Reversible Electrocatalytic\nNAD<sup>+</sup>/NADH Interconversion\nMediated by a Pyrazine-Amidate Iridium Complex

Herein, we report\nreversible\nelectrocatalytic NAD<sup>+</sup>/NADH interconversion mediated by\n[Cp*Ir(pyza)Cl] (<b>1</b>, pyza = pyrazine amidate). <b>1</b> was designed through a rational approach aimed at lowering the overpotential\nof NAD<sup>+</sup> to NADH reduction with respect to that observed\nfor electrocatalyst [Cp*Ir(pica)Cl] (<b>2</b>, pica = picolinamidate).\nThe peculiar properties of pyza, which is substantially less σ\nelectron-donator and more π electron-acceptor than pica, resulted\nin an easier bielectronic reduction process occurring at −0.29\nV (instead of ca. −0.65 V for <b>2</b>), very close to\nthe equilibrium potential of NAD<sup>+</sup>/NADH redox couple (<i>E</i>°<sub>eq</sub> = −0.32 V vs NHE, 298 K, pH\n7). <b>1</b> catalyzes both NAD<sup>+</sup> reduction and NADH\noxidation in response to even a small departure from equilibrium potential,\nwith a catalytic bias for the former (|i<sub>p</sub><sup>red</sup>/i<sub>p</sub><sup>ox</sup>| = 6.2, 333 K). The reversibility of\nNAD<sup>+</sup>/NADH interconversion was ascertained by <sup>1</sup>H EXSY NMR spectroscopy that clearly demonstrated the rapid establishment\nof <b>1</b>_H + NAD<sup>+</sup> ⇌ <b>1</b> + NADH\nequilibrium (<i>K</i><sub>eq</sub> = 3, Δ<i>G</i> = −0.6 kcal/mol, 298 K) and a similar hydridicity of NADH\n(28.9 kcal/mol, 298 K) and <b>1</b>_H (28.3 kcal/mol, 298 K).