Table of Contents

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Title

The Author

Preface

Chapter 1: Introduction

1.1 Reaction Mechanism and Reaction Arrows
1.2 Properties and Characteristics of a Reaction
1.3 Summary
Further Reading

Chapter 2: Carbocations

2.1 Introduction
2.2 History
2.3 Structures and Geometry of Carbocations
2.4 Generation of Carbocation
2.5 Carbocation Stability
2.6 Detection of Carbocations
2.7 Fate of Carbocations
2.8 Nonclassical Carbocations
2.9 Radical Cations
2.10 Summary
Further Reading

Chapter 3: Carbanions

3.1 Structure and Geometry of Carbanions
3.2 Generation of Carbanions
3.3 Stability of Carbanions
3.4 Reactions of Carbanions
3.5 Enolate Reactions with Carbonyl Groups
3.6 Rearrangements of Carbanions
3.7 Chiral Carbanions
3.8 Carbanions and Tautomerism
3.9 Summary
Further Reading

Chapter 4: Radicals

4.1 Introduction
4.2 Detection and Characterization of Radicals
4.3 Structure and Bonding of Radicals
4.4 Generation of Free Radicals
4.5 Stability of Radicals
4.6 Reactions of Free Radicals
4.7 Stereochemistry of Radical Reactions
4.8 Biradicals
4.9 Summary
Further Reading

Chapter 5: Carbenes

5.1 Structure and Geometry of Carbenes
5.2 Generation of Carbenes
5.3 Reactions of Carbenes
5.4 Carbenes and Carbene Ligands in Organometallic Chemistry
5.5 Summary
Further Reading

Chapter 6: Nitrenes

6.1 Introduction
6.2 Structure and Reactivity
6.3 Generation of Nitrenes
6.4 Reactions of Nitrenes
6.5 Summary
Further Reading

Chapter 7: Miscellaneous Intermediates

7.1 Arynes
7.2 Ketenes and Cumulenes
7.3 ortho-Quinone Methides
7.4 Zwitterions and Dipoles
7.5 Antiaromatic Systems
7.6 Tetrahedral Intermediates
7.7 Summary
Further Reading

Index

End User License Agreement

List of Illustrations

Chapter 1: Introduction

Figure 1.1 Reaction profile showing the reaction intermediate where k₂ > k₋₁.
Scheme 1.1

Chapter 2: Carbocations

Figure 2.1 Carbenium and carbonium ions.
Figure 2.2 Tropylium bromide.
Figure 2.3 Representation of the structure of CH₅⁺.
Figure 2.4 Methyl cation.
Figure 2.5 PMO description of stabilization of carbocation by methyl group.
Figure 2.6 Relative stabilities of carbocations in quantitative terms.
Figure 2.7 Effect on carbocation stability of resonance stabilization by conjugation with pi bonds.
Figure 2.8 Effect on carbocation stability of resonance stabilization through lone pair (nonbonding) electrons.
Figure 2.9 Carbocation charge stabilization through (a) conjugation and (b) aromatization.
Figure 2.10 Examples of long-lived carbenium ions.
Figure 2.11 Preference of carbocations for planar geometry (120° inter-bond angles).
Figure 2.12 ¹³C NMR chemical shifts of substituted carbocations.
Figure 2.13 ¹³C NMR spectrum of an allylic cation.
Figure 2.14 Equilibration of protons due to rapid rearrangement in the cyclopentyl carbocation.
Figure 2.15 Rapidly equilibrating classical carbocation model for the 2-norbornyl cation.
Figure 2.16 Participation of a $C02-math-0006$ bond in generating a nonclassical carbocation.
Figure 2.17 Compound 8 reacts 10¹⁴ times faster than 7 owing to anchimeric assistance.
Figure 2.18 trans-2-Hydroxycyclopentyl arene sulfonates.
Figure 2.19 Examples of organic radical cations.
Figure 2.20 Formation of a $C02-math-0007$ -radical cation.
Figure 2.21 Examples of strained alkanes.
Scheme 2.1 Reaction of triphenylmethanol with conc. H₂SO₄.
Scheme 2.2 Hypervalent and hypovalent cations.
Scheme 2.3 Generation of tert. butyl cation.
Scheme 2.4 Planar and non-planar carbocations
Scheme 2.5 (a) Stabilization of carbocation by hyperconjugation with an adjacent methyl group; (b) negative hyperconjugation.
Scheme 2.6
Scheme 2.7
Scheme 2.8
Scheme 2.9
Scheme 2.10
Scheme 2.11
Scheme 2.12
Scheme 2.13
Scheme 2.14
Scheme 2.15
Scheme 2.16
Scheme 2.17
Scheme 2.18
Scheme 2.19
Scheme 2.20
Scheme 2.21
Scheme 2.22
Scheme 2.23
Scheme 2.24
Scheme 2.25
Scheme 2.26
Scheme 2.27
Scheme 2.28
Scheme 2.29
Scheme 2.30
Scheme 2.31 Mechanism of electrophilic hydration and addition of HX to a simple alkene using H₃O⁺ X⁻ in aqueous solution.
Scheme 2.32
Scheme 2.33 Regioselectivity in the addition of HBr to 2-methyl-1-phenylcyclohexene using concentrated hydrobromic acid.
Scheme 2.34
Scheme 2.35
Scheme 2.36
Scheme 2.37
Scheme 2.38
Scheme 2.39
Scheme 2.40
Scheme 2.41
Scheme 2.42
Scheme 2.43
Scheme 2.44
Scheme 2.45
Scheme 2.46

