This book provides a comprehensive overview of nucleophilic aromatic substitutions, focusing on the mechanistic and synthetic features that govern these reactions. The first chapter presents a detailed mechanistic analysis of the factors determining the feasibility of SNAr substitutions, providing decisive information to predict regioselectivity of many reactions and to define the conditions for concerted SNAr processes. Reflecting the key role played by these species as intermediates in most SNAr reactions, chapter 2 then discusses the chemistry of anionic sigma–complexes. Chapter 3 describes the concept of superelectrophilicity in SNAr substitutions, as it has recently emerged from the reactivity of strongly electron–deficient aromatic and heteroaromatic structures. The numerous synthetic applications are considered in depth in the chapters 4 and 5 that follow on intermolecular and intramolecular nucleophilic aromatic substitutions. Then, chapter 6 focuses on substitutions proceeding formally through displacement of a hydride ion, a hot topic in the field. The final chapter brings together concise yet comprehensive discussions surrounding SNAr photosubstitutions, radical substitutions, and ANRORC substitutions. Authored by a highly respected chemist who has contributed greatly to the field over the past two decades, this is a valuable information source for all organic chemists working in academia or the pharmaceutical and agrochemical industries. INDICE: Preface XI 1 The SNAr Reactions: Mechanistic Aspects 1 1.1 Introduction 1 1.2 Activation of the Aromatic System: Driving Force for SNAr Reactions 5 1.2.1 Benzene and Related Arene Derivatives 5 1.2.2 Pyridine and Related Aza–aromatics 11 1.2.3 Five–Membered Ring Heterocycles 15 1.2.4 Activation by Electron–Withdrawing Heterocyclic Units: The Superelectrophilic Dimension in SNAr Substitutions 18 1.3 Leaving Group, Nucleophile, Solvent, and Medium Effects 24 1.3.1 The Influence of the Leaving Group 24 1.3.1.1 Halogen Nucleofugality 24 1.3.1.2 The Mobility of the Nitro Group and Other Leaving Groups 28 1.3.2 The Influence of the Nucleophile 31 1.3.2.1 Basicity and Polarizability 31 1.3.2.2 Ritchie and Mayr’s Scales 36 1.3.3 The Influence of the Solvent 38 1.3.3.1 SNAr Reactions Involving Anionic Nucleophiles 38 1.3.3.2 SNAr Reactions Involving Neutral Nucleophiles 42 1.4 Effects of Specific Structural Variations in the Activated Ring 46 1.4.1 ortho versus para Activation: Hydrogen Bonding and Built–in Solvation 46 1.4.2 Reactivity at Unsubstituted versus Substituted Ring Carbon Atoms: Side Processes 50 1.5 Spectral Evidence for the Intermediacy of σ–Complexes in SNAr Reactions 52 1.6 Base Catalysis in SNAr Reactions 57 1.6.1 The Specific Base–General Acid Mechanism 61 1.6.2 The Rate–Limiting Proton–Transfer Mechanism 65 1.7 Regioselectivity in SNAr Reactions 68 1.8 Asymmetric SNAr Substitutions 73 1.9 Concerted SNAr Substitutions 76 1.9.1 Ring Activation and Feasibility of Concerted Substitutions 76 1.9.2 Concerted Substitutions in Triazines 79 1.10 Conclusion 83 References 84 2 Structure and Reactivity of Anionic σ–Complexes 95 2.1 Introduction 95 2.2 Structural Features of σ–Complexes 96 2.2.1 X–Ray Crystallography 96 2.2.2 Gas–Phase Meisenheimer Complexes 100 2.2.3 NMR Spectroscopy 103 2.2.3.1 Complexation at Unsubstituted Carbons 103 2.2.3.2 Complexation at Substituted Carbons 114 2.2.3.3 Complexation versus Proton Abstraction 123 2.3 Thermodynamics and Kinetics of σ–Complex Formation 125 2.3.1 The Nature of the Aromatic System 126 2.3.2 The Effect of Ring Substituents 129 2.3.3 Nucleophilic Reactivity at Substituted versus Unsubstituted Carbons: Steric Effects 135 2.3.3.1 Relative Reactivities and Stabilities of 1–Substituted and 1,1–Disubstituted Complexes 135 2.3.3.2 Isomeric Addition at Substituted and Unsubstituted Carbons of Electron–Deficient Aromatics: Relevance to Nucleophilic Aromatic Substitution Processes 140 2.3.4 Intramolecular Additions: Spiro Complexes 145 2.3.5 Diadduct Formation: Meta Bridging 148 2.3.6 The Effect of the Nucleophile 150 2.3.7 Solvent and Medium Effects 152 References 156 3 The Superelectrophilic Dimension in SNAr and Related σ–Complexation Processes 