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.

The electron-transfer-catalyzed Diels-Alder reaction of indole and 1,3-cyclohexadiene was studied by a combination of experimental and theoretical methods. The (13)C kinetic isotope effects were determined at natural abundance by NMR methodology. B3LYP/6-31G* calculations allow for the first time a quantitatively accurate description of the different possible pathways and provide the basis for an analysis of the experimentally observed isotope effects. The computational results, in conjunction with experimental observations, show that the reaction has a stepwise mechanism that is initiated by attack of the diene into the 3-position of the indole. Numerical simulation of the experimentally observed isotope effects shows that the first step is rate-determining and that the electron exchange in the reactant contributes partially to the overall isotope effect. The combination of electronic structure theory, experimental isotope effects, and numerical simulation thus allows a detailed analysis of a complex reaction mechanism.

The aliphatic Claisen rearrangement of allyl vinyl ether and the aromatic Claisen rearrangement of allyl phenyl ether are investigated in a combined experimental and calculational study. Theoretically predicted kinetic isotope effects (KIEs) at all levels disagree with about half of the literature experimental heavy-atom isotope effects. New experimental C-13 and H-2 isotope effects were determined by multisite NMR methodology at natural abundance, and O-17 isotope effects were determined by novel NMR methodology. These new experimental isotope effects are inconsistent with the literature values and agree well the high-level predicted KIEs, suggesting that the prior theory/experiment disagreement results from inaccuracy in the experimental KIEs. A one-dimensional tunneling correction is found to improve kinetic isotope effect predictions in a number of reactions and is found to be sufficient to provide differences between predicted and experimental heavy-atom isotope effects on the order of the experimental uncertainty in the reactions studied. The best agreement between experimental and predicted isotope effects is seen for the highest-level calculations. On the basis of the experimentally supported transition state geometries, the nature of the Claisen and aromatic Claisen transition states is discussed.