Modern Nucleophilic Aromatic Substitution

482 Pages·3.813 MB·English

by  Prof. Francois Terrier(auth.)

Fran¸coisTerrier
ModernNucleophilicAromatic
Substitution
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Fran¸cois Terrier
Modern Nucleophilic Aromatic
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V
Contents
Preface XI
1 TheSNArReactions:MechanisticAspects 1
1.1 Introduction 1
1.2 ActivationoftheAromaticSystem:DrivingForceforS Ar
N
Reactions 5
1.2.1 BenzeneandRelatedAreneDerivatives 5
1.2.2 PyridineandRelatedAza-aromatics 11
1.2.3 Five-MemberedRingHeterocycles 15
1.2.4 ActivationbyElectron-WithdrawingHeterocyclicUnits:The
SuperelectrophilicDimensioninS ArSubstitutions 18
N
1.3 LeavingGroup,Nucleophile,Solvent,andMediumEffects 24
1.3.1 TheInfluenceoftheLeavingGroup 24
1.3.1.1 HalogenNucleofugality 24
1.3.1.2 TheMobilityoftheNitroGroupandOtherLeavingGroups 28
1.3.2 TheInfluenceoftheNucleophile 31
1.3.2.1 BasicityandPolarizability 31
1.3.2.2 RitchieandMayr’sScales 36
1.3.3 TheInfluenceoftheSolvent 38
1.3.3.1 S ArReactionsInvolvingAnionicNucleophiles 38
N
1.3.3.2 S ArReactionsInvolvingNeutralNucleophiles 42
N
1.4 EffectsofSpecificStructuralVariationsinthe
ActivatedRing 46
1.4.1 orthoversusparaActivation:HydrogenBondingandBuilt-in
Solvation 46
1.4.2 ReactivityatUnsubstitutedversusSubstitutedRingCarbonAtoms:
SideProcesses 50
1.5 SpectralEvidencefortheIntermediacyofσ-ComplexesinS Ar
N
Reactions 52
1.6 BaseCatalysisinS ArReactions 57
N
1.6.1 TheSpecificBase–GeneralAcidMechanism 61
1.6.2 TheRate-LimitingProton-TransferMechanism 65
1.7 RegioselectivityinS ArReactions 68
N
VI Contents
1.8 AsymmetricS ArSubstitutions 73
N
1.9 ConcertedS ArSubstitutions 76
N
1.9.1 RingActivationandFeasibilityofConcerted
Substitutions 76
1.9.2 ConcertedSubstitutionsinTriazines 79
1.10 Conclusion 83
References 84
2 StructureandReactivityofAnionicσ-Complexes 95
2.1 Introduction 95
2.2 StructuralFeaturesofσ-Complexes 96
2.2.1 X-RayCrystallography 96
2.2.2 Gas-PhaseMeisenheimerComplexes 100
2.2.3 NMRSpectroscopy 103
2.2.3.1 ComplexationatUnsubstitutedCarbons 103
2.2.3.2 ComplexationatSubstitutedCarbons 114
2.2.3.3 ComplexationversusProtonAbstraction 123
2.3 ThermodynamicsandKineticsofσ-ComplexFormation 125
2.3.1 TheNatureoftheAromaticSystem 126
2.3.2 TheEffectofRingSubstituents 129
2.3.3 NucleophilicReactivityatSubstitutedversusUnsubstituted
Carbons:StericEffects 135
2.3.3.1 RelativeReactivitiesandStabilitiesof1-Substitutedand
1,1-DisubstitutedComplexes 135
2.3.3.2 IsomericAdditionatSubstitutedandUnsubstitutedCarbonsof
Electron-DeficientAromatics:RelevancetoNucleophilicAromatic
SubstitutionProcesses 140
2.3.4 IntramolecularAdditions:SpiroComplexes 145
2.3.5 DiadductFormation:MetaBridging 148
2.3.6 TheEffectoftheNucleophile 150
2.3.7 SolventandMediumEffects 152
References 156
3 TheSuperelectrophilicDimensioninSNArandRelated
σ-ComplexationProcesses 163
3.1 Introduction 163
3.2 TheClassicalDomainofS ArandAnionicσ-Complexation
N
Reactivity 164
3.3 ReachingtheSuperelectrophilicDimension 167
3.3.1 TheReferenceWaterReaction 167
3.3.2 σ-ComplexationwithWeakCarbonNucleophiles 172
