Polym. Sci., Part A: Polym. Chem., 2017, 55, 894. 188 | Photochemistry, 2019, 46, 169–193

13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

41 42

P. Jagadesan, S. R. Samanta and V. Ramamurthy, J. Phys. Org. Chem., 2017, 30, e3728. B. T. Tuten, J. P. Menzel, K. Pahnke, J. P. Blinco and C. Barner-Kowollik, Chem. Commun., 2017, 53, 4501. T. Ide, S. Masuda, Y. Kawato, H. Egami and Y. Hamashima, Org. Lett., 2017, 19, 4452. X. Yuan, S. Dong, Z. Liu, G. Wu, C. Zou and J. Ye, Org. Lett., 2017, 19, 2322. S. Cuadros, L. Dell’Amico and P. Melchiorre, Angew. Chem., Int. Ed., 2017, 56, 11875. N. Ishida, T. Yano, T. Yuhki and M. Murakami, Chem. – Asian J., 2017, 12, 1905. T. Kawamata, M. Nagatomo and M. Inoue, J. Am. Chem. Soc., 2017, 139, 1814. M. Jang and B. S. Park, Bull. Korean Chem. Soc., 2016, 37, 1509. M. Arslan, B. Kiskan and Y. Yagci, Macromolecules, 2016, 49, 5026. G. Ding, C. Jing, X. Qin, Y. Gong, X. Zhang, S. Zhang, Z. Luo, H. Li and F. Gao, Dyes Pigm., 2017, 137, 456. K. Konieczny, J. Bakowicz, T. Galica, R. Siedlecka and I. Turowska-Tyrk, CrystEngComm, 2017, 19, 3044. K. Konieczny, J. Bakowicz, R. Siedlecka, T. Galica and I. Turowska-Tyrk, Cryst. Growth Des., 2017, 17, 1347. K. Konieczny, J. Bakowicz and I. Turowska-Tyrk, J. Chem. Crystallogr., 2016, 46, 77. K. Konieczny, J. Bakowicz and I. Turowska-Tyrk, J. Photochem. Photobiol., A, 2016, 325, 111. A. J.-L. Ayitou, K. Flynn, S. Jockusch, S. A. Khan and M. A. Garcia-Garibay, J. Am. Chem. Soc., 2016, 138, 2644. A. Das, E. A. Lao and A. D. Gudmundsdottir, Photochem. Photobiol., 2016, 92, 388. ´, I. M. Morera, I. Andreu and M. A. Miranda, Beilstein J. F. Palumbo, F. Bosca Org. Chem., 2016, 12, 1196. H. Li and M.-T. Zhang, Angew. Chem., Int. Ed., 2016, 55, 13132. R. J. Rapf, R. J. Perkins, H. Yang, G. M. Miyake, B. K. Carpenter and V. Vaida, J. Am. Chem. Soc., 2017, 139, 6946. A. J. Eugene, S.-S. Xia and M. I. Guzman, J. Phys. Chem. A, 2016, 120, 3817. P. Miro, M. L. Marin and M. A. Miranda, Org. Biomol. Chem., 2016, 14, 2679. M. Marazzi, M. Wibowo, H. Gattuso, E. Dumont, D. Roca-Sanjuan and A. Monari, Phys. Chem. Chem. Phys., 2016, 18, 7829. V. Ravi Kumar, F. Ariese and S. Umapathy, J. Chem. Phys., 2016, 144, 114301/1. V. Ravi Kumar and S. Umapathy, J. Raman Spectrosc., 2016, 47, 1220. E. Kumarasamy, R. Raghunathan, S. K. Kandappa, A. Sreenithya, S. Steffen, B. Raghavana and J. Sivaguru, J. Am. Chem. Soc., 2017, 139, 655. M. Nakano, Y. Nishiyama, H. Tanimoto, T. Morimoto and K. Kakiuchi, Org. Process Res. Dev., 2016, 20, 1626. M. Ralph, S. Ng and K. I. Booker-Milburn, Org. Lett., 2016, 18, 968. A. F. Kassir, S. S. Ragab, T. A. M. Nguyen, F. Charnay-Pouget, R. Guillot, M.-C. Scherrmann, T. Boddaert and D. J. Aitken, J. Org. Chem., 2016, 81, 9983. M. D’Auria, R. Racioppi, F. Rofrano, S. Stoia and L. Viggiani, Tetrahedron, 2016, 72, 5142. M. D’Auria, F. Pellegrino and L. Viggiani, J. Photochem. Photobiol., A, 2016, 326, 69. Photochemistry, 2019, 46, 169–193 | 189

43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68

69 70 71 72 73 74

R. C. Murphy, T. Okuno, C. A. Johnson and R. M. Barkley, Anal. Chem., 2017, 89, 8545. J. Ren, E. T. Franklin and Y. Xia, J. Am. Soc. Mass Spectrom., 2017, 28, 1432. C. A. Stinson and Y. Xia, Analyst, 2016, 141, 3696. F. Waeldchen, S. Becher, P. Esch, M. Kompauer and S. Heiles, Analyst, 2017, 142, 4744. X. Ma, L. Chong, R. Tian, R. Shi, T. Y. Hu, Z. Ouyang and Y. Xia, Proc. Natl. Acad. Sci., 2016, 113, 2573. V. Vendrell-Criado, V. Lhiaubet-Vallet, M. Yamaji, M. C. Cuquerella and M. A. Miranda, Org. Biomol. Chem., 2016, 14, 4110. M. Savarese, E. Bremond, C. Adamo, N. Rega and I. Ciofini, ChemPhysChem, 2016, 17, 1530. M. Kojic, M. Petkovic and M. Etinski, Phys. Chem. Chem. Phys., 2016, 18, 22168. J. Zhang, X. Zhang, T. Wang, X. Yao, P. Wang, P. Wang, J. Ping, S. Jing, Y. Liang and Z. Zhang, J. Org. Chem., 2017, 82, 12097. P. Rai, Rahila, H. Sagir and I. R. Siddiqui, Chem. Select, 2016, 1, 4550. Y. Li, L. Zeng, C. Zhong, X. Dong, Z. Mao, Z. Liu, S. Lv, Z. Zhang and J. Qin, Adv. Opt. Mater., 2017, 5, 1600696. R. Nazir, B. Thorsted, E. Balciunas, L. Mazur, I. Deperasinska, M. Samoc, J. Brewer, M. Farsari and D. T. Gryko, J. Mater. Chem. C, 2016, 4, 167. Y. Suwa and M. Yamaji, J. Photochem. Photobiol., A, 2016, 316, 69. X. Chen, S. Qiu, S. Wang, H. Wang and H. Zhai, Org. Biomol. Chem., 2017, 15, 6349. S. Cai, Z. Xiao, J. Ou, Y. Shi and S. Gao, Org. Chem. Front., 2016, 3, 354. H. F. Koolman, W. Braje and A. Haupt, Synlett, 2016, 27, 2561. A. J. Hall, S. P. Roche and L. M. West, Org. Lett., 2017, 19, 576. J. Fan, T. Wang, C. Li, R. Wang, X. Lei, Y. Liang and Z. Zhang, Org. Lett., 2017, 19, 5984. R. Sahu and V. Singh, Tetrahedron, 2017, 73, 6515. C. R. Pitts, D. D. Bume, S. A. Harry, M. A. Siegler and T. Lectka, J. Am. Chem. Soc., 2017, 139, 2208. A. Clay, N. Vallavoju, R. Krishnan, A. Ugrinov and J. Sivaguru, J. Org. Chem., 2016, 81, 7191. V. Edtmueller, A. Poethig and T. Bach, Tetrahedron, 2017, 73, 5038. H. Chu, J. M. Smith, J. Felding and P. S. Baran, ACS Cent. Sci., 2017, 3, 47. E. Gorobets, N. E. Wong, R. S. Paton and D. J. Derksen, Org. Lett., 2017, 19, 484. V. A. Migulin, A. G. Lvov and M. M. Krayushkin, Tetrahedron, 2017, 73, 4439. N. C. Pflug, M. K. Hankard, S. M. Berg, M. O’Connor, J. B. Gloer, E. P. Kolodziej, D. M. Cwiertny and K. H. Wammer, Environ. Sci., 2017, 19, 1414. G. B. Veerakanellore, B. Captain and V. Ramamurthy, CrystEngComm, 2016, 18, 4708. T. Galica, J. Ba˛kowicz, K. Konieczny and I. Turowska-Tyrk, CrystEngComm, 2016, 18, 8871. T. Itoh, F. Kondo, T. Uno, M. Kubo, N. Tohnai and M. Miyata, Cryst. Growth Des., 2017, 17, 3606. N. Vallavoju, A. Sreenithya, A. J.-L. Ayitou, S. Jockusch, R. B. Sunoj and J. Sivaguru, Chem. – Eur. J., 2016, 22, 11339. Y. Ando, T. Matsumoto and K. Suzuki, Synlett, 2017, 28, 1040. C. Thommen, M. Neuburger and K. Gademann, Chem. – Eur. J., 2017, 23, 120.

190 | Photochemistry, 2019, 46, 169–193

75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93

94 95 96 97 98 99 100 101 102 103

T. P. Mart’yanov, L. S. Klimenko and E. N. Ushakov, Russ. J. Org. Chem., 2016, 52, 1126. N. A. Len’shina, M. V. Arsenyev, M. P. Shurygina, S. A. Chesnokov and G. A. Abakumov, High Energy Chem., 2017, 51, 209. M. P. Shurygina, S. A. Chesnokov and G. A. Abakumov, High Energy Chem., 2016, 50, 356. N. K. Scharko, E. T. Martin, Y. Losovyj, D. G. Peters and J. D. Raff, Environ. Sci. Technol., 2017, 51, 9633. X. Zhang, J. Ma and D. L. Phillips, J. Phys. Chem. Lett., 2016, 7, 4860. X. Zhang, J. Ma, S. Li, M.-D. Li, X. Guan, X. Lan, R. Zhu and D. L. Phillips, J. Org. Chem., 2016, 81, 5330. V. I. Porkhun, Y. V. Aristova and I. V. Sharkevich, Russ. J. Phys. Chem. A, 2017, 91, 1358. F. Doria, A. Lena, R. Bargiggia and M. Freccero, J. Org. Chem., 2016, 81, 3665. D. Skalamera, K. Mlinaric-Majerski, I. Martin Kleiner, M. Kralj, J. Oake, P. Wan, C. Bohne and N. Basaric, J. Org. Chem., 2017, 82, 6006. L. Uzelac, D. Skalamera, K. Mlinaric-Majerski, N. Basaric and M. Kralj, Eur. J. Med. Chem., 2017, 137, 558. A. Husak, B. P. Noichl, T. Sumanovac Ramljak, M. Sohora, D. Skalamera, N. Budisa and N. Basaric, Org. Biomol. Chem., 2016, 14, 10894. L. Du, X. Zhang, J. Xue, W. Tang, M.-D. Li, X. Lan, J. Zhu, R. Zhu, Y. Weng, Y.-L. Li and D. L. Phillips, J. Phys. Chem. B, 2016, 120, 11132. J. Torres-Alacan, J. Org. Chem., 2016, 81, 1151. R. C. White, B. E. Arney Jr., J. Perry, N. Thompson, P. Pithan, S. von Gradowski and H. Ihmels, J. Heterocycl. Chem., 2017, 54, 1656. A. J. Eugene and M. I. Guzman, J. Phys. Chem. A, 2017, 121, 2924. S. Yang, H. Tan, W. Ji, X. Zhang, P. Li and L. Wang, Adv. Synth. Catal., 2017, 359, 443. W. Ji, H. Tan, M. Wang, P. Li and L. Wang, Chem. Commun., 2016, 52, 1462. J.-J. Zhang, Y.-B. Cheng and X.-H. Duan, Chin. J. Chem., 2017, 35, 311. O. Anamimoghadam, S. Mumtaz, A. Nietsch, G. Saya, C. A. Motti, J. Wang, P. Junk, A. M. Qureshi and M. Oelgemoller, Beilstein J. Org. Chem., 2017, 13, 2833. L. Mandic, K. Mlinaric-Majerski, A. G. Griesbeck and N. Basaric, Eur. J. Org. Chem., 2016, 2016, 4404. M. Sohora, N. Vidovic, K. Mlinaric-Majerski and N. Basaric, Res. Chem. Intermed., 2017, 43, 5305. S. Josland, S. Mumtaz and M. Oelgemoeller, Chem. Eng. Technol., 2016, 39, 81. D. A. Richards, S. A. Fletcher, M. Nobles, H. Kossen, L. Tedaldi, V. Chudasama, A. Tinker and J. R. Baker, Org. Biomol. Chem., 2016, 14, 455. T. Guzzo, W. Mandaliti, R. Nepravishta, A. Aramini, E. Bodo, I. Daidone, M. Allegretti, A. Topai and M. Paci, J. Phys. Chem. B, 2016, 120, 10668. M. Liu, M.-D. Li, J. Huang, T. Li, H. Liu, X. Li and D. L. Phillips, Sci. Rep., 2016, 6, 21606. ´, I. Andreu, V. T. Monje, M. C. Jime ´nez and M. A. Miranda, Chem. Res. I. Vaya Toxicol., 2016, 29, 40. M. Martinek, L. Filipova, J. Galeta, L. Ludvikova and P. Klan, Org. Lett., 2016, 18, 4892. C. D. McNitt, H. Cheng, S. Ullrich, V. V. Popik and M. Bjerknes, J. Am. Chem. Soc., 2017, 139, 14029. Q. Liu, H. Li, Z. Wu, D. Li, H. Beckers, G. Rauhut and X. Zeng, Chem. – Asian J., 2016, 11, 2953. Photochemistry, 2019, 46, 169–193 | 191

104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

131 132 133

J. H. Park, M. Hughs, T. S. Chung, A. J.-L. Ayitou, V. M. Breslin and M. A. Garcia-Garibay, J. Am. Chem. Soc., 2017, 139, 13312. H. Li, A. Migani, L. Blancafort, Q. Li and Z. Li, Phys. Chem. Chem. Phys., 2016, 18, 30785. A. G. Talero and A. C. B. Burtoloso, Synlett, 2017, 28, 1748. L. L. Rodina, O. L. Galkina, G. Maas, M. S. Platz and V. A. Nikolaev, Asian J. Org. Chem., 2016, 5, 691. S. Karthik, K. R. S. Thenna-Hewa, D. J. Shields, J. Liu, J. A. Krause and A. D. Gudmundsdottir, ChemPhotoChem, 2017, 1, 408. J. M. Toldo, M. Barbatti and P. F. B. Goncalves, Phys. Chem. Chem. Phys., 2017, 19, 19103. H. Maeda, T. Akai and M. Segi, Tetrahedron Lett., 2017, 58, 4377. D. Iguchi, R. Erra-Balsells and S. M. Bonesi, Tetrahedron, 2016, 72, 1903. M. Mizusaki, K. Nakai, S. Enomoto, Y. Hara and S.-I. Yusa, Polym. J., 2017, 49, 457. O. Nadtoka, L. Vretik, T. Gavrylko and V. Syromyatnikov, Mol. Cryst. Liq. Cryst., 2017, 642, 115. J. Li, F. Chen, L. Yang, L. Jiang and Y. Dan, Spectrochim. Acta, Part A, 2017, 184, 361. Y. Ishida, Y. Takeda and A. Kameyama, React. Funct. Polym., 2016, 107, 20. D. Iguchi, R. Erra-Balsells and S. M. Bonesi, Photochem. Photobiol. Sci., 2016, 15, 105. Y. Wu and L. Wu, Monatsh. Chem., 2017, 148, 675. E. Torti, S. Protti, D. Merli, D. Dondi and M. Fagnoni, Chem. – Eur. J., 2016, 22, 16998. P. T. Wong, E. W. Roberts, S. Tang, J. Mukherjee, J. Cannon, A. J. Nip, K. Corbin, F. Matthew and S. K. Choi, ACS Chem. Biol., 2017, 12, 1001. B. E. Aney, H. Ihmels and R. C. White, Int. J. Org. Chem., 2017, 7, 263. S. Kamo, K. Yoshioka, K. Kuramochi and K. Tsubaki, Angew. Chem., Int. Ed., 2016, 55, 10317. Y. A. Kim, J. Day, C. A. Lirette, W. J. Costain, J. Willard, L. J. Johnston and R. Bittman, Chem. Phys. Lipids, 2016, 194, 117. A. Gandioso, M. Palau, A. Nin-Hill, I. Melnyk, C. Rovira, S. Nonell, D. Velasco, J. Garcia-Amoros and V. Marchan, Chem. Open, 2017, 6, 375. A. Gandioso, M. Cano, A. Massaguer and V. Marchan, J. Org. Chem., 2016, 81, 11556. Y. Chitose, M. Abe, K. Furukawa and C. Katan, Chem. Lett., 2016, 45, 1186. D. P. Walton and D. A. Dougherty, J. Am. Chem. Soc., 2017, 139, 4655. C. J. Regan, D. P. Walton, O. S. Shafaat and D. A. Dougherty, J. Am. Chem. Soc., 2017, 139, 4729. Y. Zhang, H. Zhang, C. Ma, J. Li, Y. Nishiyama, H. Tanimoto, T. Morimoto and K. Kakiuchi, Tetrahedron Lett., 2016, 57, 5179. A. Chaudhuri, Y. Venkatesh, K. K. Behara and N. D. P. Singh, Org. Lett., 2017, 19, 1598. N. C. Kasuga, Y. Saito, N. Okamura, T. Miyazaki, H. Satou, K. Watanabe, T. Ohta, S.-S. Morimoto and K. Yamaguchi, J. Photochem. Photobiol., A, 2016, 321, 41. Y. Zhao, S. G. Bolton and M. D. Pluth, Org. Lett., 2017, 19, 2278. S. Mo, Y. Wen, F. Xue, H. Lan, Y. Mao, G. Lv and T. Yi, Sci. Bull., 2016, 61, 459. K. Fujimoto, M. Furusawa, S. Nakamura and T. Sakamoto, Chem. Lett., 2016, 45, 1078.

192 | Photochemistry, 2019, 46, 169–193

134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150

A. M. S. Soares, G. Hungerford, S. P. G. Costa, M. Goncalves and T. Sameiro, Dyes Pigm., 2017, 137, 91. A. M. S. Soares, G. Hungerford, M. S. T. Goncalves and S. P. G. Costa, New J. Chem., 2017, 41, 2997. I. Aparici-Espert, M. C. Cuquerella, C. Paris, V. Lhiaubet-Vallet and M. A. Miranda, Chem. Commun., 2016, 52, 14215. Y. Venkatesh, S. Nandi, M. Shee, B. Saha, A. Anoop and N. D. Pradeep Singh, Eur. J. Org. Chem., 2017, 2017, 6121. X. Du, Y. Jiang, R. Zhuo and X. Jiang, J. Polym. Sci., Part A: Polym. Chem., 2016, 54, 2855. S. Radl, I. Roppolo, K. Poelzl, M. Ast, J. Spreitz, T. Griesser, W. Kern, S. Schloegl and M. Sangermano, Polymer, 2017, 109, 349. H. Shen, Y. Xia, Z. Qin, J. Wu, L. Zhang, X. Lu, X. Xia and W. Xu, J. Polym. Sci. Part A: Polym. Chem., 2017, 55, 2770. M. J. Feeney, X. Hu, R. Srinivasan, N. Van, M. Hunter, I. Georgakoudi and S. W. Thomas, Langmuir, 2017, 33, 10877. W. Liu, Z. Chen, L. Li, H. Wang and C.-J. Li, Chem. – Eur. J., 2016, 22, 5888. K. Lisiecki, K. K. Krawczyk, P. Roszkowski, J. K. Maurin, A. Budzianowski and Z. Czarnocki, Tetrahedron, 2017, 73, 6316. K. Lisiecki, K. K. Krawczyk, P. Roszkowski, J. K. Maurin and Z. Czarnocki, Org. Biomol. Chem., 2016, 14, 460. ´rez-Ruiz, E. Lence, I. Andreu, D. Limones-Herrero, C. Gonza ´lez-Bello, R. Pe ´nez, Chem. – Eur. J., 2017, 23, 13986. M. A. Miranda and M. C. Jime D. E. Fast, A. Lauer, J. P. Menzel, A.-M. Kelterer, G. Gescheidt and C. Barner-Kowollik, Macromolecules, 2017, 50, 1815. M. Yamaji, A. Horimoto and B. Marciniak, Phys. Chem. Chem. Phys., 2017, 19, 17028. J. Ma, H. Li, X. Zhang, W.-J. Tang, M. Li and D. L. Phillips, J. Org. Chem., 2016, 81, 9553. ´, G. Sastre, M. C. Jime ´nez, M. L. Marin and M. A. Miranda, P. Miro, I. Vaya Chem. Commun., 2016, 2016, 713. F. Han, W. Liu, L. Zhu, Y. Wang and C. Fang, J. Mater. Chem. C, 2016, 4, 2954.

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Function containing a heteroatom different from oxygen (2016–2017) Carlotta Raviola, Stefano Protti* and Angelo Albini DOI: 10.1039/9781788013598-00194

The main photochemical processes involving chromophores containing nitrogen, boron, silicon, germanium, phosphorous, sulfur and halogen atoms reported in the 2016–2017 period have been briefly described herein. It should be noticed that the reactions occurring by means of photocatalysts/photosensitizers able to activate such chromophores have not been considered throughout the account but have been mentioned at the end of each paragraph.

1

Nitrogen containing functions

As in the previous volume (44, 2016), the reaction of nitrogen containing molecules have been described starting from those bearing a single bonded C–N function, and then multiple bond. Then, molecules with more nitrogen atoms have been reviewed in decreasing oxidation level order. 1.1 C–N, a single nitrogen atom 1.1.1 Nitro derivatives. Dong et al. recently investigated the degradation kinetics of nitro-based pharmaceuticals, namely ranitidine (1, RNTD, Fig. 1) and nizatidine (2, NZTD) and the potential generation of halonitromethanes during the photolysis. A pH-dependent reactivity was found, since the neutral species of RNTD and NZTD resulted more reactive than the corresponding anionic forms. Nitrite (and nitrate from it) anion was released upon irradiation, via either homolytic or heterolytic C–N bond cleavage. Notably, both drugs (almost at acid and neutral pH) were found to be photochemical precursors of halonitromethanes with quantum yield values of 0.056 and 0.047, respectively (pH 7.0). Cleavage of C–S bond has been also observed in both molecules.1 Starting from early experiments of Giacomo Ciamician,2 the photochemistry of ortho-nitrobenzaldehyde (3) has been investigated in details all along the history of photochemistry. This mechanism of the rearrangement of 3 to 2-nitrosobenzoic acid 5 in aqueous solution has ¨bel and Gilch by means of femtobeen recently studied in detail by Fro second IR and Raman spectroscopy. This technique was exploited to confirm the formation of the ketene intermediate 4 (Scheme 1).3 Such investigative approach has been also applied to the study of the photoinduced enolization of ortho-nitrotoluene.3 PhotoGreen Lab, Department of Chemistry, University of Pavia, V.Le Taramelli 12, 27100 Pavia, Italy. E-mail: [email protected] 194 | Photochemistry, 2019, 46, 194–217  c

The Royal Society of Chemistry 2019

Fig. 1 Ranitidine (1, RNTD) and nizatidine (2, NZTD).

Scheme 1

Fig. 2 Proposed Branching Relaxation Mechanism for 1,6-DNP Leading to the Formation of a Nitropyrenoxy Radical (NO2PyO ) or to Intersystem Crossing to the Triplet (T1) State on an Ultrafast Time Scale in Acetonitrile. Reprinted with permission from ref. 4. Copyright 2016 American Chemical Society.

The nitropolycyclic aromatic pollutant 1,6-dinitropyrene (1,6-DNP) can be photochemically (300–500 nm) degradated to 1-hydroxy-6-nitropyrene and 1,6-pyrenedione. The photoreactivity of this compound was investigated by Brister et al., who highlighted the presence of an energy barrier in the excited singlet manifold, that favors intersystem crossing to (unproductive) triplet at the expenses of photodissociation and subsequent nitropyrenoxy radical NO2PyO formation (Fig. 2).4 In these two years, nitroarenes have been used with success to visible light driven photoredox catalyzed processes.5 In a peculiar case, palladium–loaded silicon (Pd/Si) catalyst was employed in the dual role of photocatalyst (in order to generate hydrogen from formic acid) and catalyst (to promote reduction of nitroaromatics to the corresponding anilines).6 1.1.2 Hydroxylamines, amines and ammonium salts. Hydroxylamine (NH2OH) is considered a simple model molecule for investigating Photochemistry, 2019, 46, 194–217 | 195

the NH and OH bond interactions. Recently, attention has been focused on the direct photolysis of such compound (in aqueous solution) as described in eqn (1): 3NH2OH þ hn-NH3 þ 3H2O þ N2

(1)

A computational analysis carried out on different small hydroxylamine–water clusters (NH2OH(H2O)n, n ¼ 1–4) evidenced the fact that the primary process in NH2OH was O–H bond homolysis. On the other hand, complexation with water impressively affect the photodissociation pathways of NH2OH, via Excited State Proton Transfer (ESPT) to a water molecule and dissociation of one of the free O–H bond in the cluster.7 Despite the renewed interest for the photochemistry of organic groups, only little attention has been given to the behavior of amines under irradiation. The 3-(N,N-diethylamino)benzyl (DEABn) group has been proposed by Wang et al. for the release of differently substituted amines 7. The process takes place via direct photolysis of the benzylic C–N bond in the corresponding ammonium salts 6. A marked solvent dependence in the efficiency of the release process was found. Primary and secondary amines were efficiently generated in methanol, whereas tertiary amines required the use of MeCN/water mixture as solvent in order to minimize side reactions (some examples in Scheme 2).8 Asad et al. investigated by means of time resolved spectroscopy the photoreactivity of tertiary amines linked to the 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting group (PPG), with the aim of developing photoactivated caged compounds. Notably, the photoactivation of anticancer drugs tamoxifen (Compound 8 in Fig. 3) and 4-hydroxytamoxifen was achieved through both one- and two-photon excitation of CyHQ protected anilines.9 Analogously, the use dicyanocoumarinylmethyl- (DEAdcCM), and dicyanocoumarinylethyl (DEAdcCE)-based photoprotecting groups were exploited for the release of carboxylic acids and primary amines upon irradiation with visible light.10 As concerning the use of amine in photochemical synthesis, great attention has been given to their activation under photoredox catalyzed conditions.11 Apart from this approach, an intriguing case has been reported by Chen and Coworkers, that reported a light induced (UV or sunlight)

Scheme 2 196 | Photochemistry, 2019, 46, 194–217

Fig. 3

Photoactive Tamoxifen.

(a)

(b)

Scheme 3

radical perfluoroalkylation protocol by exploiting the halogen bond between a perfluoroalkyl iodide and N,N,N 0 ,N 0 -tetraethylethylenediamine (TEEDA, some examples in Scheme 3a).12 In a similar way, the solar or visible-light assisted amidation of carboxylic acids 11 was developed by having recourse to the formation of an electron donor–acceptor complex between an amine and CCl4 used as the promoter (some representative example in Scheme 3b).13 The Single Electron Transfer (SET) addition of N-trimethylsilylmethyl substituted a-aminonitriles onto fullerene C60 was exploited by Mariano et al. for the preparation of fulleropyrrolidine nitriles.14 The irradiation of 2 0 -halo-[1,1 0 -biphenyl]-2-amines in basic medium was reported to afford exclusively carbazoles via SRN1 mechanism from substrates bearing EWG Photochemistry, 2019, 46, 194–217 | 197

groups such as CN or COOR. In contrast, photolysis of 1,1 0 ,-biphenyl-2amines having electron-donating substituents (CH3, OCH3) as well as unsubstituted 1,1-biphenyl-2-amine afforded a mixture of carbazole and dehalogenated amine.15 1.1.3 Amides and imides. The photochemistry of a set of substituted N-arylsulfonimides 13 was investigated by Torti et al. by means of both steady-state and time resolved spectroscopy analysis. Importantly, it was found that the homolytic cleavage of the S–N bond takes place exclusively from the singlet state to afford, in a competitive fashion, N-arylsulfonamides 14 and the corresponding photo-Fries rearrangement product 15 in a ratio that strictly depends on the nature of the aromatic substituents and on the reaction conditions. Furthermore, sulfinic and sulfonic acids were released in the absence and in the presence of oxygen, respectively (Scheme 4). Notably, in oxygen saturated solution, 13 generated up to 2 equivalents of strong sulfonic acid for mole of substrate, highlighting the potentialities of such compounds as non ionic PhotoAcid Generators (PAGs),16a that have been used as initiators for the polymerization of epoxy-based materials.16b N,N 0 -diaryloxalyl amides (16, smoothly obtained via a three component process) were recently employed as substrates for the one-pot, two-steps photochemical preparation of complex alkaloid structures 17. In this way, bioactive products such as those bearing the imidazolidine-4,5-dione core, can be obtained in only 2 to 4 simple synthetic steps. (Scheme 5).17

Scheme 4

Scheme 5 198 | Photochemistry, 2019, 46, 194–217

Fig. 4 Double hydrazone prepared by Gordillo et al.18 Reproduced with permission from ref. 18, Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fig. 5 Photoactive precursors of iminyl and perfluoroalkyl radicals.

1.1.4 Hydrazones, imines, oximes and iminium ions. Gordillo et al. described the synthesis of a double hydrazone (18, Fig. 4) that underwent photoinduced E/Z isomerization through the CQN double bonds and pointed out the potentialities of the structure for developing molecular machines.18 Very recently, the adoption of imine and iminium catalytic approaches in enantioselective photochemical reactions has been reviewed by Bach and coworkers.19 Imines were mainly used as radical acceptors20 as well as electron donor21 in photoredox catalysis. On the other hand, oxime 19 and iminium triflate salts 20 (Fig. 5) were described as source of iminyl22 and perfluoroalyl radicals,23 respectively, under photoredox catalytic conditions. Taking inspiration from the behavior of 11-cis-retinal, the group of Melchiorre recently exploited the oxidant properties of photoexcited iminium ions to promote the enantioselective catalytic b-alkylation of enal 20 upon visible and solar light irradiation. The iminium ion is in situ generated by the intermediacy of chiral amine 21 as the organocatalyst (Scheme 6).24 An investigation of the wavelength-dependent photochemistry of oxime esters 23, 24 (Fig. 6), typically employed in photoinduced polymerization, pointed out that the highest conversion of such compounds was achieved at 405 nm, where the molar extinction coefficients of the two photoinitiators are low (eo50 M1 cm1).25 A set of pyridine and p-nitrophenyl oxime esters was synthesized and characterized, with the aim of developing a new class of photoactive derivatives able to cleave or bind DNA upon irradiation. Some of the compounds examined was found to photocleave DNA at 365 nm at a concentration of 500 mM (some of the most promising compounds are illustrated in Fig. 7).26 Photochemistry, 2019, 46, 194–217 | 199

Scheme 6

Fig. 6

Oxime esters as photoinitiators.

Fig. 7 p-Nitrophenyl oxime esters tested in ref. 26. Reproduced from ref. 26 under a CC BY 4.0 Licence (https://creativecommons.org/licenses/by/4.0/).

Oxime ethers 27 were employed with success in the three-component, (photo)catalyst-free preparation of a wide range of sulfonated 3,4dihydro-2H-pyrroles 29 that involves a N-radical-initiated cyclization as the key step (Scheme 7).27 Finally, preparation of cyclohexanone oxime, a key intermediate in the preparation of Nylon-6 was recently optimized by using tert-butyl nitrite and UV-emitting LED diode.28 1.1.5 Nitriles. 2,5-Disubstituted tetrazoles are long-time know precursors of nitrile imines. Cristiano et al. investigated in details the photochemical behavior of 1- and 2-methyl-substituted 5-aminotetrazoles when they are isolated in an argon matrix (15 K) by means of IR spectroscopy. 200 | Photochemistry, 2019, 46, 194–217

Scheme 7

Fig. 8 Photochemistry of 1- and 2 Methyl-5-aminotetrazoles. Reprinted with permission from ref 29. Copyright 2016 American Chemical Society.

The matrix system was irradiated with a narrow band UV excitation at different wavelengths in order to selectively induce photochemical transformations of different species. Whereas both isomers afforded a common diazirine intermediate (see Fig. 8) which in turn underwent subsequent photoconversion to 1-amino-3-methylcarbodiimide, an amino cyanamide species is exclusively generated from the 1-methyl isomer. In contrast a nitrile imine is obtained from photolysis (at 222 nm) of 2-methylaminotetrazole. This behavior pointed out the chance that only 2H -tetrazoles can have a direct access to nitrile imines, while observation of the amino cyanamide (that is peculiar of 1 H derivatives) represents a novel reaction pathway in the photochemistry of tetrazoles.29 The gas-phase photosynthesis of methylcyanobutadiyne, a compound significantly present in the interstellar medium, was studied starting from different acetylenes. Interestingly, formation of the examined compound was observed by irradiation at 193 nm of a mixture of 1-propyne and dicyanoacetylene, with a suggested radical mechanism.30 1.2 Two nitrogen atoms 1.2.1 Azobenzenes. As predictable, the investigation of the mechanism of the photochemical isomerization of azobenzenes is still a significant research issue. One of the challenge in this field is the precise calculation of the molar absorption coefficients (e) of both E and Z isomers, but in most case, the absorption spectra of the isomers reported in literature resulted mutually contaminated by significant amounts of Photochemistry, 2019, 46, 194–217 | 201

the other isomer. Wirtz et al. obtained recently the spectrum of cisazobenzene by means of three different approaches, the Thulstrup, Eggers and Michl (TEM) method, NMR analysis and thermal isomerization. In this way, the value of e cis at different wavelength was calculated within the limits of error (e.g. 1402  23 M1 cm1 at 436 nm).31 Ramamurthy and Raj recently reported an elegant work focused on the role of the supramolecular steric effects and free volume on photochemical processes. To this aim, they investigated the isomerization of a set of neutral alkylsubstituted azobenzenes as well as of their corresponding radical ions (in turn obtained via electron transfer with gold nanoparticles) included within an octa acid capsule.32 The photoisomerization occurring in protonated trans-azobenzene and trans-4-aminoazobenzene was recently studied in the gas phase by having recourse to a tandem ion mobility spectrometer and electronic structure calculations. Both cations underwent isomerization across their S1’S0 bands, with peaks located at 435 and 525 nm.33 The photochemical transformation taking place in 2,2 0 -dihydroxyazobenzene, 2,2 0 -azotoluene and azobenzene (AB) was investigated in argon and xenon matrices by means of infrared spectroscopy and theoretical calculations.34 Again, the ultrafast dynamics of bisazobenzenes 30 (Fig. 9) isomerization, was investigated by Wachtveitl and coworkers, in order to develop photoswitchable multiazobenzene nanostructures.35 The introduction of photoresponsible azoarenes is traditionally exploited in the preparation of photoswitchable systems.36 Precision polymers containing (cis/trans)-azo-(substituted)benzenes as defects within a polyalkylene chain were prepared via ADMET followed by hydrogenation. Such macromolecules are designed to present an azobenzene moiety after exactly 18 methylene units. The synthesized polymers are thus able to photochemically switch cis/trans configuration, and change the geometrical constraint exerted on the alkyl chain during crystallization.37 Two molecular receptors 31a,b containing an azobenzene moiety functionalized with urea hydrogen-bonding groups and D-carbohydrates as chiral selectors were developed to achieve control over the chiral recognition of a-amino acid-derived carboxylates. Such receptors exhibits two photo- and thermally interconvertible planar E-1 and concaved Z-1 conformations, with different affinities, selectivities and binding modes, that have been exploited for the use of the molecules as sensors for chiral biomolecules binding carboxylic acid groups (Fig. 10).38

Fig. 9 Bisazobenzenes 30 tested in ref. 35. Reproduced from ref. 35 with permission from the PCCP Owner Societies. 202 | Photochemistry, 2019, 46, 194–217

Fig. 10 Schematic representation of molecular receptors. 31a and b which were developed to achieve control over the chiral recognition of a-amino acid-derived carboxylates. Adapted with permission from ref. 38. Copyright 2016 American Chemical Society.

Fig. 11 Azobenzene-containing ammonium amphiphile (32) and Ionic liquids (33).

Photoswitchable reverse micelles (RMs) were prepared by the group `n by means of azobenzene-containing ammonium amphiphile of Kla 32 (Fig. 11).39 Ionic liquids containing a photoswitchable azobenzene moiety (see for instance compound 33) were prepared and their photochemical behavior investigated. Interestingly, such compounds undergo a reversible solid-to-liquid phase transition induced by both photo- and thermal-stimulation.40 A photoresponsive Zn-MOF (metal–organic framework) consisting of diarylethene and azobenzene photochromic moieties was reported by Luo et al., and its photochemical behavior used to modulate the adsorption selectivity of the MOF material.41 Azobenzene structures were also exploited in the preparation of short-interfering RNAs (siRNAs), which structure and (as consequence) activity can be modulated via light stimulation.42 Interestingly, as illustrated in Scheme 8, photoresponsive siRNAzos can be inactivated and reactivated upon irradiation with UV and visible light, respectively. A water-soluble adhesive photoswitch based on azobenzene chemistry able to binds selectively to a target enzyme in order to tune photochemically its enzymatic activity was recently described.43 1.2.2 Azo sulfones. Molecules belonging to the class of arylazo sulfones were recently investigated by Protti and Coworkers as a new class of photoactivated molecules. Such compounds (34) have been smoothly Photochemistry, 2019, 46, 194–217 | 203

Scheme 8 Reproduced with permission from ref. 42. Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

prepared by a two steps procedure from colorless and easily available anilines via diazotization and treatment of the obtained diazonium salts with sodium methansulfinate (Scheme 9a). The obtained arylazo sulfones were colored, bench-stable and a series of experimental analysis pointed out their wavelength selective photoreactivity (Scheme 9b). Indeed, visible-light irradiation of 34 populates the 1np* state, thus homolysis of the S–N bond occurs to give, after loss of a nitrogen molecule, an aryl (Ar )/methanesulfonyl (CH3SO2 ) radical pair. In contrast, irradiation with UV-light (e.g. 366 nm) induces an excitation to the 1pp* state, and the following intersystem crossing (ISC) to the triplet 3pp* favors the heterolytic cleavage of the S–N bond and generates, again after nitrogen loss, a triplet phenyl cation (3Ar1).44 Obviously, upon solar exposition both species are generated. Such derivatives have been exploited to generate selectively highly reactive intermediates under photocatalyst-free and tunable conditions. The N2–SO2CH3 structural motif able to imparts both color and photoreactivity has been dubbed as dyedauxiliary group and a wide range of arylazo sulfones has been employed in the development of arylation protocols for the preparation, under metal-free conditions, of allylarenes,45 aromatic amides46 and (hetero)biaryls.44 Furthermore, the same substrates have been involved in the visible-light promoted, gold catalyzed Suzuki coupling.47 1.2.3 Diazonium salts. The interest in photochemistry for arenediazonium salts is mainly limited to their use as aryl radical precursors in photoredox catalyzed processes.48 In the last two years, significant 204 | Photochemistry, 2019, 46, 194–217

Scheme 9

Scheme 10

attention has been given to the developed of a dual photoredox/gold protocols for different cross coupling processes, including the Suzuki reaction between a boronic acid and a diazonium salts.49 In this field, however, Hashmi and coworker reported that such coupling could occur under photocatalyst-free conditions, in the presence of tris(4-trifluoromethyl) phosphine gold(I) chloride as the catalyst50 (some examples in Scheme 10). The intermediacy of a visible light absorbing complex between the arenediazonium salt and the gold complex was pointed out as the key step in the reaction. The same research group also optimized a photocatalyst free, visible light driven, gold(I) catalyzed 1,2-difunctionalization of alkynes by arenediazonium salts, to form the corresponding a-arylketones.51 Photochemistry, 2019, 46, 194–217 | 205

1.3 Functions containing three nitrogen atoms 1.3.1 Azides. Vicinal 1,2-bromine azides can be synthesized via photoinduced addition of bromine azide (BrN3) onto alkenes. However, the reaction if performed under batch conditions, presents several drawbacks since BrN3 is a highly toxic and explosive reagent. For this aim, Cantillo et al. developed a continuous flow protocol were the compound is generated in situ from NaBr and NaN3 in aqueous solution under oxidative conditions and extracted by an organic phase containing the alkenes 36 (Scheme 11) that was then irradiated. After work-up with Na2S2O3 the desired difunctionalized products 37 were obtained in satisfactory yields.52 Acyl azides were prepared in good to excellent yields via visible light induced azidation of aldehydic C–H in the presence of carbon tetrabromide and sodium azide. Notably, the strategy was also applied to the one-pot synthesis of carbamoyl azides 40a–c from aldehydes 38a–c (Scheme 12), via C–H azidation followed by thermal Curtius rearrengement of the resulting acyl azides 39a–c.53 Organic azides have been extensively used as reactants in photoredox catalysis in the last two years.54 On the other hand, the photoreactivity of aromatic azides is still a subject of research in organic chemistry. Sydnes et al. recently reported that the photolysis of ethyl 3-azido-4,6difluorobenzoate (41, Scheme 13) at room temperature in the presence of oxygen afforded regioselectively the corresponding ethyl 5,7-difluoro-4azaspiro[2.4]-hepta-1,4,6-triene-1-carboxylate 45, via the suggested intermediacy of a ketenimine (43, in turn obtained from the corresponding nitrene 42) that then underwent a photoinduced electrocyclization to bicycle 44 followed by a rearrangement. The reaction mechanism and the structure of the final product were clarified by means of multinuclear solution NMR spectroscopic techniques supported by DFT calculations.55

Scheme 11

Adapted from ref. 52 with permission of The Royal Society of Chemistry.

206 | Photochemistry, 2019, 46, 194–217

Scheme 12

Scheme 13

Scheme 14

Recently, the aqueous nanocrystalline suspensions has emerged as efficient media to investigate the reaction mechanism in solid state by means of spectroscopy techniques. Recently, Garcia-Garibay and coworkers described the photolysis of 2-azidobiphenyls (46, Scheme 14), that affords, in nanocrystalline suspension, the corresponding carbazoles always in quantitative yields. Apart from the synthetic interest for the reaction, Laser Flash Photolysis analyses of the reaction pathways revealed the initial formation of a singlet nitrene (47) followed by cyclization to the corresponding isocarbazole 48.56 The photochemistry of p-bromophenylsulfonyl azide (BsN3), ptolylsulfonyl azide (TsN3) and methylsulfonyl azide (MsN3) in halogenated solvents (dichloromethane and tetrachloromethane) was investigated by a combined femtosecond time-resolved infrared spectroscopy/computational Photochemistry, 2019, 46, 194–217 | 207

Fig. 12 Pseudo Curtius intermediate observed in ref. 57. Reproduced from ref. 52 with permission from the PCCP Owner Societies.

Scheme 15

Scheme 16

approach. The nature and the kinetic of intermediates including singlet and triplet nitrenes as well as the formation of speudo Curtius photoproduts 50 (Fig. 12) has been characterized.57 The photoreactivity of monofluorinated 2-azido-1-methylbenzimidazoles 51 was exploited to prepare labeling agents. Indeed, UV irradiation of 4-, 5-, or 7-fluoro-2-azidoimidazole, in the presence of N-protected aminoacids 52a–c afforded regioselectively the monofluorinated 2-amino-6acyloxybenzimidazoles 53a-c (Scheme 15). Other nucleophile additives, including halide anions and carboxylic acids were also employed with satisfactory results.58 As concerning other synthetic used of aromatic azides, the photolysis of 2-azidobenzoic acids under basic conditions was exploited for the preparation of 2,1-benzisoxazole-3(1H)-ones.59 Analogously, quinazolinones were obtained upon visible-light exposition of the corresponding a-azidyl benzamides in the presence of N-Bromosuccinimide (NBS).60 Polycyclic heterocycles were obtained from arylazides also under continuous flow conditions. Collins and coworkers reported the synthesis of substituted carbazoles by following a protocols that is tolerant to a wide range of UV sensitive functional groups (some examples in Scheme 16).61

2

Functions containing other heteroatoms

2.1 Boron The photochemical properties of B,N-centered heterocycles (56a–c) have been deeply investigated. These compounds upon irradiation at 300 nm 208 | Photochemistry, 2019, 46, 194–217

Scheme 17

Fig. 13 Absorption and fluorescence spectra of 57a–c in THF. Adapted with permission from ref. 62. Copyright 2016 American Chemical Society.

undergo photoelimination affording heterocycles fused B,N-naphtalenes (57a–c) which exhibit yellow/green or blue fluorescent. In some case this transformation can occur also under thermal conditions (Scheme 17 and Fig. 13).62 The same study have been performed on compounds having two B,Nheterocycles units connected by an aromatic linker. Experimental and computational data demonstrated that while diboron B,N-heterocycles which share the central linker are unstable or poorly reactive under irradiation, those which don’t share the central linker undergo photoelimination efficiently.63 2.2 Phosphorous The photolysis of Carbon-Phosphorous bond was studied in details in the case of free radical iniziator (2,4,6-trimethylbenzoyl)diphenyl phosphine oxide (TMDPO) in dichloromethane at room temperature combining femptosecond UV pump and mild infrared probe spectroscopy.64 The first singlet excited state S1 undergoes intersystem crossing to triplet ground state T1 with a time constant of 135 ps. At this stage a cleavage of C–P bond takes place with a time constant of 15 ps affording trimethylbenzoyl Photochemistry, 2019, 46, 194–217 | 209

Fig. 14 Photochemistry of (2,4,6-trimethylbenzoyl)diphenyl phosphine oxide (TMDPO) in liquid dichloromethane. Reprinted with permission from ref. 64. Copyright 2017 American Chemical Society.

radical and diphenylbenzoyl radical which were identified throught their characteristic infrared absorption in the carbonyl and phosphoryl spectral regions (Fig. 14). On the basis of this photoreactivity TMDPO have been employed as iniziator in the reaction with disulfides, diselenides, ditellurides, diphosphines for the synthesis of the corresponding phosphinates (58a–c, Scheme 18) and esters (59b–d).65 The formation of C–P bond was mainly obtained by having recourse to photoredox catalysis.66 However, the metal-free and catalyst-free regioselective phosphonation of quinolines has been recently reported. This target can be achieved by simple irradiation of the heterocyclic substrate in presence of diphenylphosphine oxide, pyridinium salt 62 as oxidant and NaHCO3 as base.67 The excited state of the reagent acts as photosensitizer promoting the N–O bond cleavage in pyridinium salt throught a SET reduction affording 2-methylpyridine and ethoxy radical (Scheme 19). The latter undergoes hydrogen abstraction from diphenylphosphine oxide to yield phosphinoyl radical 61 which reacts with 60. The so formed radical 63 undergoes a second SET with 60 1 or products radical cation (63 1) affording cation 631 which after deprotonation gives the desidered product 63. The scope of the reaction is large and both electron-donating and electron-withdrawing group are tolerated onto the aromatic ring. The process was also extended to coumarin derivatives. In this case a mixture of mono and biphosphonated products was obtained, but monosubstitution was achieved throught a one-pot process involving phosphonation and elimination.67 2.3 Sulfur Recently fluorinations have received much attention due to the importance of fluorine containing molecules in pharmacological field. On this 210 | Photochemistry, 2019, 46, 194–217

Scheme 18

Scheme 19

topic, Studer and coworkers have reported a photo-induced metal-free difluoromethylation of (hetero)aryl thiols using readly accesible (difluormethyl)triphenylphosphonium bromide as fluorinating agent. Photochemistry, 2019, 46, 194–217 | 211

Scheme 20

Fig. 15 Photoinduced homolysis of S–H bond of 4-methylthiol at 267 nm. Adapted with permission from ref. 70. Copyright 2017. American Chemical Society.

The reaction tolerates different functional group on the (hetero)aromatic ring (OH, NH2, amide, ester) and procedes throught a SRN1 mechanism. Noteworthy the iniziation step which involved the formation of difluoromethyl radical occurs also in the dark, although less efficiently.68 (Scheme 20) An alternative approach for the synthesis of new Sulfur-(Heteroatom) Carbon bonds is represented by visible light photocatalysis.69 The importance of the thiol moiety in processes with biological relevance has prompted to develop new methods to track sulphur species (e.g. thiyl radicals, thiolate). Recently time resolved X-rays absorption spectroscopy at sulfur K-edge revealed very efficient for this purpose. Indeed its high spectral sensitivity to different oxidation states and chemical arounds of sulfur atoms allows to study chemical reactions involving sulfur functional groups. For example this technique was able to detect the formation of thiyl radical and two thione isomers obtained via photoinduced homolysis of the S–H bond of 4-methylthiol (Fig. 15).70 The photoinduced homolytic cleavage of sulfur–carbon bond has been reported to occur in thymidine phosphorilated aryl sulfides (66a,b). The so formed thymidine phosphate triester radical (67a,b) undergoes heterolysis affording thymidine radical cation (68a,b) which is supposed to be an important intermediate in DNA electron transfer with A–T rich substrates (Scheme 21).71 2.4 Halogen Chen and co-workers have developed a mild protocol for perfluoroalkylation reactions irradiating unsaturated substrate and perfluoroalkyl

212 | Photochemistry, 2019, 46, 194–217

Scheme 21

Scheme 22

iodide (RFI) in presence of amine as additive and THF as solvent. Mechanistic investigation suggested the presence of a halogen-bond interaction between RFI and amine and THF promote the photoreactivty of perfluoroalkyl iodide under low-intensity UV irradiation. This protocol allowed to prepare perfluoroalkylated alkenes, alkynes and (hetero)aromatics in modest to good yields. Noteworthy this method can be used for selective perfluoroalkylation of oligopeptides 69 at the C2 position of triptophan residue (Scheme 22).12 Melchiorre and co-workes have reported that electron-poor organic halides and chiral enamines can form photoactive electron donor– acceptor complex which play a key role in the visble light driven stereoselective a-alkylation of aldehydes.72 Few examples of photocatalytic and photoredox catalytic reactions involving halogenated compounds are reported in literature.73

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References 1 2 3 4 5

6 7 8 9 10 11

12 13 14 15 16

17 18 19 20

21 22 23 24 25

H. Dong, Z. Qiang, J. Lian and J. Qu, Water Res., 2017, 119, 83. G. Ciamician and P. Silber, Chem. Ber., 1910, 34, 2040. ¨bel and P. Gilch, J. Photochem. Photobiol. A Chem., 2016, 318, 150. S. Fro ˜ ero-Santiago, M. Morel, R. Arce and C. E. M. M. Brister, L. E. Pin ´ndez, J. Phys. Chem. Lett., 2016, 7, 5086. Crespo-Herna R. B. N. Baig, S. Verma, M. N. Nadagoud and R. S. Varma, Green Chem., 2016, 18, 1019; S. Peiris, S. Sarina, C. Han, Q. Xiao and H.-Y. Zhu, Dalton Trans., 2017, 46, 10665. K. Tsutsumi, F. Uchikawa, K. Sakai and K. Tabata, ACS Catal., 2016, 6, 4394. J. Thisuwan, S. Chaiwongwattana, M. Sapunar, K. Sagarik and N. Dosˇlı`c, J. Photochem. Photobiol. A, Chem., 2016, 328, 10. P. Wang, D. A. Devalankar and W. Lu, J. Org. Chem., 2016, 81, 6195. N. Asad, D. Deodato, X. Lan, M. B. Widegren, D. L. Phillips, L. Du and T. M. Dore, J. Am. Chem. Soc., 2017, 139, 12591. A. Gandioso, M. Palau, A. Nin-Hill, I. Melnyk, C. Rovira, S. Nonell, D. Velasco, `n, ChemistryOpen, 2017, 6, 375. J. Garcia-Amorjs and V. Marcha See for instance: C. Remeur, C. B. Kelly, N. R. Patel and G. A. Molander, ACS Catal., 2017, 7, 6065; Y. Cai, J. Wang, Y. Zhang, Z. Li, D. Hu, N. Zheng and H. Chen, J. Am. Chem. Soc., 2017, 139, 12259; M. Wang, L. Li, J. Lu, N. Luo, X. Zhang and F. Wang, Green Chem., 2017, 19, 5172; W. Shu, A. Genoux, Z. Li and C. Nevado, Angew. Chem. Int. Ed., 2017, 56, 10521; Y. Cai, R. Zhang, D. Sun, S. Xu and Q. Zhou, Synlett, 2017, 28, 1630; X. Linyong, C. Tiebo, H. Chen and L. Zhou, Chem. – Eur. J., 2017, 23, 2249; A. L. Fuentes de Arriba, F. Urbitsch and D. J. Dixon, Chem. Commun., 2016, 52, 14434; G. Pandey, S. K. Tiwari and B. Singh, Tetrahedron Lett., 2016, 57, 4480. Y. Wang, J. Wang, G.-X. Li, G. He and G. Chen, Org. Lett., 2017, 19, 1442. I. Cohen, A. K. Mishra, G. Parvari, R. Edrei, M. Dantus, Y. Eichen and A. M. Szpilm, Chem. Commun., 2017, 53, 10128. S. H. Lim, D. W. Cho, J. Choi, H. An, J. H. Shim and P. S. Mariano, Tetrahedron, 2017, 73, 6249. ´n, S. M. Barolo, R. A. Rossi and A. B. Pierini, TetW. D. Guerra, M. E. Bude rahedron, 2016, 72, 7796. (a) E. Torti, S. Protti, D. Merli, D. Dondi and M. Fagnoni, Chem. – Eur. J., 2016, 22, 16998; (b) E. Torti, S. Protti, M. Fagnoni and G. Della Giustina, ChemistrySelect, 2017, 2, 3633. D. M. Kuznetsov and A. G. Kutateladze, J. Am. Chem. Soc., 2017, 139, 16584. ´rrez, M. A. Gordillo, M. Soto-Monsalve, C. C. Carmona-Vargas, G. Gutie R. F. D’vries, J.-M. Lehn and M. N. Chaur, Chem. – Eur. J., 2017, 23, 14872. ¨rmann and T. Bach, Chem. Soc. Rev., 2018, 47, 278. Y.-Q. Zou, F. M. Ho See for instance: H.-H. Zhang and S. Yu, J. Org. Chem., 2017, 82, 9995; N. R. Patel, C. B. Kelly, A. P. Siegenfeld and G. A. Molander, ACS Catal., 2017, 7, 1766. S. Okamoto, R. Ariki, H. Tsujioka and A. Sudo, J. Org. Chem., 2017, 82, 9731. J. Davies, N. S. Sheikh and D. Leonori, Angew. Chem., Int. Ed., 2017, 56, 13361. M. Daniel, G. Dagousset, P. Diter, P.-A. Klein, B. Tuccio, A.-M. Goncalves, G. Masson and E. Magnier, Angew. Chem., Int. Ed., 2017, 56, 3997. M. Silvi, C. Verrier, Y. P. Rey, L. Buzzetti and P. Melchiorre, Nat. Chem., 2017, 9, 868. D. E. Fast, A. Lauer, J. P. Menzel, A.-M. Kelterer, G. Gescheidt and C. Barner-Kowollik, Macromolecules, 2017, 50, 1815.

214 | Photochemistry, 2019, 46, 194–217

26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

49 50 51 52

M. Pasolli, K. Dafnopoulos, N.-P. Andreou, P. S. Gritzapis, M. Koffa, A. E. Koumbis, G. Psomas and K. C. Fylaktakidou, Molecules, 2016, 21, 864. R. Mao, Z. Yuan, Y. Li and J. Wu, Chem. – Eur. J., 2017, 23, 8176. ¨fer and T. Schaub, J. Wysocki, J. H. Teles, R. Dehn, O. Trapp, B. Scha ChemPhotoChem, 2017, 2, 22. A. Ismael, R. Fausto and M. L. S. Cristiano, J. Org. Chem., 2016, 81, 11656. N. Kerisit, C. Rouxel, S. Colombel-Rouen, L. Toupet, J.-C. Guillemin and Y. Trolez, J. Org. Chem., 2016, 81, 3560. ´kova ´, V. Lada ´nyi, J. Al Anshori, P. Dvorˇ´ L. Vetra ak, J. Wirz and D. Heger, Photochem. Photobiol. Sci., 2017, 16, 1749. A. M. Raj and V. Ramamurthy, Org. Lett., 2017, 19, 6116. M. S. Scholz, J. N. Bull, N. J. A. Coughlan, E. Carrascosa, B. D. Adamson and E. J. Bieske, J. Phys. Chem. A, 2017, 121, 6413. L. Duarte, L. Khriachtchev, R. Fausto and I. Reva, Phys. Chem. Chem. Phys., 2016, 18, 16802. C. Slavov, C. Yang, L. Schweighauser, C. Boumrifak, A. Dreuw, H. A. Wegner and J. Wachtveitl, Phys. Chem. Chem. Phys., 2016, 18, 14795. A. A. Beharry and G. A. Woolley, Chem. Soc. Rev., 2011, 40, 4422. ´rez-Camargoc, A. J. Mu ¨ller and C. Appiah, G. Woltersdorf, R. A. Pe W. H. Bindera, Eur. Polym. J., 2017, 97, 299. K. Da˛brow, P. Niedbał and J. Jurczak, J. Org. Chem., 2016, 81, 3576. ´, M. Kohagen, P. ˇ ´, P. Slavı´cˇek and P. Kla ´n, L. Filipova Stacko, E. Muchova Langmuir, 2017, 33, 2306. K. Nobuoka, S. Kitaoka, T. Yamauchi, T. Harran and Y. Ishikawa, Chem. Lett., 2016, 45, 433. C. B. Fan, Z. Q. Liu, L. L. Gong, A. M. Zheng, L. Zhang, C. S. Yan, H. Q. Wu, X. F. Feng and F. Luo, Chem. Commun., 2017, 53, 763. ´panier and J.-P. Desaulniers, ChemistrySelect, M. L. Hammill, C. Isaacs-Tre 2017, 2, 9810. R. Mogaki, K. Okuro and T. Aida, J. Am. Chem. Soc., 2017, 139, 10072. S. Crespi, S. Protti and M. Fagnoni, J. Org. Chem., 2016, 81, 9612. A. Dossena, S. Sampaolesi, A. Palmieri, S. Protti and M. Fagnoni, J. Org. Chem., 2017, 82, 10687. M. Malacarne, S. Protti and M. Fagnoni, Adv. Synth. Catal., 2017, 359, 3826. C. Sauer, Y. Liu, A. De Nisi, S. Protti, M. Fagnoni and M. Bandini, ChemCatChem, 2017, 9, 4456. M. C. D. Fuerst, E. Gans, M. J. Boeck and M. R. Heinrich, Chem. – Eur. J., 2017, 23, 15312; B. Alcaide, P. Almendros, B. Aparicio, C. Lazaro-Milla, A. Luna, Amparo and O. N. Faza, Adv. Synth. Catal., 2017, 359, 2789; J. Leng, S.-M. Wang and H.-L. Qin, Beilstein J. Org. Chem., 2017, 13, 903; B. Hong, J. Lee and A. Lee, Tetrahedron Lett., 2017, 58, 2809; Z.-S. Wang, T.-D. Tan, C.-M. Wang, D.-Q. Yuan, T. Zhang, P. Zhu, C. Zhu, J.-M. Zhou and L.-W. Ye, Chem. Commun., 2017, 53, 6848; L. Liang, M.-S. Xie, H. X. Wang, H. Y. Niu, G.-R. Qu and H.-M. Guo, J. Org. Chem., 2017, 82, 5966; K. Rybicka-Jasinska, B. Koenig and D. Gryko, Eur. J. Org. Chem., 2017, 2104; T.-F. Niu, D.-Y. Jiang, S.-Y. Li, B.-Q. Ni and L. Wang, Chem. Commun., 2016, 52, 13105. V. Gauchot and A.-L. Lee, Chem. Commun., 2016, 52, 10163. S. Witzel, J. Xie, M. Rudolph and A. S. K. Hashmi, Adv. Synth. Catal., 2017, 359, 1522. L. Huang, M. Rudolph, F. Rominger and A. S. K. Hashmi, Angew. Chem., Int. Ed., 2016, 55, 4808. D. Cantillo, B. Gutmann and C. O. Kappe, Org. Biomol. Chem., 2016, 14, 853.

Photochemistry, 2019, 46, 194–217 | 215

53 54

55 56 57 58 59 60 61 62 63 64 65 66

67 68 69

V. K. Yadav, V. P. Srivastava and L. D. S. Yadav, Tetrahedron Lett., 2016, 57, 2502. See for instance: D. K. Tiwari, R. A. Maurya and J. B. Nanubolu, Chem. – Eur. J., 2016, 22, 526; D. Kalaitzakis, M. Triantafyllakis, G. I. Ioannou and G. Vassilikogiannakis, Angew. Chem., Int. Ed., 2017, 56, 4020; X. Huang, R. D. Webster, K. Harms and E. Meggers, J. Am. Chem. Soc., 2016, 138, 12636; L. Gu, C. Jin, W. Wang, Y. He, G. Yang and G. Li, Chem. Commun., 2017, 53, 4203; H.-T. Qin, S.-W. Wu, J.-L. Liu and F. Liu, Chem. Commun., 2017, 53, 1696; Y. Wang, G.-X. Li, G. Yang, G. He and G. Chen, Chem. Sci., 2016, 7, 2679; P. Kumar, C. Joshi, A. K. Srivastava, P. Gupta, R. Boukherrou and S. L. Jain, ACS Sustainable Chem. Eng., 2016, 4, 69; W.-L. Lei, T. Wang, K.-W. Feng, L.-Z. Wu and Q. Liu, ACS Catal., 2017, 7, 7941; P. T. G. Rabet, G. Fumagalli, S. Boyd and M. F. Greaney, Org. Lett., 2016, 18, 1646; A. Mishra, P. Rai, M. Srivastava, B. P. Tripathi, S. Yadav, J. Singh and J. Singh, Catal. Lett., 2017, 147, 2600. ¨fenstein, M. Isobe, M. Erde ´lyi and M. O. Sydnes, J. Org. H. Andersson, J. Gra Chem., 2017, 82, 1812. T. S. Chung, A. J.-L. Ayitou, J. H. Park, V. M. Breslin and M. A. Garcia-Garibay, J. Phys. Chem. Lett., 2017, 8, 1845. A. V. Kuzmin, C. Neumann, L. J. G. W. van Wilderen, B. A. Shainyan and J. Bredenbeck, Phys. Chem. Chem. Phys., 2016, 18, 8662. N. E. Kanitz and T. Lindel, Z. Naturforsch., 2016, 71, 1287. D. Y. Dzhons and A. V. Budruev, Beilstein J. Org. Chem., 2016, 12, 874. T. Yang, W. Wang, D. Wei, T. Zhang, B. Han and W. Yu, Org. Chem. Front., 2017, 4, 421. ´, X. A. Snape and S. K. Collins, Green Chem., 2017, S. P. Collette, C. Cruche 19, 4798. Y. G. Shi, D. T. Yang, S. K. Mellerup, N. Wang, T. Peng and S. Wang, Org. Lett., 2016, 18, 1626. D. T. Yang, Y. Shi, T. Peng and S. Wang, Organometallics, 2017, 36, 2654. ¨hringer, J. Phys. Chem. A, 2017, 121, 4914. S. Straub, J. Lindner and P. Vo Y. Sato, S. I. Kawaguchi, A. Nomoto and A. Ogawa, Synthesis, 2017, 49, 3558. ¨nig, ACS Catal., 2016, 6, 8410; ¨sel and B. Ko (a) R. S. Shaikh, S. J. S. Du ´e, A. C. Gaumont and (b) V. Quint, F. Morlet-Savary, J. F. Lohier, J. Laleve S. Lakhdar, J. Am. Chem. Soc., 2016, 138, 7436; (c) L. L. Liao, Y. Y. Gui, X. B. Zhang, G. Shen, H. D. Liu, W. J. Zhou, J. Li and D. G. Yu, Org. Lett., 2017, 19, 3735; (d) J. K. Pagano, C. A. Bange, S. E. Farmiloe and R. Waterman, Organometallics, 2017, 36, 3891. I. Kim, M. Min, D. Kang, K. Kim and S. Hong, Org. Lett., 2017, 19, 1394. N. B. Heine and A. Studer, Org. Lett., 2017, 19, 4150. (a) M. Jouffroy, C. B. Kelly and G. A. Molander, Org. Lett., 2016, 18, 876; (b) X. Zhu, X. Xie, P. Li, J. Guo and L. Wang, Org. Lett., 2016, 18, 1546; (c) Y. Ran, Q. Y. Lin, X. H. Xu and F. L. Qing, J. Org. Chem., 2017, 82, 7373; (d) Y. Li, M. Wang and X. Jiang, ACS Catal., 2017, 7, 7587; (e) S. S. Zalesskiy, N. S. Shlapakov and V. P. Ananikov, Chem. Sci., 2016, 7, 6740; (f) P. Sun, D. Yang, W. Wei, M. Jiang, Z. Wang, L. Zhang, H. Zhang, Z. Zhang, Y. Wang and H. Wang, Green Chem., 2017, 19, 4785; (g) H. Liu and H. Chung, ACS Sustainble Chem. Eng., 2017, 5, 9160; (h) M. S. Oderinde, M. Frenette, D. W. Robbins, B. Aquila and J. W. Johannes, J. Am. Chem. Soc., 2016, 138, 1760; (i) M. Jiang, H. Li, H. Yang and H. Fu, Angew. Chem., Int. Ed., 2017, 56, 874; (j) S. Phungsripheng, K. Kozawa, M. Akita and A. Inagaki, Inorg. Chem., 2016, 55, 3750; (k) J. Suzuki, K. Jeong, Yamaguchi and N. Mizuno, ´ and New J. Chem., 2016, 40, 1014; (l) J. Santandrea, C. Minozzi, C. Cruche

216 | Photochemistry, 2019, 46, 194–217

70

71 72 73

S. K. Collins, Angew. Chem., Int. Ed., 2017, 56, 12255; (m) G. Zhao, S. Kaur and T. Wang, Org. Lett., 2017, 19, 3291; (n) B. Hong, J. Lee and A. Lee, Tetrahedron Lett., 2017, 58, 2809. M. Ochmann, I. Von Ahnen, A. A. Cordones, A. Hussain, J. H. Lee, K. Hong, K. Adamczyk, O. Vendrell, T. K. Kim, R. W. Schoenlein and N. Huse, J. Am. Chem. Soc., 2017, 139, 4797. H. Sun, M. L. Taverna Porro and M. M. Greenberg, J. Org. Chem., 2017, 82, 11072. A. Bahamonde and P. Melchiorre, J. Am. Chem. Soc., 2016, 138, 8019. ¨nig, ACS Catal., 2016, 6, 8410; ¨sel and B. Ko (a) R. S. Shaikh, S. J. S. Du ´e, A. C. Gaumont and (b) V. Quint, F. Morlet-Savary, J. F. Lohier, J. Laleve S. Lakhdar, J. Am. Chem. Soc., 2016, 138, 7436; (c) L. L. Liao, Y. Y. Gui, X. B. Zhang, G. Shen, H. D. Liu, W. J. Zhou, J. Li and D. G. Yu, Org. Lett., 2017, 19, 3735; (d) J. K. Pagano, C. A. Bange, S. E. Farmiloe and R. Waterman, Organometallics, 2017, 36, 3891.

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Part 2 Highlights

Design and synthesis of two-photon responsive chromophores for application to uncaging reactions Youhei Chitosea and Manabu Abe*a,b DOI: 10.1039/9781788013598-00221

Light-responsive materials provide unique and useful techniques for investigating life phenomena. In this chapter, recent developments on design, synthesis, and application of new two-photon (TP)-responsive chromophores are summarized: (1) photo-labile protecting group; (2) molecular design of TP-responsive chromophores; and (3) examples of TP-responsive caged compounds.

1

Introduction

Light-responsive molecules and materials provide unique techniques for investigating life phenomena. For example, the method using ‘‘fluorescent probes’’ frequently utilized for visualizing bioactive substances is a standard method in physiological studies.1 The process of ‘‘caging & uncaging’’ is another powerful tool for investigating the bioactivity of a specified substance (Fig. 1), which was established by Kaplan, Engel and their coworkers in the late 1970s.2 The spatiotemporal release of bioactive substances using the photolysis of caged compounds in living tissues allows us to perform the real-time study of biological dynamics. The inactivation of bioactive compounds by masking their functional groups using photo-labile protecting groups (PPGs)3–8 produces caged compounds, which is the ‘‘caging’’ process. Upon irradiation, PPGs are removed, reproducing the bioactivity. This unmasking process of inactivated substances is called the ‘‘uncaging’’ process, by which a local rise in the concentration of bioactive compounds on the micro to millisecond time scale becomes possible.9 That is why caged compounds have been utilized as useful reagents to capture short biological responses of living tissues. Since the photo-triggered technique emerged, a large number of uncaging reactions of bioactive compounds have been attempted using one-photon (OP) excitation with UV–vis region light. However, UV–vis irradiation may cause cellular toxicity and light scattering in living tissues. The physiological applications of caged compounds include developing new chromophores with two-photon (TP) absorption10 character in the near infrared (NIR) region of light, 650–1050 nm, because three-dimensionally controlled release of bioactive compounds a

Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan. E-mail: [email protected] b Hiroshima University Research Center for Photo-Drug-Delivery Systems (HiU-P-DDS), 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan Photochemistry, 2019, 46, 219–241 | 221  c

The Royal Society of Chemistry 2019

Fig. 1 The process of ‘‘caging & uncaging’’ for physiological study.

is possible deep within living tissue using TP excitation with NIR light. In this review, typical examples of PPGs and their uncaging mechanisms are first introduced, and then, recent developments of caged compounds11 with TP-responsive character are shown.