Chapter 3: Carbanions

Figure 3.1 (a) sp³-Hybridized methanide anion; (b) inversion of configuration.
Figure 3.2 A barrier to inversion of carbanions.
Figure 3.3 Comparison of rate of inversion.
Figure 3.4 Polymeric structure of n-butyllithium in different solvents.
Figure 3.5 Jackson–Meisenheimer complex.
Figure 3.6 Stabilization through aromatization.
Figure 3.7 Structures of allylic, homoallylic, and homobenzylic carbanions.
Figure 3.8 Intermolecular hydrogen bonding favors the keto-form.
Figure 3.9 Some bicyclic and alkyl diketones.
Figure 3.10 Keto/enol forms of various compounds.
Scheme 3.1 Electron delocalization resulting in a coplanar structure.
Scheme 3.2 Retention of configuration of the cyclopropyl carbanion.
Scheme 3.3 Trapping of an α-chiral acyclic nitrile carbanion.
Scheme 3.4 Generation of carbanion.
Scheme 3.5 Stabilization of carbanion through formation of enolate.
Scheme 3.6 Resonance stabilization of carbanions.
Scheme 3.7 Stabilization of carbanion by adjacent heteroatoms.
Scheme 3.8 Stabilization of carbanion by a nonadjacent π bond.
Scheme 3.9 Negative hyperconjugation.
Scheme 3.10 Formation of kinetic and thermodynamic carbanions.
Scheme 3.11 (a) cyclopentadienyl anion and cyclopropenium and tropylium cations; (b) formation of the triphenylmethane carbanion.
Scheme 3.12 Aldol reactions.
Scheme 3.13 Aldol condensation.
Scheme 3.14 Cross-aldol reaction.
Scheme 3.15 Claisen condensation.
Scheme 3.16 Dieckmann reaction.
Scheme 3.17 Michael reaction.
Scheme 3.18 Knoevenagel reaction.
Scheme 3.19 Michael-type reaction.
Scheme 3.20 Robinson ring-forming reaction.
Scheme 3.21 Synthesis of trideutero-ketone.
Scheme 3.22 Decarboxylation of carboxylic acid.
Scheme 3.23 Carbanion acting as nucleophile.
Scheme 3.24 Carbanion as nucleophile in S_N2 reaction.
Scheme 3.25 Kolbe–Schmidt reaction.
Scheme 3.26 Oxidation of a carbanion.
Scheme 3.27 E1cB reactions.
Scheme 3.28 E1cB reaction mechanism.
Scheme 3.29 Hofmann elimination.
Scheme 3.30 Formation of ylide.
Scheme 3.31 Acidity of bicyclo[2.2.2]octan-2,6-dione.
Scheme 3.32 Homobenzylic rearrangement.
Scheme 3.33 Wittig and Stevens rearrangements.
Scheme 3.34 Favorskii rearrangement.
Scheme 3.35 Contraction of rings.
Scheme 3.36 Neber rearrangement.
Scheme 3.37 Sommelet–Hauser rearrangement.
Scheme 3.38 Chiral carbanion.
Scheme 3.39 Retention of stereochemistry.
Scheme 3.40 Retention of configuration.
Scheme 3.41 Retention of chirality.
Scheme 3.42 Tautomerization.
Scheme 3.43 Mechanism of keto-enol interconversion.
Scheme 3.44 Keto-enol equilibrium in acetone.
Scheme 3.45 Keto-enol equilibrium in pent-2,4-dione.
Scheme 3.46 Keto and enol forms of 1,3-diketones.
Scheme 3.47 Keto-enol equilibria.
Scheme 3.48 Resonance in diethyl malonate.
Scheme 3.49 Keto-enol equilibrium in benzoyl acetone.
Scheme 3.50 Keto-enol equilibrium in cyclopentane-1,2-dione.

