Electrophilic intermediate in the reaction of glutathione and nitrosoarenes

Article abstract of DOI:10.1021/ja00034a043

A kinetic study is reported of the reaction of glutathione (γ-L-glutamyl-L-cysteinylglycine, GSH) with nine substituted nitrosobenzenes (3,4-Me₂ 4-Me, 3,5-Me₂, 3-Me, parent, 3-MeO, 4-Cl, 3-Cl, 3-NO₂). Previous workers have shown that this reaction proceeds in parallel pathways, producing the appropriate N-arylhydroxylamine and GSSG or a sulfinanilide adduct ArNHS(O)G; a rapid equilibrium addition to form a common intermediate, a semimercaptal ArN(OH)SG, has also been observed. In the present study, equilibrium constants for the formation of this intermediate from ArNO and GSH have been measured by a kinetic method, and the kinetic behavior of the slower additional reactions of the semimercaptal have been examined in detail. For experiments carried out at constant pH and buffer concentration, the decay of ArN(OH)SG follows the rate law k₂^GSH[GSH] + k₂(rearr). A comparison with product ratios previously reported shows that the bimolecular term with GSH represents the process forming ArNHOH and GSSG, while the unimolecular term represents the rearrangement to the sulfmanilide. The former process is found to be proportional to [OH^-] for solutions near neutrality, is not buffer catalyzed, and has a ρ value of +1.4. This suggests a mechanism in which glutathione anion GS^- reacts at the sulfur of the adduct displacing ArN^-(OH) as a leaving group. The rearrangement reaction follows σ⁺ with a ρ⁺ value of -3.5 and has a rate law containing a pH-independent term and terms for catalysis by H⁺ and the acid component of the buffer. An ¹⁸O tracer study shows that the S=O oxygen in the sulfmanilide is derived from solvent, not the original N=O group. A mechanism is proposed with rate-limiting N-O cleavage, either uncatalyzed involving direct heterolysis with OH^- as a leaving group or catalyzed by acids with H₂O as the leaving group. The species produced is a cationic intermediate ArN⁺SG, a nitrenium ion stabilized by both the aryl ring and the directly attached sulfur atom. Aryl-stabilized nitrenium ions are commonly encountered in Bamberger-like rearrangements of hydroxylamine derivatives. The sulfur atom of PhN(OH)SG is shown to provide an approximately 10⁶ rate acceleration for N-O cleavage in a comparison with the Bamberger rearrangement of PhNHOH.