Thebenzilic acid rearrangement is formally the1,2-rearrangement of 1,2-diketones to form α-hydroxy–carboxylic acids using abase. This reaction receives its name from the reaction ofbenzil withpotassium hydroxide to formbenzilic acid. First performed byJustus von Liebig in 1838,[1] it is the first reported example of arearrangement reaction.[2] It has become a classic reaction in organic synthesis and has been reviewed many times before.[3][4][5] It can be viewed as anintramolecularredox reaction, as one carbon center is oxidized while the other is reduced.
The reaction has been shown to work inaromatic, semi-aromatic,aliphatic, andheterocyclic substrates. The reaction works best when the ketone functional groups have no adjacentenolizable protons, as this allowsaldol 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 withelectron-withdrawing groups migrate the fastest.
The reaction is a representative of 1,2-rearrangements. The long-establishedreaction mechanism was first proposed in its entirety byChristopher Kelk Ingold, and has been updated within silico data[6] as outlined below. The reaction is second order overall in terms of rate, being first order in diketone and first order in base.
Ahydroxide anion attacks one of theketone groups in1 in anucleophilic addition to form thealkoxide2. The next step requires a bond rotation toconformer3 which places the migrating group R in position for attack on the second carbonyl group. In aconcerted 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 israte-determining. This sequence resembles anucleophilic acyl substitution. Calculations show that when R ismethyl the charge build-up on this group in thetransition state can be as high as 0.22, and that the methyl group is positioned between the central carbon–carbon bond.
Thecarboxylic acid in intermediate4 is less basic than the alkoxide and therefore reversible proton transfer takes place favoring intermediate5 which is protonated on acidic workup to the final α-hydroxy–carboxylic acid6. Calculations show that an accurate description of the reaction sequence is possible with the participation of 4 water molecules taking responsibility for the stabilization of charge buildup. They also provide a shuttle for the efficient transfer of one proton in the formation of intermediate5.
The above mechanism is consistent with all available experimental evidence.[3] Theequilibrium between species1 and2 is supported by18OIsotopic labeling experiments. Indeuterated water, carbonyl oxygen exchange occurs much faster than the rearrangement, indicating that the first equilibrium is not the rate-determining step. Further experiments showed a larger relative rate in a deuterated solvent system compared to a non-deuterated solvent system of otherwise identical composition. This was explained as being due to the greater relative basicity of the deuterated hydroxide anion compared to the normal hydroxide anion, and was used to indicate that hydrogen migration did not occur in the rate determining step of the reaction. This ruled out a concerted mechanism for the reaction, as hydrogen transfer would occur in the rate determining step.
This reaction is identical to the normal benzilic acid rearrangement, except that an alkoxide or an amide anion is used in place of a hydroxide ion. The alkoxide used should not be easily oxidizable (such aspotassium ethoxide) as this favors theMeerwein–Ponndorf–Verley reduction pathway as a side reaction. The reaction is second order overall in terms of rate, being first order in terms of alkoxide and first order in terms of diketone. The product of the reaction is an α-hydroxy–ester or an α-hydroxy-amide.
Thealpha-ketol rearrangement is an interconversion of a hydroxylalpha to a carbonyl to the complementary carbonyl and hydroxyl groups, with migration of a substituent. It is mechanistically equivalent to the benzyllic acid rearrangement at the point after the nucleophile attacks the 1,2-dicarbonyl. This variation of the reaction has been known to occur in many substrates bearing theacyloin functional group. The picture below shows thering expansion of a cyclopentane to a cyclohexane ring as an example reaction.[7][8]
