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 [(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.

Synergistic Activation of Nitrite and Thiocarbonyl Compounds Affords NO and Sulfane Sulfur via (Per)thionitrite (SNO−/SSNO−)

“…Mechanistically, we propose an initial nucleophilic attack of NO 2 − on electrophilic CS 2 / in situ generated COS leading to int‐A/A′ , which subsequently undergoes transnitrosation to provide int‐B/B′ (Figures S12 and S13). Notably, CS 2 does not react with nitrite coordinated to a previously reported [Zn II ] coordination motif in [( Bn 3 Tren )Zn II ‐nitrite] + , thereby emphasizing the requirement of uncoordinated nitrite anion for the initial nucleophilic attack [22] . Furthermore, a reaction of CS 2 with [TBA][NO 2 ] in the presence of excess ( p ‐tolyl) 2 NH afforded corresponding N ‐nitrosamine ( p ‐tolyl) 2 N−NO (Figure S14), while an isolated sample of SSNO − was incapable of transforming ( p ‐tolyl) 2 NH into ( p ‐tolyl) 2 N−NO.…”

“…Aiming to understand the fate of the carbon site in CS 2 , 13 C NMR analysis of a crude reaction mixture showed a chemical shift at 124.8 ppm (Figure S4), which is consistent with the formation of CO 2 [19] . Moreover, the headspace on the reaction mixtures consisting of CS 2 and nitrite (1 : 2 molar ratio) was analyzed for various gaseous products (Schemes S1 and S2) [20–22] . A diffusion‐controlled trapping experiment using CaO (as the trap for CO 2 ) provided CaCO 3 in 65 % yield (Scheme S1 and Figure S5).…”

“…Guided by the previously reported δ( 15 N) values ranging between 750 and 850 ppm (vs. liq. NH 3 ) for S ‐nitrosothiols (RS 15 NO), [22,32] we tentatively assign the origin of these δ( 15 N) signals to [P]‐SNO ( 1′‐S ). A reaction of LR and nitrite in the presence of RSH (RSH = Ph 3 CSH or t BuBnSH) shows the generation of RSNO as assessed by UV/Vis and 15 N NMR analyses (Figures S38 and S39).…”

Synergistic Activation of Nitrite and Thiocarbonyl Compounds Affords NO and Sulfane Sulfur via (Per)thionitrite (SNO−/SSNO−)

“…Guided by the previously reported δ( 15 N) values ranging between 750 and 850 ppm (vs. liq. NH 3 ) for S-nitrosothiols (RS 15 NO), [22,32] we tentatively assign the origin of these δ( S38 and S39). Moreover, analysis of the headspace on the reaction of LR and nitrite provides 68 % yield of NO gas (Figure S40).…”

Nitrite and Nitric Oxide Interconversion at Mononuclear Copper(II): Insight into the Role of the Red Copper Site in Denitrification

“…Interestingly, a green solution of [( Me 2 PzQu ) 2 Cu II (nitrite)](ClO 4 ) ( 2 b ) in acetonitrile at room temperature undergoes self‐decomposition to provide a brownish solution after 36 h, while the color change for a solution of 2 a under the analogous conditions is less prominent. Analyses of the headspace on the reaction mixtures provide 20 % (for 2 a ) and 65 % (for 2 b ) yields of NO after 36 h, as obtained from NO‐trapping experiments using (TPP)Co II (where, TPP = tetraphenyl porphyrin) (see Supporting Information for details, Figures S29–S30) [48] . 1 H NMR study on the resultant copper product after the self‐decomposition of 2 b suggests the formation of [( Me 2 PzQu ) 2 Cu I ](ClO 4 ) ( 3 b ) along with other uncharacterized side products (Figure S31).…”