163 3.1 Introduction 163 3.2 The Classical Domain of SNAr and Anionic σ–Complexation Reactivity 164 3.3 Reaching the Superelectrophilic Dimension 167 3.3.1 The Reference Water Reaction 167 3.3.2 σ–Complexation with Weak Carbon Nucleophiles 172 3.3.3 From the pKaH2O Scale to Mayr’s Electrophilicity (E) Scale 174 3.3.4 Oxidation Potentials as Descriptors of the Superelectrophilic Dimension 180 3.4 The Synthetic Potential of σ–Complexation and SNAr Reactivity in the Superelectrophilic Dimension 182 3.4.1 σ–Complexation Reactivity 182 3.4.2 The Synthetic Potential of SNAr Substitutions: Normal (PiCl, NBD–Cl) versus Super (DNBF–Cl, DNBZ–Cl) Electrophiles 186 3.5 Origin of the Superelectrophilicity of Neutral 10π Heteroaromatics 196 References 198 4 Synthetic Aspects of Intermolecular SNAr Reactions 205 4.1 Introduction 205 4.2 Intermolecular Displacements of a Nitro Group 206 4.2.1 p–, o–, and m–Dinitrobenzenes– Related Substrates 206 4.2.2 Mononitro–Substituted Benzenes and Heteroarenes 216 4.2.3 Dinitro– and Trinitro–Substituted Benzenes and Related Derivatives 228 4.3 Intermolecular Displacements of Halogen and Other Leaving Groups 236 4.3.1 The Effect of the Leaving Group – Synthetic Implications 236 4.3.2 SNAr Couplings with Monoactivated Arenes 242 4.3.3 SNAr Couplings with Polyhaloaromatics 251 4.3.4 SNAr Couplings with Strongly Activated Arenes 255 4.3.5 SNAr Couplings with Aza and Polyaza Heteroaromatics 263 4.4 Conclusion 269 References 271 5 Intramolecular SNAr Reactions 279 5.1 Introduction 279 5.2 SNAr Cyclizations 280 5.2.1 Substitutions with Oxygen Nucleophiles 280 5.2.2 Substitutions with Nitrogen Nucleophiles 290 5.2.3 Substitutions by Sulfur Nucleophiles 296 5.2.4 Substitutions by Carbon Nucleophiles 298 5.2.5 Intramolecular SNAr Reactions in Macrocyclization 300 5.3 Smiles Rearrangements 303 5.3.1 O→N and N→O Rearrangements 304 5.3.2 N→N Rearrangements 311 5.3.3 O→O Rearrangements 315 5.3.4 N→S and S→N Rearrangements 318 5.3.5 S→O and Se→O Rearrangements 321 5.3.6 Rearrangements with C–C Bond Formation. Truce–Smiles Rearrangements 325 5.4 Conclusion 331 References 332 6 Nucleophilic Aromatic Substitutions of Hydrogen 337 6.1 Introduction 337 6.2 Reactions Involving Oxidation of σ–Complex–Type Intermediates 339 6.2.1 Spontaneous Oxidations 339 6.2.2 Reactions Involving an External Oxidizing Agent (ONSH) 351 6.2.2.1 Oxidation of Oxygen– and Nitrogen–Bonded Adducts 353 6.2.2.2 Oxidation of Carbon–Based σH Adducts 357 6.2.2.3 Electrochemical Oxidation 372 6.3 Vicarious Nucleophilic Aromatic Substitutions of Hydrogen (VNS) 374 6.3.1 VNS Amination and Hydroxylation Processes 374 6.3.2 VNS Substitutions with Carbon Nucleophiles 378 6.3.2.1 Effect of the Structure of the Nitroarene 379 6.3.2.2 Effect of the Structure of the Carbanion 384 6.4 Deoxygenative SNArH Substitutions 395 6.5 Cine and Tele Substitutions 397 6.5.1 The Von Richter Rearrangement 398 6.5.2 o–Dinitro Six–Membered Ring Aromatics and Related Derivatives 400 6.5.3 m–Diactivated Arenes and Related Substrates 404 6.5.4 Cine and Tele Substitutions in Heterocyclic Series 407 6.5.4.1 Aza and Polyaza aromatics 407 6.5.4.2 Five–Membered Ring Heteroaromatics 409 6.6 Conclusion 414 References 415 7 Other SNAr Substitution Pathways 423 7.1 SN(ANRORC) Substitutions 423 7.1.1 Introduction 423 7.1.2 Aza Aromatics without Nitro Activation 423 7.1.3 Nitro–Activated Aza Aromatics 426 7.1.4 Conclusion 429 7.2 Radical Nucleophilic Aromatic Substitutions 430 7.2.1 Introduction 430 7.2.2 Radical Anion Formation in ‘‘SNAr’’ Systems 431 7.2.3 Representative Radical Nucleophilic Aromatic Substitutions 438 7.2.4 Substitutions via Charge–Transfer Complexes of Anionic Radical Character 445 7.3 Nucleophilic Aromatic Photosubstitutions 448 7.3.1 General Features 448 7.3.2 SN2Ar∗ Reactions 450 7.3.3 SN(ET)Ar∗ Reactions 453 7.3.4 SN1Ar∗ Reactions 455 7.3.5 Regioselectivity and Chemical Theory 456 7.3.5.1 The Frontier Molecular Orbital Theory 456 7.3.5.2 The ‘‘Energy Gap’’ Model and Other Recent Approaches 458 References 459 Index 465
- ISBN: 978-3-527-31861-2
- Editorial: Wiley VCH
- Encuadernacion: Cartoné
- Páginas: 488
- Fecha Publicación: 26/06/2013
- Nº Volúmenes: 1
- Idioma: Inglés