Stable Radicals Fundamentals and Applied Aspects of Odd-Electron Compounds

Editor

ROBIN G. HICKS Department of Chemistry, University of Victoria, Canada

A John Wiley and Sons, Ltd., Publication

Editor

ROBIN G. HICKS Department of Chemistry, University of Victoria, Canada

A John Wiley and Sons, Ltd., Publication

Stable Radicals Fundamentals and Applied Aspects of Odd-Electron Compounds

Editor

ROBIN G. HICKS Department of Chemistry, University of Victoria, Canada

A John Wiley and Sons, Ltd., Publication This edition ﬁrst published c 2010 c 2010 John Wiley & Sons Ltd

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Library of Congress Cataloging-in-Publication Data

Stable radicals : fundamentals and applied aspects of odd-electron compounds / editor, Robin G. Hicks. p. cm. Includes bibliographical references and index. ISBN 978-0-470-77083-2 (hardback) 1. Radicals (Chemistry) – Stability. 2. Electron mobility. I. Hicks, Robin G. QD471.S73 2010 541.224–dc22 2010010754

A catalogue record for this book is available from the British Library.

ISBN 978-0-470-77083-2

Typeset in 10/12 Times by Laserwords Private Limited, Chennai, India Printed and bound in the United Kingdom by Antony Rowe Ltd, Chippenham, Wiltshire Contents

Preface xv List of Contributors xvii

1. Triarylmethyl and Related Radicals 1 Thomas T. Tidwell 1.1 Introduction 1 1.1.1 Discovery of the triphenylmethyl radical 1 1.1.2 Bis(triphenylmethyl) peroxide 3 1.2 Free radical rearrangements 4 1.3 Other routes to triphenylmethyl radicals 5 1.4 The persistent radical effect 7 1.5 Properties of triphenylmethyl radicals 8 1.6 Steric effects and persistent radicals 9 1.7 Substituted triphenylmethyl radicals and dimers 9 1.8 Tris(heteroaryl)methyl and related triarylmethyl radicals 12 1.9 Delocalized persistent radicals: analogues of triarylmethyl radicals 14 1.10 Tetrathiatriarylmethyl (TAM) and related triarylmethyl radicals 16 1.11 Perchlorinated triarylmethyl radicals 20 1.12 Other triarylmethyl radicals 23 1.13 Diradicals and polyradicals related to triphenylmethyl 24 1.14 Outlook 28 Acknowledgements 28 References 28

2. Polychlorotriphenylmethyl Radicals: Towards Multifunctional Molecular Materials 33 Jaume Veciana and Imma Ratera 2.1 Introduction 33 2.2 Functional molecular materials based on PTM radicals 35 2.2.1 Materials with magnetic properties 37 2.2.2 Materials with electronic properties 53 2.2.3 Materials with optical properties 65 2.3 Multifunctional switchable molecular materials based on PTM radicals 69 2.3.1 Photo switchable molecular systems 69 2.3.2 Redox switchable molecular systems 70 2.4 Conclusions 75 References 76 vi Contents

3. Phenalenyls, Cyclopentadienyls, and Other Carbon-Centered Radicals 81 Yasushi Morita and Shinsuke Nishida 3.1 Introduction 81 3.2 Open shell graphene 82 3.3 Phenalenyl 84 3.4 2,5,8-Tri-tert-butylphenalenyl radical 86 3.5 Perchlorophenalenyl radical 92 3.6 Dithiophenalenyl radicals 94 3.7 Nitrogen-containing phenalenyl systems 97 3.7.1 Molecular design and topological isomers 97 3.7.2 2,5,8-Tri-tert-butyl-1,3-diazaphenalenyl 97 3.7.3 Hexaazaphenalenyl derivatives 102 3.7.4 β-Azaphenalenyl derivatives 103 3.8 Oxophenalenoxyl systems 106 3.8.1 Molecular design and topological isomers 106 3.8.2 3-Oxophenalenoxyl (3OPO) system 108 3.8.3 4- and 6-Oxophenalenoxyl (4OPO, 6OPO) systems 110 3.8.4 Redox-based spin diversity 114 3.8.5 Molecular crystalline secondary battery 115 3.8.6 Spin-center transfer and solvato-/thermochromism 117 3.9 Phenalenyl-based zwitterionic radicals 119 3.10 π-Extended phenalenyl systems 122 3.10.1 Triangulenes 122 3.10.2 Trioxytriangulene with redox-based spin diversity nature 125 3.10.3 Bis- and tris-phenalenyl system and singlet biradical characters 125 3.11 Curve-structured phenalenyl system 130 3.12 Non-alternant stable radicals 131 3.12.1 Cyclopentadienyl radicals 131 3.12.2 Cyclopentadienyl radicals within a larger π-electronic framework 135 3.13 Stable triplet carbenes 136 3.14 Conclusions 139 Acknowledgements 139 References 140

4. The Nitrogen Oxides: Persistent Radicals and van der Waals Complex Dimers 147 D. Scott Bohle 4.1 Introduction 147 4.2 Synthetic access 149 4.3 Physical properties 149 4.4 Structural chemistry of the monomers and dimers 150 4.4.1 Nitric oxide and dinitrogen dioxide 150 4.4.2 Nitrogen dioxide and dinitrogen tetroxide 152 4.5 Electronic structure of nitrogen oxides 153 4.6 Reactivity of nitric oxide and nitrogen dioxide and their van der Waals complexes 155 4.7 The kinetics of nitric oxide’s termolecular reactions 156 4.8 Biochemical and organic reactions of nitric oxide 158 Contents vii

4.9 General reactivity patterns 160 4.9.1 Oxidation 160 4.9.2 Reduction 161 4.9.3 Coordination 162 4.9.4 Addition of nucleophiles 162 4.9.5 General organic reactions 165 4.9.6 Reactions with other nucleophiles 165 4.10 The colored species problem in nitric oxide chemistry 166 4.11 Conclusions 166 References 166

5. Nitroxide Radicals: Properties, Synthesis and Applications 173 Hakim Karoui, Franc¸ois Le Moigne, Olivier Ouari and Paul Tordo 5.1 Introduction 173 5.2 Nitroxide structure 174 5.2.1 Characteristics of the aminoxyl group 174 5.2.2 X-ray structures of nitroxides 175 5.2.3 Quantum mechanical (QM), molecular dynamics (MD) and molecular mechanics (MM) calculations 177 5.2.4 Inﬂuence of solvent polarity on the EPR parameters of nitroxides 180 5.3 Nitroxide multiradicals 181 5.3.1 Electron spin–spin exchange coupling 182 5.3.2 Miscellaneous aspects of di- and polynitroxides 184 5.4 Nitronyl nitroxides (NNOs) 185 5.4.1 Synthesis of nitronyl nitroxides 186 5.4.2 Nitronyl nitroxide as a nitric oxide trap 186 5.4.3 Nitronyl nitroxides as building blocks for magnetic materials 188 5.5 Synthesis of nitroxides 191 5.5.1 Oxidation of amines 191 5.5.2 Oxidation of hydroxylamines 191 5.5.3 Chiral nitroxides 191 5.5.4 Nitroxide design for nitroxide mediated polymerization (NMP) 193 5.6 Chemical properties of nitroxides 196 5.6.1 The Persistent Radical Effect 197 5.6.2 Redox reactions 197 5.6.3 Approaches to improve the resistance of nitroxides toward bioreduction 198 5.6.4 Hydrogen abstraction reactions 199 5.6.5 Cross-coupling reactions 200 5.6.6 Nitroxides in synthetic sequences 200 5.7 Nitroxides in supramolecular entities 206 5.7.1 Interaction of nitroxides with cyclodextrins 207 5.7.2 Interaction of nitroxides with calix[4]arenes 209 5.7.3 Interaction of nitroxides with curcubiturils 210 5.7.4 Interaction of nitroxides with micelles 211 5.7.5 Fullerene-linked nitroxides 212 viii Contents

5.8 Nitroxides for dynamic nuclear polarization (DNP) enhanced NMR 213 5.8.1 DNP for biological NMR and real-time metabolic imaging 213 5.8.2 Nitroxides as polarizing agents for DNP 214 5.9 Nitroxides as pH-sensitive spin probes 216 5.10 Nitroxides as preﬂuorescent probes 217 5.11 EPR-spin trapping technique 217 5.11.1 Immuno spin trapping 219 5.11.2 Conclusion 219 5.12 Conclusions 220 References 220

