Elucidating the intimate mechanism of NAD+ hydrogenation with phosphonic acid catalysed by Cp*Ir(pyridine-2-sulfonamidate) complexes

The reaction mechanism of nicotine amide dinucleotide hydrogenation (NAD(+) to NADH) catalysed by Cp*Ir(pyridine-2-sulfonamidate) complexes in the presence of phosphonic acid has been elucidated. Multivariate kinetic experiments and NMR spectroscopy revealed that the enhanced performance of this class of catalysts arises from the hemilability of the pyridine ligand, which is displaced during P-H bond activation and facilitates the generation of the metal-hydride intermediate. Experimental results are backed by DFT calculations showcasing the importance of hydrogen bonding interactions in the activation of phosphite anions. Direct comparison between the prototypical unsubstituted catalyst and the 6-aminopyridine-2-sulfonamidate derivative allowed tracing of the molecular origin of the superior performance of the latter, paving the way for the intelligent design of better performing catalysts for NADH regeneration.