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 12C/13C (k(12C)/k(13C)) isotope effect of approximately equal to 1.032 was observed at the C3 (beta) position of cyclohexenone, while a much smaller 12C/13C isotope effect of 1.010 was observed at the C2 (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.

A new form of kinetic isotope effect. Dynamic effects on isotopic selectivity and regioselectivity.

The intramolecular H/D kinetic isotope effect in the ene reaction of singlet oxygen with tetramethylethylene is studied using quasiclassical direct dynamics calculations on a B3LYP/6-31G* potential energy surface. Starting from the area of the energy surface around a valley-ridge inflection point, random trajectories lead to predominantly H abstraction over D abstraction, despite the symmetry of the surface and the absence of a barrier to either reaction. This demonstrates a new form of kinetic isotope effect, unrelated to the usual effect of zero-point energies on barriers. Dynamics calculations on the reaction of cis-2-pentene predict the experimentally observed mixture of regioisomeric products, while the minimum-energy path leads to only one product. For energy surfaces containing two adjacent saddle points, dynamics effects are important for understanding both product and isotopic selectivity, and this should be considered in the interpretation of experimental results.

Mechanism of ene reactions of singlet oxygen. A two-step no-intermediate mechanism.

The mechanism of the ene reaction of singlet ((1)delta(g)) oxygen with simple alkenes is investigated by a combination of experimental isotope effects and several levels of theoretical calculations. For the reaction of 2,4-dimethyl-3-isopropyl-2-pentene, the olefinic carbons exhibit small and nearly equal (13)C isotope effects of 1.005-1.007, while the reacting methyl groups exhibit (13)C isotope effects near unity. In a novel experiment, the (13)C composition of the product is analyzed to determine the intramolecular (13)C isotope effects in the ene reaction of tetramethylethylene. The new (13)C and literature (2)H isotope effects are then used to evaluate the accuracy of theoretical calculations. RHF, CASSCF(10e, 8o), and restricted and unrestricted B3LYP calculations are each applied to the ene reaction with tetramethylethylene. Each predicts a different mechanism, but none leads to reasonable predictions of the experimental isotope effects. It is concluded that none of these calculations accurately describe the reaction. A more successful approach was to use high-level, up to CCSD(T), single-point energy calculations on a grid of B3LYP geometries. The resulting energy surface is supported by its accurate predictions of the intermolecular (13)C and (2)H isotope effects and a very good prediction of the reaction barrier. This CCSD(T)//B3LYP surface features two adjacent transition states without an intervening intermediate. This is the first experimentally supported example of such a surface and the first example of a valley-ridge inflection with significant chemical consequences.