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 xxi

PREFACE xxv

PART I ELECTROPHILIC AROMATIC SUBSTITUTION 1

1 Electrophilic Aromatic Substitution: Mechanism 3
Douglas A. Klumpp

1.1 Introduction, 3

1.2 General Aspects, 4

1.3 Electrophiles, 4

1.4 Arene Nucleophiles, 12

1.5 π‐Complex Intermediates, 17

1.6 σ‐Complex or Wheland Intermediates, 22

1.7 Summary and Outlook, 27

Abbreviations, 27

References, 28

2 Friedel–Crafts Alkylation of Arenes in Total Synthesis 33
Gonzalo Blay, Marc Montesinos‐Magraner, and José R. Pedro

2.1 Introduction, 33

2.2 Total Synthesis Involving Intermolecular FC Alkylations, 34

2.3 Total Synthesis Involving Intramolecular FC Alkylations, 37

2.4 Total Synthesis Through Tandem and Cascade Processes Involving FC Reactions, 46

2.5 Total Synthesis Involving ipso‐FC Reactions, 54

2.6 Summary and Outlook, 56

2.7 Acknowledgment, 56

Abbreviations, 56

References, 57

3 Catalytic Friedel–Crafts Acylation Reactions 59
Giovanni Sartori, Raimondo Maggi, and Veronica Santacroce

3.1 Introduction and Historical Background, 59

3.2 Catalytic Homogeneous Acylations, 60

3.3 Catalytic Heterogeneous Acylations, 64

3.4 Direct Phenol Acylation, 73

3.5 Summary and Outlook, 77

Abbreviations, 78

References, 78

4 The Use of Quantum Chemistry for Mechanistic Analyses of SEAr Reactions 83
Tore Brinck and Magnus Liljenberg

4.1 Introduction, 83

4.2 The SEAr Mechanism: Quantum Chemical Characterization in Gas Phase and Solution, 87

4.3 Prediction of Relative Reactivity and Regioselectivity Based on Quantum Chemical Descriptors, 97

4.4 Quantum Chemical Reactivity Prediction Based on Modeling of Transition States and Intermediates, 100

4.5 Summary and Conclusions, 102

Abbreviations, 103

References, 103

5 Catalytic Enantioselective Electrophilic Aromatic Substitutions 107
Marco Bandini

5.1 Introduction and Historical Background, 107

5.2 Metal‐Catalyzed AFCA of Aromatic Hydrocarbons, 109

5.3 Organocatalyzed AFCA of Aromatic Hydrocarbons, 116

5.4 Merging Asymmetric Metal and Organocatalysis in Friedel–Crafts Alkylations, 125

5.5 Summary and Outlook, 126

Abbreviations, 127

References, 127

PART II NUCLEOPHILIC AROMATIC SUBSTITUTION 131

6 Nucleophilic Aromatic Substitution: An Update Overview 133
Michael R. Crampton

6.1 Introduction, 133

6.2 The SNAr Mechanism, 135

6.3 Meisenheimer Adducts, 150

6.4 The SN1 Mechanism, 159

6.4.1 Heterolytic and Homolytic Pathways, 159

6.5 Synthetic Applications, 160

Abbreviations, 167

References, 167

7 Theoretical and Experimental Methods for the Analysis of Reaction Mechanisms in SNAr Processes: Fugality, Philicity, and Solvent Effects 175
Renato Contreras, Paola R. Campodónico, and Rodrigo Ormazábal‐Toledo

