Kinetics and Mechanism of S-Nitrosothiol Acid-Catalyzed Hydrolysis: Sulfur Activation Promotes Facile NO+ Release

The denitrosation of three primary S-nitrosothiols (RSNO; S-nitrosocysteine, S-nitroso-N-acetylcysteine, and S-nitrosoglutathione) and two tertiary RSNOs (S-nitrosopenicillamine and S-nitroso-N-acetylpenicillamine) was investigated in 3.75 M H2SO4 to probe the mechanism of acid-catalyzed RSNO hydrolysis and its dependence on RSNO structure. This reversible reaction was forced to proceed in the denitrosation direction by trapping the nitrosating agent with HN3. The primary RSNOs exhibited hydrolysis kobs values of ∼2 × 10−4 s−1, and the tertiary RSNO kobs values were an order of magnitude higher. Product analysis by HPLC revealed that the parent thiols (RSHs) were formed in 90−100% yield on 79−99% RSNO denitrosation. Possible hydrolysis mechanisms were studied computationally at the CBS-QB3 level using S-nitrosomethanethiol (MeSNO) as a model RSNO. Consideration of RSNOs as a combination of conventional R−S−N═O, zwitterionic R−S+═N−O−, and RS−/NO+ ion-pair resonance structures was key in understanding the ...