6. The Only Stable Organic Sigma Radicals: Di-tert-Alkyliminoxyls 231 Keith U. Ingold 6.1 Introduction 231 6.2 The discovery of stable iminoxyls 232 6.2.1 Synthesis of di-tert-butyl ketoxime 233 6.2.2 Synthesis of di-tert-butyliminoxyl 234 6.2.3 Stability of di-tert-butyliminoxyl 235 6.3 Hydrogen atom abstraction by di-tert-butyliminoxyl 236 = 6.3.1 The O−H bond dissociation enthalpy (BDE) in (Me3C)2C NOH 236 6.3.2 Oxidation of hydrocarbons with di-tert-butyliminoxyl 237 6.3.3 Oxidation of phenols with di-tert-butyliminoxyl 238 6.3.4 Oxidation of amines with di-tert-butyliminoxyl 239 6.3.5 Oxidation of di-tert-butylketoxime with di-tert-butyliminoxyl 239 6.4 Other reactions and non-reactions of di-tert-butyliminoxyl 241 6.5 Di-tert-alkyliminoxyls more sterically crowded than di-tert-butyliminoxyl 241 6.6 Di-(1-Adamantyl)iminoxyl: a truly stable σ radical 242 References 243

7. Verdazyls and Related Radicals Containing the Hydrazyl [R2N−NR] Group 245 Robin G. Hicks 7.1 Introduction 245 7.2 Verdazyl radicals 246 7.2.1 Synthesis of verdazyls 246 7.2.2 Stability, physical properties and electronic structure of verdazyls 250 7.2.3 Verdazyl radical reactivity 256 7.2.4 Inorganic verdazyl analogues 264 7.3 Tetraazapentenyl radicals 265 7.4 Tetrazolinyl radicals 266 7.5 1,2,4-Triazolinyl radicals 268 7.6 1,2,4,5-Tetrazinyl radicals 269 7.7 Benzo-1,2,4-triazinyl radicals 270 7.8 Summary 273 References 273 Contents ix

8. Metal Coordinated Phenoxyl Radicals 281 Fabrice Thomas 8.1 Introduction 281 8.2 General properties of phenoxyl radicals 282 8.2.1 Electronic structure and stabilization 282 8.2.2 Electrochemistry of phenoxyl radicals 283 8.2.3 Structure of non-coordinated phenoxyl radicals 284 8.2.4 UV-Vis spectroscopy 284 8.2.5 EPR spectroscopy 284 8.3 Occurrence of tyrosyl radicals in proteins 285 8.4 Complexes with coordinated phenoxyl radicals 287 8.4.1 General ligand structures 287 8.4.2 Vanadium complexes 290 8.4.3 Chromium complexes 291 8.4.4 Manganese complexes 292 8.4.5 Iron complexes 294 8.4.6 Cobalt complexes 297 8.4.7 Nickel complexes 299 8.4.8 Copper complexes 303 8.4.9 Zinc complexes 310 8.5 Conclusions 313 8.6 Abbreviations 313 References 313

9. The Synthesis and Characterization of Stable Radicals Containing the Thiazyl (SN) Fragment and Their Use as Building Blocks for Advanced Functional Materials 317 Robin G. Hicks 9.1 Introduction 317 9.2 Radicals based exclusively on sulfur and nitrogen 319 9.2.1 NS• and SNS• 319 • 9.2.2 S3N3 320 •+ 9.2.3 S3N2 and related radical cations 320 9.2.4 Poly(thiazyl), (SN)x 322 9.3 “Organothiazyl” radicals 323 9.3.1 Thioaminyl radicals 323 9.3.2 1,2,3,5-Dithiadiazolyl radicals 329 9.3.3 1,3,2,4-Dithiadiazolyl radicals 336 9.3.4 1,3,2-Dithiazolyl radicals 339 9.3.5 1,2,3-Dithiazolyl radicals 342 9.3.6 Bis(1,2,3-dithiazole) and related radicals 345 9.3.7 1,2,4-Thiadiazinyl radicals 348 9.3.8 1,2,4,6-Thiatriazinyl and -selenatriazinyl radicals 349 9.3.9 Larger cyclic thiazyl radicals 355 x Contents

9.4 Thiazyl radicals as “advanced materials” 355 9.4.1 Charge transport properties of thiazyl radicals 356 9.4.2 Thiazyl radical-based charge transfer salts 360 9.4.3 Magnetic properties of thiazyl radicals 364 9.5 Conclusions 373 References 373 10. Stable Radicals of the Heavy p-Block Elements 381 Jari Konu and Tristram Chivers 10.1 Introduction 381 10.2 Group 13 element radicals 382 10.2.1 Boron 382 10.2.2 Aluminum, gallium, and indium 384 10.3 Group 14 element radicals 388 10.3.1 Cyclic group 14 radicals 389 10.3.2 Acyclic group 14 radicals 391 10.4 Group 15 element radicals 395 10.4.1 Phosphorus 395 10.4.2 Arsenic, antimony, and bismuth 400 10.5 Group 16 element radicals 400 10.5.1 Sulfur 400 10.5.2 Selenium and tellurium 401 10.6 Group 17 element radicals 402 10.7 Summary and future prospects 403 References 404 11. Application of Stable Radicals as Mediators in Living-Radical Polymerization 407 Andrea R. Szkurhan, Julie Lukkarila and Michael K. Georges 11.1 Introduction 407 11.2 Living polymerizations 408 11.2.1 Living-radical polymerization background 408 11.3 Stable free radical polymerization 409 11.3.1 Background of the work performed at the Xerox Research Centre of Canada 409 11.3.2 General considerations and mechanism 410 11.3.3 Unimolecular initiators 411 11.3.4 Persistent radical effect 413 11.3.5 Requirements of stable radicals as mediating agents 413 11.3.6 Nitroxides as mediating agents 414 11.3.7 Nitroxides and their ability to moderate polymerizations 414 11.3.8 Rate enhancement of stable free radical polymerization through the use of additives 416 11.4 Non-nitroxide-based radicals as mediating agents 416 11.4.1 Triazolinyl radicals 416 11.4.2 Verdazyl radicals 417 11.4.3 Other radicals as mediators 418 11.5 Aqueous stable free radical polymerization processes 420 11.5.1 Living-radical miniemulsion polymerization 421 11.5.2 Emulsion polymerization 422 11.5.3 Other aqueous polymerization processes 423 Contents xi

11.6 The application of stable free radical polymerization to new materials 423 11.6.1 Statistical copolymers 423 11.6.2 Block copolymers 424 11.7 Conclusions 425 List of abbreviations 425 References 425

12. Nitroxide-Catalyzed Alcohol Oxidations in Organic Synthesis 433 Christian Bruckner¨ 12.1 Introduction 433 12.2 Mechanism of TEMPO-catalyzed alcohol oxidations 434 12.3 Nitroxides used as catalysts 435 12.3.1 Monomeric nitroxides 435 12.3.2 Ionic liquid nitroxides 436 12.3.3 Supported nitroxides 436 12.4 Chemoselectivity: oxidation of primary vs secondary alcohols 437 12.5 Chemoselectivity: oxidation of primary vs benzylic alcohols 438 12.6 Oxidation of secondary alcohols to ketones 439 12.7 Oxidations of alcohols to carboxylic acids 439 12.7.1 Oxidations leading to linear carboxylic acids 439 12.7.2 (Diol) oxidations leading to lactones 443 12.8 Stereoselective nitroxide-catalyzed oxidations 444 12.9 Secondary oxidants used in nitroxide-catalyzed reactions 446 12.9.1 Elemental halogens 446 12.9.2 Sodium hypochlorite (bleach) 446 12.9.3 Bis(acetoxy)iodobenzene (BAIB) 447 12.9.4 Oxygen (air) 448 12.9.5 Peroxides 449 12.9.6 Other organic secondary oxidants 450 12.9.7 Anodic, electrochemical oxidation 451 12.10 Use of nitroxide-catalyzed oxidations in tandem reactions 451 12.11 Predictable side reactions 453 12.11.1 Oxidations of sulfur 453 12.11.2 Oxidations of nitrogen 453 12.11.3 Oxidations of carbon 454 12.12 Comparison with other oxidation methods 454 12.13 Nitroxide-catalyzed oxidations and green chemistry 455 Acknowledgements 456 References 456

