In organic chemistry, the Favorskii rearrangement is a reaction of α-halo ketones with a nucleophilic base to acyl derivatives. In the rearrangement, the substrate extrudes the carbonyl carbon to a primary position, which then acylates the base. In the case of cyclic α-halo ketones, the Favorskii rearrangement constitutes a ring contraction:
History The reaction is named for the Russian chemist Alexei Yevgrafovich Favorskii. The reaction became popular for the synthesis of strained cyclic compounds in the 1970s. For example, cubane synthesis proceeds by Favorskii rearrangements:
Reaction mechanism The Favorskii rearrangement begins when an enolate forms on the side of the ketone away from the chlorine atom. This enolate cyclizes to a cyclopropanone intermediate. In aprotic solvents, the process is concerted, and thus stereospecific, inverting configuration at the halide-substituted carbon. In protic solvents, the process is stepwise, with chloride anion leaving first. The resulting achiral, cationic oxyallyl 1,3-dipole then undergoes a disrotatory, 2-electron electrocyclization to the cyclopropanone. In either case, the base then attacks the cyclopropanone. Finally, the ring opens to yield the more stable carbanion, which is quickly protonated:
When enolate formation is impossible, harsh reaction conditions can still sometimes induce a similar reaction, called the pseudo- or quasi-Favorskii rearrangement. The alternate reaction pathway probably resembles the benzilic acid rearrangement: base initially adds to the ketone, and the resulting acetal anion collapses in concert with carbon migration and halide expulsion.
Polyhalogenated substrates In the related Wallach degradation (Otto Wallach, 1918) not one but two halogen atoms flank the ketone, resulting in a new contracted ketone after oxidation and decarboxylation α,α'‑Dihaloketones eliminate HX under the reaction conditions to give α,β-unsaturated carbonyl compounds, but α,α,α'‑trihaloketones generally do not undergo a second elimination to the ynone. Trihalomethyl ketone substrates undergo the haloform reaction instead.
Photo-Favorskii reaction Favorskii rearrangements also occur through photochemical excitation. The photo-Favorskii reaction has been used to unlock certain phosphates (for instance those of ATP) protected as para‑hydroxyphenylacetate esters. The deprotection is believed to proceed through a triplet diradical (3) and a dione spiro intermediate (4), although the latter has thus far eluded detection:
See also Benzilic acid rearrangement — similar carboxylate extrusion Trimethylenemethane cycloaddition, which can proceed via a similar mechanism Homo-Favorskii rearrangement, the rearrangement of β-halo ketones and cyclobutanones Wolff rearrangement - can react similarly Dowd-Beckwith ring-expansion reaction — radical analogue (when applied to single-carbon expansions)
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