Chapter 4: Radicals

Figure 4.1 Some common free radicals.
Figure 4.2 Representation of EPR spectra: (a) resonance signal, (b) first derivative, and (c) second derivative.
Figure 4.3 Mechanism of spin polarization for planar methyl radical.
Figure 4.4 EPR spectrum for methyl radical.
Figure 4.5 Localized model for ethyl radical.
Figure 4.6 Hyperconjugation model for ethyl radical.
Figure 4.7 PMO description of radical stabilization; interaction of SOMO with donor HOMO.
Figure 4.8 Planar and pyramidal structures of radicals.
Figure 4.9 Calculated geometry of fluoro-substituted methyl radicals.
Figure 4.10 Stabilization of ethyl radical through pyramidalization.
Figure 4.11 (a) Planar and (b) nonplanar geometries of tert-butyl radical.
Figure 4.12 (a)1-Adamantyl and (b) 7-norbornyl radical.
Figure 4.13 Stability of free radicals.
Figure 4.14 Relatively stable free radicals.
Figure 4.15 Persistent free radicals.
Figure 4.16 Selective formation of diastereomers.
Figure 4.17 Chair-like (Beckwith–Houk) transition-state model.
Figure 4.18 Mode of approach of a radical to the π-electron system.
Figure 4.19 Chair-like transition state for a six-membered ring.
Figure 4.20 Biradicals.
Figure 4.21 Singlet (a) and triplet (b) structures of a biradical.
Figure 4.22 Some aromatic diyls.
Scheme 4.1 Equilibrium between hexaphenylethane and triphenylmethyl radical.
Scheme 4.2 Structure of triphenylmethyl radical.
Scheme 4.3 Reactions of triphenylmethyl radical.
Scheme 4.4 Trapping of radicals by nitroso compounds.
Scheme 4.5 Experimental evidence for planar and pyramidal structures.
Scheme 4.6 Example of a bridgehead radical.
Scheme 4.7 Formation of free radicals.
Scheme 4.8 Photolytic generation of free radicals.
Scheme 4.9 Homolysis of organometallic compounds.
Scheme 4.10 Formation of radicals from radicals.
Scheme 4.11 Oxidation of benzene by Fenton's reagent.
Scheme 4.12 Formation of radicals through ferrous ions.
Scheme 4.13 Formation of Gomberg hydrocarbon.
Scheme 4.14 Reactions of free radicals.
Scheme 4.15 Order of reactivity of the halogens.
Scheme 4.16 Photochemical perchlorination of methyl chloroformate.
Scheme 4.17 Radical-catalyzed chlorination.
Scheme 4.18 Chlorination of iso-butane and 2-methylbutane.
Scheme 4.19 Chlorination of cyclohexane.
Scheme 4.20 Allylic bromination.
Scheme 4.21 Benzylic bromination.
Scheme 4.22 Wohl–Ziegler reaction.
Scheme 4.23 Allylic bromination of testosterone.
Scheme 4.24 Radical substitution in cycloalkanes.
Scheme 4.25 Ring-opening reactions of cyclopropane.
Scheme 4.26 Trapping of methyl radical by Bu₃SnH.
Scheme 4.27 Reaction of trialkyltin hydride with halide in the presence of AIBN.
Scheme 4.28 Oxidation of 2,6-di-tert-butylphenol.
Scheme 4.29 Pinacol reaction.
Scheme 4.30 Coupling reaction of (a) benzophenone and (b) p-cresol.
Scheme 4.31 anti-Markovnikov addition of HBr to an alkene.
Scheme 4.32 Addition of CCl₄ to propylene.
Scheme 4.33 Relative rates of alkyl radical formation.
Scheme 4.34 ΔH⁰ values of primary, secondary, and tertiary radicals.
Scheme 4.35 Regioselective bromination of 2-methylpropane.
Scheme 4.36 Radical polymerization of alkene.
Scheme 4.37 Radical rearrangement reaction.
Scheme 4.38 Radical-catalyzed addition of CCl₄ to β-pinene.
Scheme 4.39 Migration of chloro group.
Scheme 4.40 Radical dimerization.
Scheme 4.41 Radical disproportionation.
Scheme 4.42 Radical addition–elimination reaction.
Scheme 4.43 Radical reactions of aromatic rings.
Scheme 4.44 Ullmann reaction.
Scheme 4.45 Solvent dependent chlorination of 2,3-dimethylbutane.
Scheme 4.46 Kolbe synthesis.
Scheme 4.47 Hunsdiecker reaction.
Scheme 4.48 Oxidative coupling of 1-naphthol.
Scheme 4.49 Formation of racemic mixture.
Scheme 4.50 Formation of (R)- and (S)-enantiomers.
Scheme 4.51 Formation of diastereomers.
Scheme 4.52 Stereoselective reaction of an acyclic radical.
Scheme 4.53 Stereospecific addition reactions.
Scheme 4.54 Mechanism of stereospecific addition reaction.
Scheme 4.55 Regioselective substitution of chlorine.
Scheme 4.56 Chemoselective reaction.
Scheme 4.57 Stereoselective addition of hydrogen.
Scheme 4.58 Stereochemistry of cyclization of substituted 5-hexenyl radicals.
Scheme 4.59 Intramolecular addition generating rings.
Scheme 4.60 Chlorination of benzene.
Scheme 4.61 Formation of ozone.
Scheme 4.62 FCHC-initiated decomposition of stratospheric ozone.
Scheme 4.63 Decomposition of ozone by CFCs.
Scheme 4.64 Butylated hydroxyanisole (BHA) as radical inhibitor.
Scheme 4.65 Cleavage of cyclic azo compound to produce a biradical.
Scheme 4.66 Photochemistry of cyclopentanone.
Scheme 4.67 Non-stereospecific reaction.
Scheme 4.68 Irradiation of benzophenone in the presence of diphenylmethane.
Scheme 4.69 Bergman cyclization.
Scheme 4.70 Bergman cyclization.

