Arene Chemistry

Jacques Mortier, PhD, is Professor of Organic Chemistry at the University of Maine in Le Mans (France), where he teaches classes on Industrial Organic Chemistry and Reaction Mechanisms in Aromatic and Heteroaromatic Chemistry. Dr. Mortier started his career as a research chemist in the crop protection industry. At the University of Maine, his research is focused on various topics dealing with polar organometallics, directed aromatic metalation methodologies, and the study of reaction mechanisms. He has extensive experience as a consultant for the chemical industry. In recognition of his research expertise, he was distinguished as a member of the University Institute of France (IUF).

• LIST OF CONTRIBUTORS xxiPREFACE xxvPART I ELECTROPHILIC AROMATIC SUBSTITUTION 11 Electrophilic Aromatic Substitution: Mechanism 3Douglas A. Klumpp1.1 Introduction, 31.2 General Aspects, 41.3 Electrophiles, 41.4 Arene Nucleophiles, 121.5 π‐Complex Intermediates, 171.6 σ‐Complex or Wheland Intermediates, 221.7 Summary and Outlook, 27Abbreviations, 27References, 282 Friedel–Crafts Alkylation of Arenes in Total Synthesis 33Gonzalo Blay, Marc Montesinos‐Magraner, and José R. Pedro2.1 Introduction, 332.2 Total Synthesis Involving Intermolecular FC Alkylations, 342.3 Total Synthesis Involving Intramolecular FC Alkylations, 372.4 Total Synthesis Through Tandem and Cascade Processes Involving FC Reactions, 462.5 Total Synthesis Involving ipso‐FC Reactions, 542.6 Summary and Outlook, 562.7 Acknowledgment, 56Abbreviations, 56References, 573 Catalytic Friedel–Crafts Acylation Reactions 59Giovanni Sartori, Raimondo Maggi, and Veronica Santacroce3.1 Introduction and Historical Background, 593.2 Catalytic Homogeneous Acylations, 603.3 Catalytic Heterogeneous Acylations, 643.4 Direct Phenol Acylation, 733.5 Summary and Outlook, 77Abbreviations, 78References, 784 The Use of Quantum Chemistry for Mechanistic Analyses of SEAr Reactions 83Tore Brinck and Magnus Liljenberg4.1 Introduction, 834.2 The SEAr Mechanism: Quantum Chemical Characterization in Gas Phase and Solution, 874.3 Prediction of Relative Reactivity and Regioselectivity Based on Quantum Chemical Descriptors, 974.4 Quantum Chemical Reactivity Prediction Based on Modeling of Transition States and Intermediates, 1004.5 Summary and Conclusions, 102Abbreviations, 103References, 1035 Catalytic Enantioselective Electrophilic Aromatic Substitutions 107Marco Bandini5.1 Introduction and Historical Background, 1075.2 Metal‐Catalyzed AFCA of Aromatic Hydrocarbons, 1095.3 Organocatalyzed AFCA of Aromatic Hydrocarbons, 1165.4 Merging Asymmetric Metal and Organocatalysis in Friedel–Crafts Alkylations, 1255.5 Summary and Outlook, 126Abbreviations, 127References, 127PART II NUCLEOPHILIC AROMATIC SUBSTITUTION 1316 Nucleophilic Aromatic Substitution: An Update Overview 133Michael R. Crampton6.1 Introduction, 1336.2 The SNAr Mechanism, 1356.3 Meisenheimer Adducts, 1506.4 The SN1 Mechanism, 1596.4.1 Heterolytic and Homolytic Pathways, 1596.5 Synthetic Applications, 160Abbreviations, 167References, 1677 Theoretical and Experimental Methods for the Analysis of Reaction Mechanisms in SNAr Processes: Fugality, Philicity, and Solvent Effects 175Renato Contreras, Paola R. Campodónico, and Rodrigo Ormazábal‐Toledo7.1 Introduction, 1757.2 Conceptual DFT: Global, Regional, and Nonlocal Reactivity Indices, 1767.3 Practical Applications of Conceptual DFT Descriptors, 1797.4 SNAr Reaction Mechanism, 1837.5 Integrated Experimental and Theoretical Models, 1877.6 Solvent Effects in Conventional Solvents and Ionic Liquids, 1887.7 Summary and Outlook, 189Abbreviations, 190References, 1908 Asymmetric Nucleophilic Aromatic Substitution 195Anne‐Sophie Castanet, Anne