3.3.3 FromthepKaH2OScaletoMayr’sElectrophilicity(E)
Scale 174
3.3.4 OxidationPotentialsasDescriptorsoftheSuperelectrophilic
Dimension 180
Contents VII
3.4 TheSyntheticPotentialofσ-ComplexationandS ArReactivityinthe
N
SuperelectrophilicDimension 182
3.4.1 σ-ComplexationReactivity 182
3.4.2 TheSyntheticPotentialofS ArSubstitutions:
N
Normal(PiCl,NBD-Cl)versusSuper(DNBF-Cl,DNBZ-Cl)
Electrophiles 186
3.5 OriginoftheSuperelectrophilicityofNeutral10π
Heteroaromatics 196
References 198
4 SyntheticAspectsofIntermolecularSNArReactions 205
4.1 Introduction 205
4.2 IntermolecularDisplacementsofaNitroGroup 206
4.2.1 p-,o-,andm-Dinitrobenzenes– RelatedSubstrates 206
4.2.2 Mononitro-SubstitutedBenzenesandHeteroarenes 216
4.2.3 Dinitro-andTrinitro-SubstitutedBenzenesandRelated
Derivatives 228
4.3 IntermolecularDisplacementsofHalogenandOtherLeaving
Groups 236
4.3.1 TheEffectoftheLeavingGroup–SyntheticImplications 236
4.3.2 S ArCouplingswithMonoactivatedArenes 242
N
4.3.3 S ArCouplingswithPolyhaloaromatics 251
N
4.3.4 S ArCouplingswithStronglyActivatedArenes 255
N
4.3.5 S ArCouplingswithAzaandPolyazaHeteroaromatics 263
N
4.4 Conclusion 269
References 271
5 IntramolecularSNArReactions 279
5.1 Introduction 279
5.2 S ArCyclizations 280
N
5.2.1 SubstitutionswithOxygenNucleophiles 280
5.2.2 SubstitutionswithNitrogenNucleophiles 290
5.2.3 SubstitutionsbySulfurNucleophiles 296
5.2.4 SubstitutionsbyCarbonNucleophiles 298
5.2.5 IntramolecularS ArReactionsinMacrocyclization 300
N
5.3 SmilesRearrangements 303
5.3.1 O→NandN→ORearrangements 304
5.3.2 N→NRearrangements 311
5.3.3 O→ORearrangements 315
5.3.4 N→SandS→NRearrangements 318
5.3.5 S→OandSe→ORearrangements 321
5.3.6 RearrangementswithC–CBondFormation.Truce–Smiles
Rearrangements 325
5.4 Conclusion 331
References 332
VIII Contents
6 NucleophilicAromaticSubstitutionsofHydrogen 337
6.1 Introduction 337
6.2 ReactionsInvolvingOxidationofσ-Complex-Type
Intermediates 339
6.2.1 SpontaneousOxidations 339
6.2.2 ReactionsInvolvinganExternalOxidizing
Agent(ONSH) 351
6.2.2.1 OxidationofOxygen-andNitrogen-BondedAdducts 353
6.2.2.2 OxidationofCarbon-BasedσHAdducts 357
6.2.2.3 ElectrochemicalOxidation 372
6.3 VicariousNucleophilicAromaticSubstitutionsofHydrogen
(VNS) 374
6.3.1 VNSAminationandHydroxylationProcesses 374
6.3.2 VNSSubstitutionswithCarbonNucleophiles 378
6.3.2.1 EffectoftheStructureoftheNitroarene 379
6.3.2.2 EffectoftheStructureoftheCarbanion 384
6.4 DeoxygenativeS ArHSubstitutions 395
N
6.5 CineandTeleSubstitutions 397
6.5.1 TheVonRichterRearrangement 398
6.5.2 o-DinitroSix-MemberedRingAromaticsandRelated
Derivatives 400
6.5.3 m-DiactivatedArenesandRelatedSubstrates 404
6.5.4 CineandTeleSubstitutionsinHeterocyclicSeries 407
6.5.4.1 AzaandPolyazaaromatics 407
6.5.4.2 Five-MemberedRingHeteroaromatics 409
6.6 Conclusion 414
References 415
7 OtherSNArSubstitutionPathways 423
7.1 S (ANRORC)Substitutions 423
N
7.1.1 Introduction 423
7.1.2 AzaAromaticswithoutNitroActivation 423
7.1.3 Nitro-ActivatedAzaAromatics 426
7.1.4 Conclusion 429
7.2 RadicalNucleophilicAromaticSubstitutions 430
7.2.1 Introduction 430
