Chain initiation efficiency in cobalt- and nickel-mediated polypeptide synthesis

In the presence of certain ligands and solvents, nickel- and cobalt-mediated living polymerizations of alpha-amino acid-N-carboxyanhydrides (NCAs) produce polymers with molecular weights several times greater than predicted by initial molar ratios of monomer to initiator. Such molecular weight inflation could result either from competitive formation of catalytic intermediates of reduced activity or from incomplete formation of a single catalytically active species. Evidence is presented here supporting the latter possibility. Specifically, evidence is given that the concentration of the key amido-amidate metallacyclic active species is reduced in situ by (1) complexation of metal(0) preinitiator by CO liberated upon addition of an NCA monomer to another molecule of preinitiator, (2) incomplete ring contraction of a six-membered amido-alkylmetallacyclic intermediate due to inefficient proton migration, and (3) dimerization of the amido-amidate active species to give catalytically inactive complexes.