7.1 Introduction, 175

7.2 Conceptual DFT: Global, Regional, and Nonlocal Reactivity Indices, 176

7.3 Practical Applications of Conceptual DFT Descriptors, 179

7.4 SNAr Reaction Mechanism, 183

7.5 Integrated Experimental and Theoretical Models, 187

7.6 Solvent Effects in Conventional Solvents and Ionic Liquids, 188

7.7 Summary and Outlook, 189

Abbreviations, 190

References, 190

8 Asymmetric Nucleophilic Aromatic Substitution 195
Anne‐Sophie Castanet, Anne Boussonnière, and Jacques Mortier

8.1 Introduction, 195

8.2 Auxiliary‐ and Substrate‐Controlled Asymmetric Nucleophilic Aromatic Substitution, 198

8.3 Chiral Catalyzed Asymmetric Nucleophilic Aromatic Substitution, 210

8.4 Absolute Asymmetric Nucleophilic Aromatic Substitution, 213

8.5 Summary and Outlook, 214

Abbreviations, 214

References, 215

9 Homolytic Aromatic Substitution 219
Roberto A. Rossi, María E. Budén, and Javier F. Guastavino

9.1 Introduction: Scope and Limitations, 219

9.2 Radicals Generated by Homolytic Cleavage Processes: Thermolysis and Photolysis, 223

9.3 Reactions Mediated by Tin and Silicon Hydrides, 225

9.4 Radicals Generated by ET: Redox Reactions, 229

9.5 Summary and Outlook, 237

Abbreviations, 238

References, 238

10 Radical‐Nucleophilic Aromatic Substitution 243
Roberto A. Rossi, Javier F. Guastavino, and María E. Budén

10.1 Introduction: Scope and Limitations—Background, 243

10.2 Mechanistic Considerations, 245

10.3 Intermolecular SRN1 Reactions, 248

10.4 Intramolecular SRN1 Reactions, 258

10.5 Miscellaneous Ring Closure Reactions, 262

10.6 Summary and Outlook, 264

Abbreviations, 265

References, 265

11 Nucleophilic Substitution of Hydrogen in Electron‐Deficient Arenes 269
Mieczysław Mąkosza

11.1 Introduction, 269

11.2 Oxidative Nucleophilic Substitution of Hydrogen, 270

11.3 Conversion of the σH‐Adducts of Nucleophiles to Nitroarenes into Substituted Nitrosoarenes, 276

11.4 Vicarious Nucleophilic Substitution of Hydrogen, 278

11.5 Other Ways of Conversion of the σH‐Adducts, 291

11.6 Concluding Remarks, 293

Abbreviations, 295

References, 295

PART III ARYNE CHEMISTRY 299

12 The Chemistry of Arynes: An Overview 301
Roberto Sanz and Anisley Suárez

12.1 Introduction, 301

12.2 Structure and Representative Reactions of Arynes, 301

12.3 Aryne Generation, 303

12.4 Pericyclic Reactions, 306

12.5 Nucleophilic Addition Reactions to Arynes, 314

12.6 Transition Metal–Catalyzed Reactions of Arynes, 327

12.7 Conclusion, 332

Abbreviations, 332

References, 333

PART IV REDUCTION, OXIDATION, AND DEAROMATIZATION REACTIONS 337

13 Reduction/Hydrogenation of Aromatic Rings 339
Francisco Foubelo and Miguel Yus

13.1 Introduction, 339

13.2 The Birch Reaction, 339

13.3 Metal‐Catalyzed Hydrogenations, 345

13.4 Electrochemical Reductions, 357

13.5 Other Methodologies, 359

13.6 Summary and Outlook, 361

Abbreviations, 361

References, 362

14 Selective Oxidation of Aromatic Rings 365
Oxana A. Kholdeeva

14.1 Introduction, 365

14.2 Mechanistic Principles, 367

14.3 Stoichiometric Oxidations, 374

14.4 Catalytic Oxidations, 375

14.5 Photochemical Oxidations, 386

14.6 Electrochemical Oxidations, 387

14.7 Enzymatic Hydroxylation, 389

14.8 Summary and Outlook, 390

Acknowledgments, 391

Abbreviations, 391

References, 392

15 Dearomatization Reactions: An Overview 399
F. Christopher Pigge

15.1 Introduction, 399

15.2 Alkylative Dearomatization, 400

15.3 Photochemical and Thermal Dearomatization, 405

15.4 Oxidative Dearomatization, 408

15.5 Transition Metal‐Assisted Dearomatization, 413

15.6 Enzymatic Dearomatization, 418

15.7 Conclusions and Future Directions, 419

Abbreviations, 419

References, 420

PART V AROMATIC REARRANGEMENTS 425

16 Aromatic Compounds via Pericyclic Reactions 427
Sethuraman Sankararaman

16.1 Introduction, 427

16.2 Electrocyclic Ring Closure Reaction, 428

16.3 Introduction to Cycloaddition Reactions, 433

16.4 Conclusions, 448

Abbreviations, 448

References, 448

17 Ring‐Closing Metathesis: Synthetic Routes to Carbocyclic Aromatic Compounds using Ring‐Closing Alkene and Enyne Metathesis 451
Charles B. de Koning and Willem A. L. van Otterlo

17.1 Introduction, 451

17.2 Alkene RCM for the Synthesis of Aromatic Compounds, 454

17.3 Enyne Metathesis Followed by the Diels–Alder Reaction for the Synthesis of Benzene Rings in Complex Aromatic Compounds, 464