Chapter 5: Carbenes

Figure 5.1 Electronic configurations of bent and linear carbenes.
Figure 5.2 Relationship between carbene bond angle and the nature of the frontier orbitals.
Figure 5.3 Repulsion between triplet and singlet states.
Figure 5.4 Stabilization of singlet carbene through π-electron donating group.
Figure 5.5 Persistent carbenes.
Figure 5.6 Fischer and Schrock carbenoids.
Figure 5.7 Mechanism of stereospecific addition of carbene to alkene.
Figure 5.8 Diadamantylcarbene.
Figure 5.9 Fischer and Schrock carbenes.
Figure 5.10 Chemical bonding in Fischer and Schrock carbenes.
Figure 5.11 Tebbe's reagent.
Figure 5.12 Representative NHC types.
Scheme 5.1 Nucleophilic, ambiphilic, and electrophilic carbenes.
Scheme 5.2 Stabilization of dimethoxycarbene.
Scheme 5.3 Dimerization of a carbene.
Scheme 5.4 Decomposition of diazocarbonyl compounds.
Scheme 5.5 Decomposition of diazo and ketene compounds to give a carbene.
Scheme 5.6 Base-catalyzed decomposition of N-nitroso compounds.
Scheme 5.7 Bamford–Stevens reaction.
Scheme 5.8 A further Bamford–Stevens reaction.
Scheme 5.9 Formation of carbene by α-elimination.
Scheme 5.10 α-Elimination of trihaloacetate.
Scheme 5.11 Phase-transfer catalyst assisted α-elimination.
Scheme 5.12 α-Elimination via a carbocation intermediate.
Scheme 5.13 Generation of carbene via photo-elimination.
Scheme 5.14 Formation of carbene from carbenoid.
Scheme 5.15 Generation of carbene under neutral conditions.
Scheme 5.16 Generation of carbene by the photolysis of cyclopropane derivatives.
Scheme 5.17 Generation of carbene from bicyclic ketal.
Scheme 5.18 Generation of triplet carbene.
Scheme 5.19 Addition of carbenes to alkenes.
Scheme 5.20 Stereospecific addition of dibromocarbene to cis- and trans-2-butene.
Scheme 5.21 Non-stereospecific addition of a triplet methylene to a cis-alkene.
Scheme 5.22 Cycloaddition reactions of carbene.
Scheme 5.23 Cycloaddition reactions of carbene.
Scheme 5.24 Cycloaddition reactions of carbene.
Scheme 5.25 Regioselective addition of carbene.
Scheme 5.26 Stereospecific addition of carbene to a trans double bond.
Scheme 5.27 Addition of carbene to aromatic compounds.
Scheme 5.28 Addition of bis(trifluoromethylcarbene) to hexafluorobenzene.
Scheme 5.29 Ring expansion of aromatic systems.
Scheme 5.30 Regioselective addition of carbene to a bicyclic system.
Scheme 5.31 Stereoselective addition of carbene from less hindered face.
Scheme 5.32 Addition of methylene carbene to naphthalene.
Scheme 5.33 Simmons–Smith reagent.
Scheme 5.34 Simmons–Smith reactions.
Scheme 5.35 Mechanism of Simmons–Smith reaction.
Scheme 5.36 Addition of carbene to duroquinone.
Scheme 5.37 Addition of carbene to C=N double bond.
Scheme 5.38 Cycloaddition of carbene to allene.
Scheme 5.39 Addition of carbene to enamine.
Scheme 5.40 1,2-Addition of carbene to 1,3-dienes.
Scheme 5.41 Addition of carbenes to alkynes.
Scheme 5.42 Insertion of carbenes into single bonds.
Scheme 5.43 Intramolecular insertion of carbene.
Scheme 5.44 Addition of carbene to C–H as well as C=C bonds.
Scheme 5.45 Regioselective addition of carbomethoxymethylene.
Scheme 5.46 Hydrogen abstraction by the triplet carbene to give a radical pair.
Scheme 5.47 Insertion of carbene into a C–C bond.
Scheme 5.48 Insertion of carbene into O–H bonds.
Scheme 5.49 Intramolecular insertion of carbene.
Scheme 5.50 Intermolecular insertion of carbene.
Scheme 5.51 Generation and intramolecular insertion of alkylidene carbene.
Scheme 5.52 Formation of alkenes by 1,2-shift.
Scheme 5.53 Addition of dihalocarbenes to a strained double bond.
Scheme 5.54 Rearrangement leading to ring contraction.
Scheme 5.55 Addition of dichlorocarbene to 1,4-dihydrofuran to give addition as well as rearranged product.
Scheme 5.56 Generation and reaction of carbene by decomposition of the tosylhydrazone.
Scheme 5.57 Wolff rearrangement.
Scheme 5.58 Reaction of ketene with water, alcohols, and amines.
Scheme 5.59 Rearrangement of carbene to ketene.
Scheme 5.60 Ring contraction of carbene to give ketene.
Scheme 5.61 Reaction of carbene with cyclohexene.
Scheme 5.62 Rearrangement of cyclic carbenes.
Scheme 5.63 Reaction of cyclohexene with dichlorocarbene.
Scheme 5.64 Rearrangement of singlet carbene to alkene.
Scheme 5.65 Competition between inter- and intramolecular reactions.
Scheme 5.66 Conversion of ketone into alkene through the Bamford–Stevens reaction.
Scheme 5.67 Singlet carbene leading to carbocation.
Scheme 5.68 Carbene exhibiting phenyl and methyl migration.
Scheme 5.69 Formation of a strained bridgehead alkene.
Scheme 5.70 Nucleophilic reactions of carbenes.
Scheme 5.71 Trapping of carbene by methanol.
Scheme 5.72 Reimer–Tiemann reaction.
Scheme 5.73 Carbylamine reaction.
Scheme 5.74 Reactions of triazol-5-ylidene carbene.