13. Metal–Nitroxide Complexes: Synthesis and Magnetostructural Correlations 461 Victor Ovcharenko 13.1 Introduction 461 13.2 Two types of nitroxide for direct coordination of the metal to the nitroxyl group 462 13.2.1 Complexes containing only >N−•O as a coordinating group 462 13.2.2 Complexes containing >N−•O and other functional groups as donor fragments 464 xii Contents

13.3 Ferro- and ferrimagnets based on metal–nitroxide complexes 465 13.3.1 Molecular magnets based on 1-D systems 470 13.3.2 Molecular magnets based on 2-D systems 474 13.3.3 Molecular magnets based on 3-D systems 480 13.4 Heterospin systems based on polynuclear compounds of metals with nitroxides 483 13.4.1 Reactions whose products retain both the multinuclear fragment and nitroxide 484 13.4.2 Transformation of polynuclear fragments in reactions with nitroxides 487 13.4.3 Transformation of both the polynuclear fragment and the starting nitroxide 489 13.5 Breathing crystals 490 13.6 Other studies of metal–nitroxides 494 13.6.1 Analytical applications 494 13.6.2 NMR spectroscopy 494 13.6.3 Stabilization of nitroxides with β-hydrogen atoms 496 13.6.4 Increased reactivity 496 13.6.5 Hidden exchange interactions 497 13.6.6 Contrast agents 499 13.7 Conclusions 500 References 500

14. Rechargeable Batteries Using Robust but Redox Active Organic Radicals 507 Takeo Suga and Hiroyuki Nishide 14.1 Introduction 507 14.2 Redox reaction of organic radicals 508 14.3 Mechanism and performance of an organic radical battery 509 14.4 Molecular design and synthesis of redox active radical polymers 512 14.4.1 Poly(methacrylate)s and poly(acrylate)s 512 14.4.2 Poly(vinyl ether)s and poly(allene)s 514 14.4.3 Poly(cyclic ether)s 514 14.4.4 Poly(norbornene)s 514 14.4.5 Poly(acetylene)s 514 14.4.6 Poly(styrene)s 515 14.4.7 Combination of radicals with biopolymers and ionic liquids 515 14.5 A totally organic-based radical battery 515 14.6 Conclusions 517 References 518

15. Spin Labeling: A Modern Perspective 521 Lawrence J. Berliner 15.1 Introduction 521 15.2 The early years 522 15.3 Advantages of nitroxides 523 15.4 Applications of spin labeling to biochemical and biological systems 524 15.4.1 Stoichiometry and speciﬁcity: proteins and enzymes 524 15.4.2 The reporter group approach: who makes the news? 525 Contents xiii

15.5 Distance measurements 526 15.5.1 Metal–spin label distance measurements 526 15.5.2 Spin label–spin label distance measurements 526 15.5.3 Example of strong dipolar interactions 527 15.5.4 Multiple-quantum EPR and distance measurements 528 15.6 Site directed spin labeling (SDSL): how is it done? 529 15.6.1 The SDSL paradigm 530 15.6.2 SDSL parameters 530 15.7 Other spin labeling applications 531 15.7.1 pH sensitive spin labels 532 15.7.2 Spin labeled DNA – structure, dynamics and sequence analysis 532 15.8 Conclusions 534 References 534

16. Functional in vivo EPR Spectroscopy and Imaging Using Nitroxide and Trityl Radicals 537 Valery V. Khramtsov and Jay L. Zweier 16.1 Introduction 537 16.2 Nitroxyl radicals 538 16.3 Triarylmethyl (trityl) radicals 539 16.4 In vivo EPR oximetry using nitroxyl and trityl probes 539 16.4.1 Magnetic resonance approaches for in vivo oximetry 540 16.4.2 Nitroxide probes for EPR oximetry 540 16.4.3 TAM oximetric probes 545 16.5 EPR spectroscopy and imaging of pH using nitroxyl and trityl probes 547 16.5.1 pH-sensitive nitroxyl radicals 547 16.5.2 Dual function pH- and oxygen-sensitive trityl radicals 553 16.6 Redox- and thiol-sensitive nitroxide probes 556 16.6.1 Nitroxides as redox-sensitive EPR probes 556 16.6.2 Disulﬁde nitroxide biradicals as GSH-sensitive EPR probes 558 16.7 Conclusions 562 Acknowledgements 563 References 563

17. Biologically Relevant Chemistry of Nitroxides 567 Sara Goldstein and Amram Samuni 17.1 Introduction 567 17.2 Mechanisms of nitroxide reactions with biologically relevant small radicals 569 17.3 Nitroxides as SOD mimics 571 17.4 Nitroxides as catalytic antioxidants in biological systems 573 17.5 Conclusions 576 Acknowledgements 576 References 576

Index 579

Preface

Valency is a core tenet of chemical structure and bonding. In essence, valency can be thought of as a “bond-forming capability” parameter that permits understanding of the chemical formula and properties of known compounds, the prediction of the existence of new ones, and the rationalization of the non-existence (or instability) of species with incompletely satisfied valencies. This last point provides a rationale for why radicals – with an unpaired electron and, as such, quintessential examples of subvalent compounds – are typically described as short-lived, highly reactive species. To be sure, the vast majority of radicals based on s- and p-block elements are indeed thermodynamically and kinetically unstable. Thus, it should not be surprising that, since Gomberg’s paradigm-shifting discovery of the triphenylmethyl radical in 1900, the very existence of radicals stable enough to be observed or isolated has always been met with wonder (and at times skepticism) by the general chemistry community. The ongoing spate of publications highlighting the discovery of a new molecule that can be isolated but has an unpaired electron serves as evidence that stable radicals are generally regarded as exotic and esoteric compounds. In fact, several kinds of stable molecules containing one (or more) unpaired electrons have been known for decades, and several more general classes of stable radicals have been developed in recent times. Moreover, applications which explicitly make use of stable radicals abound, spanning synthesis, materials science, and medicine. Many review articles and books have dealt with particular kinds or uses of stable radicals. However, the only attempt to provide unified coverage of the stable radical literature was a book by Forrester, Hay, and Thomson (Organic Chemistry of Stable Free Radicals, Academic Press) published in 1968. The present book is, in essence, an update on the huge developments in (and diversification of) the field of stable radicals over the four decades since the book by Forrester et al. My ambitions for this book were to bring together the diverse range of topics and interests whose common theme is stable neutral radicals (the omission of radical ions was a deliberate decision, made largely due to space limitations). Thus, Chapters 1–10 introduce readers to the many different kinds (organic, inorganic, old, new) of existing stable radicals, and Chapters 11–17 provide accounts of various applications of stable radicals, ranging from synthesis (oxidation catalysts, living radical polymerization) to materials science (magnetochemistry, battery components) to chemical biology/medicine (spin labeling, EPR imaging, redox biochemistry). I offer my sincere thanks to all of the contributors to each chapter who have contributed to what I hope will be viewed as an informative, interesting, and illuminating text.

