Structural Effects on the Hydride-Tunneling Kinetic Isotope Effects of NADH/NAD+ Model Reactions: Relating to the Donor–Acceptor Distances

Contemporary H-tunneling theories predict that a longer donor–acceptor distance (DAD) corresponds to a larger kinetic isotope effect (KIE). Herein, hydride-tunneling reactions of NADH/NAD⁺ analogues in acetonitrile were used to examine the KIE–DAD relationship. Reaction pairs of similar tunneling-ready conformations were selected, so that additional factors influencing KIEs would be relatively fixed. Positive results were obtained, with some reaction pairs displaying a reversal of the traditional KIE−ΔG° relationship in favor of the KIE–DAD relationship, lending strong support to the latter.