Copper Nitrite Reduction by Thiols: Mechanistic Insights into NO Release en route to Copper Thiolate Formation

Abstract

Nitrite reduction is a critical process in biological systems, with implications for disease pathology and therapeutic development. This study investigates the copper-mediated reduction of nitrite to nitric oxide (NO) using unsymmetrical β-diketiminato copper(II) nitrito complexes with thiol derivatives as reducing agents. The reaction of LCu(NO₂) with 4-tert-butyl benzyl thiol (^tBuBzSH), benzyl thiol (BzSH), and biologically active thiols like L-cysteine (Cys), yield quantitative NO, free ligand, disulfide, and an insoluble copper(I)-thiolate polymer (YP_R), characterized by FT-IR, NMR, and X-ray photoelectron spectroscopy (XPS). Mechanistic analysis reveals a transient Cu(II)-thiolate intermediate (λ_max = 590 nm) formed via acid-base exchange, generating nitrous acid (HNO₂) that reacts with excess thiol to form S-nitrosothiol (RSNO). NO releases through RSNO and forming the stable Cu(I)-thiolate polymer. XPS confirms the presence of Cu(I) in YP_tBuBz and YP_Bz as well as mixed-valent Cu(I/II) in YP_Cys with a clear satellite peak, which is supported by Auger parameter calculations. This work highlights the potential of copper complexes for NO generation and provides a deeper understanding of the underlying mechanisms.