2 Examples of photolabile protecting groups (PPGs) and uncaging mechanism The development of new PPGs has been progressing for the last three decades to improve the uncaging efficiency, light-absorption property, thermal stability, and water solubility for physiological study. In this section, beginning from the most used o-nitrobenzyl (oNB)12–14 PPGs such as o-nitrophenylethyl (oNPE),15–19 nitroindoline (NI),20–26 p-hydroxyphenacyl (pHP),27–32 coumarin-4-yl,33,34 and quinoline35–38 types will be introduced, which are categorized according to the uncaging mechanism: (1) intramolecular rearrangement type and (2) photo-SN1 type of uncaging reactions. 2.1 Intramolecular rearrangement type o-Nitrobenzyl (oNB) and o-nitrophenylethyl (oNPE) PPGs are the most studied PPGs for protecting carboxylic acids, amides, and other functional groups (Fig. 2a). Since Shlaeger and Hoffmann started caging and uncaging studies in the 1970s,2 the oNB type of PPG is the most frequently used for physiological studies. The uncaging mechanism of NB-based caged compounds is shown in Fig. 2. After photo-induced intramolecular H-abstraction at the benzylic carbon, the leaving group X is thermally released via the aci-nitro intermediate. To avoid possible thermal hydrolysis at the benzylic position of oNB esters, the oNPE type of PPG was developed. In 1976, Amit and co-workers succeeded in the preparation of 7-nitroindoline type PPG and reported that free carboxylic 222 | Photochemistry, 2019, 46, 219–241

Fig. 2 (a) o-Nitrobenzyl (oNB) and o-nitrophenylethyl (oNPE) PPGs; (b) coumarin-4yl methyl PPG.

acids were obtained by UV irradiation of thermally and hydrolytically stable C–N bonds.19 2.2 Photo-SN1 type Givens and co-workers first applied coumarin-4yl-based caged compounds to the release of diethyl phosphate in 1984 (Fig. 2b).30 Higher thermal stability, large molar extinction coefficient in the visible region of light, and relatively high quantum yield of uncaging reactions are the advantages while using PPG. In general, the photo-induced release of the leaving group in coumarin-4yl caged compounds is proposed to occur via the singlet excited state. After SN1-type of bond cleavage, a nucleophile such as water traps the intermediary ion pair to release the corresponding bioactive compounds. 2.3 Other types of PPGs developed for UV–vis region Other examples of PPGs are summarized in Fig. 3. In 1996, Givens and coworkers discovered the use of the p-hydroxyphenacyl (pHP) group,24 which is thermally stable, highly water soluble, and efficiently undergoes the uncaging reaction under physiological conditions. In 2002, Fedoryak and co-workers reported quinoline type PPG using an 8-bromo7-hydroxy quinoline (BHQ) based structure.32 Quinoline derivatives have also been used in the photo-SN1 uncaging reaction. A new thiochromone Photochemistry, 2019, 46, 219–241 | 223

Fig. 3

Photo-SN1-type of PPGs.

based PPG was developed by Kakiuchi and co-workers in 2008.39 The caged compounds release acids via intramolecular rearrangement. For visible-light induced uncaging reactions, many types of PPGs such as BODIPY,40–42 bimane,43 coumarin (DEDCC),44,45 and carbazole (CBZ)46 derivatives possessing fluorescent characters were developed. Bimane and CBZ derivatives realized the dual uncaging of carboxylic acids with two uncaging parts.

3

Two-photon absorption and excitation

As mentioned in the introduction, the 3D-controlled release of bioactive substances in the deeper parts of living tissues is becoming important for state-of-the-art research studies in biology. To achieve such activation processes, TP excitation of chromophores using bio-permeable NIR-light is needed. In this section, the fundamental knowledge of TP absorption and their use for uncaging reactions are described. The one-photon (OP) excitation energy of near IR light (650–1050 nm ¼ 1.9–1.2 eV) is not enough for bond cleavage (necessary for the uncaging reaction). Physicist ¨ppert-Mayer first theoretically proposed two-photon absorption in the Go 1930s47 and it was experimentally observed in 1961.48 If the molecules absorb two-photons (TP) to generate the same exited state as OP excitation, less harmful low-energy NIR light can be used for molecular excitation. Another advantage of TP excitation processes is that molecules at the focal point can be excited by TP excitation, because unlike linear light-intensity (I) vs. excitation-probability (P) relationship of the OP absorption in which one photon electronically excites one molecule, 224 | Photochemistry, 2019, 46, 219–241

Fig. 4 Two-photon (TP) excitation versus one-photon (OP) excitation process.

in the nonlinear TP process the excitation probability is proportional to the square of the intensity (Fig. 4). The ground state (S0) molecule can absorb two photons to generate the corresponding electronically excited state. The half energy (hn 0 ¼ 1/2hn) of the corresponding OP excitation (E ¼ hn) is used for TP excitation to the final state (S1 and S2 for nonsymmetric and centrosymmetric compounds, respectively). Although a light source with high intensity (typically from a femtosecond laser) is required,49 TP excitation is restricted to the focal point of a lens where light intensity is optically the strongest. These factors allow: (1) less harmful excitation light to the cellular tissues, (2) higher threedimensional spatial resolution, (3) deeper penetration in living cells, and (4) lower light scattering during TP excitation (Fig. 4)50 The TP uncaging efficiency du (¼s2ju) can be evaluated using the TPA cross-section (s2) and uncaging quantum yield (ju). The unit of GM (1050 cm4s per pho¨eppert-Mayer. A similar equation to qualify OP ton) is in honor of Go uncaging efficiency has been developed: du ¼ eju (e: molar coefficient). TPA cross-section is described by s2, which corresponds to the molar coefficient in the OP case.

4 Two-photon responsive chromophores 4.1 p-conjugation The most common structure of p-conjugated molecule, benzene, possesses no TP absorption character (B0 GM). Similarly, Weitz et al. reported in 1964 that naphthalene, which has two condensed benzene rings, has a small TP absorption character (0.9 GM at 530 nm).51 In the Photochemistry, 2019, 46, 219–241 | 225

Fig. 5 TP characters of simple p-conjugated molecules.

case of the stilbene molecule, in which two benzenes are linked via a double bond, significant improvement in TP absorption crosssection (12 GM at 514 nm)52 was reported. The TP-responsive character in spite of the relatively small p-conjugated structure prompted us to design new higher TP responsive chromophores with the stilbene core (Fig. 5). 4.2 Multi-polar system combining p-conjugation and substituents Increasing the intramolecular charge transfer character by tuning the molecular structure by introducing an electron-donating or electronwithdrawing group enhances the TP cross-section. Dipolar, quadrupolar, and octupolar systems are typical examples of increase in the TP cross-sections of chromophores. This section describes the basic concepts of the TP-induced excited state on the model of chromophores. 4.2.1 Dipolar topology. The dipolar system is generally constructed by introducing an electron-donating (D) and an electron-withdrawing (A) group to the end of the chromophore. Theoretically, this TPA crosssection s2 value is proportional to the product of the squared transition dipole moment (m) of the chromophore and the squared difference between the excited and ground state dipole moments (eqn 1). In the non-centrosymmetric chromophore, electron transition results from the electron donor to the acceptor moiety, leading to high transition dipole moment, and thus, high TPA cross-section. Fig. 6 shows an example of a push-pull substituted stilbene derivative, which exhibits larger s2 value than that of the parent stilbene due to strong dipolar character.53 Since the first electronic transition is the charge-transfer process (HOMO-LUMO) that corresponds to the S0–S1 transition, the TP absorption maxima are nearly double the wavelengths of the OP absorption maxima. s2  C

m2gi m2if ðEgi =hvÞ1G

s2: TPA cross-section mgi: transition dipole moment from g-i mif : transition dipole moment from i-f G: half-width at half-maximumof the 2PA band 226 | Photochemistry, 2019, 46, 219–241

(1)

Fig. 6 TP excitation in a dipolar system.

Fig. 7

TP excitation in a quadrupolar system.

4.2.2 Quadrupolar system. Quadrupolar polarization arises in centrosymmetric structures such as electronically push–push and pull–pull structures. For example, Fig. 7 shows centrosymmetric analogues based on the D–p–D stilbene structure. The s2 value of the above is almost ten times higher (110 GM at 620 nm)54 than that of unsubstituted E-stilbene (12 GM at 514 nm). The excited states can be considered using the three states model. The lower one with rigid fluorenyl structure shows further increase in s2 value through its extended p-conjugation system (1300 GM at 740 nm).55 In this quadrupolar system, the lower and higher excited states are OP and TP allowed, respectively. In many cases, the TP absorption maxima are shorter than twice the wavelengths of OP absorption maxima.56 4.2.3 Octupolar system. As a different model of multi-polarity, the trimetric chromophore in Fig. 8 has an octupolar character, composed of three dipolar branches (D(p–A)3). This molecule also shows sizable TPA cross-section of about 450 GM at 740 nm.57,58 The excited states derived from three zwitterionic structures are separated into the highest excited state and two degenerate excited states. The two degenerate states are OP allowed, but with slight TP transition. The highest excited Photochemistry, 2019, 46, 219–241 | 227

Fig. 8 TP excitation in the octupolar system.

Fig. 9

TP excitation in a diradical system.

state can be reached by TP excitation despite vanishing transition dipolar moment. The S0–S3 transition is TP allowed in the octupolar system.53 4.2.4 Diradical character. Nakano and co-workers theoretically found large two-photon absorption character induced by third-order nonlinear optical properties in open-shell singlet molecules with diradical characters. Kamada and Nakatsuji et al. experimentally showed that ´ molecules with phenalenyl-ring possess high two-photon Kekule absorption cross-sections with diradical characters (Fig. 9).59

5

Recent developments in TP uncaging reactions

Discoveries of efficient structural modifications using classic PPGs and their potential TP activation have contributed to developments in TP uncaging reactions. In this part, we focus on TP uncaging reports since 2015. Examples of TP-induced uncaging reaction before 2015 are summarized in recent review articles.60–63 5.1 TP responsive PPGs based on classical PPG structure 5.1.1 Cooperative dyads for TP uncaging (o-nitrobenzyl type). Blanchard-Desce and co-workers selected 4,5-dimethoxy-2-nitrobenzyl 228 | Photochemistry, 2019, 46, 219–241

Fig. 10 TP-uncaging using cooperative dyads.

PPG64 combined with a rigid fluorene core via phosphorus-based clip for the NIR uncaging unit (Fig. 10).65 The FRET system from the fluorene-cored chromophore promoted the TP-induced uncaging of acetic acid. Symmetric breaking in the TPA process was obtained due to its inherent asymmetric structure. Despite the quadrupolar character based on donor–donor (R ¼ NR2, X ¼ OR) and acceptor–acceptor (R ¼ SO2CF3) substituted chromophores, all molecules showed TPA bands (720–800 nm) at twice the wavelength of OPA bands because TP excitation to the lowest excited state was allowed. The donor– donor substituted derivative showed the largest TP uncaging efficiency of du ¼ 0.25 GM (s2 ¼ 310 GM) at 800 nm. 5.1.2 Caged calcium with bis-styrylthiophene backbone (o-nitrobenzyl type). Calcium ion (Ca21), the second messenger in biology, plays important roles in the neurotransmission process. Since Ca21 itself cannot covalently bond to organic chromophores, ethylene glycol tetraacetic acid (EGTA) is selected as calcium chelator introduced to o-NB type PPG to realize selective Ca21 binding to the chromophore. Upon photolysis, the EGTA chelator releases Ca21. The chelator is photolyzed to iminodiacetic acid, which has a lower affinity for Ca21. The first TP effective caged calcium was nitrodibenzofuran-EGTA (NDBF-EGTA) developed by Ellis-Davies and co-workers in 2006.66 A new symmetric Ca21 caging chelator bearing two EGTA units based on the bis-styrylthiophene (BIST) backbone was recently developed.67 The BIST chromophore provided a sizable TPA cross-section of 350 GM at 775 nm and the chelator showed high affinity for Ca21 (Kd 84 nM at pH 7.2, 50 nM at pH 7.35, and 19 nM at pH 7.5). Fast Ca21 release (in o0.2 ms) from BIST-2EGTA was observed using 2P excitation at 810 nm (Fig. 11). 5.1.3 4-Methoxy-7-indolinyl caged auxins (nitroindoline type). The plant hormone auxin plays a crucial role in plant growth and development. However, the development of caged auxin is limited due to its instability in higher plant metabolic activities. Hayashi and co-workers Photochemistry, 2019, 46, 219–241 | 229

Fig. 11 Caged calcium with bis-styrylthiophene (BIST) backbone.

Fig. 12

Caged auxins.

used 2 0 ,5 0 -dimethoxyphenyl-2-nitrobenzyl (DMPNB)-caged auxins to perform an artificial gradient of auxin. In 2015, this group developed higher thermally stable caged auxins and 4-methoxy-7-nitroindolinyl (MNI)caged auxins (Fig. 12).68 Light-induced uncaging of indole-3-acetic acid was demonstrated using an OP laser system. In plant cell experiments, MNI-caged auxins were more stable than esterase-resistant DMPNBcaged auxins at high concentrations. Additionally, the photoproducts of MNI-caged auxins showed non-toxicity to plant cells. These results show that MNI-caged auxins will be applicable for TP-induced uncaging. 5.1.4 TP uncaging of diethyl phosphate (DEP) and ATP (p-hydroxyphenacyl type). Two-photon activation of the pHP group was demonstrated by Houk, Givens, and Elles for the first time in 2016.69 pHP diethyl phosphate (DEP) and pHP (adenosine triphosphate) ATP including the parent p-hydroxyacetophenone chromophore were examined to obtain the TPA spectrum (Fig. 13). TP broadband signal (410 GM) was observed and it was confirmed that both OP and TP absorption were assigned to the S3 (1pp*) excited state, following the previously known uncaging mechanism. Monitoring the progress of TP-induced uncaging of DEP and ATP opened the possibility for two-photon activation of the pHP protecting group in the range 500–620 nm. The deprotonation of the hydroxy group of pHP under mildly basic condition extended the excitation range to longer wavelength. The conjugate bases have redshifted absorption near 330 nm that are both one- and two-photon active. This also indicates the possibility of two-photon excitation in the range 550–720 nm. 5.1.5 Cloaked caged compounds (coumarin-4yl group). Ellis-Davies and co-workers developed DEAC450-GABA in 2013 for a highly 230 | Photochemistry, 2019, 46, 219–241

Fig. 13 TP uncaging of diethyl phosphate (DEP) and ATP using p-hydroxyphenacyl type caged compound.

Fig. 14 A cloaked caged GABA (G5-DEAC450-GABA).

TP-active caged neurotransmitter.70 However, it is concerning that most caged transmitters are severe antagonists of ionotropic gammaaminobutyric acid (GABA) receptors. To overcome this problem, new ‘‘cloaked’’ caged GABA (G5-DEAC450-GABA) bearing fifth generation (G5) 2,2-bis(methylol)propionic acid dendrimer-conjugated molecules were invented (Fig. 14).71 Embedding DEAC450-GABA within G5 dendrimers reduced antagonism to a very low level. The ‘‘cloaked’’ caged compound enabled a promising technology for highly TP responsive uncaging and essentially inert caged GABA towards its target ionotropic receptors, for the first time. 5.1.6 Three-dimensional control of DNA hybridization by orthogonal two-color two-photon uncaging (coumarin-4yl group and o-nitrobenzyl type). Heckel and co-workers developed 3D control of DNA hybridization by introducing two types of TP responsive PPG ([7-diethylaminocoumarin-4-yl] methyl and p-dialkylaminonitrobiphenyl group) into DNA strands.72 The fluorescence-based assay demonstrated TP uncaging reactions of DNA-1 and DNA-2 based on double-strand displacement in a hydrogel and in neurons. Selective uncaging of DNA-1 Photochemistry, 2019, 46, 219–241 | 231

and DNA-2 was possible by changing the irradiation wavelength (Fig. 15). 3D control will enable us to investigate more complex scenarios. 5.1.7 Two-photon photocleavable linker for triggering light-induced DNA strand breaks in oligonucleotides (coumarin-4yl type). Heckel and co-workers also developed a TP-induced cleavable linker based on the 7-diethylaminocoumarin structure, which acted as a strand break in oligonucleotides (Fig. 15).73 To demonstrate TP activity in the strand displacement assay, a coumarin-linker modified oligonucleotide in hydrogel was used for TP uncaging using irradiation at 780 nm (Fig. 16). A new class of DNA decoy (CRDD) modified by the same coumarin based photo-trigger was invented for the photochemical regulation of gene expression. 5.1.8 Effect of position isomery on photorelease properties of aminoquinoline-derived photolabile protecting groups (quinoline type). To enhance the TPA ability of DMAQ PPG, the substituent effects of the carboxyl electron-withdrawing group on TP uncaging reaction were examined by Dalko and co-workers.74 Introducing the substituent at the C5 position of parent 5-H-8-DMAQ acetate was found to be most efficient for fragmentation. A variety of groups (5-CO2H-8-DMAQ, 5acryl-8-DMAQ, and 5-Ph-8-DMAQ) were introduced to the C5 position. 5-CO2H-8-DMAQ showed roughly six times less TP efficiency (0.11 GM) at 730 nm than the parent 5-H-DMAQ acetate (0.67 GM). However, the

Fig. 15 Orthogonal two-color two-photon uncaging.

Fig. 16 Light-induced DNA strand breaks in oligonucleotides. 232 | Photochemistry, 2019, 46, 219–241

du value increase followed 5-CO2H-8-DMAQ (0.11 GM)o5-Acryl-8-DMAQ (0.25 GM)o5-Ph-8-DMAQ (2.0 GM). These results show that tuning of dipolar character by introducing electron-withdrawing group on the parent 8-DMAQ platform can promote internal charge transfer (ICT) and increase the TPA value (Fig. 17). 5.1.9 Photochemical activation of tertiary amines for applications in studying cell physiology (quinoline type). Several types of tertiary amines were caged using 8-cyano-7-hydroxyquinolinyl (CyHQ) PPG to examine photo-activation for biological use (Fig. 18).75 Phillips, Du, Dore, and co-workers demonstrated the fast release of tertiary amines (Fu ¼ 0.1–0.5, du ¼ 0.23–0.38 GM) under both OP and TP photolysis conditions (pH ¼ 7.2). The photo-activation of bioactive tamoxifen and 4-hydroxytamoxifen, which are used to temporally regulate gene expression in Cre-recombinase and CRISPR-Cas9 systems, was achieved by OP and TP excitation. However, CyHQ protected anilines underwent photoaza-Claisen rearrangement instead of releasing amines. Stern–Volmer quenching experiments and ground-state and timeresolved spectroscopy support the photolysis reaction mechanism that proceeds via a singlet excited state. This photolysis rate is 70 times

Fig. 17 Photorelease properties of aminoquinoline derivative.

Fig. 18 8-cyano-7-hydroxyquinolinyl (CyHQ) PPG. Photochemistry, 2019, 46, 219–241 | 233

faster than that of the related BHQ protected acetate, which releases carboxylates from a triplet excited state with time constant of B5 ns.75 5.1.10 Quinoline-derived two-photon sensitive quadrupolar and octupolar Probes (quinoline type). Dalko and coworkers synthesized TP-sensitive quadrupolar and octupolar probes derived from the 8dimethylaminoquinoline (8-DMAQ) structure (Fig. 19).76 As quadrupolar probes, donor–neutral–donor (D–N–D) based photolabile quinoline groups bearing fluorene as central chromophore were selected. Two probes D–N–D (C5) and D–N–D (C6) designed from fluorene coupled at C5 and C6-branched 8-DMAQ chromophores exhibited large du values (2.3 GM (C5) and 1.3 GM (C6)) measured using 1.05 ps pulses with 730 nm irradiation.76 Three probes bearing third-order rotational symmetry were chosen for the octupolar system (Fig. 20).77 The photochemical study on the effect of C6, C7, and C8 isomers on TP photolysis was presented. The C6 and C7 isomers mainly resulted in intramolecular cyclization to produce carbazole derivatives instead of releasing acid. TP uncaging of the C8 isomer was observed using 730 nm irradiation with du value 0.67 GM. 5.2 Other types of TP responsive PPGs 5.2.1 Uncaging of GABA and Tryptophan using TP-induced electrontransfer reactions (4-pyridylmethyl type). Anderson and co-workers developed a new approach for designing TP responsive PPG based on

Fig. 19 Quinoline-derived two-photon-sensitive quadrupolar probes.

Fig. 20 Quinoline-derived two-photon-sensitive octupolar probes. 234 | Photochemistry, 2019, 46, 219–241

Fig. 21 Uncaging using TP-induced electron-transfer reactions.

photoinduced intramolecular electron transfer from an electrondonating fluorene chromophore to the electron-accepting pyridinium unit (Fig. 21).78 Caged g-amino butyric acid (GABA) and caged L-tryptophan released neurotransmitters with irradiation at 700 nm and 720 nm, respectively. The photochemical release of GABA was clean (chemical yield of 495%) and the uncaging quantum yield was determined to be 1% (Fu ¼ 0.01). Caged GABA exhibited high TPA cross-section value (s2 ¼ 1100 GM at 700 nm) and high TP uncaging efficiency (du ¼ 10  3 GM). 5.2.2 Cascade photo-uncaging of diazeniumdiolate (o-nitrobenzyl type and 7-hydroxy-(coumarin-3-yl)methyl type). Diazeniumdiolates (NONOates) are attractive nitric oxide (NO) donors that can release two moles of NO under physiological conditions. Caged NONOates are considerably useful for therapeutic purposes. However, several caged NONOates cause undesirable uncaging pathways to form carcinogenic photoproducts instead of releasing NONOates. Mandal, Singh, and coworkers designed a TP triggerable cascade photocage (ONB-COU-DEANONOate) that protected NONOate without having direct linkage to PPG and avoided undesirable pathways. Successful uncaging upon OP and TP irradiation was demonstrated. ONB-COU-DEA-NONOate has shown potential anticancer activity (Fig. 22).79

6 Design and synthesis of TP responsive PPGs with stilbene core To investigate the role of neurotransmitters such as glutamic acid and calcium ion, we started to design and synthesize new TP responsive caged neurotransmitters. In particular, a caged compound should possess high water-solubility, uncaging efficiency, and TP-absorption in the NIR region for biological application. For example, our target molecules head for s2 value of at least 100 GM in the NIR region and uncaging quantum yield over 0.05. The extension of p-conjugation enhances TP absorption and increases hydrophobicity. Considering the balance of TP property and hydrophilicity, we focus on designing an inherently high TP absorbable Photochemistry, 2019, 46, 219–241 | 235

Fig. 22 Cascade photo-uncaging of nitric oxide donors.

Fig. 23 Inherent character of trans–cis isomerization of stilbene derivatives.

Fig. 24 Stilbene-based new TP-responsive chromophore.

chromophore in spite of small structure. First, as mentioned in part 4, trans-stilbene was selected for the basic backbone. However, transstilbene derivatives show cis/trans isomerization via excited states, which affects the photo-reactivity of the caged compound (Fig. 23). To avoid this undesired phenomenon, we initially decided to use a cyclic structure such as 7,8-dihydronaphthalene combined with onitrobenzyl PPG, which also behaved as a strong electron–acceptor. First, the newly designed parent chromophore 6-(4-nitrophenyl)-7,8-dihydronaphthalen-2-amine was computed to predict the TPA spectrum at the TD-B3LYP/6-31G(d) theory level (Fig. 24).80 A relatively high s2 value of B150 GM at B810 nm was predicted due to its strong dipolar character. Based on this result, we began to prepare caged glutamate, which consisted of three units (photolabile protecting group unit, rigid stilbene core, and amino groups). Water-soluble groups such as carboxylic group and polyethylene glycol group were introduced to the amino group. 236 | Photochemistry, 2019, 46, 219–241

TP induced release of glutamate was observed and the uncaging quantum yield was unfortunately low (Fu ¼ B0.01). In 2006, Ellis-Davies and co-workers reported efficient TP-induced calcium ion uncaging using a 3-nitrodibenzofuran (NDBF) derivative for the first time.63 Considering its low TP uncaging efficiency (du ¼ B0.6 GM at 720 nm), we decided to design a second TP responsive chromophore based on the 2-(4-nitropheyl)benzofuran (NPBF) structure (Fig. 24). As expected, the computational result of the NPBF chromophore showed sizable s2 value of 150 GM at 700 nm, which was higher than that of the NDBF chromophore (75 GM at 600 nm). The caged benzoate (NPBF-BA) exhibited high du value of 5.0 GM at 740 nm.81 NPBF-EGTA showed a much higher du value of 20.7 GM at 740 nm.82 Finally, our NPBF chromophore enabled biological application for calcium ion uncaging (Fig. 25). Very recently, Heckel and coworkers developed a modified NDBF chromophore, that is DMA-NDBF core, for a high TP-responsive chromophore for TP-uncaging reaction (Fig. 26).83 Recently, we developed TP responsive coumarin derivatives with rigid stilbene structure.84,85 The flexibility of the coumarin core allowed investigation of substituent effects such as donor–p–acceptor and donor– p–donor type. The NCO (donor–p–acceptor) and ACA (donor–p–donor) chromophores were designed as dipolar and quadrupolar systems, respectively. The NCO chromophore with dipolar character was computed to possess a sizable s2 of 150 GM at 700 nm. A computational value that was more than four times higher was found (700 GM at 650 nm) in

Fig. 25 A new high TP-responsive chromophore, PBF.

Fig. 26 DMA-NDBF. Photochemistry, 2019, 46, 219–241 | 237

Fig. 27 New TP-responsive chromophore of NPBF and its use for TP-uncaging.

ACA core due to its quadrupolar character. TP photolysis of caged benzoates NCO-BA and ACA-BA resulted in relatively high du of 3.4 GM at 710 nm and B16 GM at 650 nm irradiation, respectively (Fig. 27).

7

Perspective for future TP responsive PPGs

New design and synthesis of PPGs is ongoing in laboratories, which contribute to the sustainable development of our society. Recent developments in TP responsive PPGs have been remarkable. TP activation in the NIR region renders possibilities for physiological investigation in the deeper areas of living tissue. Elucidation of biological processes using photo-triggers is convenient because of the spatiotemporal control of release of bioactive substances. The principles and strategies described in this review and new techniques for efficient molecular design will contribute to future developments of TP responsive PPGs. The phototriggers bearing high uncaging efficiency, water-solubility, and TPA property will open the door to the next generation of photo-chemistry and reveal unknown biological dynamics.

References 1

(a) Fluorescence Microscopy, ed. A. Cornea and P. M. Conn, Elsevier, 2014; (b) H. M. Kim and B. R. Cho, Small molecule two-photon probes for bioimaging applications, Chem. Rev., 2015, 115, 5014. 2 (a) J. Engels and E.-J. Schlager, J. Med. Chem., 1977, 20, 907; (b) H. Kaplan, B. Forbush and J. F. Hoffmann, Biochemistry, 1978, 17, 1929. 3 J. A. Barltrop and P. Schofield, Tetrahedron Lett., 1962, 3, 697. 4 R. S. Givens, P. G. Conrad III, A. L. Yousef and J.-I. Lee, in CRC Handbook of Organic Photochemistry and Photobiology, ed. W. Horspool and F. Lench, CRC Press, Boca Raton, 2nd edn, 2003, ch. 69. 5 C. G. Bochet, J. Chem. Soc., Perkin Trans., 2002, 125. 6 N. Hoffmann, Chem. Rev., 2008, 108, 1052. 7 P. Wang, Asian J. Org. Chem., 2013, 2, 452. ´n, T. ˇ 8 P. Kla Solomek, C. G. Bochet, A. Blanc, R. Givens, M. Rubina, V. Popik, A. Kostikov and J. Wirz, Chem. Rev., 2013, 113, 119. 9 Dynamic Studies in Biology, ed. M. Goeldner and R. Givens., Wiley-VCH, 2005. 10 S. Kawata, H.-B. Sun, T. Tanaka and K. Takada, Nature, 2001, 412, 697–698. 238 | Photochemistry, 2019, 46, 219–241

11 12 13 14 15 16 17

18 19 20 21 22

23 24 25 26

27 28 29 30 31 32 33 34 35 36 37 38 39

M. Abe, Y. Chitose, S. Jakkampudi, T. T. Pham, Q. Lin, V. T. Bui, A. Yamada, R. Oyama, M. Sasaki and C. Katam, Synthesis, 2017, 49, 3337. J. A. Barltrop, P. J. Plant and P. Schofield, Chem. Commun., 1966, 822. A. Patchornik, B. Amit and R. B. Woodward, J. Am. Chem. Soc., 1970, 92, 6333. ¨rer and J. Wirz, J. Am. Chem. Soc., 2004, 126, 4581. Y. V. Il’ichev, M. A. Schwo A. Hasan, K.-P. Stengele, H. Giegrich, P. Cornwell, K. R. Isham, R. A. Sachleben, W. Pfleiderer and R. S. Foote, Tetrahedron, 1997, 53, 4247. S. Gug, S. Charon, A. Specht, K. Alarcon, D. Ogden, B. Zietz, J. Leonard, S. Haacke, F. Bolze, J.-F. Nicoud and M. Goeldner, ChemBioChem, 2008, 9, 1303. L. Donato, A. Mourot, C. M. Davenport, C. Herbivo, D. Warther, J. Lonard, F. Bolze, J.-F. Nicoud, R. H. Kramer, M. Goeldner and A. Specht, Angew. Chem., Int. Ed., 2012, 51, 1840. A. Specht, F. Bolze, L. Donato, C. Herbivo, S. Charon, D. Warther, S. Gug, N. Jean-FranÅois and M. Goeldner, Photochem. Photobiol. Sci., 2012, 11, 578. P. Anstaett, V. Pierroz, S. Ferrarib and G. Gasser, Photochem. Photobiol. Sci., 2015, 14, 1821. B. Amit and A. Patchornik, Tetrahedron Lett., 1973, 14, 2205. B. Amit, D. A. Ben-Efraim and A. Patchornik, J. Am. Chem. Soc., 1976, 98, 843. (a) J. Morrison, P. Wan, J. E. T. Corrie and G. Papageorgiou, Photochem. Photobiol. Sci., 2002, 1, 960; (b) A. D. Cohen, C. Helgen, C. G. Bochet and J. P. Toscano, Org. Lett., 2005, 7, 2845; (c) J. E. T. Corrie, A. Barth and G. J. Papageorgiou, J. Labelled Compd. Radiopharm., 2001, 44, 619. S. Pass, B. Amit and A. Patchornik, J. Am. Chem. Soc., 1981, 103, 7674. G. Papageorgiou, D. C. Ogden, A. Barth and J. E. Corrie, J. Am. Chem. Soc., 1999, 121, 6503. M. Matsuzaki, T. Hayama, H. Kasai and G. C. R. Ellis-Davies, Nat. Chem. Biol., 2010, 6, 255. ´lfi, B. Chiovini, G. Szalay, A. Kasza ´s, G. F. Turi, G. Katona, D. Pa ´bra + ´nyi-Balogh, M. Szori, ´csne ´ Haveland, P. A A. Potor, O. Frigyesi, C. Luka ´sz, A. Vasanits-Zsigrai, I. Molna ´r-Perl, B. Viskolcz, Z. Szadai, M. Madara ´zsa, Org. Biomol. Chem., 2018, 16, 1958. I. G. Csizmadia, Z. Mucsi and B. Ro R. S. Givens and C.-H. Park, Tetrahedron Lett., 1996, 37, 6259. C.-H Park and R. S. Given, J. Am. Chem. Soc., 1997, 119, 2453. R. S. Givens, A. Jung, C.-H. Park, J. Weber and W. Bartlett, J. Am. Chem. Soc., 1997, 119, 8369. R. S. Givens, J. F. W. Weber, P. G. Conrad, G. Orosz, S. L. Donahue and S. A. Thayer, J. Am. Chem. Soc., 2000, 122, 2687. ´k, D. Heger, Z. ˇ ´n, I. Bownik, P. ˇ Sebej, J. Litera Simek, R. S. Givens and P. Kla J. Org. Chem., 2015, 80, 9713. ´n, Org. Lett., 2015, T. Slanina, P. ˇ Sebej, A. Heckel, R. S. Givens and P. Kla 17, 4814. R. S. Givens and B. Matuszewski, J. Am. Chem. Soc., 1984, 106, 6860. N. Kamatham, D. C. Mendes, J. P. Da Silva, R. S. Givens and V. Ramamurthy, Org. Lett., 2016, 18, 5480. O. D. Fedoryak and T. M. Dore, Org. Lett., 2002, 4, 3419. Y. Zhu, C. M. Pavlos, J. P. Toscano and T. M. Dore, J. Am. Chem. Soc., 2006, 128, 4267. M. J. Davis, C. H. Kragor, K. G. Reddie, H. C. Wilson, Y. Zhu and T. M. Dore, J. Org. Chem., 2009, 74, 1721. Y. M. Li, J. Shi, R. Cai, X. Y. Chen, Q. X. Guo and L. Liu, Tetrahedron Lett., 2010, 51, 1609. S. Kitani, K. Sugawara, K. Tsutsumi, T. Morimoto and K. Kakiuchi, Chem. Commun., 2008, 18, 2103. Photochemistry, 2019, 46, 219–241 | 239

40 41 42

43 44 45 46 47 48 49 50 51 52 53 54

55 56 57 58 59 60 61 62 63 64 65 66 67 68

P. P. Goswami, A. Syed, C. L. Beck, T. R. Albright, K. M. Mahoney, R. Unash, E. Smith and A. H. Winter, J. Am. Chem. Soc., 2015, 137, 3783. ´, T. ˇ ´n, J. Am. E. Palao, T. Slanina, L. Muchova Solomek, L. Vı´teka and P. Kla Chem. Soc., 2016, 138, 126. T. Slanina, P. Shrestha, E. Palao, D. Kand, J. A. Peterson, A. S. Dutton, ´n, J. Am. Chem. Soc., N. Rubinstein, R. Weinstain, A. H. Winter and P. Kla 2017, 139, 15168. A. Chaudhuri, Y. Venkatesh, K. K. Behara and N. D. P. Singh, Org. Lett., 2017, 19, 1598. ´n, J. Org. Chem., 2016, A. Gandioso, M. Cano, A. Massaguer and V. Marcha 81, 11556. A. Gandioso, S. Contreras, I. Melnyk, J. Oliva, S. Nonell, D. Velasco, ´s and V. Marcha ´n, J. Org. Chem., 2017, 82, 5398. J. G. Amoro Y. Venkatesh, Y. Rajesh, S. Karthik, A. C. Chetan, M. Mandal, A. Jana and N. D. P. Singh, J. Org. Chem., 2016, 81, 11168. ¨ppert-Mayer, Ann. Phys., 1931, 401, 273. M. Go W. Kaiser and C. G. B. Garrett, Phys. Rev. Lett., 1961, 7, 229. S. Maruo, O. Nakamura and S. Kawata, Opt. Lett., 1997, 22, 132. W. Boyd, In Non-linear Optics, 2nd edn, Elsevier, London, 2003. S. Z. Weisz, A. B. Zahlan, J. Gilreath, R. C. Jarnagin and M. Silver, J. Chem. Phys., 1964, 41, 3491. R. J. M. Anderson, G. R. Holtom and W. M. McClain, J. Chem. Phys., 1979, 70, 4310. F. Terenziani, C. Sissa and A. Painelli, J. Phys. Chem. B, 2008, 112, 5079. ´das, J. E. Ehrlich, J. Y. Fu, A. Heikal, M. Albota, D. Beljonne, J. L. Bre S. E. Hess, T. Kogej, M. D. Levin, S. R. Marder, D. M. C. Maughon, J. W. Perry, ¨ckel, M. Rumi, G. Subramaniam, W. W. Webb, X. L. Wu and C. Xu, H. Ro Science, 1998, 281, 1653. O. Mongin, L. Porrs, M. Charlot, C. Katan and M. Blanchard-Desce, Chem. – Eur. J., 2007, 13, 1481. F. Terenziani, C. Katan, E. Badaeva, S. Tretiak and M. Blanchard-Desce, Adv. Mater., 2008, 20, 4641. F. Terenziani, C. Sissa and A. Painelli, J. Phys. Chem. B, 2008, 112, 5079. Y.-Z. Cui, Q. Fang, G. Xue, G.-B. Xu, L. Yin and W.-T. Yu, Chem. Lett., 2005, 34, 644. K. Kamada, K. Ohta, A. Shimizu, T. Kubo, R. Kishi, H. Takahashi, E. Botek, B. Champagne and M. Nakano, J. Phys. Chem. Lett., 2010, 1, 937. M. Pawlicki, H. A. Collins, R. G. Denning and H. L. Anderson, Angew. Chem., Int. Ed., 2009, 48, 3244. G. C. R. Ellis-Davies, ACS Chem. Neurosci. 2011, 2, 185. C. Brieke, F. Rohrbach, A. Gottschalk, G. Mayer and A. Heckel, Angew. Chem., Int. Ed., 2012, 51, 8446. G. Bort, T. Gallavardin, D. Ogden and P. I. Dalko, Angew. Chem., Int. Ed., 2013, 52, 4526. J. W. Wootton and D. R. Trentham, NATO ASI Ser., Ser. C, 1989, 272, 277. E. J. Cueto Diaz, S. Picard, V. Chevasson, J. Daniel, V. Hugues, O. Mongin, E. Genin and M. Blanchard-Desce, Org. Lett., 2015, 17, 102. A. Momotake, N. Lindegger, E. Niggli, R. J. Barsotti and G. C. R. Ellis-Davies, Nat. Methods, 2006, 3, 35. H. K. Agarwal, R. Janicek, S.-H. Chi, J. W. Perry, E. Niggli and G. C. R. Ellis-Davies, J. Am. Chem. Soc., 2016, 138, 3687. K.-I. Hayashi, N. Kusaka, S. Yamasaki, Y. Zhao and H. Nozaki, Bioorg. Med. Chem. Lett., 2015, 25, 4464.

240 | Photochemistry, 2019, 46, 219–241

69 70 71 72 73 74 75 76 77 78 79 80 81

82 83 84 85

A. Houk, R. S. Givens and C. G. Elles, J. Phys. Chem. B, 2016, 120, 3178. J. M. Amatrudo, J. P. Olson, G. Lur, C. Q. Chiu, M. J. Higley and G. C. R. Ellis-Davies, ACS Chem. Neurosci., 2014, 5, 64. M. T. Richers, J. M. Amatrudo, J. P. Olson and G. C. R. Ellis-Davies, Angew. Chem., Int. Ed., 2017, 56, 193. ¨fer, C. Herbivo, M. Coeldner, M. A. H. Fichte, X. M. M. Weyel, S. Junek, F. Scha A. Specht, J. Wachtveitl and A. Heckel, Angew. Chem., Int. Ed., 2016, 55, 8948. X. M. M. Weyel, M. A. Fichte and A. Heckel, ACS Chem. Biol., 2017, 12, 2183. C. Tran, T. Gallavardin, M. Petit, R. Slimi, H. Dhimane, M. Blanchard-Desce, F. C. Acher, D. Ogden and P. I. Dalko, Org. Lett., 2015, 17, 402. N. Asad, D. Deodato, X. Lan, M. B. Widegren, D. L. Phillips, L. Du and T. M. Dore, J. Am. Chem. Soc., 2017, 139, 12591. C. Tran, N. Berqouch, H. Dhimane, G. Clermont, M. Blanchard-Desce, D. Ogden and P. I. Dalko, Chem. – Eur. J., 2017, 23, 1860. P. Dunkel, M. Petit, H. Dhimane, M. Blanchard-Desce, D. Ogden and P. I. Dalko, ChemistryOpen, 2017, 6, 660. K. A. Korzycka, P. M. Bennett, E. J. Cueto-Diaz, G. Wicks, M. Drobizhev, M. Blanchard-Desce, A. Rebane and H. L. Anderson, Chem. Sci., 2015, 6, 2419. K. K. Behara, Y. Rajesh, Y. Venkatesh, B. R. Pinninti, M. Mandal and N. D. P. Singh, Chem. Commun., 2017, 53, 9470. S. Boinapally, B. Huang, M. Abe, C. Katan, J. Noguchi, S. Watanabe, H. Kasai, B. Xue and T. Kobayashi, J. Org. Chem., 2014, 79, 7822. N. Komori, S. Jakkampudi, R. Motoishi, M. Abe, K. Kamada, K. Furukawa, C. Katan, W. Sawada, N. Takahashi, H. Kasai, B. Xue and K. Kobayashi, Chem. Commun., 2016, 52, 331. S. Jakkampudi, M. Abe, N. Komori, R. Takagi, K. Furukawa, C. Katan, W. Sawada, N. Takahashi and H. Kasai, ACS Omega, 2016, 1, 193. Y. Becker, E. Unger, M. A. H. Fichte, D. A. Gacek, A. Dreuw, J. Wachtveitl, P. J. Wall and A. Heckel, Chem. Sci., 2018, 9, 2797. Y. Chitose, M. Abe, K. Furukawa and C. Katan, Chem. Lett., 2016, 45, 1186. Y. Chitose, M. Abe, K. Furukawa, J.-Y. Lin, T.-C. Lin and C. Katan, Org. Lett., 2017, 19, 2622.

Photochemistry, 2019, 46, 219–241 | 241

Controlled release of volatile compounds using the Norrish type II reaction Andreas Herrmann DOI: 10.1039/9781788013598-00242

The Norrish type II photofragmentation of 1-phenylalkan-1-ones (phenyl alkyl ketones) or 2-oxoacetates (a-ketoesters) is useful to control the release of volatile compounds from surfaces exposed to daylight. The reaction proceeds in the UV-A region of the solar spectrum and tolerates the presence of oxygen and water. Suitably designed photocages allow the generation of alkenes, aldehydes, ketones, esters or lactones. Mechanistic aspects are discussed in view of using the corresponding light-responsive profragrances or properfumes as delivery systems in practical applications.

1

Introduction

Following an increasing demand by the general public for sustainable and environmentally friendly processes, research activities in life sciences have been directed towards the use of natural and biocompatible reagents for molecular transformations of all kinds.1–4 Photochemical systems using natural daylight as the energy source have attracted particular interest, not only for the preparation of chemicals,5–7 but also as a trigger for the controlled release of various bioactive materials.8–15 Volatile signalling compounds, such as fragrances, pheromones or plant growth hormones, represent a particular class of compounds for triggered release applications. Because these molecules have to efficiently evaporate from a surface and travel through the air by diffusion to reach their target, they are characterised by high vapour pressures (volatilities), which limit their duration of action. To slow the evaporation of these volatile molecules and prolong their perception, researchers have developed less volatile precursors with a selectively cleavable covalent bond to generate the volatiles in situ.15,16 Because the surfaces from which volatile compounds evaporate are typically exposed to natural daylight, light-responsive precursors (so-called photocages) are particularly suitable for their release.12–16 Natural daylight as a controlled release reagent has several advantages. It is ubiquitously available and the ultraviolet (UV) region of terrestrial sunlight provides a sufficient amount of energy for the formation, isomerisation and cleavage of covalent bonds. Because the ozone layer of the atmosphere efficiently filters wavelengths below about 300 nm,17 photoreactions that are expected to proceed under ambient daylight conditions have to take place in the UV-A region (typically between 320 and 400 nm). Furthermore, the intensity of outdoor sunlight is subject to seasonal, daily or even hourly fluctuations,17–19 which has a direct impact on the efficiency of daylight-dependent processes. Firmenich SA, Division Recherche et De´veloppement, Route des Jeunes 1, B. P. 239, CH-1211 Gene`ve 8, Switzerland. E-mail: [email protected] 242 | Photochemistry, 2019, 46, 242–264  c

The Royal Society of Chemistry 2019

O

β α

O

hν

+

< 320 nm

Scheme 1 Photochemical decomposition of 2-hexanone (methyl butyl ketone) described by Norrish and Appleyard.20

To occur in an everyday environment, photochemical reactions have to work under natural daylight conditions and, furthermore, they must tolerate the presence of oxygen and water.12 One reaction fulfilling these requirements is the Norrish type II photofragmentation, which was first described in the 1930s for the photo-induced fragmentation of alkyl ketones.20,21 Photoirradiation of 2-hexanone (methyl butyl ketone) resulted almost quantitatively in the cleavage of the C(a)–C(b) bond to form acetone and propylene (Scheme 1). The originally reported reaction occurred at wavelengths below 320 nm, and therefore does not usually take place under ambient daylight. However, 1-phenylalkan-1-ones (phenyl alkyl ketones) or alkyl and phenyl 2-oxoacetates (a-ketoesters) and their derivatives fragment at higher wavelengths in the UV-A region and are thus readily cleavable upon exposure to natural daylight. Furthermore, they tolerate broad structural variability around the ketone function, provided that there is at least one abstractable hydrogen atom in the g-position to the carbonyl group. Depending on the substitution pattern of these structures, Norrish type II fragmentation can generate acetophenone derivatives together with alkenes (including exo- and endocyclic structures), aldehydes and ketones, or esters and lactones (Scheme 2), all of which can be volatile compounds with various biological functions. Most of the delivery systems described so far use the Norrish type II reaction for the controlled release of fragrances from socalled profragrances or properfumesy.12–16 Interestingly, despite many similarities between the two reactions, the mechanistic aspects of the Norrish type II reaction of phenyl alkyl ketones and a-ketoesters have rarely been directly compared.12,13 In the following sections, I discuss the general mechanism of the Norrish type II photofragmentation of phenyl alkyl ketones and a-ketoesters in view of using this reaction to develop light-responsive precursors for the controlled release of structurally different volatile compounds in practical applications.

2

Mechanism of the Norrish type II reaction

2.1 General aspects The mechanism of the Norrish type II reaction of phenyl alkyl ketones (X ¼ CHR and Y ¼ CHR)22–27 and a-ketoesters (X ¼ CO and Y ¼ O)28–34 as outlined in Scheme 3 has been studied in some detail in the scientific y

A fragrance is a single perfumery raw material, and a perfume is a mixture of fragrances. In analogy, the term ‘‘profragrance’’ should be used if one single fragrance molecule is generated, and the term ‘‘properfume’’ if several fragrances are released from the same precursor simultaneously or in several steps. Photochemistry, 2019, 46, 242–264 | 243

(a) R1

O

R2 R3

R' acetophenones

alkenes

(e)

(b) O

R1

R2

R1

O O

R'

R'

O aldehydes benzaldehydes ketones

R2 R1

Y

R2 OH

R' acetophenones

aldehydes

(c)

O

O

R1

R2 O

O R'

R' acetophenones

R1

O

variable substitution

(d) O

X

R2

esters lactones

acetophenones

aldehydes ketones

Scheme 2 Norrish type II-induced generation of acetophenone derivatives and alkenes, aldehydes, ketones, esters or lactones from phenyl alkyl ketones as a result of different substitution patterns at X and Y. Formally, the hatched bond between X and Y is cleaved in the photoreaction and a double bond (dotted line) is formed.

literature. The reaction typically proceeds from the excited n,p* singlet state of the carbonyl group (A) via efficient intersystem crossing (ISC) to the corresponding n,p* triplet state (B), followed by g-hydrogen abstraction (1,5-hydrogen shift) to form a 1,4-biradical (C). The biradical can either regenerate the starting carbonyl compound or, upon cleavage of the X–Y covalent bond, form an enol (D) and an alkene (E, if Y ¼ C) or a carbonyl compound (E, if Y ¼ O) as fragmentation products. Depending on the structure of X, the enol can then tautomerise to the corresponding carbonyl derivative (F) as the final product (Scheme 3). To some extent, d-hydrogen abstraction to yield an intermediate 1,5-biradical can be observed as a side reaction, for example if conformational constraints hinder the preferred g-hydrogen abstraction.35 2.2 Substituent effects While aliphatic ketones undergo the reaction from both excited n,p* singlet and triplet states of the carbonyl group, phenyl alkyl ketones with ISC yields that are close to unity react mainly from their lowest excited n,p* triplet state.23–26 The formation of cyclobutanols (G) as the most important side products of the photofragmentation (Yang photocyclisation) confirmed that the reaction passed through the intermediate 1,4-biradical C.36,37 In phenyl alkyl ketones, the lowest excited n,p* and p,p* triplet states lie relatively close together, with the former being by far more reactive than the latter.38–44 Electron-withdrawing substituents on the phenyl ring 244 | Photochemistry, 2019, 46, 242–264

1O* H

X

R'

R1 R2

O

hν

O

R1 R2

H

O OH

γ α

Y

Y β

X

R'

X

R'

ISC

O*

H X

R'

HOO O

Y

X

R'

K

A

3

R1 R2

R1 R2 Y

J

O2 R1 R2

γ-H abstraction

R1 R2

OH

Y

X

R'

HO O

O2 Y

X

R'

Photochemistry, 2019, 46, 242–264 | 245

C

B

O

R1 R2 Y

L

- O2 R1 HO

R2

X

R' G

OH

O

R1

Y X

R' F

X R'

+ Y

D

OH

R2

E

O + X

R' M

Y

N

R1

O +

R2 O

Scheme 3 General mechanism for the Norrish type II photofragmentation of phenyl alkyl ketones (X ¼ CHR, Y ¼ CHR or Y ¼ O) and a-ketoesters (X ¼ CO, Y ¼ O).

(R 0 ¼ F or CF3) have been shown to enhance the photochemical reactivity of the compounds, while electron-donating substituents (R 0 ¼ CH3 or OCH3) decrease it.40,44 In many cases, the desired photoreaction also occurred for compounds with the lowest p,p* triplet states if the upper n,p* triplet states were close in energy and thus partly populated.40 Only a few substituents (e.g. R 0 ¼ SCH3, Ph, OH or NH2) with very low-lying p,p* triplet states entirely prevent the Norrish type II reaction.39–42 Some differences in reactivity were also observed when the same ring substituents were placed in the ortho-, meta- or para-position.39–43 Photofragmentation of alkyl a-ketoesters can occur from both excited n,p* singlet and excited n,p* triplet states,31 while their phenyl analogues mainly react in a triplet deactivation pathway.30 If abstractable g-hydrogen atoms are present in the alkyl group of the a-ketoesters, a certain amount of alkyl chain fragmentation has been observed in addition to the desired ester chain reaction.31,34,45,46 In these cases, a-ketoesters with shorter alkyl chains are typically formed, which can then further react in a second Norrish type II process by g-hydrogen abstraction at the ester side chain (Scheme 4).34 Because both alkyl and phenyl a-ketoesters fragment upon irradiation in the UV-A region, broad structural variability is tolerated on this side of the carbonyl group. In all cases, the efficiency of the photoreaction depended on the solvent in which the irradiations were carried out. Substituent effects at the alkyl chain of phenyl alkyl ketones or at the ester chain of a-ketoesters can influence the strength of the g-hydrogen bond to be cleaved and the lifetime of the 1,4-biradical through electronic and geometric effects.24,30,34,47,48 As geometric requirements, the distance of the carbonyl group with respect to the g-hydrogen to be abstracted and their spatial orientation have to be favourable.34,48 Furthermore, arrangements that stabilise the intermediate radical or that weaken the g-hydrogen bond have a positive impact on the reactivity of the system. These arrangements are mainly influenced by the choice of substituents at C(g).49,50 Once the 1,4-biradical has been formed, there a several possibilities for further reaction (Scheme 3). Reverse hydrogen transfer regenerates the starting material, Yang cyclisation yields cyclobutanols (G) and fragmentation gives rise to the desired Norrish type II products (D–F). The choice of the substituents at C(a) and C(b) and their stereochemistry influence the ratio of the triplet 1,4-biradiacal to partition between Norrish type II fragmentation and Yang cyclisation.51–53 Ra

O

Ra

H

R O

+ O

b

R hν alkyl chain reaction

a

H γ

O

H

R γ

O

b

H

ester chain reaction

O hν O2

Rb

O +

hν

CO

+ O

H

Ra

H

Rb

O + OH

CO2

+ O

Scheme 4 Alkyl or ester chain fragmentation in aliphatic a-ketoesters by abstraction of different g-hydrogen atoms at either side of the reactive carbonyl group. 246 | Photochemistry, 2019, 46, 242–264

Overall, the structures tolerate substitution at various positions, especially at the alkyl chain of phenyl alkyl ketones or at the ester chain of a-ketoesters, thus allowing the generation of a broad variety of structurally different compounds by Norrish type II photofragmentation. Nevertheless, substituent effects impact on the ratio of the different products formed in the reaction and therefore have to be carefully chosen in order to favour the desired Norrish type II fragmentation over other side reactions. 2.3 Presence of water Humidity is ubiquitously present in our everyday life. Therefore, to be useful as a delivery system under ambient conditions, the Norrish type II reaction should efficiently proceed in a polar environment or (at least) tolerate the presence of water. The polarity of the solvent has an impact on the relative energies of n,p* and p,p* excited states, with p,p* triplets being stabilised in highly dielectric and hydrogen-bonding media,54,55 and on the solvation of the intermediate biradical.56 Polar solvents considerably enhance the quantum yields of photofragmentation, and the solvation of the intermediate biradical has a larger impact on the photoreaction than do solvent interactions with the excited state.56 The photoirradiation of phenyl alkyl ketones in water showed that the Norrish type II reaction (to form compounds E and F) and Yang cyclisation (to give two isomers of G) are the predominant pathways of photoreaction, with quantum yields close to unity.57 The reaction of alkyl or phenyl a-ketoesters in polar solvents or in water has been studied to a much lesser extent than that of phenyl alkyl ketones. Photoirradiation in alcohols resulted in the formation of 2-hydroxyester H by reaction of the solvent alcohol with Norrish type II reaction product D (Scheme 3, with X ¼ CO) and of dimer I by dimerisation and intermolecular hydrogen abstraction of biradical C from the solvent alcohol (Scheme 5).58–61 The formation of H is due to the particular structure of the a-ketoesters, for which compound D (X ¼ CO, Scheme 3) represents an unstable hydroxy ketene that further reacts by

O

H

R1 R2

OH

O R'

O

R1 R2

OH

R1

O R'

O

R'

O C

D ROH

R'

R'

OH

OH

O

O E

ROH R1

O

R2

+

OH

O

R2

O

2

R R1

OR R'

O H

I

Scheme 5 Formation of side products H and I in the Norrish type II photofragmentation of a-ketoesters according to Scheme 3 (with X ¼ CO and Y ¼ O) in alcoholic solution. Photochemistry, 2019, 46, 242–264 | 247

elimination of CO to form compound F (X ¼ H) in apolar solvents or to form compound H in polar solvents. An equivalent to H cannot be formed from the irradiation of phenyl alkyl ketones. Nevertheless, the formation of 2-hydroxyesters H implies the formation of one equivalent of E, which could still be a volatile carbonyl compound to be released. Compound I (together with other side products that are not shown) has also been formed in aprotic solution as a result of intermolecular hydrogen abstraction.32 2.4 Presence of oxygen Molecular oxygen is known to quench excited singlet or triplet states.62 Its presence under ambient everyday conditions might thus have an important impact on the outcome of the Norrish type II photoreaction. Indeed, oxygen has been reported to quench the triplet state of phenyl alkyl ketones,63,64 as well as to interact with the 1,4-biradical accompanied by the consumption of oxygen.64–67 Its interaction with the 1,4-biradical C resulted in about 25% quenching in the formation of hydroperoxides (J), e.g. via 1,6-biradical K, and in about 75% quenching in the generation of cyclobutanols (G) together with alkenes (E) and acetophenones (F) as the expected Norrish type II fragmentation products (Scheme 3).64 The yields of cyclisation and fragmentation products have even been reported to increase in the presence of oxygen,66,67 which would be an advantage for practical applications, which are necessarily carried out in a non-degassed environment. Oxygen trapping of biradical C has been suggested to afford cyclic intermediate L65 which, upon regeneration of oxygen, yields fragmentation products E and F. If no oxygen is eliminated from L, a carboxylic acid (M), an alkene (N) and a carbonyl compound (O) are obtained.68 The corresponding hydroperoxide J and the cyclic intermediate L have also been proposed for the reaction of a-ketoesters (X ¼ CO, Y ¼ O) in the presence of oxygen to account for the formation of benzoic acid derivatives (M), CO2 (N) and a carbonyl compound (O).33,69 Notably, in the case of a-ketoesters, fragmentation products E (with Y ¼ O) and O are identical, whereas in the case of phenyl alkyl ketones (Y ¼ CHR), two different structures are obtained for E and O. Environmental conditions such as ambient humidity or the presence of oxygen influence the Norrish type II reaction of phenyl alkyl ketones and a-ketoesters, but they do not inhibit the desired photofragmentation. The reaction should allow for an efficient light-induced generation of target compounds D–F and M–O, if the formation of side products G, I and J can be minimised (Schemes 3 and 5). In the following sections, I discuss this aspect in further detail in the example of practical applications.z

z

Note that most of the practical applications for using the Norrish type II reaction for the controlled release of volatile compounds were originally described in the patent literature. However, because most aspects that are relevant for the present discussion have also been reported in journal articles at a later date, the present report gives priority to the work published in the scientific literature.

248 | Photochemistry, 2019, 46, 242–264

3 Light-induced release of volatile compounds by the Norrish type II reaction 3.1 Release of acetophenones and alkenes from phenyl alkyl ketones The most straightforward approach to using Norrish type II photofragmentation for the light-induced release of volatile compounds is the generation of acetophenones and alkenes, which should be obtained as a 1 : 1 mixture from structures depicted in Scheme 2a. Several acetophenone derivatives, such as acetophenone itself, as well as 4-methylacetophenone or 4-methoxyacetophenone, are used as perfuming ingredients with pungent sweet and floral odours.70,71 Fragrance alkenes, such as b-pinene (dry-woody, resinous piney odour), limonene (sweet citrus smell) or d-damascone (fruity blackcurrant note), can be generated from photocages 1–4,72,73 and 2-phenylethyl (ethereal rosy and sweet odour) or decyl vinyl ether (citrusy-waxy, floral smell) and allyl 3-cyclohexylpropionate (sweet-fruity pineapple note) can be released from properfumes 5–7 (Fig. 1)y.68 The choice of the acetophenone and alkene to be released in the photoreaction determines the final structure of the precursor. Variable substitutions at the alkyl part of the ketone have shown that alkenes with both exo- (()-1) and endocyclic double bonds (2) can be generated. Irradiation of ()-1 in methanol resulted in an almost complete cleavage of the photocage to yield acetophenone and b-pinene with an exocyclic double bond.72 In the case of precursor 2, two chemically different g-hydrogen atoms can be abstracted to form endocyclic double bonds, giving rise either to limonene (double bond between C(1) and C(6)) or to

Fig. 1 Properfumes 1–7 studied for the controlled release of acetophenones and different alkenes (as indicated) from phenyl alkyl ketones.68,72,73 The wavy line indicates the C–C bond to be cleaved; the dotted line indicates the position of the alkene double bond to be formed.

y

The perception of odours can vary from one individual to another. The odour descriptors used here are those reported in the literature (ref. 70 and 71). Photochemistry, 2019, 46, 242–264 | 249

iso-limonene (double bond between C(1) and C(2)). Irradiation of 2a resulted in the exclusive formation of iso-limonene (26%); no limonene was obtained under these conditions.73 This observation has been rationalised by preferred hydrogen abstraction at C(2), which allows it to pass through an energetically favourable, chair-like, six-membered transition state. Limonene (15%) can be released from precursor 3a by photochemically generating the iso-propenyl double bond of the molecule, rather than the endocyclic double bond. In addition to the desired fragrances, Yang cyclisation products (ca. 45%) were obtained as major reaction products from the irradiation of 2a and 3a.73 Replacing the parahydrogen atom of the phenyl group in 2a and 3a by a methoxy group slowed the photoreaction (as in 2b) or even fully prevented the formation of limonene (in the case of 3b).73 The influence of phenyl group substituents on the efficiency of fragrance release has also been studied in the example of precursors ()-4a–e, which are expected to form propiophenones together with an enone (d-damascone) as a mixture of cis–trans isomers.72 Again, g-hydrogen atom abstraction is possible from two different positions, which results in two structurally different cyclobutanols (()-8 and ()-9, Scheme 6) upon cyclisation of the intermediate biradical. Obtaining cyclobutanols is not necessarily a problem because they are not very volatile and should not contribute to the odour of the system. Irradiation of an undegassed solution of ()-4a in methanol afforded the desired fragrance and about 30% of the two cyclobutanols, the major component being the one resulting from hydrogen abstraction from the methyl group (8). Formation of the fragrance compound with a terminal double bond was not observed. Substituting the para-hydrogen atom of the phenyl group with a methyl group (()-4b) gave similar results. However, one methoxy group in the para-position (()-4c) or two methoxy groups in the meta- and para-positions (()-4d) suppressed the formation of cyclobutanol, but increased the time required for full conversion, thus indicating an increasing p,p* character of the excited triplet states in ()-4c and ()-4d compared with that in ()-4a and ()-4b. Finally, linking the two methoxy substituents together as a 3,4-dioxolane group (()-4e) completely stopped the Norrish type II photoreaction.72 These findings suggest that optimum photocages for the controlled light-induced release of fragrances via the Norrish type II process have low-lying triplet states directing the g-hydrogen atom transfer to the desired position, combined with a slow transfer, because in the presence of oxygen, most triplets are quenched before the transfer takes place.72 Xenon arc lamps are commonly used in reproducible simulation of natural daylight irradiance under laboratory conditions, because their emission spectrum between 200 and 1000 nm correlates reasonably well to that of outdoor sunlight.74 Irradiation of properfumes 5–7 in different solvents with a xenon lamp or outdoor sunlight of comparable intensity released the target alkenes in equivalent yields.68 Detailed analysis of the product distribution obtained after irradiation of properfumes 5a–c and 6a–c with a xenon lamp in undegassed 250 | Photochemistry, 2019, 46, 242–264

HO

O

O

R''

HO

R'

O

γ

O R'

(±)-8 Photochemistry, 2019, 46, 242–264 | 251

O

R''

hν

γ

O

O (±)-4a

+ not observed

(±)-9

hν O + δ-damascone

Scheme 6 Norrish type II fragmentation and Yang cyclisation products formed upon photoirradiation of photocage ()-4a in undegassed methanol.72

acetonitrile afforded acetophenones (30–50%) and vinyl ethers (30–50%) as the major fragmentation products, together with alkyl formates (5–10%) and alcohols (5–10%) as additional volatile side products (Scheme 7).68 The formation of all four fragmentation products (with comparable product distribution ratios) has been observed independently of the substitution at the phenyl ring, and after irradiation in toluene, acetonitrile or iso-propanol. While the formation of alkyl formates can be rationalised by the rearrangement of cyclic intermediate L, as outlined in Scheme 3, the occurrence of the alcohols could not be explained from the general mechanism, but might arise from hydrolysis of the formates. Both alkyl formates and alcohols are used in perfumery,70 and their formation as side products in the Norrish type II reaction of 5 and 6 is therefore not a general problem for practical applications. Again, substituting the para-hydrogen atom of the phenyl moiety of the precursors with 4-methyl or 4-tert-butyl groups (not shown) resulted in similar product distributions, while the presence of the 4-methoxy group in 5c and 6c slowed the desired photoreaction, giving rise to lower amounts of fragmentation products.68 Repetitive preparative gas chromatography of an irradiated solution of precursor 6a led to the identification of cyclobutanol ()-10 and ester 11 as the most important non-fragmented reaction products (Scheme 7).68 Although this has not rigorously been proven, the structural similarity of 11 to hydroperoxide J or intermediates K or L suggests that it might arise from either one of these species. To my surprise, no reaction products arising from intermediate L have been reported in the studies with photocages 1–4. This might be because the authors have not specifically been looking for them or because the corresponding biradical C is sterically hindered and less easily intercepted by molecular oxygen to form species L. In the latter case, the consecutive reaction products would be formed to a much lesser extent or even not at all. Headspace analysis is a convenient method to quantitatively assess the evaporation of volatile compounds from various surfaces with a minimum effort required in sample preparation.75 This technique has been used to investigate the impact of environmental light intensity on the photoreaction in the example of properfume 7, which was exposed to variable outdoor sunlight for a day in a film of an all-purpose cleaner formulation (Fig. 2).12,13 On an unclouded day, the light intensity increases in the morning to reach a maximum around noon and then decreases again during the afternoon. The presence or absence of clouds further changes the apparent light intensity to which a sample is exposed,19 and therefore should also influence the rate of the photoreaction. The results of the headspace measurements depicted in Fig. 2, showed that short-term clouding, which was observed during the sampling of the second data point, did not significantly influence the amount of fragrance release. However, longer periods of clouding, such as occurred in the early afternoon during the sampling of data points 5 and 6, resulted in a decrease in fragrance release, with the recorded headspace concentrations correlating to the drop in light intensity.12,13 252 | Photochemistry, 2019, 46, 242–264

Fragmentation products O

O O

hν R xenon lamp

R'

O

+

R +

O

O

R +

HO

R

R' 5a-c: R = C6H5 6a-c: R = C8H17

acetophenone

vinyl ether

alkyl formate

alcohol

Photochemistry, 2019, 46, 242–264 | 253

Non-fragmentation products R hν xenon lamp

O O

6a: R = C8H17

R

HO

O

O

(±)-10: R = C8H17

O

O

R

+

11: R = C8H17

Scheme 7 Products obtained after photolysis of properfumes 5 and 6 in undegassed acetonitrile (R 0 as defined in Fig. 1).68

10

600 500

8 6

300

light intensity

4 200

amount of acetophenone

2

100 0 0.0

I x 104 / lux

c x 100 / ng L-1

400

amount of allyl 3-cyclohexylpropanoate

1.0

2.0

3.0

4.0

5.0

6.0

0 7.0

t/h Fig. 2 Dynamic headspace concentrations of acetophenone and allyl 3-cyclohexylpropionate released from properfume 7 in a film of an all-purpose cleaner after exposure to clouded and unclouded natural outdoor sunlight. Reprinted from ref. 12 with permission from the Royal Society of Chemistry.

