NO Generation from Nitrite at Zinc(II): Role of Thiol Persulfidation in the Presence of Sulfane Sulfur

[Image: see text] Nitrite-to-NO transformation is of prime importance due to its relevance in mammalian physiology. Although such a one-electron reductive transformation at various redox-active metal sites (e.g., Cu and Fe) has been illustrated previously, the reaction at the [Zn(II)] site in the presence of a sacrificial reductant like thiol has been reported to be sluggish and poorly understood. Reactivity of [(Bn(3)Tren)Zn(II)–ONO](ClO(4)) (1), a nitrite-bound model of the tripodal active site of carbonic anhydrase (CA), toward various organic probes, such as 4-tert-butylbenzylthiol ((t)BuBnSH), 2,4-di-tert-butylphenol (2,4-DTBP), and 1-fluoro-2,4-dinitrobenzene (F-DNB), reveals that the ONO-moiety in the [Zn(II)]–nitrite coordination motif of complex 1 acts as a mild electrophile. (t)BuBnSH reacts mildly with nitrite at a [Zn(II)] site to provide S-nitrosothiol (t)BuBnSNO prior to the release of NO in 10% yield, whereas the phenolic substrate 2,4-DTBP does not yield the analogous O-nitrite compound (ArONO). The presence of sulfane sulfur (S(0)) species such as elemental sulfur (S(8)) and organic polysulfides ((t)BuBnS(n)Bn(t)Bu) during the reaction of (t)BuBnSH and [Zn(II)]–nitrite (1) assists the nitrite-to-NO conversion to provide NO yields of 65% (for S(8)) and 76% (for (t)BuBnS(n)Bn(t)Bu). High-resolution mass spectrometry (HRMS) analyses on the reaction of [Zn(II)]–nitrite (1), (t)BuBnSH, and S(8) depict the formation of zinc(II)-persulfide species [(Bn(3)Tren)Zn(II)–S(n)–Bn(t)Bu](+) (where n = 2, 3, 4, 5, and 6). Trapping of the persulfide species ((t)BuBnSS(–)) with 1-fluoro-2,4-dinitrobenzene (F-DNB) confirms its intermediacy. The significantly higher nucleophilicity of persulfide species (relative to thiol/thiolate) is proposed to facilitate the reaction with the mildly electrophilic [Zn(II)]–nitrite (1) complex. Complementary analyses, including multinuclear NMR, electrospray ionization-MS, UV–vis, and trapping of reactive S-species, provide mechanistic insights into the sulfane sulfur-assisted reactions between thiol and nitrite at the tripodal [Zn(II)]-site. These findings suggest the critical influential roles of various reactive sulfur species, such as sulfane sulfur and persulfides, in the nitrite-to-NO conversion.