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. How structure affects such dependency has never been systematically studied. The weaker the temperature dependence of the 1° KIEs, the smaller the isotopic activation energy difference (ΔEa = EaD - EaH). It has been recently frequently observed that the ΔEa value is small and close to zero with 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 tightly associated TRS with DAD whose change is not sensitive to temperature resulting in weak temperature dependence of 1° KIEs, whereas a mutant has a loosely associated TRS whose DAD could vary and hence is readily altered by temperature resulting in stronger temperature dependence of 1° KIEs. In this study, we hypothesize that a smaller ΔEa value would be observed in H-transfer systems that have a more sterically hindered thus more rigid TRS. Hydride transfer reactions with various sterically hindered substrates (NADH/NAD+ models) in acetonitrile were designed to investigate this hypothesis. The steric effect on rigidity of the TRS’s and ΔEa’s will be discussed. The relationship between structure and ΔEa will be compared for reactions in solution versus in enzymes.

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

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.