17.4 Cyclotrimerization for the Synthesis of Aromatic Compounds by Metathetic Processes, 470

17.5 Strategies for the Synthesis of Aromatic Carbocycles Fused to Heterocycles by the RCM Reaction, 472

17.6 Future Challenges, 481

17.7 Conclusions, 481

Abbreviations, 482

References, 482

18 Aromatic Rearrangements in which the Migrating Group Migrates to the Aromatic Nucleus: An Overview 485
Timothy J. Snape

18.1 Introduction, 485

18.2 Mechanisms by Classification, 486

18.3 Summary and Outlook, 508

Abbreviations, 508

References, 508

PART VI TRANSITION METAL‐MEDIATED COUPLING 511

19 Transition Metal‐Catalyzed Carbon–Carbon Cross‐Coupling 513
Anny Jutand and Guillaume Lefèvre

19.1 Introduction, 513

19.2 The Mizoroki–Heck Reaction, 513

19.3 Cross‐Coupling of Aryl Halides with Anionic C‐Nucleophiles, 523

19.4 The Sonogashira Reaction, 530

19.5 The Stille Reaction, 532

19.6 The Suzuki–Miyaura Reaction, 534

19.7 The Hiyama Reaction, 539

19.8 Summary and Outlook, 541

Abbreviations, 541

References, 541

20 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 547
Masanam Kannan, Mani Sengoden, and Tharmalingam Punniyamurthy

20.1 Introduction, 547

20.2 C—N Cross‐Coupling, 550

20.3 C—O Cross‐Coupling, 561

20.4 C—S Cross‐Coupling, 569

20.5 C—Se Cross‐Coupling, 571

20.6 C—Te Cross‐Coupling, 571

20.7 C—P Cross‐Coupling, 572

20.8 C—As and C—Sb Cross‐Coupling, 578

20.9 C—B Cross‐Coupling, 578

20.10 Summary and Outlook, 579

Abbreviations, 579

References, 579

21 Transition Metal‐Mediated Aromatic Ring Construction 587
Ken Tanaka

21.1 Introduction, 587

21.2 [2+2+2] Cycloaddition, 587

21.3 [3+2+1] Cycloaddition, 601

21.4 [4+2] Cycloaddition, 602

21.5 Intramolecular Cycloaromatization, 608

21.6 Summary and Outlook, 612

References, 612

22 Ar–C Bond Formation by Aromatic Carbon–Carbon ipso‐Substitution Reaction 615
Maurizio Fagnoni and Sergio M. Bonesi

22.1 Introduction, 615

22.2 Formation of Ar–C(sp3) Bonds, 616

22.3 Formation of Ar–C(sp2) Bonds, 620

22.4 Formation of Ar–C(sp) Bonds, 638

22.5 Summary and Outlook, 639

Abbreviations, 639

References, 640

PART VII C─H FUNCTIONALIZATION 645

23 Chelate‐Assisted Arene C–H Bond Functionalization 647
Marion H. Emmert and Christopher J. Legacy

23.1 Introduction, 647

23.2 Carbon–Carbon (C–C) Bond Formations, 654

23.3 Carbon–Heteroatom (C–X) Bond Formations, 660

23.4 Stereoselective C–H Functionalizations, 668

Abbreviations, 669

References, 669

24 Reactivity and Selectivity in Transition Metal‐Catalyzed, Nondirected Arene Functionalizations 675
Dipannita Kalyani and Elodie E. Marlier

24.1 Introduction, 675

24.2 Arylation, 676

24.3 Alkenylation, 693

24.4 Alkylation, 699

24.5 Carboxylation, 701

24.6 Oxygenation, 701

24.7 Thiolation, 704

24.8 Amination, 706

24.9 Miscellaneous, 708

24.10 Summary and Outlook, 710

Abbreviations, 710

References, 710

25 Functionalization of Arenes via C─H Bond Activation Catalysed by Transition Metal Complexes: Synergy between Experiment and Theory 715
Amalia Isabel Poblador‐Bahamonde

25.1 Introduction, 715

25.2 Mechanisms of C─H Bond Activation, 716

25.3 Development of Stoichiometric C─H Bond Activation, 718

25.4 Catalytic C─H Activation and Functionalization, 730

25.5 Summary, 738

Abbreviations, 738

References, 738

PART VIII DIRECTED METALATION REACTIONS 741

26 Directed Metalation of Arenes with Organolithiums, Lithium Amides, and Superbases 743
Frédéric R. Leroux and Jacques Mortier

