Intramolecular Aminolysis of Esters. Cyclization of Esters of (o-Aminophenyl)acetic Acid

Article abstract of DOI:10.1021/ja00339a013

Rate constants have been obtained for cyclization of the methyl and trifluoroethyl esters of (o-aminophenyl)acetic acid to 2-oxindole.Cyclization occurs via both the neutral and protonated species.Hydroxide ion catalysis occurs in reactions of the methyl ester with a second-order rate constant k_OH that is 100-fold greater than for hydroxide ion catalyzed hydrolysis of methyl phenylacetate.The k_OH for cyclization of the trifluoroethyl ester is 60-fold larger at 30 deg C than that of the methyl ester.The log k₀ vs. pH profile for the trifluoroethyl ester is bell shaped at low pH, indicating that the rate-determining step is changing with pH.Consequently, an intermediate is formed in the cyclization reaction that must be a tetrahedral addition product.This is also shown by curved plots of k_obsvd vs. buffer concentration for cyclization of the methyl ester at pH less than 7, which indicate that the rate-determining step is changing with increasing buffer concentration.The rate-determining step at pH > 4 and low buffer concentration must be breakdown of a tetrahedral intermediate.The general base catalysis observed in the cyclization reaction of the methyl and trifluoroethyl esters is characterized by Broensted β coefficients of 0.5 and 0.2 respectively.Thus, in the general base-catalyzed reactions proton transfer is concerted with bond breaking, in contrast with the similar reactions of methyl 2-(aminomethyl)benzoate, in which a proton-transfer step is rate-determining. (β = 1.0).The decrease in Broensted coefficient as the leaving group is improved indicates that the general base is partially removing a proton from the neutral tetrahedral intermediate as the C-O bond breaks.Several different mechanisms and/or rate-determining steps are possible in the intramolecular aminolysis of aliphatic esters; the key features in these aminolysis reactions in regard to mechanism are the pK_a of the nucleophile, the steric fit of the nucleophile to the carbonyl, and the ease of C-O bond breaking in decomposition of a tetrahedral intermediate to products.