3.2 Release of acetophenones and aldehydes or ketones from phenyl alkyl ketones Aldehydes and ketones can be released from phenyl alkyl ketones in a Norrish type II photoreaction if the double bond generated in the process is not formed between two carbon atoms (as in the case for the structures depicted in Fig. 1), but between a carbon atom and an oxygen atom. Examples for general structures that can form aldehydes and/or ketones upon photolysis are shown in Scheme 2b and c. Again, the carbonyl compounds are obtained together with acetophenones, and substitution at both sides of the photolabile carbonyl group influences the outcome of the reaction. Aromatic aldols ()-12–()-14 obtained by condensation of propiophenone with a fragrance aldehyde or ketone allowed the light-induced generation of melonal (oily-green, vegetable-like smell), octanal (powerful harsh-fatty odour) or a-ionone (sweet-floral violet note) (Fig. 3).72 Photoirradiation with a solar simulator in solution generated the desired carbonyl compounds as a result of the Norrish type II fragmentation, together with cyclobutanols from Yang cyclisation.72 The number of abstractable g-hydrogen atoms in photocages ()-12–()-14 increased from one (CH-group in 12) to three (CH3-group in 14), which suggests differences in reactivity for the three compounds. A strong solvent dependence for the fragmentation versus cyclisation ratio was found for the photolysis of ()-12, which formed a higher amount of cyclobutanol in aprotic solution than did analogues ()-13 and ()-14, the latter of which mainly generated the desired fragmentation products.72 Phenacyl ethers, such as ()-15 and ()-16 (Fig. 3), have been prepared from a primary or secondary alcohol (derived from the fragrance aldehyde or ketone to be released) by reaction with bromoacetonitrile and consecutive addition of a phenylmagnesium halide to give ()-15, or by transacetalisation with a dialkoxyacetophenone to afford ()-16.14 If both 254 | Photochemistry, 2019, 46, 242–264

Fig. 3 Aldol photocages ()-12–()-1472 and phenacyl ethers ()-15 and ()-1614 studied for the photolytical generation of acetophenones and different carbonyl compounds (as indicated) from phenyl alkyl ketones. The wavy line indicates the C–C bond to be cleaved; the dotted line indicates the position of the carbonyl double bond to be formed.

the carbonyl compound and the acetophenone derivative are fragrances, the perceived odour of the delivery system will depend on the ratio in which the two components are released. While photolysis of properfume ()-15 is expected to release the fragrance aldehyde Lilials (with a mildflowery lily of the valley odour) and the acetophenone derivative in a ratio of 1 : 1, precursor ()-16 should generate the two compounds in a ratio of 2 : 1. Depending on the preferred final composition of the two compounds, either ()-15 or ()-16 might thus be chosen as the properfume for a given application. Photolysis of a solution of phenacyl ether ()-15 in acetonitrile showed that Norrish type II fragmentation and Yang cyclisation took place to a similar extent,14 while irradiation of ()-16 resulted in the release of only low amounts of the desired fragrances (ca. 15% of Lilials and ca. 5% of acetophenone). Furthermore, the formation of precursor ()-15 as an expected reaction intermediate was not observed. These results indicated the presence of other side reactions, which have not been further investigated. Application studies showed that despite the low amounts of Lilials released from properfume ()-16, the delivery system still provided a sufficient long-lasting fragrance effect when compared with the free fragrance reference.14 3.3 Release of acetophenones and esters or lactones from phenyl alkyl ketones Replacing one of the alkyl groups of phenacyl ethers (Scheme 2c) with an alkoxy group gives access to phenacyl acetals capable of releasing carboxylic esters (Scheme 2d). Furthermore, if both substituents R1 and R2 at the acetal moiety are linked together with an alkyl chain to form a cyclic structure, lactones can be generated.14 Phenacyl acetals ()-17–()-20 (Fig. 4) have been prepared to release Tonalides (with a musky odour) or methyl naphthyl ketone (having an orange blossom smell) as fragrance acetophenones, together with hexyl acetate (with a sweet and fruity odour) as a perfume ester (17, 18) and g-undecalactone (having a sweet, fruity peach-like smell) as a perfume Photochemistry, 2019, 46, 242–264 | 255

Fig. 4 Phenacyl acetals ()-17–()-20 prepared for the controlled release of acetophenones and different esters or lactones (as indicated).76 The wavy line indicates the C–C bond to be cleaved; the dotted line indicates the position of the ester double bond to be formed.

lactone (19, 20).76 Photoirradiation of the properfumes in ethanol released the different fragrances as expected. Depending on the structure of the phenyl and alkyl substituents, half-life times of about 15 min up to 1 h were recorded for the photolysis of ()-17 and ()-18, and a few minutes to about half an hour for ()-19 and ()-20, respectively.76 As outlined in the mechanistic discussion earlier, both parts of the molecule have an influence on the rates of light-induced fragrance release, with an increasing chromophore at the phenyl group decreasing the rate of photolysis and with lactones being more efficiently released than esters. Spraying ethanol solutions of the properfumes onto cotton sheets and exposing them to the light of a tanning lamp released perceivable amounts of the fragrances, as shown by an olfactive panel evaluation, thus demonstrating the applicability of the systems as fragrance delivery systems.76 3.4 Release of aldehydes or ketones from a-ketoesters Upon photolysis in the UV-A region, 2-oxoacetates (a-ketoesters, Scheme 2e) release aldehydes and ketones by photofragmentation of the ester side chain. a-Ketoesters are readily prepared from primary or secondary alcohols derived from the corresponding fragrance aldehyde or ketone to be released. In contrast to phenyl alkyl ketones, which require the presence of an aromatic ring next to the carbonyl group to efficiently respond to wavelengths in the UV-A region, a-ketoesters tolerate a much broader structural variability at the photolabile carbonyl group. Fig. 5 shows some typical examples of a-ketoesters that have been investigated for the release of volatile aldehydes and ketones by Norrish type II photooxidation.34,77–80 Both aryl (21–()-23) and alkyl a-ketoesters (()-24–()-26) have been prepared, releasing different fragrances such as 2-phenylacetaldehyde (with a pungent-green floral and sweet odour) (21), (Z)-3-hexenal (a deep-green leafy note) (22) and ()-3,7-dimethyl-6octenal (citronellal, a fresh, green-citrusy fragrance) (()-23–()-26). Photoirradiation of citronellal-releasing profragrances ()-23–()-26 in solution revealed additional aspects to be considered for the optimisation of the delivery system for practical applications. First, all compounds 256 | Photochemistry, 2019, 46, 242–264

Fig. 5 Aryl (21–()-23) and alkyl (()-24–()-26) a-ketoesters investigated for the lightinduced release of different aldehydes and ketones (as indicated).34,77,79 The wavy line indicates the C–O bond to be formally cleaved; the dotted line indicates the position of the carbonyl double bond to be formed.

generated the desired fragrance aldehyde by Norrish type II fragmentation of the ester chain. However, a series of interesting additional side products have been identified that result from specific particularities of their individual structural features (Scheme 8). Photoirradiation of aryl a-ketoester ()-23 in degassed or undegassed solution, for example, afforded oxetane ()-27 by the intramolecular `–Bu ¨chi reaction81 of the citronellyl double bond with the carbonyl Paterno group of the ketoester.34,78,79 Oxetane formation has generally been observed for aryl a-ketoesters with isobutylene side chains of different lengths; in the case of 22, bearing no isobutylene group in its ester side chain, cyclol ()-28 was isolated instead.79 The formation of ()-27 and ()-28 arises from charge transfer between the ketoester carbonyl group in its triplet state and the alkene function in the side chain. The resulting exciplex can form different biradicals, which then react further to the oxetane or the cyclol.79 Of two possible regioisomers, only ()-27 was formed, thus indicating that oxetane formation does not exclusively depend on the most stable radical that can be formed, but also on sterical constraints, as confirmed by density-functional calculation of the energies of the different possible biradicals in their singlet and triplet states.34,79 Oxetane formation was not observed in the photoreaction of alkyl a-ketoesters ()-24–()-26 under similar irradiation conditions.34 Epoxidation of the double bond in the citronellyl moiety was the most important side reaction for these compounds in undegassed solution. Epoxidation of olefins in the presence of a-ketoacids or esters has previously been reported, and the epoxide formation has been rationalised as a photochemical a-cleavage generating an acylperoxy radical, which then transfers an oxygen atom to the alkene.82 The identification of epoxidised precursors ()-29–()-31 indicated that the citronellyl double bond reacts (at least in part) before the desired Norrish type II reaction (Scheme 8). Furthermore, formation of small amounts of 5-(3,3-dimethyloxiran-2-yl)-3-methylpentanal (epoxy-citronellal) has been observed. This might arise from the Norrish type II reaction of ()-29–()-31 or by direct epoxidation of citronellal under the given reaction conditions. Traces of the epoxidised precursor and small amounts of epoxy-citronellal have also been identified as side products in the irradiation of aryl Photochemistry, 2019, 46, 242–264 | 257

258 | Photochemistry, 2019, 46, 242–264

Aryl α-ketoesters HO Ph

PaternòBüchi

O Ph O

O

O (±)-28 (from 22)

O (±)-27

Alkyl α-ketoesters

epoxidation

hν ester chain reaction

O

epoxy-citronellal

alkyl chain reaction

hν epoxidation

hν ester chain reaction

O

O

O O

O

O

O O

(±)-29

O

citronellal

ester chain reaction

hν (±)-26

(±)-31

ester chain reaction

hν

epoxidation

hν ester chain reaction

alkyl chain reaction

(±)-25

(±)-30

ester chain reaction

hν (±)-24

(±)-29

hν O

hν (±)-23

ester chain reaction O

O

O O

(±)-30

(±)-31

Scheme 8 Products identified from the photoirradiation of citronellal-releasing a-ketoester profragrances ()-23–()-26 in solution.34,79

a-ketoester ()-23.34 Nevertheless, the desired Norrish type II reaction to generate citronellal is the main reaction pathway, yielding 50–70% of the desired aldehyde, around 1% of the epoxidised precursor and 8–10% of epoxy-citronellal.34 The final product distribution is concentration dependent, with increasing profragrance concentrations affording higher amounts of epoxy-citronellal. As outlined earlier (Scheme 4), alkyl a-ketoesters with abstractable g-hydrogen atoms in the alkyl side chain, such as ()-25, also undergo alkyl chain fragmentation. In this case, a-ketoester ()-24 with a shorter alkyl chain is obtained, which can then further react by ester chain fragmentation to form the desired Norrish type II products (Scheme 8).34 The desired fragmentation of the ester chain can be favoured by making g-hydrogen abstraction from the alkyl part of the a-ketoesters sterically impossible, e.g. by choosing a cyclopentyl or cyclohexyl residue, as in profragrance ()-26. The desired long-lastingness of the fragrance perception of profragrances, such as ()-26, in different applications of functional perfumery has been demonstrated by dynamic headspace analysis.80 The amount of the unmodified reference fragrance decreases continuously over time, while that released from the profragrance remains more or less constant during the measurement. During storage in aqueous product formulations over prolonged periods, a-ketoesters partially hydrolyse, which limits their applicability in some consumer products. To stabilise the precursors against premature hydrolysis during product storage and to maintain the performance of the light-induced delivery systems in application, we have investigated polymer-based delivery systems of a-ketoesters. To achieve this goal, we have addressed two complementary approaches, namely the (co-)polymerisation of a suitable a-ketoester monomer into latex nanoparticles and the encapsulation of the profragrances into core-shell microcapsules.83 The two concepts are outlined in Scheme 9 in the example of profragrance 21. Grignard reaction of 4-bromostyrene with dialkyloxalate affords polymerisable 2-oxo-2-(4-vinylphenyl)acetates, such as 32. Radical copolymerisation with methyl methacrylate in the presence of small amounts of a cross-linker yielded dispersions of latex particles with an average diameter varying between 200 and 1200 nm.83 Alternatively, 21 has been encapsulated from an oil-in-water emulsion by interfacial polymerisation into aminoplast83 or polyurea84 microcapsules, with capsule sizes typically ranging between 10 and 25 mm. On the one hand, the rather hydrophobic environment within the polymeric systems has been shown to protect the a-ketoester moiety against hydrolysis. On the other hand, the delivery systems still efficiently released the desired fragrance aldehyde when exposed to light.83,84 The polymeric environment thus does not prevent the Norrish type II photoreaction, and the targeted fragrance has been released even at low light intensities. Furthermore, the latex particles and microcapsules performed even better than just the profragrance.83 However, this might be due to specific

Photochemistry, 2019, 46, 242–264 | 259

260 | Photochemistry, 2019, 46, 242–264 Scheme 9 Stabilisation of a-ketoester profragrances against hydrolysis in application by (co-) polymerisation into latex nanoparticles and encapsulation into core– shell microcapsules.83,84

conditions of the application, such as a different amount of deposition of the various delivery systems on the target surface. Studies with a-ketoester-containing polyurea microcapsules revealed that the photoreaction taking place under UV-A light is sufficiently fast that the gas (CO and/or CO2) formed as a side product in Norrish type II fragmentation (see Scheme 4) generated overpressure inside the capsules, which extended or cleaved the capsule wall and resulted in a burst release of the capsule content (Scheme 9).84 This observation considerably increases the potential of the present delivery system, because it not only allows the light-induced controlled release of aldehydes or ketones from the profragrance, but it also allows the release of any active compound that has been co-encapsulated with the ketoester.

4 Conclusions and learnings We have seen that the Norrish type II photofragmentation is a robust process that readily occurs under everyday conditions in our environment. The reaction proceeds in the UV-A region of the sunlight spectrum. Its speed directly depends on the apparent intensity of the UV-A light and is influenced by fluctuations, such as seasonal changes, variable daylight intensities and the presence or absence of clouds. The reaction performs in an aqueous environment and in the presence of oxygen, both of which have an impact on the mechanism of the photodegradations, but do not prevent the potential practical use of the system. Although light-induced delivery systems based on the Norrish type II reaction have mainly been described for the controlled release of fragrances, they can theoretically be used to form any kind of bioactive material, such as pheromones, plant growth hormones, agrochemicals and many others, as long as these materials are generated on a surface from a suitable precursor that is exposed to ambient daylight. Both phenyl alkyl ketones and a-ketoesters work well, and their structures can be varied to a large extent to enable the release of different types of compounds, such as acetophenones and aldehyde or carboxylic acid derivatives on the one hand, and alkenes, aldehydes, ketones, esters or lactones on the other hand. Structural variations at either side of the molecule have an important impact on the desired photoreaction, in particular if additional side products are formed. Understanding the mechanism of the photoreaction under environmental conditions is therefore an important aspect for the design of efficient delivery systems. The formation of side products is not necessarily a problem, e.g. if they are fragrance molecules themselves or if they are non-volatile and thus have no inherent smell. In some cases, the formation of particular side products might have to be avoided, which then requires modification of the precursor structure. Considerable effort has been made to optimise photocages for an efficient controlled release and to understand the structural and environmental impacts on the Norrish type II process by identifying and quantifying side products in order to favour or disfavour their formation. Photochemistry, 2019, 46, 242–264 | 261

Nevertheless, the successful development of delivery systems for practical applications with a commercial purpose implies consideration of specific additional restrictions. These restrictions, which might still cause the failure of the delivery system in practice, have not been discussed in much detail here. In particular, the rates at which the compounds need to be released and their absolute concentrations vary from one application to another. This implies that a system that performs in one application does not automatically work in another, and that individual adaptations are usually required. Furthermore, biodegradability, bioaccumulation, toxicological and economic considerations (which have in part been addressed in a previous report)15 are decisive parameters for the successful development of delivery systems for practical use. Despite the knowledge acquired so far, it is not possible to easily predict whether a given structure will work in application or not. As is usually the case in science, it will be the experiment that determines the success or failure of a given technology on its way to the marketplace.

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Green Chemistry: Environmentally Benign Reactions, ed. V. K. Ahluwalia, CRC Press, Boca Raton, 2012. Green Chemistry for Environmental Remediation, ed. R. Sanghi and V. Singh, Scrivener Publishing, Salem, 2012. Green Chemistry: Fundamentals and Applications, ed. S. C. Ameta and R. Ameta, Apple Academic Press, Oakville, 2014. A. Albini and S. Protti, Paradigms in Green Chemistry and Technology, Springer International Publishing, Cham, 2016. N. Hoffmann, Photochem. Photobiol. Sci., 2012, 11, 1613–1641. ¨r, Coord. Chem. Rev., 2016, 325, 102–115. G. Kno ¨ller, Chem. Rev., 2016, 116, 9664–9682. M. Oelgemo Dynamic Studies in Biology – Phototriggers, Photoswitches and Caged Biomolecules, ed. M. Goeldner and R. Givens, Wiley-VCH, Weinheim, 2005. H. Yu, J. Li, D. Wu, Z. Qiu and Y. Zhang, Chem. Soc. Rev., 2010, 39, 464–473. C. Brieke, F. Rohrbach, A. Gottschalk, G. Mayer and A. Heckel, Angew. Chem., Int. Ed., 2012, 51, 8446–8476. ´n, Acc. Chem. Res., 2015, 48, 3064–3072. T. ˇ Solomek, J. Wirz and P. Kla A. Herrmann, Photochem. Photobiol. Sci., 2012, 11, 446–459. A. Herrmann, Spectrum, 2004, 17(2), 10–13 and 19. S. Derrer, F. Flachsmann, C. Plessis and M. Stang, Chimia, 2007, 61, 665–669. A. Herrmann, Angew. Chem., Int. Ed., 2007, 46, 5836–5863. A. Herrmann, Chimia, 2017, 71, 414–419. J. E. Frederick, H. E. Snell and E. K. Haywood, Photochem. Photobiol., 1989, 50, 443–450. G. Rottman, J. Atmos. Sol.-Terr. Phys., 1999, 61, 37–44. F. Kasten and G. Czeplak, Sol. Energy, 1980, 24, 177–189. R. G. W. Norrish and M. E. S. Appleyard, J. Chem. Soc., 1934, 874–880. C. H. Bamford and R. G. W. Norrish, J. Chem. Soc., 1935, 1504–1511. P. J. Wagner, Acc. Chem. Res., 1971, 4, 168–177. P. J. Wagner, Top. Curr. Chem., 1976, 66, 1–52. P. J. Wagner and B.-S. Park, in Organic Photochemistry, ed. A. Padwa, Marcel Dekker Inc., New York, 1991, vol. 11, pp. 227–366.

262 | Photochemistry, 2019, 46, 242–264

25

26

27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57

´n, in CRC Handbook of Organic Photochemistry and P. J. Wagner and P. Kla Photobiology, ed. W. Horspool and F. Lenci, CRC Press, Boca Raton, 2nd edn, 2004, pp. 52/1–52/31. T. Hasegawa, in CRC Handbook of Organic Photochemistry and Photobiology, ed. W. Horspool and F. Lenci, CRC Press, Boca Raton, 2nd edn, 2004, pp. 55/1–55/14. J. C. Scaiano, E. A. Lissi and M. V. Encina, Rev. Chem. Intermed., 1978, 2, 139–196. P. A. Leermakers, P. C. Warren and G. F. Vesley, J. Am. Chem. Soc., 1964, 86, 1768–1771. R. S. Davidson and D. Goodwin, J. Chem. Soc., Perkin Trans. II, 1982, 993–997. M. V. Encinas, E. A. Lissi, A. Zanocco, L. C. Stewart and J. C. Scaiano, Can. J. Chem., 1984, 62, 386–391. A. L. Zanocco, E. A. Soto, E. A. Lissi and J. C. Scaiano, J. Photochem. Photobiol., A, 1990, 53, 77–85. S. Hu and D. C. Neckers, J. Org. Chem., 1996, 61, 6407–6415. S. Hu and D. C. Neckers, J. Photochem. Photobiol., A, 1998, 118, 75–80. S. Rochat, C. Minardi, J.-Y. de Saint Laumer and A. Herrmann, Helv. Chim. Acta, 2000, 83, 1645–1671. P. J. Wagner, Acc. Chem. Res., 1989, 22, 83–91. N. C. Yang and D.-D. H. Yang, J. Am. Chem. Soc., 1958, 80, 2913–2914. P. J. Wagner, P. A. Kelso and R. G. Zepp, J. Am. Chem. Soc., 1972, 94, 7480– 7488. N. C. Yang, D. S. McClure, S. L. Murov, J. J. Houser and R. Dusenbery, J. Am. Chem. Soc., 1967, 89, 5466–5468. E. J. Baum, J. K. S. Wan and J. N. Pitts Jr., J. Am. Chem. Soc., 1966, 88, 2652– 2659. P. J. Wagner, A. E. Kemppainen and H. N. Schott, J. Am. Chem. Soc., 1973, 95, 5604–5614. N. C. Yang and R. L. Dusenbery, J. Am. Chem. Soc., 1968, 90, 5899–5900. J. N. Pitts Jr., D. R. Burley, J. C. Mani and A. D. Broadbent, J. Am. Chem. Soc., 1968, 90, 5902–5903. P. J. Wagner and E. J. Siebert, J. Am. Chem. Soc., 1981, 103, 7329–7335. P. J. Wagner, P. A. Kelso, A. E. Kemppainen, J. M. McGrath, H. N. Schott and R. G. Zepp, J. Am. Chem. Soc., 1972, 94, 7506–7512. T. R. Evans and P. A. Leermakers, J. Am. Chem. Soc., 1968, 90, 1840–1842. R. S. Davidson, D. Goodwin and P. Fornier de Violet, Tetrahedron Lett., 1981, 22, 2485–2486. P. J. Wagner, Acc. Chem. Res., 1983, 16, 461–467. H. Ihmels and J. R. Scheffer, Tetrahedron, 1999, 55, 885–907. P. J. Wagner and A. E. Kemppainen, J. Am. Chem. Soc., 1972, 94, 7495–7499. J. N. Pitts Jr., D. R. Burley, J. C. Mani and A. D. Broadbent, J. Am. Chem. Soc., 1968, 90, 5900–5902. M. Leibovitch, G. Olovsson, J. R. Scheffer and J. Trotter, J. Am. Chem. Soc., 1998, 120, 12755–12769. J. M. Moorthy, A. L. Koner, S. Samanta, N. Singhal, W. M. Nau and R. G. Weiss, Chem. – Eur. J., 2006, 12, 8744–8749. A. G. Griesbeck and H. Heckroth, J. Am. Chem. Soc., 2002, 124, 396–403. A. A. Lamola, J. Chem. Phys., 1967, 47, 4810–4816. J. A. Barltrop and J. D. Coyle, J. Am. Chem. Soc., 1968, 90, 6584–6588. P. J. Wagner, J. Am. Chem. Soc., 1967, 89, 5898–5901. R. G. Zepp, M. M. Gumz, W. L. Miller and H. Gao, J. Phys. Chem. A, 1998, 102, 5716–5723. Photochemistry, 2019, 46, 242–264 | 263

58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75

76

77 78 79 80 81 82 83 84

E. S Huyser and D. C. Neckers, J. Org. Chem., 1964, 29, 276–278. N. C. Yang and A. Morduchowitz, J. Org. Chem., 1964, 29, 1654–1655. Y. Chiang, A. J. Kresge, P. Pruszynski, N. P. Schepp and J. Wirz, Angew. Chem., Int. Ed., 1990, 29, 792–794. Y. Chiang, A. J. Kresge, V. V. Popik and N. P. Schepp, J. Am. Chem. Soc., 1997, 119, 10203–10212. F. Wilkinson, Pure Appl. Chem., 1997, 69, 851–856. H. Lutz and L. Lindqvist, Chem. Commun., 1971, 493–494. R. D. Small Jr. and J. C. Scaiano, J. Am. Chem. Soc., 1978, 100, 4512–4519. M. Yoshioka, K. Funayama and T. Hasegawa, J. Chem. Soc., Perkin Trans. I, 1989, 1411–1414. J. Grotewold, C. M. Previtali, D. Soria and J. C. Scaiano, J. Chem. Soc., Chem. Commun., 1973, 207. R. D. Small Jr. and J. C. Scaiano, Chem. Phys. Lett., 1977, 48, 354–357. B. Levrand and A. Herrmann, Photochem. Photobiol. Sci., 2002, 1, 907–919. M. C. Pirrung and R. J. Tepper, J. Org. Chem., 1995, 60, 2461–2465. S. Arctander, Perfume and Flavor Chemicals, published by the author, Montclair 1969. H. Surburg and J. Panten, Common Fragrance and Flavor Materials: Preparation, Properties and Uses, Wiley-VCH, Weinheim, 5th edn, 2006. ¨rner, U. Huchel, C. Kropf, U. Sundermeier A. G. Griesbeck, O. Hinze, H. Go and T. Gerke, Photochem. Photobiol. Sci., 2012, 11, 587–592. A. G. Griesbeck, B. Porschen, C. Kropf, A. Landes, O. Hinze, U. Huchel and T. Gerke, Synthesis, 2017, 49, 539–553. R. M. Sayre, C. Cole, W. Billhimer, J. Stanfield and R. D. Ley, Photodermatol. Photoimmunol. Photomed., 1990, 7, 159–165. L. S. Ettre, in Headspace Analysis of Foods and Flavors, Theory and Practice, ed. R. L. Rouseff and K. R. Cadwallader, Kluwer Academic/Plenum Publishers, New York, 2001, pp. 9–32. M. Gautschi, C. Plessis and S. Derrer (to Givaudan SA), Eur. Pat. 1 146 033, 2001; M. Gautschi, C. Plessis and S. Derrer (to Givaudan SA), Eur. Pat. 1 167 362, 2002. B. Levrand and A. Herrmann, Chimia, 2007, 61, 661–664. S. Hu and D. C. Neckers, J. Org. Chem., 1997, 62, 564–567. S. Hu and D. C. Neckers, J. Org. Chem., 1997, 62, 6820–6826. A. Herrmann, C. Debonneville, V. Laubscher and L. Aymard, Flavour Fragrance J., 2000, 15, 415–420. M. D’Auria and R. Racioppi, Molecules (Basel), 2013, 18, 11384–11428. Y. Sawaki and Y. Ogata, J. Am. Chem. Soc., 1981, 103, 6455–6460. M. Charlon, A. Trachsel, N. Paret, L. Frascotti, D. L. Berthier and A. Herrmann, Polym. Chem., 2015, 6, 3224–3235. N. Paret, A. Trachsel, D. L. Berthier and A. Herrmann, Angew. Chem., Int. Ed., 2015, 54, 2275–2279.

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Recent advances in the design of light-activated tissue repair Christopher D. McTiernan,a Justina Pupkaite,a Irene E. Kochevar,b Erik J. Suuronena and Emilio I. Alarcon*a,c DOI: 10.1039/9781788013598-00265

Fundamental concepts, key mechanisms, and future challenges in light-activated tissue repair techniques including photo-tissue bonding, laser tissue welding, and in situ photopolymerization are reviewed in this chapter. We aim to present a fresh perspective on the fundamental concepts of the photochemistry involved that will allow further advancement in the development ofsafe technologies and efficient clinical translation.

1

Overview of light-activated tissue bonding

Light-initiated in vivo tissue bonding has the potential to address needs in many medical treatments. This chapter will discuss three distinct approaches to the use of photocrosslinking in medical applications: Laser Tissue Welding (LTW),1 Photochemical Tissue Bonding (PTB),2 and in situ photo-polymerization (PHP). While all of these techniques involve the use of light to generate cross-links in vivo, LTW and PTB are considered to be tissue adhesive technologies, whereas the more general photopolymerization terminology can be used to describe light-mediated methods for the generation of matrices and scaffolds which can both support and promote endogenous tissue regeneration (see Fig. 1). LTW involves the use of high energy lasers, and in some cases dye molecules, to aid in laser light absorption to raise local temperatures and denature extracellular matrix (ECM) proteins to create a weld. This differs from PTB, in which the end result is the creation of covalent crosslinks between the proteins at or near the tissue surface. Typically, visible light absorbing molecules have been utilized for this technique, with Rose Bengal,3–6 and Riboflavin5,7,8 being the more popular choices. While the precise mechanism by which PTB forms these crosslinks is still up for debate, it is commonly accepted that these linkages are formed through reactions with singlet oxygen or other reactive oxygen species that are generated upon the sensitization of the excited chromophore.9 One of the main advantages PTB has over LTW is that the heat damage caused to surrounding tissues is alleviated by replacing the photo-thermal reaction with photochemical ones. a

Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7, Canada. E-mail: [email protected] b Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, 40 Blossom Street, Boston, Massachusetts 02114, USA c Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Canada Photochemistry, 2019, 46, 265–280 | 265  c

The Royal Society of Chemistry 2019

Fig. 1 Schematic representation for the three-main light-activated processes used for in situ tissue repair: laser tissue welding (LTW), photobonding tissue (PTB), and photopolymerization (PHP). The main operative mechanisms for each strategy are also shown.

While PHP is not an adhesive technique it has found an important role in tissue repair and regeneration through its ability to produce polymeric biomimetic matrices. Owing to its unique spatial and temporal control plus the ability to adopt complex shapes, its minimally invasive in situ implantation, ease of application, ability to entrap a variety of molecules, drugs, or cells, and finally the ability to store the various components of the mixture under ideal conditions until they are ready to be mixed and applied; PHP is a powerful tool in biomaterial design and implementation.

2 Sutureless tissue bonding: from laser tissue welding to tissue photobonding The concept of using light as a replacement for stitches was first proposed in the late 1970s, when Jain and Gorisch reported employing a laser to close incisions made in blood vessels of rats.10 The advantages of this procedure include the quick creation of a water tight seal, and the ability to close very small incisions easily. Additionally, this procedure has an absence of foreign materials, such as sutures or staples, which is important in reducing inflammation and potential scarring. However, this type of laser tissue welding is a thermal process, wherein light absorption by tissue components results in heating. In this process, the extracellular matrix (ECM) components undergo thermal changes, followed by cooling and interlinking of the altered collagen fibers, which leads to bonding of the molecules on the opposing edges of the wound or incision.11,12 An improvement to the laser tissue welding procedure was the introduction of a soldering agent, which may be a protein,13 dye,14 or a dyeprotein solution.15 Akin to the soldering of metals; the dye-protein solder is applied to the wound and laser light is used to locally heat and seal the solder to the edges of the wound. This method provides a few advantages, 266 | Photochemistry, 2019, 46, 265–280

compared to classical laser welding. Firstly, it lowers the risk of thermal tissue damage as the dye molecules preferentially absorb light, resulting in local heating of the solder solution. Secondly, the superior absorption property of the solder allows lower laser irradiation dose, thus reducing the time of exposure and/or laser power required. Thirdly, using a dye solution with known absorption parameters and thermal properties makes it easier to estimate laser dose requirements for reproducible results. In addition, the protein creates a solder that can fill the gap between and around the edges of the wound and provide additional bonds, thus increasing the strength of the bonded tissue. The downside of the laser soldering method is the requirement to introduce a foreign material, which may create an unexpected reaction or toxicity, although published reports indicate that the dye and protein solutions commonly used in this procedure are safe. A number of dye-protein solders have been reported. The initial report by Oz et al. described the use of fibrinogen mixed with indocyanine green (ICG) dye (lex ¼ 805 nm) in a rabbit model of vascular anastomosis.15 Over a period of 90 days,the dye-protein solder did not induce any apparent foreign body response and the fibrinogen was infiltrated by cells and almost completely degraded. Albumin and ICG solutions have also became a popular solder choice to weld cartilage,16 blood vessels,17–19 and urinary tract.20 A few other dyes, such as methylene blue (lex ¼ 670 nm) and Janus Green (lex ¼ 665 nm) have also been used in combination with albumin to perform vascular anastomosis,21 and corneal incision repair,22 respectively. The bonding caused by thermal denaturation processes and subsequent interlinking of ECM proteins does not reliably produce covalent crosslinks although they may sometimes form.23,24 Introducing covalent bonds would arguably result in stronger tissue bonding. One of the first reports of photochemical laser welding (nowadays also termed PTB25) was made by Judy et al., in the early 90s.26 In this case, laser-excited dye molecules interact with oxygen creating reactive oxygen species and radicals, which in turn interact with the proteins in the ECM resulting in covalent crosslinks bonding the edges of the wound. Thermal denaturation of ECM components is not required. This allows for use of a lower laser irradiation dose, protecting tissues from thermal damage. PTB can even be achieved using light-emitting diode (LED) illumination,27 which admittedly requires longer exposure times but reduces cost and can be done with simple LED equipment. However, while PTB eliminates the concern of thermal tissue damage, it introduces additional considerations regarding potential damage caused by excess reactive oxygen species and radicals produced by light-activated sensitizers. A few photoactive molecules have been reported as PTB agents. Judy et al. introduced a 1,8-naphthalimide dye (lex ¼ 420 nm), which they used to bond two sheets of ex vivo porcine dura mater,26 as well as ex vivo human cartilage.28 The bonded tissues demonstrated superior shear strength compared to thermal laser welding. Preclinical large animal studies were also carried out. A sheep model was used to demonstrate photochemical bonding of meniscal tears and articular cartilage defects. Photochemistry, 2019, 46, 265–280 | 267

No adverse effects were observed within 6 months post-operation, and histology showed cell recruitment and ECM deposition. Additionally, the animals that received the photochemical bonding operation showed no limping and were exercising similarly to healthy controls within 2–3 weeks post-operation.29 However, there does not appear to be any published data of clinical studies using this dye. The use of the xanthene dye rose Bengal (lexcE532 nm RB) excited by green light (532 nm) as a tissue photobonding agent was first used to seal incisions in cornea.5 Since then this approach has been used to seal wounds in vivo in several tissues including skin,30 cornea,31 and vocal cords.32 In addition, PTB using RB and green light has been demonstrated in vivo in small and large animals to reattach severed nerves,33 blood vessels,4 and tendons.34 Other in vivo studies have shown that PTB can be used to seal wounds by bonding a biological membrane over wounds in cornea6 and bowel.35 A 30-patient clinical study clearly demonstrated that RB/green light PTB sealed skin wounds effectively and with substantially reduced scarring and greater patient satisfaction.36 The major concern regarding RB is that it demonstrates high cytotoxicity in vitro.37,38 However, this effect does not appear to be present in vivo under conditions used for PTB and RB use in the clinic as a diagnostic tool in ophthalmology was approved long before its introduction as a tissue bonding agent.39 Different in vitro and in vivo cell responses were investigated by Yao et al.,38 who found that in vivo PTB requires much higher irradiance compared to all prior studies investigating RB cytotoxicity in vitro. Higher irradiance results in singlet oxygen depletion reducing the consequent cell death. Additionally, cells grown in a monolayer in vitro are affected by the lack of surrounding 3D matrix. One of the downsides of using RB or a different photosensitizer solution of low viscosity is that the edges of the wound or incision need to be pressed together closely so that the ECM proteins on opposite sides are in contact in order for them to be close enough to form covalent bonds. This is not often possible as most wounds are not precise surgical incisions. As such, the next logical step is to introduce a filler, akin to the protein solutions used in laser tissue soldering, except in this case the high viscosity polymer solution needs the ability to form covalent crosslinks via a sensitizer-mediated light activated mechanism. A few different approaches have been proposed. One of the earliest attempts was published in the 90s shortly after the introduction of the concept of PTB: the Ernest group used fibrinogen and riboflavin (lexE445 nm) to repair corneal incisions.40 They also showed that photochemical bonding resulted in higher eye burst pressure than the laser soldering method.7 Our group has proposed the use of methacrylated collagen and RB solution as a light-activated agent and demonstrated its use on a mouse skin incision model.27 Elvin et al. created a tyrosine-rich protein photobonding agent crosslinked with [RuII(bpy)3] (lexE450 nm). They used fibronectin41 and modified gelatin.42 Although the use of a ruthenium catalyst raises toxicity concerns, in vitro studies demonstrated no significant toxicity on murine fibroblast cells and human chondrocytes, when [RuII(bpy)3] concentrations necessary for cross linking of gelatin 268 | Photochemistry, 2019, 46, 265–280

sealant was used. Additionally, in vivo studies using sheep lung as well as rabbit and canine colon models demonstrated air- and water-tight sealing of incisions and no adverse effects were observed for the duration of the studies (2 weeks and 7 days, respectively).43 Another alternative to solve the low viscosity problem was proposed by Lauto et al., who introduced a photoactive chitosan sealant in the form of a thin sheet, doped with ICG.44 After applying the sheet in such a way that it overlaps with the tissue on both sides of the incision, the sheet is irradiated to form a tight seal. This method was used to perform light-activated repair of sciatic nerves45 and intestines.46 A variation of the chitosan film doped with RB was also used with success in vivo for nerve anastomosis in a rat model and showed superior healing compared to sutures during the observation period of 12 weeks.47 Despite many promising preclinical animal studies demonstrating efficient photoactivated wound closure and no immediate adverse effects, only a few laser welding/soldering and PTB methods have been investigated in terms of long-term in vivo effects. Even fewer have progressed to clinical application. In two of the earliest trials, albumin and ICG solutions were used in clinical studies for urinary tract reconstruction and hypospadias repair.20,48 In these trials, patients were followed for up to 9 months and 12 months, respectively. No complications were observed in the first trial which was a small first-in-human study, while the second study showed that laser soldering surgery decreased the complication rate by 2-fold compared to traditional surgery, in addition to decreasing surgery time. More recently, PTB using RB solution was used to close skin wounds.36 No phototoxicity was observed and there was only minimal inflammation. After 6 months, photobonded tissue showed less scarring than traditionally sutured wounds.

3

Photo tissue bonding (PTB)

Rose Bengal (RB), a member of the halogenated fluorescein family, whose properties have been exhaustively investigated in aqueous solution,49,50 and also clinically used for assessing ocular surfaces,51 is among the most archetypical dyes used in PTB. Typically in rose Bengal-PTB, an aqueous solution of the dye is applied directly to the tissues to be bound, they are then placed in contact and irradiated with green light for a few minutes. A major advantage of RB-PTB, and of PTB in general, is the minimal scarring and fibrosis when compared to traditional suturing reported for wound sealing of skin, cornea, tendon, blood vessels, and even nerves.4–6,35,36,52,53 Using rose Bengal for PTB reactions also results in reduced inflammation of tissues, which has been coined as ‘‘photochemical tissue passivation.’’54 Rose Bengal-PTB has also been used for increasing the strength and stiffness of tissues allowing them to tolerate shape changes as in the case of certain cornea diseases and arteriovenous fistulas.55–58 As hinted above, Rose Bengal is commonly used as a photosensitiser for singlet oxygen (1O2) generation for chemical transformations.59 Some studies have suggested that the observed phenomenon is due to this Photochemistry, 2019, 46, 265–280 | 269

reactive oxygen species reacting with histidine residues to form protein– protein crosslinks.60 The ultimate goal of PTB is rapid wound closure, which directly involves proteins of the extracellular matrix (ECM) and radicals generated upon dye excitation, like singlet oxygen. Thus, photophysical models aimed at understanding the behaviour of dyes must consider alterations in dye photochemistry upon its interaction with proteins. In the case of RB, we, and others, have demonstrated that this dye readily binds to a variety of proteins such as albumin, collagen, hemo-proteins, lactoferrin, lysozyme, and transferrin.9,61–65 For PTB, binding of RB to type I collagen is most relevant as it is the most abundant protein in connective tissues such as skin, a typical target of PTB.9,62 Using a short peptide sequence that mimics type I collagen, we recently demonstrated that the binding of RB to collagen leads to changes in the dye’s photophysical properties.9,62 Such changes were found to be linked to ground state interactions between the dye and the protein structure, with terminal amino groups of lysine and hydroxyproline residues involved in 1 : 1 binding of RB.9,62 Furthermore, multi-cooperative binding of RB to the protein was observed. In contrast to the multi-occupation of RB found in other proteins such as human serum albumin,61,63 the binding observed for collagen was unique as it involved dye aggregation promoted by the first dye molecule bound to the protein followed by p–p stacking for the subsequently bounded dyes. This particular type of dye association has important implications on the photophysical properties of the photosensitizer (see Table 1). Although the photo-behaviour of a given dye within a complex biological matrix will vary depending on the photophysical properties of the dye; some lessons can be learned from our recently reported study on RB incorporated within a 3D collagen matrix. Table 1 contains selected photophysical and photochemical properties of the dye when incorporated within a 3D type I collagen matrix (bottom row). Firstly, changes in the absorption spectra of the dye account for modifications in the electronic configuration of the dye upon collagen binding. For the case of RB3D-collagen there was a red shift of E7 nm in the absorption maximum Table 1 Selected photophysical properties for rose Bengal measured in aqueous solutions or in the presence of proteins like human serum albumin and type I collagen. Data compiled using a collagen matrix containing rose Bengal is also included. Original data taken from ref. 9 and 61–63.

Aqueous solutions Human serum albuminc Type I collagenc Type I 3D-collagen matrix

lnma

jF

jT

tT (ms)

jD

tD (ms)

549 563 559 556

0.018 0.12 nd E0.004

0.90 E0.45 nd

40  5.0 130  10 nd E3.0

0.75 0.33 nd

66  3.0b 68  5.0d nd E10

a

e

e

Absorption maximum in nm. nd ¼ not detectable. Measured in deuterium oxide. c Measured at occupation numbers of 1.0 (1 dye per protein). d Long-lived component for 1270 nm emission. e Quantum yields calculation was not possible due to scattering interferences derived from the nature of the sample. b

270 | Photochemistry, 2019, 46, 265–280

alongside a 4.5 times decrease in fluorescence quantum yield. Meanwhile, the triplet lifetime of the dye was shortened upon incorporation within the 3D matrix by E13 times, and the singlet oxygen lifetime was measured as E6 times shorter than for what is measured in fluid solutions (see Table 1). These changes are attributable to fast quenching mechanisms taking place in the RB-collagen, most likely due to the formation of intra-protein aggregates, which are known to reduce the triplet lifetime. Reduction in the singlet oxygen lifetime can be linked directly to how the intrinsic 3D nature of the matrix affects the oxygen mobility. Additionally, the interactions between RB and the 3D collagen matrix result in a considerable reduction in the rate of photodegradation for the incorporated dye. While one could blindly extrapolate the solution based findings to in vivo tissue settings,4–6,34–36,52,53,55 the findings using the 3D collagen structure reveal the relevance of considering the interaction between RB and collagen as a key factor in dictating the photophysical and photochemical performance of the dye. However, when making such assumptions it is also important to take into consideration that the reactivity of singlet oxygen in solution and tissue may be markedly different as the rigidity of the protein chains, oxygen depletion within the tissue, and radical migration within the protein backbone could have an effect on this diffusion controlled process.

4 Recent advances in in situ photo-polymerization Recently, there has been a push to develop techniques and materials which are amenable to the in situ photo-polymerization of biomaterials and biomimetic matrices. In general, photo-polymerization is a lightmediated technique that uses light to both initiate and propagate a polymerization reaction to give rise to either linear, branched, or crosslinked polymer structures. Light-mediated polymerizations have found a role in a variety of areas, such as in photolithographic resists in optoelectronics,66 non-linear fibre optic communications and data storage,67 coating and painting industries,68 as well as in three-dimensional lithography;69 however, its use in the production of biomimetic matrices has somewhat lagged behind. This is not to say there has not been much research in the use of light as a tool to polymerize/cross-link materials in situ, the problem is that much of the developed technologies have not yet made their way to the clinical setting. In the next few sections, we will discuss some of the key features that make light an interesting and useful tool in the development of biomimetic matrices. There are many reasons photo-polymerization has found a place in the production of polymeric biomimetic matrices. Some of these ideal qualities relate to the spatial and temporal control of the process, the ability to easily generate complex shapes, and the ability to perform the polymerization in situ. These properties allow for matrix production and implantation using minimally invasive techniques, with ease of application, the ability to entrap a variety of molecules, drugs, or cells, and the ability to store the various components of the mixture under ideal conditions until they are ready to be mixed and employed. It is for these Photochemistry, 2019, 46, 265–280 | 271

reasons that one will find photo-polymerized materials being used in areas such as tissue engineering,70 cell encapsulation and drug delivery,71 as well as restorative biomaterials such as dental fillings.72 4.1 Components of photopolymer systems Typically, photopolymerization technologies comprise a polymerizable monomer, a photoinitiator, and an appropriate light source. These 3 key components can be mixed alongside other cross-linkers, bioactive molecules, cells, and a variety of supplements to give rise to matrices that are best suited for its particular function and placement within the body. 4.1.1 Light source. A variety of different light sources have been employed in the photopolymerization of matrices for tissue engineering. While historically UV, halogen, and plasma arc lamps, as well as femto-second pulsed lasers have been the light source of choice, light emitting diodes (LEDs) are quickly gaining popularity as they are a relatively cheap and widely available in a variety of colours meaning it is easier to match the absorption spectrum of the chromophore/ photoinitiator with the emission spectrum of the light source.73 The emission spectrum of the LED light sources also tends to be quite narrow, and as such, through the use of simple filters one can easily ensure that only the photoinitiator is being excited, thereby decreasing the likelihood of side reactions and photodegradation of other components of the matrices. While both UV and visible wavelengths of light can be employed in the in situ photopolymerization, it is important to realize that the high energy UV photons do not have the ability to penetrate tissues to any significant depth and can actually result in tissue damage. Visible light photons are typically safer for these types of applications, and as one approaches the Red/Near-IR region of the spectrum the photons tend to have more penetrating power as there are typically less interfering absorbers in this region.74 4.1.2 Photoinitiator/chromophore. The photoinitiator or chromophore in these systems is the molecule which is responsible for absorbing the incident light and generating the reactive intermediates that will initiate the polymerization reaction. A variety of different molecules have been employed as photoinitiators for in situ polymerizations; Table 2 lists some of these photoinitiators along with a brief description of the components of the employed system as well as target tissue/organ of the resulting biomimetic matrix. While for the most part these photoinitiators are UV absorbers, there has been a recent push to develop systems which absorb in the visible light spectrum.75,76 Typically, these systems will employ tertiary amines as sacrificial electron donors.77 Due to the fact that there are so many different types of photoinitiatior systems, it can be beneficial to classify these systems according to (i) the type of polymerization they bring about (e.g. free radical,76 anionic,78 cationic79), (ii) the number of components required to initiate polymerization (e.g. one-, two-, n-component system), and (iii) the mechanism of initiation.80 Photoinitiation of the polymerization can take place either directly through excitation of the photoinitiator, or indirectly through excitation 272 | Photochemistry, 2019, 46, 265–280

Table 2 Summary of studies employing in situ photopolymerization to generate scaffolds/biomimetic matrices.

Photoinitiator Irgacure Eosin Y

s

184

Light

Monomer

Additive

UV light Visible light

Methyl methacrylate PEG-tetra-acrylate/PEG-tetraacrylamide/PEG-tetra-allylether/ PEG-tetra-methacrylate and DTT or bis-cysteine containing peptides p-Azide benzoic acid and lactobionic acid modified chitosan PEG diacrylate and acrylate modified RGD peptide Acrylate and lactic acid modified hydroxy PEG

Dermis N-vinylpyrrolidone (NVP) Bone

95 96

—

Dermis

97

1-vinyl-2-pyrrolidinone

Multiple tissues

88

Monomer

UV light

2,2-Dimethoxy-2-phenylacetophenone (DMPA) 2,2-Dimethoxy-2-phenylacetophenone (DMPA)

UV light

Photochemistry, 2019, 46, 265–280 | 273

2,2-Dimethoxy-2-phenylacetophenone (DMPA) Camphorquinone

UV light UV light

Lactic acid modified di(ethylene glycol) Visible light Acrylate functionalized bovine Type I Collagen 1-Hydroxycyclohexyl phenyl UV light Poly(ethylene oxide)-dimethacrylate ketone and poly(ethylene oxide) 2,2-Dimethoxy-2-phenylUV light Methacrylated sebacic acid and acetophenone (DMPA) poly(carboxyphenoxy hexane) Eosin Y Visible light PEG core with flanking lactic acid oligomer and terminal tetraacrylate functionalities 2,2-Dimethoxy-2-phenylUV or Visible Dimethacrylated anhydride acetophenone (DMPA) or Light monomers (Sebacic acid, 1,3-bisCamphorquinone or Ethyl-4(p-carboxyphenoxy)propane, N,N-dimethylaminobenzoate 1,6-bis(p-carboxyphenoxy)hexane 2,2-Dimethoxy-2-phenylUV light PEG core with flanking lactic acid acetophenone (DMPA) oligomer and terminal tetraacrylate functionalities

Target tissue/model

References

N-vinylpyrrolidone (NVP) Rat cecum abrasion model 98 and rabbit uterine horn ischemia model NaCl crystals Cranial defect 93 Triethanolamine —

Transdermal – Mandibular Joint Dermis – Athymic mice

—

94 99

Bone – Sprague Dawley Rat N-vinylpyrrolidone (NVP) Vasculature – Sprague and Triethanolamine Dawley Rat

100

—

102

Bone – Sprague Dawley Rat

N-vinylpyrrolidone (NVP) Vasculature – Sprague Dawley Rat

101

103

of a photosensitizer that works in conjunction with another molecule(s) that can act as initiator and bring about the required initiating species. In the direct photoinitiation technique the initiating species is derived upon excitation of the photoinitiator. In some instances, this process can be catalytic in nature (that is the photoinitiator is not consumed during the initiation process and is turned over through some type of catalytic cycle). While under catalytic conditions the required loading of photoinitiator is significantly reduced. In some instances where the initiator is consumed (i.e. Norrish type cleavage),73 a chain reaction/propagation can occur that increases the efficiency of the process; thus equimolar amounts of photoinitiator are not always required. In the indirect initiation mechanism, the light absorbing molecule, typically referred to as the photosensitizer, is excited by an appropriate wavelength of light. This generates an excited state (singlet or triplet – depending on the employed photosensitizer), whereby the excited chromophore will likely either undergo energy transfer or react with an appropriately selected initiator molecule to generate a reactive intermediate which can initiate the polymerization reaction.81 Typical excited state processes which lead to the generation of reactive intermediates include: (i) redox reactions/electron transfers, (ii) hydrogen abstraction, and (iii) photocleavage.81 All of these processes give rise to free radicals which happen to be the most common type of initiation employed in these in situ polymerizations. Finally, in selecting an appropriate photoinitiator/photosensitizer for the employed system there are a few things that must be taken into consideration. (i) Typically, the photosensitizer should have a high extinction coefficient for the wavelength of light employed; however, one should ensure that the light is capable of penetrating the entire depth of the material. If the light is absorbed only at the interface, the polymerization process may not be homogeneous. To get around this one could either decrease the loading of photosensitizer or excite the molecule in the tail region of its absorption spectrum. (ii) The photosensitizer should have a high initiation efficiency and have high rates of initiation (Efficiency ¼ # photons absorbed/# of events initiated), and (iii) lastly, the photosensitizer and its photoproducts should be biocompatible (i.e. not toxic locally or systemically), as they will likely become entrapped within the matrix and be in close proximity to cells and other tissues. 4.1.3 Monomers. There is currently a wide variety of commercially available and designer molecules which can or have been utilized as monomers in photo-polymerizations for the generation of biomimetic matrices. Typically, these monomers will have one or more photopolymerizable units, as well as other functionalities that allow for post polymerization modifications such as cross-linking or the addition of marker molecules and other bioactive components. While the initial examples/studies typically employed methacrylated or acrylated derivatives as monomers, recently other polymerizable functionalities and bio-inspired monomers have been employed (see Table 2). It is through the addition of functionalities and biomolecules that one can modify and introduce specific properties into the resulting matrix 274 | Photochemistry, 2019, 46, 265–280

such as degradability/non-degradability,82 cell and protein adhesiveness,83,84 as well as mechanical properties such as strength, flexibility, and viscosity.85 Of these properties, degradability and cell adhesiveness are quite important for materials intended to mimic biological tissue and deliver both cells and other factors to target areas. Regarding degradability, the type of chemical bonds created during the polymerization will largely dictate the degradability and as such the rate of degradability and release of cells or other molecules included in these matrices. For the most part, degradability will arise from crosslinks formed between lateral side chains of the monomer as these are typically enzymatically degradable functionalities such as esters, and amides. While there have been photopolymerizable monomers designed to be enzymatically degraded,86 the commonly employed acryclic and methacrylic monomers tend to give rise to polymeric structures with hydrocarbon based backbones which are not enzymatically degradable. As such, one must also look at controlling other properties such as the molecular weight and hydrophobicity of the resulting polymeric network as both of these properties can drastically influence the rate of degradation.87 Cell adhesion on photopolymerized matrices can also be difficult to attain. Typically, photo-crosslinked hydrogels are composed of swollen and insoluble hydrophilic polymeric networks. While this is great for the encapsulation and viability of cells capable of growing in suspension, it can be quite difficult for such types of materials to support adherent cell types, which are quite important in various applications. As such there has been a push to increase the adhesiveness of the materials through the modification of monomers with a variety of amino acid sequences such as an Arg-Gly-Asp (RGD), or other peptides and proteins known to be involved in cell adhesion.88–90 4.1.4 In situ applications. For the most part, in situ photopolymerizations involve free radical mechanisms. Many of these polymerizations involve the classical steps of initiation, propagation, and termination. Recently, there has been a push to improve these types of lightmediated processes through the introduction of ‘‘living’’ or controlled free radical processes; however there are not many examples of these processes being used to generate biomimetic scaffolds in situ.91 In general, there are two different types of photo-polymerization, which are classified as (i) bulk and (ii) interfacial.92 As its name suggests, in bulk polymerizations all of the components are first mixed and then the resulting mixture is polymerized via irradiation with an appropriate wavelength of light. In the interfacial technique, the photosensitizer/ initiator is first adsorbed onto the target surface and then the rest of the mixture is added and irradiated to form a thin polymeric network at the interface. When performing these types of polymerizations in situ the resulting shape of the polymeric network will be the same as the cavity in which the material is placed or injected. Additionally, it has been demonstrated that one can introduce porosity into the network through the addition of salts and other molecules which can be washed out post Photochemistry, 2019, 46, 265–280 | 275

polymerization.93 One of the main advantages of photo-polymerization in the context of biomaterials is that the technique may in some cases serve as an alternative to otherwise invasive surgeries. By exploiting the temporal and spatial control of the process, one can encapsulate and deliver cells and other biologically active molecules to the site of interest using laparoscopic instruments and needles, while initiating the polymerization process via irradiation directly through the needle or depending on the employed photosensitizer directly through the tissue in a subcutaneous fashion.94

5

Conclusion and outlook

The advancements in understanding polymerization mechanisms and the development of novel biocompatible matrices and incorporation of less expensive irradiation sources like LEDs have enormously impacted the field of photo-activated matrices for wound closure and tissue repair. However, some fundamental questions remain to be answered including the underlying mechanism for in vivo PTB. Novel approaches in PTB and PHP should also incorporate the use of biomimetic matrices whose composition and mechanical properties can be fine-tuned for application in different tissues. In addition, the development of novel composite materials for PTB as well as for PHP that are able to modulate inflammatory responses and reduce tissue remodelling will provide powerful tools for reconstructive and plastic surgery. Undoubtedly, there is much left to learn; however, identifying key clinical needs are pivotal for focussing our efforts to develop novel and improved clinically translatable technologies.

Acknowledgements This work was made possible thanks to funding from the Natural Sciences and Engineering Research Council (E.I.A.) and the Canadian Institutes of Health Research (E.I.A. & E.J.S.). C.D.M. was supported by a University of Ottawa Cardiac Endowment Fund postdoctoral fellowship award.

References 1 2 3

4

5

M. Talmor, C. B. Bleustein and D. P. Poppas, Arch. Facial Plastic Surg., 2001, 3, 207–213. M. Ark, P. H. Cosman, P. Boughton and C. R. Dunstan, Inter. J. Adhesion Adhesives, 2016, 71, 87–98. S. B. Seif-Naraghi, J. M. Singelyn, M. A. Salvatore, K. G. Osborn, J. J. Wang, U. Sampat, O. L. Kwan, G. M. Strachan, J. Wong, P. J. Schup-Magoffin, R. L. Braden, K. Bartels, J. A. DeQuach, M. Preul, A. M. Kinsey, A. N. DeMaria, N. Dib and K. L. Christman, Sci. Trans. Med., 2013, 5, 173ra125. A. C. O’Neill, J. M. Winograd, J. L. Zeballos, T. S. Johnson, M. A. Randolph, K. E. Bujold, I. E. Kochevar and R. W. Redmond, Lasers Surg. Med., 2007, 39, 716–722. L. Mulroy, J. Kim, I. Wu, P. Scharper, S. A. Melki, D. T. Azar, R. W. Redmond and I. E. Kochevar, Invest. Ophthalmol. Vis. Sci., 2000, 41, 3335–3340.

276 | Photochemistry, 2019, 46, 265–280

6 7 8 9 10 11 12

13 14 15 16 17 18 19 20 21 22 23 24 25 26

27

28 29

30

31 32

E. E. Verter, T. E. Gisel, P. Yang, A. J. Johnson, R. W. Redmond and I. E. Kochevar, Invest Ophthalmol Vis. Sci, 2011, 52, 9470–9477. J. Khadem, T. Truong and J. T. Ernest, Cornea, 1994, 13, 406–410. S. L. Littlechild, G. Brummer, Y. Zhang and G. W. Conrad, Invest. Ophthalmol. Vis. Sci., 2012, 53, 4011–4020. E. I. Alarcon, H. Poblete, H. Roh, J.-F. Couture, J. Comer and I. E. Kochevar, ACS Omega, 2017, 2, 6646–6657. K. K. Jain and W. Gorisch, Surgery, 1979, 85, 684–688. R. Schober, F. Ulrich, T. Sander, H. Durselen and S. Hessel, Science, 1986, 232, 1421–1422. P. Matteini, F. Rossi, F. Ratto and R. Pini, Laser Imaging and Manipulation in Cell Biology, Wiley-VCH Verlag GmbH & Co. KGaA, 2010, DOI: 10.1002/ 9783527632053, ch. 9, pp. 203–231. D. P. Poppas, S. M. Schlossberg, I. L. Richmond, D. A. Gilbert and C. J. Devine Jr., J. Urol., 1988, 139, 415–417. M. C. Oz, R. S. Chuck, J. P. Johnson, S. Parangi, L. S. Bass, R. Nowygrod and M. R. Treat, Vasc. Surg., 1990, 24, 564–570. M. C. Oz, J. P. Johnson, S. Parangi, R. S. Chuck, C. C. Marboe, L. S. Bass, R. Nowygrod and M. R. Treat, J. Vasc. Surg., 1990, 11, 718–725. B. J. Zuger, B. Ott, P. Mainil-Varlet, T. Schaffner, J. F. Clemence, H. P. Weber and M. Frenz, Lasers Surg. Med., 2001, 28, 427–434. D. E. Hodges, K. M. McNally and A. J. Welch, J. Biomed. Opt., 2001, 6, 427–431. K. M. McNally, B. S. Sorg, A. J. Welch, J. M. Dawes and E. R. Owen, Phys. Med. Biol., 1999, 44, 983–1002, discussion 1002 pages follow. B. Ott, M. A. Constantinescu, D. Erni, A. Banic, T. Schaffner and M. Frenz, Lasers Surg. Med., 2004, 35, 312–316. A. J. Kirsch, M. I. Miller, T. W. Hensle, D. T. Chang, R. Shabsigh, C. A. Olsson and J. P. Connor, Urology, 1995, 46, 261–266. J. F. Birch and P. R. Bell, Eur. J. Vasc. Endovasc. Surg., 2002, 23, 325–330. J. Khadem, M. Martino, F. Anatelli, M. R. Dana and M. R. Hamblin, Lasers Surg. Med., 2004, 35, 304–311. L. S. Bass, N. Moazami, J. Pocsidio, M. C. Oz, P. LoGerfo and M. R. Treat, Lasers Surg. Med., 1992, 12, 500–505. L. S. Bass and M. R. Treat, Lasers Surg. Med., 1995, 17, 315–349. B. P. Chan, I. E. Kochevar and R. W. Redmond, J. Surg. Res., 2002, 108, 77–84. M. M. Judy, J. L. Matthews, R. L. Boriak, A. Burlacu, D. E. Lewis and R. E. Utecht, OE/LASE’93: Optics, Electro-Optics, and Laser Applications in Scienceand Engineering,1993. J. Pupkaite, M. Ahumada, S. McLaughlin, M. Temkit, S. Alaziz, R. Seymour, M. Ruel, I. Kochevar, M. Griffith, E. J. Suuronen and E. I. Alarcon, ACS Appl. Mater. Interface, 2017, 9, 9265–9270. M. M. Judy, H. R. Nosir, R. W. Jackson, J. L. Matthews, D. E. Lewis, R. E. Utecht and D. Yuan, Photonics West, 1996, 96. M. M. Judy, R. W. Jackson, H. R. Nosir, J. L. Matthews, J. D. Loyd, D. E. Lewis, R. E. Utecht and D. Yuan, BiOS ’97, Part of Photonics West, 1997. Y. Kamegaya, W. A. Farinelli, A. V. Vila Echague, H. Akita, J. Gallagher, T. J. Flotte, R. R. Anderson, R. W. Redmond and I. E. Kochevar, Lasers Surg. Med., 2005, 37, 264–270. C. E. Proano, L. Mulroy, E. Jones, D. T. Azar, R. W. Redmond and I. E. Kochevar, Invest. Ophthalmol. Vis. Sci., 2004, 45, 2177–2181. R. A. Franco, J. R. Dowdall, K. Bujold, C. Amann, W. Faquin, R. W. Redmond and I. E. Kochevar, Laryngoscope, 2011, 121, 1244–1251. Photochemistry, 2019, 46, 265–280 | 277

33

34

35 36 37 38 39 40 41

42

43

44 45 46 47 48 49 50 51 52 53

54

55

T. S. Johnson, A. C. O’Neill, P. M. Motarjem, C. Amann, T. Nguyen, M. A. Randolph, J. M. Winograd, I. E. Kochevar and R. W. Redmond, J. Surg. Res., 2007, 143, 224–229. T. Ni, P. Senthil-Kumar, K. Dubbin, S. D. Aznar-Cervantes, N. Datta, M. A. Randolph, J. L. Cenis, G. C. Rutledge, I. E. Kochevar and R. W. Redmond, Lasers Surg. Med., 2012, 44, 645–652. P. Senthil-Kumar, T. Ni, M. A. Randolph, G. C. Velmahos, I. E. Kochevar and R. W. Redmond, Lasers Surg. Med., 2016, 48, 530–537. S. Tsao, M. Yao, H. Tsao, F. P. Henry, Y. Zhao, J. J. Kochevar, R. W. Redmond and I. E. Kochevar, Br. J. Dermatol., 2012, 166, 555–563. S. Ibusuki, G. J. Halbesma, M. A. Randolph, R. W. Redmond, I. E. Kochevar and T. J. Gill, Tissue Eng., 2007, 13, 1995–2001. M. Yao, C. Gu, F. J. Doyle Jr., H. Zhu, R. W. Redmond and I. E. Kochevar, Photochem. Photobiol., 2014, 90, 297–305. M. Yao, A. Yaroslavsky, F. P. Henry, R. W. Redmond and I. E. Kochevar, Lasers Surg. Med., 2010, 42, 123–131. K. M. Goins, J. Khadem, P. A. Majmudar and J. T. Ernest, J. Cataract. Refract. Surg., 1997, 23, 1331–1338. C. M. Elvin, A. G. Brownlee, M. G. Huson, T. A. Tebb, M. Kim, R. E. Lyons, T. Vuocolo, N. E. Liyou, T. C. Hughes, J. A. Ramshaw and J. A. Werkmeister, Biomaterials, 2009, 30, 2059–2065. C. M. Elvin, T. Vuocolo, A. G. Brownlee, L. Sando, M. G. Huson, N. E. Liyou, P. R. Stockwell, R. E. Lyons, M. Kim, G. A. Edwards, G. Johnson, G. A. McFarland, J. A. Ramshaw and J. A. Werkmeister, Biomaterials, 2010, 31, 8323–8331. T. Vuocolo, R. Haddad, G. A. Edwards, R. E. Lyons, N. E. Liyou, J. A. Werkmeister, J. A. Ramshaw and C. M. Elvin, J. Gastrointest. Surg., 2012, 16, 744–752. A. Lauto, J. Hook, M. Doran, F. Camacho, L. A. Poole-Warren, A. Avolio and L. J. Foster, Lasers Surg. Med., 2005, 36, 193–201. A. Lauto, L. J. Foster, A. Avolio, D. Sampson, C. Raston, M. Sarris, G. McKenzie and M. Stoodley, Photomed. Laser Surg., 2008, 26, 227–234. A. Lauto, M. Stoodley, M. Barton, J. W. Morley, D. A. Mahns, L. Longo and D. Mawad, J. Vis. Exp., 2012. DOI: 10.3791/4158. M. J. Barton, J. W. Morley, M. A. Stoodley, S. Shaikh, D. A. Mahns and A. Lauto, J. Biopho., 2015, 8, 196–207. A. J. Kirsch, C. S. Cooper, J. Gatti, H. C. Scherz, D. A. Canning, S. A. Zderic and H. M. Snyder 3rd, J. Urol., 2001, 165, 574–577. L. Ludvikova, P. Fris, D. Heger, P. Sebej, J. Wirz and P. Klan, Phys. Chem. Chem. Phys., 2016, 18, 16266–16273. D. C. Neckers, J. Photochem. Photobiol., A, 1989, 47, 1–29. M. J. Doughty, Cont. Lens Anterior Eye, 2013, 36, 272–280. B. P. Chan, C. Amann, A. N. Yaroslavsky, C. Title, D. Smink, B. Zarins, I. E. Kochevar and R. W. Redmond, J. Surg. Res., 2005, 124, 274–279. N. G. Fairbairn, J. Ng-Glazier, A. M. Meppelink, M. A. Randolph, I. L. Valerio, M. E. Fleming, I. E. Kochevar, J. M. Winograd and R. W. Redmond, J. Reconstr. Microsurg., 2016, 32, 421–430. J. R. Fernandes, H. M. Salinas, G. F. Broelsch, M. C. McCormack, A. M. Meppelink, M. A. Randolph, R. W. Redmond and W. G. Austen Jr., Plast. Reconstr. Surg., 2014, 133, 571–577. D. Cherfan, E. E. Verter, S. Melki, T. E. Gisel, F. J. Doyle Jr., G. Scarcelli, S. H. Yun, R. W. Redmond and I. E. Kochevar, Invest. Ophthalmol. Vis. Sci., 2013, 54, 3426–3433.

278 | Photochemistry, 2019, 46, 265–280

56 57

58

59 60 61 62 63

64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86

H. Zhu, C. Alt, R. H. Webb, S. Melki and I. E. Kochevar, Cornea, 2016, 35, 1234–1241. R. N. Goldstone, M. C. McCormack, R. L. Goldstein, S. Mallidi, M. A. Randolph, M. T. Watkins, R. W. Redmond and W. G. Austen Jr., Ann. Surg., 2016. DOI: 10.1097/SLA.0000000000002046. R. N. Goldstone, M. C. McCormack, S. I. Khan, H. M. Salinas, A. Meppelink, M. A. Randolph, M. T. Watkins, R. W. Redmond and W. G. Austen Jr., J. Am. Heart Assoc., 2016, 5. I. E. Kochevar and R. W. Redmond, Methods Enzymol., 2000, 319, 20–28. H. R. Shen, J. D. Spikes, P. Kopeckova and J. Kopecek, J. Photochem. Photobiol., B, 1996, 35, 213–219. E. Alarcon, A. M. Edwards, A. Aspee, C. D. Borsarelli and E. A. Lissi, Photochem. Photobiol. Sci., 2009, 8, 933–943. M. J. Simpson, H. Poblete, M. Griffith, E. I. Alarcon and J. C. Scaiano, Photochem. Photobiol., 2013, 89, 1433–1441. E. Alarcon, A. M. Edwards, A. Aspee, F. E. Moran, C. D. Borsarelli, E. A. Lissi, D. Gonzalez-Nilo, H. Poblete and J. C. Scaiano, Photochem. Photobiol. Sci., 2010, 9, 93–102. S. C. Tseng and S. H. Zhang, Cornea, 1995, 14, 427–435. A. F. Coulson and T. Yonetani, Eur. J. Biochem., 1972, 26, 125–131. J. T. M. Stevenson and A. M. Gundlach, J. Physics E: Sci. Instrum., 1986, 19, 654. J. Guo, M. R. Gleeson and J. T. Sheridan, Phys. Res. Interface, 2012, 2012, 16. P. Garra, C. Dietlin, F. Morlet-Savary, F. Dumur, D. Gigmes, J.-P. Fouassier and J. Lalevee, Polym. Chem., 2017, 8, 7088–7101. ¨lhaupt, Chem. Rev., 2017, S. C. Ligon, R. Liska, J. Stampfl, M. Gurr and R. Mu 117, 10212–10290. B. Baroli, J. Chem. Tech. Biotechnol., 2006, 81, 491–499. I. Mironi-Harpaz, D. Y. Wang, S. Venkatraman and D. Seliktar, Acta Biomater., 2012, 8, 1838–1848. S. C. Ligon-Auer, M. Schwentenwein, C. Gorsche, J. Stampfl and R. Liska, Polym. Chem., 2016, 7, 257–286. S. Chatani, C. J. Kloxin and C. N. Bowman, Polym. Chem., 2014, 5, 2187– 2201. ´rez and L. Anasagasti, J. Photochem. Photobiol., S. Stolik, J. A. Delgado, A. Pe B, 2000, 57, 90–93. ´e, X. Allonas and C. Ley, Materials, J.-P. Fouassier, F. Morlet-Savary, J. Laleve 2010, 3, 5130. M. Chen, M. Zhong and J. A. Johnson, Chem. Rev., 2016, 116, 10167–10211. J. S. D. Kumar and S. Das, Res. Chem. Interm., 1997, 23, 755–800. N. Hadjichristidis, M. Pitsikalis, S. Pispas and H. Iatrou, Chem. Rev., 2001, 101, 3747–3792. S. Aoshima and S. Kanaoka, Chem. Rev., 2009, 109, 5245–5287. S. Dadashi-Silab, S. Doran and Y. Yagci, Chem. Rev., 2016, 116, 10212–10275. N. J. Turro, J. C. Scaiano and V. Ramamurthy, Principles of Molecular Photochemistry: An Introduction, University Science Books, 2009. Y. D. Park, N. Tirelli and J. A. Hubbell, Biomaterials, 2003, 24, 893–900. S. Halstenberg, A. Panitch, S. Rizzi, H. Hall and J. A. Hubbell, Biomacromolecules, 2002, 3, 710–723. K. T. Nguyen and J. L. West, Biomaterials, 2002, 23, 4307–4314. D. L. Elbert and J. A. Hubbell, Biomacromolecules, 2001, 2, 430–441. B. K. Mann, A. S. Gobin, A. T. Tsai, R. H. Schmedlen and J. L. West, Biomaterials, 2001, 22, 3045–3051. Photochemistry, 2019, 46, 265–280 | 279

87 88 89 90 91 92 93 94 95 96 97

98 99 100 101 102 103

S. Lyu and D. Untereker, Int. J. Mol. Sci., 2009, 10, 4033–4065. D. L. Hern and J. A. Hubbell, J. Biomed. Mater. Res., 1998, 39, 266–276. H. D. Kim, J. Heo, Y. Hwang, S.-Y. Kwak, O. K. Park, H. Kim, S. Varghese and N. S. Hwang, Tissue Eng. Part A, 2015, 21, 757–766. A. S. Gobin and J. L. West, J. Biomed. Mater. Res. A, 2003, 67A, 255–259. J. Xu, K. Jung, N. A. Corrigan and C. Boyer, Chem. Sci., 2014, 5, 3568–3575. G. M. Cruise, O. D. Hegre, D. S. Scharp and J. A. Hubbell, Biotechnol. Bioeng., 1998, 57, 655–665. J. A. Burdick, D. Frankel, W. S. Dernell and K. S. Anseth, Biomaterials, 2003, 24, 1613–1620. A. K. Poshusta and K. S. Anseth, Cells Tissues Organs, 2001, 169, 272–278. K. Nam, Y. Shimatsu, R. Matsushima, T. Kimura and A. Kishida, Eur. Polym. J., 2014, 60, 163–171. Y. Hao, H. Shih, Z. Munoz, A. Kemp and C. C. Lin, Acta Biomater., 2014, 10, 104–114. M. Ishihara, K. Nakanishi, K. Ono, M. Sato, M. Kikuchi, Y. Saito, H. Yura, T. Matsui, H. Hattori, M. Uenoyama and A. Kurita, Biomaterials, 2002, 23, 833–840. A. S. Sawhney, C. P. Pathak, J. J. van Rensburg, R. C. Dunn and J. A. Hubbell, J. Biomed. Mater. Res., 1994, 28, 831–838. J. Elisseeff, K. Anseth, D. Sims, W. McIntosh, M. Randolph, M. Yaremchuk and R. Langer, Plastic Reconstr. Surg., 1999, 104, 1014–1022. J. A. Burdick, K. S. Anseth, A. K. Poshusta and M. J. Yaszemski, presented in part at the 48th Annual Meeting of the Orthopaedic Research Society, 2002. J. L. Hill-West, S. M. Chowdhury, M. J. Slepian and J. A. Hubbell, Proc. Natl. Acad. Sci. U. S. A., 1994, 91, 5967. K. S. Anseth, V. R. Shastri and R. Langer, Nat. Biotechnol., 1999, 17, 156. J. L. Hill-West, S. M. Chowdhury, A. S. Sawhney, C. P. Pathak, R. C. Dunn and J. A. Hubbell, Obst. Gynecol., 1994, 83, 59–64.

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Photoresponsive molecular devices targeting nucleic acid secondary structures Michela Zuffo,y Valentina Pirota and Filippo Doria* DOI: 10.1039/9781788013598-00281

Non B-DNA structures are non-canonical nucleic acid conformations adopted by single strands fulfilling specific sequence requirements. Numerous experimental evidences support their roles as regulators of biological processes, involving genetic information transfer. However, direct visualization of the folding and unfolding of such structures in live cells still remains elusive, as well as a detailed understanding of their mechanisms of action and functions. Fluorescent light-up probes are excellent tools to address these pending questions. This review aims at classifying the multitude of dyes available to date in terms of operating mechanism (conformational restriction, TICT, aggregation related phenomena, conjugation, etc.) and targeted structures. The most promising results are presented for each conformational class, contextually highlighting the main criticalities and the remaining gaps.

