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Synthetic polypeptides, mainly prepared through the ring-opening polymerization (ROP) of amino acid N -carboxyanhydrides (NCAs), have garnered significant interest for biomedical and material applications. Tertiary amines, such as triethylamine (TEA), typically initiate the polymerization of NCAs through the activated monomer mechanism (AMM), which proceeds in a fast but uncontrolled manner, and thus are no longer used for polypeptide synthesis. In this study, we demonstrate that the addition of acetic acid (AcOH) effectively modulates the reactivity of tertiary amines to suppress the AMM initiation while retaining its accelerating role, enabling rapid and controlled preparation of polypeptide materials. With the sequential addition of AcOH and TEA, well-defined polypeptides are synthesized with predictable molecular weights and narrow dispersity within minutes. Detailed mechanistic studies suggest that the partial protonation of TEA by AcOH facilitates the monomer activation while minimizing the NCA deprotonation. This work provides new insights into the role of tertiary amines in ROP of NCA, offering a simple and efficient strategy for the scalable production of high-quality polypeptide materials.
Zheng et al. (2026) studied this question.