7.2.2 RadicalAnionFormationin‘‘S Ar’’Systems 431
N
7.2.3 RepresentativeRadicalNucleophilicAromatic
Substitutions 438
7.2.4 SubstitutionsviaCharge-TransferComplexesofAnionicRadical
Character 445
7.3 NucleophilicAromaticPhotosubstitutions 448
7.3.1 GeneralFeatures 448
7.3.2 S 2Ar∗Reactions 450
N
7.3.3 S (ET)Ar∗Reactions 453
N
Contents IX
7.3.4 S 1Ar∗Reactions 455
N
7.3.5 RegioselectivityandChemicalTheory 456
7.3.5.1 TheFrontierMolecularOrbitalTheory 456
7.3.5.2 The‘‘EnergyGap’’ModelandOtherRecentApproaches 458
References 459
Index 465
XI
Preface
It is now well documented that nucleophilic aromatic substitutions represent a
class of reactions of fundamental importance in organic synthesis. In fact, the
interest in the field goes back to 60 years ago when J.F. Bunnett published an
authoritative review emphasizing the overwhelming importance of the presence
of electron-withdrawing substituents, especially a nitro group, to achieve such
reactions (Chem. Rev. 1951). This induced a number of investigations but, at
the time, the focus was essentially on those substitutions that proceeded via the
simpletwo-stepaddition–eliminationmechanismproposedbyBunnett,knownas
the S Ar mechanism. As the first significant recognition of the potential of these
N
reactions,J.Miller,oneofthepioneeringcontributorstothefield,publishedabook
in1968.Forthemostpart,thisbookwasbasedonthemechanisticunderstanding
ofsimplesubstitutionsandithasservedasanS Ar‘‘Bible’’for20years.
N
Onthebasisoftheinformationsofaraccumulated,theperiod1970–1990has
seenmanydevelopmentsintheS Arfield.Inadditiontoanimprovedunderstand-
N
ingofthefactorsgoverningthetwo-stepaddition–eliminationpathwayformulated
by Bunnett, many investigations have focused on the synthetic applicability of
S Arprocesses,especiallythoseinvolvingarenestructuresactivatedbyatleastone
N
NO group. In this context, new reaction pathways have been discovered, which
2
have considerably broadened the scope and importance of nucleophilic aromatic
substitutions.OfparticularimportancewastherecognitionbyMakosza(1983)of
reactions in which an aromatic hydrogen atom can be replaced by a nucleophile
under experimental conditions that lead overall to a formal S Ar departure of
N
an extremely unstable hydride anion. The so-called vicarious and oxidative sub-
stitutions of hydrogen are representative of these reactions that give access to
promisingsyntheticapproaches.Anothertypeofsubstitutionproceedingformally
asanS Arreaction,butoccurringinfactthroughmultistepsequencesinvolving
N
nucleophilic addition, ring opening, and ring closure, was discovered by van der
Plasin1968.CommonlyreferredtoasS (ANRORC)substitutions,theseprocesses
N
provide a useful entry to the functionalization of aza-activated heteroaromatics.
Other significant investigations carried out in the 1970–1990 period dealt with
the photostimulation of S Ar substitutions (Havinga, Wubbels, Mutai) and the
N
possible role of electron transfer in the reactions (Shein, Marquet, Scorrano). In
the late 1980s, it become clear that the efforts so far devoted to the mechanistic