Acidity and nucleophilic reactivity of persulfides

Abstract

Persulfides(RSSH/RSS‐) are chemical compounds related to thiols (RSH) and hydrogen sulfide (H2S). They participate in sulfur trafficking and processing, and are proposed to be transducers of the signaling effects of H2S in mammals. Despite the increasingly recognized relevance of persulfides, their biochemical properties are poorly understood. In this work, we studied the acidity of six low molecular weight persulfides, as well as their nucleophilic reactivity towards the synthetic probe monobromobimane. Kinetic determinations were performed at different pHs exploiting that monobromobimane does not accept or release protons within the pH range studied and produces fluorescent products. The persulfides of glutathione, cysteine, homocysteine, cysteamine, cysteine methyl ester and β‐mercaptoethanol, presented pKa values of 4.7‐6.5 and pH‐independent rate constants of 3.2‐9.0 × 103 M‐1s‐1. The persulfides were more acidic than the corresponding thiols, which have pKa values of 6.5‐9.6. The ranges of pKa values suggest that the substituents in persulfides affect the acidity to a lesser extent than in thiols, probably due to the longer distances to the acidic sulfur atom because of the additional sulfur. We constructed a Br⊘nsted plot (log k vspKa) which showed a correlation between the nucleophilicity and basicity of persulfides, which resulted weaker than the observed for thiolates. In addition, the persulfides presented higher nucleophilicity than the expected for thiolates with the same pKa values. This can be rationalized in terms of the alpha effect: the increased reactivity of a nucleophile when the adjacent atom has high electron density. Overall, our work suggests that, at physiological pH, persulfides have higher reactivity compared to thiols due to two factors: the increased availability of the ionized species and the enhanced intrinsic reactivity. We are currently investigating protein persulfides to rationalize how the protein environment could affect the biochemical properties of the persulfides. Our study contributes to the understanding of the biochemistry and the biological functions of persulfides.