Química Orgânica Avançada · Advanced synthesis
Rearranjos nomeados para heteroátomos
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O que você vai aprender
- Find the electron-poor oxygen or nitrogen that is losing a leaving group in Baeyer–Villiger, Beckmann, Curtius, Hofmann, Schmidt and related rearrangements, and move the migrating group onto it with its bonding pair.
- Predict which group migrates from migratory aptitude in Baeyer–Villiger-type oxidations and from C=N geometry in the Beckmann rearrangement.
- Follow isocyanate intermediates to amines with loss of one carbon, and recognise carbon-to-carbon shifts in the Favorskii, Wolff, Tiffeneau–Demjanov and dienone–phenol rearrangements.
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Migration to an electron-poor atom
In the heteroatom rearrangements of this topic a group moves with its bonding pair from carbon to a neighbouring atom that is losing a leaving group: oxygen in the Baeyer–Villiger oxidation, nitrogen in the Beckmann, Curtius, Hofmann and Schmidt reactions. The Criegee intermediate shown forms when mCPBA adds to acetophenone. Its O–O bond is weak and the far oxygen leaves as m-chlorobenzoate, so the near oxygen becomes electron-poor. The phenyl group, anti-periplanar to the O–O bond, slides onto that oxygen as the bond breaks, and the hydroxyl lone pair re-forms C=O. The migrating group never leaves the molecule, so a migrating stereocentre keeps its configuration.
Anti to the leaving group
An oxime rearranges to an amide once its oxygen becomes a leaving group, by protonation in sulfuric acid or by bonding to phosphorus in PCl5. The C–C bond that migrates is the one anti-periplanar to the N–O bond, because only that σ bond overlaps with the back lobe of the breaking N–O bond. The C=N geometry therefore decides the product: an (E)-ketoxime and its (Z)-isomer give different amides, whatever the migratory aptitudes. Cyclohexanone oxime is symmetrical, so either ring bond gives the same result. Migration inserts nitrogen into the ring, water captures the nitrilium ion, and tautomerisation gives ε-caprolactam, the seven-membered lactam behind nylon 6.
Isocyanates: three roads, one intermediate
The Curtius, Hofmann and Lossen rearrangements start from different acyl derivatives: an acyl azide, an N-bromoamide anion and an O-acyl hydroxamic acid. Each has an acyl nitrogen carrying a leaving group (N2, bromide or a carboxylate). The group on the carbonyl carbon migrates to that nitrogen as the leaving group departs, and the nitrogen lone pair forms C=N, giving an isocyanate R–N=C=O. Benzoyl azide, N-bromobenzamide and O-acetylbenzohydroxamic acid all give the phenyl isocyanate shown. Water adds to the isocyanate carbon to make a carbamic acid that loses CO2, so the amine has one carbon fewer than the acid derivative; an alcohol instead gives a stable carbamate.
Carbon skeleton classics
Some rearrangements move a group from carbon to carbon. In the Favorskii reaction an α-halo ketone with an α′ hydrogen is deprotonated, and the enolate displaces the halide internally to give a cyclopropanone; from 2-chlorocyclohexanone this is the bicyclic ketone shown. Alkoxide adds to the strained carbonyl and the three-membered ring opens to the more stable carbanion, so a cyclic substrate contracts by one ring atom to an ester. The Wolff rearrangement moves a group onto a carbon losing N2 to make a ketene, the Tiffeneau–Demjanov reaction moves a ring bond onto a CH2 losing N2, and the dienone–phenol rearrangement shifts a methyl so that a blocked ring can become aromatic.
What to carry forward
Find the electron-poor atom that is losing a leaving group, pick the group anti-periplanar to that bond, and move it with its bonding pair; let the neighbouring oxygen or nitrogen lone pair stabilise the new cationic centre, then finish with the proton transfers of the medium.
Problemas de prática (18)
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Desenhe o mecanismo 13
Migration to oxygen
- Baeyer–Villiger ring expansion of 2-methylcyclohexanoneDraw how mCPBA converts 2-methylcyclohexanone into the seven-membered lactone 7-methyloxepan-2-one, deciding which ring carbon migrates to oxygen in the Criegee intermediate.
- Baeyer–Villiger oxidation of acetophenone to phenyl acetateDraw the Baeyer–Villiger mechanism that turns acetophenone into phenyl acetate with mCPBA: activation of the ketone, addition of the peracid to form the Criegee intermediate, phenyl migration to oxygen, and the final deprotonation.
