Accelerated and controlled polymerization of N-carboxyanhydrides assisted by acids

It has been widely accepted that acidic species, such as HCl, inhibit the polymerization process of N-carboxyanhydrides (NCAs), which have to be removed to guarantee the successful synthesis of polypeptides. Herein, we showed that the impact of organic acids on NCA polymerization was dependent on their pKa values in dichloromethane. While stronger acids like trifluoroacetic acids completely blocked the chain propagation as expected, weaker acids such as acetic acids accelerated the polymerization rate instead. The addition of acids not only protonated the propagating amino groups but also activated NCA monomers, whose balance determined the accelerating or inhibitory effect. Additionally, the acid-assisted polymerization exhibited one-stage kinetics that differed from conventional cooperative covalent polymerizations, resulting in excellent control over molecular weights even with an accelerating rate. The pKa-dependence inspired us to turn the inhibitory acids into accelerating acids on demand, promoting the controlled polymerization from non-purified NCA monomers. This work highlights the possibility to change the conventional understanding of an activator /inhibitor by altering reaction conditions, which not only sheds light on the design of new accelerating strategy, but also offers a practical strategy to prepare polypeptide materials in an efficient and controlled manner.