In its resting state, DNA occurs in the renowned double helix B-form, wound around histones in nucleosome arrays and then packaged in a dense complex, called chromatin. However, in order to be accessible to enzymes and thus allow genetic information transfer, DNA must be unwound. The resulting single-stranded regions may thus fold into alternative secondary structures modelled by unusual nucleobases interactions (e.g. Hoogsteen hydrogen bonds).1 Adoption of a peculiar one depends on several factors, such as oligonucleotide sequence, hydration state, super-helical stress, molecular crowding and interaction with ions, protein partners and exogenous ligands. To date, more than ten alternative DNA conformations, collectively called non-B DNA, have been studied and characterized. Besides alternative double helix conformations, such as A, S and Z-DNA, these include bulges, hairpins, parallel-stranded helices, triplexes, quadruplexes and i-motif structures (Fig. 1).2–6 Some of these were also observed in RNA transcripts. Research on such extensive polymorphism shed light on its active roles in directing biological processes (Fig. 2).7 Experimental data suggest that these alternative structures represent hotspots for mutations, such as deletions or expansions, as well as interacting with proteins involved in replication, gene expression and recombination. In more detail, they are believed to act as roadblocks to proteins processing single-stranded DNA templates during such transactions.6,8,9

Department of Chemistry, University of Pavia, V.le Taramelli 10, 27100 Pavia, Italy. E-mail: [email protected] y Present address: CNRS UMR9187, INSERM U1196, Institut Curie -Centre de Recherche, Rue Henri Bequerel, 91400, Orsay, France; E-mail: michela.zuffo@ curie.fr Photochemistry, 2019, 46, 281–318 | 281  c

The Royal Society of Chemistry 2019

Fig. 1 Schematic representation of non-B DNA structures. (1) G-quadruplex; (2) I-Motif; (3) A-Motif; (4) Three-way junction; (5) Holliday junction; (6) Triplex; (7) Hairpin; (8) Z-DNA; (9) S-DNA; (10) Bulge; (11) Mismatch.

Fig. 2 Schematic representation of the main biological roles of (1) G-quadruplex;22–24 (2) I-Motif;25–27 (3) A-Motif;28,29 (4) Three-way junction;30–32 (5) Triplex;33–35 (6) Holliday junction;36–38 (7) Bulge;39–42 (8) Hairpin;43–45 (9) Mismatch;46,47 (10) S-DNA;48,49 (11) Z-DNA.50–52

Accordingly, RNA secondary structures seem to affect transcription with analogous mechanisms. Despite these interferences with genetic information transfer are generally recognized, debate is still ongoing on 282 | Photochemistry, 2019, 46, 281–318

their nature, either as native regulatory mechanisms or aberrant toxic elements.10,11 Occurrence in vivo of many of these non-canonical DNA structures has been proven in the recent past. In other cases, evidences are still indirect, based on biochemical and molecular genetics data. In both cases, extensive mechanistic models of their action are still missing and should be the target of future research. Moreover, many of these structures have been linked to various diseases, such as cancer and genetic disorders. Demonstration and detailing of such correlations would pave the way to develop treatments based on DNA secondary structures targeting.12,13 Direct visualization of non-canonical DNA structures with fluorescent probes is accepted as a valuable approach to address these questions. In fact, it allows to directly monitor folding and unfolding events in a time- and space-controlled manner. Sensitivity compares favourably to other detection methods, such as colorimetric and electrochemical ones. Moreover, it is a fast and easily applicable technique, with the necessary equipment (e.g. fluorometers, plate readers, confocal microscopes) being available to most users.14 Certainly, this method requires probes with a high degree of specificity, to target peculiar secondary structures. Excellent sensitivity and high affinity for the structures in question are also necessary. Even if fluorescent monoclonal antibodies15–18 fulfil most of these requirements, they display several limitations in terms of handling and costs. Moreover, artefacts arising from chromatin fixation cannot be excluded when targeting transient DNA conformations. A complementary approach is represented by small molecules.19–21 In fact, if properly designed they can penetrate the cellular membrane without the need to permeabilize it with exogenous agents. For this reason, they allow to monitor the cell cycle in real time. This is particularly relevant when trying to elucidate transient secondary structure roles during cell life. Certainly, selectivity, affinity and sensitivity vary depending on the probe, but outstanding results have already been achieved. In this review, we describe the considerable number of fluorescent probes designed to selectively bind the different nucleic acid secondary structures, focussing on the most efficacious. Regardless of their target, fluorescent sensors can be divided in three categories, light-up probes, light-off probes and fluorescent tags, depending on how the binding event affects their emission. Light-up probes display a more or less marked fluorescence enhancement when interacting with the analyte. On the contrary, light-off probes have their fluorescence quenched. Finally, fluorescent tags do not undergo any modification in terms of emission intensity. Among these three groups, light-up probes are the most sensitive, as they are only slightly affected by background fluorescence. For this reason, herein we will focus on light-up probes. In particular, we will discuss the most common light-up mechanisms and then present specific examples of their applications in the targeting of various secondary nucleic acid structures. Photochemistry, 2019, 46, 281–318 | 283

1

Light-up mechanisms

1.1 Light-up via conformational restriction Compounds working according to this mechanism are non-emissive in the unbound state, due to their conformational freedom. In fact, free rotation or vibration of the two moieties around a single bond produces a thermal deactivation of the excited species. Moreover, twisting of one of the molecule sections outside the plane relieves steric hindrance at the expense of p-system conjugation. Once the probe binds to the analyte, it is forced to adopt a planar, conjugated conformation, resulting in a marked light-up (Fig. 3). A good exemplification of this mechanism is constituted by cyanine dyes.53,54 These consist in two hetero-aryl moieties conjugated through a methine or polymethine bridge (Fig. 4).

Fig. 3 Exemplification of the conformational restriction mechanism for the cyanine dye thiazole orange.

Fig. 4 Structures of some representative cyanine dyes. 284 | Photochemistry, 2019, 46, 281–318

Nature of the aromatic moieties and length of the bridge define the absorption and emission wavelength, as well as the dye quantum yield. Although being particularly promiscuous in DNA binding, light-up intensity is generally affected by the nature of the interacting structure. A selection of cyanine dyes of increasing complexity is shown in Fig. 4.55–58 Other dye families belonging to this class are constituted by carbazole,59–64 benzimidazole65–67 and alkynil68 derivatives. As cyanines, they tend to bind multiple secondary structures, rather than being specific. For this reason, benzimidazole derivative Hoechst 33258 is widely used as a nuclear stainer. Interestingly, though, carbazoles display different emission wavelengths and fluorescence lifetimes, depending on the peculiar analyte. The alkynyl Ant-PIm (Fig. 5) is one of the few selective G4 sensors engineered to afford NIR emission, achieved by two-photon excitation. Additional advantages of this probe are its excellent photostability and biocompatibility. Additionally, various natural alkaloids belonging to the family of isoquinoline (IQAs, Fig. 6) fit into this class of sensors. Many different IQAs, e.g. chelerythrine (CHE),69 berberine (BER),70 epiberberine (EPI)71 and palmitine (PAL)72 display interesting bioactivities, ascribable to their binding to DNA secondary structures. Despite exhibiting similar scaffolds, the substitution patterns on the different family members seem to govern their selectivity for different secondary structures.

Fig. 5 Structures of selected carbazole derivatives, benzimidazole dye Hoechst 33258 and poly-cationic ANT-PIm probe. Photochemistry, 2019, 46, 281–318 | 285

Fig. 6 Scaffold of IQAs. All IQAs contain A, C, and D aromatic rings. For Sanguinarine (SAN), chelerythrine (CHE), and nitidine (NIT), the unsaturated ring B is involved. Palmatine (PAL), berberine (BER) and epiberberine (EPI), contain the saturated ring E instead.

Fig. 7 Examples of ‘‘turn-on’’ fluorescent sensors designed according to the TICT mechanism.

The conformational restriction mechanism can be further enriched by the twisted intramolecular charge transfer (TICT) phenomenon (Fig. 7).73 This occurs when two or more p-systems containing electron donor and acceptor groups are connected through single bonds. Fast intramolecular electron transfer between the two groups occurs in polar environments (e.g. physiological medium) and is followed by twisting of one or more aromatic units outside the plane. As in the previous cases, the twisted structure has a large number of relaxation pathways available, resulting in fluorescence quenching. Planarization occurring upon DNA interaction is responsible once again for fluorescence light-up, as it impedes the charge transfer process. Examples of probes working by a TICT mechanism are triphenylmethane (TPM),74–76 thioflavin,77,78 indol,79 bodipy,80 diarylaminoanthracene81 and julolidine82,83 derivatives. In some cases, the planarization of the sensor’s structure that occurs upon DNA binding allows the conjugation of several aromatic moieties, which yield the actual fluorophore structure. DAOTA84 is one of the most studied probes lighting up via this mechanism. 286 | Photochemistry, 2019, 46, 281–318

1.2 Aggregation-related processes Many organic probes tend to aggregate in aqueous solution, due to their hydrophobic aromatic scaffolds. Although the propensity to form such supramolecular assemblies depends on the specific structure, it always increases with the dye concentration. The process has a remarkable influence on the compounds spectroscopic properties. Most probes undergo an emission quenching, frequently referred to as ‘‘aggregationcaused quenching’’ (ACQ). However, a number of probes behave in the opposite manner, undergoing the so called aggregation-induced emission (AIE).85 While being non-emissive in dilute solution, such dyes start to fluoresce upon aggregate formation. Rationalization of such phenomenon has relied on various hypotheses, including the restriction of intramolecular motion (RIM),86,87 excimer formation,88 J-aggregates,89–91 inhibition of TICT process,92,93 and excited state intramolecular proton transfer (ESIPT).94,95 In general, the spectroscopic outcome strongly depends on the aggregate geometry. Briefly, the nature of the aggregate depends on the relative alignment of the transition dipole moments of the adjacent molecules. Monomers can interact with each other adopting a face-to-face (Haggregates) or head-to-tail (J-aggregates) arrangement (Fig. 8). The formation of such aggregates has important consequences on the energies of the excited states, strongly affecting the dyes’ absorption and emission behaviour. In most cases, the H-aggregates are non-emitting compared to the monomer. In contrast, J-aggregates display a marked fluorescence, at a wavelength peculiar to the new structure. As the interactions that govern aggregates formation can also trigger the interaction with the

Fig. 8 Cartoon representing the aggregation process of H- and J-Aggregates. Photochemistry, 2019, 46, 281–318 | 287

DNA analyte, many groups have exploited these mechanisms for secondary structures sensing. In the case of H-aggregates, emission is quenched in the absence of the analyte. Then, interaction with DNA induces the disaggregation, restoring the monomer emission. In the case of J-aggregates, aggregation and thus emission light-up are selectively triggered by DNA binding. Examples of J-aggregates exploited in this sense are TPE (tetraphenylethene),96–98 cyanines91,99–102 and silole85 derivatives. TPE belong to the category of ionic AIE sensors (Fig. 9), with nonconjugated and conjugated linkages between the ionic moieties and central hydrophobic core. Their emission turns on upon DNA binding, according to the RIM mechanism. J-aggregates of cationic cyanine dyes can be formed by complexation with a variety of biomacromolecules,103 including DNA (Fig. 10). Dye design implementation can serve to achieve the target specificity necessary for practical applications. A few examples of ACQ J-aggregates able to switch on their fluorescence upon binding were also reported (Fig. 11).104,105 They are mostly DNA groove binders, although some modified cyanine derivatives display good selectivity for non B-DNA structures. Certainly, reports on H-aggregates for sensing scopes are more numerous. Some examples are constituted by dicyano vinilene squaraines,106,107 core extended naphthalene diimmides108,109 and perylene bisimides110,111 (Fig. 12).

Fig. 9 TPE derivatives working via J-aggregates formation. 288 | Photochemistry, 2019, 46, 281–318

Fig. 10 Cyanine e Pseudo Isocyanine derivatives.

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Fig. 11 Structure of MTC and DMSB derivatives.

Fig. 12 Probes used for G4 sensing working via H-aggregates formation.

1.3 Dimeric and multimeric sensors This third family of sensors includes multiple dyes, with different mechanisms of action. The feature common to all the group components is the partitioning in two or more moieties with peculiar and distinct functions. One is the real DNA ligand, the other mediates the sensing event, either behaving as a proper fluorophore or acting as a harvesting antenna. Although conjugation is commonly utilized to build permanent tags, the uniqueness of this third approach resides in the new role attributed to it. In fact, the two moieties are able to interact with each other when in close proximity, as in a conjugate. This induces remarkable changes in the spectroscopic properties of the two components, in the absence of the analyte. In most cases, the respective emission of one or both moieties is switched off due to the interaction, via mechanisms such as D–A ground state interaction, eT, ET and contact quenching. Upon interaction with DNA, the two moieties split up, behaving as free monomers. The resulting change in fluorescence is used to signal the binding event (Fig. 13). This is the case of naphthalene diimide (NDI) based dyads reported by Freccero’s group,112,113 in which one NDI works as G4 ligand and either a coumarin or another NDI work respectively as a harvesting antenna and a proper fluorescent reporter. Using the same light up mechanism, a multimeric polyethylenimine– pyrene composite,114 a Hoechst-naphthalimide dyad115 and a quinolinenaphthalimide dyad116 are able to selectively recognize other DNA secondary structures. Analogously, twice-as-smart G4 ligands reported by Monchaud and coworkers117,118 are constituted by a central aromatic core attached to four guanines. Interaction with a G4 contributes to restore the core fluorescence, which is quenched by the free guanines in the unbound state. 1.4 Metal complex sensors Metal complexes are widely exploited for DNA binding and sensing.119,120 Examples are numerous and involve an increasing number of transition metals and lanthanides. Applicability to DNA sensing relies on the intense metal-to-ligand charge transfer (MLCT) bands that are often 290 | Photochemistry, 2019, 46, 281–318

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Fig. 13 (A) Structure and schematic representation of the proposed mechanism of action for NI-quinoline and NDI–NDI dyads; (B) Structure and proposed functioning mechanism of the NDI-coumarin dyad.

observed for complexes of such metals. In fact, these are normally coupled to intense luminescence in the visible region. Electronic transitions of this type are particularly sensitive to the surrounding environment. Complexation to the DNA secondary structures induces significant changes in this sense, as the ligand passes from a hydrophilic environment to a highly hydrophobic one. As a result, the emission behaviour is affected as well and can thus be exploited for sensing. 1.5 Integrated probes A critical issue encountered when designing DNA probes and with sensing in general is that the analyte secondary structure could be modified when the interaction takes place. In the worst-case scenario, the probe could even induce the folding of the structure of interest. As a consequence, a certain stream of research has been focussed on producing internal probes by modification of the nucleobases composing the sequence. Folding of the structure affects the probe spectroscopic behaviour and thus enables to discriminate between the adopted conformations. For example, Luedtke’s group produced probes of this sort for both G-quadruplexes and i-motifs.121–123 Besides being useful for in vitro investigation, production of nucleobases that are recognized and incorporated by polymerase enzymes could be a valuable mean to observe sequences folding in live cells. 1.6 Miscellaneous probes Despite the usefulness of the presented classification, this is not fully comprehensive. In fact, multiple probes cannot be assigned to any of the discussed categories, either because they present an extremely peculiar mechanism of action or because the details were not deeply investigated. Compounds of this kind will be discussed in more detail in the specific subsections.

2 Fluorescent sensing of non B-DNA secondary structures 2.1 G-quadruplex In recent years, G-quadruplexes (G4s) certainly had the lion share of attention among the non B-DNA secondary structures. G4s are constituted by stacks of two or more guanine quartets, cyclically connected through Hoogsteen hydrogen bonds. Additional stabilization is provided by alkali metal cations – chiefly K1 and Na1 – positioned in the internal channel.124,125 Robust, although not conclusive, empirical proofs suggest their implication in a number of DNA and RNA transactions, such as telomeres maintenance, transcription, translation, alternative splicing etc.126 Impairment of G4 stability via small molecules is regarded as an effective way to gain control over such processes, and the related pathological states.127,128 Therefore, the last decades have seen a goldrush to G4 ligands.129 However, G4s significance extends beyond 292 | Photochemistry, 2019, 46, 281–318

biological investigation. In fact, they found diverse applications e.g. as DNAzymes, aptamers, logic gate components, etc. Due to this widespread interest, numerous red-NIR absorbing and emitting sensors are now available, displaying excellent turn-on effects and selectivity.21,130 A considerable number works via the conversion from a quenched, conformationally-free state into a fluorescent, rigid one upon binding (mono- and polymethine dyes,56,131,132 triphenylmethane probes,133,134 thioflavine T,135–138 etc.). The most remarkable results were recently provided by Chen et al., with the probe QUMA-1 (Fig. 14).139 Stacking onto the RNA G4 external tetrads is responsible for the rotation restriction around the methine bridge, connecting the N-methylated quinoline and coumarin moieties. This results in a 60-fold increase of the emission at 660 nm (Kd ¼ 0.57 mM for TERRA G4), which was used to track RNA G4 folding in live cells cytoplasm. Notably, this is the first report of time-resolved visualization of such structures. Aggregation was also extensively explored for G4 sensing. In this regard, most probes rely on the shift of the fluorescent monomer – quenched aggregate equilibrium towards the monomeric species, by

Fig. 14 G-quadruplex light-up probes working via conformational locking or aggregation related phenomena. Photochemistry, 2019, 46, 281–318 | 293

complexation to the G4 structure. This is the case of Red-NIR (near infrared) emitting distyrilpyridinium dyes (BCVP),140 core-extended naphthalene diimides (cex-NDIs)141,142 and squaraines (Fig. 14).143,144 Both BCVP and cex-NDIs interact not only with G4s but also with dsDNA. Interestingly, though, the binding produces a moderate light-up with G4s and a quenching with dsDNA. cex-NDIs were further optimized to implement a topologically-selective response, obtaining a light-up exclusively with anti-parallel and hybrid G4s.142 Squaraine SQgI was even more effective in this sense, since the sharp selectivity for parallel G4 structures was coupled with high fluorescence quantum yield and sensitivity.143 On the contrary, a few G4 probes function through an aggregation induced emission (AIE) mechanism, forming a fluorescent J-aggregate upon binding (Fig. 14). This was achieved, for example, with the silole scaffold.145 Blue emission (l ¼ 470 nm) of the resulting complex was successfully employed to monitor G4 survival during enzymatic degradation. Tetraphenylethene salt (TTAPE) behaved similarly. In fact, interaction with the G4 resulted in an intense concentration-dependent light-up (l ¼ 492 nm).146 The probe was also incorporated in an oligonucleotide conjugate.147 Hybridization of four independent constructs with the flanking regions of a tetramolecular G4 induced the spatially controlled aggregation of the dyes and the related AIE phenomenon. Transition metal complexes were also exploited as G4 sensors, due to the effect of binding on their luminescence. Numerous metal centres have been examined in this respect, including Ru(II), Ir(III),148 Pt(II)149 and Zn(II).150 One notable example is that of [Ru(bpy)2(dppz)]21. Starting from its tight interaction with dsDNA, the affinity was redirected towards G4s through some stratagems, such as the insertion of more extended aromatic ligands151,152 or polyarginine chains.153 For example, Liao et al. reported [Ru(bpy)2(bqdppz)]21, in which the dipyridophenazine ligand is fused to a benzo[j]quinoxaline polycycle.151 The remarkable enhancement of the CT emission band (l ¼ 600 nm) is 45-fold more intense with the telomeric G4 sequence 5 0 -d[AG3(T2AG3)3]-3 0 (250-fold) with respect to dsDNA. Finally, the rational design of fluorophore-ligands dimeric sensors has found wide application in the G4 field (Fig. 15). We recently reported two NDI-based dimer types, one containing two optically complementary NDIs154 and the other a tetra-substituted NDI conjugated to a coumarin.155,156 In the first case, the emission of the displaced tetrasubstituted NDI was restored upon binding of the tri-substituted one. In the second case, the coumarin behaved as an antenna, transferring the harvested light to the bound NDI (l ¼ 666 nm). Moreover, Monchaud and co-workers reported the so-called twice-as-smart G4 ligands (TASQ).117 Conjugation of four guanines to a central polycycle quenches the fluorescence of the core by eT. When Gs assemble in a synthetic quartet, recognizing the G4, lowering of their HOMO restores the polycycle emission. Notably, a multi-photon mechanism can be used to excite the probe via ET from the G4 structure to the emitting core,157 with interesting applications in RNA G4s sensing in live cells.158 294 | Photochemistry, 2019, 46, 281–318

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Fig. 15 Transition metal and dimeric light-up probes for G4 structures.

Fig. 16 G4 probes working via uncommon sensing methods.

Aside from this categorization, a handful of uncommon sensing methods were described (Fig. 16). Ladame and co-workers reported the fluorogenic assembly of a cyanine dye, templated by the G4 structure.159 In more detail, its non-emitting components were conjugated to peptide nucleic acid (PNA) sequences, complementary to the nucleobases adjacent to the G4 structure. The close proximity and the correct orientation provided by the G4 shifted the equilibrium towards the fluorescent product. Moreover, Luedtke’s group introduced fluorescent 8-substituted guanine analogues (e.g. 2PyG) in G4 forming sequences.121,122 These work as internal folding reporters due to the variation of ET efficiency from G to 2PyG in the different conformations. Finally, Vilar and co-workers reported DAOTA-M2.160 Despite displaying only a small fluorescent enhancement and poor G4 selectivity, its fluorescence had significantly longer lifetimes upon G4 binding than with double and single stranded DNA. Notably, fluorescence lifetime imaging (FLIM) revealed that this feature is maintained in live osteosarcoma cells, providing a conceptually new method for the tracking of G4 folding. 2.2 i-Motif As well as G-rich strands, the complementary C-rich strands can adopt their own secondary structure, called i-motif.161,162 This is constituted by stacks of hemiprotonated C : C þ base pairs. These form two parallel-stranded intercalated duplexes, which run anti-parallel to each other. Since protonation of each base pair is required for optimal hydrogen bonding, i-motifs are generally stable at slightly acidic pH (4.2–5.2). For long time, this was regarded as a major obstacle to in vivo folding. Therefore, biological investigation on i-motifs advanced at a much slower pace than that on G4s, despite 40% of genes, and notably oncogene promoters and telomeres, contain putative i-motif sequences. However, recent advances demonstrated that stability of i-motifs also depends on factors other than pH, such as length of C stretches and loops, as well as environmental conditions. Such findings renewed the interest in their cellular occurrence. To date, a number of i-motif putative sequences have been identified and characterized163 and their cellular folding has been proven by means of fluorescent antibodies.164 For these reasons, research on i-motif sensing with small molecules was mostly directed towards the construction of label-free DNA switches and nanomachines,165 instead of focussing on their biological 296 | Photochemistry, 2019, 46, 281–318

Fig. 17 i-Motif fluorescent probes.

occurrence. This is the case of crystal violet (CV)166 and berberine (BBR),167 both working via a conformational restriction mechanism (Fig. 17). Ma et al. reported the application of the former in a ‘‘OR’’ logic gate, based on simultaneous or alternate fluorescent sensing of i-motif and G4 folding upon H1 or K1 stimuli. Similarly, fluorescence enhancement of the latter (l ¼ 530 nm) upon telomeric i-motif binding was used to construct ‘‘INHIBIT’’, ‘‘AND’’ and OR’’ logic gates by Xu et al. These applications do not require highly selective sensors (e.g. CV and BBR are not i-motif specific binders). Nonetheless specificity would be desirable for biological investigation. Unfortunately, the first probes reported for this scope suffered from similar limitations, due to the difficulties in the selective targeting of such a narrow structure. This is the case for several TICT probes (Fig. 17). For example, ThT lights-up upon binding to the i-motif sequence formed in the retinoblastoma (Rb) gene,168 but, at the same time, yields similar outcomes with the RET proto-oncogene hairpin and G4 structures.135,168 Similarly, promiscuous binding and light-up (151-fold, l ¼ 630 nm) was reported for Quinaldine Red.169 Analogous selectivity issues were observed for metal complexes as well. This is the case of the Ir(III) based complex reported by Lu et al., whose luminescence increased upon i-motif and G4 binding (lMLCTE590 nm).170 However, the complex found useful application in indirect TdT (terminal deoxynucleotidyl transferase) activity tracking, through the sensing of the i-motif structure synthesized by the enzyme. The only sensor reported to date showing meaningful sensing selectivity for i-motif structures is Neutral Red (NR, Fig. 17).171 The sensing mechanism relies on NR protonation in the pH range relevant for telomeric i-motif folding. This triggers both the fluorescence lightup and the binding. In turn, the emission is further enhanced by the interaction with the C : C þ base pair. Although the calculated association constants are similar for telomeric i-motif and G4, the emission light-up is reported to be peculiar to the i-motif structure, providing a useful sensing tool. Photochemistry, 2019, 46, 281–318 | 297

Finally, many groups reported modified i-motif forming oligonucleotides, yielding a fluorescent emission upon folding. Among these, Mata et al. presented a fluorescent cytosine analogue, resulting from the fusion of N,N-dimethylaniline to the nucleobase core (DMAC, lmax ¼ 548 nm upon protonation and folding).123 Despite its fluorescence is greatly reduced upon folding, ET from C to DMAC is efficient only in the folded i-motif structure. This effect was exploited to gain insights on the unexpected kinetic barriers in i-motif unfolding. 2.3 A-motif Poly(A) sequences can adopt two distinct conformations depending on the pH.172 Above pH 7, poly(A) single strands form a right-handed helix. When lowering the pH, protonation of adenine N1 induces the assembly of two strands into a parallel right-handed duplex. Tightness of the packaging depends on protonation extent. The structure is held together by reverse hydrogen bonds and is further stabilized by electrostatic attraction between the protonated bases and the phosphate backbone. Interest in such structures mainly arises from their putative occurrence in mRNA tails, which contain sequences of up to 200 A bases in eukaryotes.173 Assembly of two different tails into a poly(A) duplex might be a way to control polyadenylation extent.174 More in general, A-motifs might control poly(A) binding proteins synthesis and the production of alternative protein forms.175 Despite the relevance of such motifs, reports on light-up probes for their investigation are quite limited. Attention was mostly focussed on isoquinoline alkaloids (berberine, sanguinarine, palmatine, coralyne, Fig. 18). Emission of all these structures is centred between 525 and 570 nm and is turned on upon interaction with the NA structure. Among these, berberine, sanguinarine and palmatine preferentially interact with the single stranded poly(A) helix in an intercalative fashion.176–178 On the

Fig. 18 A-motif light-up probes. 298 | Photochemistry, 2019, 46, 281–318

contrary, coralyne induces the self-assembly of an anti-parallel duplex.179 The light-up mechanism was not investigated in detail. However, based on their extended aromatic structure, with some saturated C–C bonds, either an aggregate-monomer equilibrium or the presence of a TICT state can be hypothesized. Safranin T, a phenazine dye, was also reported to undergo a moderate light-up upon binding of the single stranded poly(A) helix (l ¼ 580 nm), with affinity constants comparable to isoquinoline alkaloids.180 2.4 Three-way junctions Three-way junctions (TWJ) are non-canonical NA structures consisting of three duplex branches converging in a single central point.181 TWJ forming sequences are composed of three inverted repeats, able to pair with each other. The three resulting arms are disposed around a central cavity, with a C3 axis. TWJ putative sequences exist in both DNA and RNA, playing definite biological roles. In more detail, TWJs are intermediates of DNA replication and are associated with triplet repeat expansions in several genetic diseases.182 In RNA, TWJs are involved in translation and splicing.183 Compared to other NA secondary structures, interest in the development of TWJ ligands is more recent. These currently include only three classes of small molecules, all fitting in the TWJ central cavity: metallosupramolecular helicates,184 tryptycenes185 and macrocyclic azacryptands.186 As a consequence, research on suitable fluorescent probes is only at an early stage. Yang et al. recently reported a cationic calix[3]carbazole as the first selective TWJ sensor (Fig. 19).187 After an initial quenching, a bright light-up was observed at 389 nm, resulting from the 1 : 1 complex formation (Ka ¼ 4.33104 M1). This new emission was assigned to the ‘‘trap II’’ excimer formed by the overlap of the carbazole moieties. This particular orientation was obtained through the restriction of the moieties rotation when locked in the TWJ cavity.

Fig. 19 TWJ light-up probe. Photochemistry, 2019, 46, 281–318 | 299

2.5 Holliday junctions Holliday junctions (HJ) are constituted by four duplex branches converging towards a central cavity.188 Such four-way junctions can adopt two possible conformations: anti-parallel stacked-X and open planar. Occurrence of such structures was initially postulated by R. Holliday, as transient conformations adopted by DNA during homologous recombination (HR),189 and was later confirmed by electron-microscopy.190 Their stabilization by small molecules is regarded as a mean to stall HR, by blocking resolvases activity, and induce related DNA damage. However, only a handful of compounds were reported for the task. These include acridine dimers,191 hexa-peptides,192 porphyrins193 and a number of cleaving complexes, such as methidiumpropyl-EDTA-FeII.194 Unfortunately, no fluorescent probe has been reported yet.

2.6 Triplex Triplex-forming oligonucleotides (TFOs) are supramolecular structures in which a third strand of nucleic acid binds to a double helix, through Hoogsteen or reverse Hoogsteen hydrogen bonds. The prerequisite for the existence of this structure is the presence of polypurinepolypyrimidine repeats in the DNA duplex target.195 There are three classes of triplex DNA that differ in NA sequence and in phosphate backbone orientation of the oligopurine strand with respect to the duplex: TC, GT and GA triplexes.196 In TC triplexes the third strand presents the same orientation as the duplex (from 5 0 to 3 0 orientation) forming TA*T or CG*C triplets through Hoogsteen hydrogen bonds. In GT triplexes the third strand can be either anti-parallel or parallel to the purinic strand of the duplex, interacting through reverse Hoogsteen and Hoogsteen bonds respectively and forming CG*G or TA*T triplets. Finally, in GA triplexes the third strand has an anti-parallel orientation with respect to the bound duplex and forms reverse Hoogsteen CG*G and TA*A triplets.196 Each of these structures is thermodynamically stable under physiological conditions.197 Nevertheless, high levels of multivalent cations, such as Mn21, Ni21, Mg21,198 or polyamines are necessary to compensate the unfavourable charge repulsion between the three negatively charged backbones. As much as other non B-DNA secondary structures, TFOs have been identified as bioactive structures involved in the regulation of gene expression,199–201 in DNA damage202 and repair,203–205 and even in progression of some diseases.206 Therefore, their detection has been of fundamental interest over the last 15 years. Fan et al.207 synthesised a highly selective triplex fluorescent sensor based on the conjugation of a 4-aminonaphthalimide unit, already used as a biomolecular sensor, and a 2-(2-naphthyl)quinoline moiety, inasmuch recognized as potent TA*T triplex intercalator.208 Fluorescent enhancement is selectively observed with TFOs at pH higher than 6.5. The sensor exhibits a two-fold difference in fluorescence response upon binding with the triplex in comparison with duplex and ssDNA. 300 | Photochemistry, 2019, 46, 281–318

Weisz et al.209 studied 11-phenyl-substituted indolo[3,2-b]quinoline derivatives (Fig. 20), that exhibited significant in vitro anticancer activity thanks to the high binding affinity to TFOs. Fluorescence emission spectra of these compounds showed 20-fold fluorescence enhancement upon TFOs binding with respect to ss-DNA. Recent in vitro studies demonstrated that also the renowned dye Thiazole Orange has a higher affinity for TFOs structures than for duplex DNA.210 Nevertheless, comparable affinity for G4 structures impedes biological applications in TFOs sensing.211 Although these small molecules are easily modifiable by synthetic means, they all exhibit at least a moderate binding to other DNA structures. Finding a selective and sensitive ligand exclusively interacting with triplex structures is instead crucial for the development of viable analytical and therapeutic tools. The first breakthrough in this sense were provided by Shao et al.212 They identified Fisetin (FIS, Fig. 21) as a high performance and selective sensor for TFOs, screening a family of 18 flavonoids. FIS interacts with triplexes in an end-stacking mode with a binding constant of about 3.6106 M1 and provides considerable stabilization (DTm ¼ 14 1C). The interaction activates FIS green emission via an ESIPT mechanism. Interestingly, FIS is highly selective for the triplex structure over other secondary structures (e.g. ds-, ssNA, hairpins and DNA/RNA G4s). Moreover, this selectivity is maintained in a wide pH range and does not depend on molecularity (intra- and intermolecular), sequence and length of the TFOs. In a more recent work, the same group proposed the natural product chelerythrine (CHE, Fig. 21) as a triplex specific binder, inducer and sensor, screening a variety of natural isoquinoline alkaloids.213 CHE is able to bind TA*T triplets with a fluorescence response 20- and 54-fold higher than those observed with dsDNA and G4s, respectively. The proposed binding stoichiometry is 2 : 1 (CHE:triplex), regardless of TFO type, loop sequence and stem length. Binding constants are between 5 and 6.4106 M1, depending on the specific triplex. Another interesting approach to the development of novel triplexbased sensors was proposed by Zhao et al.214 They exploited the triplex DNA structures to create a multi-functional platform based on a fluorescence ‘‘turn off-on’’ mechanism, designed to discriminate cisplatin from transplatin compounds. The ZnCdSe quantum dots fluorescence is quenched by the interaction with cisplatin anti-cancer drugs through electron transfer. The presence of DNA restores this emission, by interaction with the metal complex. Triplex DNA binding efficiency exceeds that of ss-DNA and duplex of about 20% and 10%, respectively. This is due to its larger aromatic surface and to the presence of more negative charges able to attract positively-charged hydrolysates of cisplatin.

2.7 Hairpin Hairpin structures, or stem-loops, are intramolecular structures. In particular, they occur when two regions of the same filament form a double Photochemistry, 2019, 46, 281–318 | 301

302 | Photochemistry, 2019, 46, 281–318

Fig. 20 Triplex-selective fluorescent sensors.

Fig. 21 Fisetin and Chelerythrine structures.

helix ending in a loop, with unpaired or non-Watson–Crick-paired nucleotides. Generally, they can arise in ssDNA or, more commonly, in RNA regions containing complementary sequences running in opposite directions.215 Hairpins play an essential role in the regulation of gene expression, in replication initiation and in transcription.215 Moreover, they can guide RNA folding, protect mRNA from degradation, act as a substrate for enzymatic reactions and as a binding site for a large number of RNA binding proteins.216 An interesting attempt to recognize and sense this particular secondary structure was done by Hong et al., who developed a sandwich-type DNA biosensor.217 Despite the recognized necessity to develop highly specific fluorescent sensors for the labelling of hairpin structures, such tools are completely missing to date. More than considering them as analytes, most research groups have devoted their efforts to exploit hairpins as fluorescently labelled probes.218,219 For example, they have found fruitful application as probes attached to gold nanoparticles,220 in the fluorescent imaging and detection of miRNA221,222 in vitro and in live cells,223 and in metal ion detection inside cells.224

2.8 Z-DNA Z-DNA is a DNA duplex conformation with left-handed helicity.225 This imposes relevant structural differences with respect to B-DNA. In fact, the phosphate backbone has a zig–zag shape, with negatively charged groups lying closer to each other than in B-DNA (8 Å vs. 11.7 Å). Moreover, the distinction between the major and minor grooves is lost, in favour of a single deep one. Nucleobases are located farther from the central axis than in B-DNA and are oriented perpendicularly to the backbone. Finally, glycosidic bonds are forced to adopt an alternate anti-syn orientation. Therefore, the Z-DNA conformation is observed mostly in sequences with alternating purines and pyrimidines (e.g. d(GC)n, occurring every 3000 bp),226 under specific circumstances. For example, high ionic strength favours B-to-Z DNA transition, since it relieves phosphate–phosphate repulsion.225 Interestingly, a number of evidences (e.g. specific binding proteins) demonstrate Z-DNA occurrence in vivo, with negative supercoiling apparently triggering the transition from B-DNA.227 Proposed biological roles concern regulation of gene expression.50 Selective sensing of Z-DNA with respect to B-DNA is quite demanding and reports of specific ligands are limited. Attention was mostly focussed on porphyrins, not as fluorescent sensors, but as chiroptical probes (Fig. 22).228 However, slight modifications of their emission were observed upon complexation. Moreover, metal ions inserted in the central cavity (Zn21, Ni21) take up guanine N7 in their coordination sphere upon interaction with DNA. For these reasons, implementation of the scaffolds for Z-DNA fluorescent sensing could be envisaged. Fluorophores insertion into the sequence was proposed as a mean to monitor B-to-Z helix transition in vitro (Fig. 22). For example, Okamoto et al. reported a DNA sequence containing adjacent pyrene ethynyl-G and Photochemistry, 2019, 46, 281–318 | 303

304 | Photochemistry, 2019, 46, 281–318

Fig. 22 Z-DNA fluorescent reporters.

pyrene propargyl-C.229 Shifting of the conformation from B- to Z-DNA forced the two pyrene moieties in the correct orientation to form an excimer. As a result, a marked red-shift (from 440 to 507 nm) in absorption and the related fluorescence were observed. Insertion of a single pyrene ethynyl-A or U at the oligonucleotide terminus yielded similar results.230 In fact, the monomer fluorescence lights-up upon transition to the Z-DNA conformation and subsequent suppression of p-stacking with the helix nucleobases. 2.9 S-DNA Slipped-strand DNA (S-DNA) are sequence-specific non-Watson–Crick DNA structures, displaying remarkable stability at physiological salt concentrations. These are involved in dynamic mutations associated with a large number of genetic diseases.231,232 These occur when the complementary strands comprehend at least two copies of identical repeats. Unpairing of one repeat and subsequent bulging out of one of the single strands forces the remaining strand to pair with the second repeat, thus producing a misalignment. Therefore, S-DNA motifs could cause errors during DNA replication, repair, recombination or transcription.233,234 Structural DNA changes occurring during overstretching235 seem to play a key role in many genomic processes. Therefore, identification of the conditions leading to S-DNA formation is a fundamental step to understand their implication in mechanical DNA stress. Their cellular occurrence is supported by the existence of proteins able to bind them in a structure-specific mode.232 Despite these promising experimental data and the biological significance of the structure, no specific fluorescent light-up probe is available yet. However, Peterman et al.231 recently demonstrated by indirect means the formation of S-DNA when the dsDNA is overstretched in high ionic strength conditions. In particular, they guessed S-DNA formation due to the lack of binding to the target DNA by fluorescently labelled replication protein A (RPA), a ssDNA binding protein,236 and the switch off of Syntox fluorescence, a dsDNA probe.237 The same method had previously been applied using YOYO, as dsDNA-specific dye, and Alexa-555-labeled human mitochondrial single-stranded DNA-binding proteins (mtSSB).236 This possible structural transition was additionally supported in the work of Zhang et al. with a complementary technique, singlemolecule calorimetry, in the aforementioned overstretching DNA conditions.238 2.10 DNA bulges Bulged structures are interruptions in double-helical DNA caused by the absence on one strand of the nucleotides complementary to the opposite strand tract. This induces a tight junction in the duplex.239 As other noncanonical NA structures, bulges seem to be involved in a large number of biological processes, for example as intermediates in RNA splicing,240 regulatory protein binders,241 mediators of frameshift and intercalatorinduced mutagenesis242 and of imperfect homologous recombination.243 Photochemistry, 2019, 46, 281–318 | 305

Fig. 23 Neocarzinostatin and b-aminoglucose chromophores structures.

Fig. 24 a- and b-aminofucosylated structures.

Although the involvement in such processes is linked to some relevant diseases, such as HIV-1241 and neurodegenerative pathologies,244 rather few endeavours have been made to identify fluorescent small molecules able to recognize bulge structures. Starting from the observation that the neocarzinostatin chromophore (NCSi-gb, Fig. 23) was capable of binding bulged DNA with good selectivity over the duplex form,245 Goldberg et al.240 synthetized a new thermodynamically stable analogue. This consisted in a spiro-alcohol conjugated to b-aminoglucose (Fig. 23). Its ability to adopt of the right wedge-shape is the key to its good affinity for bulges. Association constants with two-base bulges were in the submicromolar range. Unfortunately, the interaction only produced a fluorescence quenching. Subsequently, Jones et al. synthetized two a-aminofucosylated diastereomeric adducts (Fig. 24) that selectively bind two-base bulges with affinity constants of E80 nM.246 In this case, a fluorescence quenching occurred for bulges located next to a GC base pair. Conversely, an increase in fluorescence intensity was observed with AT base pairs close the bulge. In any case, results demonstrated a remarkable selectivity for two-base bulge structures against duplex DNA. The difference in dissociation constants was more than two orders magnitude. Interestingly, the probe was even able to discriminate against one-base and three-base bulge, displaying Kd values one order magnitude lower than for two-base bulges. 306 | Photochemistry, 2019, 46, 281–318

Two years later, recognizing the key role of stereochemistry, the same group synthetized b analogues of the structures,247 lowering the dissociation constant value for two-base bulges to 200 nM. No discernible binding was observed to duplex DNA and unbulged hairpins.

2.11 Mismatches and apurinic/apyrimidinic sites Mismatched base pairs statistically occur in cells every 106–108 nucleobases.248 Endogenous causes for their generation include replication errors, HR related events and spontaneous nucleobases deamination.249,250 Moreover, exogenous agents (reactive species, alkylating molecules, UV light, etc.) also have a role in their production.251 Structure and stability of the mismatch depend on the nature of the bases involved, with G being the most promiscuous one and C the least adaptable one. Apurinic/ apyrimidinic sites (AP sites, or abasic sites) production is closely related to mismatch repair, and in particular to the base excision mechanism.252 Intervening glycosilases flip out the incorrect base and cleave it in the first step, to then let other enzymes repair the lesion. Alternatively, AP sites can be produced spontaneously. Targeting of these structures by small molecules has been widely explored for medical purposes, as recently reviewed by Granzhan et al.253 In fact, deficiency of repair enzymes is associated with carcinogenesis.254 In addition, mismatches accumulation in trinucleotides subject to expansion can be used to tackle the related pathologies (e.g. fragile X syndrome).255 Moreover, mismatches targeting and signalling has relevant in vitro applications, e.g. in single nucleotide polymorphism (SNP) typing.256 Some light-up probes have already been reported, targeting either proper mismatches or AP sites. Concerning mismatches sensing, Zeglis et al. reported a dimer constituted by Oregon Green 514 fluorophore and [Rh(phen)(bpy)(chrysi)]31 metalloinsertor (Fig. 25).257 Electrostatic interaction brings the two moieties in close proximity in the unbound state. In such conformation, the fluorophore emission is quenched by eT. Selective insertion of the Rh ligand into the mismatch cavity separates the two moieties, partially restoring Oregon Green 514 emission (E8-fold enhancement). Interestingly, the dimer is able to sense most mismatches, except for particularly stable ones. Mismatches sensing was also achieved through modified nucleotides, mostly for SNP typing (Fig. 25). This is the case of 8-aza-2 0 -deoxyguanosine.258 Conversion to the fluorescent anion is favoured for the unpaired nucleotide (F ¼ 0.55, pKa ¼ 8.8) and the resulting emission can be used to monitor the formation of mismatches with complementary strands. Similarly, fluorescent pyrrolo-dC click adducts (F ¼ 0.32) were incorporated in single strand probes.259 Such emission was maintained only in the absence of Watson–Crick base pairing, with the signal intensity being inversely dependent on the mismatch stability. Multiple probes for AP sites were designed, adapting the wellestablished 2-amino-1,8-naphthyridine scaffold of ATMND. For example, Wang et al. reported an ATMND-DBD dimer (Fig. 26), which signals the ligand binding to the AP site through the light-up of DBD Photochemistry, 2019, 46, 281–318 | 307

Fig. 25 Mismatched DNA fluorescent probes.

Fig. 26 AP sites fluorescent probes.

emission (l ¼ 585 nm, LOD ¼ 1.4–32 nM depending on the AP site).260 Affinity for dsDNA with C or T opposite to the AP site is comparable (KaE106 M1). Instead, association constants are two orders of magnitude lower for G and A, suggesting a role of the cavity size in determining the affinity. ATMND-TO (l ¼ 530 nm) and DMP-BO (l ¼ 483 nm) dimers combined use was reported for apurinic and apyrimidinic sites discrimination, due to their affinities for AP site facing C/T and G, respectively.261 Fluorescent AP site recognition relying on hydrogen bonding was also achieved with 3,5-diamino-6-chloro-2-pyrazine carbonitrile (DCPC, Fig. 26).262 Weak emission of DCPC is significantly 308 | Photochemistry, 2019, 46, 281–318

enhanced (l ¼ 412 nm, 35-fold) upon binding of AP sites facing a T, although the sensitivity depends on the flanking nucleobases identity. Finally, FIS signals AP sites facing C or T nucleobases through an ESIPT (excited state intramolecular proton transfer) mechanism.263 The intramolecular process occurs exclusively inside a hydrophobic pocket, such as that of an AP site, preventing proton transfer from the solvent. Formation of the active tautomer in the excited state (lE550 nm) produces the fluorescent sensing. Since the compound is selective for AP sites facing T and C bases, recognition likely happens via intercalation in the size-matching cavity or by partial hydrogen bonding to the involved nucleobases.

3

Conclusions

Mounting evidence suggest that DNA is far from being a passive molecule, simply undergoing enzymes action during genetic information transfer. Non-B DNA structures and their RNA counterparts seem to play active roles in regulating these processes, in a complex interplay of enzymes controlling their folding and unfolding. Deeper understanding of their biological roles and of their occurrence at specific stages of cell cycles is the focus of current research. The use of fluorescent probes, and in particular light-up ones, holds great potential in this investigation, due to the advantages in terms of costs, rapidity and sensitivity. Certainly, considerable advances have been made in the last decades in terms of specificity and affinity of the available fluorophores, culminating in cellular visualization of some of the structures (e.g. G4, triplex and i-motifs). However, the effort devoted to the search of suitable and selective dyes and the subsequent results vary greatly depending on the NA conformation, with some of them still lacking a proper detection system. Filling these gaps should be the aim of the future research, contextually to exploiting the available probes for deeper biological investigation of the structures already addressed.

References 1 2 3 4

J. D. Watson and F. H. Crick, Nature, 1953, 171, 737. A. Bacolla and R. D. Wells, Mol. Carcinog., 2009, 48, 273. M. Gueron and J. L. Leroy, Curr. Opin. Struct. Biol., 2000, 10, 326. J. H. Vandesande, N. B. Ramsing, M. W. Germann, W. Elhorst, B. W. Kalisch, E. Vonkitzing, R. T. Pon, R. C. Clegg and T. M. Jovin, Science, 1988, 241, 551. 5 J. H. Zhao, A. Bacolla, G. L. Wang and K. M. Vasquez, Cell. Mol. Life Sci., 2010, 67, 43. 6 A. Bacolla, D. N. Cooper and K. M. Vasquez, Genome Med., 2013, 5, 51. 7 G. L. Wang and K. M. Vasquez, DNA Repair, 2014, 19, 143. 8 G. Wang and K. M. Vasquez, Mutat. Res., 2006, 598, 103. 9 C. E. Pearson, H. Zorbas, G. B. Price and M. Zannis-Hadjopoulos, J. Cell. Biochem., 1996, 63, 1. 10 L. A. Cahoon and H. S. Seifert, Science, 2009, 325, 764. 11 N. Maizels, Nat. Struct. Mol. Biol., 2006, 13, 1055. Photochemistry, 2019, 46, 281–318 | 309

12 13 14 15 16 17 18 19 20 21 22 23 24 25

26 27 28 29 30 31

32 33 34 35 36 37 38 39 40 41 42 43

S. L. Cree and M. A. Kennedy, Front. Pharmacol., 2014, 5, 160. R. Simone, P. Fratta, S. Neidle, G. N. Parkinson and A. M. Isaacs, FEBS Lett., 2015, 589, 1653. S. M. Hampel, A. Pepe, K. M. Greulich-Bode, S. V. Malhotra, A. P. Reszka, S. Veith, P. Boukamp and S. Neidle, Mol. Pharm., 2013, 83, 470. Y. M. Agazie, J. S. Lee and G. D. Burkholder, J. Biol. Chem., 1994, 269, 7019. G. Biffi, D. Tannahill, J. McCafferty and S. Balasubramanian, Nat. Chem., 2013, 5, 182. A. Henderson, Y. Wu, Y. C. Huang, E. A. Chavez, J. Platt, F. B. Johnson, R. M. Brosh, Jr., D. Sen and P. M. Lansdorp, Nucleic Acids Res., 2014, 42, 860. M. Ohno, T. Fukagawa, J. S. Lee and T. Ikemura, Chromosoma, 2002, 111, 201. A. S. Boutorine, D. S. Novopashina, O. A. Krasheninina, K. Nozeret and A. G. Venyaminova, Molecules, 2013, 18, 15357. E. Largy, A. Granzhan, F. Hamon, D. Verga and M. P. Teulade-Fichou, Top. Curr. Chem., 2013, 330, 111. Y. V. Suseela, N. Narayanaswamy, S. Pratihar and T. Govindaraju, Chem. Soc. Rev., 2018, 47, 1098. A. Bedrat, L. Lacroix and J. L. Mergny, Nucleic Acids Res., 2016, 44, 1746. J. Lopes, A. Piazza, R. Bermejo, B. Kriegsman, A. Colosio, M. P. TeuladeFichou, M. Foiani and A. Nicolas, EMBO J., 2011, 30, 4033. D. Renciuk, J. Rynes, I. Kejnovska, S. Foldynova-Trantirkova, M. Andang, L. Trantirek and M. Vorlickova, BBA – Gene Regul. Mech., 2016, 1860, 175. Y. Chen, S. Zhang and S. Xu, in Green Radio Communication Networks, ed. E. Hossain, G. P. Fettweis and V. K. Bhargava, Cambridge University Press, Cambridge, 2012, pp. 3–23. D. Sun and L. H. Hurley, J. Med. Chem., 2009, 52, 2863. S. Kendrick, H.-J. Kang, M. P. Alam, M. M. Madathil, P. Agrawal, V. Gokhale, D. Yang, S. M. Hecht and L. H. Hurley, J. Am. Chem. Soc., 2014, 136, 4161. P. Giri and G. Suresh Kumar, Mol. BioSyst., 2010, 6, 81. J. Choi and T. Majima, Chem. Soc. Rev., 2011, 40, 5893. C. Guthrie and B. Patterson, Annu. Rev. Genet., 1988, 22, 387. B. T. Wimberly, D. E. Brodersen, W. M. Clemons, Jr., R. J. Morgan-Warren, A. P. Carter, C. Vonrhein, T. Hartsch and V. Ramakrishnan, Nature, 2000, 407, 327. M. R. Singleton, S. Scaife and D. B. Wigley, Cell, 2001, 107, 79. J. R. Goni, X. de la Cruz and M. Orozco, Nucleic Acids Res., 2004, 32, 354. B. P. Belotserkovskii, E. De Silva, S. Tornaletti, G. Wang, K. M. Vasquez and P. C. Hanawalt, J. Biol. Chem., 2007, 282, 32433. K. M. Vasquez, L. Narayanan and P. M. Glazer, Science, 2000, 290, 530. M. Bzymek, N. H. Thayer, S. D. Oh, N. Kleckner and N. Hunter, Nature, 2010, 464, 937. S. Sarbajna and S. C. West, Trends Biochem. Sci., 2014, 39, 409. S. Dutertre, R. Sekhri, L. A. Tintignac, R. Onclercq-Delic, B. Chatton, C. Jaulin and M. Amor-Gueret, J. Biol. Chem., 2002, 277, 6280. J. W. Harper and N. J. Logsdon, Biochemistry, 1991, 30, 8060. P. W. Huber, J. P. Rife and P. B. Moore, J. Mol. Biol., 2001, 312, 823. M. L. Colgrave, H. E. Williams and M. S. Searle, Angew. Chem., Int. Ed. Engl., 2002, 41, 4754. M. Havrila, M. Zgarbova, P. Jurecka, P. Banas, M. Krepl, M. Otyepka and J. Sponer, J. Phys. Chem. B, 2015, 119, 15176. T. Katayama, S. Ozaki, K. Keyamura and K. Fujimitsu, Nat. Rev. Microbiol., 2010, 8, 163.

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68

69 70

S. Bates, R. A. Roscoe, N. J. Althorpe, W. J. Brammar and B. M. Wilkins, Microbiology, 1999, 145, 2655. M. E. Val, M. Bouvier, J. Campos, D. Sherratt, F. Cornet, D. Mazel and F. X. Barre, Mol. Cell, 2005, 19, 559. V. W. Silva, G. Askan, T. D. Daniel, M. Lowery, D. S. Klimstra, G. K. Abou-Alfa and J. Shia, Chin. Clin. Oncol., 2016, 5, 62. K. S. Gates, Chem. Res. Tox., 2009, 22, 1747. J. D. Cleary, K. Nichol, Y. H. Wang and C. E. Pearson, Nat. Genet., 2002, 31, 37. C. E. Pearson, M. Tam, Y. H. Wang, S. E. Montgomery, A. C. Dar, J. D. Cleary and K. Nichol, Nucleic Acids Res., 2002, 30, 4534. B. K. Ray, S. Dhar, A. Shakya and A. Ray, Proc. Natl. Acad. Sci. U. S. A., 2011, 108, 103. A. Rich and S. Zhang, Nat. Rev. Genet., 2003, 4, 566. D. Kim, Y. H. Lee, H. Y. Hwang, K. K. Kim and H. J. Park, Curr. Drug Targets, 2010, 11, 335. L. G. Lee, C. H. Chen and L. A. Chiu, Cytometry, 1986, 7, 508. H. S. Rye, M. A. Quesada, K. Peck, R. A. Mathies and A. N. Glazer, Nucleic Acids Res., 1991, 19, 327. H. Zipper, H. Brunner, J. Bernhagen and F. Vitzthum, Nucleic Acids Res., 2004, 32, e103. Q. Yang, J. Xiang, S. Yang, Q. Zhou, Q. Li, Y. Tang and G. Xu, Chem. Commun., 2009, 1103. Q. Yang, J.-F. Xiang, S. Yang, Q. Li, Q. Zhou, A. Guan, L. Li, Y. Zhang, X. Zhang, H. Zhang, Y. Tang and G. Xu, Anal. Chem., 2010, 82, 9135. L. Zhang, J. C. Er, X. Li, J. J. Heng, A. Samanta, Y.-T. Chang and C.-L. K. Lee, Chem. Commun., 2015, 51, 7386. X. Fei, R. Li, D. Lin, Y. Gu and L. Yu, J. Fluor., 2015, 25, 1251. Y. Gu, D. Lin, Y. Tang, X. Fei, C. Wang, B. Zhang and J. Zhou, Spectrochim. Acta. A, 2018, 191, 180. W. C. Huang, T. Y. Tseng, Y. T. Chen, C. C. Chang, Z. F. Wang, C. L. Wang, T. N. Hsu, P. T. Li, C. T. Chen, J. J. Lin, P. J. Lou and T. C. Chang, Nucleic Acids Res., 2015, 43, 10102. M. Q. Wang, G. Y. Ren, S. Zhao, G. C. Lian, T. T. Chen, Y. Ci and H. Y. Li, Spectrochim. Acta A, 2018, 199, 441. C. C. Chang, I. C. Kuo, I. F. Ling, C. T. Chen, H. C. Chen, P. J. Lou, J. J. Lin and T. C. Chang, Anal. Chem., 2004, 76, 4490. C. C. Chang, J. Y. Wu, C. W. Chien, W. S. Wu, H. Liu, C. C. Kang, L. J. Yu and T. C. Chang, Anal. Chem., 2003, 75, 6177. A. K. Jain, V. V. Reddy, A. Paul, M. K and S. Bhattacharya, Biochemistry, 2009, 48, 10693. S. A. Latt and G. Stetten, J. Histochem. Cytochem., 1976, 24, 24. V. Satam, B. Babu, P. Patil, K. A. Brien, K. Olson, M. Savagian, M. Lee, A. Mepham, L. B. Jobe, J. P. Bingham, L. Pett, S. Wang, M. Ferrara, C. D. Bruce, W. D. Wilson, M. Lee, J. A. Hartley and K. Kiakos, Bioorg. Med. Chem. Lett., 2015, 25, 3681. M. Deiana, B. Mettra, L. Martinez-Fernandez, L. M. Mazur, K. Pawlik, C. Andraud, M. Samoc, R. Improta, C. Monnereau and K. Matczyszyn, J. Phys. Chem. Lett., 2017, 8, 5915. Y. H. Hu, F. Lin, T. Wu, Y. Wang, X. S. Zhou and Y. Shao, Chem. – Asian J., 2016, 11, 2041. L. J. Xu, S. N. Hong, N. Sun, K. W. Wang, L. Zhou, L. Y. Ji and R. J. Pei, Chem. Commun., 2016, 52, 179. Photochemistry, 2019, 46, 281–318 | 311

71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91

92

93 94 95 96 97

98 99

L. H. Zhang, H. Liu, Y. Shao, C. Lin, H. Jia, G. Chen, D. Z. Yang and Y. Wang, Anal. Chem., 2015, 87, 730. Y. Yu, C. Y. Long, S. Q. Su and J. P. Liu, Anal. Lett., 2001, 34, 2659. S. Sasaki, G. P. C. Drummen and G. Konishi, J. Mater. Chem. C, 2016, 4, 2731. A. C. Bhasikuttan, J. Mohanty and H. Pal, Angew. Chem., 2007, 46, 9305. J. H. Guo, L. N. Zhu, D. M. Kong and H. X. Shen, Talanta, 2009, 80, 607. D. M. Kong, Y. E. Ma, J. H. Guo, W. Yang and H. X. Shen, Anal. Chem., 2009, 81, 2678. L. Liu, Y. Shao, J. Peng, H. Liu and L. Zhang, Mol. BioSyst., 2013, 9, 2512. N. Amdursky, Y. Erez and D. Huppert, Acc. Chem. Res., 2012, 45, 1548. S. I. Reja, I. A. Khan, V. Bhalla and M. Kumar, Chem. Commun., 2016, 52, 1182. G. P. Drummen, L. C. van Liebergen, J. A. Op, den Kamp and J. A. Post, Free Radical Biol. Med., 2002, 33, 473. S. Sasaki, K. Hattori, K. Igawa and G. Konishi, J. Phys. Chem. A, 2015, 119, 4898. W. L. Goh, M. Y. Lee, T. L. Joseph, S. T. Quah, C. J. Brown, C. Verma, S. Brenner, F. J. Ghadessy and Y. N. Teo, J. Am. Chem. Soc., 2014, 136, 6159. J. Sutharsan, M. Dakanali, C. C. Capule, M. A. Haidekker, J. Yang and E. A. Theodorakis, ChemMedChem, 2010, 5, 56. A. Shivalingam, M. A. Izquierdo, A. Le Marois, A. Vysniauskas, K. Suhling, M. K. Kuimova and R. Vilar, Nat. Commun., 2015, 6, 8178. J. Luo, Z. Xie, J. W. Lam, L. Cheng, H. Chen, C. Qiu, H. S. Kwok, X. Zhan, Y. Liu, D. Zhu and B. Z. Tang, Chem. Commun., 2001, 1740. J. W. Chen, C. C. W. Law, J. W. Y. Lam, Y. P. Dong, S. M. F. Lo, I. D. Williams, D. B. Zhu and B. Z. Tang, Chem. Mater., 2003, 15, 1535. Y. Hong, J. W. Lam and B. Z. Tang, Chem. Commun., 2009, 4332. G. Han, D. Kim, Y. Park, J. Bouffard and Y. Kim, Angew. Chem., 2015, 54, 3912. D. Liao, W. Li, J. Chen, H. Jiao, H. Zhou, B. Wang and C. Yu, Anal. Chim. Acta, 2013, 797, 89. K. E. Achyuthan, D. G. Whitten and D. W. Branch, Anal. Sci., 2010, 26, 55. G. Y. Guralchuk, A. V. Sorokin, I. K. Katrunov, S. L. Yefimova, A. N. Lebedenko, Y. V. Malyukin and S. M. Yarmoluk, J. Fluor., 2007, 17, 370. R. R. Hu, E. Lager, A. Aguilar-Aguilar, J. Z. Liu, J. W. Y. Lam, H. H. Y. Sung, I. D. Williams, Y. C. Zhong, K. S. Wong, E. Pena-Cabrera and B. Z. Tang, J. Phys. Chem. C, 2009, 113, 15845. G. Gupta, A. Das, N. B. Ghate, T. Kim, J. Y. Ryu, J. Lee, N. Mandal and C. Y. Lee, Chem. Commun., 2016, 52, 4274. L. Peng, S. Xu, X. Zheng, X. Cheng, R. Zhang, J. Liu, B. Liu and A. Tong, Anal. Chem., 2017, 89, 3162. Z. Gao, B. Han, K. Chen, J. Sun and X. Hou, Chem. Commun., 2017, 53, 6231. Y. Hong, M. Haussler, J. W. Lam, Z. Li, K. K. Sin, Y. Dong, H. Tong, J. Liu, A. Qin, R. Renneberg and B. Z. Tang, Chem. – Eur. J., 2008, 14, 6428. Y. Hong, H. Xiong, J. W. Lam, M. Haussler, J. Liu, Y. Yu, Y. Zhong, H. H. Sung, I. D. Williams, K. S. Wong and B. Z. Tang, Chem. – Eur. J., 2010, 16, 1232. Z. Wang, Y. Gu, J. Liu, X. Cheng, J. Z. Sun, A. Qin and B. Z. Tang, J. Mater. Chem. B, 2018, 6, 1279. G. Licari, P. F. Brevet and E. Vauthey, Phys. Chem. Chem. Phys., 2016, 18, 2981.

312 | Photochemistry, 2019, 46, 281–318

100 101 102 103 104 105

106 107 108 109 110

111 112 113 114 115 116 117 118 119 120

121 122 123 124 125 126 127 128

K. E. Achyuthan, J. L. McClain, Z. Zhou, D. G. Whitten and D. W. Branch, Anal. Sci., 2009, 25, 469. S. Yarmoluk, V. Kovalska and M. Losytskyy, Biotech. Histochem., 2008, 83, 131. T. Ogul’chansky, M. Losytskyy, V. B. Kovalska, V. M. Yashchuk and S. M. Yarmoluk, Spectrochim. Acta A, 2001, 57, 1525. A. S. Tatikolov, J. Photoch. Photobiol. C, 2012, 13, 55. H. X. Sun, J. F. Xiang, W. Gai, Y. Liu, A. Guan, Q. F. Yang, Q. Li, Q. Shang, H. Su, Y. L. Tang and G. Z. Xu, Chem. Commun., 2013, 49, 4510. W. Gai, Q. F. Yang, J. F. Xiang, L. J. Yu, A. J. Guan, Q. Li, H. X. Sun, Q. Shang, W. Jiang, H. Zhang, Y. Liu, L. X. Wang and Y. L. Tang, Phys. Chem. Chem. Phys., 2013, 15, 5758. B. Jin, X. Zhang, W. Zheng, X. Liu, J. Zhou, N. Zhang, F. Wang and D. Shangguan, Anal. Chem., 2014, 86, 7063. V. Grande, F. Doria, M. Freccero and F. Wurthner, Angew. Chem., 2017, 56, 7520. F. Doria, M. Nadai, M. Zuffo, R. Perrone, M. Freccero and S. N. Richter, Chem. Commun., 2017, 53, 2268. M. Zuffo, F. Doria, S. Botti, G. Bergamaschi and M. Freccero, BBA-Gen. Subjects, 2017, 1861, 1303. J. Gershberg, M. Radic Stojkovic, M. Skugor, S. Tomic, T. H. Rehm, S. Rehm, C. R. Saha-Moller, I. Piantanida and F. Wurthner, Chem. – Eur. J., 2015, 21, 7886. B. Fu, J. Huang, D. Bai, Y. Xie, Y. Wang, S. Wang and X. Zhou, Chem. Commun., 2015, 51, 16960. M. Zuffo, F. Doria, V. Spalluto, S. Ladame and M. Freccero, Chem. – Eur. J., 2015, 21, 17596. F. Doria, A. Oppi, F. Manoli, S. Botti, N. Kandoth, V. Grande, I. Manet and M. Freccero, Chem. Commun., 2015, 51, 9105. N. Narayanaswamy, M. Unnikrishnan, M. Gupta and T. Govindaraju, Bioorg. Med. Chem. Lett., 2015, 25, 2395. F. Yang, C. Wang, L. Wang, Z. W. Ye, X. B. Song and Y. Xiao, Chin. Chem. Lett., 2017, 28, 2019. E. H. Lu, X. J. Peng, F. L. Song and J. L. Fan, Bioorg. Med. Chem. Lett., 2005, 15, 255. A. Laguerre, L. Stefan, M. Larrouy, D. Genest, J. Novotna, M. Pirrotta and D. Monchaud, J. Am. Chem. Soc., 2014, 136, 12406. J. Zhou, B. T. Roembke, G. Paragi, A. Laguerre, H. O. Sintim, C. Fonseca Guerra and D. Monchaud, Sci. Rep., 2016, 6, 33888. F. R. Keene, J. A. Smith and J. G. Collins, Coord. Chem. Rev., 2009, 253, 2021. R. Kieltyka, P. Englebienne, N. Moitessier and H. Sleiman, in G-Quadruplex DNA: Methods and Protocols, ed. P. Baumann, Humana Press, Totowa, NJ, 2010, pp. 223–255. A. Dumas and N. W. Luedtke, J. Am. Chem. Soc., 2010, 132, 18004. A. Dumas and N. W. Luedtke, Nucleic Acids Res., 2011, 39, 6825. G. Mata and N. W. Luedtke, J. Am. Chem. Soc., 2015, 137, 699. ¨nsel-Hertsch, M. Di Antonio and S. Balasubramanian, Nat. Rev. Mol. R. Ha Cell Biol., 2017, 18, 279. P. Murat and S. Balasubramanian, Curr. Opin. Genet. Dev., 2014, 25, 22. D. Rhodes and H. J. Lipps, Nucleic Acids Res., 2015, 43, 8627. S. Balasubramanian, L. H. Hurley and S. Neidle, Nat. Rev. Drug Discovery, 2011, 10, 261. S. Neidle, Curr. Opin. Struct. Biol., 2009, 19, 239. Photochemistry, 2019, 46, 281–318 | 313

129 130

131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153

154 155 156

D. Monchaud and M.-P. Teulade-Fichou, Org. Biomol. Chem., 2008, 6, 627. E. Largy, A. Granzhan, F. Hamon, D. Verga and M.-P. Teulade-Fichou, in Quadruplex Nucleic Acids, ed. J. B. Chaires and D. Graves, Springer Berlin Heidelberg, Berlin, Heidelberg, 2013, pp. 111–177. D. Monchaud, C. Allain and M.-P. Teulade-Fichou, Bioorg. Med. Chem. Lett., 2006, 16, 4842. E. Largy, F. Hamon and M.-P. Teulade-Fichou, Anal. Bioanal. Chem., 2011, 400, 3419. A. C. Bhasikuttan and J. Mohanty, Chem. Commun., 2015, 51, 7581. D.-M. Kong, Y.-E. Ma, J.-H. Guo, W. Yang and H.-X. Shen, Anal. Chem., 2009, 81, 2678. A. Renaud de la Faverie, A. Guedin, A. Bedrat, L. A. Yatsunyk and J. L. Mergny, Nucleic Acids Res., 2014, 42, e65. S. Xu, Q. Li, J. Xiang, Q. Yang, H. Sun, A. Guan, L. Wang, Y. Liu, L. Yu, Y. Shi, H. Chen and Y. Tang, Sci. Rep., 2016, 6, 24793. A. J. Guan, X. F. Zhang, X. Sun, Q. Li, J. F. Xiang, L. X. Wang, L. Lan, F. M. Yang, S. J. Xu, X. M. Guo and Y. L. Tang, Sci. Rep., 2018, 8, 2666. S. Zhang, H. Sun, H. Chen, Q. Li, A. Guan, L. Wang, Y. Shi, S. Xu, M. Liu and Y. Tang, Biochim. Biophys. Acta, 2018, 1862, 1101. X.-C. Chen, S.-B. Chen, J. Dai, J.-H. Yuan, T.-M. Ou, Z.-S. Huang and J.-H. Tan, Angew. Chem., Int. Ed., 2018, 57, 4702. X. Xie, A. Renvoise, A. Granzhan and M.-P. Teulade-Fichou, New J. Chem., 2015, 39, 5931. F. Doria, M. Nadai, M. Zuffo, R. Perrone, M. Freccero and S. N. Richter, Chem. Commun., 2017, 53, 2268. M. Zuffo, F. Doria, S. Botti, G. Bergamaschi and M. Freccero, BBA – Gen. Subjects, 2017, 1861, 1303. ¨rthner, Angew. Chem., Int. Ed., V. Grande, F. Doria, M. Freccero and F. Wu 2017, 56, 7520. B. Jin, X. Zhang, W. Zheng, X. Liu, J. Zhou, N. Zhang, F. Wang and D. Shangguan, Anal. Chem., 2014, 86, 7063. J. Huang, M. Wang, Y. Zhou, X. Weng, L. Shuai, X. Zhou and D. Zhang, Bioorg. Med. Chem., 2009, 17, 7743. ¨ußler, J. W. Y. Lam, Z. Li, K. K. Sin, Y. Dong, H. Tong, J. Liu, Y. Hong, M. Ha A. Qin, R. Renneberg and B. Z. Tang, Chem. – Eur. J., 2008, 14, 6428. L. Zhu, J. Zhou, G. Xu, C. Li, P. Ling, B. Liu, H. Ju and J. Lei, Chem. Sci., 2018, 9, 2559. H.-Z. He, D. S.-H. Chan, C.-H. Leung and D.-L. Ma, Chem. Commun., 2012, 48, 9462. D.-L. Ma, C.-M. Che and S.-C. Yan, J. Am. Chem. Soc., 2009, 131, 1835. J. Alzeer, B. R. Vummidi, P. J. Roth and N. W. Luedtke, Angew. Chem., 2009, 48, 9362. G. L. Liao, X. Chen, L. N. Ji and H. Chao, Chem. Commun., 2012, 48, 10781. J. L. Yao, X. Gao, W. Sun, S. Shi and T. M. Yao, Dalton Trans., 2013, 42, 5661. D. Bouzada, I. Salvado, G. Barka, G. Rama, J. Martinez-Costas, R. Lorca, A. Somoza, M. Melle-Franco, M. E. Vazquez and M. Vazquez Lopez, Chem. Commun., 2018, 54, 658. F. Doria, A. Oppi, F. Manoli, S. Botti, N. Kandoth, V. Grande, I. Manet and M. Freccero, Chem. Commun., 2015, 51, 9105. M. Zuffo, F. Doria, V. Spalluto, S. Ladame and M. Freccero, Chem. – Eur. J., 2015, 21, 17596. M. Zuffo, S. Ladame, F. Doria and M. Freccero, Sens. Actuators, B, 2017, 245, 780.

