THERMAL CHEMISTRY
OF AMINO ACIDS:
STEPHEN J.
ROBINSON
October 1993
ABSTRACT
Self-condensation of amino acids to form cyclic dipeptides on heating in ethane‑1,2‑diol is well-known. Investigation of the basic chemistry of these reactions (including side-chain reactivity) presents an opportunity to (i) re‑examine the synthetic potential of the method in the light of modern separation techniques, (ii) determine selectivity factors controlling priority of linkage in the condensation of a mixture of amino acids with possible relevance to the origin of biological information and (iii) to determine the nature and extent of competitive side-chain chemistry as an indicator of modes of thermal degradation of amino acids and their derivatives. In this project, product analyses have been performed by HPLC following the thermal reactions of the 20 protein amino acids, their close relatives and their simple derivatives in ethane-1,2-diol.
Self-condensation proceeds in two steps: formation of amino acid 2‑hydroxyethyl esters by reaction with ethane-1,2-diol (via H-bonded assisted displacement of OH by carboxylate), followed by rate-determining bimolecular condensation. With the exceptions of proline (lower DS°‡) and histidine (side-chain assistance), the rate of bimolecular condensation decreases with increasing steric hindrance of the side-chain or N-substituent. Kinetic selectivity data from reactions involving mixtures of amino acids demonstrates the feasibility of self-ordering in polycondensation reactions to produce non-random peptide sequences, arising from the intrinsic steric hindrance of the amino acid side-chains. Preparative-scale condensations are simple, cheap and high‑yielding, affording readily separable diastereomeric mixtures of cyclic dipeptides.
Side-chain chemistry competes effectively with self-condensation in many cases. b‑Alanine, aspartic acid and asparagine undergo E1CB deamination, whilst glutamic acid, glutamine and lysine undergo intramolecular condensations. The guanidino group of arginine appears to decompose solvolytically to give the lactam of ornithine. Serine and threonine degrade via retro-aldol and b-elimination pathways, whilst heating cystine esters in protic solvents produces esters of 2‑methylthiazolidine‑2,4‑dicarboxylic acid via a primary b-elimination step. These particular reactivities would appear to exclude most of these amino acids from peptide bond formation in thermal proteinoids; nevertheless, they have important implications for the thermal chemistry of free and peptide-bound amino acids in food and textiles.