Chapter 6: Nitrenes

Figure 6.1 Common nitrene derivatives.
Figure 6.2 Triplet and singlet nitrenes.
Figure 6.3 Stabilization of singlet nitrene by donor substituents.
Figure 6.4 Delocalized structure of triplet phenylnitrene.
Figure 6.5 Cyanonitrene.
Scheme 6.1 Generation and trapping of nitrene.
Scheme 6.2 Generation and trapping of phenylnitrene.
Scheme 6.3 Formation of ortho-tolyl-nitrene.
Scheme 6.4 Electronic/steric effects of substituents in aromatic nitrene.
Scheme 6.5 Aryl azides for photoaffinity labeling.
Scheme 6.6 Generation of nitrenes from azides and isocyanates.
Scheme 6.7 Generation of nitrenes from their relevant precursors.
Scheme 6.8 Formation and rearrangement of acyl nitrene.
Scheme 6.9 Formation of sulfonyl nitrene.
Scheme 6.10 Generation of nitrenes from isocyanates.
Scheme 6.11 Cyclization of an imidoyl nitrene generated from different precursors.
Scheme 6.12 Photochemical generation of nitrenes from oxaziridines.
Scheme 6.13 Decomposition of heterocycles to give nitrenes.
Scheme 6.14 Generation of nitrenes by α-elimination.
Scheme 6.15 Possible mechanism for phosphorus(III)-mediated deoxygenation of nitro and nitroso compounds.
Scheme 6.16 Generation of aminonitrenes by oxidation of 1,1-disubstituted hydrazines.
Scheme 6.17 Thermolysis of sulfinylamines to give aromatic nitrenes.
Scheme 6.18 Stereospecific addition of nitrenes to alkenes.
Scheme 6.19 Mechanistic aspects of nitrene cycloaddition.
Scheme 6.20 Intramolecular addition of nitrene.
Scheme 6.21 Formation of aziridines by initial 1,3-dipolar cycloaddition of an azide.
Scheme 6.22 Coupling of alkyl and aryl nitrenes.
Scheme 6.23 1,2-Addition to 1,3-dienes to give vinylaziridines.
Scheme 6.24 Addition of phthalimidonitrene to an alkyne to give 2H-azirine.
Scheme 6.25 Addition of aminonitrene to alkynes.
Scheme 6.26 1,3-Dipolar cycloaddition of an azide to an alkyne to give 1,2,3-triazole.
Scheme 6.27 Addition of a nitrene to an aromatic ring.
Scheme 6.28 Insertion of singlet and triplet nitrenes into a C–H bond.
Scheme 6.29 Insertion of nitrene into a saturated hydrocarbon.
Scheme 6.30 Functionalization of cyclohexanes by nitrene insertion.
Scheme 6.31 Intramolecular nitrene C–H insertion with retention of configuration.
Scheme 6.32 Electrocyclic ring closure of aryl and vinyl nitrenes.
Scheme 6.33 Insertion of sulfonyl nitrene into an aromatic ring.
Scheme 6.34 Rearrangement of nitrene by a 1,2-shift.
Scheme 6.35 Rearrangement in nitrenes.
Scheme 6.36 Curtius rearrangement.
Scheme 6.37 Hofmann rearrangement.
Scheme 6.38 Conversion of amide into amine.
Scheme 6.39 Lossen rearrangement.
Scheme 6.40 (a) DMSO as a nucleophilic trap for nitrenes; (b)insertion of nitrene into amine.
Scheme 6.41 The copper-catalyzed azido-NBD nitrene reaction in DMSO.
Scheme 6.42 Proposed mechanisms of the azido-NBD “reduction” reaction leading to the amine product via a triplet intermediate and DMSO conjugate formation.
Scheme 6.43 Nitrene formation from sulfonimidamides.

