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

J. Am. Chem. Soc., 2018, 140 (16), 5500–5515


The kinetics of epoxide formation by Darzens condensation of aliphatic ketones  with arylsulfonyl-substituted chloromethyl anions (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, which subsequently cyclize with formation of the oxiranes. 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, 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  at the ketones. These kCC values and the previously reported reactivity parameters N and sN for the arylsulfonyl-substituted chloromethyl anions 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  and thus predict potential nucleophilic reaction partners. Density functional theory calculations of the intrinsic reaction pathways showed that the reactions of the ketones  with the chloromethyl anions  yield two rotational isomers of the intermediate halohydrin anions, 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. 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.

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