Q4(c). Favorskii rearrangement; bromine addition in methanol; indole anions

Introduction. (i) is α-bromination of a ketone followed by the base-induced Favorskii rearrangement. (ii) is electrophilic addition of bromine, whose rate depends on how well the alkene stabilises the positive charge that builds up in the RDS. (iii) compares the N-metallated indoles of lithium and magnesium.

(i) E and F

E. In acetic acid the ketone enolises (acid-catalysed, the RDS), and the enol attacks Br₂. One equivalent introduces one Br on an α-carbon: E = (1-bromocyclohexyl)(cyclohexyl)methanone. The first Br lowers the basicity of the C=O, so a second bromination is slow in acid.

F (Favorskii mechanism).

1. OH⁻ removes the α'-H (on the other cyclohexyl ring) to form the enolate.
2. The enolate carbon displaces bromide intramolecularly (SN2-like, 3-exo): a cyclopropanone intermediate, here a dispiro compound.
3. OH⁻ adds to the strained cyclopropanone C=O.
4. The tetrahedral anion collapses and breaks one cyclopropane C–C bond, releasing the more stable carbanion. The two bonds are equivalent here (both give a tertiary carbanion on a cyclohexane ring).
5. Proton transfer gives the carboxylate; acidification gives the acid.

Scheme: Favorskii rearrangement by way of a dispiro cyclopropanone.

F = 1-cyclohexylcyclohexane-1-carboxylic acid (as its potassium salt before acidification). The carbonyl carbon ends up as COOH attached to what was the α-carbon; the carbon skeleton is rearranged.

(ii) Order of reactivity towards Br₂/MeOH

The RDS is attack of Br₂ on the alkene to give the bromonium ion; positive charge builds up on the carbon that will be attacked by methanol (Markovnikov). Every alkyl group on the C=C stabilises this charge and raises the HOMO; a phenyl group on the same carbon stabilises it further by conjugation (benzylic character), so a 1-aryl-1-alkyl alkene reacts fastest. 4 (ethene) < 2 (trans-but-2-ene) < 1 (2-methylpropene) < 3 (α-methylstyrene) Ethene has no donor group. trans-But-2-ene has two alkyl groups, one on each carbon. 2-Methylpropene has two on the same carbon, which can carry a tertiary-like δ+. α-Methylstyrene puts methyl and phenyl together on the charged carbon, giving a tertiary benzylic δ+.

(iii) Indole with BuLi and with BuMgBr, then CO₂

The N–H of indole (pKₐ about 17 in water, 21 in DMSO) is removed by both organometallic bases; the difference lies in the metal.

• Reaction 1. The N–Li bond is largely ionic: the negative charge sits on nitrogen, which attacks CO₂. The product is the N-carboxylate, giving indole-1-carboxylic acid on careful acidification (a carbamic acid that loses CO₂ easily on warming).
• Reaction 2. The N–Mg bond is more covalent, and magnesium stays on nitrogen. The indolyl Grignard reagent reacts through C-3, the most nucleophilic carbon (an enamine-like position). Proton loss restores the aromatic ring: indole-3-carboxylic acid.

Scheme: N-attack with the ionic lithium salt; C-3 attack with the covalent magnesium salt.

Conclusion. (i) E = the α-bromo ketone, F = 1-cyclohexylcyclohexanecarboxylic acid, formed through a cyclopropanone (Favorskii). (ii) 4 < 2 < 1 < 3. (iii) Lithium gives N-carboxylation (indole-1-carboxylic acid); magnesium gives C-3 carboxylation (indole-3-carboxylic acid).

Application. The Favorskii rearrangement gives ring-contracted and branched acids (cubane synthesis, ibuprofen-type acids); indolyl Grignard reagents are the classical route to 3-substituted indoles such as tryptophol and gramine.