Robin G. Hicks Victoria, Canada

List of Contributors

D. Scott Bohle, Department of Chemistry, McGill University, 801 Sherbrooke St.W., Montreal, Canada H3A 2K6 Lawrence J. Berliner, Department of Chemistry and Biochemistry, University of Denver, 2190 E. Iliff Avenue, Denver, CO 80208, USA Christian Bruckner,¨ Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA Tristram Chivers, Department of Chemistry, University of Calgary, Calgary, AB, Canada T2N 1N4 Michael K. Georges, Department of Chemical and Physical Sciences, University of Toronto at Mississauga, 3359 Mississauga Road, Mississauga, Ontario, Canada L5L 1C6 Sara Goldstein, Institute of Chemistry and the Accelerator Laboratory, The Hebrew University of Jerusalem, Jerusalem 91904, Israel Robin G. Hicks, Department of Chemistry, University of Victoria, Victoria, British Columbia, Canada V8W 3V6 Keith U. Ingold, National Research Council, Ottawa, Ontario, Canada K1A 0R6

Hakim Karoui, Laboratoire Chimie Provence, UMR 6264, Aix-Marseille Universite´ and CNRS, Centre de St Jer´ ome,ˆ 13397, Marseille Cedex´ 20, France Valery V. Khramtsov, Dorothy M. Davis Heart and Lung Research Institute, 201 HLRI, 473 W 12th Ave, The Ohio State University, Columbus, OH 43210, USA Jari Konu, Department of Chemistry, University of Calgary, Calgary, AB, Canada T2N 1N4

Franc¸ois Le Moigne, Laboratoire Chimie Provence, UMR 6264, Aix-Marseille Universite´ and CNRS, Centre de St Jer´ ome,ˆ 13397, Marseille Cedex´ 20, France Julie Lukkarila, Department of Chemical and Physical Sciences, University of Toronto at Mississauga, 3359 Mississauga Road, Mississauga, Ontario, Canada L5L 1C6 Yasushi Morita, Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan Shinsuke Nishida, Department of Chemistry, Graduate School of Science, Osaka City University, Osaka 558-8585, Japan Hiroyuki Nishide, Department of Applied Chemistry, Waseda University, Tokyo 169–8555, Japan

Olivier Ouari, Laboratoire Chimie Provence, UMR 6264, Aix-Marseille Universite´ and CNRS, Centre de St Jer´ ome,ˆ 13397, Marseille Cedex´ 20, France xviii List of Contributors

Victor Ovcharenko, International Tomography Center, Novosibirsk, Russia

Imma Ratera, Institut de Ciencia` de Materials de Barcelona (ICMAB-CSIC), 08193 Bellaterra (Barcelona), Spain Amram Samuni, Department of Molecular Biology, The Hebrew University of Jerusalem - Hadassah Medical School, Jerusalem 91120, Israel Takeo Suga, Department of Applied Chemistry, Waseda University, Tokyo 169-8555, Japan Andrea R. Szkurhan, Department of Chemical and Physical Sciences, University of Toronto at Missis- sauga, 3359 Mississauga Road, Mississauga, Ontario, Canada L5L 1C6 Fabrice Thomas, Inorganic Redox Chemistry, Department of Molecular Chemistry (UMR-5250), Univer- sity of Grenoble, BP 53, 38041, Grenoble Cedex 9, France Thomas T. Tidwell, Department of Chemistry, University of Toronto, Toronto, Ontario, Canada M5S 3H6

Paul Tordo, Laboratoire Chimie Provence, UMR 6264, Aix-Marseille Universite´ and CNRS, Centre de St Jer´ ome,ˆ 13397, Marseille Cedex´ 20, France

Jaume Veciana, Institut de Ciencia` de Materials de Barcelona (ICMAB-CSIC), 08193 Bellaterra (Barcelona), Spain Jay L. Zweier, Dorothy M. Davis Heart and Lung Research Institute, 611 HLRI, 473 W 12th Ave, The Ohio State University, Columbus, OH 43210, USA 1 Triarylmethyl and Related Radicals

Thomas T. Tidwell Department of Chemistry, University of Toronto, Ontario, Canada

1.1 Introduction

1.1.1 Discovery of the triphenylmethyl radical During the Nineteenth Century the understanding of the structure of organic compounds was beginning to evolve. The theory of free radicals had risen to prominence, and then fallen into disrepute. This changed abruptly with the bold announcement in 1900 by Moses Gomberg of the formation of the stable and persistent free radical triphenylmethyl 1, with its radical character shown by its facile reaction with oxygen forming the peroxide 2 (Equation 1.1).1 This had an immediate impact, and was a major landmark that set the stage for the rapid development of free radical chemistry in the Twentieth Century. Gomberg’s work attracted the attention of the world chemical community, and led to careful scrutiny and the ultimate acceptance of this controversial discovery.2

Ag O2 Cl C• O O −AgCl (1.1)

1 2

Gomberg treated triphenylmethyl chloride with silver or zinc metal and obtained a colored solution, which upon reaction with oxygen yielded peroxide 2. The species in solution was confidently identified by Gomberg as the triphenylmethyl radical 1, and he published his discovery in both German and English.1 Over the next decade there was much dispute as to the identification of 1, but Wilhelm Schlenk and

Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds Edited by Robin G. Hicks c 2010 John Wiley & Sons, Ltd 2 Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds coworkers in 1910 obtained tris(4-biphenylyl)methyl 3 as a deeply colored solid that was almost completely dissociated in solution, which conﬁrmed the existence of 1.2i

Ph C•

Ph 3

Upon removal of the solvent for the isolation of 1, a solid dimer was obtained, for which the symmetrical head-to-head structure 4 as well as the unsymmetrical structure 5 (head-to-tail, Jacobson structure)3a and 6 (tail-to-tail, Heintschel structure)3b,c were given serious consideration. However, as recounted by McBride,3d the wrong structure for the dimer, namely the head-to-head structure 4, became accepted for more than half a century, before this was corrected to the unsymmetrical structure 5 based on spectroscopic data.3e In retrospect, not only was the original evidence for the misidentiﬁed structure rather ﬂimsy, but techniques, such as NMR, IR, and UV, were also widely available that would have permitted correction of this structure well before 1968. This provides a cautionary tale that skepticism and a critical look at the evidence available for supposed chemical truths is warranted even in the face of conventional wisdom.

4 5

The preparation and identification of the stable triphenylmethyl radical was one of the great chemical discoveries of the Twentieth Century, but surprisingly this was not honored by the award of the Nobel Prize. As revealed by the investigation by Lennart Eberson in the Nobel archives, Gomberg was repeatedly nominated for the award but, due to a series of unfortunate circumstances, the nominations were not accepted.3f Despite Gomberg’s confident assertion in his first paper that he had proof of the existence of the radical there was later some equivocation, and some contrary opinions, which were enough for the Nobel Committee not to approve the award. With the later preparation of the tris(4-biphenylyl)methyl radical 3 as a stable solid the uncertainty vanished,2i but then subsequent nominations were turned down Triarylmethyl and Related Radicals 3 either because both Gomberg and Schlenk were not nominated in the same year, or because too much time had elapsed since the initial discovery. Even in 1940 Gomberg was still being nominated, but without success. Gomberg’s discovery was a clearly momentous discovery by a single individual, and although well recognized he did not receive the ultimate accolade he deserved. Paradoxically, Gerhard Herzberg was awarded the 1971 prize in chemistry “for his contributions to the knowledge of electronic structure and geometry of molecules, particularly free radicals”, studies which had occupied him for 30 years. By 1968 the study of stable free radicals had advanced to the stage that the book Organic Chemistry of Stable Free Radicals appeared,4 but in Chapter 2 entitled “Triarylmethyls and Other Carbon Radicals” the introductory paragraph describing the discovery of triphenylmethyl in 1900 ended with the dispiriting words “The behaviour of such radicals was elucidated during the following twenty years, mainly by the work of Gomberg, Schlenk and Wieland, since then little new chemistry has come to light although numerous triarylmethyls have been prepared and more physical data are available.” However six pages later, under “Dimerisation” there was the alarming statement “Much of what has been said in this section may require revision in light of the recent communication by Lankamp, Nauta and MacLean”, which described the surprising but in retrospect completely predictable finding3d,e that the triphenylmethyl dimer had the head-to-tail structure 5. The rapid development in triarylmethyl radical chemistry since 1968 also belies the tacit assumption of the authors noted above that such studies had become an intellectual backwater. Much of the rather extensive chemistry of triarylmethyl radicals described in this earlier review is not repeated here. The period from 1968 has been a new golden age for free radical chemistry, and this was given great impetus by the widespread use of electron paramagnetic resonance (EPR) spectroscopy, which led to a rapid development of free radical chemistry, and includes many advances in the study of triarylmethyl radicals.

