Mechanistic Studies on the pH-Controllable Hydrogenation of NAD⁺ by H₂ and Generation of H₂ from NADH by a Water-Soluble Biomimetic Iridium Complex

Functional biomimicking of hydrogenases at ambient conditions is challenging. Recently an Ir­(III)-cyclometalated complex (J. Am. Chem. Soc. 2012, 134, 367) has been shown to catalyze the pH-dependent reversible reduction of NAD⁺ (nicotinamide adenine dinucleotide) by dihydrogen in water medium. Yet, the reaction mechanism for the catalysis has not been unravelled comprehensively. Hence in this work, mechanisms for catalytic hydrogenation of NAD⁺ to the reduced form of NAD⁺ (NADH) and the reverse reaction catalyzed by the Ir­(III)-cyclometalated complex have been proposed using the results obtained from density functional theory based calculations. The mechanism suggests that the carboxylate group of the Ir­(III) complex can act as a proton relay between hydrogen and water molecules. As a consequence, the direction of the reaction is controlled by the pH of the medium. Splitting of H₂ and generation of H₂ are the rate-determining steps in the two directions with the same activation barrier height of 34.6 kcal/mol. Also, the mechanism supports that the σ-bond metathesis is preferred over oxidative addition of hydrogen. Results show that NADH may act as an inhibitor of the substrate at high basic pH.