26.1 Introduction, 743

26.2 Preparation and Reactivity of Organolithium Compounds, 744

26.3 Directed ortho-Metalation (DoM), 748

26.4 Directed remote Metalation (DreM), 757

26.5 Peri Lithiation of Substituted Naphthalenes, 759

26.6 Lithiation of Metal Arene Complexes, 760

26.7 Lateral Lithiation, 761

26.8 Analytical Methods, 762

26.9 Synthetic Applications, 765

26.10 Conclusion, 770

Abbreviations, 771

References, 771

27 Deprotonative Metalation Using Alkali Metal–Nonalkali Metal Combinations 777
Floris Chevallier, Florence Mongin, Ryo Takita, and Masanobu Uchiyama

27.1 Introduction, 777

27.2 Preparation of the Bimetallic Combinations and their Structural Features, 778

27.3 Behavior of Alkali Metal–Nonalkali Metal Combinations, 779

27.4 Mechanistic Studies on the Deprotometalation Using Alkali Metal–Nonalkali Metal Combinations, 780

27.5 Scope and Applications of the Deprotometalation, 790

27.6 Conclusion and Perspectives, 807

Acknowledgments, 807

Abbreviations, 807

References, 807

28 The Halogen/Metal Interconversion and Related Processes (M = Li, Mg) 813
Armen Panossian and Frédéric R. Leroux

28.1 Introduction, 813

28.2 Generalities, 814

 

28.3.1 Reactivity, 815

28.2.1 Monometallic Organolithium Reagents, 814

28.3 Mechanism of the Halogen/Metal Interconversion, 815

28.4 Halogen Migration on Aromatic Compounds, 817

28.5 Selective Synthesis via Halogen/Metal Interconversion, 818

28.6 The Sulfoxide/Metal and Phosphorus/Metal Interconversions, 822

28.7 Aryl─Aryl Coupling Through Halogen/Metal Interconversion, 827

28.8 Summary and Outlook, 830

Abbreviations, 830

References, 830

PART IX PHOTOCHEMICAL REACTIONS 835

29 Aromatic Photochemical Reactions 837
Norbert Hoffmann and Emmanuel Riguet

29.1 Introduction, 837

29.2 Aromatic Compounds as Chromophores, 838

29.3 Photosensitized and Photocatalyzed Reactions, 849

29.4 Conclusion, 864

Abbreviation, 865

References, 865

30 Photochemical Bergman Cyclization and Related Reactions 869
Rana K. Mohamed, Kemal Kaya, and Igor V. Alabugin

30.1 Introduction: The Diversity of Cycloaromatization Reactions, 869

30.2 Electronic Factors in Photo‐BC, 870

30.3 Scope and Limitations of the Photo‐BC, 876

30.4 Enediyne Photocyclizations: Tool for Cancer Therapy, 883

30.5 Conclusion, 883

Abbreviations, 885

References, 885

31 Photo‐Fries Reaction and Related Processes 889
Francisco Galindo, M. Consuelo Jiménez, and Miguel Angel Miranda

31.1 Introduction, 889

31.2 Mechanistic Aspects, 889

31.3 Scope of the Reaction, 894

31.4 (Micro)Heterogeneous Systems as Reaction Media, 897

31.5 Applications in Organic Synthesis, 900

31.6 Biological and Industrial Applications, 902

31.7 Summary and Outlook, 905

Abbreviations, 906

References, 906

PART X BIOTRANSFORMATIONS 913

32 Biotransformations of Arenes: An Overview 915
Simon E. Lewis

32.1 Introduction, 915

32.2 Dearomatizing Arene Dihydroxylation, 915

32.3 Dearomatizing Arene Epoxidation, 918

32.4 Arene Alkylation (Biocatalytic Friedel–Crafts), 919

32.5 Arene Deacylation (Biocatalytic Retro Friedel–Crafts), 922

32.6 Arene Carboxylation (Biocatalytic Kolbe–Schmitt), 923

32.7 Arene Halogenation (Halogenases), 925

32.8 Arene Oxidation with Laccases, 925

32.9 Tetrahydroisoquinoline Synthesis (Biocatalytic Pictet–Spengler), 929

32.10 Arene Hydroxylation, 930

32.11 Arene Nitration, 932

32.12 Summary and Outlook, 933

Abbreviations, 934

References, 934

INDEX 939