Accelerated and Controlled Polymerization of N-Carboxyanhydrides Assisted by Acids

Abstract

The general consensus is that acidic species such as HCl inhibit the polymerization process of N-carboxyanhydrides (NCAs), which require their removal to guarantee the successful synthesis of polypeptides. Herein, we show that the impact of organic acids on NCA polymerization was dependent on their pKa values in dichloromethane (DCM). While strong acids like trifluoroacetic acid (TFA) completely blocks the chain propagation as expected; in contrast, weaker acids such as acetic acid accelerates the polymerization rate. The addition of acids not only protonates the propagating amino groups but also activates NCA monomers, whose balance determined the accelerating or inhibitory effect. Additionally, the acid-assisted polymerization exhibits one-stage kinetics that differs from the conventional cooperative covalent polymerizations, resulting in excellent control over molecular weights even at the accelerating rate. We were able to use this acid-catalyzed mechanism to control the polymerization of nonpurified NCAs. This work shows the possibility of tuning the pH of reaction solution to control NCA polymerization, providing new insights of water-phase polypeptide synthesis.