Aqueous-phase NADH regeneration using Rh(N-heterocyclic carbene) catalyst with enhanced hydride kinetics

Abstract

Nicotinamide adenine dinucleotide (NADH) serves as a two-electron and one-proton donor in redox biocatalysis, yet its high cost and stoichiometric consumption limit large-scale applications. A [Cp*Rh(N^C)Cl]⁺ complex featuring a mono(NHC–pyridyl) chelating ligand has been developed for the efficient regeneration of NADH in aqueous media. Kinetic investigations demonstrate that this Rh(III) complex forms the key Rh–H intermediate over ten times faster than its bipyridine-based analogs, owing to the favorable electronic and steric effects of the NHC ligand. Mechanistic analysis indicates that the Rh–H species, rather than Cp*–H, acts as the primary reducing agent, facilitating regioselective conversion of NAD⁺ to biologically active 1,4-NADH. Under optimized conditions, the catalyst achieves a turnover frequency (TOF) of 7000 h⁻¹, marking the highest reported activity among Rh-based systems for chemical NADH regeneration in aqueous medium. These results highlight a new structure–reactivity relationship in hydride-transfer catalysis and provide a design blueprint for high-performance regeneration systems in biocatalytic and green chemical applications.