Amino Acid Chemistry in Dipolar Aprotic Solvents: Dissociation Constants and Ambident Reactivity

Article abstract of DOI:10.1021/jo00363a033

The pK_a's of 10 amino acids and their esters were measured spectrophotometrically in dilute Me2SO solution.The pK_a's of the α-amino acids ranged from 6.3 to 7.5 and the esters from 6.4 to 8.7.The ratio of zwitterion to uncharged form of the amino acids in Me2SO ranged from 2 to 40, compared to 10⁴-10⁵ in aqueous solution.The primary reason for this difference is the greater solvation of the carboxylate anion in water compared to Me2SO, with solvation of the ammonium ion being similar in the two solvents.Although the zwitterion predominates in dipolar aprotic solvents, N-alkylation was competitive with O-alkylation.Reaction of the unprotected amino acids with alkyl halides gave 50-70percent yield of esters.Using alkylating agents with "harder" leaving groups increased the ester yield to 75-85percent.O-Alkylation yields were improved from 50-70percent to 85-90percent by addition of 2 equiv of LiBr to the reaction mixture.The improvement in O vs.N selectivity was attributed to a salting in of the zwitterionic form of the amino acid.