The conversion of 4-chlorobenzoate to 4-hydroxybenzoate is carried out by first esterifying 4-chlorobenzoate by coenzyme A, and the resulting 4-chlorobenzoyl CoA serves as substrate for the 4-chlorobenzoyl CoA dehalogenase. To gain a better appreciation of the catalytic mechanism and factors controlling the catalytic efficacy of this dehalogenase, the nucleophilic aromatic substitution reaction between 4-Cl-Ph-CO-SCH3 and CH3COO- was investigated in detail in both gas phase and solution (the -CH2COO- entity of Asp145 is the enzyme nucleophile). Quantum mechanical methods (HF/6-31G*, B3LYP/6-311+G**, and PM3) were used to elucidate the gas phase reaction. The gas phase reaction profile is best described as a two-well potential surface, with the two minima corresponding to reactant-side and product-side ion-molecule complexes. There is a small overall potential energy barrier, but the free energy barrier is significant. On the HF/6-31G* potential energy surface, no minimum corresponding to the Meisenheimer intermediate was found; however, there is a shallow one on the PM3 surface. Overall, the PM3 results match the density functional theory results (B3LYP/6-311+G**) closely, suggesting that PM3 is a reasonable method to study this kind of reaction. This finding will allow us to investigate the enzymatic reaction directly using a hybrid PM3/MM approach. As shown from the influence of solvation effect on the reaction profile determined by a self-consistent reaction field model, there is a large reaction barrier in solution. On the basis of the above findings, the factors controlling the catalytic efficacy of the 4-chlorobenzoyl CoA dehalogenase were examined. We also studied the hydrolysis of the aryl-enzyme intermediate and a related nucleophilic aromatic substitution reaction between tetrachlorohydroquinone and glutathione (as modeled by thiomethoxide). In addition, a simple explanation concerning the previously unresolved abnormal Bronsted behavior of Tyr6Phe mutant of a mu class glutathione S-transferase is provided.