The Favorskii Rearrangement

Treatment of α-halogenated ketones, having acidic α'-hydrogens, with nucleophilic bases often leads to a skeletal rearrangement known as the Favorskii rearrangement. As depicted in the following diagram, this reaction is believed to proceed by way of a cyclopropanone intermediate. Facile conversion of cyclopropanones to hydrates and hemiacetals (relief of angle strain) occurs, and the cyclopropoxide conjugate base undergoes ring opening and solvent protonation. In the case of unsymmetrical cyclopropanones the ring cleavage takes place on the side that yields the more stable carbanion or leads to elimination of a stable anion (second example). A debate concerning the nature of the carbon-carbon bond formation step now favors direct (synchronous) formation of the cyclopropanone by a 1,3-elimination, as shown, rather than initial ionization of the enolate to a zwitterionic species such as that drawn in the green box. However, in polar solvents this intermediate may play a role.

  Here the unsymmetrical cyclopropanone opens to favor the less substituted α-carbon, reflecting the carbanion stability order: 1º > 2º > 3º .
When stereoisomeric substrates were examined, the rearrangement proved to be stereospecific, ruling out a common zwitterionic intermediate. The examples in the green-shaded area clearly demonstrate inversion of configuration in the carbon-carbon bond forming step. An application of the Favorskii rearrangement in synthesis will be shown above by clicking on the diagram a second time. In this case cleavage of the cyclopropanol at the more substituted α-carbon probably reflects the inductive effect of the THPO substituent.