Mechanism of Nucleophilic Aromatic Substitution of 1-Chloro-2,4-dinitrobenzene by Glutathione in the Gas Phase and in Solution. Implications for the Mode of Action of Glutathione S-Transferases

Abstract

The reaction mechanism of nucleophilic aromatic substitution of 1-chloro-2,4-dinitrobenzene by glutathione (as modeled by a thiomethoxide ion) in the gas phase and in solution was elucidated using ab initio molecular orbital theory in combination with a continuum solvent model at the HF/6-31G*, HF/6-31+G**, and MP2/6-31+G** levels of theory. Two ion−molecule complexes were located in the gas phase at the HF level, but only one exits at the MP2/6-31+G** level, while neither exits in aqueous solution. In aqueous solution, there is a large free energy barrier and C−S bond formation is the rate-determining step, which is in agreement with experimental observation. The calculated free energy barrier (30.2 kcal/mol) at the HF/6-31+G** level of theory seems to be in good agreement with experiment (23.8 kcal/mol), while the MP2/6-31+G** barrier is too low, indicating that the MP2/6-31+G** level of theory probably overestimates the stability of the transition state for C−S bond formation. Implications for the mode...