Reaction mechanisms in peptide synthesis. Part 2. Tautomerism of the peptide bond.

We had concluded in previous work that ring opening of a 2-alkyl-5(4H)-oxazolone by water or ammonia leads to transient high-energy imidol intermediates which instantly tautomerize to the native amides. Using the MOPAC molecular orbital program, detailed geometric and energetic characteristics of the tautomerism of a peptide bond have been determined on the AM1 level. The results demonstrate that tautomerism of a peptide bond comprises a three-stage process involving three successive transition states and a bimolecular mechanism: (i) E----Z peptide bond isomerization followed by dimerization, (ii) concerted double-hydrogen exchange leading to an alpha-hydroxyimine (imidic acid) followed by splitting of the dimer, and (iii) Z----E N-methylimine inversion. While pathway (iii----ii----i) is predicted as a feasible route terminating in the formation of a peptide bond, the inverse route (iii----ii----i) is excluded as a possible initial step in the generation of a 5(4H)-oxazolone intermediate.