Boussonnière, and Jacques Mortier8.1 Introduction, 1958.2 Auxiliary‐ and Substrate‐Controlled Asymmetric Nucleophilic Aromatic Substitution, 1988.3 Chiral Catalyzed Asymmetric Nucleophilic Aromatic Substitution, 2108.4 Absolute Asymmetric Nucleophilic Aromatic Substitution, 2138.5 Summary and Outlook, 214Abbreviations, 214References, 2159 Homolytic Aromatic Substitution 219Roberto A. Rossi, María E. Budén, and Javier F. Guastavino9.1 Introduction: Scope and Limitations, 2199.2 Radicals Generated by Homolytic Cleavage Processes: Thermolysis and Photolysis, 2239.3 Reactions Mediated by Tin and Silicon Hydrides, 2259.4 Radicals Generated by ET: Redox Reactions, 2299.5 Summary and Outlook, 237Abbreviations, 238References, 23810 Radical‐Nucleophilic Aromatic Substitution 243Roberto A. Rossi, Javier F. Guastavino, and María E. Budén10.1 Introduction: Scope and Limitations—Background, 24310.2 Mechanistic Considerations, 24510.3 Intermolecular SRN1 Reactions, 24810.4 Intramolecular SRN1 Reactions, 25810.5 Miscellaneous Ring Closure Reactions, 26210.6 Summary and Outlook, 264Abbreviations, 265References, 26511 Nucleophilic Substitution of Hydrogen in Electron‐Deficient Arenes 269Mieczysław Mąkosza11.1 Introduction, 26911.2 Oxidative Nucleophilic Substitution of Hydrogen, 27011.3 Conversion of the σH‐Adducts of Nucleophiles to Nitroarenes into Substituted Nitrosoarenes, 27611.4 Vicarious Nucleophilic Substitution of Hydrogen, 27811.5 Other Ways of Conversion of the σH‐Adducts, 29111.6 Concluding Remarks, 293Abbreviations, 295References, 295PART III ARYNE CHEMISTRY 29912 The Chemistry of Arynes: An Overview 301Roberto Sanz and Anisley Suárez12.1 Introduction, 30112.2 Structure and Representative Reactions of Arynes, 30112.3 Aryne Generation, 30312.4 Pericyclic Reactions, 30612.5 Nucleophilic Addition Reactions to Arynes, 31412.6 Transition Metal–Catalyzed Reactions of Arynes, 32712.7 Conclusion, 332Abbreviations, 332References, 333PART IV REDUCTION, OXIDATION, AND DEAROMATIZATION REACTIONS 33713 Reduction/Hydrogenation of Aromatic Rings 339Francisco Foubelo and Miguel Yus13.1 Introduction, 33913.2 The Birch Reaction, 33913.3 Metal‐Catalyzed Hydrogenations, 34513.4 Electrochemical Reductions, 35713.5 Other Methodologies, 35913.6 Summary and Outlook, 361Abbreviations, 361References, 36214 Selective Oxidation of Aromatic Rings 365Oxana A. Kholdeeva14.1 Introduction, 36514.2 Mechanistic Principles, 36714.3 Stoichiometric Oxidations, 37414.4 Catalytic Oxidations, 37514.5 Photochemical Oxidations, 38614.6 Electrochemical Oxidations, 38714.7 Enzymatic Hydroxylation, 38914.8 Summary and Outlook, 390Acknowledgments, 391Abbreviations, 391References, 39215 Dearomatization Reactions: An Overview 399F. Christopher Pigge15.1 Introduction, 39915.2 Alkylative Dearomatization, 40015.3 Photochemical and Thermal Dearomatization, 40515.4 Oxidative Dearomatization, 40815.5 Transition Metal‐Assisted Dearomatization, 41315.6 Enzymatic Dearomatization, 41815.7 Conclusions and Future Directions, 419Abbreviations, 419References, 420PART V AROMATIC REARRANGEMENTS 42516 Aromatic Compounds via Pericyclic Reactions 427Sethuraman Sankararaman16.1 Introduction, 42716.2 Electrocyclic Ring Closure Reaction, 42816.3 Introduction to Cycloaddition Reactions, 43316.4 Conclusions, 448Abbreviations, 448References, 44817 Ring‐Closing Metathesis: Synthetic Routes to Carbocyclic Aromatic Compounds using Ring‐Closing Alkene and Enyne Metathesis 451Charles B. de Koning and Willem A. L. van Otterlo17.1 Introduction, 45117.2 Alkene RCM for the Synthesis of Aromatic Compounds, 45417.3 Enyne Metathesis Followed by the Diels–Alder Reaction for the Synthesis of Benzene Rings in Complex Aromatic Compounds, 46417.4 Cyclotrimerization for