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] (<b>1</b>, pyza = pyrazine amidate). <b>1</b> 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] (<b>2</b>, 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 <b>2</b>), very close to the equilibrium potential of NAD⁺/NADH redox couple (<i>E</i>°_eq = -0.32 V vs NHE, 298 K, pH 7). <b>1</b> catalyzes both NAD⁺ reduction and NADH oxidation in response to even a small departure from equilibrium potential, with a catalytic bias for the former (|i_p^red/i_p^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 <b>1</b>_H + NAD⁺ ⇌ <b>1</b> + NADH equilibrium (<i>K</i>_eq = 3, Δ<i>G</i> = -0.6 kcal/mol, 298 K) and a similar hydridicity of NADH (28.9 kcal/mol, 298 K) and <b>1</b>_H (28.3 kcal/mol, 298 K).