Reversible Electrocatalytic NAD+/NADH Interconversion Mediated by a Pyrazine-Amidate Iridium Complex

Herein, we report reversible electrocatalytic NAD+/NADH interconversion mediated by [Cp*Ir­(pyza)­Cl] (1, pyza = pyrazine amidate). 1 was designed through a rational approach aimed at lowering the overpotential of NAD+ to NADH reduction with respect to that observed for electrocatalyst [Cp*Ir­(pica)­Cl] (2, pica = picolinamidate). The peculiar properties of pyza, which is substantially less σ electron-donator and more π electron-acceptor than pica, resulted in an easier bielectronic reduction process occurring at −0.29 V (instead of ca. −0.65 V for 2), very close to the equilibrium potential of NAD+/NADH redox couple (E°eq = −0.32 V vs NHE, 298 K, pH 7). 1 catalyzes both NAD+ reduction and NADH oxidation in response to even a small departure from equilibrium potential, with a catalytic bias for the former (|ip red/ip ox| = 6.2, 333 K). The reversibility of NAD+/NADH interconversion was ascertained by 1H EXSY NMR spectroscopy that clearly demonstrated the rapid establishment of 1_H + NAD+ ⇌ 1 + NADH equilibrium (K eq = 3, ΔG = −0.6 kcal/mol, 298 K) and a similar hydridicity of NADH (28.9 kcal/mol, 298 K) and 1_H (28.3 kcal/mol, 298 K).