Mechanism of thiolate-disulfide interchange reactions in biochemistry

[GRAPHICS] Both density functional theory (DFT) (B3LYP) and CCSD ab initio calculations were employed in a theoretical investigation of the mechanism of thiolate-disulfide exchange reactions. The reaction pathway for degenerate thiolate-disulfide exchange reactions with dimethyl disulfide has been shown to proceed through a S(N)2-like transition structure that is very close in energy to the corresponding trisulfur anionic intermediate ([S delta--S-S delta-]). When relatively small substituents are involved, the level of theory must be increased to CCSD to make this rather subtle mechanistic distinction. With the more sterically hindered exchange reaction involving t-butyl mercaptide and di-t-butyl disulfide, the potential energy surface exhibits a distinct preference for the S(N)2 displacement pathway with an activation barrier of 9.8 kcal/mol. When corrections for solvent polarity are included (COSMO), an SN2 mechanism is also implicated in both polar and nonpolar solvents. DFT studies on thiolate-disulfide exchange, when the substituent is a model peptide, strongly support the intermediacy of a trisulfur intermediate that lies 10.7 kcal/mol below isolated reactants. A well depth of this magnitude should provide a sufficient lifetime of the intermediate to accommodate the requisite conformational adjustments that accompanies formation of the new disulfide bond.