Unique Metal–Ligand Proton Tautomerism Underlying the Reversible Electrocatalytic NAD + /NADH Interconversion

: The NAD+/NADH electrochemical interconversion mediated by [Cp*Ir(R-pyza)Cl] (Cp* = pentamethylcyclopentadienyl, pyza = pyrazine-2-carboxyamidate, R = H, 1 and R = Me, 2) represents a rare example of a process occurring at nearly zero overpotential, i.e., under conditions of reversible electrocatalysis. Here, we provide compelling evidence that the initial reduction of 1 and 2 is ligand-centered and leads to dearomatized and protonated complexes 1_LH and 2_LH, respectively, where the iridium center remains in its original oxidation state. Successively, 1_LH and 2_LH undergo a peculiar Metal-Ligand Proton Tautomerism (MLPT) leading to the metal hydride species 1_H and 2_H, respectively, without any change in the Ir oxidation state. Ultimately, 1_H and 2_H transfer a hydride to NAD+ producing NADH. Remarkably, 1_LH/2_LH and 1_H/2_H showed to be sufficiently stable to allow direct observation of their interconversion by NMR spectroscopy and quantification of accurate thermodynamic and kinetic parameters for such transformation. This work provides solid evidence for the beneficial role of such unique MLPT in enabling reversible electrocatalysis.