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

Abstract

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.

Density Functional Theory Studies on the Synthesis of Poly(α-Amino Acid)s Via the Amine-Mediated Ring Opening Polymerizations of N-Carboxyanhydrides and N-Thiocarboxyanhydrides

“…In an experimental kinetic investigation ( Fetsch et al, 2011 ) the ROP of NNCA follows pseudo first-order kinetics, and the apparent polymerization rate of NNCA is in the order of Sar >> EtGly > PrGly > nBuGly > iBuGly in benzonitrile. In the DFT calculation of the ROP of six NNCA monomers, the propagating chain ends rather than employing simple secondary amines to model real propagation ( Bai and Ling, 2019 ). The rate-determining steps in all NNCA cases are still carbonyl addition in a three-step framework, but the energy barriers in the carbonyl addition step highly depend on the branched structure of substituents, as shown in Figure 2B .…”

Insight into the synthesis of N-methylated polypeptides

“…Very recently, Ling and co-workers have shown in a detailed DFT study that linear and γ-C branched N-substituents lead to similar reaction barriers, regarding the calculated Gibbs free energies for nucleophile addition. 17 Given the observed differences in polymerization efficiency between NMLeu-NCA and NMMet-NCA, we conclude that branching in the side chains of α-substituted and N-methylated αNNCAs decreases the carbonyl reactivity much more compared to branching in the aliphatic side chains of N-alkylated and α-unsubstituted NCAs.…”

“…10 The reason for lower polymerization rates is the steric hindrance for β-C branched NNCAs and the aggregation of the side chains for linear or γ-C branched NNCAs. 17 One of the most studied αand N-substituted polypeptides is poly(N-methyl-L-alanine), which was first synthesized by a ROP of the corresponding NNCA by Goodman and Fried in 1967. 18 Using conformational energy calculations, CD and NMR techniques, it was shown that this structure adopts a right-handed helix with all-trans peptide bonds.…”

Ring-Opening Polymerization of CO2-Based Disubstituted δ-Valerolactone toward Sustainable Functional Polyesters

“…DFT calculations − are applied to analyze the Gibbs free energy barriers in both EVL and BBL additions onto Sc­(OTf) 3 -coordinated EVL and BBL units (Figures S9 and S10). The additions on BBL or EVL chain ends by the same monomer, that is, homopropagation, are not favored, with higher energy barrier than the alternating propagation.…”