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 Asymmetrie 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 рКа Н2О 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-, о-, 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 О → N and N → О Rearrangements .................... 304
5.3.2 N → N Rearrangements .............................. 311
5.3.3 О → О Rearrangements .............................. 315
5.3.4 N → S and S → N Rearrangements .................... 318
5.3.5 S → О and Se → О 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
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