1.1.2 Bis(triphenylmethyl) peroxide The reaction of the triphenylmethyl radical with oxygen to form the peroxide discovered by Gomberg in 1900 (Equation 1.1) was a strong piece of evidence for the radical structure 1.5,6 The afﬁnity of carbon- centered radicals for oxygen remains one of their deﬁning characteristics, and was a striking chemical property that provided strong evidence for the proposed free radical character. The addition of oxygen to 1 had been shown to discharge the color,5a and this formation of an initial peroxy radical was later shown to be reversible.5b Just as for the triphenylmethyl radical dimer, there were three conceivable structures for the peroxide corresponding to the dimer structural models, namely head-to-head (2), head-to-tail (7), and tail-to-tail (8). The head-to-head structure 2 proved to be correct, but substituted derivatives of 7 and 8 were later found.6

H O O O O H H

8 7

The tris(2,6-dimethoxyphenyl)methyl radical 9 was crystallized and found to have a structure with two of the aryl rings twisted out the plane of the central carbon by 61◦, while the third was almost coplanar with an 11◦ twist angle.6 Reaction of 9, and of the bis(2,6-dimethoxyphenyl)phenylmethyl radical 10, 4 Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds in solution in the presence of air resulted in crystallization of the substituted Heintschel and Jacobson peroxides 11 and 12, respectively, with the structures proven by NMR, and by X-ray, respectively.6

Me Me Me O O O Me Me O O •C •C O O Me Me O O Me O Me Me

9 10

Me Me O OMe O Me Me Me H Me O O O O MeO O O Me O O Me O O Me Me O O O O O Me O Me O H Me H Me Me O O O Me Me Me

11 12

1.2 Free radical rearrangements

Substrates containing the triphenylmethyl group have been important in the discovery and elucidation of the ﬁrst free radical rearrangements.7 Wieland observed in 1911 that the Gomberg peroxide 2 rearranged upon heating to the pinacol ether 15 and attributed this to initial dissociation forming an intermediate oxyl radical 13, and this rearranged forming the radical 14 which dimerized to give 15 (Equation 1.2).7a Recent experimental and computational studies indicate this reaction occurs via a phenyl-bridged intermediate.7g

Ph Ph ∆ 2 O• •C O PhO OPh (1.2) Ph Ph

13 14 15

There was a long delay from this observation by Wieland of a radical rearrangement of Gomberg’s peroxide until the generality of radical rearrangements was recognized. A key discovery by Urry and Kharasch in 1944 of the neophyl rearrangement (Equation 1.3)7d included the proposal for the neophyl radical intermediate 16 and radical 17 forming 18 and other products after work-up (Equation 1.3).7c Triarylmethyl and Related Radicals 5

The McBay rearrangement of acyl radical 19 forming 20 leading to the benzyl radical by decarbonylation is a more recent example (Equation 1.4).7e,f

CH CH3 CH CH 3 PhMgBr 3 3 • • CH2Cl CH2 C H CoCl (1.3) CH3 CH3 CH3 CH3

16 17 18

O −CO • Ph CH • = • 2 CH2C O CH2 (1.4)

19 20

Thermolysis of bis(triphenylmethyl) peroxide 2 in the presence of triphenylmethyl radical resulted in the observation of luminescence from both benzophenone and triphenylmethyl radical.8 The reaction was interpreted as involving chemiluminescent activation of the triphenylmethyl radical by triplet benzophenone, and was claimed to be the ﬁrst observed chemical activation of an organic free radical. A mechanism was proposed involving disproportionation of the triphenylmethyloxyl radical 13 (Equation 1.5), but further substantiation of this mechanism appears warranted.

• Ph3C (s) Ph COOCPh • Ph COPh +Ph C=O* Ph C•(T) 3 3 2Ph3CO 3 2 − = 3 Ph2C O (1.5)

2 13

1.3 Other routes to triphenylmethyl radicals

Gomberg had already used phenylazotriphenylmethane 21 in the classic preparation of tetraphenylmethane 9a,b 9c • 22 in 1897 (Equation 1.6). Wieland, et al, in 1922, showed that Ph3C 1 was formed in this reaction, and proposed that phenyl radicals were also formed (Equation 1.6). Triphenylmethyl radicals were generated thermally from the perester 23 even at 25 ◦C (Equation 1.7)10a and at much higher temperature from the signiﬁcantly less reactive N -triphenylacetoxy 2,2,6,6-tetramethylpiperidine 25 (Equation 1.8).10b Reactivity studies demonstrated that both 23 and 25 reacted thermally via concerted two-bond cleavage (24 and 26, respectively) forming triphenylmethyl radicals 1 and carbon dioxide.

N ∆ N C• • − C N2 (1.6)

21 1 22 6 Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds

O 25 °C O −t-BuO• C• −CO O OBu-t O OBu-t 2 (1.7)

23 24 1

_ •N

O 146 °C O C• (1.8) C H −CO O N 6 6 ON 2

25 26 1

Many other dissociations of triarylmethyl substituted compounds can form triarylmethyl radicals,10c • including, for example, formation of the radical 4-Me2NC6H4(Ph)2C by photodissociation of 10d 4-Me2NC6H4(Ph)2CSiMe3. Pulse radiolysis of trityl derivatives Ph3CR (R = 2-naphthS, PhO, • PhNH, PhNMe, and PhCH2) in n-BuCl led to observation of Ph3C by generation of the radical cation +• +• n-BuCl( ) by electron removal followed by free electron transfer (FET) forming Ph3CR( ),which • + 10e dissociated to Ph3C and to Ph3C by separate reaction channels. These were proposed to form +• from two different conformations of Ph3CR( ), both from a planar radical cation, which follows the • + thermodynamically favored pathway generating R and Ph3C , and from a twisted radical cation, which + • 10e produces the thermodynamically unfavorable product pair R and Ph3C . Triphenylmethanol at high • temperature and pressure in subcritical water gave Ph3C , as detected by EPR spectroscopy, and 1 was 10f also formed in supercrtitical water, as shown by capture with hydrogen donors giving Ph3CH. A number of triphenylmethyl derivatives have been found to have potent anticancer properties,10g although there is no suggestion that this is due to triphenylmethyl radicals. A novel route for generation of triarylmethyl radicals was by reaction of 1-(haloalkenyl)-2- allenylbenzenes 27 in tetrahydrofuran (THF) at room temperature in the presence of mercury, resulting in cyclization to 2-naphthyldiphenylmethyl radical 28, as detected by EPR (Equation 1.9).11a The radical formed a head-to-tail dimer involving the phenyl group, and was captured by oxygen to give the peroxide (Equation 1.9).11a Several related ene–yne cyclizations have been examined, including a route to a di(radical) 29, which forms 30 (Equation 1.10).11b–d

H Ph C • Ph Ph C Hg Ph O2 O Ph C O THF Ph Ph (1.9) Ph rt

Hal 27 28 Triarylmethyl and Related Radicals 7

Bu-t Bu-t

C Bu-t 76 °C • Bu-t Bu-t (1.10) Bu-t • 29 30

1.4 The persistent radical effect

The persistent radical effect12 is an important phenomenon in radical chemistry that was ﬁrst discovered through studies of triphenylmethyl radicals. One manifestation of this effect is seen in the reaction of carbon tetrachloride with phenyl radicals and triphenylmethyl radicals generated from phenylazotriphenylmethane 21, which gives excellent yields of chlorobenzene and of 1,1,1-trichloro-2,2,2-triphenylethane 31 (Equation 1.11).12

∆ CCl4 1 Ph CN=NPh Ph C• +Ph• PhCl +CCl • Ph CCCl 3 − 3 3 3 3 N2 (1.11)

21 1 31

The azo compound 21 decomposes into phenyl and trityl radicals, together with a molecule of nitrogen. The more reactive phenyl radical then abstracts chlorine from carbon tetrachloride and radical coupling of the trichloromethyl radicals with the persistent trityl radicals 1 produces 31. It is striking that only unsymmetrical coupling takes place, and no appreciable amount of hexachloroethane is formed. The explanation is that formation of even trace amounts of hexachloroethane would also lead to formation of the dimer 5 of triphenylmethyl in equilibrium with the monomeric radical. Therefore, the concentration of triphenylmethyl will greatly exceed that of the transient trichloromethyl radical, and since the rates of reactions of trichloromethyl with itself and with triphenylmethyl are both close to the diffusion limit, unsymmetrical coupling will predominate. However, the concentration of triphenylmethyl will remain essentially constant, since for every trichloromethyl formed another triphenylmethyl is also produced. Experimental conﬁrmation is provided by EPR examination of the reacting solution, which shows a high concentration of the triphenylmethyl radical. This phenomenon was correctly analyzed in 1936 by Gomberg’s student Bachmann, who studied the role of triphenylmethyl in the reaction of pentaphenylethane 32 solution at 100 ◦C (Equation 1.12).12f This ethane dissociates rapidly and reversibly into triphenylmethyl and diphenylmethyl, but dimerization of the diphenylmethyl radical 33 to form detectable quantities of tetraphenylethane (which is stable under the reaction conditions) seldom occurs.

