Methyl thionitrite CH 3 SNO is an important model of S-nitrosated cysteine aminoacid residue (CysNO), a ubiquitous biological S-nitrosothiol (RSNO) involved in numerous physiological processes. As such, CH 3 SNO can provide insights into the intrinsic properties of the -SNO group in CysNO, in particular, its weak and labile S-N bond. Here, we report an ab initio computational investigation of the structure and properties of CH 3 SNO using a composite Feller-Peterson-Dixon (FPD) scheme based on the explicitly-correlated coupled cluster with single, double, and perturbative excitations calculations extrapolated to the complete basis set limit, CCSD(T)-F12/CBS, with a number of additive corrections for the effects of quadruple excitations, core-valence correlation, scalar-relativistic and spin-orbit effects, as well as harmonic zero-point vibrational energy (ZPE) with an anharmonicity correction. These calculations suggest that the S-N bond in CH 3 SNO is significantly elongated (1.814 Å), has low stretching frequency and dissociation energy values,
To address a long-standing problem of finding efficient reactions for chemical labeling of protein-based S-nitrosothiols (RSNOs), we computationally explored hitherto unknown (3+2) cycloaddition RSNO reactions with alkynes and alkenes. Nonactivated RSNO cycloaddition reactions have high activation enthalpy (>20 kcal/mol at the CBS-QB3 level) and compete with alternative S-N bond insertion pathway. However, the (3+2) cycloaddition reaction barriers can be dramatically lowered by coordination of a Lewis acid to the N atom of the -SNO group. To exploit this effect, we propose to use reagents with Lewis acid and a strain-activated carbon-carbon multiple bond linked by a rigid scaffold, which can react with RSNOs with small activation enthalpies (∼5 kcal/mol) and high reaction exothermicities (∼40 kcal/mol). The proposed efficient RSNO cycloaddition reactions can be used for future development of practical RSNO labeling reactions.
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