Hydride Reduction of NAD⁺ Analogues by Isopropyl Alcohol: Kinetics, Deuterium Isotope Effects and Mechanism

Abstract

Observed pseudo-first-order rate constants (k(obs)) of the hydride-transfer reactions from isopropyl alcohol (i-PrOH) to two NAD(+) analogues, 9-phenylxanthylium ion (PhXn(+)) and 10-methylacridinium ion (MA(+)), were determined at temperatures ranging from 49 to 82 degrees C in i-PrOH containing various amounts of AN or water. Formations of the alcohol-cation ether adducts (ROPr-i) were observed as side equilibria. The equilibrium constants for the conversion of PhXn(+) to PhXnOPr-i in i-PrOH/AN (v/v = 1) were determined, and the equilibrium isotope effect (EIE = K(i-PrOH)/K(i-PrOD)) at 62 degrees C was calculated to be 2.67. The k(H) of the hydride-transfer step for both reactions were calculated on the basis of the k(obs) and K. The corresponding deuterium kinetic isotope effects (e.g., KIE(OD)(H) = k(H)(i-PrOH)/k(H)(i-PrOD) and KIE(beta-D6)(H) = k(obs)(i-PrOH)/k(obs)((CD3)2CHOH)), as well as the activation parameters, were derived. For the reaction of PhXn(+) (62 degrees C) and MA(+) (67 degrees C), primary KIE(alpha-D)(H) (4.4 and 2.1, respectively) as well as secondary KIE(OD)(H) (1.07 and 1.18) and KIE(beta-D6)(H) (1.1 and 1.5) were observed. The observed EIE and KIE(OD)(H) were explained in terms of the fractionation factors for deuterium between OH and OH(+)(OH(delta+)) sites. The observed inverse kinetic solvent isotope effect for the reaction of PhXn(+) (k(obs)(i-PrOH)/k(obs)(i-PrOD) = 0.39) is consistent with the intermolecular hydride-transfer mechanism. The dramatic reduction of the reaction rate for MA(+), when the water or i-PrOH cosolvent was replaced by AN, suggests that the hydride-transfer T.S. is stabilized by H-bonding between O of the solvent OH and the substrate alcohol OH(delta+). This result suggests an H-bonding stabilization effect on the T.S. of the alcohol dehydrogenase reactions.

Structure–reactivity relationship for alcohol oxidations via hydride transfer to a carbocationic oxidizing agent

“…We have recently reported the kinetic and mechanistic study of the oxidation of 2‐propanol via hydride‐transfer to carbocationic oxidants (R + ) in various solvent systems to form the corresponding ketone product, the hydride reduction products of carbocations (RH) and a proton (Eqn (1), R 1 = R 2 = CH 3 ) 31–33. R + used include PhXn + and 10‐methylacridinium ion.…”

“…Product analysis for the reaction of 1‐phenylethanol was carried out; corresponding PhXnH and acetophenone products were isolated and their structures were characterized by 1 H NMR spectroscopy. Here, absorption decay at 373 nm was due to the PhXn + consumption and absorption rise at 285 nm due to the formation of PhXnH 32, 33. Representative kinetic scans for the reactions of other alcohols are shown in the Supplemental Information (Figs.…”

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

“…[24][25][26][27] Here, kinetics of the hydride-transfer reactions from alcohols to Xn + ClO 4 À in MeCN were similarly determined by following the decay of the Xn + UV-Vis absorption (Fig. S1, ESIw).…”

Unusual Reaction Constant for Hydride Transfer from a Carbanion to 9‐Arylxanthyliums

“…The "intermediate" with quotation mark implies that the species involved in the reactions could also be in a side equilibrium [14] with the XH -and 9-GPhXn + reactants (Scheme 5). According to the existing literature, [5,14,18] such a possible "intermediate" during hydride transfer may have been the CT complex [5,18] or the adduct. [14] However, we did not find an absorption in the long-wave field region during the reaction that was characteristic of the CT complex.…”

“…According to the existing literature, [5,14,18] such a possible "intermediate" during hydride transfer may have been the CT complex [5,18] or the adduct. [14] However, we did not find an absorption in the long-wave field region during the reaction that was characteristic of the CT complex. [17,18] This indicated that the formation of the CT complex in this reaction was not possible.…”