- Dakin oxidation of 4-hydroxybenzaldehyde to hydroquinoneDraw the Dakin oxidation of 4-hydroxybenzaldehyde with basic hydrogen peroxide: formation of the two anions, hydroperoxide addition, aryl migration to oxygen, hydrolysis of the aryl formate, and neutralisation to hydroquinone and formate.
- Hock rearrangement of cumene hydroperoxide to phenol and acetoneDraw the acid-catalysed Hock rearrangement of cumene hydroperoxide: protonation of the terminal oxygen, phenyl migration to oxygen with loss of water, water addition to the oxocarbenium ion, and fragmentation of the hemiketal into phenol and acetone.
Migration to nitrogen
- Beckmann rearrangement of (E)-acetophenone oxime to acetanilideDraw the PCl5-promoted Beckmann rearrangement of (E)-acetophenone oxime: activation of the oxime oxygen by phosphorus, migration of the phenyl group anti to it, and hydrolysis of the nitrilium ion to acetanilide.
- Beckmann rearrangement of cyclohexanone oxime to ε-caprolactamDraw the sulfuric-acid Beckmann rearrangement of cyclohexanone oxime: activation of the hydroxyl, ring-bond migration to nitrogen with loss of water, capture of the nitrilium ion by water, and tautomerisation to the seven-membered lactam ε-caprolactam.
- Curtius rearrangement of benzoyl azide and hydrolysis to anilineDraw the Curtius rearrangement of benzoyl azide to phenyl isocyanate with loss of N2, then the addition of water and decarboxylation that turn the isocyanate into aniline and CO2.
- Hofmann rearrangement of butanamide to propan-1-amineDraw the Hofmann rearrangement of butanamide with bromine and aqueous hydroxide: N-bromination, the second deprotonation, migration of the propyl group to nitrogen as bromide leaves, and the hydrolysis and decarboxylation that give propan-1-amine.
- Schmidt reaction of cyclohexanone with hydrazoic acidDraw the Schmidt reaction that converts cyclohexanone into ε-caprolactam: addition of hydrazoic acid to the protonated ketone, dehydration to the iminodiazonium ion, ring-bond migration with loss of N2, water capture and tautomerisation.
Carbon skeleton classics
- Dienone–phenol rearrangement of 4,4-dimethylcyclohexa-2,5-dien-1-oneDraw the acid-catalysed dienone–phenol rearrangement of 4,4-dimethylcyclohexa-2,5-dien-1-one: protonation of the carbonyl, the resonance form with charge beside the quaternary carbon, the 1,2-methyl shift, and loss of a proton to give 3,4-dimethylphenol.
- Favorskii rearrangement of 2-chlorocyclohexanoneDraw the Favorskii rearrangement of 2-chlorocyclohexanone with sodium methoxide: enolate formation on the far side of the ketone, closure to the cyclopropanone, methoxide addition, ring opening, and protonation to methyl cyclopentanecarboxylate.
- Tiffeneau–Demjanov ring expansion of 1-(aminomethyl)cyclohexan-1-olDraw the Tiffeneau–Demjanov reaction of 1-(aminomethyl)cyclohexan-1-ol: diazotisation of the primary amine by nitrosonium, then ring expansion with loss of N2 and deprotonation to cycloheptanone.
- Wolff rearrangement of 1-diazo-3-phenylpropan-2-one in methanolDraw the photochemical Wolff rearrangement of 1-diazo-3-phenylpropan-2-one in methanol: loss of N2 with migration of the benzyl group to give a ketene, addition of methanol to the ketene, and the proton transfers that give methyl 3-phenylpropanoate.
Preveja o produto 1
- Beckmann product of (Z)-acetophenone oximeUse the C=N geometry of an oxime to predict which amide its Beckmann rearrangement gives.
Classificar 1
- Rearrangements that lose a carbonClassify heteroatom rearrangements by whether the product keeps the original carbonyl carbon.
Comparar 1
- Migratory aptitude in a Baeyer–Villiger oxidationApply the Baeyer–Villiger migratory-aptitude order to predict the ester formed from 3,3-dimethylbutan-2-one.
Trabalhe de trás para frente 1
- Work back to a Baeyer–Villiger substrateIdentify the cyclic ketone whose Baeyer–Villiger oxidation gives ε-caprolactone.
Explique por quê 1
- One intermediate behind three rearrangementsExplain why the Curtius, Hofmann and Lossen rearrangements give the same amine from the same acyl group.
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