Chapter 7: Miscellaneous Intermediates

Figure 7.1 Representative examples of aryne intermediates.
Figure 7.2 Structures of ortho-benzyne.
Figure 7.3 ortho-, meta-, and para-benzynes.
Figure 7.4 Bent alkyne form of benzyne.
Figure 7.5 Structure of quinone methides.
Figure 7.6 ortho-Quinone methides.
Figure 7.7 ortho-Quinone methide behaves as a combination of charged zwitterions and the biradical.
Figure 7.8 Common examples of dipolar species.
Figure 7.9 Antiaromatic species (13–19).
Figure 7.10 Some stable antiaromatic species.
Figure 7.11 Strained three-membered rings.
Scheme 7.1 Generation and trapping of meta-benzyne with dimethylamine to give fulvene.
Scheme 7.2 Bergman cyclization of enediynes to give para-benzyne (benz-1,4-diyl).
Scheme 7.3 Formation and trapping of para-benzyne.
Scheme 7.4 Interconversion of 1,2- and 1,3-didehydrobenzenes (ortho and meta, respectively).
Scheme 7.5 Methods for the generation of ortho-benzyne.
Scheme 7.6 Generation and reactions of ortho-benzyne.
Scheme 7.7 Low-temperature photolytic generation of ortho-benzyne.
Scheme 7.8 Generation of ortho-benzyne from o-dihaloaromatics.
Scheme 7.9 Generation of ortho-benzyne from directed lithiation.
Scheme 7.10 Ipso and cine substitution through an ortho-benzyne intermediate.
Scheme 7.11 Generation of ortho-benzyne from aryl triflates.
Scheme 7.12 Formation of unsymmetrical arynes.
Scheme 7.13 Decomposition of benzenediazonium-2-carboxylate to give ortho-benzyne.
Scheme 7.14 Isolable zwitterion in the case of benzenediazonium-2-carboxylate.
Scheme 7.15 Decomposition of diphenyliodonium-2-carboxylate to give ortho-benzyne.
Scheme 7.16 Formation of ortho-benzyne by ring fragmentation reactions.
Scheme 7.17 Oxidative fragmentation of 1-aminobenzotriazole.
Scheme 7.18 Decomposition of benzothiadiazole-1,1-dioxide to give ortho-benzyne.
Scheme 7.19 Formation of ortho-benzyne from 1,2-diiodobenzene/phthalic anhydride.
Scheme 7.20 Spectroscopic properties of benzyne.
Scheme 7.21 Dimerization of ortho-benzyne.
Scheme 7.22 Nucleophilic addition to ortho-benzyne.
Scheme 7.23 Addition of tertiary amines, phosphines, and sulfides to ortho-benzyne.
Scheme 7.24 Regiochemistry of triple bond formation.
Scheme 7.25 Regiochemistry of the addition of nucleophile to the triple bond.
Scheme 7.26 Diels–Alder cycloaddition involving aryne.
Scheme 7.27 Diels–Alder reactions involving ortho-benzyne.
Scheme 7.28 Unexpected formation of an aryne by [4+2] cycloaddition.
Scheme 7.29 [2+2] Cycloaddition via diradical excited state of benzyne.
Scheme 7.30 Synthesis of taxodione utilizing [2+2] cycloaddition.
Scheme 7.31 Cycloaddition to alkenes.
Scheme 7.32 Ene reaction of ortho-benzyne.
Scheme 7.33 1,3-Dipolar cycloadditions.
Scheme 7.34 Diels–Alder reaction of ortho-benzyne in the synthesis of a polycyclic system.
