A surprising effect of leaving group on the nucleophilic aromatic substitution reaction catalyzed by 4-chlorobenzoyl CoA dehalogenase

Abstract

We have begun our mechanistic studies of 4-chlorobenzoyl-CoA dehalogenase with a determination of the relative leaving group abilities for bromide, chloride, and fluoride in the dehalogenation reaction. Dehalogenation of 4-bromobenzoyl-CoA is twice as fast as dehalogenation of 4-chlorobenzoyl-CoA, while dehalogenation of 4-fluorobenzoyl-CoA is over 400-fold slower. These data are in striking contrast to the relative leaving group abilities observed for the glutathione-S-transferase-catalyzed dehalogenation of 4-halo-3-nitro-1-(trifluoromethyl)benzenes. Our data also differ from those observed for nonenzymic nucleophilic aromatic substitution reactions that occur by the S[sup N]Ar mechanism. The most reasonable mechanism for the enzymic dehalogenation reaction is probably the S[sub N]Ar mechanism. Nucleophilic aromatic substitution reactions that take place by this mechanism generally proceed fastest when the leaving group is fluoride, even though fluoride is the poorest leaving group among the halogens. The nucleophilic aromatic substitution reaction catalyzed by 4-chlorobenzoyl-CoA dehalogenase shows leaving group abilities in the order opposite that expected on the basis of nonenzymic S[sub N]Ar reactions and the glutahione-S-transferase reaction. Two alternative explanations may account for these data. Our data do not permit a distinction between the various possible mechanisms for the dehalogenation reaction. 17 refs., 1 tab.