Temperature dependence of primary (1°) kinetic isotope effects (KIEs) for H-transfer reactions has been used as a measure to determine the H-tunneling mechanism. However, how structures affect such dependency has never been systematically studied until the beginning of this century when the differences in such dependencies were found between enzymes and their various mutants of different active site structures. The temperature dependence of 1° KIEs can be reflected by the isotopic activation energy difference, e.g., ΔEa(D-H) = EaD - EaH. The ΔEa(D-H) value is often small and close to zero in wild-type enzymes but increases as the active site of the enzyme is deformed due to mutation. This has been explained in terms of different structures of tunnelling ready states (TRS’s) that have different donor-acceptor distances (DADs), following a full-tunneling model within which the 1° KIE is DAD dependent. The wild type enzyme has a densely packed TRS with DAD whose change is not sensitive to temperature resulting in weak temperature dependence of 1° KIEs, whereas a mutant has a loosely packed TRS whose DAD can readily vary and hence is readily altered by temperature resulting in stronger temperature dependence of 1° KIEs. In this study, we hypothesize that a greater ΔEa(D-H) value should be observed in H-transfer systems that have a loosely associated TRS. Hydride transfer reactions from dihydropyridines of various structures to N-methylacridinium ion in acetonitrile were studied to investigate this hypothesis. The structural effect on ΔEa(D-H) will be discussed providing insight into this hypothesis. The relationship between structures and ΔEa(D-H) will be compared for reactions in solution vs. enzymes.

Structural effects on the temperature dependence of primary kinetic isotope effects in hydride transfer reactions in solution

2019 Spring National Meeting

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