Isotope effects and the mechanism of epoxidation of cyclohexenone with tert-butyl hydroperoxide

The mechanism of the epoxidation of 2-cyclohexen-1-one with tert- butyl hydroperoxide mediated by DBU was studied by a combination of experimental kinetic isotope effects ( KIEs) and theoretical calculations. A large C-12/C-13 (k(12C)/k(13C)) isotope effect of approximate to 1.032 was observed at the C-3 (beta) position of cyclohexenone, while a much smaller C-12/C-13 isotope effect of 1.010 was observed at the C-2 (alpha) position. Qualitatively, these results are indicative of nucleophilic addition to the enone being the rate-limiting step. Theoretical calculations support this interpretation. Transition structures for the addition step lead to predicted isotope effects that approximate the experimental values, while the predicted isotope effects for the ring-closure step are not consistent with the experimental values. The calculations correctly favor a rate-limiting addition step but suggest that the barriers for the addition and ring-closure steps are crudely similar in energy. The stereochemistry of these epoxidations is predicted to be governed by a preference for an initial axial addition, and the role of this preference in experimental diastereoselectivity observations is discussed.