Polymerization rate difference of N-alkyl glycine NCAs: Steric hindrance or not?

Polypeptoids synthesized from N-substituted glycine N-carboxyanhydrides (NNCAs) are widely applied in biological fields. The effect of side groups in NNCA polymerizations is a key to develop novel polypeptoids with complex topologies and constituents. In this work, density functional theory (DFT) calculations are employed to investigate the propagation of a series of alkyl substituted NNCAs with solvation model. According to both computational and experimental results, carbonyl addition is confirmed as rate determining step and steric hindrance is recognized as the major factor of low reactivity in β-C branched NNCAs. However, in linear and γ-C branched case, aggregation of side groups instead of bulkiness is considered responsible for low polymerization rate.