100 °C • • + (1.12)

32 1 33 8 Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds

= 12g The decomposition of Ph3CN NPh 21 in benzene has also been subjected to kinetic analysis and the effect of less persistent radicals, such as t-alkylperoxyls, which do decay irreversibly but only by relatively slow processes, was analyzed.12a A recent review on this subject is available.12h

1.5 Properties of triphenylmethyl radicals

The theoretical basis for the understanding of free radicals was first provided by G. N. Lewis in 1916.13a,b His clear recognition of the electron pair bond and the possibility of odd electron systems was heavily influenced by the work of pioneers such as Gomberg, Schlenk, and Wieland, who had shown remarkable prescience in formulating free radical structures without using the principles of electron pair bonding. The theoretical study of the triphenylmethyl radical was later provided by Erich Huckel¨ at the 1933 Faraday conference on free radicals, which brought together many, but not all, of the pioneers in this field.13c The electron-nuclear double resonance (ENDOR) and EPR spectra of triphenylmethyl 1,(4- biphenylyl)diphenyl-methyl 34), bis(4-biphenylyl)phenylmethyl 35, and tris(4-biphenylyl)methyl 4 radicals were measured in 1968 by Maki et al.13d and the signals for specific protons were assigned based on the observed and calculated spectra. Computations of the spin density distributions were compared to the experimental values. Other spectroscopic measurements of triarylmethyl radicals include the laser induced fluorescence and emission spectra.13e

Ph • Ph •

34 35

Studies of reactions of triarylmethyl radicals include kinetic measurements of hydrogen atom abstraction from thiols,14a electrochemical generation by oxidation of triaryl anions and the subsequent further oxidation to the carbocations,14b and reduction of carbocations to the radicals using cyclic voltammetry.14c The oxidation/reduction potentials of triphenyl- or tributyl-substituted silicon-, germanium-, or tin- centered radicals 36 were measured in acetonitrile, tetrahydrofuran, or dimethylsulfoxide by photomodu- lated voltammetry and through oxidation of the corresponding anions using linear sweep voltammetry for comparison to those of the carbon analogues (Equation 1.13).15 The order of reduction potentials follows Sn > Ge > C > Si, and is C > Si for the two oxidation potentials. Computational methods gave qualitative interpretation of the experimental results by considering a combination of effects, such as charge capacity, resonance stabilization, and solvation effects.

− − − −e _ e M M• M + (1.13)

36 (M = C, Si, Sn, Ge) Triarylmethyl and Related Radicals 9

1.6 Steric effects and persistent radicals

In his first paper Gomberg1a recognized that steric factors make a contribution to the stability of the triphenylmethyl radical, and Conant and Bigelow16a reported in 1928 the reversible dissociation at 50 ◦C of 1,2-(di-tert-butyl)tetraphenylethane 37 to the yellow radical 38 (Equation 1.14),16a which reacts rapidly • with oxygen. The radical 38 generated in the presence of Ph3C forms the mixed dimer 39 (Equation 1.14).16b The di-tert-butylbenzyl radical 40 was stable for several days in solution at room temperature, and the EPR spectrum indicated the phenyl group was twisted into coplanarity with the singly occupied p orbital, preventing spin delocalization.16c,d Other work showed that purely aliphatic radicals without β hydrogens, such as di-tert-methyl 41,17a and tri-tert-butylmethyl 42,17a and even triisopropylmethyl 4317b were sufficiently long lived in solution for direct observation by EPR. These radicals also did not dimerize but decayed by other undetermined routes. Such radicals with kinetic stability have been classified as persistent radicals.17c

Ph CH3 CH3 Ph CH3 • CH Ph3C 3 • t-Bu Bu-t 2 CH3 C Ph H CH3 (1.14)

37 38 39

CH3 CH3 CH3 CH3 H CH3 CH3 CH3 CH3 CH3 • Bu-t CH3 • • • CH3 CH CH3 C C Bu-t CH3 CH3 CH3 H H CH3 CH3 CH3 CH3 CH3 CH3

40 41 42 43

The importance of resonance stabilization of triarylmethyl radicals was emphasized by Pauling and Wheland in 1933.17d It had already been shown by Marvel and Munro that alkynyl groups with minimal steric barriers were also effective at promoting dissociation of the ethane 44 by stabilization of diarylmethyl radicals 45 (Equation 1.15).17e

Ph Ph 2 Ph C• (1.15)

44 45

1.7 Substituted triphenylmethyl radicals and dimers

The effect of substituents in stabilizing triarylmethyl radicals has been measured by determining the equilibrium constants for dissociation of the dimers of a large number of such radicals by EPR spectroscopy 10 Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds

Table 1.1 Equilibrium constants for the dimerization of triarylmethyl radical derivatives 46 and correlation with substituent constants

• • • • R, R1 σσσ +0.01σ logK R, R1 σσσ +0.01σ logK

H,H 0.00 0.0000 0.0000 −3.48 H,NO2 0.78 0.0630 0.0710 −2.55 H,t-Bu −0.20 0.0080 0.0055 −3.10 t-Bu,t-Bu −0.20 0.0080 0.0055 −2.39 H,CF3 0.54 −0.0086 −0.0019 −3.15 CF3,CF3 0.54 −0.0086 0.0019 −2.82 H,CN 0.70 0.040 0.0400 −2.66 CN,CN 0.70 0.0488 0.0488 −2.03 H,PhCO 0.42 0.0554 0.0554 −2.49 PhCO,PhCO 0.42 0.0554 0.0607 −2.05 H,Ac 0.50 0.0597 0.0597 −2.70 MeO,MeO −0.28 0.0185 0.0150 −2.63 H,MeO −0.28 0.0185 0.0185 −2.82 Ph,Ph −0.01 0.0615 0.0614 −1.57 H,Ph −0.01 0.0615 0.0614 −2.56 PhO,PhO −0.32 0.0185 0.0145 −2.78 H,PhO −0.32 0.0185 0.0145 −3.21 MeS,MeS 0.00 0.0630 0.0630 −1.72 H,MeS 0.00 0.0630 0.630 −2.78

(Equation 1.16).18a A Hammett-like equation was found correlating logK with σ • +0.01σ , which relates the monomer/dimer equilibrium constants with the radical stabilizing parameter σ • with a minute contribution from the polar substituent constant σ (Table 1.1). Captodative effects were not found in this study,18a but 1 an ENDOR study showed that radicals 46 (R = PhO; R = CF3, CN, phenyl) are stabilized with respect to dimerization to 47 by 0.6, 1.2, and <0.2 kcal/mol over the amounts expected on the basis of substituent additivity, suggesting some inﬂuence of captodative effects.18b

R R1 R1

Keq R1 C• (1.16) H R

R 46 47

Triarylmethyl radicals 9 and 48 fully substituted with 2,6-oxygen substituents on all three rings were prepared and characterized by EPR.19a The radical 9 had a twisted geometry as shown by EPR, and did not dimerize. As noted above, 9 was obtained in crystalline form and its X-ray structure determined; this was consistent with the interpretation of the EPR spectrum.6a The radical 49 with only two oxygen bridges was quite sensitive to oxygen and was extensively dissociated in the solid state, and the 2,6-hydrogens cause twisting out of the plane,19b while the dimer of 48 is undissociated in the solid, with a central C–C bond length of 1.63 A˚ measured by X-ray.19a,c,d

O O O H H C C • •

O O

48 49 Triarylmethyl and Related Radicals 11

Other hexaphenylethane molecules with structures determined by X-ray include 50, which is restricted from forming a head-to-tail dimer by the bulky substituents, with a central C–C bond length of 1.67(3) A.˚ 19e A different type of hexaphenylethane derivative is typiﬁed by 51, which had already been already prepared in 1933 for R = hydrogen,19f and has the central bond constrained by its intramolecular character. The central C–C bond of 51 (R = MeO) was measured as 1.670(3) A,˚ 19g and related examples with similar intramolecular constriction have bond lengths that are even longer.19h,i

R R t-Bu Bu-t

t-Bu Bu-t Bu-t R t-Bu R

t-Bu Bu-t t-Bu Bu-t

t-Bu Bu-t

50 51

A variety of triarylmethyl radicals 52 with electron donating substituents were prepared by reduction of the corresponding carbocations using cyclic voltametry (Table 1.2), including the ferrocenyl substituted radical 53 (Equation 1.17).20a These showed strong downward shifts in the reduction potentials due to the strongly electron donating substituents, and reversible redox behavior was even observed in aqueous solution.