314 | Photochemistry, 2019, 46, 281–318

157 158

159 160 161 162 163 164

165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188

A. Laguerre, J. M. Wong and D. Monchaud, Sci. Rep., 2016, 6, 32141. A. Laguerre, K. Hukezalie, P. Winckler, F. Katranji, G. Chanteloup, M. Pirrotta, J.-M. Perrier-Cornet, J. M. Y. Wong and D. Monchaud, J. Am. Chem. Soc., 2015, 137, 8521. K. Meguellati, G. Koripelly and S. Ladame, Angew. Chem., 2010, 49, 2738. A. Shivalingam, M. A. Izquierdo, A. L. Marois, A. Vysˇniauskas, K. Suhling, M. K. Kuimova and R. Vilar, Nat. Commun., 2015, 6, 8178. H. A. Day, P. Pavlou and Z. A. Waller, Bioorg. Med. Chem., 2014, 22, 4407. T. A. Brooks, S. Kendrick and L. Hurley, FEBS J., 2010, 277, 3459. ˜o ´, R. Eritja, C. Gonza ´lez and R. Gargallo, RSC Adv., 2014, S. Benabou, A. Avin 4, 26956. M. Zeraati, D. B. Langley, P. Schofield, A. L. Moye, R. Rouet, W. E. Hughes, T. M. Bryan, M. E. Dinger and D. Christ, Nat. Chem., 2018. DOI: 10.1038/ s41557-018-0046-3. A. Dembska, Anal. Chim. Acta, 2016, 930, 1. D. L. Ma, M. H. Kwan, D. S. Chan, P. Lee, H. Yang, V. P. Ma, L. P. Bai, Z. H. Jiang and C. H. Leung, Analyst, 2011, 136, 2692. L. Xu, S. Hong, N. Sun, K. Wang, L. Zhou, L. Ji and R. Pei, Chem. Commun., 2016, 52, 179. I. J. Lee, S. P. Patil, K. Fhayli, S. Alsaiari and N. M. Khashab, Chem. Commun., 2015, 51, 3747. G. Jiang, L. Xu, K. Wang, X. Chen, J. Wang, W. Cao and R. Pei, Anal. Methods, 2017, 9, 1585. L. Lu, M. Wang, L. J. Liu, C. Y. Wong, C. H. Leung and D. L. Ma, Chem. Commun., 2015, 51, 9953. L. Xu, J. Wang, N. Sun, M. Liu, Y. Cao, Z. Wang and R. Pei, Chem. Commun., 2016, 52, 14330. S. Chakraborty, S. Sharma, P. K. Maiti and Y. Krishnan, Nucleic Acids Res., 2009, 37, 2810. G. R. Bjork, J. U. Ericson, C. E. D. Gustafsson, T. G. Hagervall, A. Y. H. Jonsson and P. M. Wikstrom, Ann. Rev. Biochem., 1987, 56, 263. M. I. Zarudnaya and D. M. Hovorun, IUBMB Life, 1999, 48, 581. F. W. Alt, A. L. M. Bothwell, M. Knapp, E. Siden, E. Mather, M. Koshland and D. Baltimore, Cell, 1980, 20, 293. R. C. Yadav, G. S. Kumar, K. Bhadra, P. Giri, R. Sinha, S. Pal and M. Maiti, Bioorg. Med. Chem., 2005, 13, 165. P. Giri and G. S. Kumar, Biochim. Biophys. Acta, 2007, 1770, 1419. P. Giri, M. Hossain and G. S. Kumar, Bioorg. Med. Chem. Lett., 2006, 16, 2364. G. N. Roviello, D. Musumeci, V. Roviello, M. Pirtskhalava, A. Egoyan and M. Mirtskhulava, Beilstein J. Nanotechnol., 2015, 6, 1338. A. B. Pradhan, L. Haque, S. Roy and S. Das, PLoS One, 2014, 9, e87992. C. Altona, J. Mol. Biol., 1996, 263, 568. F. Jensch and B. Kemper, EMBO J., 1986, 5, 181. H. F. Noller, Ann. Rev. Biochem., 1991, 60, 191. A. Oleksy, A. G. Blanco, R. Boer, I. Uson, J. Aymami, A. Rodger, M. J. Hannon and M. Coll, Angew. Chem., 2006, 45, 1227. S. A. Barros and D. M. Chenoweth, Angew. Chem., 2014, 53, 13746. J. Novotna, A. Laguerre, A. Granzhan, M. Pirrotta, M. P. Teulade-Fichou and D. Monchaud, Org. Biomol. Chem., 2015, 13, 215. Z. Yang, Y. Chen, G. Li, Z. Tian, L. Zhao, X. wu, Q. Ma, M. Liu and P. Yang, Chem. – Eur. J., 2018, 24, 6087. Y. Liu and S. C. West, Nat. Rev. Mol. Cell Biol., 2004, 5, 937. Photochemistry, 2019, 46, 281–318 | 315

189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222

R. Holliday, Genet. Res., 2008, 89, 285. J. A. Y. Doniger, R. C. Warner and I. Tessma, Nat. New Biol., 1973, 242, 9. A. L. Brogden, N. H. Hopcroft, M. Searcey and C. J. Cardin, Angew. Chem., 2007, 46, 3850. K. Ghosh, C. K. Lau, F. Guo, A. M. Segall and G. D. Van Duyne, J. Biol. Chem., 2005, 280, 8290. M. Lu, Q. Guo, R. F. Pasternack, D. J. Wink, N. C. Seeman and N. R. Kallenbach, Biochemistry, 1990, 29, 1614. Q. Guo, M. Lu, N. C. Seeman and N. R. Kallenbach, Biochemistry, 1990, 29, 570. M. D. Frank-Kamenetskii and S. M. Mirkin, Ann. Rev. Biochem., 1995, 64, 65. M. Duca, P. Vekhoff, K. Oussedik, L. Halby and P. B. Arimondo, Nucleic Acids Res., 2008, 36, 5123. M. M. Seidman and P. M. Glazer, J. Clin. Invest., 2003, 112, 487. R. Floris, B. Scaggiante, G. Manzini, F. Quadrifoglio and L. E. Xodo, Eur. J. Biochem., 1999, 260, 801. V. Dahmen, S. Schmitz and R. Kriehuber, Mutat. Res., 2017, 823, 58. J. D. Toscano-Garibay and G. Aquino-Jarquin, Biochim. Biophys. Acta, 2014, 1839, 1079. A. Bacolla, G. Wang and K. M. Vasquez, PLoS Genet., 2015, 11, e1005696. F. A. Rogers and M. K. Tiwari, Yale J. Biol. Med., 2013, 86, 471. A. Mukherjee and K. M. Vasquez, Biochimie, 2011, 93, 1197. A. Jain, G. Wang and K. M. Vasquez, Biochimie, 2008, 90, 1117. J. Y. Chin and P. M. Glazer, Mol. Carcinog., 2009, 48, 389. J. J. Bissler, Front. Biosci., 2007, 12, 4536. E. Lu, X. Peng, F. Song and J. Fan, Bioorg. Med. Chem. Lett., 2005, 15, 255. J. B. Chaires, J. Ren, M. Henary, O. Zegrocka, G. R. Bishop and L. Strekowski, J. Am. Chem. Soc., 2003, 125, 7272. F. Riechert-Krause, K. Autenrieth, A. Eick and K. Weisz, Biochemistry, 2013, 52, 41. E. Gorab and P. L. Pearson, J. Histochem. Cytochem., 2018, 66, 143. I. Lubitz, D. Zikich and A. Kotlyar, Biochemistry, 2010, 49, 3567. Y. Wang, Y. Hu, T. Wu, X. Zhou and Y. Shao, Anal. Chem., 2015, 87, 11620. Y. Hu, F. Lin, T. Wu, Y. Wang, X. S. Zhou and Y. Shao, Chem. – Asian J., 2016, 11, 2041. X. Xu, F. Gao, X. Xiao, Y. Hu, C. Zhu and D. Zhao, J. Pharm. Biomed. Anal., 2017, 134, 94. D. Bikard, C. Loot, Z. Baharoglu and D. Mazel, Microbiol. Mol. Biol. Rev., 2010, 74, 570. P. Svoboda and A. Di Cara, Cell. Mol. Life Sci., 2006, 63, 901. G. Hong, Y. Liu, W. Chen, S. Weng, Q. Liu, A. Liu, D. Zheng and X. Lin, Int. J. Nanomed., 2012, 7, 4953. N. E. Broude, Trends Biotechnol., 2002, 20, 249. J. S. Paige, T. Nguyen-Duc, W. Song and S. R. Jaffrey, Science, 2012, 335, 1194. Y. Cheng, T. Stakenborg, P. Van Dorpe, L. Lagae, M. Wang, H. Chen and G. Borghs, Anal. Chem., 2011, 83, 1307. S. A. Oladepo, Appl. Spectrosc., 2018, 72, 79. Z. Li, B. Li, Y. Zhou, H. Yin, J. Wang and S. Ai, Anal. Biochem., 2017, 538, 20.

316 | Photochemistry, 2019, 46, 281–318

223 224 225 226 227 228 229 230 231 232 233 234 235 236

237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255

J. Liu, P. Du, J. Zhang, H. Shen and J. Lei, Chem. Commun., 2018, 54, 2550. Z. Wu, H. Fan, N. S. R. Satyavolu, W. Wang, R. Lake, J. H. Jiang and Y. Lu, Angew. Chem., Int. Ed. Engl., 2017, 56, 8721. A. H. J. Wang, G. J. Quigley, F. J. Kolpak, J. L. Crawford, J. H. van Boom, G. van der Marel and A. Rich, Nature, 1979, 282, 680. P. Khuu, M. Sandor, J. DeYoung and P. S. Ho, Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 16528. A. Rich and S. Zhang, Nat. Rev. Genet., 2003, 4, 566. A. D’Urso, A. Mammana, M. Balaz, A. E. Holmes, N. Berova, R. Lauceri and R. Purrello, J. Am. Chem. Soc., 2009, 131, 2046. A. Okamoto, Y. Ochi and I. Saito, Chem. Commun., 2005, 1128. Y. J. Seo and B. H. Kim, Chem. Commun., 2006, 150–152. G. A. King, P. Gross, U. Bockelmann, M. Modesti, G. J. Wuite and E. J. Peterman, Proc. Natl. Acad. Sci. U. S. A., 2013, 110, 3859. C. E. Pearson and R. R. Sinden, Biochemistry, 1996, 35, 5041. R. R. Sinden, M. J. Pytlos-Sinden and V. N. Potaman, Front. Biosci., 2007, 12, 4788. C. E. Pearson, Y. H. Wang, J. D. Griffith and R. R. Sinden, Nucleic Acids Res., 1998, 26, 816. S. Whitelam, P. L. Geissler and S. Pronk, Phys. Rev. E Stat. Nonlin. Soft Matter Phys., 2010, 82, 021907. J. van Mameren, P. Gross, G. Farge, P. Hooijman, M. Modesti, M. Falkenberg, G. J. Wuite and E. J. Peterman, Proc. Natl. Acad. Sci. U. S. A., 2009, 106, 18231. X. Yan, R. C. Habbersett, J. M. Cordek, J. P. Nolan, T. M. Yoshida, J. H. Jett and B. L. Marrone, Anal. Biochem., 2000, 286, 138. X. Zhang, H. Chen, S. Le, I. Rouzina, P. S. Doyle and J. Yan, Proc. Natl. Acad. Sci. U. S. A., 2013, 110, 3865. F. A. Gollmick, M. Lorenz, U. Dornberger, J. von Langen, S. Diekmann and H. Fritzsche, Nucleic Acids Res., 2002, 30, 2669. Y. Lin, G. B. Jones, G. S. Hwang, L. Kappen and I. H. Goldberg, Org. Lett., 2005, 7, 71. D. M. Lilley, Proc. Natl. Acad. Sci. U. S. A., 1995, 92, 7140–7142. D. H. Turner, Curr. Opin. Struct. Biol., 1992, 2, 334. R. H. Singer, Science, 1998, 280, 696. M. F. Perutz, Curr. Opin. Struct. Biol., 1996, 6, 848. Z. Xi, Q. K. Mao and I. H. Goldberg, Biochemistry, 1999, 38, 4342. G. B. Jones, Y. Lin, Z. Xiao, L. Kappen and I. H. Goldberg, Bioorg. Med. Chem., 2007, 15, 784. D. Ma, Y. Lin, Z. Xiao, L. Kappen, I. H. Goldberg, A. E. Kallmerten and G. B. Jones, Bioorg. Med. Chem., 2009, 17, 2428. T. A. Kunkel, J. Biol. Chem., 2004, 279, 16895. M. Lichten, C. Goyon, N. P. Schultes, D. Trecou, J. W. Szostak, J. E. Haber and A. Nicolas, Proc. Natl. Acad. Sci. U. S. A., 1990, 87, 7653. K. S. Gates, Chem. Res. Toxicol., 2009, 22, 1747. R. De Bont and N. van Larebeke, Mutagenesis, 2004, 19, 169. H. E. Krokan and M. Bjoras, Cold Spring Harbor Perspect. Biol., 2013, 5, a012583. A. Granzhan, N. Kotera and M. P. Teulade-Fichou, Chem. Soc. Rev., 2014, 43, 3630. J. R. Eshleman and S. D. Markowitz, Hum. Mol. Genet., 1996, 5, 1489. L. T. Timchenko and C. T. Caskey, FASEB J., 1996, 10, 1589. Photochemistry, 2019, 46, 281–318 | 317

256 257 258 259 260 261 262 263

K. Nakatani, ChemBioChem, 2004, 5, 1623. B. M. Zeglis and J. K. Barton, J. Am. Chem. Soc., 2006, 128, 5654. F. Seela, D. Jiang and K. Xu, Org. Biomol. Chem., 2009, 7, 3463. X. Ming and F. Seela, Chem. – Eur. J., 2012, 18, 9590. C.-X. Wang, Y. Sato, M. Kudo, S. Nishizawa and N. Teramae, Chem. – Eur. J., 2012, 18, 9481. Y. Sato, M. Kudo, Y. Toriyabe, S. Kuchitsu, C. X. Wang, S. Nishizawa and N. Teramae, Chem. Commun., 2014, 50, 515. C. Zhao, A. Rajendran, Q. Dai, S. Nishizawa and N. Teramae, Anal. Sci., 2008, 24, 693. S. Xu, Y. Shao, K. Ma, Q. Cui, G. Liu, F. Wu and M. Li, Analyst, 2011, 136, 4480.

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Transition metal complexes in ECL: diagnostics and biosensing A. Aliprandi,a B. N. DiMarcoa and L. De Cola*a,b DOI: 10.1039/9781788013598-00319

This chapter addresses the main principles, challenges and achievements in ECL using metal complexes. Selected applications in diagnostics and biosensing are described.

1

Introduction to electrochemiluminescence

Luminescent molecular excited-states can be generated through several different processes that include light absorption (photoluminescence), mechanical action (mechanoluminescence), chemical reaction (chemiluminescence) or by charge injection across the electrodes (electroluminescence). Electrochemiluminescence, or electrogenerated chemiluminescence (ECL), is a process that uses an applied electrical bias to generate reactive species at an electrode surface that undergo subsequent electron-transfer reactions to generate luminescent species. This technique can be considered as the combination of electroluminescence (EL) and chemiluminescence (CL), since the electrical bias is used to generate the reactive species in situ, which then react to form the luminescent species, in contrast to the direct generation of the luminescence species through electrochemical reduction/oxidation or a spontaneous chemical reaction. The ability to electrochemically generate the reactive species provides several advantages over chemiluminescence such as excellent stability, simplicity, and great spatial and temporal control. Additionally, this technique retains the extremely high signalto-noise ratio typical of conventional CL measurements, due to the elimination of the background noise from the excitation source used in traditional photoluminescent measurements, thus making it an extremely powerful analytical technique.1 In general, there are two main categories of ECL reactions that are classified based on the specific mechanism for the electrochemical generation of the excited state. Annihilation ECL (Fig. 1a) takes place between the oxidized and the reduced forms of the luminophore, where the two oxidation states are generated sequentially by applications of alternating oxidative and reductive bases at the working electrode. In contrast, co-reactant ECL (Fig. 1b) involves the use of a secondary reagent that converts to a reactive and potent sacrificial electron donor/acceptor upon oxidation/reduction a

Institut de Science et d’Inge´nierie Supramole´culaires (ISIS), University of Strasbourg & CNRS, 8 Rue Gaspard Monge, 67000 Strasbourg, France. E-mail: [email protected] b Institute of Nanotechnology (INT) and Karlsruhe Nano Micro Facility, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 EggensteinLeopoldshafen, Germany Photochemistry, 2019, 46, 319–351 | 319  c

The Royal Society of Chemistry 2019

Fig. 1 (a) Schematic representation of annihilation ECL of a generic luminophore A. (b) Schematic representation for co-reactant ECL where A is a generic luminophore and B a sacrificial agent.

and subsequently reacts with the luminophore during a single potential step or can. When a sacrificial agent is used as co-reactant there are two possible scenario: (i) the luminophore can be electrochemically oxidized at the anode in the presence of a strong reducing agent such as C2O42 or amines such as tripropylamine (TPA), oxidative-reduction ECL; (ii) the luminophore can be electrochemically reduced at the cathode in the presence of a strong oxidant such as S2O82, reductive-oxidation ECL. The decomposition pathways of the co-reactants are often complicated, and can involve highly reactive radicals species2 that make it difficult to identified the mechanism with certainty. Understanding the processes occurring during the generation of the ECL (i.e. electron transfer reactions, products formation, and charges recombination) is important for improving the efficiency of the process. To this end, mechanisms for the most common co-reactants have been confirmed in the last decade through EPR investigation.3 The first observation of electrochemically generated light dates back a century,4 while the first discussion of possible analytical applications occurred more than a decade later.5 However, it was not until the middle of the 1960s6–10 that the modern field of ECL was definitively born. The studies at the time focused primarily on organics luminophores and low ECL yields were generally observed. In 1973 Tokel and Bard11 published their seminal work that demonstrated efficient ECL from the transition metal complex [Ru(bpy)3]Cl2 (bpy ¼ 2,2 0 -bipyridine) through the annihilation mechanism. Since then, ruthenium polypyridyl complexes have 320 | Photochemistry, 2019, 46, 319–351

become the dominant luminophores over the past 40 years, having been extensively studied. Although the photoluminescent quantum yields (PLQY) of such compounds are relatively low, even under anaerobic conditions12 (PLQY ¼ 6.3%), the highly favourable electrochemical properties, both in terms of electrochemical stability and oxidation potentials, results in an intense emission suitable for practical ECL applications. It is indeed the superior detection limits of an analyte (down to picomolar levels) of emission-based techniques, combined with the simplicity of the experimental setup, that makes ECL extremely important and an area of increasing interest. At the time of writing, there are nearly 5000 references focused on ECL listed on Web of Science (see Fig. 2). Improvements in the electrochemical understanding of the mechanism involved in ECL has opened new frontiers for the exploration of additional transition metal complexes as well as the use of modified electrodes, and the development of systems based on organic and aqueous solutions. More recently, novel approaches employing nanomaterial and supramolecular chemistry have also been reported. Furthermore, the development of ECL has been boosted by the parallel growth of OLED technologies that are based on electroluminescence. Indeed, these two phenomena share many distinct similarities. One particular example is the role of the spin statistics during the formation of the exciton, which in the context of OLEDs led to the use of triplet emitters and on the stability of the luminescent excited states. The realization that phosphorescent emitters also outperform fluorescent dyes13 for ECL applications resulted in numerous reports of OLED phosphorescent emitters being used as ECL luminophores. This is

Fig. 2 The number of published journal papers per year on electrochemiluminescence as of 13 March 2018. Source: Web of Science. Photochemistry, 2019, 46, 319–351 | 321

particularly true for the highly emissive and color tunable Ir(III) complexes, which have been in the focus for ECL applications over the past decade. The growth of these two fields lead many researchers to start investigating the role of the chemical design on the photophysical and electrochemical properties of Ru(II), Ir(III), and other metal complexes. Many attempts are reported to correlate the spectroscopic behaviour with the ECL performances to develop guidelines for the design of efficient ECL systems, however the complexity of the ECL processes often prevent a full understand and prediction of the systems. Some general characteristics of efficient ECL emitters are described in the next section. 1.1 Characteristics of ECL emitters Many parameters must be considered for the design of ECL system which consider both optical and electrochemical properties. The luminophore must be highly emissive since the ECL efficiency is inherently limited by the PLQY.14 As anticipated, spin statistics plays an important role in ECL since the lowest excited singlet (S1) and triplet (T1) state of a luminophore formed by non-radiative process, such as ion annihilation (ECL, EL or CL), are considered to be in a 1 : 3 ratio.15 However, for most fluorescent molecules radiative decay between the triple state T1 and the ground state is not possible due to spin conservation in the induceddipole energy-transfer process, and thus the maximum ECL efficiency is expected to be 25% for the majority of the fluorescent materials with intrinsic PLQY of 100%. In order to overcome this limitation both singlet and triplet states must contribute to luminescence. An efficient solution to this problem is the use of phosphorescent transition metal complexes, where the presence of the heavy metal reduces the phosphorescence lifetime through increased spin–orbit coupling which mixes the singlet and triplet characters of the excited-state. The heavy metal also increases the efficiency of intersystem crossing from the first singlet excited state to the triplet excited state manifold.13,16 Another strategy is to minimize the energy gap between the singlet and triplet excited states (DEST) through molecular design, thus promoting a highly efficient spin up-conversion process from the non-radiative triplet states to radiative singlet states while maintaining high radiative decay constants.17,18 This process, known as thermally activated delayed fluorescence (TADF), requires a combination of a small DEST (o100 meV) and a fast radiative decay rate 4106 s1, to overcome competitive non-radiative decay pathways. Because these two properties conflict with each other, the overlap of the highest occupied molecular orbital and the lowest unoccupied molecular orbital need to be carefully balanced while maintaining a rigid structure in order to minimize the geometrical changes between the ground state and the singlet excited state that result in non-radiative decay. Though TADF molecules can be considered an attractive alternative to phosphorescent molecules based on rare-earth metals, such as Ir and Pt, factors including stability, electrochemical activity and biocompatibility limit their applicability for use in bioanalytical assays. The electrochemical properties of a compound and the stability of the reduced or oxidized species, are of paramount importance for 322 | Photochemistry, 2019, 46, 319–351

determining ECL applications. Photophysical properties are often less important, since it is very hard to rationalize the emission properties and in particular the correlation between the observed PLQY and ECL intensity.19 Indeed, the overall ECL performance depends on how efficiently the excited state is formed during the ECL reaction. As an example, the ECL reaction efficiencies for [Ru(bpy)3]21 has been reported to be near unity under certain conditions.11 This high efficiency is due to a number of factors that include a high degree of electrochemical reversibility that ensures the rapid generation of a stable Ru(III) species capable of undergoing subsequent electron transfer reactions, and a favourable oxidation potential (Eox ¼ þ1.2 V vs. NHE) that is potent enough to provide sufficient driving force for desired reactions, but low enough as to not give rise to parasitic side reactions. This high efficiency has also important implications in terms of electron transfer theory since such quantitative yield can only be obtain if the emitting state is populated directly and not through an energy transfer reaction. The reaction is also thermodynamically favoured while reactions that lead to the direct formation of the ground state product are kinetically inhibited. These observations can be explained through Marcus theory. The deactivation reaction which leads to two ground state Ru(II) species is highly exergonic, while the desired reaction leading to and excite Ru(II)* species, annihilation reaction, is less so. Given the similar reorganization energies for both reactions, they will likely falls within the Marcus inverted region, where increasing driving force leads to a decrease in the electron transfer rate. In all cases, the deactivation reaction with formation of only ground state species will be more exergonic and therefore slower in rate when compared to the desired annihilation reaction. However, this may be an oversimplification as it does not take electron spin configurations into consideration. Due to the 100% efficiency in the generation of the excited states, the photophysical and electrochemical properties of [Ru(bpy)3]21 have been used as model for developing novel ECL emitters and, in particular, those based on the Ir(ppy)314 (ppy ¼ 2-phenylpyridine) which is known to possess a PLQY of 100%20 thus making it extremely appealing as ECL emitter. The extremely high PLQY of iridium(III) complexes has motivated scientist to systematically investigate the effects of the ligand design on the electrochemical and photophysical properties, and consequently their effects on the ECL efficiency.21,22 Besides the choice of the emitter, the development of efficient coreactants for ECL is central to the advancement of the field. For example, the discovery of the co-reactant tripropylamine (TPA) was especially important since it allowed efficient ECL not only in aqueous media, but also at physiological pH (B7.4), thus enabling bioanalytical applications.2 For obtaining efficient ECL using TPA the oxidation potential of the emitter should be positive enough for an efficient generation of TPA1 (E0TPA/TPA 1¼ þ 0.9 V vs. SCE23) while the potential of the TPA should be more negative than the reduction potential of the emitter (E0TPA ¼ 1.7 V vs. SCE23).24,25 As a result the best performing ECL emitters have similar emission energy of the [Ru(bpy)3]21 with luminescence in the red region Photochemistry, 2019, 46, 319–351 | 323

(l¼600  40 nm). Consequently, tuning the emission colour while keeping high ECL yield is still an important challenge since it would allow novel applications such as multiplexed detection, but new coreactants are needed to fulfil the different redox properties. Solubility in aqueous media and resistance to oxygen quenching impose new challenges in emitter design beyond the electrochemical and photophysical properties. Charged species, such as the Ru(II)-polypyridyl complexes, possess an intrinsic water solubility, especially if a halogen anion is used as counterion, while neutral complexes require specific ligand design to achieve sufficient solubility to translate efficient ECL system from organic solvent to aqueous media. Often these strategies rely in the introduction of polar groups in the ligand architecture or in the engineering of the coordination sphere such that the complex is charged rather than neutral. However, substitution of the coordinated ligands often has a profound impact on the photophysical and electrochemical properties of the emitter. Another interesting approach is the encapsulation of the hydrophobic luminophore inside water dispersible structures, such as nanoparticles, which offer both water solubility and protection against oxygen quenching. The combination of nanostructures with ECL luminophore is probably the most recent trend in the field, since the scaffold may possess intrinsic conductive or semiconductive properties that can be used to enhance the ECL intensity. Furthermore, it is generally possible to further functionalize the nanomaterial with groups suitable for bioconjugation such that the hybrid system can be used for detection of proteins (e.g. immunoassays) or DNA (e.g. DNA hybridisation assays).

1.2 Diagnostics and biosensing Commercial ECL analytical platforms rely on molecular architectures for the recognition of specific analytes. Typically, the surface of the electrode is modified with an agent that binds to the analyte with high specificity in order to keep it close to the electrode itself. Upon immobilization of the component, a second agent capable of binding to it and bearing the ECLactive label is added, to give a ‘‘sandwich’’ structure. In this way, the presence of the ECL label indicates the presence of the analyte and the total intensity of the ECL signal can be correlated to the concentration of the latter.26–28 A general strategy utilized by Roche Diagnostics takes advantage of microparticles immobilization on a Pt electrode to perform highly sensitive immunoassays able to detect more than 150 analytes with subpicomolar sensitivity. The assay consists in the incubation of a patient sample with two antibodies (or oligonucleotide sequences) of which one is labelled with ruthenium as ECL emitter and the second is labelled with biotin, both are highly specific to binding site on a target antigen (or the matching oligonucleotide). The two antibodies form a sandwich complex with the antigen (Fig. 3, stage 1). Next paramagnetic microbeads coated with streptavidin are introduced in the solution, the streptavidin forms a strong complex with biotin (Fig. 3, stage 2). Then the completed immunoassay sandwich complex is transferred to the 324 | Photochemistry, 2019, 46, 319–351

Photochemistry, 2019, 46, 319–351 | 325

Fig. 3 Simplified view of all the steps for an ECL immunoassay, based on the capture, immobilization and detection of the analyte.

measuring cell where a magnet pushes the microbeads against the electrode. The cell is then washed with a solution containing the coreactant (TPA) in order to both separate the bounded immunoassay complex from the free remaining particles and enable the ECL reaction (Fig. 3, stage 3). Voltage is then applied to trigger the ECL reaction. The emitted light is then detected by a photomultiplier and it is directly proportional to the concentration of the analyte (Fig. 3, stage 4).

2

Ruthenium complexes

The complex Ru(bpy)321 has been of paramount importance in the field of ECL since the first report by Tokel and Bard in 1972.11 As mentioned in the introduction, a bright luminescence was observed from a simple acetonitrile solution containing Ru(bpy)321 after the application of an alternate oxidative and reductive electrochemical potential. Though this was not the first report of ECL, the observation of ECL from a metal complex opened many possibilities for expansion of the field. The authors asserted that the luminescence resulted from an electron transfer reaction between the reduced and the oxidized forms of Ru(bpy)321 that generated the luminescent excited state. Since these early observations, Ru(bpy)321 and its derivatives have become the most important luminophores used for ECL analysis, as evidenced by its frequency of use in academic study and the fact that it is currently used in all commercially available ECL immunoassay devices and in more than 150 assays. The remarkable electrochemical and photophysical properties of Ru(bpy)321 have been well recognized in other fields, but of particular attraction to ECL are its superior electrochemical properties, low toxicity29 and is good solubility in a wide range of solvents, including buffer aqueous solutions. The low toxicity and water solubility also make it ideal for biological applications. An additional draw of Ru(bpy)321 is the high efficiency of the ECL reaction, which is often consider to be quantitative in annihilation mode.30 As mentioned in the introduction, a major drawback of these luminophores are the low intrinsic PLQYs, which do not exceed 0.05 in oxygen free solutions and ultimately sets an upper limit to the luminescence achieved through ECL. Additionally, the luminescence profile is difficult to tune due to the limited ligand-field splitting of the octahedral Ru(II) centre. This often limits its use for ECL lighting applications, though it has not greatly impacted its applicability for biological assays, where the wavelength of emission is less relevant. It is worth noting that several organic and transition metal based luminophores have recently begun to rival the classic Ru(II) based systems, though it may still be few years until Ru(II) systems are replaced.21,31 In addition to the numerous applications of Ru(bpy)321, these molecules have served as model systems for understanding the mechanisms governing both annihilation and co-reactant ECL. Such information is vital for creating the next generation of luminophores, co-reactants and assays built around ECL.32 A review of fundamental studies are beyond the scope of this chapter, and an interested reader is directed towards several high-quality reviews which discuss the fundamentals of 326 | Photochemistry, 2019, 46, 319–351

ECL.30,31,33 Instead, this section will focus on recent advancements in ECL based biological assay which employ Ru(bpy)321 as the primary luminophore. Commonly, Ru(bpy)321 forms a bioconjugate with an antibody, single-strand DNA or other biologically relevant molecule that can bind with an analyte of interest. Several recent trends have been focused on the amplification of the signal from Ru(bpy)321 by encapsulation of multiple emissive cores within a nanoparticle or polymer matrix, which can then be attached to the biological tag with the goal of increasing the luminescence. Encapsulation of multiple luminophores can also impart additional benefits, such as increase solubility in aqueous media and reduced quenching by oxygen.34 A recent example of this strategy has been published by Paolucci et al.35 and focused on the encapsulation of Ru(bpy)321 within silica nanoparticles. The SiNPs were prepared through standard synthetic methods in the presence of a Ru(II) species that possessed a trietheoxysilane functional group, Fig. 4, allowing the luminescent tag to be covalently

Fig. 4 (A) Structure of Ru(II) luminophore and its assembly into a silica nanoparticle. (B) Change of ECL mechanism observed as the concentration of Ru(II) inside the nanoparticle increases. Adapted with permission from ref. 35, Copyright 2016 American Chemical Society. Photochemistry, 2019, 46, 319–351 | 327

linked to the SiNP and thus eliminated the possibility of the dye leaching from the system after preparation. By varying the concentration of the Ru(II) complex during NP synthesis, the doping level can be tuned between 0.05–0.8% wt/wt. The dye-doped nanoparticles (DDNPs) possessed a hard B10 nm core and a hydrodynamic radius of B25 nm due to the presences of a PEG shell, which was included to increase the water solubility of the NPs. Interestingly, the DDNPs zeta-potential was found to be Ru(II) loading dependent, with an increase from 10 to 0.9 mV being observed from the lowest to highest doping concentrations. This was likely due to the inclusion of the cation Ru(II) species within the NP. This change in zeta potential was not observed to impact the dispersability of the nanoparticles. As expected, encapsulation of the Ru(II) reduced the quenching of the sensitizers by dioxygen, as evidenced by the excited state lifetime and emission quantum yields measurements. ECL studies of the lowest doping concentrations found a strong intensity emission which associated well with the oxidation of the 2-(dibutylamino)ethanol co-reactant, in addition to a weak emission signal found in the potential range for Ru(III/II) chemistry. In general, the ECL intensity increased with increases Ru(II) doping, though the intensity increase was not linear with concentration and eventually plateaued at the highest concentrations. This is likely due to self-quenching reactions that introduces an additional non-radiative decay pathway. Interestingly, increasing in Ru(II) doping also saw a decrease in intensity in over the potential range for co-reactant oxidation, though an increase in intensity was seen over the potential range associated with Ru(II) oxidation. The change was attributed to a decrease in a favorable attractive interaction between cationic products of co-reactant oxidation and the negative zeta potential of the NP as higher Ru(II) loading. The increase in intensity over the Ru(III/II) potential was thought to be due to direct co-reactant oxidation by Ru(III). Since the Ru species are imbedded within the NP, this likely occurs through an electron self-exchange reaction between the Ru within the NP. This report demonstrates that one cannot assume a linear relationship between luminophore loading and intensity and more complex parameters must be considered in ECL. Nevertheless, the increased luminesce intensity of these nano-particle systems contributes to the development of biological assays, where an increase in the tag luminesce can increase the sensitive of the device. Polymer systems can also be used to encapsulate multiple Ru(II) species. Similar to the silica NPs, these species provide protection from quenching by dioxygen, and can be modified to improve solubility or to impart target specificity. A recent example by Ju et al. generated a multinuclear polymer tag through a simple flash injection technique.36 The authors flash injected a THF solution containing the hydrophobic salt [Ru(bpy)3][B(C6F5)4]2 and a precursor for the formation of nano polymer dots (Pdots) into water under sonication. The rapid injection saw the formation of Pdots spheres which encapsulated Ru(bpy)321. The weight percentage of the Ru(II) within the Pdots could be varied by altering the Ru(II) concentration in the THF solution, and this was used to investigate the influence of loading on the ECL properties. The Ru(II) species were 328 | Photochemistry, 2019, 46, 319–351

confirmed to be encapsulated inside the spherical polymer matrix primarily through TEM-EDX. The Pdots themselves have previously been shown to be emissive and ECL active.37 Interestingly the strong spectral overlap between the Pdot emission and the Ru(II) absorption allows a ¨rster energy transfer that was observed between the polymer shell and Fo the encapsulated Ru(II). This energy transfer pathway increased the ECL luminescence for the hybrid Ru-Pdot, which out-performed on Au electrodes functionalized with Pdot or for the unencapsulated Ru(II). Concentration dependent studies proved the highest ECL performance arising from a 2 : 1 ratio of Ru(II) to polymer, with a decrease in ECL observed at higher concentrations. As a result, the 2 : 1 material was used to develop an assay for the detection of mutant strands of DNA through the functionalization of the Ru-Pdots with complimentary strands of the mutant DNA. These assays demonstrated that the Ru-Pdots could provide superior detection limit when compared to the non-encapsulated RNA, achieving a limit of detection of 0.8 fM. This value was significantly lower than all current analytical methods, including those of nanoparticleenhanced plasmon resonance imaging (1 pM) and of the magnetic beadsECL systems often used in commercial apparatuses (10 fM). Such an achievement corroborated the potential of polymer encapsulation of luminophore for biological assays. ECL signals can also been boosted by the addition of secondary structures into the device. An interesting example has been published by Guo et al. that focused on the generation of an ultrasensitive ECL assay using Ru(bpy)321 functionalized SiO2 NPs in conjunction with AuNPs for the detection of carcinoembryonic antigen (CEA).38 Surface enhanced ECL (SEECL) had previously been observed by Lakowicz and co-workers, who employed a gold film coated glass substrate to enhances the ECL efficiency of Ru(bpy)321.39,40 This effect is similar to SERS, though in this example the presence of a Au surface enhances the ECL efficiency of Ru(bpy)321. In order to detect the presence of CEA, the authors functionalized a polished gold electrode with two different CEA specific aptamers. Samples containing a known concentration of CEA were introduced, which bound to the aptamers on the gold surface. The introduction of a single layer of Ru–SiO2NPs that was functionalized with a CEA specific aptamer, allowed the tag to bind the target strand. When CEA is present in the analyte and bound at the interface, ECL was observed using TPA as the co-reactant. The signal from this initial setup was then enhanced using two different techniques. The first was based on the use of an assembly of multiple layers of the Ru–SiO2 that provided an increase in the concentration of emissive species, while the second was to incorporate aptamer functionalized gold nanoparticles into the assembled structure. The multiple Ru–SiO2 provided more emissive cores to the centre, while the Au was expected to enhance the emission from each Ru–SiO2 though the aforementioned SEECL effect. The author demonstrated that both of these techniques improved the signal compared to the one for the Ru–SiO2 layer, though the best performance was observed with combination of these two factors and reported a 30 increase in intensity over the initial setup. When arranged in this configuration, the Photochemistry, 2019, 46, 319–351 | 329

assay achieved a limit of detection for 1.52106 ng mL1, several orders of magnitudes lower than prior literature reports. Such an appreciable increase in sensitive merits further investigation on the use of AuNP for SEECL in other biologically relevant assays. Another recent trend in the quantification of an ECL signal has been based on a ratiometric approach, where two signals are compared rather than taking the absolute value from a single emitter. This has the added benefit of eliminating background emission from the co-reactant, oxygen, etc. Ru(bpy)321 and its derivatives find themselves perfectly amenable to this technique. Systems used for ratiometric ECL can be relatively simple, as demonstrated by Peng et al.41 The system described the ratio of the emission from a Ru(II) and Os(II) polypyridyl dyad complex, where the two emissive cores were tethered together with an alkyl chain. The two species have significantly different emission profiles that allows them to be easily distinguished. Os(II) polypyridyl complexes are also known to efficiently quench the emission of Ru(II) polypyridyl complexes through energy transfer. The authors were able to determine the concentration of a coreactant present in the electrolyte by rationing the emission for between Ru(II) and Os(II). Such a simple system could be used to detect the presence of naturally occurring co-reactants, such as NADH. An additional example of ratiometric ECL was described by Chen et al., which took advantage of the strong spectral overlap between the emission profile of gold doped carbon nitride nanosheets (Au–g–C3N4) and the absorption profile of Ru(bpy)321 to develop a FRET based device for microRNA detection.42 Au–g–C3N4 itself was previously shown to be ECL active and provided a signal when no microRNA was present. In this report, a glassy carbon, GC, electrode was first functionalized with Au–g–C3N4, which allowed for a thiol terminated hairpin molecular beacon probe to be bound to the gold, Fig. 5. A microRNA chain of interest was then introduced that could interact and open this beacon probe, forming a linear hybrid DNA/RNA duplex. Duplex selective nuclease (DSN) was then used to cleave the duplex species, leaving a shortened DNA chain bound to the Au–g–C3N4 nanosheet. Finally, a Ru(bpy)321 moiety functionalized with a DNA strand, that was complimentary to the shortened surface bound DNA, was introduced to complement with the surface hairpin beacon probes that were previously opened by the target RNA. This entire process ensures that only hairpin probe beacon probes which interacted with the target RNA strand would be available for binding to the DNA functionalized Ru(bpy)321 and thus cuts down on background noise. Ultimately, an increase in the concentration of the target microRNA results in an increase in the Ru(bpy)321 concentration at the interface. ECL measurements found that an increase in the concentration of the Ru(bpy)321 resulted in a decrease in the Au–g–C3N4 emission (460 nm) concomitant with an increase in the emission from the Ru(bpy)321 (630 nm). The changes in the emission intensities is caused by the contribution to the normal ECL process, from Ru(bpy)321, of the energy transfer between the Au–g–C3N4 to the Ru(bpy)321. The ratio between the two signals allowed for the determination of Ru(bpy)321 present at the interface, and therefore the 330 | Photochemistry, 2019, 46, 319–351

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Fig. 5 MicroRNA determination using a combination of gold doped carbon nitride nanosheets (Au-g-C3N4) and Ru(bpy)32 þ used as ECL detection unit. Reprinted with permission from ref. 42, Copyright 2015 American Chemical Society.

evaluation of the concentration of RNA applied in the previous step. Calibration testing using target RNA concentrations that varied between 1.0 fM and 1.0 nM found a highly linear trend (Correlation coefficient ¼ 0.9914) between the log of the concentration and log of the ratio of the two signals. Linear regression analysis determined a limit of detection 0.5 fM, based on a S/N ratio of 3, which outperformed all previous reports for ECL based microRNA analyses. The high sensitivity results from the ratiometric approach to this analysis, and highlights the benefits of such an analysis. Another trend in ECL analyses is the use of potential dependent ECL, which often used multiple luminophores with different turn-on potentials to impart both wavelength and voltage dependence to the electrochemically generated emission.43 Multiple emission ECL was originally demonstrated as a proof-of-concept by Richter and coworkers using a combination of Ru(bpy)321 and Ir(ppy)3 (ppy ¼ 2-phenyl pyridine).44 However, applications of this technique did not appear for many years, though several notable reports have been recently published. One example is a recent study by Xu et al. that combined the two ECL luminophores, Ru(bpy)321 and Ir(ppy)3, within a bipolar electrode based device.45 In this example, the two luminophores were dissolved within a chamber containing an acetonitrile electrolyte. It was previously shown that increasing in the applied potential results in the ECL profile transition from red, to yellow, to green as the emission transition from primarily Ir(ppy)3 in character to Ru(bpy)321. Though such mixed emissive properties have been previously reported,43,44 the authors took advantage of this interesting observation to designed a bipolar electrode setup, where the anodic and cathodic chambers were separated by a small gap that could be bridged by a resistor. The anodic chamber was filled with an acetonitrile electrolyte containing the two luminophores and the TPA co-reactant, while the cathodic chamber was filled with an aqueous solution containing a buffered salt solution. Using a resistor to bridge the chambers, a 5.5V external bias was applied across the two sample chambers. ECL was observed from the chamber containing the luminophores, with the color of emission being controlled by the resistor size used to bridge the two chambers. This was due to the relationship between the resistor and the cell potential, which increased with increasing resistance. As the cell voltage increased, the colors changed from green to red. This experiment provided as a proof of concept for the design of an analytical tool for the facile detection of the clinical biomarker prostatespecific antigen (PSA). Subsequent experiments did not use a resistor, but instead functionalized the gap with an anti-PSA antibody. The device was realized using a microfluidic design that allowed multiple reagents to flow over the gap in order to introduce different analytes and reagents to the interface, Fig. 6. A solution containing a known concentration of PSA was first flowed through the gap, followed by a second solution containing a second gold-labelled PSA antibody that created a sandwich complex with PSA. A silver reagent was then introduced, which reacted with the gold labelled antibody, creating a conductive pathway between the two sample chambers. An increase in the amount of PSA present in the analyte 332 | Photochemistry, 2019, 46, 319–351

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Fig. 6 Colorimetric bipolar electrode ECL device for the detection of PSA employing two ECL active complexes. Adapted with permission from ref. 45, Copyright 2017 American Chemical Society.

solution controls how much silver reagent will be deposited between the two chambers and there for controls the resistance, which ultimately controls the ECL color. As a final proof of concept, the authors obtained a series of PSA samples from hospital patients that had the concentration PSA previously determined through standard clinical techniques. Remarkably, the design of the device triggered the transition green to yellow at PSA concentrations which corresponds to a cut-off value for possible prostate cancer (4.0 ng mL1), while a transition from yellow to red was observed at higher concentrations (10.0 ng mL1) where a prostate biopsy is highly recommended. The entire sample process required approximately 35 minutes, demonstrating that this device could be used as a fast assay for determining prostate cancer risk. Self-enhancement ECL, where the co-reactant and the luminophore are combined within a single molecule or system, have received increased attention over the past few years. This likely due to the improved performance and longevity of the system when compared to traditional co-reaction methods, where the luminophore and co-reactant are present separately, and to the intrinsic toxicity and volatility of some of the coreactants. In a recent example by Yuan et al., the authors prepared the complex Ru(bpy)2(mcbpy)21-TAPA, Fig. 6, which contained amine functional groups that could be used as the ECL coreactant.46 The authors developed a highly sensitive assay for the detection of N-acetyl-B-Dglucosamidnidase (NAG), which can be used for the detection of diabetic nephropathy. Upon solvent evaporation, the complex forms a rod-shaped structure, with an average length of 260  30 nm and a width of 100  20 nm. These rods were found to have excellent electrochemical properties, and produced efficient ECL. A mechanism for ECL was proposed in this article, which involved the formation of a radical on the TAPA moiety after oxidation that undergoes an intramolecular electron transfer to the bound Ru(III) species to form the excited state Ru(II)*. In an effort to improve the conductivity of these rods, Pt nanoparticles (PtNPs) were also incorporated. The Pt functionalized rods showed an increase in electroconductivity, as evidenced with electrochemical experiments using the well know Fe(CN)63/2 redox couple as the redox shuttle. To form the ECL label, a bioconjugate between the Pt nanoparticles functionalized Ru(bpy)2(mcbpy)21-TAPA rods was made with bovine serum albumin (BSA). The final assembly was then generated after the introduction of the targeting antibody. A polished Au electrode was also functionalized with the detection antibody. The target of interest, here NAG, was incubated on this surface. After washing, the Ru(II) labelled antibody was introduced to create the commonly used sandwich structure for ECL analysis, Fig. 7. After optimization of the experiment conditions, including incubation time, a linear trend was observed between the concentration of NAG present during incubation and the ECL signal obtained. Based on these values, a limit of detection for NAG of 0.17 pg mL1 was achieved, which outperformed the previous best detection limit (50 pg mL1) by over two orders of magnitude. The authors also demonstrated that different interfering agents had little influence of the ECL performance, showing good specificity for the target of interest. 334 | Photochemistry, 2019, 46, 319–351

Fig. 7 Schematic representation of an assay for the detection NAG using a selfenhancing Ru(II) luminophore. Reprinted with permission from ref. 46, Copyright 2016 American Chemical Society.

Fig. 8 Self-enhanced ECL from a Ru(II)-NCND hybrid system. Reprinted with permission from ref. 47, Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Our group recently reported a self-enhanced ECL system obtained by combining Ru(bpy)321 with amine functionalized carbon nano-dots (NCNDs), where the NCNDs were capable of acting as the co-reactant in the ECL experiment.47 The combination of these two species in an aqueous PBS buffer afforded efficient ECL, that was 4 times as intense as the signal obtained in the absence of the NCND, upon the application of an oxidative bias. The use of NCND as co-reactant afforded superior stability over multiple electrochemical cycles when compared to TPA, likely due to the abundance of amino-group present on each carbon dot (Fig. 8). Further enhancement of the ECL signal was observed after methylation of the amines, consistent with previous literature reports. In a final effort to increase the intensity of ECL, the Ru(II) complex was covalently linked to the NCND through the formation of an amide linkage. This hybrid structure yielded a two-fold increase in ECL efficiency when compared to the free Ru(II)/co-reactant system. Additionally, no evidence of quenching of the Ru(II) emission by the NCND was observed, Photochemistry, 2019, 46, 319–351 | 335

as evidenced by the similar emission quantum yields between the full assembly and the free Ru(bpy)321. This self-enhancement effect, in addition to the use of a novel, more stable co-reactant represents a significant improvement over the classic TPA system. A final area of interest has been the development of low-cost, pointof-care devices which rely on ECL. The majority of these technologies currently rely on Ru(bpy)321 and its derivatives. Simple devices have been generated by Hogan et al. based on now ubiquitous smart phones combined with cheap and printable paper based electrodes.48 These clever examples utilize the phone’s camera as the detector, and use the phones headphone-jack as a potential source. A simple tone is played through the headphone-jack, which generates an oscillating potential wide enough to generate ECL from Ru(bpy)321 in the presence of a coreactant. Later versions have also utilized the mini-USB port of the phone to provide a more consistent voltage.49 These innovative technologies open opportunities to perform ECL based diagnostic tests in areas that do not have access to more advanced testing equipment. Despite the first ECL reports occurring more than 40 years ago, Ru(bpy)321 remains the dominating luminophore in ECL. This is clearly evidenced by the abundance of studies which continue to use Ru(bpy)321. This emitter has been of paramount importance to the development of this field, and will likely continue to be studied for many years to come.

3

Iridium complexes

Ir(III) complexes have attracted considerable attention as novel luminophores for ECL applications over the past decade.21,50 A major promise of Ir(III) complexes comes from the fact they often possess significantly higher PLQYs and longer luminescence lifetimes than the prototypical Ru(II) complexes. Though this does not necessarily translate to a higher ECL performance, as evidenced by numerous reports, the higher PLQY translates to a higher upper limit for ECL quantum yields relative to Ru(II) polypyridyl complexes. An additional feature of Ir(III) based emitters is the ease in which the emission energies can be tuned across the visible spectrum with simple modifications of the coordinated ligands. This is in contrasts to Ru(bpy)321 and its derivatives which generally emit in the red region, around 630 nm. For the iridium complexes it has been shown that ligand substitution can be used to shift the electrogenerated emission from the blue to the red or NIR, a property already utilized for light emitting devices, including ECL based lighting applications.51 The use of Ir(III) complexes for ECL applications in aqueous solutions is relatively recent, despite several earlier reports investigating ECL in different conditions from several systems.50 Indeed most of the initial studies utilized electrochemical potentials which were not sufficient to oxidize or reduce the complex to generate ECL through an annihilation mechanism. The first modern reports of Ir(III) based ECL appeared only in the early 2000s by several groups.21,44,50 In these cases the ECL was generated through the previously discussed annihilation mode, where the emissive species is produced through an electron transfer reaction between an 336 | Photochemistry, 2019, 46, 319–351

oxidized and a reduced form of the luminophore. Co-reactant ECL for iridium complexes took an additional few years to be realized, likely due to the use of co-reactants optimized for Ru(II) chemistry, which often has different electrochemical properties than Ir(III) based systems. In early attempts the Ir(III) complexes were less potent oxidizers when compare to their Ru counterparts, which meant that the driving force for co-reactant oxidation was often insufficient to drive the electron transfer reaction. A major breakthrough in Ir(III) based ECL came from the group of Lee in a publication released in 2005.52 The report investigated the ECL performance of a series of cyclometalated Ir(III) species in acetonitrile solutions. Most impressive were the complexes Ir(pq)2(acac) and (pq)2Ir(tmd) (pq ¼ 2-phenylquinoline anion, acac ¼ acetylacetonate and tmd ¼ 2,2 0 ,6,6 0 -tetramethylhepta-3,5-dione anion), which were found to significantly outperform the classic Ru(bpy)321 system using a TPA coreactant, by factors of 77 and 44 respectively. This study highlighted the promise that Ir(III) held in increasing the luminescent output of various ECL applications, even though the investigation were based in an organic solvent and the translation to water was not fast. For ECL based bioassays, an increase in luminophore luminescence means lower detection limits, as fewer probes would be need to generate a measurable amount of light. Unfortunately, more than 10 years after this report, Ru(bpy)321 remains the main luminophores for ECL applications, most likely due to the poor water solubility of these often neutral species, which limits their applications for biological assay. This has not stopped innovative scientists from developing new ligand systems to increase solubility, incorporating Ir(III) species into more advance materials or designing new ECL assay that can take full advantage of the luminescence properties of Ir(III) compounds. This section will focus on several recent examples of Ir(III) based luminophores that highlight the progress being made in creating new ECL based biological assays. As mentioned, poor water solubility and low emission quantum yields in aereated aqueous solution often plagues Ir(III) from being used in biological applications. In an effort to ameliorate this problem, De Cola et al. recently reported intense ECL emission from a series of neutral Ir(III) complexes utilizing phenylpyridine-based ligands in water, Fig. 9.53 In order to achieve ECL in aqueous solutions, this series of compounds was first dissolved into a very small amount of DMSO before being added to the commercially available ECL aqueous buffer ProCell, that contains the TPA co-reactants and a number of different surfactants. Typical concentrations of the complexes in the ProCell buffer were on the order of mM. The photophysical properties of these compound were quantified in both acetonitrile and ProCell solutions. The photoluminescence peaks for these complexes dissolved in acetonitrile was found to vary between 583–648 nm. A slight blue-shift was observed upon solvation within the ProCell solution, with values ranging between 578–645 nm. Excited-state lifetimes in acetonitrile under inert atmosphere were found to be between 1.69–1.99 us, while the PLQY were found to be vary between 0.27–0.70. The PLQY in the ProCell buffer in the presence of oxygen were found to be lower, ranging between 0.11–0.20, but the quenching was not Photochemistry, 2019, 46, 319–351 | 337

Fig. 9 Ir(III) complexes investigated in ECL by De Cola et al. Reproduced with permission from ref. 53, Copyright 2016 American Chemical Society.

so efficient as expected. Such behaviour was rationalized by the presence of surfactants within the ProCell solution, which could form protective micelles around the emissive compounds, shielding them from dioxygen. This was further supported by the observed blue shift in the photoluminescence relative to acetonitrile that was attributed to hydrophobic interactions within the micelles. The electrochemical properties of this family of compounds was quantified in air free acetonitrile in order to assess the compatibility with the TPA co-reactant. The oxidation potentials for all the complexes fell within a narrow range of 1.07–0.93 V vs. SCE. The oxidation was thought to be metal-aryl centre and therefore more profoundly influenced by substitution on the aryl ligand. This was evidenced by complex and 3–5, which showed nearly identical oxidation potentials, while complex 2 showed a significant shift to lower potential. Reduction potentials for all the complexes were nearly identical, while 5 was shifted to less reductive potentials due to the increase conjugation on the ring. The ECL activities of each Ir(III) compound was evaluated in the ProCell buffer using Ru(bpy)321 as reference. A positive potential was applied and interestingly complexes 5 was able to outperform the Ru(bpy)321 standard. The emission for this compound was found to be 3.72 times higher that of Ru(bpy)321 under the same conditions. This 338 | Photochemistry, 2019, 46, 319–351

study highlights the promise that Ir(III) complexes have in replacing traditional Ru(II) based luminophore while demonstrating the amount of work still needed until these compounds can effectively replace the emitter on the market. Often reports simple take biological assays which work well using a Ru(II) based chromophore, and introduce an Ir(III) complex to greatly improve the sensitive. Zhang et al. recently developed the cationic species [Ir(bt)2(dmphen)]1 (bt ¼ 2-phenylbenzothiazole, dmphen ¼ 5,6-dimethyl1,10-phenanthroline).54 The compound displayed an intense yellowgreen luminescence that possess maxima at 522 and 561 nm, with a high PLQY (0.92). Reversible oxidative and reductive electrochemistry was observed for this compound, with reversible waves being observed at þ1.51 and 1.29 V vs. SCE, respectively. ECL experiments confirmed the intense yellow-green emission during annihilation mode. Remarkably, the compound displayed 12 times higher ECL efficiency over the prototypical Ru(bpy)321 luminophore in a non-aqueous medium, in annihilation mode. Efficient ECL was also observed in aqueous-media while using TPA as a co-reactant and interestingly the Ir(III) luminophore was found to be capable of intercalating within double-stranded DNA. Intercalation greatly improves the PLQY and the ECL efficiency for this compound. This effect is well known for several Ru(II) emitters, and has been used previously for studying DNA. The observation was central to the development of an ECL assay for the detection of m-RNA122, a potential biomarker for different liver diseases. A self-assembled layer of short thiolate dss-DNA on a gold electrode surface was exposed to the m-RNA analyte present in an aqueous buffer, Fig. 10. The m-RNA then hybridized with the surface bound DNA, forming a hybrid DNA/RNA double-helix. The DNA was specifically selected as to not fully conjugate with the RNA, leaving additional RNA nucleotides available for subsequent interactions. A second auxiliary probe double-helix was then introduced, which bound with the RNA nucleotides which were not yet bound to the surface anchored DNA, creating a so called ‘‘supersandwich

Fig. 10 Schematic representation of a biological assay that utilized a Ir(III) luminophore capable of intercalating within double stranded DNA/RNA for the detection of microRNA. Reprinted with permission from ref. 54, Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Photochemistry, 2019, 46, 319–351 | 339

double-stranded helix’’. Finally, the Ir(III) species was introduced, able to intercalate in the groves of the double helix strand. This assembled structure generated efficient ECL through the co-reactant mechanism in an aqueous buffer. A much lower ECL signal was detected in the absence of the RNA, which represented a control for the experiment. The introduction of the second auxiliary probe double-helix was justified on the basis of the approximate two-fold increase in intensity when compared to the system based solely on the original DNA/RNA system. A linear relationship was observed between the concentration of the analyte RNA strand and the ECL intensity, confirming this technique as a feasible analytical tool. Moreover, a limit of detection of 1.31014 M for m-RNA122 was achieved. This compared extremely well to other similar assays. In another report, Wang et al. developed a series of Ir(III) complexes bearing pendant carboxylic acid functional groups capable of forming covalent bonds to antibodies used in biological assays, Fig. 11.55 An analogous Ru(II) was also prepared which acted as a control to compare against the Ir(III) labels. The photophysical properties of these complexes were quantified in acetonitrile solution. The emission wavelength peaks varied between 508–707 nm, dependent on the nature of the noncarboxylic acid bearing ligand, while the PLQY for the Ir(III) complexes varied between 0.13–0.28 in nitrogen saturated acetonitrile. The nature of this emissive state was further investigated through DFT studies. In general, the excited-state was assigned to a HOMO to LUMO transition, with the observed charge distribution allowing the assignment of a mixture of metal-to-ligand and ligand-to-ligand charge transfer to the transition. Due to its importance to ECL, the authors then investigated the electrochemical properties of each compound, and found that most compound possessed a reversible oxidation between 0.78–1.26 V vs. Fc1/0, and irreversible reduction behaviour between 1.39 and 1.66 V. ECL measurement were then performed for each compound using TPA as a co-reactant. The ECL intensity were compared against Ru(bpy)321 under the same experimental conditions. All Ir(III) based luminophores were

Fig. 11 Series of Ir(III) complexes for bioconjugation prepared by Wang et al. Reproduced from ref. 55 with permission from The Royal Society of Chemistry. 340 | Photochemistry, 2019, 46, 319–351

found to outperform the standard, with the greatest increase arising from Complex 10 at nearly 10 the intensity of Ru(bpy)321. In order to calculate the absolutely ECL quantum efficiencies, ECL signals were obtained from each label in annihilation mode using a previously reported method for determine the yields. Remarkable, label 3 reached a quantum yield of 0.85, nearly 18 times higher than the standard Ru(bpy)321. The authors selected this label for subsequent experiments for the development of a probe using the model protein bovine serum albumin. For this experiment, the carboxylic acid was transformed into a N-hydroxysuccinimide (NHS) ester, and the transformed molecule was added to a PBS buffer containing BSA, which then formed the active label. The same procedure was followed for the preparation of the Ru based dye, as to provide a standard for the Ir(III). Bicinchoninic acid protein assay was used to quantify the amount of BSA present, and the absorbance of the label was used to quantify the amount of metal complex presence. The Ir(III) based label gave a more intense signal (1.9 times) under the same label concentration relative to Ru(II). Though no assays were performed in this report, such an observation suggest that Ir(III) could improve the sensitive of many assay and improve the detection limit for the quantification of proteins. A recent example of biological ECL assays using Ir(III) emitters for the detection of specific cell-surface carbohydrates was presented by Zhang et al.56 These carbohydrates are important for many cellular processes, including cell adhesion, differentiation and detection of different pathological processes. Abnormal expression of surface carbohydrates are also associated with many diseases such as cancer and Alzheimer. In this report, the authors combined previously prepared Ir(III) luminophores with mesoporous silica nanoparticles and Au nanoparticles to prepare a composite material (Au/Ir-MSN) as a novel ECL signaling probe. The composite functioned by encapsulating the Ir complex, [Ir(ppy)2(dcbpy)]1 (dcbpy ¼ 4,4 0 -dicarboxy-2,2 0 -bipyirinde) within the pores of the MSN, and then sealing the pores with the AuNPs. The system was based on the binding between concanavalin A (Con A) and mannose. Con A was attached to both a GC electrode previously functionalized with a modified graphene layer and to the AuNP used to seal the pores of the MSNs. Test cells were first introduced to the functionalized GC electrode, where the cells adhered to the electrode if they expressed the target carbohydrates. After washing away the unbound cells, the Au/Ir-MSN was introduced creating a sandwich-type system consisting of the GC electrode, target cell, and the Au/Ir-MSN, Fig. 12. The presence of a TPA coreactant in the external electrolyte led efficient ECL from the cells present at the interface, allowing for the quantification of cells expressing the target carbohydrate. No ECL was observed in the absence of Au/Ir-MSN, demonstrating that the hybrid system was the source of the emission. Additionally, the absence of a target cell shows no significant ECL, demostrating that this system was effective for the detection of cells expressing the target carbohydrate. The performance Au/Ir-MSN was compared against a similar structured probe utilizing Ru(bpy)321 instead of the Ir(III) luminophore. The authors claimed a 24-fold increase in the Photochemistry, 2019, 46, 319–351 | 341

Fig. 12 Assay for the detection of specific surface carbohydrates based on a Au/Ir-MSN probe. Reprinted with permission from ref. 56, Copyright 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

ECL emission of free Ir-MSN when compared to Ru-MSN before incubation with the cells, while a 20-fold increase was observed for the full Ir assembly after incubation with 1.0105 cell mL1 when compared to signal observed from the Ru system under analogous conditions. A linear relationship between cell concentration and signal was observed from the Ir system, and a lower limit of detection of 100 cells mL1 was determined through a linear regression, similar to several other techniques for surface carbohydrate detection. Specificity towards a specific carbohydrate was demonstrated by a lack of ECL signal when the system was incubated with cells that did not express the target carbohydrate. The above summarized studies highlight the progress being made in developing Ir(III) luminophores for biological assay. Arguable, Ir(III) represent the most promising alternative to Ru(bpy)321, and novel developments will lead to more performant systems for biomedical assays. Though solubility, non specific binding and long term stability remain a problem, ligand modification and incorporation into hybrid systems can solve the problems. Nevertheless, considerable work remains before the full potential of Ir(III) complexes can be realized.

4 Platinum complexes The first example of ECL from platinum complexes date back 1984 by Vogler et al.57 who showed ECL through annihilation method from Tetrakis(diphosphonato)diplatinate(II). Interestingly, such complexes are characterized by a dual emission at room temperature in solution: a weak fluorescence (lmax ¼ 407 nm) of the singlet 1A2u state, and an intense phosphorescence (lmax ¼ 517 nm) of the triplet 3A2u state. However when ECL experiment were performed by alternating current electrolysis with variable frequency using TBABF4 as supporting electrolyte in dry acetonitrile only a marked green luminescence was observed at the electrode, which was visible even by eye. Such a result suggested that the 342 | Photochemistry, 2019, 46, 319–351

recombination of the oxidized and reduced species furnishes sufficient energy to generate one of the two states: the lowest luminescent excited state, the triplet 3A2u while the highest energy one cannot be populated or immediately decay to the triplet state. A few years later, another example of ECL of luminescent platinum(II) complex was reported by Balzani et al.58 in 1986 using the cyclometalated Pt(Thpy)2 where Thpy is 2-(2thienyl)-2-pyridine. This compound is characterized by photoluminescence in fluid solution at room temperature in dimethylformamide at lmax ¼ 580 nm, while its electrochemistry is characterized by two one-electron reversible reduction processes (Epc ¼ 1.80 and 2.11 V vs. SCE) and one irreversible oxidation (EpaEþ0.82V vs. SCE). Also in that case ECL was observed trough annihilation method by alternating current electrolysis experiments stepping the potential between 1.80 and þ0.85 V. Interesting they also investigated the effect of a co-reactant in the system. In particular, in presence of S2O82 ECL was generated upon continuous reduction at 1.80 V. Also in that case the ECL spectrum was consistent with the photoluminescence spectrum, indicating that the chemical reactions that follow the electrochemical processes lead to the same metal-to-ligand charge-transfer excited state that is generated by light excitation. Pt(II) porphyrins showing ECL have been reported at the beginning of 2000 by Kulmala et al.59 who showed that cathodic pulse polarisation of oxide-covered aluminium electrodes can generate electrochemiluminescence (ECL) from platinum(II) coproporphyrin (PtCP) and its bovine serum albumin (BSA) conjugate. This allows the detection of this molecule below nanomolar concentrations while the relatively long luminescence lifetime allows discrimination from the background ECL signal using time resolved measurements, further increasing the sensitivity of the system. Furthermore the detection of PtCP-BSA clearly indicated the potential use of platinum porphyrins as labels in ECL-based bioassays. Another example was reported few years later by Richter et al.60 that showed ECL of platinum (II) octaethyl-porphyrin (PtOEP) in organic solvents. In this case ECL was generated by co-reactant method using TPA and the efficiency of the process was evaluated versus Ru(bpy)3 and found to be 18%. An important step towards the design of new ECL emitters based on platinum(II) complexes has been made by Hogan et al.61 that reported a series of platinum(II) Schiff base complexes in which the electronic density can be directed selectively toward the LUMO or HOMO by ligand design. As anticipated in the introduction, the possibility of tuning independently the HOMO and LUMO of a luminophore is extremely important in ECL since it allows the modulation of the emission colour without altering the oxidation (HOMO not altered) or reduction (LUMO not altered) potential of the complex thus enabling multiplexed detection. In the Schiff base compounds reported by Hogan (see Fig. 13) the modulation of the electronic density was obtained by varying the number and position of the methoxy substituents on the phenoxy ring. The effects of the change in the electronic properties were then correlated with their photophysical, electrochemical and electrochemiluminescent (ECL) properties. Photochemistry, 2019, 46, 319–351 | 343

Fig. 13 Schiff base Pt(II) complexes 12–18 reported by Hogan. Reproduced with permission from ref. 61, Copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Table 1 Properties of the Schiff base Pt(II) complexes 12–18 reported by Hogan.61 Electrochemical potential are reported against ferrocene (Fc) which was 0.35 versus Ag/AgCl. ECL intensities are calculated against the standard [Ru(bpy)3]21. Reproduced with permission from ref. 61, Copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Complex

lem [nm]

Fem [%]

12

620

3.8

13 14

587 590

1.6 5.6

15

615

4.9

16

647

3.5

17

698

4.8

18

739

0.6

[Ru(bpy)3]21 620

2.7

labs [nm] 534, 498, 463, 321, 252 496, 401, 381, 505, 475, 441, 315, 254 526, 505, 461, 334, 254 538, 516, 468, 351, 263 575, 545, 498, 322, 263 581, 548, 508, 335, 254 450, 270

Eox [V] Ered [V] ECLann ECLTPA 381, 362,

0.73

1.98

489.6

0.1

361, 254 381, 365,

0.45 0.63

2.11 2.05

229.0 73.5

0.2 1.0

407, 384,

0.68

1.97

0.6

2.0

395, 373,

0.35

1.80

0.6

49.5

387, 366,

0.46

1.75

1.0

35.6

396, 370,

0.53

1.83

3.9

1.9

100

100

When an electron-donating and ortho/para directing such as OMe is placed at positions R3 and/or R5 it can destabilise the imine-localised LUMO whilst having virtually no impact on the HOMO. Contrarily, if the electron-donating group is placed at positions R6 or R4 which are ortho/ para positions respect to the Pt-O the HOMO is destabilised without impacting the energy of the LUMO. This resulted in a clear trend in the photophysical properties across the series, with the MLCT absorbance bands progressively shifting from 496 to 581 nm and the emission maxima shifting from 587 to 739 nm going from complex 13 to complex 18 (see Table 1). In particular in the complexes 13, 14 and 15 which contain the methoxy group at positions ortho and/or para to the imine group (R6 and R4) the emission energy increases according to the following pattern: orthoopara oortho and para. This is consistent with a LUMO residing substantially on the imine moiety, which is progressively destabilised on going from 15 to 14 to 13. The same trend has been observed for the electrochemical reduction potentials: the more electron density is located on the imine 344 | Photochemistry, 2019, 46, 319–351

moieties (LUMO) the higher is the reduction potential which moves from 1.97 to 2.11 V. A similar argument applies to complexes 16, 17 and 18, which are substituted at positions R3 and R5, ortho and/or para to the metal bonded oxygen. In this case the reduction potential is almost unchanged while the complexes display the lowest emission energy thus indicating that HOMO level must have been increased. Unfortunately, the quasi-reversible nature of the electron transfer processes complicates the interpretation of the anodic part of the cyclic voltammetry thus obscuring the correlation between the oxidation potential and the molecular design. The selective modulation of the electron density has been further confirmed by DFT calculation showing that is also possible to employ other substituents such as methyl, NH2 or CN group, the latter having an effect equal but opposite to OMe. The annihilation ECL was observed for all the complexes and the mechanism proposed the generation of the oxidized and reduced species (eqn 1 and 2) followed by two electron transfer reaction (eqn 3 and 4) the latest resulting in the formation of the excited state. [PtIISal]-[PtIVSal]21 þ 2e [PtIISal] þ e-[PtIISal]

(1) (2)

[PtIVSal]21 þ [PtIISal]-[PtIIISal]1 þ [PtIISal]

(3)

[PtIIISal]1 þ [PtIISal]-[PtIISal]* þ [PtIISal]

(4)

Indeed the driving force in the annihilation reactions, calculated from the electrochemical potential (Eox  Ered) are sufficiently exergonic to form the excited state for all the complex of at least 0.27 eV. However the most intense ECL emitters under annihilation conditions are complex 12, 13 and 14 that possess also the most negative reduction potentials even exceeding the Ru(bpy)3 benchmark in the same conditions. Also coreactant ECL was observed for all complexes using TPA as sacrificial agent at the potential corresponding to the oxidation of the platinum complex. The mechanism proposed in that case is similar to the one generally reported for Ru(bpy)3 in which the TPA is oxidized at the same potential of the metal followed by electron transfer from the oxidized TPA to the oxidized metal complex resulting in the generation of the excited state. The only difference is that most likely there are two consecutive reduction steps. [PtIISal]-[PtIVSal]21 þ 2e

(5)

TPA-TPA 1-TPA þ H

(6)

[PtIVSal]21 þ TPA -[PtIIISal]1

(7)

[PtIIISal]1 þ TPA -[PtIISal]*

(8)

Contrarily to the annihilation ECL, the most intense ECL emitter under such conditions were complex 16 and 17 that were the worst performing Photochemistry, 2019, 46, 319–351 | 345

in the annihilation ECL. Interestingly both complexes possess the least negative reduction potentials (1.80 and 1.75 V respectively) thus less negative then the TPA (B2.1 V vs. Fc) which is a fundamental requirement as pointed out in the introduction. Also the fact that they possess the lowest oxidation potentials while being still high enough to oxidize TPA can have an important impact on the ECL efficiency since it assure a fast generation of the oxidized species and probably less parasitic reactions. Due to their square planar geometry, Pt(II) complexes generally display a high tendency to stack resulting into the formation of supramolecular structures. This self-assembly process is often accompanied by a dramatic change in the electronic properties which is due to the establishment of Pt  Pt metallophilic interaction. Such peculiar property has attracted particular attention in the last decade since such complexes can be weakly emissive in the molecularly dissolved state and become extremely emissive in the aggregate form with PLQY up to 90%.62 Furthermore the control of the degree of metallophilic interactions can be used to tune the emission spectra over almost the entire visible spectrum63,64 thus making them extremely appealing for light emitting application such OLED. Even if the change of the photophysical properties due to the establishment of Pt  Pt metallophilic interactions was already reported by in 197465 it was only last year that an example of ECL system based on aggregated species has been reported.66 The amphiphilic complexes reported by De Cola et al. contain an hydrophobic terdentate ligand (see Fig. 14) and an hydrophilic ancillary 4-amino pyridine substituted with one (complex 19) or two triethylene glycol chains (complex 20). Interestingly when 19 or 20 are dissolved in dichloromethane (DCM) solution at room temperature they display the same photophysical features, in particular they are characterized by intense absorption bands in the UV region, mainly attributed to the intraligand (1IL) and metalperturbed interligand charge transfer (1ILCT) states and low energy transitions up to 420 nm assigned to a metal-to-ligand charge transfer transitions (MLCT). Also upon photoexcitation, in organic solvents, they exhibit the same structured blue luminescence with low emission quantum yield (PLQY ¼ 1%), assigned mainly to the ligand-centered triplet excited state (3LC) typical of the monomeric form (molecularly dissolved state), Fig. 14. For both complexes ECL experiments performed in such solvent using TPA as co-reactant gave rise to negligible light emission. The main difference between the two complexes relies indeed in their different tendency to self-assemble in aqueous media; while 19 is not water soluble 20 readily dissolves forming stable clear suspension of spherical nanoaggregates of 22 nm of diameters. Such particles showed a strong yellow–orange emission centred at 600 nm with PLQY up to 72% which is due to the establishment of Pt  Pt metallophilic interactions. Furthermore, it was found that, conversely to the molecularly dissolved state, the aggregates are extremely ECL active. Indeed, ECL experiments in aqueous media with TPA as co-reactant, have shown an ECL efficiency 20% higher than Ru(bpy)321 while employing Na2C2O4 as co-reactant 346 | Photochemistry, 2019, 46, 319–351

Photochemistry, 2019, 46, 319–351 | 347

Fig. 14 Structures of the complex 19 and 20 reported by De Cola et al. and their photophysical and ECL properties.

instead of TPA increased the ECL intensity dramatically, exceeding the standard Ru(bpy)321 by a factor of 14. The Pt  Pt metallophilic interactions does not only change the photophysical properties of the emitter but also its electrochemical behaviour since it destabilizes the HOMO, resulting in a lower oxidation potential of the species. Indeed, in the monomeric form, the oxidation of the Pt(II) falls above the electrochemical window of the solvent thus it could not be detected while, in the aggregated form, an irreversible oxidation peak at þ1.33 V vs. Ag/AgCl was observed and ascribed to the oxidation of Pt21 to Pt41. The presence of two hydrophilic chains allows the solubilisation of the complex in aqueous media but also keep the particle size relatively small. Complex 19, which features a single PEG chain, required instead a presolubilization in organic solvent (i.e. dioxane) followed by flash injection in distilled water to form the orange emitting suspension which consist of 130 nm particles that tends to increase their size over time.67 It is likely the large size of the aggregates as well as the stability of the dispersion that causes the failure of the ECL experiment for such complex since it can limit the diffusion of the species to the electrode surface. Even if ECL could not be performed in solution using complex 19, a further evidence that the establishment of Pt  Pt metallophilic interactions is responsible of the electrochemical generation of light was obtained in the solid state. Profiting of the mechanochromic properties of the complexes,68 compound 19 in the blue emitting form was physically transfer on carbon screen-printed electrodes (SPEs) and oxidize in presence of the co-reactant resulting in a very weak emission. Then it was mechanical stress with a gentle grinding to convert the blue emitting form into to orange bright emissive one resulting into a 20 times higher intensity than that before grinding. Even though the mechanism of the electrochemical light generation in such kind of system has not been explored yet, the formation of supramolecular systems involving metallophilic interactions opens the route for the design of new efficient ECL emitters that can be applied for biosensing and immunoassays. In conclusion only few examples of ECL based on luminescent platinum complexes has been reported so far. Probably one of the biggest limitation is the irreversible character of the oxidation of the Pt(II) to Pt(IV) which result in a change of the coordination geometry from square planar to octahedral. Due to such change of the coordination geometry, the chemical or electrochemical formation of the Pt(IV) should be followed by an insertion of two or more ligands in the coordination sphere which can come from the co-reactant, the solvent or from some electrogenerated species as well. The resulting complex can possess different stability and (opto)electronic properties and its reduction back to the square planar Pt(II) complex in the excited state should also be preceded by the expulsion of the two ligands in excess which can be different from the ones captured during the oxidation step. In order to amplify the ECL signal the emitter should be able to undergo many oxidation/reduction cycles being the co-reactant the only specie consumed since it is this process that 348 | Photochemistry, 2019, 46, 319–351

results in the amplification of the signal. Indeed many challenges have still to be addressed from the mastering of the metallophilic interactions through supramolecular approaches to the understanding of the mechanism involved in the ECL and the design of new ligands which takes into account the geometry switch between Pt(II) and Pt(IV). In conclusions only noble metals have been so far employed for ECL and to the best of our knowledge no examples employing cheap and abundant metals have been developed for bioassays. There is plenty of room for other systems and the advancement in ligand design, corroborated by calculations and spectroscopic measurements can definitely lead to exciting new systems.

