Amino-acids and peptides. Part XXXV. The effect of solvent on the rates of racemisation and coupling of some acylamino-acid p-nitro-phenyl esters; the base strengths of some amines in organic solvents, and related investigations

Abstract

The rates of racemisation by triethylamine of benzyloxycarbonylglycyl-L-phenylalanine p-nitrophenyl ester (A) and of benzyloxycarbonyl-L-phenylalanine p-nitrophenyl ester (B) in nine different solvents have been determined. The rates of condensation of the ester (B) with glycine ethyl ester in the same solvents have been measured; the rate for dimethyl sulphoxide is ca. 500 times that for chloroform as solvent. The ratios of the rates of racemisation of (A) and (B) to that of the condensation reaction are relatively low for the solvents tetrahydrofuran, dimethylformamide, and dimethyl sulphoxide, but exceptionally high for chloroform, dichloromethane, acetonitrile, and nitromethane, which are unfavourable solvents in this respect. The effect of the nature of the amine on the rate of racemisation of esters (A) and (B) and of benzoyl-L-leucine p-nitrophenyl ester in acetonitrile and in dimethyl sulphoxide is reported, and the base strengths of some amines in organic solvents have been measured by use of 2,4-dinitrophenol as spectrophotometric indicator. The change in the base strength of glycine ethyl ester with solvent runs roughly parallel with the change in its nucleophilicity as measured by the rate of its reaction with ester (B). The rates of racemisation of the p-chloro-, 2,4-dichloro-, m-nitro-. 2,4,5-trichloro-, and p-nitro-phenyl esters of benzoyl-L-leucine by base increase in the order given. Benzyltrimethylammonium chloride and iodide racemise benzoyl-L-leucine p-nitrophenyl ester in acetonitrile, but the corresponding fluoroborate does not, although it increases the rate of racemisation by bases. It is concluded that the effect of chloride ion in increasing racemisation during coupling is due both to its basicity and to the increase in the ionic strength of the solution.