Scheme 7.35 Synthesis of the antitumor alkaloid ellipticine by Diels–Alder addition to 3,4-pyridyne.
Scheme 7.36 Benzyne in a synthesis of a lysergic acid N,N-diethylamide precursor.
Scheme 7.37 Generation and trapping of diphenylketene.
Scheme 7.38 Formation of fluoroketene by enzymatic elimination.
Scheme 7.39 Generation of difluoroketene.
Scheme 7.40 Gas-phase formation of difluoroketene.
Scheme 7.41 Dissociation of parent ketene.
Scheme 7.42 Formation of an N-heterocyclic ketene.
Scheme 7.43 In situ formation of acylketene.
Scheme 7.44 Formation of silyl-substituted ferrocenyl-ketene.
Scheme 7.45 Generation of stable aryl(trialkylsilyl) ketene.
Scheme 7.46 Formation of ketene using ZrO₂-promoted Ni catalysis.
Scheme 7.47 Formation of ketenes by thermal decomposition of malonic anhydrides.
Scheme 7.48 Photochemical formation of ketenes.
Scheme 7.49 Formation of ketenes by femtosecond photolysis.
Scheme 7.50 Dimerization of phenyl(ethyl) ketene.
Scheme 7.51 trans-Selective [2+2] cycloaddition of ketene with aldehyde.
Scheme 7.52 Cycloaddition of diphenylketene with cyclopentadiene.
Scheme 7.53 Lewis acid catalyzed ketene–alkene cycloaddition.
Scheme 7.54 Reaction of methylketene with a bis-imine to form a cis-monoadduct.
Scheme 7.55 Reaction of acylketene with imine to give a β-lactam.
Scheme 7.56 Metal-catalyzed generation of o-quinone methides and subsequent cycloaddition reactions.
Scheme 7.57 Photochemical and thermal generation of o-quinone methide (o-QM).
Scheme 7.58 Thermal generation of o-quinone methides.
Scheme 7.59 Generation of o-quinone methides and synthesis of trans-2,3-dihydrobenzofurans.
Scheme 7.60 Reactivity of o-quinone methide with alkenes.
Scheme 7.61 Synthesis of coumarins using substituted arynes.
Scheme 7.62 Example of intermolecular Michael-type hydroarylation of in situ generated o-quinone methides with tertiary aromatic amines.
Scheme 7.63 Reactions of o-quinone methide with various reagents.
Scheme 7.64 Synthesis of 2′-aminobenzothiazolo-(4-methylphenyl)methyl-4-nitrophenol and 2′-aminobenzothiazolomethyl-2-naphthols via o-quinone methide intermediate.
Scheme 7.65 Examples of zwitterions.
Scheme 7.66 Formation of furan derivatives via isocyanide zwitterion.
Scheme 7.67 Nucleophilic substitution of carbonyl compounds through tetrahedral intermediate.
Scheme 7.68 Fate of a tetrahedral intermediate.
Scheme 7.69 Formation of various products through a tetrahedral intermediate.
Scheme 7.70 Carbinol formation through a tetrahedral intermediate.
Scheme 7.71 Extent of hydration of some carbonyl compounds.
Scheme 7.72 Mechanism of hemiacetal and acetal formation.
Scheme 7.73 Example of a protecting group.
Scheme 7.74 Stable tetrahedral adduct.
Scheme 7.75 Tetrahedral intermediate stabilized by coordination.

