Reaction of Thiols with N-Bonded Sulfenamide Complexes of Cobalt(III):  Steric Effect and Reaction Pathway

Abstract

The products and kinetics of the reaction of several thiols (RSH = 2-aminoethanethiol, cysteine, penicillamine, cysteine ethyl ester) with N-bonded sulfenamide complexes ([Co(en)(2)(NH(2)S(CH(2))(2)NH(2)](3+) (IA), [Co(en)(2)(NH(2)SCH(2)CH(CO(2)H)NH(2)](3+) (IC), [Co(en)(2)(NH(2)SC(CH(3))(2)CH(CO(2)H)NH(2)](3+) (IP)) have been studied. The reaction proceeds by nucleophilic attack at sulfur with cleavage of the N-S bond to form a disulfide and leave a coordinated NH(3) ligand. The kinetics (pH 4-10) reveal that the deprotonated thiol, RS(-), is the reactive nucleophile and that the N-deprotonated sulfenamide complex is unreactive. The reactions of IP are approximately 10(4) times slower than those of IA or IC, and the reasons and consequences of this large steric effect are discussed. It is concluded, on the basis of these and other observations from the literature, that there will be substantial steric retardation to nucleophilic attack at two-coordinate sulfur in a R-C(CH(3))(2)-S-X-R' unit because of the regiospecificity of the reaction. The acid dissociation constants of IP and the X-ray structure of its bromide salt also are reported.

In vitro Conversion of Model Sulfenamide Prodrugs in the Presence of Small Molecule Thiols

“…[12][13][14][15][16] The reaction of thiols with sulfenamides is expected to be very similar to the reaction of the thiols with the disulfides; thus, the reaction of the thiols to cleave the sulfenamide bond is expected to be either via a concerted S N 2 attack or an addition-elimination reaction.…”

Mechanisms of reactions in solution

“…penicillamine, with complexes such as [Co(en) 2 (NH 2 S(CH 2 ) 2 NH 2 ] 3+ result in severing the ligand N-S bond to yield coordinated disulfide and NH 3 . 157 A kinetic study showed that the mechanism involves nucleophilic attack by deprotonated thiol to form the disulfide moiety. The reaction is very susceptible to steric retardation resulting from ''backside attack'' on the S in the disulfide bond.…”