Nitrosation by alkyl nitrites. Part 6. Thiolate nitrosation

Abstract

Each of the following thiols react with a range of alkyl nitrites in water at 25 °C in the pH range 6–13 to give the corresponding thionitrites in solution: L-cysteine, N-acetyl-L-cysteine, L-cysteine methyl ester, L-cysteine ethyl ester, glutathione and thioglycolic acid. The pH-dependence of the rate constant clearly shows that reaction occurs only via the thiolate anions RS^–. For N-acetyl-L-cysteine and thioglycolic acid only one RS^– species is possible and a quantitative kinetic analysis yields pK_a values for RSH ionisation in good agreement with the literature values. For each of the remaining thiols two thiolate ions (NH₂RS^– and NH₃RS^–) are possible and the measured rate constants for all alkyl nitrites generally followed the total thiolate ion concentration (as a function of pH) obtained from the published microscopic pK_a values. An alternative approach of fitting the kinetic results to the concentration curve by computer yields microscopic pK_a values generally in good agreement with the literature values. One exception is L-cysteine where the measured (pK_a)_D value (for NH₂-RSH → NH₂RS^–) differs significantly from the literature value. With simple alkyl nitrites (ethyl, isopentyl, isopropyl and t-butyl) steric effects appear to be the major influences in reactivity, whereas electron-withdrawing substituents in the 2-position greatly increase the rate constants. The reactions of 2,2,2-trichloroethyl nitrite were too fast to measure at all pH values, whereas the reaction of 2,2-dichloroethyl nitrite could only be followed kinetically in the pH range 6–8.25, even by stopped-flow spectrophotometry. The possible relevance of these reactions to the vasodilatory action of alkyl nitrites is discussed. The kinetic results for thiolate nitrosation by N-methyl-N-nitrosotoluene-p-sulphonamide also correlate well with the total concentration of the thiolate ion, with the interesting exception of the reactions of the carboxylic esters of L-cysteine, where there appears to be a preference for reaction via the NH₂RS^– form.