Mechanism of the nucleophilic substitution of acyl electrophiles using lithium organocuprates

The mechanism of nucleophilic substitution reaction at an sp² carbon center of a thioester or an acid chloride with a lithium organocuprate reagent has been investigated. Density functional calculations indicated that the thioester undergoes oxidative addition of the C-S bond to the copper(I) atom through a three-centered transition state to afford an organocopper(III) intermediate, which gives the product through reductive elimination of the alkyl and the acyl groups. On the other hand, the acid chloride loses a chloride anion very easily when it interacts with the cuprate, because the chloride anion is captured by a lithium(I) cation rather than a copper(I) atom. ¹³C kinetic isotope effect (KIE) experiments showed excellent agreement with computational predictions for the thioester reaction, but suggested that the nucleophilic displacement transition state of the acid chloride occurs much more advanced than the calculations predict.