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2012

ISBN: 978-3-527-32349-4

Nicolaou, K.C., Chen, J.S.

Classics in Total Synthesis III

Further Targets, Strategies, Methods

2011

ISBN: 978-3-527-32957-1

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Preface

Organic chemistry has always been, and continues to be, the branch of chemistry that best connects structure with properties, which attracts particular attention because of its immense importance to life and society. Organic synthesis is a creative science involving the construction and cleavage of bonds, the strategies for which represent the central theme in organic synthesis. More than any other branch of organic chemistry, synthesis has improved our understanding of the structure, dynamics, and transition of molecules. Most synthetic problems have more than one solution, and the trick is to judge which of these is likely to have the best chance of success. Even the most experienced chemists develop routes that work well on paper but fail miserably in the laboratory. However, there are some guidelines and principles that are helpful in designing a suitable route for a particular synthesis. Whether one seeks to understand nature or to create the new materials and medicines of the future, a key starting point is thus to understand structure and mechanism of a particular reaction. For synthetic chemists it is very important to understand in detail what is going on when the molecules in the starting materials react with each other and create the molecules characteristic of the product. Knowledge about mechanisms makes it possible to develop better and less expensive methods to prepare products of technical importance.

Writing a textbook of any level is always a challenging mission. This book has been designed in view of the growing importance of intermediates in the synthesis of natural and/or non-natural molecules. The ideas of functionality and stereochemistry have their origins in the second half of the nineteenth century, and the concepts of bonding and reaction mechanism undoubtedly belong to the twentieth century. The goal of this text is to incorporate basic conceptual tools and recent advances in the area of organic synthesis and particularly in the field of reactive intermediates, which are the key steps of any transformation. A systematic understanding of the mechanisms of organic reactions is necessary as without it organic chemistry is chaos, and impossible to learn.

Theory, mechanism, synthesis, structure, and stereochemistry are discussed throughout the book in a qualitative to semiquantitative fashion. During the writing of this book I have always tried to anticipate the questions of a student and to challenge them to think about the subject, motivating them to understand and to realize why, rather than just memorizing material. Chemists present chemistry in terms of structural diagrams and for this reason all reactions have been drawn using curly arrows; the handwriting of chemistry. Curved arrows and chemical reactions introduce students to the notational systems employed in all of the mechanistic discussions in the text. Such a course is frequently offered as a course material in organic chemistry at the undergraduate and beginning graduate level. I guess one will enjoy many fruitful hours of insight in the course of studying this book and I welcome your constructive comments on its content and approach. In attempting to accomplish these objectives, my approach is substantially different from currently available titles.

I have tried to put equal weight to the three basic fundamental aspects of the study of reactive intermediates, that is, reactions, mechanisms, and stereochemistry. The organization is based on these concepts, so that students can understand the large number of organic reactions based on relatively few principles. Accordingly, this book is divided into seven chapters. The first gives a brief introduction dealing with some basic, very frequently used terms, concepts of steric and electronic effects, and sites of chemical reactivity. The student is also told why such information will be important in the study of a particular reaction mechanism. Chapters 2–6 cover specific reactive intermediates in detail regarding their structure, geometry, generation, stability, and reactions. Chapter 7 gives a brief survey of the miscellaneous intermediates. End-of-chapter summaries review the major concepts of the chapter in a concise narrative format to help readers to understand the key points. The problems at the end of each chapter represent the application of concepts, rather than a review of material explicitly presented in the text. They are designed so that students can test themselves on the material just covered before they go on to the next section. I hope the level of difficulty will present a considerable challenge to students. These problems allow students to practice and test their mastery of core principles within each chapter. A concerted effort was made to make none of the problems so difficult that the student loses confidence.

I would greatly appreciate comments and suggestions from users that will improve the text or correct errors. I can only conclude by expressing my wish that others will enjoy using this text as much as I have enjoyed writing it. In particular, I want to thank the many wonderful and talented students I have had over the years, who taught me how to be a teacher and researcher. I also want to thank the dedicated people at Wiley-VCH, Germany, Dr. Anne Brennführer (Commissioning Editor), Lesley Belfit (Project Editor), and Claudia Nussbeck (Editorial Assistant), for their truly superior editorial ability and for keeping me happy and on track.

Finally, I am grateful to my wife Meera and my son Keshav whose contributions to the project are beyond measure, and so I thank them for their understanding, love, encouragement, and assistance during the lengthy process of writing this book.

Related Titles

Reactive Intermediates in Organic Chemistry

Structure, Mechanism, and Reactions

The Author

Preface