Proton Transfer Shuttle Mediated Dormant–Active Balance for Accelerated and Controlled Polymerization of <i>N</i> ‐Carboxyanhydrides

Since its inception in 2003, the concept of "reversible deactivation" to control chain propagation has emerged as a promising, though still evolving, strategy for precise polypeptide synthesis. Beyond a simple polymerization method, this concept is expected to promote unique reaction pathways. Nevertheless, achieving both rapid and well-controlled ring-opening polymerization of N-carboxyanhydrides through the equilibrium between dormant and active species is rare and challenging. In this study, we report a proton transfer shuttle-assisted strategy that accelerates chain growth via trifluoroacetic acid (TFA) /tetrabutylammonium acetate (TBAA) cooperative system. Central to this strategy is reversible acceptance and donation of proton, thereby shifting the dormant-active equilibrium without disrupting it. This modulation increases the proportion of active chain ends while maintaining control over rapid polymerization process. Moreover, cooperative TFA/TBAA catalysis has streamlined the synthesis of well-defined polypeptides, which are amenable to further chemical modifications. Control experiments and density functional theory calculations provide insights into the origin of controllability and critical role of TFA/TBAA in regulating the reversible deactivation equilibrium. Consequently, this work establishes a robust and efficient approach for accelerated yet controlled preparation of polypeptides and generates fundamental insights that advance understanding and application of the "reversible deactivation" concept for precision polypeptide synthesis.