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

L. Li, Y. Chen and J.-J. Zhu, Anal. Chem., 2017, 89, 358. M. M. Richter, Chem. Rev., 2004, 104, 3003. C. M. Hindson, P. S. Francis, G. R. Hanson and N. W. Barnett, Chem. Commun., 2011, 47, 7806. H. B. Lemon, Science, 1918, 47, 170. N. Harvey, J. Phys. Chem., 1928, 33, 1456. D. M. Hercules, Science, 1964, 145, 808. T. Kuwana, B. Epstein and E. T. Seo, J. Phys. Chem., 1963, 67, 2243. G. S. Springer, Rev. Sci. Instrum., 1964, 35, 1277. K. S. V. Santhanam and A. J. Bard, J. Am. Chem. Soc., 1965, 87, 139. R. E. Visco and E. A. Chandross, J. Am. Chem. Soc., 1964, 86, 5350. N. E. Tokel and A. J. Bard, J. Am. Chem. Soc., 1972, 94, 2862. H. Ishida, S. Tobita, Y. Hasegawa, R. Katoh and K. Nozaki, Coord. Chem. Rev., 2010, 254, 2449. M. A. Baldo, D. F. O’Brien, Y. You, A. Shoustikov, S. Sibley, M. E. Thompson and S. R. Forrest, Nature, 1998, 395, 151. A. Kapturkiewicz and G. Angulo, Dalton Trans., 2003, 3907. DOI: 10.1039/ B308964A. Neal R Armstrong, R Mark Wightman and E. M. Gross, Annu. Rev. Phys. Chem., 2001, 52, 391. C. Adachi, M. A. Baldo, M. E. Thompson and S. R. Forrest, J. Appl. Phys., 2001, 90, 5048. H. Uoyama, K. Goushi, K. Shizu, H. Nomura and C. Adachi, Nature, 2012, 492, 234. R. Ishimatsu, S. Matsunami, T. Kasahara, J. Mizuno, T. Edura, C. Adachi, K. Nakano and T. Imato, Angew. Chem., Int. Ed., 2014, 53, 6993. M. Zhou, G. P. Robertson and J. Roovers, Inorg. Chem., 2005, 44, 8317. Y. Kawamura, K. Goushi, J. Brooks, J. J. Brown, H. Sasabe and C. Adachi, Appl. Phys. Lett., 2005, 86, 071104. M. A. Haghighatbin, S. E. Laird and C. F. Hogan, Curr. Opin. Electrochem., 2018, 8, 52. E. Zysman-Colman, Iridium(III) in Optoelectronic and Photonics Applications, Wiley, 2017. R. Y. Lai and A. J. Bard, J. Phys. Chem. A, 2003, 107, 3335. J. I. Kim, I.-S. Shin, H. Kim and J.-K. Lee, J. Am. Chem. Soc., 2005, 127, 1614. F. Kanoufi, Y. Zu and A. J. Bard, J. Phy. Chem. B, 2001, 105, 210. W. Miao, Chem. Rev., 2008, 108, 2506. Z. Liu, W. Qi and G. Xu, Chem. Soc. Rev., 2015, 44, 3117. Photochemistry, 2019, 46, 319–351 | 349

28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63

Y.-T. Hsueh, S. D. Collins and R. L. Smith, Sens. Actuators, B, 1998, 49, 1. M. R. Gill and J. A. Thomas, Chem. Soc. Rev., 2012, 41, 3179. M. M. Richter, Chem. Rev., 2004, 104, 3003. L. Li, Y. Chen and J. J. Zhu, Anal. Chem., 2017, 89, 358. W. Miao, J. P. Choi and A. J. Bard, J. Am. Chem. Soc., 2002, 124, 14478. Z. Liu, W. Qi and G. Xu, Chem. Soc. Rev., 2015, 44, 3117. S. Zanarini, E. Rampazzo, L. D. Ciana, M. Marcaccio, E. Marzocchi, M. Montalti, F. Paolucci and L. Prodi, J. Am. Chem. Soc., 2009, 131, 2260. G. Valenti, E. Rampazzo, S. Bonacchi, L. Petrizza, M. Marcaccio, M. Montalti, L. Prodi and F. Paolucci, J. Am. Chem. Soc., 2016, 138, 15935. Y. Feng, F. Sun, N. Wang, J. Lei and H. Ju, Anal. Chem., 2017, 89, 7659. Y. Feng, C. Dai, J. Lei, H. Ju and Y. Cheng, Anal. Chem., 2016, 88, 845. D. Wang, Y. Li, Z. Lin, B. Qiu and L. Guo, Anal. Chem., 2015, 87, 5966. J. Zhang, Z. Gryczynski and J. R. Lakowicz, Chem. Phys. Lett., 2004, 393, 483. D. Wang, L. Guo, R. Huang, B. Qiu, Z. Lin and G. Chen, Sci. Rep., 2015, 5, 7954. S. Sun, W. Sun, D. Mu, N. Jiang and X. Peng, Chem. Commun., 2015, 51, 2529. Q.-M. Feng, Y.-Z. Shen, M.-X. Li, Z.-L. Zhang, W. Zhao, J.-J. Xu and H.-Y. Chen, Anal. Chem., 2016, 88, 937. E. H. Doeven, G. J. Barbante, C. F. Hogan and P. S. Francis, ChemPlusChem, 2015, 80, 456. D. Bruce and M. M. Richter, Anal. Chem., 2002, 74, 1340. Y.-Z. Wang, C.-H. Xu, W. Zhao, Q.-Y. Guan, H.-Y. Chen and J.-J. Xu, Anal. Chem., 2017, 89, 8050. H. Wang, Y. Yuan, Y. Zhuo, Y. Chai and R. Yuan, Anal. Chem., 2016, 88, 2258. S. Carrara, F. Arcudi, M. Prato and L. De Cola, Angew. Chem., Int. Ed., 2017, 56, 4757. J. L. Delaney, C. F. Hogan, J. Tian and W. Shen, Anal. Chem., 2011, 83, 1300. E. H. Doeven, G. J. Barbante, A. J. Harsant, P. S. Donnelly, T. U. Connell, C. F. Hogan and P. S. Francis, Sens. Actuators, B, 2015, 216, 608. S. E. Laird and C. F. Hogan, in Iridium(III) in Optoelectronic and Photonics Applications, ed. E. Zysman-Colman, Wiley, 2017, vol. 2, pp. 359–414. S. H. Kong, J. I. Lee, S. Kim and M. S. Kang, ACS Photonics, 2018, 5, 267. J. I. Kim, I.-S. Shin, H. Kim and J.-K. Lee, J. Am. Chem. Soc., 2005, 127, 1614. J. M. Fernandez-Hernandez, E. Longhi, R. Cysewski, F. Polo, H.-P. Josel and L. De Cola, Anal. Chem., 2016, 88, 4174. Y. Zhao, X. Yang, D. Han, H. Qi, Q. Gao and C. Zhang, ChemElectroChem, 2017, 4, 1775. Y. Zhou, K. Xie, R. Leng, L. Kong, C. Liu, Q. Zhang and X. Wang, Dalton Trans., 2017, 46, 355. H. Zhou, Y. Yang, C. Li, B. Yu and S. Zhang, Chem. – Eur. J., 2014, 20, 14736. A. Vogler and H. Kunkely, Angew. Chem., Int. Ed., 1984, 23, 316. S. Bonafede, M. Ciano, F. Bolletta, V. Balzani, L. Chassot and A. Von Zelewsky, J. Phys. Chem., 1986, 90, 3836. ¨re, M. Håkansson, A. M. Spehar, D. Papkovsky, T. Ala-Kleme, P. Canty, L. Va J. Kankare and S. Kulmala, Anal. Chim. Acta, 2002, 453, 269. T. R. Long and M. M. Richter, Inorg. Chim. Acta, 2005, 358, 2141. E. F. Reid, V. C. Cook, D. J. D. Wilson and C. F. Hogan, Chem. – Eur. J., 2013, 19, 15907. C. A. Strassert, C. H. Chien, M. D. G. Lopez, D. Kourkoulos, D. Hertel, K. Meerholz and L. D. Cola, Angew. Chem., Int. Ed., 2011, 50, 946. V. W.-W. Yam, K. M.-C. Wong and N. Zhu, J. Am. Chem. Soc., 2002, 124, 6506.

350 | Photochemistry, 2019, 46, 319–351

64 65 66 67 68

B. Ma, J. Li, P. I. Djurovich, M. Yousufuddin, R. Bau and M. E. Thompson, J. Am. Chem. Soc., 2005, 127, 28. R. S. Osborn and D. Rogers, J. Chem. Soc., Dalton Trans., 1974, 1002. S. Carrara, A. Aliprandi, C. F. Hogan and L. De Cola, J. Am. Chem. Soc., 2017, 139, 14605. A. Aliprandi, M. Mauro and L. De Cola, Nat. Chem., 2016, 8, 10. D. Genovese, A. Aliprandi, E. A. Prasetyanto, M. Mauro, M. Hirtz, H. Fuchs, Y. Fujita, H. Uji-I, S. Lebedkin, M. Kappes and L. D. Cola, Adv. Funct. Mater., 2016, 26, 5271–5278.

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Photoinduced bond activation via Ru and Rh dihydrides: principles and selectivity Barbara Procacci DOI: 10.1039/9781788013598-00352

This account reports on the fundamental principles of photoinduced bond activation through reductive elimination and oxidative addition reactions at group 8 and group 9 metal dihydrides. A recap of the seminal studies on the two elementary steps is presented. In addition, new developments employing laser pump-NMR probe methods are described with relevant examples. Kinetic and thermodynamic selectivities on C–H, C–C, C–F, B–H and Si–H bond activations are discussed.

1

Introduction

Over the years, a massive effort by the organometallic community has been directed into gaining a better understanding of the activation and functionalisation of strong bonds (C–H, C–F, Si–H and B–H) by homogeneous metal complexes. Several comprehensive reviews have covered this topic.1–13 The understanding of selective bond cleavage, although of significance, is often neglected in the investigation of catalytic processes. For instance, very good borylation9,14 and hydrosilylation catalysts8 selectively cleave the B–H and Si–H bond, without altering other functional groups in the molecule. Selectivity becomes most important when the products of a reaction may also react with the catalyst and is critical in scenarios where the catalyst can react with the product in preference to the starting material.15 Oxidation of alkanes to alcohols (e.g. methane to methanol)16 faces this issue; the latter will readily oxidize to yield aldehydes or ketones. The photochemistry of metal dihydride complexes has proved a powerful tool to generate unsaturated reactive intermediates which can activate strong bonds in various molecules. Although many catalytic cycles are thermally driven the possibility to use photochemistry has helped a great deal in understanding the fundamental principles of catalysis through the detection of unstable products via irradiation at low temperature17,18 and the use of time-resolved methods19,20 to determine reaction kinetics. We have recently produced a wide-ranging review on this topic covering very early metal dihydride photochemistry through to the latest discoveries, including a systematic survey of photochemical reactions of metal hydrides by group, and the analysis of the theory on metal dihydride photochemistry. The techniques for studying photochemical mechanisms were also surveyed.21 Group 8 (Fe,14,22–27 Ru,28–31 Os32–34) and group 9 (Rh,35–45 Ir46–53) metal dihydrides have been found to possess the best qualities for use as homogeneous catalysts for the oxidative addition of very strong bonds via Centre for Hyperpolarisation in Magnetic Resonance, Department of Chemistry, York Science Park, University of York, York YO10 5NY, UK. E-mail: [email protected] 352 | Photochemistry, 2019, 46, 352–369  c

The Royal Society of Chemistry 2019

Scheme 1 Reaction scheme showing the H2 reductive elimination step (dashed circle) to the formation of the unsaturated fragment (intersection point), the oxidative addition step (solid circle) with the cleavage of the EX bond follow to generate a saturated product.

photogeneration of the unsaturated intermediates; their reactivity has been explored over the years and these results contributed to a better understanding of bond-breaking and bond-making. In examining photoreaction as a tool to activate a strong bond, one of the preferred routes is via the formation of a vacant site on the metal centre by photoreductive elimination of a ligand with subsequent oxidative addition of the substrate (Scheme 1) creating two new metal bonds. This report will be concerned with this class of reactions providing a summary of the seminal studies for the reductive elimination step, as exemplified via group 8 metal dihydrides. The same approach will be adopted for the oxidative addition step using group 9 metal dihydrides. In addition, thermodynamic and kinetic selectivity on the activation of C–H bond will be discussed with a focus on the latest discoveries on competition reactions between C–H and the hetero bonds, C–C, C–F, B–H and Si–H. The process will be analysed as two stand-alone reactions (Scheme 1): (1) The photochemical reductive elimination which yields the reactive intermediate. (2) The thermal oxidative addition of the EX bond that forms the product.

2 Group 8 metal dihydrides for the reductive elimination step One of the main pathways to access a reactive intermediate is by the reductive elimination of a photolabile ligand. This causes a decrease in oxidation state at the metal centre (usually by two), and the generation of an unsaturated 16e complex.54,55 Group 8 mutually cis-dihydrides are among the best photoactive species to yield reactive intermediates; studies of their reactivity via steady state photochemistry but particularly via time resolved methods have helped to unveil the nature of photochemical processes involved. Many reports have reviewed these early experiments21,56 and therefore only a brief summary of the key findings is provided here. A highlight of recent results obtained on group 8 dihydrides in the development of a new pump–probe method which involves nuclear magnetic resonance (NMR) as a probing step follows. 2.1 Seminal studies Reductive elimination of H2 from group 8 metal dihydride complexes is a well-understood photoprocess. The reductive elimination was established Photochemistry, 2019, 46, 352–369 | 353

to be concerted and to compete successfully with loss of other ligands such as CO or phosphines.57–59 Fe(CO)4H2 was among the first metal complexes for which H2 reductive elimination was observed by matrix photochemistry; the microscopic reverse oxidative addition of H2, was also reported to take place in matrices at longer wavelengths.60 An extensive theoretical description of the reductive elimination mechanism for the tetracarbonyldihydridoiron complex supported the experimental observation for H2 reductive elimination as the preferred photochemical pathway.61,62 Mass spectrometry was used to look at H/D cross over experiments in the photolysis of Ru(dmpe)2H2 and Ru(dppe)2H2; only a very minor amount of HD was detected in these experiments and therefore H2 reductive elimination was postulated as the main photochemical process.63 Since then, other techniques such as matrix photochemistry,55,56,64–68 time resolved UV–Vis absorption29–31,34,66,69–72 and more recently time resolved-IR57,73 have allowed detection of the transients, establishing prompt cleavage of the M–H bond (ca. 16 ps for [Ru(dmpe)2])70 with concomitant formation of molecular hydrogen. H2 readdition to the transient species [Ru(dmpe)2] was measured to take place almost at the diffusion limit ((6.8  0.3)109 M1 s1).66 Experiments to prove homolytic cleavage of the M–H bond were unconvincing63 while measurement in the presence of a D2 atmosphere corroborated the concerted nature of H2 reductive elimination.31

2.2 Trends A variety of group 8 dihydride complexes (M-carbonyl, M-phosphine, or mixed-ligand compounds) consistently showed the same photochemical mechanism in which H2 is photoejected within timescale of the laser flash (typically nanosecond). The rates reported for the oxidative addition of the quencher varied depending on the electronic and the steric properties of the ligands around the metal centre. As an example, a trend in the k2 values (Fig. 1, top) for a series of Ru(H)2 complexes with different bidentate phosphine ligands (Fig. 1, bottom) in the presence of H2 and HBpin is analysed; second order rate constants k2 are larger for complexes with less bulky phosphines, (e.g. dmpe, depe). The fragment [Ru(dppe)2] shows 10 times greater reactivity towards HBpin than towards the BPE analogue.31 The transient [Ru(DuPHOS)2] is almost 100 times slower to react with HBpin than the [Ru(dppe)2] transient. The difference in reactivity can be explained by the use of phoshines Me-BPE and Me-DuPHOS where the methyl substituent on the phosholane ring causes steric congestion and limits the access for the ligands to the unsaturated Ru centre. The reduction in reactivity towards HBpin observed on going from [Ru(dmpe)2] to [Ru(dppe)2] spans a factor of 1500 and it is probably due to the sum of a steric effect played by the bulkier dppe phosphine and the smaller electron donation from the ligand to the Ru centre. The same trend is observed for reactions with H2. [Ru(dppe)2] is again less reactive than [Ru(depe)2] and [Ru(dmpe)2] and the rate constants for complexes 354 | Photochemistry, 2019, 46, 352–369

Fig. 1 Top: Plot of log10 k2 versus the different Ru(PP)2H2 complexes in the presence of HBpin (dense lines) and H2 (sparse lines) where k is the second order rate constant for substrate oxidative addition. Bottom: Structures of the various PP bidentate phosphines used. Relevant ref. 30, 31, 66. iPr-BPE ref. 74.

[Ru(BPE)2] and [Ru(DuPHOS)2] are even smaller than those observed for [Ru(dppe)2]. However, since H2 is a small ligand, the steric effects of the methyl groups on the phospholane ring are less significant than in reactions with HBpin. For the reaction with HBpin a reduction in rate constant by a factor of 80 is observed when going from [Ru(dppe)2] to [Ru(DuPHOS)2], while for the reaction with H2 a reduction in rate constants of just a factor of 4 is observed when going from [Ru(dppe)2] to [Ru(DuPHOS)2]. A huge effect on the rate constants is observed with the [Ru(iPr-BPE)2] fragment in which the rate constant for reaction with H2 is massively reduced and no reactivity is observed in the presence of HBpin.74 The geometry of the transient formed by reductive elimination of H2 is found to greatly influence the reactivity towards the same molecule.75 The reaction of [Ru(dmpe)2] with H2 in solution was measured to be 7500 times faster than the same reaction for the [Fe(dmpe)2] transient, these findings were rationalised on the basis of a butterfly C2v geometry Photochemistry, 2019, 46, 352–369 | 355

for the Fe complex and a square planar D2d geometry for the Ru analogue.75 2.3 Laser pump-NMR probe & para-H2: revisiting old insights The degenerate reaction of ruthenium dihydrides in the presence of an H2 atmosphere was particularly suitable to the development of our laser pump-NMR probe method.76 The use of hyperpolarisation (deviation of nuclear magnetisation from the standard Boltzmann distribution through the selective population of energy levels, Fig. 2, top) afforded by the para-isomer of H277,78 yielded an exceptional increase in the sensitivity of NMR spectroscopy allowing measurements to be done with a single NMR scan on optically dilute samples (nanomoles of product). Briefly, para-H2 is one of the two nuclear spin isomers of H2, it is a nuclear spin singlet state. This singlet state has no net angular momentum. As such, it is disconnected from the other nuclear spin isomer (triplet states) and therefore it possesses a much longer lifetime than the common triplet states.79,80 However, the absence of a net angular momentum also makes it NMR silent. In order to unlock the signal intensity benefits of the hyperpolarisation the symmetry of the singlet state needs to be broken; this can be achieved by oxidative addition to a metal centre to generate a metal dihydride where the two hydrides will be either chemically or magnetically inequivalent.81 The degenerate product formed by para-H2 addition is now in a hyperpolarised state (Fig. 2, bottom), the 1H NMR spectrum will show characteristic antiphase signals (Fig. 2, top) greatly enhanced in comparison to a standard NMR spectrum. In the pump–probe experiments a single laser shot photoinitiates the reaction and a single NMR pulse detects the outcome; a well-controlled delay t, between the two steps is what resolves the method in time (Scheme 2); this delay can be as short as few ms.76 The observation of hyperpolarised hydride signals for a series of RuH2 complexes has been

Fig. 2 Top: State population for a para-H2-derived reaction product containing nuclei I1 and I2, under hyperpolarised conditions with the resultant antiphase NMR peaks illustrated. Reprinted with permission from ref. 76, Copyright 2014 American Chemical Society. Bottom: General reaction for the photochemical reactivity of a metal dihydride toward para-H2. Blue denotes hyperpolarized 1H nuclei originating from para-H2 oxidative addition. Reproduced from ref. 82 with permission from The Royal Society of Chemistry. 356 | Photochemistry, 2019, 46, 352–369

Scheme 2 NMR pump–probe sequence used in the laser pump-NMR probe experiments. Reprinted with permission from ref. 76, Copyright 2014 American Chemical Society.

Fig. 3 Metal complexes that undergo concerted reductive elimination of H2 investigated by the laser pump-NMR probe method.

reported by the use of this new approach (Fig. 3).76,81 The method has also been applied successfully to a Vaska Ir dihydride system and the kinetics of H2 oxidative addition to the unsaturated fragment determined (Fig. 4, left).82 In all of the systems shown in Fig. 3, a concerted reductive elimination and readdition of H2 was decisively confirmed by the laser pump-NMR probe method; these results found agreement with those previously reported by different time resolved techniques. Interestingly, the development of this novel technique has not just contributed to the understanding of the elementary photochemical steps but has also allowed the observation of magnetic phenomena in the form of signal oscillations (zero quantum coherences, ZQ). ZQ coherences are not directly observable in NMR. The synchronous initiation step (laser pulse) in this method allows these phenomena to be chemically created and detected; the frequency at which ZQ coherences oscillates is dictated by the difference in chemical shift (Dn) of the chemically inequivalent hydrides derived by para-H2 addition or by the P–H coupling network | JPHtrans  JPHcis| in the case of chemical equivalence but magnetic nonequivalence of the para-H2 derived hydrides.76,81 The importance of ZQ coherences has been recently reviewed.83 The reactivity of Ru(H)2(CO)(PPh3)3 has been reinvestigated by photochemistry inside an NMR spectrometer in conjunction with para-H2 induced polarisation.57 In addition, nanosecond time resolved-IR spectroscopy was employed to provide parallel information on shorter timescales. Two competing photochemical pathways were determined to take place with approximately the same quantum yield at 355 nm: H2 reductive elimination as previously reported,73 and PPh3 loss. The hyperpolarised hydride peak confirmed the concerted H2 photoejection; Photochemistry, 2019, 46, 352–369 | 357

358 | Photochemistry, 2019, 46, 352–369 Fig. 4 Left: Hydride signal integral values of Ir(PPh3)2(CO)H2 versus t (time) taken from a series of 1H{31P} NMR spectra that were recorded under 3.31 bar of paraH2 pressure. Coloured squares/circles are the experimental points while the lines show the best fit to the points yielding kobs for para-H2 oxidative addition. Reproduced from ref. 82 with permission from The Royal Society of Chemistry. Right: Integral of the hyperpolarized hydride signal of Ru(ddpe)2H2 in a series of 1H laser pump-NMR probe experiments acquired with increasing delay t, demonstrating the impact of ZQ coherence evolution. Blue squares: experimental points. Red line: fit to a decaying sine-wave of frequency 84  0.1 Hz. Reprinted with permission from ref. 76, Copyright 2014 American Chemical Society.

H2, pyridine and triphenylarsine substitution products, all of which were characterised by NMR supported PPh3 loss. TRIR allowed detection of the transients [Ru(CO)(PPh3)3] and [Ru(H)2(CO)(PPh3)2] generated via both the photochemical pathways.57

3 Group 9 metal dihydrides for the oxidative addition step The reactive intermediate formed by reductive elimination of H2 will undergo a chemical transformation to restore the 18e configuration. Oxidative addition is one route to restore the initial oxidation state at the metal centre through the cleavage of a strong bond and the formation of two new M–X and M–E bonds (Scheme 1, step 2). For many years the organometallic community has focused on C–H bond activation of hydrocarbons; this process has proved to be a challenge due to the strength and apolar nature of the C–H bond. Nevertheless, substantial discoveries have been made since the initial studies.84 Similarly, the understanding of Si–H and B–H bond cleavage along with the control of site selectivity has been fundamental to achieve C–H bond functionalisation.9 Fluorine also forms a very strong bond with carbon resulting in inertness of perfluorinated compounds against chemical attack and as a consequence they have proved very good solvents in many organometallic reactions.85 However, selective C–F activation was found to be feasible when certain metal complexes were employed.2,86,87 Photogenerated Rh and Ir fragments have proved excellent in lowering the energy barriers for the activation of strong bonds and the study of their reactivity has provided a better understanding of the thermodynamics and kinetics properties that govern bond activation. A brief summary of the seminal studies on C–H activation will be given here with a focus on the most recent findings in intramolecular and intermolecular selectivity between the activation of C–H bonds and the ‘‘hetero bonds’’ (Si–H, B–H, C–F and C–C). 3.1 Seminal studies Cp*Ir(H)2(PMe3) was one of the first photochemical C–H activator of alkanes to be reported.46 The extraordinary reactivity of the unsaturated metal fragment [Cp*Ir(PMe3)] formed by photochemical H2 elimination made it impossible to find a suitable inert solvent. Solution photochemistry in C6H6, C6H12, and (CH3)4C all resulted in the formation of the respective hydrido alkyl/aryl–Ir complexes.46 Liquid xenon was employed as a medium to investigate oxidative addition reactions at B195 K; activation of CH4 and secondary C–H bonds of cyclic alkanes was observed under this conditions.88 C–H bond cleavage in alcohols was obtained with isopropyl alcohol and tert-butyl alcohol; whereas methanol and ethanol underwent O–H bond cleavage.88 The selectivity for the activation of primary C–H bonds over secondary ones was determined via competition experiments;47 the kinetic isotope effect was used to establish the preference for intermolecular C–H activation of the reactants Photochemistry, 2019, 46, 352–369 | 359

over intramolecular C–H activation of the bonds of the ligands on the metal complex; intramolecular C–H activation of the phosphine phenyl C–H bond was observed in the photochemical reaction of Cp*Ir(H)2(PPh3) to yield a metallacycle. The rates at which the intermediate [Cp*Ir(PMe3)] reacts with different types of C–H bonds were established relative to cyclohexane (1.0) to be: benzene (4.0), cyclopropane (2.65), cyclopentane (1.6), neopentane (1.14), cyclodecane (0.23), and cyclooctane (0.09). The C–H activation process was determined to take place via a concerted three centres oxidative addition mechanism.47 Similar reactivity was observed when Cp* was replaced with Cp89 and indole51 ligands, the substitution of the phosphine by CO did not alter the reactivity of the metal fragment.50,90 The analogous rhodium complex Cp*Rh(H)2(PMe3) was also reported to activate C–H bonds via photoinduced H2 elimination with a wide variety of substrates spanning from C–H activation of arenes to many different alkanes.40 Similar to the iridium analogue, selectivity for primary over secondary C–H bonds in alkanes was observed; intramolecular kinetic selectivity for the aryl C–H bonds of toluene over the aliphatic C–H bond was also determined.35 Mechanistically, evidence for a Z2-alkane intermediate was established via isotope investigations; this route would allow for activation of secondary C–H bonds but isomerization to the preferred primary alkyl complex delivered the final product.38 Activation of aromatic C–H bonds was postulated to go through the formation of a p-coordinated-arene species instead of direct C–H cleavage as a consequence of a high kinetic selectivity for the activation of aryl bonds (benzene/cyclopentane ¼ 5.4/1).91 A detailed energy diagram was constructed from a series of photochemical competition reactions of the [Cp*Rh(PMe3)] fragment in the concomitant presence of C6H6 and C3H8 at low temperature (Fig. 5); the strength of the Rh–C bond of the product formed via the oxidative addition process was established as an overwhelming thermodynamic driving force for the product distribution (a slight kinetic preference of 4 : 1 for C6H6 over C3H8 was determined). If the bond strength of the reactants played a key role, more facile formation of the propyl–hydride rhodium complex would have been preferred to the formation of the aryl complex. The C–H bond of propane is weaker than the one of benzene but the Rh–C bond formed in the phenyl C–H activation is 16–17 kcal mol1 stronger than the Rh–C bond formed via activation of the propane C–H bond (similarly, the activation of weaker secondary C–H bonds of alkanes over primary ones would have been preferred). As a result of these studies a general trend in the M–C bond strength was established for different types of C–H bonds: M–PhcM–vinylc M–CH3cM–CH2RcM–CHR2cM–CR3cM–CH2Ph.40

3.2 C–H and the hetero-bonds: the selectivity issue C–H versus C–CN bond activation was the subject of a recent study that looked at the photochemical reaction of Cp*Rh(H)2(PMe3) in neat CH3CN.42 360 | Photochemistry, 2019, 46, 352–369

Fig. 5 Diagram showing the difference in free energy of activation for competition experiments of benzene vs propane. Adapted with permission from ref. 40, Copyright 1989 American Chemical Society.

The C–H activated compound Cp*Rh(PMe3)(CH2CN)H was formed with kinetic preference, conversion to the C–C activated species Cp*Rh(PMe3)(CH3)(CN) was obtained upon heating the reaction mixture establishing the latter as thermodynamic product. The same distribution of products was observed when the complex was photolysed in neat benzonitrile.42 The reactivity of three novel rhodium–dihydride complexes of the type Tp 0 Rh(L)(H)2 (L ¼ PMe3, PMe2Ph, CNCH2CMe3) was investigated photochemically and all of the complexes were found to photogenerate a transient capable of inserting into C–H bonds of arenes, thermolysis in C6D6 up to 400 K showed no reactivity.41 Intramolecular C–H activation to form a rhodacycle was observed only in the case of the Tp 0 Rh(PMe2Ph)(H)2 complex and C–C bond cleavage of biphenylene was reported for the PMe3 complex. In a striking investigation, Tp 0 Rh(PMe3)(H)2 was photochemically initiated and the fragment used to look at intramolecular competition reactions between C–H and C–F bonds in a variety of fluoroaromatics. Selectivity for the activation of the C–H bond over the C–F bond was observed but notably the C–H bond cleaved was the one with the greater number of fluorines ortho to it. The origin of the selectivity was once more explained by the strength of the Rh–C bond formed which showed linear correlation to the C–H bond dissociation energy (Fig. 6a); a slope of 2.15 was extrapolated.43 This value closely matched the DFT-calculated slope of 2.05 (Fig. 6b) as well as the slope determined for a series of Tp 0 Rh(CNneopentyl)(ArF)H of 2.14.92 Reaction of the same compound in neat CH3CN yielded the C–H activated product with kinetic preference. Near quantitative conversion Photochemistry, 2019, 46, 352–369 | 361

Fig. 6 Plot of relative Rh–ArF bond strength vs. calculated C–H bond strength (kcal mol1); Experimental result (a) and DFT calculated result (b). Reproduced from ref. 43 with permission from The Royal Society of Chemistry.

to the C–CN activated species (thermodynamic product) was achieved upon heating a solution of the Tp 0 Rh(PMe3)(CH2CN)H to 373 1K for five days.44 Similar reactivity was observed for the PPhMe2 analogue except for the detection of a small amount of the intramolecular C–H activation product. The photochemical reaction in the presence of succinonitrile, designed to look at preferential activation of secondary C–H bonds over terminal C–CN bonds proved uninformative; a thermal route for looking at these studies employing the Tp 0 Rh(PMe3)(Ph)H as a precursor was preferred.44 The complex Tp 0 Rh(PMe3)(H)2 was also the subject of a more recent study that looked at intramolecular and intermolecular selectivity between C–H and Si–H, B–H and C–F bonds (Fig. 7).45 The reaction in neat silanes yielded rhodium silyl hydride compounds as major products; total selectivity for activation of the Si–H bond to form Tp 0 Rh(PMe3)(SiEt2H)H was determined in neat Et2SiH2, no evidence for C–H activation on the ethyl groups was established. Reaction with PhSiH3 produced the rhodium silyl hydride Tp 0 Rh(PMe3)(SiPhH2)H as the major product with 20% of byproducts formed via orto- meta- and para-phenyl C–H activation. The same metal fragment was employed in the reaction with pinacolborane HBpin, and the main product was the rhodium boryl hydride Tp 0 Rh(PMe3)(Bpin)H, with no activation of the C–H bonds on the pinacol moiety observed. DFT calculations supported the experimental results; a thermodynamic preference for intramolecular B–H over C–H activation and for Si–H over C–H activation was computed. Most surprisingly, the intermediate was found capable of activating C–F bonds of pentafluoropyridine. The C–F activated products were fully characterised and assigned as two rotamers of the same complex resulting from selective activation of the C–F bond ortho to the nitrogen; activation of the C–F bonds in meta and para positions were not observed. The photochemical reaction in the presence of neat 2,3,5,6-tetrafluoropyridine was undertaken to explore intramolecular competition between C–H and C–F activation. At 30% NMR conversion, a ratio of 4 : 1 was observed in favour of C–H activation. This was a surprising result as 362 | Photochemistry, 2019, 46, 352–369

Fig. 7 Photochemical reactivity of Tp 0 Rh(PMe3)H2 in the presence of the hetero bonds. Adapted with permission from ref. 45, Copyright 2014 American Chemical Society.

the detection of the C–F activated product contradicted previous studies where total selectivity for the cleavage of the C–H bond in the presence of fluoroarenes was reported.43,92 Irradiation of Tp 0 Rh(PMe3)H2 in neat C6F6 did not yield any metal fluoride product nor did it provide any evidence for perfluoroarene Z2-coordination. As a consequence, hexafluorobenzene was identified as an inert solvent and used for intermolecular competition reactions. A strong intramolecular selectivity towards the activation of the hetero-bonds versus alkyls C–H bonds within the same molecule was established; less prominent was the selectivity in the presence of aromatic C–H bonds. Monochromatic photolysis (355 nm) inside the NMR probe was used to generate the [Tp 0 Rh(PMe3)] fragment to investigate intermolecular competition reactions between the hetero-bonds and the C–H bond of benzene which was employed as standard (Fig. 8). The results were added to a previous set of competition reactions run for different types of C–H bonds93 and are shown in Table 1. Kinetic selectivity followed the order Si–H (PhSiH3)4C–H(C6H6)4B–H (HBpin)cC–F (C5NF5); these reactions together with those previously reported span a factor of 37 in rates. The possible mechanisms that give rise to the selectivities were analysed by the authors. For comparison, CpRh(PPh3)(C2H4) showed no significant selectivity between H–Bpin, H–C6F5, and Photochemistry, 2019, 46, 352–369 | 363

364 | Photochemistry, 2019, 46, 352–369 Fig. 8 Product distribution of photochemical competition reactions of Tp 0 Rh(PMe3)(H)2 with the substrates and C6H6 as competing ligand (a) HBpin/C6H6, (b) PhSiH3/C6H6, (c) C5NF5/C6H6. Reprinted with permission from ref. 45, Copyright 2014 American Chemical Society.

Table 1 Intermolecular selectivity derived from photochemical competition reactions. Adapted with permission from ref. 45, Copyright 2014 American Chemical Society. Substrate krel

Si–H (PhSiH3) 2.3

CH2F2 1.6

C6H6 1

HCCPh 0.47

Pentane 0.41

CH4 0.39

Substrate krel

B–H (HBpin) 0.36

CH3CF3 0.20

(CH3)2CO 0.16

C–F (C5NF5) 0.07

c-C5H10 0.063

CH3CF3 0.20

H–SiMe2Et substrates,94 whereas the trend for [Ru(DuPHOS)2] was established as H–SiH2Ph4H–Bpin4H–C6F5 by laser flash photolysis.31 The full set of photochemical reactions discussed earlier was paralleled using the thermal precursor Tp 0 Rh(PMe3)(CH3)H; interestingly the same product distribution was observed but the mechanism proved to be substantially different. A dissociative mechanism was experimentally established for the photochemical reactions while a bimolecular pathway (associative mechanism) was found to be operative in the thermal chemistry.

3

Conclusions and outlook

The study of the photoactivity of group 8 dihydrides towards H2 reductive elimination has provided extensive knowledge on the nature of this photoprocess. Particularly, the use of specialist techniques (time resolved spectroscopy, matrix isolation and computational methods) has allowed determination of structures and reactivity of the intermediate towards different substrates. The role played by the so called ‘‘spectator ligands’’ has proved highly influential in determining the type of chemistry that will take place at the unsaturated metal fragment. Substantial differences in the rates for the oxidative addition of substrates have been reported for a class of ‘‘apparently’’ similar RuH2 complexes with bidentate phosphines. The recent development of our laser pump-NMR probe method in conjunction with para-H2 induced hyperpolarisation has offered the possibility of creating metal hydrides in a selected nuclear spin state by incorporation of para-H2. The concerted nature of H2 elimination was confirmed by these experiments but most importantly, the possibility of recording diagnostic NMR spectra at the same time as quantifying rates of reaction allowed identification of the products unambiguously. This differs from conventional laser flash photolysis where a broad UV/vis absorption of the reaction intermediate or an average spectrum of the intermediates is obtained. It is important to mention that the detection limit of NMR spectroscopy is enhanced into a similar range to timeresolved UV/vis absorption methods by this new approach. The potential of this method can be expanded to a broader range of hydrogenation processes; moreover reactions with a number of molecules that can be prepared in a singlet state (N2, fumarate, stilbene) offer scope for investigation.95 Fundamental physical organometallic studies, designed to unveil the mechanism and driving forces of catalytic cycles, have been and will Photochemistry, 2019, 46, 352–369 | 365

continue to be of vital importance to the optimisation and the applicability of these processes on a large scale. The understanding of kinetic and thermodynamic selectivity has come a long way since the advent of strong bond activation via metal complexes, especially for C–H bond cleavage which has had a major impact on synthetic chemistry. Such detailed mechanistic investigations often do not receive significant interest. However, the recent experiments on the reactivity of the [Tp 0 Rh(PMe3)] fragment towards hetero bonds demonstrated how a much wider variety of bonds than had been previously realised can be activated by this system. While this fragment was well established as C–H bond activator, it showed almost total photochemical intramolecular selectivity for the activation of Si–H and B–H bonds expanding on the scope of this system. Similarly, activation of the Si–H bond over aromatic C–H bonds was favoured in intermolecular competition reactions.

Acknowledgements BP is very thankful to Professor Robin Perutz for all the knowledge on metal hydrides photochemistry he has bestowed to her over many years.

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

20

T. Gensch, M. J. James, T. Dalton and F. Glorius, Angew. Chem., Int. Ed., 2018, 57, 2296. O. Eisenstein, J. Milani and R. N. Perutz, Chem. Rev., 2017, 117, 8710. X. S. Xue, P. J. Ji, B. Y. Zhou and J. P. Cheng, Chem. Rev., 2017, 117, 8622. T. H. Rehm, Chem. Eng. Technol., 2016, 39, 66. J. Y. Corey, Chem. Rev., 2016, 116, 11291. M. F. Kuehnel, D. Lentz and T. Braun, Angew. Chem., Int. Ed., 2013, 52, 3328. T. Ahrens, J. Kohlmann, M. Ahrens and T. Braun, Chem. Rev., 2015, 115, 931. C. Cheng and J. F. Hartwig, Chem. Rev., 2015, 115, 8946. J. F. Hartwig, Acc. Chem. Res., 2012, 45, 864. I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy and J. F. Hartwig, Chem. Rev., 2010, 110, 890. G. Alcaraz and S. Sabo-Etienne, Angew. Chem., Int. Ed., 2010, 49, 7170. W. D. Jones, Inorg. Chem., 2005, 44, 6138. W. D. Jones, Acc. Chem. Res., 2003, 36, 140. T. Dombray, C. G. Werncke, S. Jiang, M. Grellier, L. Vendier, S. Bontemps, J. B. Sortais, S. Sabo-Etienne and C. Darcel, J. Am. Chem. Soc., 2015, 137, 4062. J. F. Hartwig, J. Am. Chem. Soc., 2016, 138, 2. L. Johansson, M. Tilset, J. A. Labinger and J. E. Bercaw, J. Am. Chem. Soc., 2000, 122, 10846. O. Torres, J. A. Calladine, S. B. Duckett, M. W. George and R. N. Perutz, Chem. Sci., 2015, 6, 418. J. A. Calladine, S. B. Duckett, M. W. George, S. L. Matthews, R. N. Perutz, O. Torres and Q. V. Khuong, J. Am. Chem. Soc., 2011, 133, 2303. J. Guan, A. Wriglesworth, X. Z. Sun, E. N. Brothers, S. D. Zaric, M. E. Evans, W. D. Jones, M. Towrie, M. B. Hall and M. W. George, J. Am. Chem. Soc., 2018, 140, 1842. J. A. Calladine, O. Torres, M. Anstey, G. E. Ball, R. G. Bergman, J. Curley, S. B. Duckett, M. W. George, A. I. Gilson, D. J. Lawes, R. N. Perutz, X. Z. Sun and K. P. C. Vollhardt, Chem. Sci., 2010, 1, 622.

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R. N. Perutz and B. Procacci, Chem. Rev., 2016, 116, 8506. M. V. Baker and L. D. Field, J. Am. Chem. Soc., 1986, 108, 7433. M. V. Baker and L. D. Field, J. Am. Chem. Soc., 1986, 108, 7436. M. V. Baker and L. D. Field, J. Am. Chem. Soc., 1987, 109, 2825. L. D. Field, A. V. George and B. A. Messerle, J. Chem. Soc., Chem. Commun., 1991, 1339. I. E. Buys, L. D. Field, T. W. Hambley and A. E. D. McQueen, J. Chem. Soc., Chem. Commun., 1994, 557. L. C. M. Castro, D. Bezier, J. B. Sortais and C. Darcel, Adv. Synth. Catal., 2011, 353, 1279. L. Cronin, M. C. Nicasio, R. N. Perutz, R. G. Peters, D. M. Roddick and M. K. Whittlesey, J. Am. Chem. Soc., 1995, 117, 10047. C. Bianchini, J. A. Casares, R. Osman, D. I. Pattison, M. Peruzzini, R. N. Perutz and F. Zanobini, Organometallics, 1997, 16, 4611. P. L. Callaghan, R. Fernandez-Pacheco, N. Jasim, S. Lachaize, T. B. Marder, R. N. Perutz, E. Rivalta and S. Sabo-Etienne, Chem. Commun., 2004, 242. M. V. Campian, R. N. Perutz, B. Procacci, R. J. Thatcher, O. Torres and A. C. Whitwood, J. Am. Chem. Soc., 2012, 134, 3480. W. A. Kiel, R. G. Ball and W. A. G. Graham, J. Organomet. Chem., 1990, 383, 481. R. Osman, D. I. Pattison, R. N. Perutz, C. Bianchini and M. Peruzzini, J. Chem. Soc., Chem. Commun., 1994, 513. R. Osman, D. I. Pattison, R. N. Perutz, C. Bianchini, J. A. Casares and M. Peruzzini, J. Am. Chem. Soc., 1997, 119, 8459. W. D. Jones and F. J. Feher, J. Am. Chem. Soc., 1984, 106, 1650. R. A. Periana and R. G. Bergman, Organometallics, 1984, 3, 508. W. D. Jones and F. J. Feher, J. Am. Chem. Soc., 1986, 108, 4814. R. A. Periana and R. G. Bergman, J. Am. Chem. Soc., 1986, 108, 7332. R. A. Periana and R. G. Bergman, J. Am. Chem. Soc., 1986, 108, 7346. W. D. Jones and F. J. Feher, Acc. Chem. Res., 1989, 22, 91. D. D. Wick and W. D. Jones, Inorg. Chim. Acta, 2009, 362, 4416. M. E. Evans, T. Li and W. D. Jones, J. Am. Chem. Soc., 2010, 132, 16278. T. Tanabe, W. W. Brennessel, E. Clot, O. Eisenstein and W. D. Jones, Dalton Trans., 2010, 39, 10495. T. Tanabe, M. E. Evans, W. W. Brennessel and W. D. Jones, Organometallics, 2011, 30, 834. B. Procacci, Y. Jiao, M. E. Evans, W. D. Jones, R. N. Perutz and A. C. Whitwood, J. Am. Chem. Soc., 2015, 137, 1258. A. H. Janowicz and R. G. Bergman, J. Am. Chem. Soc., 1982, 104, 352. A. H. Janowicz and R. G. Bergman, J. Am. Chem. Soc., 1983, 105, 3929. R. G. Bergman, Science, 1984, 223, 902. M. J. Burk, R. H. Crabtree and D. V. McGrath, J. Chem. Soc., Chem. Commun., 1985, 1829. P. E. Bloyce, A. J. Rest, I. Whitwell, W. A. G. Graham and R. Holmessmith, J. Chem. Soc., Chem. Commun., 1988, 846. T. Foo and R. G. Bergman, Organometallics, 1992, 11, 1801. A. Ferrari, E. Polo, H. Ruegger, S. Sostero and L. M. Venanzi, Inorg. Chem., 1996, 35, 1602. H. Gerard, O. Eisenstein, D. H. Lee, J. Y. Chen and R. H. Crabtree, New J. Chem., 2001, 25, 1121. R. N. Perutz, Pure Appl. Chem., 1998, 70, 2211. R. N. Perutz, Chem. Soc. Rev., 1993, 22, 361. L. Andrews, Chem. Soc. Rev., 2004, 33, 123. Photochemistry, 2019, 46, 352–369 | 367

57

58

59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76

77 78 79 80 81 82 83

84 85 86

B. Procacci, S. B. Duckett, M. W. George, M. W. D. Hanson-Heine, R. Horvath, R. N. Perutz, X. Z. Sun, K. Q. Vuong and J. A. Welch, Organometallics, 2018, 37, 855. K. A. M. Ampt, S. Burling, S. M. A. Donald, S. Douglas, S. B. Duckett, S. A. Macgregor, R. N. Perutz and M. K. Whittlesey, J. Am. Chem. Soc., 2006, 128, 7452. V. Montiel-Palma, R. N. Perutz, M. W. George, O. S. Jina and S. Sabo-Etienne, Chem. Commun., 2000, 1175. R. L. Sweany, J. Am. Chem. Soc., 1981, 103, 2410. M. C. Heitz, D. Guillaumont, I. Cote-Bruand and C. Daniel, J. Organomet. Chem., 2000, 609, 66. M. C. Heitz and C. Daniel, J. Am. Chem. Soc., 1997, 119, 8269. P. Bergamini, S. Sostero and O. Traverso, J. Organomet. Chem., 1986, 299, C11. V. E. Bondybey, A. M. Smith and J. Agreiter, Chem. Rev., 1996, 96, 2113. R. J. Mawby, R. N. Perutz and M. K. Whittlesey, Organometallics, 1995, 14, 3268. C. Hall, W. D. Jones, R. J. Mawby, R. Osman, R. N. Perutz and M. K. Whittlesey, J. Am. Chem. Soc., 1992, 114, 7425. R. N. Perutz, Chem. Rev., 1985, 85, 77. R. N. Perutz, Chem. Rev., 1985, 85, 97. V. Montiel-Palma, D. I. Pattison, R. N. Perutz and C. Turner, Organometallics, 2004, 23, 4034. R. Osman, R. N. Perutz, A. D. Rooney and A. J. Langley, J. Phys. Chem., 1994, 98, 3562. M. C. Nicasio, R. N. Perutz and A. Tekkaya, Organometallics, 1998, 17, 5557. M. C. Nicasio, R. N. Perutz and P. H. Walton, Organometallics, 1997, 16, 1410. M. Colombo, M. W. George, J. N. Moore, D. I. Pattison, R. N. Perutz, I. G. Virrels and T. Q. Ye, J. Chem. Soc., Dalton Trans., 1997, 2857. B. Procacci, PhD thesis, University of York, 2012. S. A. Macgregor, O. Eisenstein, M. K. Whittlesey and R. N. Perutz, J. Chem. Soc., Dalton Trans., 1998, 291. O. Torres, B. Procacci, M. E. Halse, R. W. Adams, D. Blazina, S. B. Duckett, B. Eguillor, R. A. Green, R. N. Perutz and D. C. Williamson, J. Am. Chem. Soc., 2014, 136, 10124. C. R. Bowers and D. P. Weitekamp, J. Am. Chem. Soc., 1987, 109, 5541. C. R. Bowers and D. P. Weitekamp, Phys. Rev. Lett., 1986, 57, 2645. R. A. Green, R. W. Adams, S. B. Duckett, R. E. Mewis, D. C. Williamson and G. G. R. Green, Prog. Nucl. Magn. Reson. Spectrosc., 2012, 67, 1. J. Natterer and J. Bargon, Prog. Nucl. Magn. Reson. Spectrosc., 1997, 31, 293. M. E. Halse, B. Procacci, S. L. Henshaw, R. N. Perutz and S. B. Duckett, J. Magn. Reson., 2017, 278, 25. B. Procacci, P. M. Aguiar, M. E. Halse, R. N. Perutz and S. B. Duckett, Chem. Sci., 2016, 7, 7087. G. D. Scholes, G. R. Fleming, L. X. Chen, A. Aspuru-Guzik, A. Buchleitner, D. F. Coker, G. S. Engel, R. van Grondelle, A. Ishizaki, D. M. Jonas, J. S. Lundeen, J. K. McCusker, S. Mukamel, J. P. Ogilvie, A. Olaya-Castro, M. A. Ratner, F. C. Spano, K. B. Whaley and X. Y. Zhu, Nature, 2017, 543, 647. J. F. Hartwig and M. A. Larsen, ACS Central Sci., 2016, 2, 281. S. D. Pike, M. R. Crimmin and A. B. Chaplin, Chem. Commun., 2017, 53, 3615. L. Zamostna, S. Sander, T. Braun, R. Laubenstein, B. Braun, R. Herrmann and P. Klaring, Dalton Trans., 2015, 44, 9450.

368 | Photochemistry, 2019, 46, 352–369

87 88 89 90 91 92 93 94 95

E. Clot, O. Eisenstein, N. Jasim, S. A. Macgregor, J. E. McGrady and R. N. Perutz, Acc. Chem. Res., 2011, 44, 333. M. B. Sponsler, B. H. Weiller, P. O. Stoutland and R. G. Bergman, J. Am. Chem. Soc., 1989, 111, 6841. M. G. Partridge, A. McCamley and R. N. Perutz, J. Chem. Soc., Dalton Trans., 1994, 3519. P. E. Bloyce, A. J. Rest and I. Whitwell, J. Chem. Soc., Dalton Trans., 1990, 813. W. D. Jones and F. J. Feher, J. Am. Chem. Soc., 1982, 104, 4240. M. E. Evans, C. L. Burke, S. Yaibuathes, E. Clot, O. Eisenstein and W. D. Jones, J. Am. Chem. Soc., 2009, 131, 13464. Y. Z. Jiao, M. E. Evans, J. Morris, W. W. Brennessel and W. D. Jones, J. Am. Chem. Soc., 2013, 135, 6994. M. V. Campian, J. L. Harris, N. Jasim, R. N. Perutz, T. B. Marder and A. C. Whitwood, Organometallics, 2006, 25, 5093. M. H. Levitt, Annu. Rev. Phys. Chem., 2012, 63, 89.

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Aromatic hydrocarbons as catalysts and mediators in photoinduced electron transfer reactions Benjamin Lipp and Till Opatz* DOI: 10.1039/9781788013598-00370

Aromatic hydrocarbons are frequently used as catalysts and mediators in photoinduced electron transfer reactions. For more than forty years, significant developments in this field have helped to expand the general understanding of free radical chemistry and to pave the way for today’s era of visible light photoredox catalysis. This article reviews these developments and the impact they have had alongside modern applications of aromatic hydrocarbons in photoinduced electron transfer chemistry. The theoretical background as well as future prospects of such reactions are explained with a focus on organic synthesis.

1

Introduction and theoretical background

Beginning with the publication of several landmark papers by the groups of MacMillan,1 Yoon2 and Stephenson3 in 2008 and 2009, visible light photoredox catalysis has emerged as one of the most vital research areas within the field of preparative organic chemistry.4 The roots of this technique however date back more than four decades and the first applications of photoredox catalysis to organic synthesis were already reported in the 1970s.5–9 This decade has also been marked by seminal works concerning the utilisation of aromatic hydrocarbons (AHs) as catalysts for synthetically useful photoinduced electron transfer (PET) reactions.10–12 Further exploration of this field has ever since led to a deeper understanding of free radical chemistry which has also contributed to the recent revitalization of visible light photoredox catalysis.13–17 Although they are less in the focus of current interest than polypyridyl complexes of ruthenium or iridium18 and organic dyes,19 AHs continue to be employed for the most challenging light-induced redox transformations.20–22 The aim of this chapter is to review the past, present and potential future of AHs as catalysts and mediators (vide infra) in PET reactions. The theoretical background as well as the impact of these transformations will be highlighted, followed by improvements needed to ensure that AHs continue to find broad application in the era of visible light photoredox catalysis. This review is limited in scope and it will only cover AHs devoid of any heteroatoms. Furthermore, only findings with applicability to organic synthesis will be treated. 1.1 The basics of direct, catalysed and mediated PET reactions Fundamental processes associated with uncatalysed (direct) PET are depicted in Scheme 1a.23 For a more detailed description, the reader is Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany. E-mail: [email protected] 370 | Photochemistry, 2019, 46, 370–394  c

The Royal Society of Chemistry 2019

(a)

(b)

(c)

Scheme 1 Fundamental processes and catalytic cycles associated with (a) direct PET, (b) catalysed PET, commonly referred to as photosensitisation or photoredox catalysis, and (c) redox mediated versions of these two. D ¼ electron donor, A ¼ electron acceptor, cat. ¼ catalyst, RM ¼ redox mediator, BET ¼ back electron transfer.

directed to excellent reviews by Kavarnos and Turro.13,23 The absorption of a photon results in either the donor (D) or the acceptor (A) reaching the first excited singlet state S1*, which might eventually convert into the lowest excited triplet state T1*. These electronically excited species can then either return to the ground state by radiative or nonradiative decay pathways or engage in bimolecular reactions such as PET if they encounter a suitable reaction partner within their lifetime. Regardless of whether the donor or the acceptor has been excited, electron exchange results in the same pair of radical ions (A  and D 1, as contact ion pair ¼ CIP, or solvent-separated ion pair ¼ SSIP). These radical ions can then diffuse apart (free, solvated ions) and undergo various transformations affording new product/s. They can however also undergo back electron transfer (BET) leading to the ground state species. BET is a severe limitation for PET processes and the main reason for their typically low quantum yields.14,23,24 To facilitate the separation of the ion pairs, PET reactions are usually performed in polar solvents and sometimes in the presence of added salts.23,25,26 As depicted in Scheme 1b, PET processes can also be accelerated or even enabled by catalysts which have traditionally been referred to as photosensitisers (probably the most accurate name in the case of AHs).4,14,27 Nowadays, this expression is closely linked to energy transfer processes and the term ‘‘photoredox catalyst’’ has become common, especially for visible light absorbing complexes or dyes.4,19,27 Although it was pointed out by Mizuno and co-workers that there is a difference between photocatalysts and photosensitisers or photoredox catalysts, we will refer to all of these species simply as catalysts throughout this Photochemistry, 2019, 46, 370–394 | 371

review.27 Upon absorption of a photon, the catalyst reaches an excited state (S1* or T1*). It is then converted back to the electronic ground state by two successive electron transfer reactions, the first one being called oxidative or reductive quenching. Substrates of the reaction mixture or sacrificial acceptors/donors engage in both redox steps. In many cases, the acceptor or donor of the second electron transfer is a reaction intermediate derived from trapping the radical ion produced during the quenching process or a fragment of the latter. Thus, net-redox neutral transformations can be performed in a one-pot fashion.18 The most obvious reason for the addition of a catalyst would be that the substrates themselves do not absorb light of the provided wavelength (in particular visible light).4 This is often not the case for AHs which are frequently not used to enable but rather to enhance UV-driven PET reactions. Their beneficial effect may then be a result of their longer excited state lifetimes or the more efficient use of the provided UV-light due to the AHs absorbing light of longer wavelengths.19,28,29 They can also suppress BET. For an oxidative quenching cycle, this is the case if the oxidised form of the catalyst has a higher oxidation potential than the electron donor.25 Assuming that BET is operating in the so-called Marcus-inverted region where increasing exergonicity results in a lower rate constant,30 BET from the ion pair (Cat 1/A ) should be slower than from the original ion pair (D 1/A ).14,24,31 As shown in Scheme 1c, PET reactions can also benefit from the addition of a redox mediator (RM), regardless of whether a catalyst is used or not.14,16 An RM does not enhance PET by absorbing light and then triggering SET, but rather serves as an electron shuttle undergoing two consecutive redox reactions with both the excited species (donor/ acceptor/catalyst) and the ground state acceptor/donor.32 Such RMs are also referred to as co-sensitisers or electron relays.14,33 An RM might enhance PET reactions suffering from endergonic and inefficient quenching of the excited species by the ground state acceptor/ donor.16,34,35 If endergonic quenching is intercepted by an RM (i.e. a better quencher), SET between the resulting radical ions of the RM and the ground state acceptor/donor is then of course endergonic.35 This electron transfer is however favoured, given that the RM’s radical ions have a longer lifetime than the excited species.16,35,36 RMs may also enhance PET reactions operating through an exergonic quenching process which is hindered for other reasons such as electrostatic repulsion.37 However, in most PET processes of synthetic interest, quenching of the excited species by the acceptor/donor is exergonic and efficient. In these cases, an RM can still enhance the overall reaction by means of its longlived radical ions favouring substrate oxidation/reduction16,38,39 and by impeding BET. Therefore, the RM needs to be significantly more oxidising or reducing than the original acceptor or donor.24,40 This leads to increased exergonicity for BET, which, due to the location within the Marcus-inverted region, is then slowed down.24,30,41 1.1.1 Photophysical and electrochemical properties of selected aromatic hydrocarbons. This section deals with photophysical and 372 | Photochemistry, 2019, 46, 370–394

electrochemical properties of selected AHs and the question why some of them have outcompeted others as catalysts and mediators in PET reactions. Table 1 summarises relevant properties of selected AHs. They are often used in combination with certain aromatic nitriles, which are therefore also included in the table. Excited state redox potentials have been calculated using eqn (1) (excited state oxidation potentials) or (2) (excited state reduction potentials), whereat E*00 is the zero–zero excitation energy for the singlet or triplet state (conversion factor of 1 eV V1 on a per molar basis).19,42,43 E1/2(D 1/D*) ¼ E1/2(D 1/D)  E*00

(1)

E1/2(A*/A ) ¼ E(1/2)(A/A ) þ E*00

(2)

Increased p-conjugation of the aromatic system results in a decreased energy gap between HOMO and LUMO, lower excitation energies, longer excitation wavelengths and reduced excited state redox potentials.44 This effect is less pronounced for angular systems than for linear ones.44 In polar solvents such as acetonitrile (in which Coulombic interactions can be neglected), the thermodynamic feasibility of a PET process can be approximated solely on the basis of the involved excited and ground state redox potentials.13,19,42 Accordingly, oxidative quenching of a catalyst by a substrate is thermodynamically feasible when the excited state oxidation potential of the catalyst is more negative than the ground state reduction potential of the substrate. Similarly, reductive quenching of a catalyst by a substrate is thermodynamically favourable when the excited state reduction potential of the catalyst is more positive than the ground state oxidation potential of the substrate. Thus, a catalyst for challenging transformations will have a large excited state oxidation or (negative) reduction potential. In this respect, the excited singlet state is obviously better suited than the triplet state, although the latter has a much longer lifetime. Consequently, an ideal AH will have a long-lived S1*-state and display a high fluorescence quantum yield.13,19 For the second electron transfer (Scheme 1b) to be useful, the potential catalyst should also have a large ground state oxidation or reduction potential as this will increase the scope of substrates which can be employed in redox reactions. Importantly, this will also lead to increased exergonicity for BET, which is then slowed down.14,24,31 The catalyst should of course be the main lightabsorbing species within the reaction mixture and thus, absorb light of longer wavelength than the substrates.13 In addition, the ideal AHcatalyst will be chemically inert under the reaction conditions, inexpensive, readily available and as harmless as possible. Phenanthrene (4) has become the most frequently used AH for oxidatively quenched reactions (vide infra). Except for its relatively low fluorescence quantum yield, it fulfils all the requirements mentioned above. Reductive quenching cycles are generally less common with AHs as catalysts and in these cases pyrene (6), perylene (7) and p-terphenyl (9) have proven useful (vide infra). Furthermore, aromatic nitriles such as 9,10-DCA (12) are versatile catalysts for reductively quenched reactions and they are frequently used in combination with AHs as RMs.16 In contrast to a catalyst, the mediator Photochemistry, 2019, 46, 370–394 | 373

374 | Photochemistry, 2019, 46, 370–394

Table 1 Photophysical and electrochemical properties of selected aromatic hydrocarbons and aromatic nitriles.a Number 1 2 3 4 5 6 7 8 9 10 11 12

S1 (eV) E00

Compound Naphthalene Anthracene Tetracene Phenanthrene Chrysene Pyrene Perylene Biphenyl p-Terphenyl 1,4-DCB 1,4-DCN 9,10-DCA

1 (nm) lS00

45

45

312 37550 47150 34758 36050 37364 43966 30668 310 (np)62 29073 336 (np)76 42878

3.98 3.3050 2.6350 3.5758 3.4450 3.3264 2.8366 4.0568 3.99 (np)62 4.2773 3.69 (np)76 2.9078

jfl

ts (ns) 46

jISC 47

105 5.851 6.4 (np)54 60.759 42.662 19065 6.051 16.0 (np)62 0.95 (np)62 9.774 10.174 15.178

0.21 0.2752 0.1655 0.1347 0.1747 0.7247 0.9452 0.15 (np)69 0.77 (np)69 n. a. n. a. 0.8779

47

0.71 0.6653 0.6655 0.8047 0.8247 0.2747 0.0167 0.84 (np)70 0.11 (np)63 n. a. 0.1977 0.008519

T1 E00 (eV)

ts (ms)

2.6448 1.8450 1.27 (np)56 2.6660 2.4860 2.0964 1.5666 2.8471 2.5372 3.0675 2.4074 1.81 (np)80

180049 330049 400 (np)57 91061 710 (np)63 1100066 500066 130 (np)63 450 (np)63 n. a. 4077 100 (np)81

Number

1

2

3

4

5

6

7

8

9

10

11

12

E1/2(R 1/R) E1/2(R 1/1[R]*) E1/2(R 1/3[R]*) E1/2(R/R ) E1/2(1[R]*/R ) E1/2(3[R]*/R )

þ1.54b,82 2.44 1.10 2.49c,28 þ1.49 þ0.15

þ1.09b,82 2.21 0.75 1.95c,28 þ1.35 0.11

þ0.77b,82 1.86 0.50 1.58c,85 þ1.05 0.31

þ1.50b,82 2.07 1.16 2.44c,85 þ1.13 þ0.22

þ1.35b,82 2.09 1.13 2.25c,85 þ1.19 þ0.23

þ1.16b,82 2.16 0.93 2.09c,85 þ1.23 0.00

þ0.85b,82 1.98 0.71 1.67c,85 þ1.16 0.11

þ1.95b,83 2.10 0.89 2.55c,28 þ1.50 þ0.29

þ1.80b,84 2.19 0.73 2.63c,86 þ1.36 0.10

n. a. n. a. n. a. 1.64b,87 þ2.63 þ1.42

n. a. n. a. n. a. 1.27b,88 þ2.42 þ1.13

n. a. n. a. n. a. 0.91b,88 þ1.99 þ0.90

a

Unless indicated in brackets (np ¼ non-polar), all photophysical values were obtained in polar solvents. All redox potentials are given in V versus the saturated calomel electrode (SCE). Excited state redox potentials were calculated as described in the text. b Measured in MeCN. c Measured in DMF. DCB ¼ dicyanobenzene, DCN ¼ dicyanonaphthalene, DCA ¼ dicyanoanthracene, n. a. ¼ not available. For definitions and an extensive compilation of the listed photophysical quantities see Steven L. Murovs Handbook of Photochemistry, see ref. 28.

ideally does not absorb light of the wavelength range used to drive the reaction.38 Unless the quenching process which is to be intercepted is endergonic,35 the RM should be more oxidising than the ground state acceptor or more reducing than the ground state donor.24 As explained above, this will lead to reduced BET.24,30,41 Thus, for 9,10-DCA (12) as well as for other highly oxidising catalysts, biphenyl (8) has been established as a suitable RM (vide infra).