the Synthesis of Aromatic Compounds by Metathetic Processes, 47017.5 Strategies for the Synthesis of Aromatic Carbocycles Fused to Heterocycles by the RCM Reaction, 47217.6 Future Challenges, 48117.7 Conclusions, 481Abbreviations, 482References, 48218 Aromatic Rearrangements in which the Migrating Group Migrates to the Aromatic Nucleus: An Overview 485Timothy J. Snape18.1 Introduction, 48518.2 Mechanisms by Classification, 48618.3 Summary and Outlook, 508Abbreviations, 508References, 508PART VI TRANSITION METAL‐MEDIATED COUPLING 51119 Transition Metal‐Catalyzed Carbon–Carbon Cross‐Coupling 513Anny Jutand and Guillaume Lefèvre19.1 Introduction, 51319.2 The Mizoroki–Heck Reaction, 51319.3 Cross‐Coupling of Aryl Halides with Anionic C‐Nucleophiles, 52319.4 The Sonogashira Reaction, 53019.5 The Stille Reaction, 53219.6 The Suzuki–Miyaura Reaction, 53419.7 The Hiyama Reaction, 53919.8 Summary and Outlook, 541Abbreviations, 541References, 54120 Transition Metal‐Mediated Carbon–Heteroatom Cross‐Coupling (C─N, C─O, C─S, C─Se, C─Te, C─P, C─As, C─Sb, and C─B Bond Forming Reactions): An Overview 547Masanam Kannan, Mani Sengoden, and Tharmalingam Punniyamurthy20.1 Introduction, 54720.2 C—N Cross‐Coupling, 55020.3 C—O Cross‐Coupling, 56120.4 C—S Cross‐Coupling, 56920.5 C—Se Cross‐Coupling, 57120.6 C—Te Cross‐Coupling, 57120.7 C—P Cross‐Coupling, 57220.8 C—As and C—Sb Cross‐Coupling, 57820.9 C—B Cross‐Coupling, 57820.10 Summary and Outlook, 579Abbreviations, 579References, 57921 Transition Metal‐Mediated Aromatic Ring Construction 587Ken Tanaka21.1 Introduction, 58721.2 [2+2+2] Cycloaddition, 58721.3 [3+2+1] Cycloaddition, 60121.4 [4+2] Cycloaddition, 60221.5 Intramolecular Cycloaromatization, 60821.6 Summary and Outlook, 612References, 61222 Ar–C Bond Formation by Aromatic Carbon–Carbon ipso‐Substitution Reaction 615Maurizio Fagnoni and Sergio M. Bonesi22.1 Introduction, 61522.2 Formation of Ar–C(sp3) Bonds, 61622.3 Formation of Ar–C(sp2) Bonds, 62022.4 Formation of Ar–C(sp) Bonds, 63822.5 Summary and Outlook, 639Abbreviations, 639References, 640PART VII C─H FUNCTIONALIZATION 64523 Chelate‐Assisted Arene C–H Bond Functionalization 647Marion H. Emmert and Christopher J. Legacy23.1 Introduction, 64723.2 Carbon–Carbon (C–C) Bond Formations, 65423.3 Carbon–Heteroatom (C–X) Bond Formations, 66023.4 Stereoselective C–H Functionalizations, 668Abbreviations, 669References, 66924 Reactivity and Selectivity in Transition Metal‐Catalyzed, Nondirected Arene Functionalizations 675Dipannita Kalyani and Elodie E. Marlier24.1 Introduction, 67524.2 Arylation, 67624.3 Alkenylation, 69324.4 Alkylation, 69924.5 Carboxylation, 70124.6 Oxygenation, 70124.7 Thiolation, 70424.8 Amination, 70624.9 Miscellaneous, 70824.10 Summary and Outlook, 710Abbreviations, 710References, 71025 Functionalization of Arenes via C─H Bond Activation Catalysed by Transition Metal Complexes: Synergy between Experiment and Theory 715Amalia Isabel Poblador‐Bahamonde25.1 Introduction, 71525.2 Mechanisms of C─H Bond Activation, 71625.3 Development of Stoichiometric C─H Bond Activation, 71825.4 Catalytic C─H Activation and Functionalization, 73025.5 Summary, 738Abbreviations, 738References, 738PART VIII DIRECTED METALATION REACTIONS 74126 Directed Metalation of Arenes with Organolithiums, Lithium Amides, and Superbases 743Frédéric R. Leroux and Jacques Mortier26.1 Introduction, 74326.2 Preparation and Reactivity of Organolithium Compounds, 74426.3 Directed ortho-Metalation (DoM), 74826.4 Directed remote Metalation (DreM), 75726.5 Peri Lithiation of Substituted Naphthalenes, 75926.6 Lithiation of Metal Arene Complexes, 76026.7 Lateral Lithiation, 76126.8 Analytical Methods, 76226.9 Synthetic Applications, 76526.10 Conclusion, 