Ar2 Ph Ph Ar C• C + C• 1 1 1 Ar Fe Ar Fe Ar (1.17)

52 53

The bis(diphenylpentafulvene) iron complex 54 was also prepared, for which the structure was considered as either the bis(radical) 54a or the bis(fulvene) 54b.20b The fact that the X-ray and calculated structure (Figure 1.1) showed the exocyclic groups on the same side of the molecule was taken as favoring the

Table 1.2 Triarylmethyl radicals 52 studied by cyclic voltammetry

Ar Ar1‘ Ar2

2,4,6-(MeO)3C6H2 2,4,6-(MeO)3C6H2 2,4,6-(MeO)3C6H2 2,4,6-(MeO)3C6H2 2,6-(MeO)2C6H3 2,6-(MeO)2C6H3 2,6-(MeO)2C6H3 2,6-(MeO)2C6H3 2,6-(MeO)2C6H3 4-MeOC6H4 2,6-(MeO)2C6H3 2,6-(MeO)2C6H3 2-MeOC6H4 2,6-(MeO)2C6H3 2,6-(MeO)2C6H3 Ph 2,6-(MeO)2C6H3 2,6-(MeO)2C6H3 Ferrocenyl Ph 2,6-(MeO)2C6H3 Ferrocenyl 2,6-(MeO)2C6H3 H 12 Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds

Figure 1.1 Calculated structure of 54a. (Reproduced by permission of Professor Mathias Tacke.) diradical structure, with some attraction between the two radical sites.20b Later computational studies agreed with this conclusion, and also found that the diradical was a ground state singlet.20c

Ph Ph C• C Ph Ph Fe Fe Ph Ph C• C Ph Ph 54a 54b

1.8 Tris(heteroaryl)methyl and related triarylmethyl radicals

Tris(2-thienyl)methyl and tris(3-thienyl)methyl radicals generated by zinc reduction of the corresponding carbocations were directly observed by EPR and characterized by their distinctive spectra.21a Tris(2- thienyl)methyl radical 55 generated by reduction of the corresponding cation with zinc dimerizes to a mixture of the tail to tail dimer 56 and head to tail dimer 57 (Equation 1.18).21b

S S S S S H S Zn H C + C• S S + C S DME S S S S S S S S 65 °C H S

55 56 57 (1.18) Triarylmethyl and Related Radicals 13

The 3- and 4-pyridyldiphenylmethyl radicals 58 were generated by treatment of the corresponding triarylmethyl chlorides with silver in benzene at room temperature (Equation 1.19), while the corresponding conversion of the 2-pyridyl isomer required silver in tetrahydofuran with ultrasound activation.22 All three radicals were observed by EPR and characterized by their distinctive spectra, and all formed dimers by head-to-tail coupling involving addition to a pyridyl ring. Dimers 59 and 60 from the 2- and 3-pyridyl radicals, respectively, resulted from hydrogen migration in the initial coupling products. The 4-pyridyl radical gave the N -trityl bonded dimer 61 that, upon heating at 70 ◦C, rearranged to 62, proposed to form by dissociation to the radical followed by dimerization involving a phenyl ring and irreversible formation of the product by hydrogen migration. In the range −27 to −15 ◦C reversible formation of the initial dimers was observed. Bond dissociation energies were determined that were about 42 kJ/mol larger than for the corresponding dimer of triphenylmethyl radical, and the greater stability of the pyridyl dimers was attributed to reduced steric repulsions in the pyridyl dimers due to the absence of two hydrogen atoms. Other factors, such as lower stability of the pyridyl radicals or attractive interactions between the nitrogen atoms and the other groups in the dimers, may also be involved.

Ag (N) Cl (N) C• (1.19)

N N N N

59 60

N N N

N 61 62

2-Triazolyldiarylmethanes 63 upon reaction with n-BuLi followed by iodine evidently gave unobserved free radicals 64, based on the isolation of dimers 65 (Equation 1.20).23 1-Triazolyldiarylmethanes 66 upon reaction with n-BuLi followed by iodine gave the radicals 67, which were the ﬁrst triarylmethyl radicals reported with a directly attached heteroatom at the radical center. The radicals formed the dimers 68 as 24 well as phenanthridines 69 (Equation 1.21). The latter were proposed to form from loss of N2 from 67 with cyclization (Equation 1.22). Radicals 71 generated from the corresponding triarylmethanes were 24 detected by EPR, and gave dimers 72, while 73 formed by loss of N2 with cyclization (Equation 1.23). 14 Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds

N Ar N Ar N Ar N N 1) n-BuLi (1.20) N N • N 2) I2 N Ph N Ph N Ph Ar

63 64 65

X 1 1 1 N Ar N Ar N Ar Ar1 N 1) n-BuLI N N X N N C• N + 2) I2 Ar Ar Ar N 3) H2O N (1.21) N N Ar

66 67 68 69

X X X

− N2 Ar • Ar Ar N N N (1.22) N N •

67 70 69

N N N N N N • + N (1.23) N N N

71 72 73

1.9 Delocalized persistent radicals: analogues of triarylmethyl radicals

The discovery by Gomberg of the triphenylmethyl radical opened the way for the discovery of a variety of related persistent radicals. Some of these are covered in greater detail elsewhere in this book. Schlenk and Mark reported the preparation of the equilibrating pentaphenylethyl radical 74,25a which exists as a long lived species (Equation 1.24). Karl Ziegler and coworkers prepared the tetraphenylallyl radical 7525b and the pentaphenylcyclopentadienyl radical 76.25c Triarylmethyl and Related Radicals 15

C• •C (1.24)

• •

75 76

The long-lived radical 77 wasﬁrstreportedbyLowenbein¨ and Folberth: it reversibly forms a dimer, and reacts only slowly with oxygen to give a peroxide.25d,e Radical 77 and its analogues have found extensive recent application as chain breaking antioxidants.25f,g These function by trapping peroxyl radicals and can completely suppress autoxidation. Diarylacetate radicals 78 have long been known and undergo reversible dimer formation25h,i and react with oxygen to form peroxides.25j,k Addition of the tetramethylpiperidiny- loxyl radical (TO•) to diphenylketene gave the radical 79, which reacted with oxygen forming the peroxide 80, with the structure determined by X-ray crystallography (Equation 1.25).25l

Ar O • • C O Ar OR O

77 78

O• Ph Ph Me Me N Ph Ph O TO2C O TO• O2 O CO T Me Me C O •C 2 Ph Ph (1.25) Ph Ph OT TO• 79 80

The Koelsch radical 81 was prepared in 1931 but, somewhat surprisingly, even at this date, the idea of stable radicals met some resistance. Koelsch prepared and submitted for publication a report of the 16 Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds long lived radical, but the lack of reactivity of the radical towards oxygen seemed improbable, and the manuscript was rejected. In 1957, EPR spectroscopy of the same sample conﬁrmed the identiﬁcation, and the original manuscript was resubmitted and published.26a Nitrogen analogues 82 were reported in 2000.26b More recently, the Koelsch-type diradicals 83 and 84 have been reported and found to have singlet and triplet ground states, respectively.26c,d

