Benzilic acid rearrangement

The benzilic acid rearrangement is formally the 1,2-rearrangement of 1,2-diketones to form α-hydroxy–carboxylic acids using a base. This reaction receives its name from the reaction of benzil with potassium hydroxide to form benzilic acid. First performed by Justus von Liebig in 1838, it is the first reported example of a rearrangement reaction. It has become a classic reaction in organic synthesis and has been reviewed many times before. It can be viewed as an intramolecular redox reaction, as one carbon center is oxidized while the other is reduced. The reaction has been shown to work in aromatic, semi-aromatic, aliphatic, and heterocyclic substrates. The reaction works best when the ketone functional groups have no adjacent enolizable protons, as this allows aldol condensation to compete. The reaction is formally a ring contraction when used on cyclic diketones. It has been found that aryl groups more readily migrate than alkyl groups, and that aryl groups with electron-withdrawing groups migrate the fastest. Reaction mechanism The reaction is a representative of 1,2-rearrangements. The long-established reaction mechanism was first proposed in its entirety by Christopher Kelk Ingold, and has been updated with in silico data as outlined below. The reaction is second order overall in terms of rate, being first order in diketone and first order in base. A hydroxide anion attacks one of the ketone groups in 1 in a nucleophilic addition to form the alkoxide 2. The next step requires a bond rotation to conformer 3 which places the migrating group R in position for attack on the second carbonyl group. In a concerted step, the migrating R group attacks the α-carbonyl group forming another alkoxide with concomitant formation of a keto-group at the other carbon. This migration step is rate-determining. This sequence resembles a nucleophilic acyl substitution. Calculations show that when R is methyl the charge build-up on this group in the transition state can be as high as 0.22 and that the methyl group is positioned between the central carbon carbon bond!