Electrocatalytic NAD⁺ reduction via hydrogen atom-coupled electron transfer

Nicotinamide adenine dinucleotide cofactor (NAD(P)H) is regarded as an important energy carrier and charge transfer mediator. Enzyme-catalyzed NADPH production in natural photosynthesis proceeds via a hydride transfer mechanism. Selective and effective regeneration of NAD(P)H from its oxidized form by artificial catalysts remains challenging due to the formation of byproducts. Herein, electrocatalytic NADH regeneration and the reaction mechanism on metal and carbon electrodes are studied. We find that the selectivity of bioactive 1,4-NADH is relatively high on Cu, Fe, and Co electrodes without forming commonly reported NAD₂ byproducts. In contrast, more NAD₂ side product is formed with the carbon electrode. ADP-ribose is confirmed to be a side product caused by the fragmentation reaction of NAD⁺. Based on H/D isotope effects and electron paramagnetic resonance analysis, it is proposed that the formation of NADH on these metal electrodes proceeds via a hydrogen atom-coupled electron transfer (H_adCET) mechanism, in contrast to the direct electron-transfer and NAD˙ radical pathway on carbon electrodes, which leads to more by-product, NAD₂. This work sheds light on the mechanism of electrocatalytic NADH regeneration, which is different from biocatalysis.