Imbalanced tunneling ready states in alcohol dehydrogenase model reactions: rehybridization lags behind H-tunneling

Abstract

The secondary kinetic isotope effects for the hydride transfer reactions from aliphatic alcohols to two carbocations (NAD(+) models) in acetonitrile were determined. The results suggest that the hydride transfer takes place by tunneling and that the rehybridizations of both donor and acceptor carbons lag behind the H-tunneling. This is quite contrary to the observations in alcohol dehydrogenases where the importance of enzyme motions in catalysis is manifested.

Computational Replication of the Abnormal Secondary Kinetic Isotope Effects in a Hydride Transfer Reaction in Solution with a Motion Assisted H-Tunneling Model

“…aSee texts for details.bFrom ref (29); within experimental error there is no 1° isotope effect on 2° KIEs.cBest-fit to the 2° KIE on alcohol.dBest-fit to the 2° KIE on cation.e2° KIEs from TRS with DAD = 3.0 Å fit the 2° KIEs on both reactants.fA discussion of the difference in the two values may be meaningless; see footnote b and text.…”

“…The 1° KIE reported for this reaction is 2.8, indicating the hydride transfer is rate-determining. 29 In Table 2, the column (calcd (1)) shows the TRS/DAD with best-fit to the β-D 6 2° KIE on the 2-propanol moiety of the TRS, and the column (calcd (2)) with best-fit to the α-2° KIE on the Xn + . Within expectation, the two corresponding DADs are quite close showing that one TRS structure fits to the experimental 2° KIEs on both reactants.…”

“…47 The quantitative comparison between the two systems manifests the role of protein motions in such catalysis: protein motions advance the geometry change of the system, providing favorable orbital conditions for H-tunneling to occur. 28,29 …”

“…29 These hydride transfer processes strictly follow the second-order kinetics and are thus proper systems to study the relationship between the magnitude of 2° KIEs and 1° H-tunneling. 29−32 The 2° KIEs on both the β-CH 3 /CD 3 position of the 2-propanol (β-D 6 2° KIE = 1.05) and on the α-9-H/D position of the Xn + (α-D 2° KIE = 0.99) (Scheme 1, R = R′ = CH 3 , R″ = H) were found to be very close to unity and far from the corresponding EIEs (1.52 and 0.89, respectively). 29 They are expected to be closer to the corresponding EIEs, though, since Hammond’s Postulate predicts a late TS for such reactions that produce a highly unstable α-hydroxy carbocation product (C + –OH).…”

“…29−32 The 2° KIEs on both the β-CH 3 /CD 3 position of the 2-propanol (β-D 6 2° KIE = 1.05) and on the α-9-H/D position of the Xn + (α-D 2° KIE = 0.99) (Scheme 1, R = R′ = CH 3 , R″ = H) were found to be very close to unity and far from the corresponding EIEs (1.52 and 0.89, respectively). 29 They are expected to be closer to the corresponding EIEs, though, since Hammond’s Postulate predicts a late TS for such reactions that produce a highly unstable α-hydroxy carbocation product (C + –OH). Furthermore, the KIEs contradict the observed large negative Hammett constant (−2.66) for the hydride transfer reactions from substituted benzyl alcohols to PhXn + , which is also consistent with a late TS.…”