2 Examples of PET reactions catalysed by aromatic hydrocarbons In this section, synthetically useful PET reactions catalysed by AHs as well as the impact they have had on visible light photoredox catalysis will be surveyed. The transformations are categorised according to their catalytic cycles (Scheme 1b). Reactions occurring through oxidative quenching cycles will be covered first, followed by those involving reductive quenching. 2.1 Reactions involving oxidative quenching of aromatic hydrocarbons In 1977, the groups of Pac,10 Tazuke11 and Yamamoto12 independently reported that the photoinduced dimerization of electron-rich alkenes such as indene6 (13), N-vinylcarbazole5 and styrene derivatives89,90 15 could be catalysed by AHs like phenanthrene (4) or perylene (7). To the best of our knowledge, these are the first reports of synthetically useful PET reactions using AHs as catalysts. Exemplary results are summarised in Scheme 2 (compounds 14, 17, 21).10,12,91

Scheme 2 Photoinduced dimerization of exemplary electron-rich alkenes 13, 16 and addition of water or alcohols catalysed by AHs using aromatic nitriles as RMs.10,12,91 Phen ¼ phenanthrene (4). Photochemistry, 2019, 46, 370–394 | 375

Detailed mechanistic investigations, mainly by Pac et al.,91 provided evidence for oxidative quenching of the AH’s excited singlet state by the aromatic nitrile (1,2-, 1,3- or 1,4-DCB) acting as an RM (see also: Scheme 1c).12 Electron transfer from the alkene to the AH’s radical cation regenerates the catalyst and affords the radical cation of the olefin.11,12,91 The latter is attacked by another alkene molecule, which results in a dimeric (distonic) radical cation. Reduction by the aromatic nitrile’s radical anion completes the catalytic cycle and is followed by ring closure.6,91 When performed in non-polar solvents such as benzene, the aromatic nitrile’s radical anion can add to the olefin’s radical cation in a formal [4 þ 2]-cycloaddition (not shown in Scheme 2).92 This allows for the synthesis of isoquinolines from 1,1-diphenylethylene derivatives and 1,4-DCB (10).92 In the presence of water and alcohols, these nucleophiles add to the alkene’s radical cation to form the anti-Markovnikov products 15, 18, 22 upon reduction and subsequent protonation.89,91 Unlike 1,1diphenylethylene (16a), a-methylstyrene (16b) mainly affords product 23 resulting from the addition of the alcohol to the dimeric radical cation.12 Similar transformations using different alkenes and nucleophiles have been reported.93,94 Dienes95,96 and polyenes97 give rise to complex cyclisation products. Exemplarily, Scheme 3 highlights a stereoselective tandem cyclisation of 1,1-diphenyl-1,n-alkadienes 24 reported by Hirano and Niwa et al. in 1998.98 If an alkene is oxidised in the presence of a nucleophile and the addition of the latter to the olefin’s radical cation is not followed by reduction and protonation, the photo-NOCAS (nucleophile-olefin combination aromatic substitution) reaction might occur (Scheme 4).14 The intermediate radicals are then trapped by the radical anions of the aromatic nitriles, followed by elimination of cyanide. This is usually the case if the oxidised alkenes are not aryl substituted.14 Exemplary reactions presented by Arnold et al. in 1984 are highlighted in Scheme 4.29 Interestingly, alkene radical cations are quite acidic and if no nucleophile is present in reasonable concentration to trap them, they might instead be deprotonated to form allylic radicals which subsequently engage in ipsosubstitutions.29,99 Similar transformations have been reported using amines100 or malononitrile101–103 as nucleophiles and furan derivatives10,91 instead of electron-rich alkenes as the coupling partners. It is noteworthy that alkene oxidations can also be achieved in the absence of the AHs, either via direct PET (ipso-substitutions such as those in Scheme 4) or with the DCBs operating as catalysts themselves (transformations similar to those in Schemes 2 and 3).89–91,97 Such PET reactions are however far less efficient14,29,91,97,104 and require the use of higher-energy UV-irradiation.11,12 This is due to the reasons outlaid in Section 1. If the added AH is the main light-absorbing species, it will act as catalyst being oxidatively quenched by the DCBs.29,91,104 Photoinduced anti-Markovnikov additions to alkenes (Scheme 2) have recently been revitalized using strongly oxidising visible light photoredox catalysts such as acridinium salts.105–114 Visible light-induced [2 þ 2] cycloadditions (see Scheme 2) of olefins have also been reported.115,116 In contrast, the ipso-substitution of aromatic nitriles by radicals derived from 376 | Photochemistry, 2019, 46, 370–394

Photochemistry, 2019, 46, 370–394 | 377

Scheme 3 Stereoselective tandem cyclisation of 1,1-diphenyl-1,n-alkadienes 24.98

378 | Photochemistry, 2019, 46, 370–394 Scheme 4 Exemplary photo-NOCAS reaction and simple ipso-substitution of DCBs 10, 20 or 26 with 2,3-dimethyl-2-butene (27) catalysed by phenanthrene (4).29

alkenes (Scheme 4) is highly challenging regarding the redox potentials (E1/2(10/10 ) ¼  1.64 V87 and E1/2(27 1/27) ¼ þ1.62 V104, both in MeCN vs SCE) and cannot be achieved with the common visible light absorbing catalysts.18,19 This reaction has thus not played a significant role in the recent renaissance of photoredox catalysis.4 Oxidation potentials of several alkenes can be taken from ref. 117. They are usually very high and in cases where electron transfer to the AH’s radical cation would be thermodynamically unfavourable, the formation of a p-complex between these two species has been suggested.10,91,104 The photoinduced ipso-substitution of aromatic nitriles by oxidatively generated alkyl radicals (for the proposed mechanism see Scheme 4) is a general transformation of great synthetic utility.118,119 Scheme 5 highlights two exemplary transformations reported by Mizuno, Otsuji, Yoshimi, Hatanaka and their co-workers using group 14 organometallic compounds (a) or carboxylates (b) as radical precursors.120,121 While 1,4- (10) and 1,2-DCB (26) are suited for such reactions, 1,3-DCB (20) affords only very low yields (see also Scheme 4). The radical anion of 20 might not be stable (long-lived) enough for the radical coupling to occur efficiently.122 Indeed, the reason such ipso-substitution reactions mainly afford the cross-coupling products probably is the persistent radical effect.123 A significant factor governing the regioselectivity of radical combinations is spin density. In the radical anions of 10 and 26, the highest spin density is found at the nitrile-substituted carbons, where the attack of alkyl radicals can be followed by fast rearomatisation through elimination of cyanide.122 This is not the case for the radical anions of 20 possessing the largest spin density in 4- and 6-position.122 Alkylation of these positions is usually observed when 1,3-DCB (20) is employed, albeit in low yields.121 Such products are formed via oxidative (a)

(b)

Scheme 5 Phenanthrene-catalysed ipso-substitution of dicyanobenzenes 10, 20 or 26 by radicals generated from (a) group 14 organometallic compounds and (b) carboxylates.120,121 Photochemistry, 2019, 46, 370–394 | 379

(a)

(b)

Scheme 6 Phenanthrene-catalysed (a) ipso-substitution of aromatic nitriles 33 with carboxylic acids and activated alcohols as radical precursors and (b) C(sp3)–C(sp3)-sbond metathesis using 1-benzyl tetrahydroisoquinoline derivatives 35.132,133 aFrom carboxylic acids. bFrom oxalate half-esters.

rearomatisation (Minisci reaction).124,125 The works highlighted in Scheme 5 have likely been a source of inspiration for the recent discovery of a multitude of visible light driven ipso-substitutions of aromatic nitriles using precious iridium-based catalysts.126–131 Also inspired by the work of Yoshimi,121 the Opatz group has presented some additions to the portfolio of phenanthrene-catalysed ipso-substitution reactions (Scheme 6).132,133 In these works, the scope of aromatic nitriles 33 (cyanobenzenes, -pyridines, -pyrimidine and -isoquinoline) and radical precursors (carboxylic acids, alcohols activated as their oxalate half-esters and 1-benzyl tetrahydroisoquinolines 35) was significantly extended. The use of very weak UV lamps or even sunlight as the sole energy source is also noteworthy. When similar transformations are performed in the presence of a more effective radical trap such as electron-deficient olefins 39, the alkyl radicals do not combine with the radical anions of the nitriles but preferentially attack the Michael acceptors in a photoinduced Giese reaction (Scheme 7).17,134,135 In the resulting radical adducts, the unpaired electron is located next to the electron-withdrawing group (EWG) rendering

380 | Photochemistry, 2019, 46, 370–394

Scheme 7 Phenanthrene-catalysed Giese reaction with amino acids 38 as radical precursors.136

Scheme 8 Phenanthrene-catalysed Giese reaction with allylic silanes 42 as radical precursors.145

these radicals electrophilic and preventing polymerisation. Instead, they are reduced to carbanions, followed by protonation to yield saturated products such as 40.17 Throughout the past decade, the group of Yoshimi has put remarkable effort into the exploration of such reactions using carboxylic acids,136–141 esters,142 and arylboronic or alkenylboronic acids143 as radical precursors. Their findings cannot be covered in detail here and have recently been reviewed.17 Scheme 7 summarises some of their early results (2009).136 Alternatively, group 14 organometallic compounds144–149 such as 42 or cyclopropanone acetals150,151 have been used as radical precursors. These species often afford stabilized allylic or benzylic radicals. The latter cannot be trapped efficiently by olefins, unless they are highly electron-deficient (easily reducible).37 In these cases, product formation likely involves combination of the stabilised radicals with the radical anions 41  generated by reduction of the olefins 41, followed by protonation of the resulting carbanions (Scheme 8).145 A multitude of such reactions have been reported.144,145,148,149,152 Exemplary results presented by Mizuno and Otsuji et al. in 1988 are summarised in Scheme 8.145 If such easily reducible olefins are not conjugated with an aromatic moiety, alkylation occurs in a-position to the EWGs.145 Photoinduced Giese-type reactions catalysed by AHs have certainly had an impact on the Photochemistry, 2019, 46, 370–394 | 381

revitalisation of visible light photoredox catalysis and there are meanwhile numerous reports of related transformations.153–157 As explained previously, reactions using aromatic nitriles either as RMs (Schemes 2, 3, 7) or as substrates (Schemes 4–6) can often also be performed in the absence of AHs, albeit with lower efficiency (see Section 1). This means that reaction times are prolonged,29,91,122 side reactions such as the polymerisation of olefins are enhanced,91,140 yields are lower29,91,121,158 and stronger lamps121 as well as light of shorter wavelengths12,92,98,150 might be required. In reactions affording product mixtures, the addition of AHs can alter the product distribution.95,101 It is difficult to give a quantitative estimate of the reaction enhancement. Even in a single reaction such as the photo-NOCAS process (Scheme 4), some substrates benefit much more from the addition of an AH than others104 and temperature effects have been reported as well.100 It is also difficult to estimate the quantity of an AH required to achieve optimal enhancement and it is obvious that this will depend on the specific reaction. There are only very few optimisation studies concerning the AHloading.132,133,143 As expected, an inverse correlation to the required irradiation time has been found.140,143 However, a reduction of the catalyst loading cannot always be compensated by prolonged irradiation as side reactions might behave differently.140 In practice, the AH has sometimes been used in catalytic amounts (r10 mol%),10,100,140,150 but in the majority of reports, stoichiometric quantities have been employed.17,92,98,121,136 Most AHs are inexpensive, readily available and can usually be recovered in very high yields (480%) so that their use is not an economic factor.10,29,91,92,98,132,136,137,148,159 2.1.1 Reactions involving reductive quenching of aromatic hydrocarbons. Although long considered,160 electron transfer has only been experimentally proven a mechanism for fluorescence quenching when the radical anions of perylene (7) were detected upon irradiation of this AH in the presence of N,N-dialkylanilines about sixty years ago.161–164 However, PET reactions operating through reductive quenching cycles have found only few applications to organic synthesis until very recently.11,20,21,165–167 Thus, such transformations did not have significant impact on the revitalisation of visible light photoredox catalysis.4,19 In 2016 and 2017, the group of Sudo reported perylene-catalysed reductive couplings of aromatic aldehydes and ketones 44 or imines 46 in the presence of N,N-diisopropylethylamine (DIPEA) as sacrificial reductive quencher (Scheme 9).166,167 These reactions afford a variety of 1,2-diols 45 and 1,2-diamines 47. Except for its S1*-state being relatively short-lived, perylene (7) offers advantageous photophysical properties, namely a high fluorescence quantum yield and absorption of visible light.168 For very challenging transformations, its radical anion might however not be a sufficiently strong reductant (see Table 1). In these cases, other AHs such as pyrene (6) are better suited. The necessity of using UV-light for pyrene-excitation can be circumvented by taking advantage of energy transfer from the visible light absorbing [Ru(bpy)3]21-complex,169 which is one of the most 382 | Photochemistry, 2019, 46, 370–394

(a)

(b)

Scheme 9 Perylene-catalysed reductive coupling of (a) aromatic aldehydes or ketones 44 and (b) imines 46. aIsolated after acylation of hydroxy groups. bRatio D/L:meso.166,167

Scheme 10 Subsequent energy and electron transfer for the visible light-induced coupling of aryl halides and triflates with electron-rich aromatics using a [Ru(bpy)3]21complex and pyrene (6) as catalysts.22

frequently used photoredox catalysts, readily available and significantly less expensive than its Ir-based counterparts.4,18 ¨nig et al. used this strategy for the photoreduction of In 2017, Ko electron-deficient aryl chlorides, bromides and triflates 48 (Scheme 10).22 Reduction potentials of some aryl halides can be taken from ref. 28 and 117. Trapping of the resulting aryl radicals by electron-rich aromatics 49 affords the cross coupling products 50.22 Photochemistry, 2019, 46, 370–394 | 383

Energy transfer from the 3MLCT1-state of [Ru(bpy)3]21 to pyrene (6) is much faster than reductive quenching of the excited Ru-complex by DIPEA and gives rise to the T1*-state of 6.22 The subsequent mechanistic steps are not fully elucidated yet. Reductive quenching of pyrene’s T1*state by DIPEA was proposed, but should be significantly endergonic.170 Instead, Ceroni, Balzani and co-workers suggested that triplet–tripletannihilation (TTA) might afford S1*-pyrene, which would then be quenched by the amine resulting in the radical anion of 6.170 This species is a sufficiently strong reductant to transfer an electron to electron-deficient aryl halides or triflates 48, which, upon mesolytic cleavage, gives rise to aryl radicals. These are then trapped by the electron-rich aromatics, followed by oxidative rearomatisation.22 The radical anions of 6 might however also be formed via reductive quenching of pyrene’s T1*-state by the reduced Ru-complex (produced either during the rearomatisation or via quenching by DIPEA).171 A more detailed discussion of the underlying mechanism is included in ref. 22, 170 and 171. For even more challenging transformations, p-terphenyl (9) has proven useful (see Table 1). Recently, the group of Jamison exemplified the enormous utility of this AH as catalyst for the photoreduction of carbon dioxide (E1/2(CO2/CO2  ¼ 2.21 V vs. SCE in DMF)172 in continuous flow.20 The resulting CO2-radical anions have been used for the synthesis of a-amino acids 52 from tertiary amines 51 and for the b-selective hydrocarboxylation of styrenes 53 (Scheme 11).20,21 The utilisation of a continuous flow reactor (Beeler’s photoreactor)173 was crucial to achieve high yields as the applied segmented flow allows for a better gas-liquid mixing.174 These works were preceded by studies concerning the photoreduction of carbon dioxide86,175–183 and water184–188 by oligo- or poly(pphenylene)s, albeit (with few exceptions)165,184,189–191 not with a focus on organic synthesis. This section has sought to give an overview over synthetically useful PET reactions using AHs as catalysts. Due to the limited length of this chapter, the survey has of course not been exhaustive, but rather intended to showcase general findings and the most recent developments.

3 Examples of PET reactions mediated by aromatic hydrocarbons In electrochemical transformations, AHs are commonly employed to mediate cathodic reductions via their radical anions.192,193 This is a fundamental difference to PET reactions, which AHs mediate by reductive quenching of the catalyst, followed by substrate oxidation via their radical cations (see Scheme 1c). Since the use of RMs in PET processes has recently been covered as part of an excellent review by Yoon et al.,16 this section will only provide a short survey of akin transformations. Different modes of action by which RMs enhance PET processes have been explained in Section 1. Here, we will try to highlight situations in which one or the other of these mechanistic modes is especially important. As early as 1975, the group of Farid and Evans reported the 9cyanoanthracene-catalysed dimerization of phenyl vinyl ether.34 384 | Photochemistry, 2019, 46, 370–394

(a)

(b)

Scheme 11 p-Terphenyl-catalysed (a) synthesis of a-amino acids 52 from tertiary amines 51 and (b) hydrocarboxylation of styrenes 53, both via photoreduction of carbon dioxide in continuous flow.20,21 PMP ¼ 1,2,2,6,6-pentamethylpiperidine (54).

Quenching of the catalyst by the olefin is endergonic and extremely slow. The addition of AHs, which quench the catalyst more efficiently, increased the quantum yield tremendously, albeit electron transfer from the alkene to the oxidised AH was endergonic.34 However, the radical cations of AHs have much longer lifetimes than the excited catalyst, which is beneficial for the alkene oxidation.36 One should also consider the formation of a p-complex between the AH’s radical cation and the olefin as stated previously.10,91,104 In 2013, Nicewicz and co-workers reported a related dimerization of styrene derivatives such as 56 using pyrylium salt 57 as visible lightabsorbing catalyst alongside naphthalene (1) or anthracene (2) as RM (Scheme 12a).33 Photochemistry, 2019, 46, 370–394 | 385

(a)

(b)

Scheme 12 (a) Dimerization of (E)-asarone (56) and (b) anti-Markovnikov addition of water to polyene 59 with subsequent radical cascade cyclisation, both via PET reactions mediated by AHs.33,194 PMP ¼ p-methoxyphenyl.

They applied this method to the synthesis of the lignan natural product magnosalin (58).33 In this study, the RM was adjusted to the respective styrene whose oxidation potential it should outperform only marginally. In this fashion, the RM does not trigger oxidative degradation of the cyclobutane products and prevents the stronger-oxidising catalyst from doing so.33 As explained in the previous section, alkene oxidations give rise to the anti-Markovnikov addition products when performed in the presence of nucleophiles and such transformations, both in inter195- and intramolecular fashion,196,197 can be mediated by AHs. These reactions have had significant impact on the recent revitalisation of photoredox catalysis.198 If polyenes are employed, the neutral radicals derived from addition of a nucleophile to the initial radical cation can induce cyclisation.38,39,95,194,199–203 As an example, Scheme 12b highlights a biphenyl-mediated cascade cyclisation of the (E,E,E)geranylgeranylmethyl dioxinone 59 reported by the group of Demuth in 1999.194 In this case, addition of water to the radical cation is followed by four trans ring fusions creating eight stereogenic centres in a single step. The S1*-state of 60 is quenched at comparable rates by both, polyenes like 59 and biphenyl (8).38 In such reactions, the beneficial effect of the AH is mostly attributed to its long-lived radical cations increasing the rate of substrate oxidation.16,38,39 Redox-mediated Giese reactions have been studied intensively.204–206 Over decades, the groups of Albini and Fagnoni at the University of Pavia have contributed significantly to a deeper understanding of such transformations.37,146,152,207,208 Scheme 13 highlights the tetra-n-butylammonium decatungstate (TBADT, 64)-catalysed benzylation of easily reducible 386 | Photochemistry, 2019, 46, 370–394

Scheme 13 Benzylation of electron-deficient olefins (63) using arylacetic acids (62) as radical precursors, TBADT (64) as catalyst and biphenyl (8) as RM.37

olefins209 63 with arylacetic acids 62 as radical precursors reported by Ravelli and Fagnoni et al. in 2016.37 Upon excitation, TBADT (64) rapidly converts to an unknown catalytically active species,210,211 the oxidation potential of which is estimated to be far superior to those of carboxylates.37 Nevertheless, reductive quenching of the negatively charged tungstate catalyst by carboxylates is inefficient, due to electrostatic repulsion. The addition of biphenyl (8) as RM, which can overcome this repulsion, was found to be crucial to achieve high yields.37 Given that biphenyl’s oxidation potential is significantly larger than that of carboxylates, but still smaller than that of the catalyst, this transformation is also a good example for impeding BET by increasing its exergonicity.24,30,37,41 Biphenyl (8) has also proven a useful RM for the 9,10-DCA (12)-catalysed photooxygenation of cyclopropanes35,212–214 and epoxides,35,215–217 the photo-NOCAS reaction14 as well as for oxidative rearrangements.218–221 In most PET reactions mediated by AHs, high loadings of the latter are required (see above) as the RM competes with the substrates for reductive quenching of the catalyst.

4 Conclusion and outlook Ever since the synthetic utility of PET reactions catalysed or mediated by AHs has been exemplified in seminal publications in the 1970s, significant developments in this field have greatly expanded the general understanding of free radical chemistry. This has unarguably been a contributing factor to the recent resurgence of visible light photoredox catalysis. AHs offer distinct advantages such as low costs, good availability and very high recovery rates. Their ground and excited state redox potentials are superior to those of common photoredox catalysts (see Table 1), which renders them especially useful for challenging transformations.18,19 However, AHs such as phenanthrene (4) and p-terphenyl (9) are used less commonly as catalysts than polypyridyl complexes of ruthenium or iridium and organic dyes.4,19 This is likely due to the fact that most AHs Photochemistry, 2019, 46, 370–394 | 387

do not absorb visible light. In contrast, they are often utilised in combination with classical mercury lamps, which is not appealing to the broader photoredox community. Thus, future research on AHs as catalysts for PET reactions should include screening for alternative light sources as the use of high-power UV-lamps may likely be avoided in many cases. The Opatz lab has for example recently shown that some phenanthrene-catalysed transformations can be efficiently driven by a 25 W UV/vis CFL bulb with no reduction of yield when compared to a 400 W Hg lamp.132,133 This laboratory and the group of Yoshimi have also recently reported that such reactions can be initiated by sunlight, whereat reaction times are greatly reduced when employing a microcapillary flow reactor.132,133,141,222 The recent reports on perylene (7) as low-priced and powerful visible light absorbing catalyst for PET reactions are also promising and may inspire future applications.166–168 Furthermore, the concept of utilising visible light absorbing sensitisers for energy transfer to AHs, which may then display their powerful redox chemistry, holds significant potential.22 AHs are valuable RMs for PET reactions and their application in this regard is likely to continue.33,37

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

D. W. C. MacMillan and D. A. Nicewicz, Science, 2008, 322, 77. M. A. Ischay, M. E. Anzovino, J. Du and T. P. Yoon, J. Am. Chem. Soc., 2008, 130, 12886. J. M. R. Narayanam, J. W. Tucker and C. R. J. Stephenson, J. Am. Chem. Soc., 2009, 131, 8756. M. H. Shaw, J. Twilton and D. W. C. MacMillan, J. Org. Chem., 2016, 81, 6898. A. Ledwith, Acc. Chem. Res., 1972, 5, 133. S. Farid and S. E. Shealer, J. Chem. Soc., Chem. Commun., 1973, 677. D. M. Hedstrand, W. H. Kruizinga and R. M. Kellogg, Tetrahedron Lett., 1978, 19, 1255. T. J. Van Bergen, D. M. Hedstrand, W. H. Kruizinga and R. M. Kellogg, J. Org. Chem., 1979, 44, 4953. D. G. Whitten, Acc. Chem. Res., 1980, 13, 83. C. Pac, A. Nakasone and H. Sakurai, J. Am. Chem. Soc., 1977, 99, 5806. S. Tazuke and N. Kitamura, J. Chem. Soc., Chem. Commun., 1977, 515. T. Asanuma, T. Gotoh, A. Tsuchida, M. Yamamoto and Y. Nishijima, J. Chem. Soc., Chem. Commun., 1977, 485. G. J. Kavarnos and N. J. Turro, Chem. Rev., 1986, 86, 401. D. Mangion and D. R. Arnold, Acc. Chem. Res., 2002, 35, 297. M. Fagnoni, D. Dondi, D. Ravelli and A. Albini, Chem. Rev., 2007, 107, 2725. K. L. Skubi, T. R. Blum and T. P. Yoon, Chem. Rev., 2016, 116, 10035. Y. Yoshimi, J. Photochem. Photobiol., A, 2017, 342, 116. C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013, 113, 5322. N. A. Romero and D. A. Nicewicz, Chem. Rev., 2016, 116, 10075. H. Seo, M. H. Katcher and T. F. Jamison, Nat. Chem., 2016, 9, 453. H. Seo, A. Liu and T. F. Jamison, J. Am. Chem. Soc., 2017, 139, 13969. ¨nig, Angew. Chem., Int. Ed., 2017, 56, 8544. I. Ghosh, R. S. Shaikh and B. Ko

388 | Photochemistry, 2019, 46, 370–394

23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58

G. J. Kavarnos, Topics in Current Chemistry, ed. J. Mattay, Springer-Verlag, Berlin, 1990, 156, 21–58. I. R. Gould, D. Ege, J. E. Moser and S. Farid, J. Am. Chem. Soc., 1990, 112, 4290. H. Masuhara and N. Mataga, Acc. Chem. Res., 1981, 14, 312. A. Loupy, B. Tchoubar and D. Astruc, Chem. Rev., 1992, 92, 1141. K. Mizuno, Y. Nishiyama, T. Ogaki, K. Terao, H. Ikeda and K. Kakiuchi, J. Photochem. Photobiol., C, 2016, 29, 107. S. L. Murov, I. Carmichael and G. L. Hug, Handbook of Photochemistry, Marcel Dekker Inc., New York, 2 edn, 1993. R. M. Borg, D. R. Arnold and T. S. Cameron, Can. J. Chem., 1984, 62, 1785. G. Grampp, Angew. Chem., Int. Ed., 1993, 32, 691. A. Rosspeintner, M. Koch, G. Angulo and E. Vauthey, J. Am. Chem. Soc., 2012, 134, 11396. T. Tamai, N. Ichinose, T. Tanaka, T. Sasuga, I. Hashida and K. Mizuno, J. Org. Chem., 1998, 63, 3204. M. Riener and D. A. Nicewicz, Chem. Sci., 2013, 4, 2625. S. Farid, S. E. Hartman and T. R. Evans, in The Exciplex, ed. M. Gordon and W. R. Ware, Academic Press Inc., New York, 1975, pp. 327–343. A. P. Schaap, S. Siddiqui, G. Prasad, E. Palomino and L. Lopez, J. Photochem., 1984, 25, 167. S. L. Mattes and S. Farid, Acc. Chem. Res., 1982, 15, 80. L. Capaldo, L. Buzzetti, D. Merli, M. Fagnoni and D. Ravelli, J. Org. Chem., 2016, 81, 7102. ¨rner, K.-D. Warzecha and M. Demuth, J. Phys. Chem. A, 1997, H. Go 101, 9964. K.-D. Warzecha, H. Gorner and M. Demuth, J. Chem. Soc., Faraday Trans., 1998, 94, 1701. F. D. Lewis, A. M. Bedell, R. E. Dykstra, J. E. Elbert, I. R. Gould and S. Farid, J. Am. Chem. Soc., 1990, 112, 8055. J. Mattay and M. Vondenhof, in Topics in Current Chemistry, ed. J. Mattay, Springer-Verlag, Berlin, 1991, vol. 159, pp. 219–255. D. Rehm and A. Weller, Isr. J. Chem., 1970, 8, 259. V. Balzani, F. Bolletta, M. T. Gandolfi and M. Maestri, Topics in Current Chemistry, Springer-Verlag, Berlin, 1978, vol. 75, pp. 1–64. R. Dabestani and I. N. Ivanov, Photochem. Photobiol., 1999, 70, 10. E. Clar, Spectrochim. Acta, 1950, 4, 116. B. Stevens and M. F. Thomaz, Chem. Phys. Lett., 1968, 1, 549. C. A. Parker and T. A. Joyce, Trans. Faraday Soc., 1966, 62, 2785. G. N. Lewis and M. Kasha, J. Am. Chem. Soc., 1944, 66, 2100. D. N. Dempster, T. Morrow and M. F. Quinn, J. Photochem., 1973, 2, 329. D. D. Morgan, D. Warshawsky and T. Atkinson, Photochem. Photobiol., 1977, 25, 31. W. R. Ware, J. Phys. Chem., 1962, 66, 455. W. R. Dawson and M. W. Windsor, J. Phys. Chem., 1968, 72, 3251. S. W. J. Komorowski, Z. R. Grabowski and W. Zielenkiewicz, J. Photochem., 1985, 30, 141. I. B. Berlman, Handbook of Fluorescence Spectra of Aromatic Molecules, Academic Press, New York, 1965. A. Kearvell and F. Wilkinson, Chem. Phys. Lett., 1971, 11, 472. S. P. McGlynn, T. Azumi and M. Kasha, J. Chem. Phys., 1964, 40, 507. P. Jardon and R. Gautron, J. Chim. Phys., 1985, 82, 353. ¨mer and M. Zander, Z. Naturforsch. A, 1979, 34A, 909. G. P. Blu Photochemistry, 2019, 46, 370–394 | 389

59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96

J. B. Birks and S. Georghiou, J. Phys. B, 1968, 1, 958. H. Goerner, J. Phys. Chem., 1989, 93, 1826. G. Porter and F. Wilkinson, Proc. R. Soc. London, Ser. A, 1961, 264, 1. I. B. Berlman, Handbook of Fluorescence Spectra of Aromatic Molecules, Academic Press, 2 edn, 1971. W. Heinzelmann and H. Labhart, Chem. Phys. Lett., 1969, 4, 20. M. Zander, Z. Naturforsch. A, 1978, 33A, 998. F. V. Bright, Appl. Spectrosc., 1988, 42, 1531. C. A. Parker, Photoluminescence of Solutions: With Applications to Photochemistry and Analytical Chemistry, Elsevier Publishing Company, 1968. C. A. Parker and T. A. Joyce, Chem. Commun., 1966, 108b. M. Zander, Z. Naturforsch. A, 1977, 32a, 339. J. B. Birks, Photophysics of Aromatic Molecules, Wiley-Interscience, New York, 1970. B. Amand and R. Bensasson, Chem. Phys. Lett., 1975, 34, 44. V. V. Trusov and P. A. Teplaykov, Opt. Spectrosc., 1964, 16, 27. A. P. Marchetti and D. R. Kearns, J. Am. Chem. Soc., 1967, 89, 768. A. Maiti and G. S. Kastha, Indian J. Phys. Chem. B, 1986, 60B, 336. D. R. Arnold and A. J. Maroulis, J. Am. Chem. Soc., 1976, 98, 5931. H. Hayashi and S. Nagakura, Mol. Phys., 1970, 19, 45. C. Pac, T. Fukunaga, T. Ohtsuki and H. Sakurai, Chem. Lett., 1984, 13, 1847. P. K. Das, A. J. Muller and G. W. Griffin, J. Org. Chem., 1984, 49, 1977. K. A. Abdullah and T. J. Kemp, J. Photochem., 1985, 28, 61. W. R. Ware and W. Rothman, Chem. Phys. Lett., 1976, 39, 449. A. P. Darmanyan, Chem. Phys. Lett., 1984, 110, 89. I. V. Soboleva, N. A. Sadovskii and M. G. Kuz’min, Dokl. Phys. Chem., 1978, 238, 70. E. S. Pysh and N. C. Yang, J. Am. Chem. Soc., 1963, 85, 2124. G. Guirado, C. N. Fleming, T. G. Lingenfelter, M. L. Williams, H. Zuilhof and J. P. Dinnocenzo, J. Am. Chem. Soc., 2004, 126, 14086. K. Mizuno, N. Ichinose, T. Tamai and Y. Otsuji, Tetrahedron Lett., 1985, 26, 5823. C. K. Mann and K. K. Barnes, Electrochemical Reactions in Nonaqueous Systems, Marcel Dekker, Inc., New York, 1970. S. Matsuoka, T. Kohzuki, C. Pac, A. Ishida, S. Takamuku, M. Kusaba, N. Nakashima and S. Yanagida, J. Phys. Chem., 1992, 96, 4437. Y. Mori, Y. Sakaguchi and H. Hayashi, J. Phys. Chem. A, 2000, 104, 4896. Y. Wang, O. Haze, J. P. Dinnocenzo, S. Farid, R. S. Farid and I. R. Gould, J. Org. Chem., 2007, 72, 6970. R. A. Neunteufel and D. R. Arnold, J. Am. Chem. Soc., 1973, 95, 4080. T. Asanuma, M. Yamamoto and Y. Nishijima, J. Chem. Soc., Chem. Commun., 1975, 608. T. Majima, C. Pac, A. Nakasone and H. Sakurai, J. Am. Chem. Soc., 1981, 103, 4499. H. Ishii, Y. Imai, T. Hirano, S. Maki, H. Niwa and M. Ohashi, Tetrahedron Lett., 2000, 41, 6467. T. Hirano, S. Shiina and M. Ohashi, J. Chem. Soc., Chem. Commun., 1992, 1544. M. Ohashi, K. Nakatani, H. Maeda and K. Mizuno, Org. Lett., 2008, 10, 2741. H. Weng, C. Scarlata and H. D. Roth, J. Am. Chem. Soc., 1996, 118, 10947. H. Ishii, T. Hirano, S. Maki, H. Niwa and M. Ohashi, Tetrahedron Lett., 1998, 39, 2791.

390 | Photochemistry, 2019, 46, 370–394

97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134

U. Hoffmann, Y. Gao, B. Pandey, S. Klinge, K. D. Warzecha, C. Krueger, H. D. Roth and M. Demuth, J. Am. Chem. Soc., 1993, 115, 10358. H. Ishii, R. Yamaoka, Y. Imai, T. Hirano, S. Maki, H. Niwa, D. Hashizume, F. Iwasaki and M. Ohashi, Tetrahedron Lett., 1998, 39, 9501. R. Torriani, M. Mella, E. Fasani and A. Albini, Tetrahedron, 1997, 53, 2573. M. Jin, Y. Yusuke, H. Akiko, K. Tomohiro, Y. Toshiaki, S. Tsutomu and Y. Masahide, Bull. Chem. Soc. Jpn., 2011, 84, 1130. M. Ohashi, K. Nakatani, H. Maeda and K. Mizuno, J. Org. Chem., 2008, 73, 8348. O. Maki, M. Hajime and M. Kazuhiko, Chem. Lett., 2010, 39, 462. M. Ohashi, K. Nakatani, H. Maeda and K. Mizuno, J. Photochem. Photobiol., A, 2010, 214, 161. D. R. Arnold and M. S. Snow, Can. J. Chem., 1988, 66, 3012. D. S. Hamilton and D. A. Nicewicz, J. Am. Chem. Soc., 2012, 134, 18577. T. M. Nguyen and D. A. Nicewicz, J. Am. Chem. Soc., 2013, 135, 9588. A. J. Perkowski and D. A. Nicewicz, J. Am. Chem. Soc., 2013, 135, 10334. M. A. Zeller, M. Riener and D. A. Nicewicz, Org. Lett., 2014, 16, 4810. T. M. Nguyen, N. Manohar and D. A. Nicewicz, Angew. Chem., Int. Ed., 2014, 53, 6198. D. A. Nicewicz and D. S. Hamilton, Synlett, 2014, 25, 1191. N. A. Romero and D. A. Nicewicz, J. Am. Chem. Soc., 2014, 136, 17024. A. J. Musacchio, L. Q. Nguyen, G. H. Beard and R. R. Knowles, J. Am. Chem. Soc., 2014, 136, 12217. N. J. Gesmundo, J.-M. M. Grandjean and D. A. Nicewicz, Org. Lett., 2015, 17, 1316. Z. Yang, H. Li, S. Li, M.-T. Zhang and S. Luo, Org. Chem. Front., 2017, 4, 1037. M. A. Ischay, Z. Lu and T. P. Yoon, J. Am. Chem. Soc., 2010, 132, 8572. R. Li, B. C. Ma, W. Huang, L. Wang, D. Wang, H. Lu, K. Landfester and K. A. I. Zhang, ACS Catal., 2017, 7, 3097. H. G. Roth, N. A. Romero and D. A. Nicewicz, Synlett, 2016, 27, 714. A. N. Frolov, Russ. J. Org. Chem., 1998, 34, 139. S. M. Bonesi and M. Fagnoni, Chem. – Eur. J., 2010, 16, 13572. K. Mizuno, K. Nakanishi and Y. Otsuji, Chem. Lett., 1988, 17, 1833. T. Itou, Y. Yoshimi, T. Morita, Y. Tokunaga and M. Hatanaka, Tetrahedron, 2009, 65, 263. N. Kazuhisa, M. Kazuhiko and O. Yoshio, Bull. Chem. Soc. Jpn., 1993, 66, 2371. A. Studer, Chem. – Eur. J., 2001, 7, 1159. C. Punta and F. Minisci, Trends Heterocycl. Chem., 2008, 13, 1. J. Tauber, D. Imbri and T. Opatz, Molecules, 2014, 19, 16190. A. McNally, C. K. Prier and D. W. C. MacMillan, Science, 2011, 334, 1114. K. Qvortrup, D. A. Rankic and D. W. C. MacMillan, J. Am. Chem. Soc., 2014, 136, 626. Z. Zuo and D. W. C. MacMillan, J. Am. Chem. Soc., 2014, 136, 5257. J. D. Cuthbertson and D. W. C. MacMillan, Nature, 2015, 519, 74. C. Yan, L. Li, Y. Liu and Q. Wang, Org. Lett., 2016, 18, 4686. K. Nakajima, S. Nojima, K. Sakata and Y. Nishibayashi, ChemCatChem, 2016, 8, 1028. B. Lipp, A. M. Nauth and T. Opatz, J. Org. Chem., 2016, 81, 6875. B. Lipp, A. Lipp, H. Detert and T. Opatz, Org. Lett., 2017, 19, 2054. ´lez-Go ´mez and T. Witzel, Angew. Chem., Int. Ed., 1984, B. Giese, J. A. Gonza 23, 69. Photochemistry, 2019, 46, 370–394 | 391

135 136 137

138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168

R. M. Borg, D. Franke and A. Vella, Can. J. Chem., 2003, 81, 723. Y. Yoshimi, M. Masuda, T. Mizunashi, K. Nishikawa, K. Maeda, N. Koshida, T. Itou, T. Morita and M. Hatanaka, Org. Lett., 2009, 11, 4652. Y. Yoshimi, K. Kobayashi, H. Kamakura, K. Nishikawa, Y. Haga, K. Maeda, T. Morita, T. Itou, Y. Okada and M. Hatanaka, Tetrahedron Lett., 2010, 51, 2332. Y. Yoshimi, S. Hayashi, K. Nishikawa, Y. Haga, K. Maeda, T. Morita, T. Itou, Y. Okada, N. Ichinose and M. Hatanaka, Molecules, 2010, 15, 2623. K. Nishikawa, Y. Yoshimi, K. Maeda, T. Morita, I. Takahashi, T. Itou, S. Inagaki and M. Hatanaka, J. Org. Chem., 2013, 78, 582. Y. Yoshimi, S. Washida, Y. Okita, K. Nishikawa, K. Maeda, S. Hayashi and T. Morita, Tetrahedron Lett., 2013, 54, 4324. Y. Yoshimi, A. Nishio, M. Hayashi and T. Morita, J. Photochem. Photobiol., A, 2016, 331, 17. H. Saito, T. Kanetake, K. Osaka, K. Maeda, T. Morita and Y. Yoshimi, Tetrahedron Lett., 2015, 56, 1645. Y. Iwata, Y. Tanaka, S. Kubosaki, T. Morita and Y. Yoshimi, Chem. Commun., 2018, 54, 1257. M. Kazuhiko, T. Susumu and O. Yoshio, Chem. Lett., 1987, 16, 203. M. Kazuhiko, I. Munehiro and O. Yoshio, Chem. Lett., 1988, 17, 1507. M. Fagnoni, M. Mella and A. Albini, J. Am. Chem. Soc., 1995, 117, 7877. M. C. Courtney, M. Mella and A. Albini, J. Chem. Soc., Perkin Trans. 2, 1997, 1105. T. Hayamizu, H. Maeda, M. Ikeda and K. Mizuno, Tetrahedron Lett., 2001, 42, 2361. T. Hayamizu, H. Maeda and K. Mizuno, J. Org. Chem., 2004, 69, 4997. M. Abe, M. Nojima and A. Oku, Tetrahedron Lett., 1996, 37, 1833. O. Akira, M. Toshiyuki, A. Manabu, O. Masatoshi and K. Tohru, Bull. Chem. Soc. Jpn., 1999, 72, 511. M. Fagnoni, M. Mella and A. Albini, J. Org. Chem., 1998, 63, 4026. K. Okada, K. Okamoto, N. Morita, K. Okubo and M. Oda, J. Am. Chem. Soc., 1991, 113, 9401. L. Chu, C. Ohta, Z. Zuo and D. W. C. MacMillan, J. Am. Chem. Soc., 2014, 136, 10886. T. Chinzei, K. Miyazawa, Y. Yasu, T. Koike and M. Akita, RSC Adv., 2015, 5, 21297. G.-Z. Wang, R. Shang, W.-M. Cheng and Y. Fu, Org. Lett., 2015, 17, 4830. A. Millet, Q. Lefebvre and M. Rueping, Chem. – Eur. J., 2016, 22, 13464. D. Matsuoka and Y. Nishigaichi, Chem. Lett., 2014, 43, 559. K. Mizuno, K. Terasaka, M. Ikeda and Y. Otsuji, Tetrahedron Lett., 1985, 26, 5819. J. Weiss and H. Fischgold, Z. Phys. Chem., 1936, 32B, 135. ¨rster and K. Kasper, Z. Phys, Chem. N.F., 1954, 1, 275. T. Fo H. Leonhardt and A. Weller, Z. Phys, Chem. N.F., 1961, 29, 277. M. Koizumi, S. Kato, N. Mataga, T. Matsuura and Y. Usui, Photosensitized Reactions, Kagakudojin Publishing Co., Inc., Kyoto, 1978. H. D. Roth, Topics in Current Chemistry, ed. J. Mattay, Springer-Verlag, Berlin, 1990, 156, pp. 1–19. Y. Wada, T. Kitamura and S. Yanagida, Res. Chem. Intermed., 2000, 26, 153. S. Okamoto, K. Kojiyama, H. Tsujioka and A. Sudo, Chem. Commun., 2016, 52, 11339. S. Okamoto, R. Ariki, H. Tsujioka and A. Sudo, J. Org. Chem., 2017, 82, 9731. N. Noto, T. Koike and M. Akita, Chem. Sci., 2017, 8, 6375.

392 | Photochemistry, 2019, 46, 370–394

169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188

189 190 191

192 193 194 195 196 197 198 199 200

J. Solarski and A. Kapturkiewicz, J. Photochem. Photobiol., A, 2014, 292, 10. M. Marchini, G. Bergamini, P. G. Cozzi, P. Ceroni and V. Balzani, Angew. Chem., Int. Ed., 2017, 56, 12820. ¨nig, Angew. Chem., Int. Ed., 2017, 56, 12822. I. Ghosh, J. I. Bardagi and B. Ko E. Lamy, L. Nadjo and J. M. Saveant, J. Electroanal. Chem. Interfacial Electrochem., 1977, 78, 403. R. Telmesani, S. H. Park, T. Lynch-Colameta and A. B. Beeler, Angew. Chem., Int. Ed., 2015, 54, 11521. C. J. Mallia and I. R. Baxendale, Org. Process Res. Dev., 2016, 20, 327. S. Matsuoka, T. Kohzuki, C. Pac and S. Yanagida, Chem. Lett., 1990, 19, 2047. S. Matsuoka, K. Yamamoto, C. Pac and S. Yanagida, Chem. Lett., 1991, 20, 2099. S. Matsuoka, K. Yamamoto, T. Ogata, M. Kusaba, N. Nakashima, E. Fujita and S. Yanagida, J. Am. Chem. Soc., 1993, 115, 601. T. Ogata, S. Yanagida, B. S. Brunschwig and E. Fujita, J. Am. Chem. Soc., 1995, 117, 6708. T. Dhanasekaran, J. Grodkowski, P. Neta, P. Hambright and E. Fujita, J. Phys. Chem. A, 1999, 103, 7742. J. Grodkowski, T. Dhanasekaran, P. Neta, P. Hambright, B. S. Brunschwig, K. Shinozaki and E. Fujita, J. Phys. Chem. A, 2000, 104, 11332. J. Grodkowski and P. Neta, J. Phys. Chem. A, 2000, 104, 4475. J. Grodkowski, P. Neta, E. Fujita, A. Mahammed, L. Simkhovich and Z. Gross, J. Phys. Chem. A, 2002, 106, 4772. H. Takeda, C. Cometto, O. Ishitani and M. Robert, ACS Catal., 2017, 7, 70. T. Shibata, A. Kabumoto, T. Shiragami, O. Ishitani, C. Pac and S. Yanagida, J. Phys. Chem., 1990, 94, 2068. S. Matsuoka, H. Fujii, C. Pac and S. Yanagida, Chem. Lett., 1990, 19, 1501. S. Matsuoka, H. Fujii, T. Yamada, C. Pac, A. Ishida, S. Takamuku, M. Kusaba, N. Nakashima and S. Yanagida, J. Phys. Chem., 1991, 95, 5802. H. Fujiwara, T. Kitamura, Y. Wada, S. Yanagida and P. V. Kamat, J. Phys. Chem. A, 1999, 103, 4874. R. S. Sprick, B. Bonillo, R. Clowes, P. Guiglion, N. J. Brownbill, B. J. Slater, F. Blanc, M. A. Zwijnenburg, D. J. Adams and A. I. Cooper, Angew. Chem., Int. Ed., 2016, 55, 1792. O. Tomoyuki, H. Kunizo, M. Shinjiro, W. Yuji and Y. Shozo, Chem. Lett., 1993, 22, 983. M. Zhang, W. D. Rouch and R. D. McCulla, Eur. J. Org. Chem., 2012, 2012, 6187. J. T. Petroff Ii, A. H. Nguyen, A. J. Porter, F. D. Morales, M. P. Kennedy, D. Weinstein, H. E. Nazer and R. D. McCulla, J. Photochem. Photobiol., A, 2017, 335, 149. E. Steckhan, Angew. Chem., Int. Ed., 1986, 25, 683. R. Francke and R. D. Little, Chem. Soc. Rev., 2014, 43, 2492. C. Heinemann and M. Demuth, J. Am. Chem. Soc., 1999, 121, 4894. P. G. Gassman and K. J. Bottorff, Tetrahedron Lett., 1987, 28, 5449. P. G. Gassman and K. J. Bottorff, J. Am. Chem. Soc., 1987, 109, 7547. P. G. Gassman and S.A. De Silva, J. Am. Chem. Soc., 1991, 113, 9870. K. A. Margrey and D. A. Nicewicz, Acc. Chem. Res., 2016, 49, 1997. ¨ger, K. D. Warzecha, X. Xing, M. Demuth, R. Goddard, M. Kessler and C. Kru Helv. Chim. Acta, 1995, 78, 2065. K.-D. Warzecha, M. Demuth and H. Gorner, J. Chem. Soc., Faraday Trans., 1997, 93, 1523. Photochemistry, 2019, 46, 370–394 | 393

201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222

C. Heinemann and M. Demuth, J. Am. Chem. Soc., 1997, 119, 1129. X. Xing and M. Demuth, Eur. J. Org. Chem., 2001, 537. M. E. Ozser, H. Icil, Y. Makhynya and M. Demuth, Eur. J. Org. Chem., 2004, 3686. E. Meggers, E. Steckhan and S. Blechert, Angew. Chem., Int. Ed., 1995, 34, 2137. G. Gutenberger, E. Steckhan and S. Blechert, Angew. Chem., Int. Ed., 1998, 37, 660. M. Jonas, S. Blechert and E. Steckhan, J. Org. Chem., 2001, 66, 6896. M. Fagnoni, M. Mella and A. Albini, Tetrahedron, 1995, 51, 859. G. Campari, M. Fagnoni, M. Mella and A. Albini, Tetrahedron: Asymmetry, 2000, 11, 1891. S. Montanaro, D. Ravelli, D. Merli, M. Fagnoni and A. Albini, Org. Lett., 2012, 14, 4218. C. Tanielian, Coord. Chem. Rev., 1998, 178–180, 1165. V. D. Waele, O. Poizat, M. Fagnoni, A. Bagno and D. Ravelli, ACS Catal., 2016, 6, 7174. A. P. Schaap, L. Lopez, S. D. Anderson and S. D. Gagnon, Tetrahedron Lett., 1982, 23, 5493. M. Kazuhiko, K. Nobuhiro and O. Yoshio, Chem. Lett., 1983, 12, 477. K. Mizuno, N. Kamiyama, N. Ichinose and Y. Otsuji, Tetrahedron, 1985, 41, 2207. A. P. Schaap, S. Siddiqui, S. D. Gagnon and L. Lopez, J. Am. Chem. Soc., 1983, 105, 5149. A. P. Schaap, L. Lopez and S. D. Gagnon, J. Am. Chem. Soc., 1983, 105, 663. A. Paul Schaap, S. Siddiqui, G. Prasad, E. Palomino and M. Sandison, Tetrahedron, 1985, 41, 2229. H. Ikeda, T. Minegishi, H. Abe, A. Konno, J. L. Goodman and T. Miyashi, J. Am. Chem. Soc., 1998, 120, 87. S. S. Hixson, P. S. Mariano and H. E. Zimmerman, Chem. Rev., 1973, 73, 531. ´zar, F. H. Cano, M. J. Ortiz and A. R. Agarrabeitia, J. Mol. M. P. Martı´nez-Alca Struct., 2003, 648, 19. D. Armesto, O. Caballero, M. J. Ortiz, A. R. Agarrabeitia, M. Martin-Fontecha and M. R. Torres, J. Org. Chem., 2003, 68, 6661. A. M. Nauth, A. Lipp, B. Lipp and T. Opatz, Eur. J. Org. Chem., 2017, 2099.

394 | Photochemistry, 2019, 46, 370–394

Photo-induced multi-component reactions b Loı¨c Pantaine,a,b Christophe Boura and Ge ´ raldine Masson*

DOI: 10.1039/9781788013598-00395

The recent advances in the field of photochemical, photocatalyzed and photoredox catalyzed Multi-Component Reactions (MCRs) are resumed in this highlight chapter.

1

Introduction

Over the past decades, one of the main concerns in the field of organic chemistry and synthesis has been reducing, recycling or even eliminating the waste it creates. This trend has in recent years known a surge in popularity, due to ever greater economic strain and growing environmental awareness. A reaction’s yield and selectivity are no longer the only criteria that determine its success: it must also have a limited financial and environmental impact. Several methods have been developed throughout the years to reach such goals. One is for example the use of Multi-Component Reactions, or MCRs, which are defined as 3 or more compounds reacting together in a multistep one pot sequence to afford a product possessing most or all the atoms of the reagents involved.1–3 They allow for the generation of complex compounds from simple material through the formation of numerous new bonds in a single process. Such reactions reduce a multistep sequence’s time and cost (both to the environment and the experimenter) by eliminating any need for isolation and purification of the intermediates. It can also allow for better yields and new reactivities, should any of these intermediates be unstable, since they are consumed quickly after they are formed, limiting their potential degradation. MCRs can either be a linear reaction sequence, in which each reagent is added to the product one after the other, or a convergent sequence, in which several intermediates can be formed from different starting material and only then react together to form the final product (Scheme 1). On the other hand, photoinduced reactions, defined as any reaction in which light (visible or UV) activates the reaction in some way, have been substantially developed because of their considerable advantages, most notable of all is the obvious fact that light is a renewable and cheap

a

Institut de Chimie Mole´culaire et des Mate´riaux d’Orsay, CNRS UMR 8182, ˆtiment 420, 91405 Orsay Cedex, Universite´ Paris-Sud, Universite´ Paris-Saclay, ba France b Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Universite´ ParisSud, Universite´ Paris-Saclay, 1, avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France. E-mail: [email protected] Photochemistry, 2019, 46, 395–431 | 395  c

The Royal Society of Chemistry 2019

Scheme 1 General Scheme for a multi-component reaction.

energy source.4–8 If considering sunlight itself, rather than artificial light, it can also be said that it is non-polluting, free, unexhaustible and accessible to all. Photoinduced reactions can be divided into two main categories: photoactivation of the starting material and photocatalysis (which can be divided in the use of photoredox catalyst and photosensitisors). Photoactivation needs nothing else but light to directly activate the reaction. However, it requires at least one of the reagents to be light-sensitive, which is a rare trait in most chemical compounds. This is particularly true regarding visible light, so photoactivation often requires the use of stronger UV light to allow the reaction to happen. Photopromotion solves this issue by introducing a relay substance between light and reagents. These relay compounds can absorb light and allow chemical transformations by electron or energy transfer to the reagents. If this promoter can be brought back to its ground state in the reaction, through the reactive pathway or the introduction of a sacrificial species, then they can be refered to as photocatalysts. Catalysis in general is a well-known means to develop greener alternatives to synthetic pathways: the use of another molecule, separate from the starting material, can accelerate reaction rates or even enable new reactivity and selectivity. The regeneration of the relay species means it can be introduced in sub-stoichiometric amounts and even be recycled, limiting its cost and environmental impact. As a sub-group of the field of catalysis, photocatalysis shares all of these advantages, while also providing the benefits of light activation. 396 | Photochemistry, 2019, 46, 395–431

The definitions of photocatalysts and photosensitizers are very similar and can be interchangeable in most situations; however for the sake of clarity, we will be using those terms in separate cases: – The use of a photocatalyst, or photoredox catalyst, will be defined as the use of a species that, after passing into an excited state through light activation, undergoes single electron transfers (SET) with the reagents to enable the reaction (Scheme 2). The photocatalytic cycle can go through 2 different pathways: after reaching the photoinduced excited state, the photocatalyst can either return to its ground state by reductive or oxidative quenching. In the reductive quenching, as the name indicates, the excited photocatalyst is reduced by a SET. This intermediate reduced species then undergoes a second SET to be oxidated back to its initial state. The oxidative quenching goes through the same double SET process, but swaps over oxidation and reduction. Whether the photocatalyst will go through one or the other depends on the reaction conditions, the compounds present in the solution and the nature (particularly its redox potential) of the photocatalyst itself. Depending on the reaction, the reagents (and subsequent intermediates) can be responsible for either or both of the SET steps. In the case of the former, a sacrificial oxidant/reductant species must be added to close the photocatalytic cycle. In any case, the catalytic cycle is redox neutral, i.e. it will gain as many electrons as it loses. The word photosensitizer will in this chapter be a shortcut to refer to non-electron transferring photocatalysts: in these cases, such species are also activated by light to an excited state, but transfer only energy to activate the reagents. We must stress that this is not the strict definition of a photosensitisor, but merely a means for us to clearly differentiate them from photoredox catalysts. Photoinduced reactions can therefore go through three distinct reactive pathways (Scheme 3): either direct photoactivation of at least one of the starting material or the use of an intermemdiate species that absorbs light and retransmits it to the reagents through electron or energy transfer. In most cases, a photoinduced MCR begins by direct or indirect photoactivation of one of the reagents which will produce a radical species that will then go on to react with an unsaturated reagent, most

Scheme 2 General Scheme for the photoredox catalytic cycle Photochemistry, 2019, 46, 395–431 | 397

Scheme 3 General Scheme for a photoinduced reaction.

Scheme 4 Photoactivated mechanistic pathways.

often an olefin, to form an intermediate radical (Scheme 4). This radical reaction chain can go on for several steps depending on the nature and number of reagents involved, however its conclusion can be through 2 main pathways: either another radical species will add onto the intermediate, therefore closing the cycle with a radical–radical mechanism, or alternatively the intermediate can be oxidized/reduced to the cationic/ anionic species and then react with a nucleophile/electrophile to end the reaction. This second option is called radical–polar crossover (Scheme 4). While any number of species can play the role of oxidant or reductant, in the case of photoredox catalysis, this is most often used to regenerate the photoredox catalyst to its ground state and close the photocatalytic cycle. A less common option is for the newly reactive intermediate to directly terminate either on itself or by reacting with a second activated species thereby modifying the initial reagent. Both radical–radical and radical–polar crossover routes have been explored to develop new photoinduced MCR, either involving insertion processes or light induced substrate modifications that will further react with other reagents. 398 | Photochemistry, 2019, 46, 395–431

The development of photoinduced MCRs allows for a vast array of possible reactivities to be explored as well as combining the benefits of both photochemistry and MCRs, making for a significant synthetic means to achieve great complexity from simple starting material in an efficient and cost-effective manner in time, money and environmental impact. While such reactions have been given a substantial amount of attention,9 there is still much to develop within this field. This chapter will focus on the achievements and advances concerning photoinduced MCRs up to the end of 2017.

2

Direct photoactivation of reagents

Reactions based on the direct activation of substrates via light irradiation, are the simplest and most straightforward of the photoinduced reactions, since they do not require any intermediate between the energy source (light) and the reagents. Therefore, they have been developed and reported for over a century.11 Multicomponent photochemical reactions however are far more recent, only starting around the end of the 20th century. These reactions can be divided into different subgroups depending on the type of photoactivated reagent and photoinduced reactivity they generate. 2.1 Photoactivated organometallic compounds as radical initiators Among the earliest examples of direct photo activation MCRs is the olefin dialkylation performed by the group of Otsuji in 1988 (Scheme 5).12 This reaction uses electron-deficient alkenes, organoiodo compounds and allylic stannates, the latter being used as both reagent and radical initiator. Though the reaction can be initiated by AIBN in refluxing conditions, Otsuji and co-workers have shown that UV light can also initiate the reaction at room temperature, even affording, in some cases, better yields. The light activates the stannate compound, forming the

Scheme 5 Organo-stannates and -plumbates as photoactivated radical precursors.12–14 Photochemistry, 2019, 46, 395–431 | 399

Bu3Sn radical that breaks the C–I bond, forming the alkyl radical that adds to the alkene. The new resulting radical then adds to the allylstannate, forming the desired product and enabling the radical propagation by releasing another Bu3Sn radical. A similar reaction sequence, replacing organostannates with organoplumbates, was also reported in 1992 by Toru and co-workers, starting from a,b-unsaturated ketones and derivatives, as electron-poor alkenes (Scheme 5).13 In 1993, Keck and Kordik presented another light activated vicinal dialkylation, with dimethoxy-(phenylthio)-methane instead of organoiodo compounds (Scheme 5).14 In this case, the stannate species used as initiator is different from the allylic stannate used as reagent. 2.2 Photoactivated selenides and sulphides as radical initiators Non-metallic photosensitive compounds have also been used as light activated radical sources. In particular, the S–S and Se–Se bonds can be cleaved by UV light irradiation, forming the corresponding thio- and seleno-radicals that then react with alkenes or alkynes (Scheme 5). The new radical formed then reacts again with a second thio or seleno radical, which ends the radical chain. When both disulfide and diselenide are introduced, the differences in their reactivity leads to the multicomponent formation of functionalized compounds carrying both vicinal C–S and C–Se bonds.15 When in the presence of an alkyne and an alkene (or isocyanate), an extra radical step is added: as before, the radical PhSe adds to the alkyne, generating a new radical. However, this radical adds preferentially to the alkene, before the radical chain is ended by addition of a second diselenide radical.16,17 This radical chain can be even more expanded when the alkene is added in excess or when two different alkenes are introduced, leading to an intramolecular radical cyclization before the chain-ending PhSe second addition occurs.18 Furthermore, organoselenides have also shown to be UV-light sensitive, promoting multi-component olefin difunctionalization (Scheme 6): in 1996, Sonoda and co-workers developed a photoinduced alkylative carbonylation from alkenes, carbon monoxide and organoselenides.19 The mechanistic pathway is similar than the one previously described: UV light irradiation induces the rupture of the C–Se bond, forming a radical which in turn adds to an alkene. The resulting alkyl radical is trapped by CO, forming the carbonyl radical species, and finally the radical chain reaction is closed by addition of the phenylselenenyl radical, formed by the initial photoinduced C–Se bond breaking. 2.3 Photoactivated functionalized arenes as cationic initiators Alkene difunctionalization can also be initiated by the photoactivation of specific alkenes or aromatic compounds. Photochemical NucleophileOlefin Combination, Aromatic Substitution reactions, or photo-NOCAS, have been thoroughly developed throughout the past decades, most notably by Arnold and co-workers, and is still being improved upon today (Scheme 7).20,21 As the name implies, this reaction is initiated by photoactivation of both a 1,4-di or 1,2,4,5-tetra-cyano aromatic 400 | Photochemistry, 2019, 46, 395–431

Scheme 6

Selenides as photoactivated radical precursors.15–19

Scheme 7 General Scheme for a photo-NOCAS reaction.

compound and an alkene, which undergo an electron transfer forming 2 radical species: an aromatic anionic radical and an aliphatic cationic radical. In the presence of a nucleophile (historically methanol, used as co-solvent with acetonitrile), the latter undergoes addition upon the aliphatic electrophilic radical, generating a new radical intermediate that reacts with the aromatic radical through a radical pair combination. Photochemistry, 2019, 46, 395–431 | 401

Scheme 8 An alternative to the photo-NOCAS.

The final product is then obtained by rearomatisation via the elimination of one of the cyano groups. It is important to note that, while not necessary to the reaction process, the addition of a photosensitisor, often phenanthrene or biphenyl, can help accelerate the reaction by reducing electron back transfer from the aromatic ring to the alkene. Advances regarding this particular reaction have enabled to broaden the scope by modifying certain reagents. Concerning nucleophiles, other alcohols, ammonia and (primary) amines, fluoride anions, cyanides, or more recently, malonates, 1,3-diketones and ketoesters, have been used. Variations upon the alkenes have also been tried out, such as allenes or dienes. An alternative to this method was reported by Fagnoni and co-workers: the photoactivation of the aromatic species leads to the cleavage of a leaving group and the formation of an aromatic cation, upon which an enol ether can be added, producing a oxonium intermediate that undergoes addition from a nucleophilic alcohol species (Scheme 8).10 This case appears similar to the photoNOCAS previously described, however the mechanistic pathway is notably different, involving a photogenerated triplet phenyl cation and enabling the use of aromatic species other than di or tetra-cyanophenyls. Indeed, a number of electron-donating functional groups and electron-withdrawing leaving groups were found to be compatible with these reaction conditions. 2.4 Photoactivated alkylhalides as radical initiators In 1997, Sonoda and co-workers developed a new photoinduced radical carboxylation, starting from secondary or tertiary alkyl iodides, alcohols and carbone monoxide gas, in the presence of a base (Scheme 9, left).22 In this new reactive pathway, UV light activates the iodoalkyl, forming the corresponding alkyl radical that then reacts with CO to form the aldehyde radical. This intermediate reacts with the iodoalkyl to produce the corresponding acyl iodide and the radical alkyl, allowing for the propagation of the radical reaction. Esterification of the acyl iodide by the alcohol in the presence of a base affords the final product. The mechanistic pathway 402 | Photochemistry, 2019, 46, 395–431

Scheme 9 Photoinduced radical carboxylation using CO gas.22,23

is made up of equilibriums that are not in favour of the product, therefore the base is crucial in the last step to deprotonate the product and pull the reaction forward. The reaction is even more unfavourable to the formation of primary alkyl radicals and the reaction requires longer reaction times. Many different versions of this reaction have since then been developed, with the most notable modification being the addition of a Pd(0) complex to increase yields and lower reaction times, by facilitating the formation of the radical from the alkyliodide (Scheme 9, right).23–29 In those cases, the mechanism is altered accordingly: while it is generally accepted that the Pd(0) improves the first step through a SET with the alkyliodide, forming the corresponding radical and Pd(I)I, which later complexes to the radical carbonyl and is regenerated as Pd(0) by substitution of the iodide by the alcohol, followed by reductive elimination. Other variations include extending the initial scope to primary alkyliodides (easily accessible in the presence of the Pd catalyst) and aryliodides, as well as replacing the alcohol by an amine to lead to the corresponding amide.23,24,30,31 It is also possible to obtain the corresponding primary alcohol by replacing the nucleophilic species (alcohol or amine) by a reductant. The radical carbonyl will in this case yield the aldehyde and then be reduced to the alcohol.32 Alternatively, adding an alkene to the reaction mix allows for an extra radical step to be included, as in this case the alkyl radical will first add to the alkene (Scheme 10).25,31,33 The new radical intermediate will then add to CO and pursue the previously described mechanism. Among the most recent developments, the group of Ryu has replaced the alcohol by a boronic ester,27 alkene,28 or alkyne,34 yielding the corresponding ketones through photoactivated Suzuki, Heck or Sonogashira type cross-couplings as completary alternatives to their thermal counterparts that favour aryl-halides or allylhalides (Scheme 10). It is important to note the main limitation to this type of synthetic method is not so much its scope but rather its technical requirements: indeed, this method uses both photochemistry and high pressure, meaning the reactor must have an autoclave with a quartz window allowing the light to shine through while maintaining Photochemistry, 2019, 46, 395–431 | 403

works of Gosh, Singh and co-workers recently developed an alternative to the synthesis of new polycyclic chromene derivatives, in which the chromene core is itself generated in situ (Scheme 12).39 The sequence starts with a similar condensation/cyclization as seen reported by Ghosh, but using hydrazines rather than hydroxylamines. The Knoevenagel condensation/cyclization sequence from malononitrile and 2-hydroxybenzaldehyde provides the iminochromene core. Once both heterocycles are formed in situ, they can undergo light-activated radical addition, leading to the final product. Other groups have elaborated multi-component convergent sequences in which light is used only to activate and form a single one of the two products generated in situ, which then react together to give the desired final product. This is the case for the work performed by Sun and coworkers: 1,2-dihydrofurane (or variations thereupon) is generated from THF by light activated radical transformation (Scheme 13).40 Once generated, the dihydrofurane undergoes a nucleophilic addition on an in situ formed iminium species from the aldehyde. A second intramolecular addition between the thiourea and the previously generated oxonium form the end heterocyclic product. Another such example was reported by Pusch and Opatz: again, only one branch of the convergent

Scheme 13 Single photoactivated step in convergent MCRs.40,41 406 | Photochemistry, 2019, 46, 395–431

multi-component reaction is light activated, while the other is simply the condensation of the cyanoamine onto the aldehyde (Scheme 13).41 The light induced branch of the sequence is a photoisomerisation of the initial isoxazol into azirine. In the presence of a base, the cyanoimine formed in situ is deprotonated and adds to the azirine. This step is followed by an addition of the azirine anion onto the imine, elimination of the cyano group, deprotonation and opening of the azirine ring. Recently, a new photoinduced 3-component reaction was developed by Basso and co-workers, starting from a diazoketone, a carboxylic acid and an isocyanide in batch or flow conditions (Scheme 14).42–44 The UV light irradiation activates the diazoketone that undergoes a Wolff rearrangement into a reactive ketene. This ketene reacts with the carboxylic acid and isocyanide through a passerini type reaction to provide acyloxyacrylamides, a useful synthon in organic synthesis. In 2017 the Xiao group has reported a photoinduced reaction starting from 1-aminostyrene, a radical source and a sulphur ylide (Scheme 15).45 The reaction goes through a radical addition on the aminostyrene’s double bond, forming a stabilized radical that is oxidized to the cationic species, then deprotonated to form the azaquinone methides. These intermediates are further submitted to a [4 þ 1] cycloaddition with the sulphur ylides, followed by rearomatizaion, yielding the final indol derivatives. When the radical precursor is an iodoalkyl, a photoredox catalyst is required for the reaction to take place, and will therefore be addressed in the second part of this chapter. However, when the radical precursor is the Umemoto reagent, leading to a CF3 radical, the photoredox cycle is not necessary. Instead, the radical initiation is produced by the formation of a colored Electron–Donor–Acceptor (EDA) complex between the aminostyrene and the Umemoto reagent. Moreover, the oxidation to the cationic species is not undertaken by the photocatalyst but by a second Umemoto reagent molecule, affording not only the cation intermediate but also another CF3 radical, allowing for radical chain propagation of the reaction. It is relevant to note that strictly speaking this is a 2 step one pot reaction in which light activation is only used in the first step. If the photoactivation step were considered on its own, it would not be a MCR, however as it is part of a one-pot reaction sequence, it can be included as relevant to this chapter.

Scheme 14 Photoactivation of diazoketones into reactive ketenes. Photochemistry, 2019, 46, 395–431 | 407

Scheme 15 Photochemical indole synthesis.

