Interlocked Polymerization inside Cocrystal versus Interfacial Polymerization at Solid of Racemic Leucine N -Thiocarboxyanhydride

Poly(amino acid)s have garnered significant attention in biomedical materials due to their excellent biocompatibility and degradability. The ring-opening polymerization of N -thiocarboxyanhydrides (NTAs) represents a promising synthetic approach owing to their air and moisture stability. However, challenges of controllability arise when NTAs cannot be fully dissolved. To address this, a thermal regulation strategy was employed to control the polymerization loci, realizing Interfacial Polymerization at Solid (iPaS) to interlocked polymerization inside cocrystals (iPiC) via decreasing temperature. Using dl -leucine NTA as a model monomer, polymerization at 15 and 25 °C produced polypeptides with broad molecular weight distributions (D̵ = 1.3–1.5) and mixed kinetic manners, which were further deconvoluted into zeroth-order and first-order terms. On the contrary, polymerization at low temperature (0 °C) followed the iPiC mechanism and enabled precise control (D̵ < 1.1). Adsorption energy calculations and polymerization pathway mapping were introduced to demonstrate the difference between iPiC and iPaS. This work established both theoretical and practical foundations for developing robust and efficient temperature-driven heterogeneous NTA polymerization systems.