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

Abstract

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 [(Bn₃Tren)Zn^II–ONO](ClO₄) (1), a nitrite-bound model of the tripodal active site of carbonic anhydrase (CA), toward various organic probes, such as 4-tert-butylbenzylthiol (^tBuBnSH), 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. ^tBuBnSH reacts mildly with nitrite at a [Zn^II] site to provide S-nitrosothiol ^tBuBnSNO 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 (S⁰) species such as elemental sulfur (S₈) and organic polysulfides (^tBuBnS_nBn^tBu) during the reaction of ^tBuBnSH and [Zn^II]–nitrite (1) assists the nitrite-to-NO conversion to provide NO yields of 65% (for S₈) and 76% (for ^tBuBnS_nBn^tBu). High-resolution mass spectrometry (HRMS) analyses on the reaction of [Zn^II]–nitrite (1), ^tBuBnSH, and S₈ depict the formation of zinc(II)-persulfide species [(Bn₃Tren)Zn^II–S_n–Bn^tBu]⁺ (where n = 2, 3, 4, 5, and 6). Trapping of the persulfide species (^tBuBnSS^–) 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.