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.