3

Photocatalysis

While direct photoactivation of starting material remains the most economic photoreactive pathway, both financially and environmentally, it relies on the innate ability of certain specific compounds to absorb light. Unfortunately, they are the exceptions, not the norm, as photosensitive compounds remain scarce, particularly when switching from UV to visible light. To broaden the scope of available reaction and starting materials, it is necessary to introduce an intermediate. This energy relay or promoter will absorb light and go into an activated state. From there it can return to its ground state by transmitting either electrons (photoredox catalyst) or energy (photosensitizer) to the reagents, starting off a reaction that would not have been possible by direct light activation. 3.1 Photoredox catalysis Photoredox catalysis is a fairly new concept that has known an explosive popularity since its discovery a decade ago.5,6 This concept has grown exponentially during the last decade and is still developing, producing new families of products through novel reactive pathways.46,47 While many different reactions and reactivities have been either discovered or improved upon through this concept, one key reaction stands out as the main MCR developed with this method: olefin difunctionalization.48 It can be divided into the two main reaction subgroups described in the introduction: radical–radical reactions (two radical species will be added onto the alkene) or radical–polar cross over reactions (a radical species and a nuclephile/electrophile will be added onto the alkene). One crucial aspect of photocatalysis is ensuring the quenching of the catalyst and its return to the ground state to ensure turnover. This can be achieved either from the reaction intermediates or from compatible additional sacrificial reagents (such as amines, thiols and O2). 3.1.1 Olefin difunctionalization 3.1.1.1 Radical–radical olefin difunctionalization. Most radical–radical photoredox olefin difunctionalisation reported in the literature are 408 | Photochemistry, 2019, 46, 395–431

actually hydroalkylations: after the first alkyl radical species adds to the alkene, a hydrogen atom transfer (HAT) occurs between a H donor and the newly generated radical intermediate. This means the third reagent of these multi-component reactions is simply a hydrogen source, placing it at the limit of what can be conceived as an MCR, as the definition states that all or most of the atoms of the reagents should be included in the final product for them to be part of the component count. Nevertheless, while debatable, these reactions are recognised as MCR and have their place in this chapter. Among these photoredox hydroalkylations of alkenes, most of those are used to add tri- or di-fluorinated methyl groups, from various CF3 or CF2 radical precursors. For instance, the group of Nicewicz developed in 2013 a photoredox hydrotrifluoromethylation of alkenes using sodium trifluoromethanesulfinate (Langlois’ reagent) as the radical precursor and TFE as the hydrogen atom source (Scheme 16).49 While both TFE and thiol are required for the reaction to give good yields, they do concede other mechanistic pathways, such as the direct HAT between the intermediate radical and the thiol, bypassing the TFE, cannot be dismissed. A similar reaction was reported by Rueping and co-workers in 2016, in which they either used a diarylketone (under UV light) or an iridium complex (under visible light) as photocatalyst (Scheme 17).50 Furthermore they adapted their method to flow chemistry to obtain similar or better yields in a fraction of the time (30 min instead of 6 h). Other like-minded reactions include the separate works of the groups of Qing51 and of Gouverneur,52 who respectively used CF2Br2 or the Umemoto reagent as fluorinated radical precursors, THF or methanol as H donors respectively, and an eosin Y or a ruthenium complex as photocatalyst (Scheme 17). It is

Scheme 16 Hydrotrifluoromethylation of alkenes through radical addition/HAT Photochemistry, 2019, 46, 395–431 | 409

Scheme 17 Tri/difluoromethylation & HAT reaction sequences.50–53

noteworthy to mention that the work of Gouverneur and co-workers was expanded to alkynes as well. Using relatively similar conditions , Qing’s group went on to use another difluoroalkyl radical in 2015 to access RCF2H moieties (Scheme 17).53 In all these cases, the species providing the hydrogen atom (HFIP, MeOH or THF) is consequently turned into a radical species that undergoes oxidation with the photoredox catalyst, enabling it to return to its ground state and close the photocatalytic cycle. Non-fluorinated radicals have also been used in photoredox hydro´ used glycosyl halides as radical alkylation of alkenes: the group of Gagne precursors to add onto alkenes, with Hantsch esters as a H source (Scheme 18).54 The additional amine is used as a sacrificial reductant to return the photocatalyst to its ground state and close the photocatalytic cycle. This method inspired the Overman group, who used similar conditions in a late stage step of the total synthesis towards ()-Aplyviolene.55 In this case, the radical precursor is no longer a simple alkylhalide but a (N-acyloxy)phthalimide that undergoes decarboxylative reduction to provide the corresponding alkyl radical. Another family of photocatalyst was developed by the Ryu group: tetrabutylammonium decatungstate TBADT (Scheme 19).56 Mechanistic studies have shown that TBADT is both the photocatalyst, initiating the formation of the alkyl radical, as well as an H radical trap and donor later in the reaction pathway, therefore eliminating the need for an extra H source and ensuring catalyst regeneration. In that case, the hydroalkyaltion is no longer a MCR (the first radical and the final HAT come 410 | Photochemistry, 2019, 46, 395–431

Scheme 18 Radical addition/HAT reactions and application in total synthesis.54,55

Scheme 19 Radical–radical olefin difunctionalization towards ketone synthesis.

from the same starting material). However, in the presence of a CO atmosphere, the alkyl radical first adds to the CO, before the new radical intermediate adds to the alkene, forming the corresponding ketones as 3-component photoredox reactions. The same group used this synthetic method on electron-deficient azo compounds instead of alkenes, yielding the corresponding hydrazides (Scheme 19).57 While obviously not an olefin difunctionalisation, the paralleles between the two reactions called for it to be mentioned here. Photochemistry, 2019, 46, 395–431 | 411

A few other photoredox MCR radical–radical reactions have been reported that do not go through a HAT as a final mechanistic step. Indeed, following the previous works in the field and adding further diversity to the potentially accessible products, the group of Xiao developed an azotrifluoromethylation of alkenes from Langlois’ reagent by replacing the HAT step by the radical addition of a diazonium salt (Scheme 20).58 While most photoredox reactions take a substantial number of hours to reach completion, this particular reaction only takes 40 min. In 2015, Guo and co-workers reported the use of F3CCH2I as a radical precursor, forming the F3CCH2 radical, that adds to the alkene (Scheme 21).59 From there, the reaction depends on the presence or absence of dioxygene: if no oxygene is present (N2 atm), then the intermediate radical will dimerize, forming the final product through an ABB MCR type reaction. However, if dioxygene (and water) is present, then the corresponding alcohol is formed. Mechanistic studies using 18O in both the water and oxygene show that the alcohol actually comes from the oxygene, not the water. This weighs in favour of a purely radical pathway, rather than an oxidation/nucleophilic addition final step. In both cases, Hunig’s base is used as sacrificial reductant to ensure catalyst regeneration. The same year, another group also described a similar radical–radical photoredox MCR with O2 as a reagent (Scheme 22).60 Diazonium salts is also used here, but as a radical precursor towards aryl radicals, not towards azo compounds as seen reported by Xiao et al.,58 obtaining the corresponding ketones rather than the alcohols as previously described by Guo et al.59 The photoactivated catalyst is oxidized in the presence of diazonium salt, generating the aryl radical which adds to the styrene

Scheme 20 Azotrifluoromethylation of alkenes from diazonium salts.58

Scheme 21 Hydroxyalkylation of alkenes with O2 412 | Photochemistry, 2019, 46, 395–431

Scheme 22 Carbonylalkylation of alkenes with O2.

Scheme 23 Xanthates in photoredox radical–radical alkene difuntionalization.

derivative. The newly formed benzyl radical reacts with dioxygene to give a peroxy radical that turns into an alkoxy radical. A final SET yields the desired product and closes the photocatalytic cycle. In this case, the reaction shuts down completely if the styrene derivative carries an EDG on the aryl moiety, which the authors attribute to the increased ease of radical quenching of the benzyl radical intermediate in the presence of dioxygen via hydrogen abstraction. Another like-minded work produced the corresponding hydroperoxyls from similar reagents, rather than the alcohol or ketone, in the presence of a photosensitisor, which will be discussed later on (see Section 3.2). O2 was also used by Yadav and Yadav for the formation of 1,3-oxathiolane-2-thiones (Scheme 23).61 In this work, xanthates are formed in situ from methanol and CS2, before being converted to their radical equivalents by eosin Y as photocatalyst. This radical adds to the styrenes and, while the rest of the mechanism is not precisely described in this work, we can follow the assumption that the new radical in turn reacts with oxygene to give the peroxide, which is reduced (possibly by the photoredox catalytic cycle) to the alcohol. The reaction ends with the addition of the alcohol on the xanthate and elimination of the methanol, affording the heterocyclic final product. Photochemistry, 2019, 46, 395–431 | 413

Scheme 24 Double carbon–carbon bond formation through photoredox radical– radical olefin difunctionalization.

Finally, a 3-component photoredox radical reaction was reported in 2017 starting from a carboxylic acid, an electron deficient alkene and a TMS protected enol (Scheme 24).62 In the presence of Dimethyl dicarbonate DMDC, the carboxylic acid is transformed into the anhydride, which is reduced by the photocatalyst to the acyl radical. The acyl radical then adds onto the alkene, forming a new radical intermediate which in turn adds to the protected enol. This final radical undergoes oxidation/ deprotection to afford the final product. While involving a cationic intermediate, the ligation of the 3 reagents together goes through a radical– radical pathway warranting its place among the radical–radical MCRs. 3.1.1.2 Olefin defunctionalisation, radical–polar crossover. Compared to the radical–radical photoredox MCRs, this synthetic pathway is much more common regarding olefin difunctionalization and have become the most reported photoredox MCR. They can be divided by sub-type, mostly depending on the nucleophilic species used: oxyalkylation (or -arylation), aminoalkylation, haloalkylation, double alkylation, oxyamination, and so on. Among these sub-types, the most common is oxyalkylation/oxyarylation, in which the intermediate cation is trapped by water or an alcohol used as co-solvent. In that aspect, Akita and co-workers developed in 2012 a photoredox oxytrifluoromehtylation of alkenes using Umemoto reagent as CF3 radical precursor and water/alcohols as nucleophiles (Scheme 25).63 The mechanism starts with the Umemoto reagent being reduced by an oxidative quenching of the activated photocatalyst. The CF3 radical then adds to the alkene. The corresponding new radical is oxidated to the cation by the oxidated form of the photocatalyst. This brings the photocatalyst back to its former ground state and closes the photocatalytic cycle. As for the cation, it undergoes nucleophilic addition by either water or various alcohols, forming the final product. While radical precursors and nucleophiles will vary significantly in the examples to come, this mechanistic pathway can be generalized to all or most of the radical–cation 414 | Photochemistry, 2019, 46, 395–431

Scheme 25 Photoredox hydroxytrifluoromethylation of alkenes.63

polar crossovers of alkene difunctionalization reactions mentioned in this part. Furthermore, one might have noticed the similarities between Akita’s reaction conditions and those reported a year later by Gouverneur52 (Scheme 17) but the first case reaction goes through a radical–cation polar crossover, while the second reaction involves a radical–radical difunctionalization. This is a testimony of the delicate balance between the two possible pathways, which may come into competition: whether the reaction pathway preferentially goes one way (formation of the cation and nucleophilic addition of the methanol) or another (HAT between the radical and the methanol) depends mostly on the photoredox potential of the catalyst and the stability of the intermediate radical. Both these key elements should be carefully looked into when developing a new methodology of that type. Akita’s group was also performed the same reaction but with Togni’s reagent and in DMSO, rather than the aprotic solvent/water (or alcohol) mix (Scheme 26).64 In that case, they could access a-trifluoromethylketones instead of the corresponding alcohols, without the use of a further oxidant. Indeed, the DMSO adds to the intermediate cation, just as the alcohol does, and then goes through a Kornblum type oxidation via a second photocatalytic cycle, yielding the ketone. Other groups have since then reported similar MCR photoredox oxyalkylation reactions (Scheme 26), through the diversification of the radical precursor, such as alkylbromides65 and N-(acyloxy)phthalimides66 (generating alkyl radicals), or difluoromethylsulfoximines (generating a difluoromethyl radical).67 The group of Zhou even used cyclobutanone oximes as radical precursors, that undergo radical photoredox N–O and C–C bond cleavage to yield the linear radical.68 Recently a collaboration Photochemistry, 2019, 46, 395–431 | 415

Scheme 26 Photoredox oxyalkylation of alkenes.64–69

between the Masson and Magnier groups has developed a new type of radical precursor : Fluorinated Sulfilimino Iminiums,69 which have been used as a source of diverse fluorinated radicals such as CF3, CF2Br, CFCl2 or C4F9. The reaction has also shown good results beyond the use of aryl bearing alkenes. Alternatively, the team of Masson directed the general method in another direction with the use of enecarbarmates rather than alkenes, with either organohalides70 or the Togni reagent as radical precursors (Scheme 27).71 The Masson group also used this type of reactivity to form functionalized Phtalans from 2-Vinylbenzaldehyde, through a slightly modified mechanistic pathway (Scheme 28).72 In this particular case, the nucleophilic species (TMSCN or TMSN3) does not close the reaction pathway, but starts it, by adding onto the aldehyde moiety, forming the azido- or cyano-alcoholate. This in situ generated species still possesses an alkene, which reacts with the CF3 radical formed during the photocatalyst’s oxidative quenching by Umemoto’s reagent. As usual for this type of 416 | Photochemistry, 2019, 46, 395–431

Scheme 27 Photoredox oxyalkylation of enecarbamates.70,71

Scheme 28 Photoredox synthesis of phthalans and isoindolines.

Scheme 29 Photoredox oxyarylation of alkenes.73,74

reaction, the new radical is oxidated to the cation (closing the photocatalytic cycle) and is trapped by a (this time intramolecular) nucleophilic addition of the alcoholate, forming the corresponding cyano- or azidophthalans. This reaction has also been extended to the formation of isoindolines by replacing the vinylbenzaldehydes by their imine equivalents through an aminotrifluoromethylation reaction. Oxyarylations have also been developed (Scheme 29), following similar reaction conditions and mechanistic pathways, using various aryl radical precursors, such as hypervalent iodine73 or diazonium salts.74 When using the latter, a mix of water and DMF as solvent afforded Photochemistry, 2019, 46, 395–431 | 417

the O-addition of DMF (rather than an alcohol) onto the in situ generated cation, leading to formyloxyarylations through a photo Meerwein addition. In the work of Greaney and colleagues, the addition of Zn(OAc)2 was shown to improve yields when methanol was used as nucleophilic species, but was not essential to the reaction. In the very last days of 2017, the group of Yu published the oxydifluoroalkylation of allylamines with a RCF2 radical precursor and CO2 gas (Scheme 30). In the presence of DABCO, the amine reacts with CO2 to form the carbamates.75 The alkene chain carried by the newly formed carbamate undergoes the usual photoredox radical addition and oxidation to the cation. An intramolecular nucleophilic addition between the cation and the carbamate forms the final product. In this case however, the first SET of the reaction is not the first SET of the photocatalytic cycle, therefore DABCO is required to initiate the reductive quenching that will later be performed by the intermediate radical species. It is essential we address here a main limitation of the radical–polar crossover method: as an observant reader may have already realized, most of these reactions are limited to the use of styrene derivatives, which help stabilize the radical intermediate long enough for the oxidation into a cation to occur without radical side-reactions. Very few examples are shown using alkenes that do not possess at least one aromatic substituent. An alternative previously described here is the use of enamines/enamides by the Masson group. Another approach diverging from styrene was reported by Glorius and co-workers in 2014 (Scheme 31).76 In their work, both reagents and final products are similar to those seen in the previously described photoredox oxyarylation, however the mechanistic pathway is very different : rather than a purely photoredox catalytic cycle, they employ a dual gold/photoredox catalytic cycle. In this case, the cationic gold species coordinates to the alkene, allowing for the nucleophilic addition of the alcohol. The gold I complex then undergoes two single electron transfers (SET) with the photoredox

Scheme 30 CO2 in photoredox alkene difunctionalization. 418 | Photochemistry, 2019, 46, 395–431

Scheme 31 Merging gold and photoredox catalysis.76

catalytic cycle, affording the gold(III) complex. Au(III) being an unstable species, it undergoes a reductive elimination, regenerating the Au(I) species and affording the desired product. This method allows for a wide range of non aromatic alkenes to be used and represents a complementary method to the one described above. As with the example seen above (Scheme 28),72 most groups have developed the amino counterparts of the oxy-alkylations and -arylations described above (Scheme 25–30), by replacing the nucleophile from water or alcohol to an amine. The mechanism follows the same pathway as the previous reactions. In this way, the year after publishing their oxytrifluoromethylation, Akita and co-workers reported the corresponding aminotrifluoromethylation, with very similar reaction conditions, save for the solvent (Scheme 32).77 Here the solvent is no longer a DCM/ alcohol mix but a RCN/water mix, forming the a-CF3-amides through a Ritter-type amination. Similar reactions were developed, by switching to a nitrogen-containing nucleophile, by the groups of Masson,71,78 Greany73 ¨nig.79 and Ko Besides from these two main subgroups, various other radical–polar crossover photoredox MCRs involving olefin difunctionalization have been reported. The Masson group has developed numerous alkene or enamides trifluoromethylations in the presence of nucleophiles other than alcohols and amines, such as cyanide71 and halide salts80 or electron-rich (hetero)aromatic compounds (Scheme 33).81 In 2017, Magnier and co-workers extended this synthetic pathway to sulfoarylations through the use of Ntrifluoromethylthiosaccharin as an SCF3 radical precursor, with electronrich aromatic species as nucleophiles once more (Scheme 33).82 Lastly, a few photoredox MCR olefin difunctionalization have also allowed for the formation of two carbon–heteroatom bonds to be formed. While a first example was vaguely reported by Griesbeck and co-workers in 2010,83 double-heteroatomic olefin functionalization is still very rare, with only two recent examples to date (Scheme 34). The Greaney group used a Togni-like radical precursor, upon which the CF3 has been exchanged for an azide, to achieve a photoredox oxyazidation with an unusual copper based photoredox catalyst, rather than the classic Photochemistry, 2019, 46, 395–431 | 419

Scheme 32 Photoredox amino-alkylation and -arylation.71,77–79

iridium or ruthenium ones.84 Following the usual synthetic pathway, this has allowed for the formation of a C–N bond (by radical addition of the N3 on the alkene) and a C–O bond (by the nucleophilic addition of an alcohol on the cation formed by oxidation of the intermediate radical). The same year, Akita and co-workers reported an aminohydroxylation by using aminopyridinium salts as precursors for an electrophilic amine radical and water as the nucleophile.85 While this method works for nonaromatic bearing alkenes, the styrene derivatives still give far better yields. All these alkene difunctionalizations described above go through an oxidative quenching of the photoexcited catalyst, with the photocatalytic cycle being closed by the reduction of the PC1 species through oxidation of the intermediate radical into a cation. The reductive quenching mechanism is far less common and, to the best of our knowledge, has only one example as an MCR: a hydroalkoxy-methylation developed by the group of Akita in 2013.86 Here the radical initiator is an alkoxymethyl 420 | Photochemistry, 2019, 46, 395–431

Scheme 33 Radical–polar crossover photoredox alkene difunctionalization other than amino- or oxy-alkylation or -arylation.71,80–82

Scheme 34 Photoredox double carbon–heteroatom vicinal bond formation.84,85

trifluoroborate, which is oxidated by reductive quenching of the photocatalyst. The alkoxymethyl radical then adds onto the alkene, forming a new radical that is reduced to the anion, closing the photocatalytic cycle. This anionic species is then hydrated, yielding the final product (Scheme 35). 3.1.2 Other photoredox reactions. Reactions involving a photoredox process between 2 reagents to create a new species that further reacts with a third reagent have been developed beyond olefin difunctionalization in numerous different directions. Such reactions include the formation of a-amino amides from tertiary amines and isocyanides, developed in batch or flow, with various organo, metallic or organometallic photocatalysts (Scheme 36),87–89 as well as the double substitution Photochemistry, 2019, 46, 395–431 | 421

Scheme 35 Hydroalkylation through a photoredox reductive quenching pathway.

Scheme 36 Photoredox synthesis of a-amino amides.

of fluorobromoesters towards symmetrical or unsymmetrical diarylated esters,90 through a multiphotocatalytic reactive pathway (Scheme 37). It is important to note that the authors of the latter do concede that, while the first steps are definitely the radical cleavage of the C–Br bond and subsequent radical addition onto the aromatic species, the rest of the reactive sequence is up for debate. Besides from those reactions, photoredox MCR reactions leading to hetero- and/or poly-cycles have received a substantial amount of attention. Starting from 2-aminostyrene, the group of Xiao developed a new photoredox access to functionalized indoles (Scheme 38), with a synthetic pathway that starts off very similar to the radical–polar crossover seen previously (Scheme 15).45 However, when the intermediate cation is formed, after the radical addition, the typical nucleophilic addition does 422 | Photochemistry, 2019, 46, 395–431

Photochemistry, 2019, 46, 395–431 | 423

Scheme 37 Photoredox synthesis of symmetrical or unsymmetrical diarylated esters.

Scheme 38

Photoredox synthesis of indoles.

not occur. Instead, the amine is deprotonated, leading to a conjugated imine. This imine is then used in a [4 þ 1] cycloaddition that affords the desired compound. This particular reaction was already described in a previous chapter when the Umemoto is used as radical precursor, as in that case there is no need for a photocatalyst and therefore the reaction is considered simply photochemical. The same group also developed the photoredox generation of aryl esters from diazonium salts, methanol and CO gas (Scheme 39).91 This alkoxycarbonylation has a mechanism similar to the photochemical reactions involving CO, previously described (Schemes 9–10), however the original radical is here generated by oxidative quenching of excited fluorescein. This aryl radical adds to CO, forming the carbonyl radical which is oxidized, returning fluorescein to its ground state in the process, following the classic mechanistic pathway seen in radical–polar cross overs. The final step is the nucleophilic addition of methanol upon this intermediate, to yield the desired product. Using specifically functionalized diazonium salts leads to the formation of a benzofuran core. Alternatively, Jacobi von Wangelin and co-workers developed a photocatalyzed chlorosulfonylation, based around a SO insertion, rather than a CO insertion, onto diazonium salts (Scheme 39). These salts can potentially be generated in situ from the corresponding amines and can lead to an efficient one-pot photo-MCR synthesis of Saccharin.92 Several other MCR photoredox reactions were used to achieve various ¨nig and coheterocyclic and/or polycyclic compounds.46 In 2016, Ko workers developed an ABB MCR photocatalytic reaction to access pyridine scaffolds (Scheme 40).93 The reactive imine is formed by oxidation of benzylamine (by reductive quenching of the excited eosin), followed by nucleophilic addition of a second equivalent of benzylamine and elimination of ammonia. The Imine undergoes a double nucleophilic addition of enol, assited by a second photoredox catalytic cycle, and the ammonia closes the ring by double condensation upon the ketone moieties. Elimination of a benzylamine molecule allows for aromatisation of 424 | Photochemistry, 2019, 46, 395–431

Scheme 39 Photoredox carboxylation.91,92

Scheme 40 Photoredox synthesis of pyridines.

the heterocycle to pyridine. Here Oxygen is essential in the process as it enables catalytic turnover by bringing the PC back to its ground state. A double photoredox catalytic cycle with eosin was also used by Singh and co-workers to generate organoazides in situ for a click chemistry [3 þ 2] cycloaddition.94 Photochemistry, 2019, 46, 395–431 | 425

426 | Photochemistry, 2019, 46, 395–431 Scheme 41 Final step photoredox reaction amidst a cascade MCR.95,96

In these previous cases, the photoredox cycle was an integral part of the heterocyclic synthesis. However, there exist some examples in which the photoredox step is only used at the end of a cascade reaction sequence (Scheme 41). In the work of Ananthakrishnan and Gazi, the photoredox step is simply used after a Hantzsch reaction to aromatize the product to the corresponding pyridine.95 In the MCR reported by Lin and Yang, most of the reaction is acid catalyzed, with only the last intramolecular cyclization/aromatisation step being photocatalyzed.96 3.2 Use of a photosensitizer In this last part, we shall address MCR catalysed by an energy transfer, rather than an electron transfer, through the use of a photosensitizer. Compared to photoactivated or photoredox catalyzed reactions, examples of such reactions are rare, and MCR versions are even less developped. In these cases, the photosensitizer is excited by light (visible or UV) and the excited state photosensitizer then undergoes intersystem crossing to reach a triplet state. It is this state that allows for the transfer of energy towards another compound. In the cases we present, the energy-receiving compound is oxygen, with reaches a singlet state upon which it becomes very reactive (Scheme 42). While it does appear very similar to oxygene  being reduced to O2 - via a SET mechanism in a photoredox catalytic cycle, it should be considered as separate reactivity in which the oxygene is only activated to an excited state (with no electron transfer happening) before reacting with the other reagents. In 2009, Che and co-workers developed a one-pot MCR combining the photooxidation of secondary amines to the corresponding imines by photogenerated singlet oxgen, with an Ugi-type reaction (Scheme 43).97 A similar photoinduced MCR was developed by Azarifar and co-workers in 2017 in which an alcohol, rather than an amine, was oxidized to the corresponding aldehyde by singlet oxygene, itself produced by a lightactivated MOF species (Scheme 43).98 The aldehydes were then submitted to a Passerini type reaction. Building on previously described radical– radical oxyarylations, the group of Leow developed a similar reaction to the separate works of Guo59 and Cai60 (Schemes 21 and 22), but starting from a hydrazine in the presence of Remazol Brilliant Blue R (RBBR) as photosensitizer (Scheme 43). Unlike the works of Cai and Guo, this reaction leads to the hydroperoxyl, not the corresponding alcohol or ketone. Finally in 2015, the group of Greck reported the use of BODIPY as

Scheme 42 General Scheme for the photooxygenation reaction. Photochemistry, 2019, 46, 395–431 | 427

Scheme 43 Use of a photosensitizer to form reactive singlet oxygen.97–100

photosensitizers in a MCR reaction (Scheme 43):99 under light irradiation, the BODIPY would produce singlet oxygene which would react with naphthol, generating naphthoquinones by photooxygenation. The in situ generated naphthoquinones would then undergo an asymmetric aminocatalysed reaction sequence, leading to polycyclic 3D chiral architectures from a multi-catalytic MCR. In these last 2 cases, it is interesting to note that oxygen is part of the compound count for the MCR as it is integrated into the final product.

4 Conclusions Photoinduced multi-component reactions have shown a broad scope of reactivity. Whether via direct reagent photoactivation or photocatalysis, they have known a recent surge in popularity which should continue as both the fields of MCRs and photochemistry continue to be developed -separately or concomitantly-, helping the field of organic synthesis to build ever more cost-efficient and environmentally benign means to reach ever more complex architectures. 428 | Photochemistry, 2019, 46, 395–431

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

B. Jiang, T. Rajale, W. Wever, S.-J. Tu and G. Li, Chem. – An Asian J., 2010, 5, 2318. ¨mling, W. Wang and K. Wang, Chem. Rev., 2012, 112, 3083. A. Do M. S. Singh and S. Chowdhury, RSC Adv., 2012, 2, 4547. M. N. Hopkinson, B. Sahoo, J.-L. Li and F. Glorius, Chem. – A Eur. J., 2014, 20, 3874. C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013, 113, 5322. N. A. Romero and D. A. Nicewicz, Chem. Rev., 2016, 116, 10075. J. M. R. Narayanam and C. R. J. Stephenson, Chem. Soc. Rev., 2011, 40, 102. J. Xuan and W. J. Xiao, Angew. Chem., Int. Ed., 2012, 51, 6828. S. Garbarino, D. Ravelli, S. Protti and A. Basso, Angew. Chem., Int. Ed., 2016, 55, 15476. S. Lazzaroni, S. Protti, M. Fagnoni and A. Albini, Org. Lett., 2009, 11, 349. H. D. Roth, Angew. Chem., Int. Ed., 1989, 28, 1193. K. Mizuno, M. Ikeda, S. Toda and Y. Otsuji, J. Am. Chem. Soc., 1988, 4, 1288. T. Toru, Y. Watanabe, M. Tsusaka, R. K. Gautam, K. Tazawa, M. Bakouetila, T. Yoneda and Y. Ueno, Tetrahedron Lett., 1992, 33, 4037. G. E. Keck and C. P. A. Kordik, Tetrahedron Lett., 1993, 34, 6875. A. Ogawa, R. Obayashi, H. Ine, Y. Tsuboi, N. Sonoda and T. Hirao, J. Org. Chem., 1998, 63, 881. A. Ogawa, M. Doi, I. Ogawa and T. Hirao, Angew. Chem., Int. Ed., 1999, 38, 2027. K. Tsuchii, M. Doi, I. Ogawa, Y. Einaga and A. Ogawa, Bull. Chem. Soc. Jpn., 2005, 78, 1534. K. Tsuchii, M. Doi, T. Hirao and A. Ogawa, Angew. Chem., Int. Ed., 2003, 42, 3490. I. Ryu, H. Muraoka, N. Kambe, M. Komatsu and N. Sonoda, J. Org. Chem., 1996, 61, 6396. D. Mangion, D. R. Arnold, T. S. Cameron and K. N. Robertson, J. Chem. Soc., Perkin Trans. 2, 2001, 1, 48. D. Mangion and D. R. Arnold, Acc. Chem. Res., 2002, 35, 297. K. Nagahara, I. Ryu, M. Komatsu and N. Sonoda, J. Am. Chem. Soc., 1997, 119, 5465. T. Fukuyama, S. Nishitani, T. Inouye, K. Morimoto and I. Ryu, Org. Lett., 2006, 8, 1383. T. Fukuyama, Y. Inouye and I. Ryu, J. Organomet. Chem., 2007, 692, 685. A. Fusano, S. Sumino, T. Fukuyama and I. Ryu, Org. Lett., 2011, 13, 2114. A. Fusano, S. Sumino, S. Nishitani, T. Inouye, K. Morimoto, T. Fukuyama and I. Ryu, Chem. – A Eur. J., 2012, 18, 9415. S. Sumino, T. Ui and I. Ryu, Org. Lett., 2013, 15, 3142. S. Sumino, T. Ui, Y. Hamada, T. Fukuyama and I. Ryu, Org. Lett., 2015, 17, 4952. S. Sumino, T. Ui and I. Ryu, Org. Chem. Front., 2015, 2, 1085. T. Kawamoto, A. Sato and I. Ryu, Chem. – Eur. J., 2015, 21, 14764. S. Sumino, A. Fusano, T. Fukuyama and I. Ryu, Synlett, 2012, 23, 1331. S. Kobayashi, T. Kawamoto, S. Uehara, T. Fukuyama and I. Ryu, Org. Lett., 2010, 12, 1548. I. Ryu, S. Kreimerman, F. Araki, S. Nishitani, Y. Oderaotoshi, S. Minakata and M. Komatsu, J. Am. Chem. Soc., 2002, 124, 3812. A. Fusano, T. Fukuyama, S. Nishitani, T. Inouye and I. Ryu, Org. Lett., 2010, 12, 2410.

Photochemistry, 2019, 46, 395–431 | 429

35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68

P. P. Ghosh, S. Paul and A. R. Das, Tetrahedron Lett., 2013, 54, 138. S. Ghosh, F. Saikh, J. Das and A. K. Pramanik, Tetrahedron Lett., 2013, 54, 58. F. Saikh, J. Das and S. Ghosh, Tetrahedron Lett., 2013, 54, 4679. J. Tiwari, M. Saquib, S. Singh, F. Tufail, M. Singh and J. Singh, Green Chem., 2016, 18, 3221. D. Jaiswal, A. Mishra, P. Rai, M. Srivastava, B. P. Tripathi, S. Yadav, J. Singh and J. Singh, Res. Chem. Intermed., 2018, 44, 231. H. Guo, C. Zhu, J. Li, G. Xu and J. Sun, Adv. Synth. Catal., 2014, 356, 2801. S. Pusch and T. A. Opatz, Org. Lett., 2014, 16, 5430. A. Basso, L. Banfi, S. Garbarino and R. Riva, Angew. Chem., Int. Ed., 2013, 52, 2096. S. Garbarino, L. Banfi, R. Riva and A. Basso, J. Org. Chem., 2014, 79, 3615. S. Garbarino, S. Protti and A. Basso, Synthesis, 2015, 47, 2385. Y. Y. Liu, X. Y. Yu, J. R. Chen, M. M. Qiao, X. Qi, D. Q. Shi and W. J. Xiao, Angew. Chem., Int. Ed., 2017, 56, 9527. O. Boubertakh and J. P. Goddard, Eur. J. Org. Chem., 2017, 2017, 2072. ¨nig, Acc. Chem. Res., 2016, I. Ghosh, L. Marzo, A. Das, R. Shaikh and B. Ko 49, 1566. T. Koike and M. A. Akita, Org. Chem. Front., 2016, 3, 1345. D. J. Wilger, N. J. Gesmundo and D. A. Nicewicz, Chem. Sci., 2013, 4, 3160. Q. Lefebvre, N. Hoffmann and M. Rueping, Chem. Commun., 2016, 52, 2493. Q.-Y. Lin, X.-H. Xu and F.-L. Qing, Org. Biomol. Chem., 2015, 13, 8740. S. Mizuta, S. Verhoog, K. M. Engle, T. Khotavivattana, M. O. Duill, K. Wheelhouse, G. Rassias and M. Me, J. Am. Chem. Soc., 2013, 135, 2505. Q. Y. Lin, X. H. Xu, K. Zhang and F. L. Qing, Angew. Chem., Int. Ed., 2016, 55, 1479. ´, Angew. Chem., Int. Ed., 2010, R. S. Andrews, J. J. Becker and M. R. Gagne 49, 7274. M. J. Schnermann and L. E. A. Overman, Angew. Chem., Int. Ed., 2012, 51, 9576. I. Ryu, A. Tani, T. Fukuyama, D. Ravelli, M. Fagnoni and A. Albini, Angew. Chem., Int. Ed., 2011, 50, 1869. I. Ryu, A. Tani, T. Fukuyama, D. Ravelli, S. Montanaro and M. Fagnoni, Org. Lett., 013, 15, 2554. X. L. Yu, J. R. Chen, D.-Z. Chen and W.-J. Xiao, Chem. Commun., 2016, 52, 8275. L. Li, M. Huang, C. Liu, J. C. Xiao, Q. Y. Chen, Y. Guo and Z. G. Zhao, Org. Lett., 2015, 17, 4714. M. Bu, T. F. Niu and C. Cai, Catal. Sci. Technol., 2015, 5, 830. A. K. Yadav and L. D. S. Yadav, Green Chem., 2016, 18, 4240. F. Pettersson, G. Bergonzini, C. Cassani and C.-J. Wallentin, Chem. – Eur. J., 2017, 7444. Y. Yasu, T. Koike and M. Akita, Angew. Chem., Int. Ed., 2012, 51, 9567. R. Tomita, Y. Yasu, T. Koike and M. Akita, Angew. Chem., Int. Ed., 2014, 53, 7144. H. Yi, X. Zhang, C. Qin, Z. Liao, J. Liu and A. Lei, Adv. Synth. Catal., 2014, 356, 2873. A. Tlahuext-Aca, R. A. Garza-Sanchez and F. Glorius, Angew. Chem., Int. Ed., 2017, 56, 3708. Y. Arai, R. Tomita, G. Ando, T. Koike and M. Akita, Chem. – Eur. J., 2016, 22, 1262. L. Li, H. Chen, M. Mei and L. Zhou, Chem. Commun., 2017, 53, 11544.

430 | Photochemistry, 2019, 46, 395–431

69

M. Daniel, G. Dagousset, P. Diter, P. A. Klein, B. Tuccio, A. M. Goncalves, G. Masson and E. Magnier, Angew. Chem., Int. Ed., 2017, 56, 3997. 70 T. Courant and G. Masson, Chem. – Eur. J., 2012, 18, 423. 71 A. Carboni, G. Dagousset and E. Magnier, Org. Lett., 2014, 16, 1240. 72 L. Jarrige, A. Carboni, G. Dagousset, G. Levitre, E. Magnier and G. Masson, Org. Lett., 2016, 18, 2906. 73 G. Fumagalli, S. Boyd and M. F. Greaney, Org. Lett., 2013, 15, 4398. ¨nig, ACS Catal., 2015, 5, 2935. 74 C. J. Yao, Q. Sun, N. Rastogi and B. Ko 75 Z.-B. Yin, J.-H. Ye, W.-J. Zhou, Y.-H. Zhang, L. Ding, Y.-Y. Gui, S.-S. Yan, J. Li and D.-G. Yu, Org. Lett., 2018, 20, 190. 76 M. N. Hopkinson, B. Sahoo and F. Glorius, Adv. Synth. Catal., 2014, 356, 2794. 77 Y. Yasu, T. Koike and M. Akita, Org. Lett., 2013, 15, 2136. 78 G. Dagousset, A. Carboni, E. Magnier and G. Masson, Org. Lett., 2014, 16, 4340. ¨nig, Angew. Chem., Int. Ed., 2014, 53, 725. 79 D. Prasad Hari, T. Hering and B. Ko 80 A. Carboni, G. Dagousset, E. Magnier and G. Masson, Synthesis, 2015, 47, 2439. 81 A. Carboni, G. Dagousset, E. Magnier and G. Masson, Chem. Commun., 2014, 50, 14197. 82 G. Dagousset, C. Simon, E. Anselmi, B. Tuccio, T. Billard and E. Magnier, Chem. – Eur. J., 2017, 23, 4282. ¨ler and J. Uhlig, Photochem. Photobiol. Sci., 83 A. G. Griesbeck, M. Reckentha 2010, 9, 775. 84 G. Fumagalli, P. T. G. Rabet, S. Boyd and M. F. Greaney, Angew. Chem., Int. Ed., 2015, 54, 11481. 85 K. Miyazawa, T. Koike and M. Akita, Chem. – Eur. J., 2015, 21, 11677. 86 K. Miyazawa, Y. Yasu, T. Koike and M. Akita, Chem. Commun., 2013, 49, 7249. 87 M. Rueping, C. Vila and T. Bootwicha, ACS Catal., 2013, 3, 1676. 88 C. Vila and M. Rueping, Green Chem., 2013, 15, 2056. 89 M. Rueping and C. Vila, J. ChemInf., 2013, 15, 10. 90 S. D. Jadhav, D. Bakshi and A. Singh, J. Org. Chem., 2015, 80, 10187. 91 W. Guo, L. Q. Lu, Y. Wang, Y. N. Wang, J. R. Chen and W. J. Xiao, Angew. Chem., Int. Ed., 2015, 54, 2265. ´jek, M. Neumeier and A. Jacobi von Wangelin, ChemSusChem, 2017, 92 M. Ma 10, 151. 93 R. S. Rohokale, B. Koenig and D. D. Dhavale, J. Org. Chem., 2016, 81, 7121. 94 A. Mishra, P. Rai, M. Srivastava, B. P. Tripathi, S. Yadav, J. Singh and J. Singh, Catal. Lett., 2017, 147, 2600. 95 R. Ananthakrishnan and S. Gazi, Catal. Sci. Technol., 2012, 2, 1463. 96 W.-C. Lin and D.-Y. Yang, Org. Lett., 2013, 15, 4862. 97 G. Jiang, J. Chen, J. S. Huang and C. M. Che, Org. Lett., 2009, 11, 4568. 98 D. Azarifar, R. Ghorbani-Vaghei, S. Daliran and A. R. A. Oveisi, ChemCatChem, 2017, 9, 1992. 99 L. Pantaine, V. Coeffard, X. Moreau and C. Greck, Eur. J. Org. Chem., 2015, 2015, 2005. 100 D. Leow, Y.-H. Chen, T.-H. Hung, Y. Su and Y.-Z. Lin, Eur. J. Org. Chem., 2014, 7347–7352.

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Asymmetric catalysis of triplet-state photoreactions Evan M. Sherbrook and Tehshik P. Yoon* DOI: 10.1039/9781788013598-00432

For many decades, stereocontrol in triplet-state photoreactions was widely regarded an elusive goal. Catalytic strategies to influence the reactivity of transient electronically excited intermediates remains a significant challenge, but many distinctive molecular scaffolds are uniquely available through excited-state chemistry . This Chapter summarizes studies ranging from the first asymmetric photoisomerizations to recent developments in highly enantioselective photocycloaddition reactions.

1

Introduction

The stereochemistry of organic molecules is crucial to their function and to their chemical and biological properties. Thus, the controlled construction of complex chiral molecules ranks among the most important challenges facing contemporary synthetic organic chemistry.1 Asymmetric catalysis has become as an essential tool for the enantioselective preparation of a variety of molecular scaffolds including drugs and new drug targets, functional organic materials, and chemical feedstocks. One important frontier for continued research in this area is the development of new, highly enantioselective catalytic strategies that are applicable to a broader range of reaction types and product structures. Photochemical reactions constitute a large and diverse class of synthetically useful transformations for which stereocontrol has long proven to be challenging.2 Photochemical activation frequently results in the generation of highly energetic intermediates that react in distinctive ways and provide access to structural patterns that are otherwise difficult to access. However, these highly reactive intermediates are also generally quite short-lived, which can challenge the ability of exogenous chiral catalysts to intercept them and modulate their reactivity. Indeed, robust strategies for the design of highly enantioselective catalytic photoreactions have only become available within the last decade. The majority of these successful enantioselective photoreactions, however, can be classified as secondary photoreactions: they are reactions of photogenerated reactive intermediates such as radicals or radical ions in their ground-state electronic configurations.3 The reactions that are accessible using photoredox catalysis belong to this class, and the recent renewal of interest in these reactions4 has motivated much of the development in enantioselective photocatalysis. Stereocontrol in primary photoreactions, in which the key bond-forming steps occur from electronically excited-state intermediates, has proven to be a more challenging objective. This discrepancy has practical implications. While photoredox Department of Chemistry, University of Wisconsin–Madison, 1101 University Avenue, Madison, Wisconsin, 53726, USA. E-mail: [email protected] 432 | Photochemistry, 2019, 46, 432–448  c

The Royal Society of Chemistry 2019

catalysis offers a particularly convenient means to access the reactivity of open-shelled odd-electron intermediates, there exist numerous classical non-photochemical methods for the initiation of radical reactions.5 The chemistry of electronically excited organic molecules, on the other hand, is uniquely accessible using photochemical activation and cannot be recapitulated through alternate means. Much of the early research in enantioselective excited-state reactions involved chiral analogues of well-studied organic photosensitizers. These studies, however, generally resulted in low enantioselectivities, a feature that was attributed to weak, poorly-defined associations with the excitedstate intermediates. More successful subsequent studies have shown that preassociation between the substrate and chiral catalyst prior to the excitation process can confer higher levels of selectivity in these reactions. This Chapter will focus both upon early exploratory investigations, which helped to establish an understanding of how to best control excited-state reactivity, as well as more recent developments, which have made use of these insights to develop highly enantioselective excitedstate photoreactions. The broadest class of enantioselective photoreactions are those that utilize enantiopure photocatalysts to transfer stereochemical information to prochiral or racemic substrate molecules. Sections 2 and 3 address these types of reactions using purely organic photosensitizers, while Sections 4 and 5 cover the use of Lewis acids and transition metalcentered photocatalysts. Overall, this Chapter summarizes asymmetric photochemical transformations enabled by substoichiometric smallmolecule catalysts. Photoreactions involving superstoichiometric chiral environments, complex supramolecular catalyst scaffolds (e.g. enzymes and zeolites), chiral auxiliaries, and circularly polarized light have not been included. For surveys of these areas, we direct the reader to several important reviews published in recent years.2a,6

2

Arenes and aryl ketones

The first enantioselective catalytic excited-state photoreaction, reported in 1965 by Hammond and Cole, was the desymmetrization of trans-1,2diphenylcyclopropane (DPC) (rac-1, Scheme 1) using the modified chiral naphthalene sensitizer 3.7 The process itself is a relatively simple geometrical photoisomerization; 1 was recovered from the reaction in 7% ee, along with meso cyclopropane 2. Although the magnitude of the enantioselectivity in this experiment is low by modern standards, the insight that chiral sensitizers could perturb the stereochemical course of a photoreaction was profound. The original report proposed a mechanism involving triplet energy transfer; however, it was later determined that the reaction occurs through a singlet manifold.8 Indeed, this latter discovery is consistent with a general trend observed using chiral modified arene photosensitizers, which often form singlet-state exciplexes with their substrates. In contrast to arenes, ketones often undergo efficient intersystem crossing (ISC) and thus have a greater propensity to participate in Photochemistry, 2019, 46, 432–448 | 433

Scheme 1 Geometrical photoisomerization of diphenylcyclopropane by arene and ketone sensitizers.

Scheme 2 Photochemical rearrangement of oxapinone 7 by naphthyl carbonyls.

catalyst-to-substrate triplet energy transfer processes. The desymme`s trization of racemic DPC using indanone 4 was reported by Ouanne in 1980. This example was the first asymmetric photoreaction known `s proposed that the low-energy to occur via a triplet manifold.9 Ouanne triplet of trans-DPC (ca. 53 kcal mol1) would easily be sensitized by a high triplet energy aryl ketone.10 This experiment produced enantiomerically enriched 1 in 3% ee. Other aromatic ketones were reported to be less successful: tetralones 5 and 6 afford lower selectivity. Sato reported the first asymmetric triplet-state photorearrangement in 1980.11 The sensitization of oxepinone rac-7 (Scheme 2) was explored using several naphthyl carbonyls such as 10–12 at a variety of catalyst loadings (0.5 to 2.0 equiv). This effects a 1,5-phenyl shift to 8, followed by a di-p-methane rearrangement to give oxabicyclo[4.1.0]heptanone 9 as the product. When the reactions were halted at 50% conversion, both the starting oxepinone 7 and the product 9 were found to be optically active. The enrichment of both starting material and product suggest that the stereochemistry-determining step is the initial sensitization itself. 434 | Photochemistry, 2019, 46, 432–448

Contemporaneous with these studies, Demuth and Schaffner investigated the oxa-di-p-methane rearrangement of bicyclo[2.2.2]octenone rac14 (Scheme 3) to tricyclo[3.3.0.0]octenone 15 using 16 as a sensitizer.12 Quantitative evaluation of optical rotation showed that the product was formed in 4.5% ee at room temperature and 10% ee at  78 1C. This provided an excellent demonstration of the potential utility of sensitized excited-state reactions, as the product generated through energy transfer (15) is different from the product of direct irradiation (13), which arises from a 1,3-acyl shift. The asymmetric photoextrusion occurring in trans-3,5-diphenylpyrazoline (DPY) (rac-17, Scheme 4) to give 1 and 2 (meso) was reported by Rau and Horman in 1981.13 ()-Rotenone (18) and (þ)-testosterone (19) were studied as chiral photosensitizers and gave 1 in 4% ee and 1% ee, respectively. While DPY can react to afford racemic 1 upon direct photolysis,14 it also has a low triplet energy (55 kcal mol1).15 Both 18 and 19 possess triplet energies near 70 kcal mol1, which makes them competent photosensitizers for this reaction. Irradiation was thus conducted at wavelengths above 350 nm where the absorbance of DPY is minimal but where 18 and 19 absorb strongly, in an effort to prevent direct absorption and maximize the photosensitized process. An intramolecular variant of this reaction was also explored in which the pyrazoline is covalently tethered to the ketone, but levels of enantioenrichment were low.16 The first asymmetric [2þ2] photocycloaddition to be accomplished through a triplet manifold was published over 20 years later by Krische,17

Scheme 3 Reaction outcomes for rac-14 under direct irradiation and triplet energy transfer.

Scheme 4 Desymmetrization of diphenylpyrazoline 17 to diphenylcyclopropanes by rotenone and testosterone. Photochemistry, 2019, 46, 432–448 | 435

Scheme 5 Intramolecular [2þ2] photocycloaddition of quinolone 20 using a chiral H-bonding bisamide.

who studied the reaction of quinolone 20 in the presence of benzophenone-modified bisamide 22 (Scheme 5) as a chiral, hydrogenbonding host. When this mixture was irradiated at 70 1C, cyclobutane 21 was produced in good yield and in 19%, 20%, and 22% ee with 25, 50, and 100 mol% of the catalyst, respectively. This catalyst design differed from previous efforts because the hydrogen-bonding scaffold results in a significant ground-state preassociation between the substrate and the photosensitizer. This both maximizes the probability that the reactive excited-state intermediate is generated within a well-defined chiral environment defined by the hydrogen-bonding sensitizer and extends the lifetime of the substrate–catalyst interaction. Although the enantioselectivities observed in these experiments remained relatively modest by modern standards, the improvement over previous approaches shifted the focus of research in this field towards other catalysts capable of similar ground-state interactions.

3

H-bonding xanthones, thioxanthones, and thioureas

The first true photocatalysts capable of producing synthetically relevant enantioselectivities in triplet-state asymmetric photoreactions were developed by Bach and coworkers. In previous work, Bach had demonstrated that Kemp’s triacid-derived hydrogen-bonding host structures bearing benzoxazole units (23, Fig. 1) could be used as superstoichiometric chiral hosts to control a number of photocycloadditions and photocyclization reactions.18 The benzoxazole moiety in this design serves as a steric shield that blocks one of the prochiral p faces of bound quinolone substrates. By replacing the benzoxazole with benzophenone (24), Bach was later able to design a photocatalytically active hydrogen-bonding scaffold. This compound was shown to be a highly enantioselective photocatalyst at sub-stoichiometric loadings for a spirocyclization reaction of a photogenerated a-aminoradical.19 The first excited-state photoreaction using this strategy involved a modified catalyst (25a) featuring a photoactive xanthone moiety. This photosensitizer has the benefit of both a red-shifted absorption profile 436 | Photochemistry, 2019, 46, 432–448

Fig. 1 A series of chiral H-bonding photocatalysts.

Scheme 6 Intramolecular [2þ2] photocycloadditions of quinolone 20 by a chiral H-bonding xanthone.

(40 nm) compared to benzophenone, and a higher triplet energy (74 vs. 69 kcal mol1). This catalyst was used to sensitize the intramolecular cycloaddition of quinolone 20 (Scheme 6). Both regioisomers ent-21a and 26 were produced in 91% ee (3.3 : 1 r.r.) at a catalyst loading of 10 mol% and a reaction temperature of 25 1C.20 Subsequent studies of the scope of this reaction21,22 revealed that high enantioselectivities could be obtained for various modified substrates provided that the [2þ2] cycloaddition proceeds at a fast rate. Bach suggested that compounds that underwent cycloaddition more slowly (e.g., 21b) gave poorer ee’s because the rate of dissociation from the chiral photocatalyst could become competitive, enabling some proportion of the product to be formed in an achiral environment. This catalyst can also be used to carry out intermolecular [2þ2] cycloadditions (Scheme 7) between pyridone 27 and acetylenedicarboxylates to give cyclobutene products 28a–f with good enantioselectivities.23 Catalyst loadings were reduced to only 2.5–5.0 mol% and reactions were performed at 65 1C using a trifluorotoluene/hexafluoro-m-xylene (HFX) solvent mixture. Photochemistry, 2019, 46, 432–448 | 437

Scheme 7 Intermolecular acetylenedicarboxylates.

[2þ2]

photocycloaddition

of

pyridones

and

Thioxanthone catalyst 25b is structurally analogous to xanthone 25a but exhibits a longer-wavelength absorption spectrum.24 As such, this thioxanthone catalyst is capable of mediating reactions using visible light, rather than UV. Initially, Bach demonstrated that this catalyst enables several quinolones to undergo cycloaddition with 400–700 nm light. Selectivities were found to be consistently high using 10 mol% of the catalyst at 25 1C. For example, using 25b, cycloadduct 21d was generated in 86% yield and 91% ee, improving on the reaction outcome observed with 25a. This was attributed to the fact that the longer wavelength irradiation minimizes the formation of product by direct irradiation of the quinolone, which in turn minimizes the rate of formation of racemic cycloadduct. This improved thioxanthone catalyst also enables the highly enantioselective intermolecular cycloaddition of quinolone 29 (Scheme 8) with ethyl vinyl ketone to give cyclobutane 30a as a single diastereomer in high yields and ee (25 1C, 419 nm light, 10 mol% catalyst).25 A variety of other alkenes, including benzyl acrylate, methyl vinyl ketone, acrolein, and similar variants offer good results, although a large excess of the acceptor alkene is required for optimal results. In 2014, concurrent with much of Bach’s work on chiral xanthones and thioxanthones, Sibi and Siviguru reported an intramolecular [2þ2] photocycloaddition of 4-alkenyl coumarins using chiral binaphthyl thiourea 33a as a photocatalyst (Scheme 9).26 Irradiation of coumarin 31 in the presence of this thiourea catalyst using 350 nm light at 78 1C gave 438 | Photochemistry, 2019, 46, 432–448

Scheme 8 Intermolecular [2þ2] photocycloaddition of quinolones and electron poor olefins by a chiral H-bonding thioxanthone.

Scheme 9 thioureas.

Intramolecular [2þ2] photocycloadditions of coumarin 31 by naphthyl

32a in 84% yield and 74% ee in only 30 min. Iterative structural optimizations of the catalyst led to the identification of 33b, which afforded quantitative yield of the product in 96% ee with only 10 mol% catalyst loading. From a design perspective, this thiourea catalyst is similar to Bach’s xanthone catalysts in that it couples a hydrogen-bonding domain to a p-conjugated chromophore. Mechanistically, however, the mode of catalysis in the Sivaguru system appears distinct. First, energy transfer was determined to not be energetically feasible because fluorescence spectroscopy revealed that both the lowest singlet and triplet excited states were insufficiently energetic to sensitize coumarin 31. Instead, Sivaguru and Sibi proposed the formation of an absorption complex. UV/vis spectroscopic analysis revealed that the catalyst-substrate complex exhibited a distinct Photochemistry, 2019, 46, 432–448 | 439

bathochromic shift compared to the catalyst or substrate species in isolation. Thus, a chiral substrate–catalyst complex was proposed to absorb long-wavelength light preferentially over the free substrate. Moreover, these investigators observed a nonlinear Stern-Volmer response to the concentration of coumarin substrate, which is indicative of both static and dynamic quenching mechanisms occurring competitively. As a result, a concentration-dependent mechanism was proposed. At low substrate concentration (high concentrations of thiourea), the higher optical density of the biaryl catalyst results in its selective photoexcitation; product formation was proposed to proceed the formation of an exciplex. At high substrate concentration, on the other hand, the pre-associated absorption complex is selectively photoexcited, similarly leading to product. A variety of structurally diverse chiral thiourea scaffolds were also investigated as catalysts for the same intramolecular coumarin cycloaddition.27 Interestingly, while none of these catalysts gave enantioselectivities comparable to 33a or 33b, the precise mechanism of photochemical activation varied as a function of catalyst structure.

4 Lewis acids The ability of Lewis acids to modulate excited-state photocycloadditions has been known for some time. The most thorough studies of this phenomenon were conducted by Lewis in the 1980s.28 Although the [2þ2] photocycloaddition of coumarin can be achieved through direct excitation, this process is inefficient because the singlet excited state of coumarin relaxes rapidly to the ground state, decreasing its propensity to undergo intermolecular cycloaddition reactions. Coordination of the coumarin to a Lewis acid significantly increases the lifetime of the excited state. Thus, intermolecular cycloadditions between coumarins and alkenes are considerably faster in the presence of Lewis acids such as BF3 and EtAlCl2.29 Similar effects on the rate of cinnamate photocycloadditions have been documented as well.30 This effect was successfully exploited in enantioselective photocatalysis by Bach.31,32 Chiral oxazaborolidine catalyst 34a (50 mol%, Fig. 2) is an effective asymmetric catalyst for the cycloaddition of 4-alkenyl coumarin 31 to afford cyclobutane ent-32a in 84% yield and 82% ee. In addition, this catalyst allows for alteration of the alkene tether (Fig. 3) while maintaining high yields and good selectivities. While the uncatalyzed reaction proceeds through a singlet excited-state manifold, Bach proposed that the catalysed reaction proceeds through a triplet-state biradical intermediate. Consistent with this hypothesis, coumarins featuring isomeric (E) and (Z) alkene-containing substituents undergo stereoconvergent cycloaddition, suggesting a stepwise triplet-state mechanism. Bach also observed that the UV–vis absorption spectra of this class of coumarin compounds undergoes a bathochromic shift in the presence of Lewis acids. An important feature of this successful strategy, therefore, is selective irradiation at the red-shifted tail of the coumarin absorption with a monochromatic light (l ¼ 366 nm), which maximizes 440 | Photochemistry, 2019, 46, 432–448

Fig. 2

A series of chiral oxazaborolidine-AlBr3 Lewis acids.

H

Fig. 3 Representative scope of intramolecular [2þ2] coumarin photocycloadditions using chiral Lewis acid 34a.

the photoexcitation of the Lewis acid-bound substrate and minimizes direct photoexcitation of unbound coumarin. This Lewis acid-mediated strategy has enabled asymmetric photocycloaddition reactions to be applied to a much broader range of enone substrates.33 Bach has developed conditions for the highly enantioselective [2þ2] cycloaddition of dihydropyridone 35 (Scheme 10) to afford 36a in 84% yield and 88% ee, again using catalyst 34a. The mode of catalysis for this substrate features a subtle but important mechanistic difference. Unlike coumarin photocycloadditions, there is no change in the reactive spin state of photoexcited 35 in the presence of a Lewis acid catalyst; both the free and Lewis-acid-bound pyridine undergo cycloaddition through the triplet state when irradiated at 366 nm. Indeed, the intrinsic rate of cycloaddition is somewhat depressed upon coordination of 35 to a Lewis acid. However, in addition to a significant 50 nm bathochromatic shift of the p,p* transition feature, the UV–vis spectrum of the Lewis acid-pyridone complex exhibits a marked increase in molar absorptivity. Thus the high selectivity appears largely to be a consequence of the higher extinction coefficient of the Lewis acid-bound substrate compared to the achiral free pyridone, which provides an alternative means to minimize the participation of racemic background cycloaddition.34 Subsequent investigations by Bach have continued to extend the scope of this strategy towards simpler enone substrates. Catalyst 34b has been applied in the intramolecular photocycloaddition of b-alkoxysubstituted Photochemistry, 2019, 46, 432–448 | 441

Scheme 10 Intramolecular [2þ2] photocycloaddition of pyridones.

cycloalkenones.35 Very recently, oxazaborolidine 34c was identified as an optimal catalyst for the intermolecular cycloadditions of simple cycloalkenones such as 37 (Scheme 11) with an impressive variety of alkenes to give 38a–h.36 This is an important contribution because many of the classic applications of photocycloadditions to the synthesis of natural products have involved such simple cycloalkenone substrates.37 Bach’s strategy thus appears to provide a strategy to render these syntheses enantioselective. Although the alkene coupling partner must be used in significant excess, the structural variety of olefins that participate in this reaction is impressive and distinctive to this approach. Although nearly all methodologies in asymmetric triplet state photochemistry employ chiral enantiopure photocatalysts, several dual catalyst strategies for highly enantioselective photoredox reactions have been developed.38 The approach is appealing because it allows for independent optimization of the chiral stereocontrolling co-catalyst without altering the robust photophysical and photoelectrochemical properties of an achiral or racemic photoredox catalyst.39 Until recently, however, this strategy had not been applied to transformations involving excited-state photochemistry. In 2016, Yoon reported a dual catalytic approach to asymmetric intermolecular [2þ2] photocycloadditions between 2 0 -hydroxychalcone 39 (Scheme 12) and dienes to give 40a in 84% yield, 93% ee, and 3:1 d.r.40 This result constitutes a rare example of a highly enantioselective photocycloaddition reaction involving an acyclic enone. In this transformation, Ru(bpy)3(PF6)2 acts as a photosensitizer and a (pybox)Sc(OTf)3 Lewis acid co-catalyst (41) serves as the chiral controller. The distinctive mechanistic feature of this process is a Lewis acid-mediated lowering of the triplet energy (ET) of the substrate. This renders triplet energy transfer 442 | Photochemistry, 2019, 46, 432–448

Scheme 11 Intermolecular [2þ2] photocycloaddition of cyclohexenones and aliphatic alkenes.

Scheme 12 Intermolecular [2þ2] photocycloadditions of 2 0 -hydroxychalcones and dienes to using a chiral Lewis acid complex. Photochemistry, 2019, 46, 432–448 | 443

Scheme 13 Expansion of intermolecular [2þ2] photocycloadditions with chalcones to include syrenes and vinyl sulfides.

from Ru*(bpy)321 to the substrate feasible only when bound to the chiral Lewis acid catalyst, making the free substrate unreactive and thus minimizing racemic background photocycloaddition. To support this hypothesis, Yoon utilized a combination of computational and spectroscopic studies to show that the ET of 41 decreases from from 54 kcal/mol to 33 kcal mol1 upon coordination to the Lewis acid. Thus sensitization by Ru(bpy)321, which has an ET of 47 kcal mol1, is indeed thermodynamically feasible only to the Lewis acid-bound complex. The reaction demonstrates both modest functional group tolerance and works well with several other dienes (40b–f). Other alkenes such as styrenes and vinyl sulfides could also function as acceptor alkenes to give diaryl cyclobutane products such as 40g–i (Scheme 13)41 This method was applied to a concise synthesis of norlignin cyclobutane 42.

5

Transition metal photocatalysts

Almost all chiral photocatalysts investigated for organic transformations have relied on the tetrahedral chirality of chiral organic sensitizers or cocatalysts. Alternate approaches exploiting the helical chirality of octahedral transition metal complexes have recently been reported. Meggers has played a pioneering role in designing chiral-at-metal octahedral Lewis acidic catalysts capable of controlling the stereochemistry of a variety of photoredox reactions with exceptional enantiocontrol (e.g., 43a, Fig. 4).42 Very recently, Meggers demonstrated that this class of catalysts can also control excited state photoreactions through the formation of direct absorption complexes.43 Chiral-at-rhodium complex 43b binds to imidazoyl enone 44 to form a new species that features a distinct new absorption feature that is red-shifted compared to the UV–vis spectra of either the enone or Rh catalyst alone (Scheme 14). 444 | Photochemistry, 2019, 46, 432–448

Fig. 4 Chiral-at-metal iridium and rhodium photocatalysts.

Scheme 14 Intermolecular [2þ2] photocycloadditions of imidazoyl, pyridyl, and Pyrazoyl enones with alkenes.

When this complex is excited with visible light, it undergoes a facile intermolecular [2þ2] photocycloaddition with electron rich alkenes to afford a diverse array of vinylcyclobutanes 45a–g in excellent yield and ee using quite low catalyst loadings (2–4 mol%). Interestingly, the reaction was found to be feasible without a catalyst, albeit at a substantially slower rate. The origin of the extremely high selectivities is attributable to a nearly 170-fold increase in molar extinction coefficient for the complex as compared to the substrate, effectively outcompeting any direct background cycloaddition. Yoon recently designed a chiral-at-iridium catalyst 48 (Scheme 15) that employs outer-sphere hydrogen-bonding interactions via a functionalized pyrazole ligand rather than substrate-metal interactions.44 Using this catalyst, quinolone 46 undergoes highly enantioselective intramolecular Photochemistry, 2019, 46, 432–448 | 445

Scheme 15 Intramolecular [2þ2] photocycloadditions of quinolones with an H-bonding chiral-at-metal iridium photocatalyst.

[2þ2] cycloaddition to afford 47 in 98% yield and 91% ee using visible light and only 1 mol% of catalyst at 78 1C. The mode of interaction between the quinolone substrate and the pryazole ligand is unique; Yoon proposed that the primary hydrogen-bonding interaction occurs between the Brønsted acidic N–H moiety of the pyrazole and the quinolone carbonyl, and that a weak, secondary H–bonding interaction from the quinolone N–H to the pyrazole p-surface orients the substrate relative to the chiral Ir stereocenter and facilitates rapid triplet energy transfer. Consistent with this model, coumarin and N-methylquinoline undergo rapid but essentially unselective cycloaddition upon sensitization with 48.

6

Summary and looking forward

Over the past decade, the development of multiple highly enantioselective excited-state photoreactions has demonstrated conclusively that stereocontrol in this class of transformations is indeed feasible using small-molecule chiral catalysts. A key feature common to all of these successful catalytic asymmetric photoreactions has been the use of ground-state preassociations between the substrate and the chiral controller that facilitate the photoactivation step. Many of the most successful chiral catalyst structures reported to date for these applications are the same well-understood privileged catalysts that have been broadly applied to other non-photochemical transformations. Thus, the field of asymmetric photochemistry is poised for a period of significant growth as synthetic chemists learn to apply these principles to a broader range of excited-state photoreactions. The reactivity of these photogenerated intermediates afford structurally unique products that have previously been difficult to access in enantiomerically enriched form, and these efforts to develop stereoselective photochemistry into a robust 446 | Photochemistry, 2019, 46, 432–448

contemporary synthetic tool is an exciting prospect for modern organic chemistry.

References 1

2

3

4

5 6

7 8 9 10

11 12 13 14 15 16 17 18

19 20 21 22

(a) P. J. Walsh and M. C. Kozlowski, Fundamentals of Asymmetric Catalysis, University Science Books, Sausalio, CA, 2009; (b) I. Ojima, Catalytic Asymmetric Synthesis, Wiley, Hoboken, NJ, 2010; (c) R. E. Gawley and J. Aube, Principles of Asymmetric Synthesis, Elsevier, Oxford, 2nd edn, 2012. (a) H. Rau, Chem. Rev., 1983, 83, 535; (b) Y. Inoue, Chem. Rev., 1992, 92, 741; (c) Y. Inoue and V. Ramamurthy, Molecular and Supramolecular Photochemistry, Chiral Photochemistry, Marcel Dekker, New York, NY, vol. 11, 2004. (a) M. N. Hopkinson, B. Sahoo, J.-L. Li and F. Glorius, Chem. – Eur. J., 2014, 20, 3874; (b) R. Brimioulle, D. Lenhart, M. M. Maturi and T. Bach, Angew. Chem., Int. Ed., 2015, 54, 3872–3890; (c) E. Meggers, Chem Commmun., 2015, 51, 3290. (a) A. Albini and M. Fagnoni, Photochemically Generated Intermediates in Synthesis, Wiley & Sons, Hoboken, NJ, 2013; (b) C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013, 113, 5322; (c) C. R. J. Stephenson, T. P. Yoon and D. W. C. MacMillan, Visible Light Photocatalysis in Organic Chemistry, Wiley-VCH, Weinheim, 2018. A. Studer and D. P. Curran, Angew. Chem., Int. Ed., 2016, 55, 58. ¨nig, Chem. Rev., 2006, 106, 5414; (b) C. Yang and (a) J. Svoboda and B. Ko Y. Inoue, Chem Soc. Rev., 2014, 43, 4123; (c) B. Bibal, C. Mognin and D. M. Bassini, Chem Soc. Rev., 2014, 43, 4179. G. S. Hammond and R. S. Cole, J. Am. Chem. Soc., 1965, 87, 3256. S. L. Murov, R. S. Cole and G. S. Hammond, J. Am. Chem. Soc., 1968, 90, 2957. `s, R. Beugelmans and G. Rossi, J. Am. Chem. Soc., 1973, 95, 8472. C. Ouanne Based on the triplet energy of 1-indanone (76.6 kcal/mol), which should be very similar to 3-methyl-1-indanone; W. A. Case and D. R. Kearns, J. Chem. Phys., 1970, 52, 2175 N. Hoshi, Y. Furukawa, H. Hagiwara, H. Uda and K. Sato, Chem. Lett., 1980, 47. M. Demuth, P. R. Raghavan, C. Carter, K. Nakano and K. Schaffner, Helv. Chim. Acta, 1980, 63, 2434. ¨rman, J. Photochem., 1981, 16, 231. H. Rau and M. Ho ¨rman, J. Chem. M. P. Schneider, H. Bippi, H. Rau, D. Ufermann and M. Ho Soc., Chem. Commun., 1980, 957. P. S. Engel and C. Steel, Acc. Chem. Res., 1973, 6, 275. E. Becker, R. Weiland and H. Rau, J. Photochem. Photobiol., A, 1988, 41, 311. D. F. Cauble, V. Lynch and M. J. Krische, J. Org. Chem., 2003, 68, 15. Selected examples: (a) T. Bach, H. Bergmann and K. Harms, Angew. Chem., Int. Ed., 2000, 112, 2391; (b) T. Bach and H. Bergmann, J. Am. Chem. Soc., ¨ller, Chem. Commun., 2000, 122, 11525; (c) T. Bach, T. Aechtner and B. Neumu 2001, 607; (d) T. Bach, H. Bergmann, B. Grosch and K. Harms, J. Am. Chem. Soc., 2002, 124, 7982; (e) B. Grosch, C. Orlebar, E. Herdtweck, W. Massa and T. Bach, Angew. Chem., Int. Ed., 2003, 115, 3822. ¨mper, S. Grimme and T. Bach, Nature, 2005, 436, 1139. A. Bauer, F. Westka ¨ller, A. Bauer and T. Bach, Angew. Chem., Int. Ed., 2009, 48, 6640. C. Mu ¨ller, A. Bauer, M. M. Maturi, M. C. Cuquerella, M. A. Miranda and C. Mu T. Bach, J. Am. Chem. Soc., 2011, 133, 16689. ¨thig, E. Riedle and M. M. Maturi, M. Wenninger, R. Alonso, A. Bauer, A. Po T. Bach, Chem. – Eur. J., 2013, 19, 7962. Photochemistry, 2019, 46, 432–448 | 447

23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

M. M. Maturi and T. Bach, Angew. Chem., Int. Ed., 2014, 53, 7661. R. Alonso and T. Bach, Angew. Chem., Int. Ed., 2014, 53, 4368. A. Troster, R. Alonso, A. Bauer and T. Bach, J. Am. Chem. Soc., 2016, 138, 7808. N. Vallavoju, S. Selvakumar, S. Jockusch, M. P. Sibi and J. Sivaguru, Angew. Chem., Int. Ed., 2014, 53, 5604. N. Vallavoju, S. Selvakumar, S. Jockusch, M. J. Prabhakaran, M. P. Sibi and J. Sivaguru, Adv. Synth. Catal., 2014, 356, 2763. F. D. Lewis, D. K. Howard and J. D. Oxman, J. Am. Chem. Soc., 1983, 105, 3344. F. D. Lewis and S. V. Barancyk, J. Am. Chem. Soc., 1989, 111, 8653. F. D. Lewis, S. L. Quillen, P. D. Hale and J. D. Oxman, J. Am. Chem. Soc., 1988, 110, 1261. H. Guo, E. Herdtweck and T. Bach, Angew. Chem., Int. Ed., 2010, 49, 7782. R. Brimioulle, H. Guo and T. Bach, Chem. – Eur. J., 2012, 18, 7552. R. Brimioulle and T. Bach, Science, 2013, 342, 840. R. Brimioulle, A. Bauer and T. Bach, J. Am. Chem. Soc., 2015, 137, 5170. R. Brimioulle and T. Bach, Angew. Chem., Int. Ed., 2014, 53, 12921. S. Poplata and T. Bach, J. Am. Chem. Soc., 2018, 140, 3228. N. Hoffman, Chem. Rev., 2008, 108, 1052. K. L. Skubi, T. R. Blum and T. P. Yoon, Chem. Rev., 2016, 116, 10035. T. P. Yoon, Acc. Chem. Res., 2016, 49, 2307. T. R. Blum, Z. D. Miller, D. M. Bates, I. A. Guzei and T. P. Yoon, Science, 2016, 354, 1391. Z. D. Miller, B. J. Lee and T. P. Yoon, Angew. Chem., Int. Ed., 2017, 129, 12053. ¨se, L. A. Chen, K. Harms, H. Huo, X. Shen, C. Wang, L. Zhang, P. Ro M. Marsch, G. Hilt and E. Meggers, Nature, 2014, 515, 100. X. Huang, T. R. Quinn, K. Harms, R. D. Webster, L. Zhang, O. Wiest and E. Meggers, J. Am. Chem. Soc., 2017, 139, 9120. K. L. Skubi, J. B. Kidd, H. Jung, I. A. Guzei, M.-H. Baik and T. P. Yoon, J. Am. Chem. Soc., 2017, 139, 17186.

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