Self‐promoted Controlled Ring‐opening Polymerization via Side Chain‐mediated Proton Transfer for the Synthesis of Tertiary Amine‐pendant Polypeptoids

Abstract Proton transfer is essential in virtually all biochemical processes, with enzymes facilitating this transfer by optimizing the proximity and orientation of reactants through site‐specific hydrogen bonds. Proton transfer is also crucial in the rate‐determining step for the ring‐opening polymerization of N ‐carboxyanhydrides (NCAs), widely used to prepare various peptidomimetic materials. This study utilizes side chain‐assisted strategy to accelerate the rate of chain propagation by using NCAs with tertiary amine pendants. This moiety enables hydrogen bond formation between the incoming NCA and the polymer amino growing end. The tertiary amine side chain of the NCA forms a proton shuttle, via a less constrained transition state, to facilitate the proton transfer process. Moreover, the tertiary amine side chains enable the precipitation of NCA monomers through in situ protonation during the monomer synthesis. This greatly facilitates the synthesis of these unreported monomers, allowing the direct controlled synthesis of tertiary amine‐pendant polypeptoids. This side chain‐promoted polymerization has rarely been reported. Additionally, the tertiary amine side chains, as widely used functional groups, endow the polymers with unique properties including pH‐ and thermo‐responsiveness, tunable p K a s, and siRNA transfection capability. The self‐promoted synthesis, facile monomer preparation, and attractive properties make tertiary amine‐pendant polypeptoids promising materials for various applications.