Accelerated and controlled polymerization of N-carboxyanhydrides catalyzed by acids and crown ether

The recent advances in the polymerization of N -carboxyanhydrides (NCAs) potentiated the biomedical applications of polypeptide materials. However, the two-stage kinetics in solvents with low polarity, such as dichloromethane (DCM), typically led to ill-defined polypeptides, as chains entered the faster propagating stage outpaced those remaining in the initiation stage and consumed most of the monomers. Herein, we reported the acetic acid (AcOH) and crown ether (CE) cooperative system to modulate the polymerization process, enabling accelerated and controlled synthesis of polypeptides. The sequential addition of AcOH and CE decoupled the initiating/early propagating stage from the later propagating stage, which guaranteed simultaneous chain growth, yielding well-defined polypeptides with predictable molecular weights and narrow dispersity. Specifically, AcOH attenuated the rate difference and enabled all polypeptides entering propagating stage simultaneously, generating α-helix for CE-catalyzed acceleration. This strategy advances the understanding of the two-stage kinetics in NCA polymerization and offers a robust synthetic route to polypeptide materials, thereby facilitating their downstream biomedical applications.