Neighbouring group participation by the carboxy-group in the solvolysis of the acylamino-acids in acetic acid at low water concentrations

Abstract

The kinetics of solvolysis of some acylamino-acids have been studied in acetic acid solution containing 0·25M water. For the alkyl-substituted compounds the rates pass through a maximum at relatively low acid concentrations of ca. 0·05M. Increasing methylation at the carbon atoms adjacent to the amide bond produces increasing rates, which is a behaviour characteristic of ring closure reactions. The interpretation of the data is consistent with the rate-controlling step at the higher acid concentrations being a participation by the terminal carboxy-group to form an azlactone or its solvate which is followed by a rapid acid catalysed ring fission to form the products. When account is taken of the acid–base equilibria in the system, it is shown that the ring closure consists of simultaneous reactions by the protonated amide and the non-protonated amide through its zwitterion. The acid–base equilibrium constants which have been estimated from the kinetic data vary with structure in a similar manner to those of the corresponding acetamides which previously had been determined spectrophotometrically. Formylglycine has a faster rate than acetylglycine and its homologous acylglycines which is inconsistent with its lack of methyl groups to aid a ring closure reaction. These slower rates of the homologous acylglycines are due to the inductive effect of the α-carbon atom which is located at the point of ring closure. Methyl groups, therefore, are ambiguous in their behaviour and their position in the molecule determines whether they cause a rate increase or decrease. Strongly electronegative groups such as trifluoroacetyl and the positive terminal amino-group of a dipeptide have a reaction order of one with respect to the acid concentration and show no rate maximum even at the very high acid concentrations. It is suggested in these cases that the rate-controlling step is the acid catalysed ring fission for which the strongly electronegative groups will cause a decrease in the rate of ring fission and an acceleration in the ring closure.