Polymerization Mechanism of N-Phenyloxycarbonyl Amino Acids: Polycondensation or Cyclization to NCA?

N-Phenyloxycarbonyl-amino acids (NPCs) are promising monomers to synthesize both polypeptides and polypeptoids exhibiting great tolerance for nucleophiles. However, the polymerization mechanism of NPCs remains unclear since it is hard to distinguish intermediates including N-carboxyanhydrides (NCA) from byproducts of direct polycondensation. In this contribution, the polycondensation pathway is disproved by the impossible polymerization of alanine dimer NPC. Isocyanate acid (ICA) has been captured as an intermediate of NPC polymerization. In an attempt to monitor the polymerization of ¹⁵N-labeled leucine-NPC by ¹⁵N NMR for the first time, reactive species including ICA are identified and traced. A kinetic model is established based on the ¹⁵N NMR data and validated by Monte Carlo simulation. Two possible polymerization pathways are evidenced by a density functional theory (DFT) calculation. The ICA-meditated NCA ring-closing pathway is preferred over the direct NCA ring-closing pathway for lower Gibbs energy barriers. A direct ring-closing path is feasible only for Sar-NPC, which explains its low polymerization reactivity.