R1 R R1

• N •

81 82

• •

83 84

1.10 Tetrathiatriarylmethyl (TAM) and related triarylmethyl radicals

Specialized triarylmethyl radicals are finding extensive and increasing use in imaging applications using EPR spectroscopy because of their extraordinary stability in cells and tissues, narrow line widths resulting in high analytical resolution at concentrations in the µM range, and enhanced sensitivity to oxygen.27 Derivatives which vary in their state of ionization as a function of pH show a corresponding dependence upon of their EPR spectra with pH and are being examined for a variety of biomedical applications. Tetrathiatriarylmethyl (TAM) trityl radicals 86 and various structural variations were originally developed in industry for use as contrast agents in Overhauser magnetic resonance imaging (OMRI),27–29 and were first reported in the patent literature.27c– f Their properties are discussed in detail in Chapter 16. Important characteristics of these materials are the narrow signals promoted by the absence of inhomogeneous hyperfine couplings. An earlier preparation of these compounds29c has been improved by a convenient large scale synthesis of the sodium salt of 86 (known as Finland trityl).28 The oxygen substituted analogue 87 and the methyl deuterated derivative have also been studied, and together with 86 are soluble in water with single sharp lines in the EPR spectra.27a The radical 86 was formed in one step in quantitative yield by treatment of the tri(tert-butyl ester) 85 in neat trifluoroacetic acid at room temperature (Equation 1.26).28 Other trityl alcohols formed radicals in a similar fashion.28 Triarylmethyl and Related Radicals 17

S CO2Bu-t S CO2H

S S S S S S S S

S CF3CO2H S • t-BuO2C C OH HO2C C S S (1.26) SS S SS S S S

S S CO2Bu-t CO2H

85 86

CO2Me O

O O

O Ar C• O

O O

O CO2Me 87

The presence of ionizable carboxyl groups on the TAM radicals leading to pH sensitivity of the EPR parameters has been examined, as has the presence of limited numbers of aryl ring protons leading to doublet or triplet EPR signals.29a These serve as dual function pH and oxygen probes. Dendritic TAM molecules were prepared in which encapsulation of the radical by the dendrimer enhances their stability and solubility in water over a wide pH range, and the copper(II) complex of 88 is a highly effective pH probe.29f Amino substituted TAMs 90 and related derivatives were prepared by selective reduction of one or more carboxyl groups of 85 to hydroxylmethyl substituents, and these were converted to mesylates that were displaced by amino groups forming 89. Conversion to radicals 90 was accomplished using trifluoroacetic acid (Equation 1.27), and provides derivatives useable in other pH ranges.29b Collisions of these probe molecules reduce relaxation times of the probes and provide a measure of local oxygen concentration; to investigate the viscosity and frequency dependence on the EPR spectra, measurements of TAM radicals in glycerol/water ranging from 10 to 90 % concentration were carried out, including the use of deuterated solvents.30a The conformations of the TAM radicals in solution were investigated using 1H, 2H, and 13C measurements,30b with hyperfine coupling tensors determined using X-band pulsed electron-nuclear double resonance (ENDOR) spectroscopy for two triarylmethyl (trityl) radicals used in EPR imaging and oximetry.30b Calculated geometries were used to predict the experimental hyperfine tensors, and these gave satisfactory agreement.30b Rapid-scan EPR spectra of a 0.2 mM aqueous solution of deuterated 86 (trityl-CD3) radical at 9.8 GHz using a rectangular resonator were obtained.31a Larger effects of magnetic field inhomogeneities were found for the extended structure of 86 than in smaller lithium phthalocyanine crystals. 18 Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds

O O

LiO2C CO2Li N OLi LiO N

O NH HN O

N N O S S O HN S S NH NH O O • S C S N N S S LiO2C CO2Li S S

CO LI LiO C 2 S S 2

LiO2C HN O CO2Li

N N N

LiO2C HN NH CO2Li O O

S CH(D)2NR2 S CH(D)2NR2

S S S S S S S S

S 1) KOH S • EtO2C C OH HO2C C S 2) CF3CO2H S (1.27) SS S SS S S S

S S CH(D)2NR2 CH(D)2NR2

89 90

Continuous wave spectra at W-band of four triarylmethyl (trityl) radicals at 100 K in 1 : 1 water/glycerol exhibit rhombic EPR spectra.31b The results are consistent with assignment of the Raman process and a local mode as the dominant relaxation processes. Low frequency (300 MHz) pulsed EPR with pulsed FID detection of triarylmethyl radicals injected in mice was used to obtain three-dimensional oxymetric images.32a,b Single-point imaging, a technique developed for solid state NMR, applied to pulsed EPR imaging yielded artifact-free spatial images.32a Continuous wave EPR imaging was used to obtain slice-selective images of free radicals without measuring three-dimensional (3D) projection data.32c Triarylmethyl and Related Radicals 19

Notable among these widely studied radicals is 91, which has been extensively derivatized for optimum 27b,29a •− properties. This reacts with superoxide (O2 ) radicals with an apparent second order rate constant of 3.1 × 103 M−1 s−1, and this was used for analysis of the superoxide.33a,b Assay of superoxide by monitoring the newly formed product absorption peak at 546 nm33a or by EPR33b gave good agreement with the widely used cytochrome c method of superoxide detection.33a The identity of the species giving rise to the observed absorption at 546 nm, which was stable for 12 hours, was not identiﬁed. Hydroperoxide was detected by ferrous oxidation-xylenol orange (FOX) assay,33b but mass spectrometric analysis did not detect a covalent adduct, and formation of an ion pair 92 of hydroperoxide anion and the trityl cation was proposed (Equation 1.28).33a

HO HO HO HO HO S CO2H HO S CO2H

HO S HO S S S S OH S S S OH •− S OH O2 S OH • + HO2C C HO2C C S OH S OH (1.28)

SS S OH SS S OH HO S HO S _ HO S HO S CO2H CO2H OOH HO HO HO HO

91 92

Dynamic nuclear polarization of the substrate by microwave irradiation of 91 permitted the measurement of the kinetics of trypsin catalyzed hydrolysis of Nα-benzoyl-l-arginine ethyl ester by 13C NMR using stopped ﬂow.33c Extension of this method to the study of other enzyme catalyzed reactions is anticipated. The dynamic nuclear polarization (DNP) of the triphenylmethyl radical in water has been compared to that of the 4-hydroxyTEMPO radical 93 and the latter showed considerably larger DNP enhancements up to 100 (9 GHz) and −20 (94 GHz) using continuous microwave irradiation.33d

HO N O•

The degradation of tetrathiatriarylmethyl radicals 86 used as oximetry probes for EPR imaging applications due to reaction with oxygen was investigated experimentally and by using computational methods.33e Tricarboxylate salts bearing CO2Na groups were the most stable, and it was proposed that degradation by oxygen attack on the TAMs preferentially occurred at unsubstitued 4-positions of the aryl rings leading to • hydroperoxide intermediates. Radical pathways with addition of O2 or HO2 to 86 forming 94 or 95 were − considered (Equation 1.29), as well as ionic routes, such as the addition of the anion HO2 to the cation of 74 forming 80.33e 20 Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds

S R S R S R

S S S S S S S S S S S S HO •O

O S HOO• S O2 O S C• H S S H S (1.29) SS S SS S SS S S S S

S R S R S R

95 86 94

1.11 Perchlorinated triarylmethyl radicals

Perchlorination of aromatic compounds using a reagent composed of sulfur monochloride and aluminum chloride in sulfuryl chloride (SCM reagent) was introduced in 1960,34a and has proved very effective. In 1971 this method was applied to the formation of perchlorodiphenylmethyl 97 and perchlorotri- phenylmethyl 99 radicals, both of which have lifetimes in air of decades and are characterized as inert carbon free radicals.34b,c Conversion of the chlorocarbon 96 to 97 could be effected by reduction with sodium iodide (Equation 1.30). More generally, radical 99 and its derivatives are prepared by deproto- nation of the corresponding tris(pentachlorophenyl)methane 98 followed by oxidation of the anion with iodine (Equation 1.31).34b,c The ortho-chorines on the aryl rings effectively shield the central radical site, preventing reactions of the chlorinated radicals (Figure 1.2). This family is reviewed in detail in Chapter 2.

Cl Cl Cl Cl

Cl Cl S2Cl2, AlCl3 Cl NaI Cl C SO Cl Cl (1.30) 2 2 Cl Cl

Cl Cl Cl Cl

Cl Cl Cl Cl 96 97

Cl Cl Cl Cl

Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl 1. NaOH Cl CH Cl C• 2. I Cl 2 Cl (1.31) Cl Cl Cl Cl Cl Cl Cl Cl

Cl Cl Cl Cl 98 99