Kinetics and Mechanism of Oxirane Formation by Darzens Condensation of Ketones: Quantification of the Electrophilicities of Ketones

The kinetics of epoxide
formation by Darzens condensation of aliphatic
ketones 1 with arylsulfonyl-substituted chloromethyl
anions 2 (ArSO2CHCl–) have
been determined photometrically in DMSO solution at 20 °C. The
reactions proceed via nucleophilic attack of the carbanions at the
carbonyl group to give intermediate halohydrin anions 4, which subsequently cyclize with formation of the oxiranes 3. Protonation of the reaction mixture obtained in THF solution
at low temperature allowed the intermediates to be trapped and the
corresponding halohydrins 4-H to be isolated. Crossover
experiments, i.e., deprotonation of the halohydrins 4-H in the presence of a trapping reagent for the regenerated arylsulfonyl-substituted
chloromethyl anions 2, provided the relative rates of
backward (k–CC) and ring closure
(krc) reactions of the intermediates.
Combination of the kinetic data (k2exptl) with the splitting ratio (k–CC/krc) gave the second-order rate constants kCC for the attack of the carbanions 2 at the ketones 1. These kCC values and the previously reported reactivity parameters N and sN for the arylsulfonyl-substituted
chloromethyl anions 2 allowed us to use the linear free
energy relationship log k2(20 °C)
= sN(N + E) for deriving the electrophilicity parameters E of the ketones 1 and thus predict potential nucleophilic
reaction partners. Density functional theory calculations of the intrinsic
reaction pathways showed that the reactions of the ketones 1 with the chloromethyl anions 2 yield two rotational
isomers of the intermediate halohydrin anions 4, only
one of which can cyclize while the other undergoes retroaddition because
the barrier for rotation is higher than that for reversal to the reactants 1 and 2. The electrophilicity parameters E correlate moderately with the lowest unoccupied molecular
orbital energies of the carbonyl groups, very poorly with Parr’s
electrophilicity indices, and best with the methyl anion affinities
calculated for DMSO solution.