770Abbreviations, 771References, 77127 Deprotonative Metalation Using Alkali Metal–Nonalkali Metal Combinations 777Floris Chevallier, Florence Mongin, Ryo Takita, and Masanobu Uchiyama27.1 Introduction, 77727.2 Preparation of the Bimetallic Combinations and their Structural Features, 77827.3 Behavior of Alkali Metal–Nonalkali Metal Combinations, 77927.4 Mechanistic Studies on the Deprotometalation Using Alkali Metal–Nonalkali Metal Combinations, 78027.5 Scope and Applications of the Deprotometalation, 79027.6 Conclusion and Perspectives, 807Acknowledgments, 807Abbreviations, 807References, 80728 The Halogen/Metal Interconversion and Related Processes (M = Li, Mg) 813Armen Panossian and Frédéric R. Leroux28.1 Introduction, 81328.2 Generalities, 814  28.3.1 Reactivity, 81528.2.1 Monometallic Organolithium Reagents, 81428.3 Mechanism of the Halogen/Metal Interconversion, 81528.4 Halogen Migration on Aromatic Compounds, 81728.5 Selective Synthesis via Halogen/Metal Interconversion, 81828.6 The Sulfoxide/Metal and Phosphorus/Metal Interconversions, 82228.7 Aryl─Aryl Coupling Through Halogen/Metal Interconversion, 82728.8 Summary and Outlook, 830Abbreviations, 830References, 830PART IX PHOTOCHEMICAL REACTIONS 83529 Aromatic Photochemical Reactions 837Norbert Hoffmann and Emmanuel Riguet29.1 Introduction, 83729.2 Aromatic Compounds as Chromophores, 83829.3 Photosensitized and Photocatalyzed Reactions, 84929.4 Conclusion, 864Abbreviation, 865References, 86530 Photochemical Bergman Cyclization and Related Reactions 869Rana K. Mohamed, Kemal Kaya, and Igor V. Alabugin30.1 Introduction: The Diversity of Cycloaromatization Reactions, 86930.2 Electronic Factors in Photo‐BC, 87030.3 Scope and Limitations of the Photo‐BC, 87630.4 Enediyne Photocyclizations: Tool for Cancer Therapy, 88330.5 Conclusion, 883Abbreviations, 885References, 88531 Photo‐Fries Reaction and Related Processes 889Francisco Galindo, M. Consuelo Jiménez, and Miguel Angel Miranda31.1 Introduction, 88931.2 Mechanistic Aspects, 88931.3 Scope of the Reaction, 89431.4 (Micro)Heterogeneous Systems as Reaction Media, 89731.5 Applications in Organic Synthesis, 90031.6 Biological and Industrial Applications, 90231.7 Summary and Outlook, 905Abbreviations, 906References, 906PART X BIOTRANSFORMATIONS 91332 Biotransformations of Arenes: An Overview 915Simon E. Lewis32.1 Introduction, 91532.2 Dearomatizing Arene Dihydroxylation, 91532.3 Dearomatizing Arene Epoxidation, 91832.4 Arene Alkylation (Biocatalytic Friedel–Crafts), 91932.5 Arene Deacylation (Biocatalytic Retro Friedel–Crafts), 92232.6 Arene Carboxylation (Biocatalytic Kolbe–Schmitt), 92332.7 Arene Halogenation (Halogenases), 92532.8 Arene Oxidation with Laccases, 92532.9 Tetrahydroisoquinoline Synthesis (Biocatalytic Pictet–Spengler), 92932.10 Arene Hydroxylation, 93032.11 Arene Nitration, 93232.12 Summary and Outlook, 933Abbreviations, 934References, 934INDEX 939

"The broad covering of topics, made possible by the collaboration of world-renowned experts in differentfields of organic chemistry and by a good balance in depth of coverage, positions [this book] as a deskbook that would be extremely useful for students of advanced courses of organic chemistry, instructors and professors, as well as experienced chemists in both academy and industry, and to those interested in arene chemistry and its application." -- Chemistry International" ... Jacques Mortier has brought together contributions from leading practitioners in universities and research institutes from around the world to create a concise but comprehensive text on aromatic chemistry. ... They have effectively condensed the essential material, and made an ideal source of information ..." -- Applied Organometallic Chemistry