Nucleophilic reactivity of thiolate, hydroxide, and phenolate ions toward a model O²-arylated diazeniumdiolate prodrug in aqueous and cationic surfactant media

The kinetics of aromatic nucleophilic substitution of the nitric oxide-generating diazeniumdiolate ion, DEA/NO, by thiols (L-glutathione, L-cysteine, DL-homocysteine, 1-propanethiol, 2-mercaptoethanol, and sodium thioglycolate) from the prodrug, DNP-DEA/NO, has been examined in aqueous solution and in solutions of cationic DOTAP vesicles. Second-order rate constants in buffered aqueous solutions (k_RS-=3.48-30.9M^-1 s^-1; 30°C) gave a linear Brønsted plot (β_nuc=0.414±0.068) consistent with the rate-limiting S_NAr nucleophilic attack by thiolate ions. Cationic DOTAP vesicles catalyze the thiolysis reactions with rate enhancements between 11 and 486-fold in Tris-HCl buffered solutions at pH 7.4. The maximum rate increase was obtained with thioglycolate ion. Thiolysis data are compared to data for nucleophilic displacement by phenolate (k_PhO-=0.114M^-1 s^-1) and hydroxide (k_OH-=1.82×10^-2M^-1 s ^-1, 37°C) ions. The base hydrolysis reaction is accelerated by CTAB micelles and DODAC vesicles, with the vesicles being ca 3-fold more effective as catalysts. Analysis of the data using pseudo-phase ion-exchange (PIE) formalism implies that the rate enhancement of the thiolysis and base hydrolysis reactions is primarily due to reactant concentration in the surfactant pseudo-phase.