Mechanism of SN2 disulfide bond cleavage by phosphorus nucleophiles. Implications for biochemical disulfide reducing agents.
The B3LYP variant of DFT has been used to study the mechanism of S-S bond scission in dimethyl disulfide by a phosphorus nucleophile, trimethylphospine (TMP). The reaction is highly endothermic in the gas phase and requires significant external stabilization of the charged products. DFT calculations (B3LYP) were performed with explicit (water molecules added) and implicit solvent corrections (COSMO model). The transition structures for this SN2 displacement reaction in a number of model systems have been located and fully characterized. The reaction barriers calculated with different approaches for different systems are quite close (around 11 kcal/mol). Remarkably, the calculations suggest that the reaction is almost barrierless with respect to the preorganized reaction complex and that most of the activation energy is required to rearrange the disulfide and TMP to its most effective orientation for the SMe group transfer way. Different reactivities of different phosphorus nucleophiles were suggested to be the result of steric effects, as manifested largely by varying amounts of hindrance to solvation of the initial product phosphonium ion. These data indicate that the gas-phase addition of a phosphine to the disulfide moiety will most likely form a phosphonium cation-thiolate anion salt, in the presence of four or more water molecules, that provide sufficient H-bonding stabilization to allow displacement of the thiolate anion, a normal uncomplicated SN2 transition state is to be expected.
Dmitrenko
Olga
O
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
Thorpe
Colin
C
Bach
Robert D
RD
D004220:Disulfides / Q000737:chemistry*; D007700:Kinetics; D008956:Models, Chemical; D010755:Organophosphates / Q000737:chemistry*; D010084:Oxidation-Reduction; D019163:Reducing Agents / Q000737:chemistry*
D004220:Disulfides; D010755:Organophosphates; D019163:Reducing Agents; C003715:trimethyl phosphate