Ring Opening Mechanism Of α-Amino Acid NCA/ NTA:Quantum Chemical Calculations

Polypeptides and polypeptoids are the polymer consisting of a-amino acid connected by peptide bond (amide bond), which are expected to be widely used in the biomedical, tissue engineering, biomaterials and so on because of their excellent biocompatibility and biodegradability. Ring opening polymerization (ROP) of a-amino acid N-carboxyanhydrides (NCAs) and N-thiocarboxyanhydrides (NTAs) are the most promising method to prepare polypeptides and polypeptoids so far. In the past century, scientists have studied a variety of mechanisms to prepare polypeptides and polypeptoids which have controlled molecular weight, controlled composition and sequence, narrow molecular weight distribution and diverse topologies. Wherein the normal amine mechanism (NAM) is very effective and is widely accepted. However, NCAs are high activity and are sensitive to humidity so the reaction must be carried out under extremely harsh conditions. Most of the intermediates and transition states (TS) are difficult or impossible to isolate or characterize in experiments, which results in the fact that the proposed mechanism is built on hypotheses and indirect evidence. Whether the decarboxylation is the rate-determining step in this mechanism is controversial. NTAs have very good stability so it is challenging to prepare polypeptides and polypeptoids with high molecular weight and the research has just begun. Therefore, it is quite difficult to directly reveal the details of NAM according to the current technical conditions.Quantum chemical calculations have developed to be a powerful tool to reveal the mechanistic details. The Nobel Prize has been twice awarded to the scientists in the field. Its reliability and efficiency have been widely accepted. In this work, B3LYP/6-31G(d,p) and B3LYP/Midix and MP2/6-31G(d,p) were applied to investigate the ROPs of L-alanine-NCA (Ala-NCA) initiated by primary amine, secondary amine and the secondary amine with an electron withdrawing group. We found that secondary amine can initiate the ROPs of Ala-NCA as fast as primary amine and the rate-determining step are all the amine addition steps. Because of its reduced nucleophilicity, the secondary amine with an electron withdrawing group can hardly initiate the ROP of Ala-NCA. Then we investigated the ROPs of N-substituted glycine N-carboxyanhydride and found that initiation capability of secondary amine is nearly the same as the primary amine and the rate-determining step are all the amine addition steps. We applied CCSD(T)-6-311G(d,p) method to compute the most precise energies for the reaction pathways mentioned previously and analyzed the data obtained from the other three methods. We found that NCAs and NNCAs could perform random copolymerization. What’s more, we investigated the ROP of NCA with different substituted group on C4 atom initiated by primary amine and secondary amine. The rate-determining steps were still the amine addition steps, which means that the substituted group would not change the reaction pathway. In order to compare calculated results with experimental phenomena, we investigated the solvent effect on the ROP mechanism of NCA and NNCA initiated by primary amine and secondary amine but we found that it didn’t change the rate-determining step in the whole reaction pathway.In the chemical reaction systems, amines would not attack the NCAs only in one direction. After the calculation, we found that the direction of attacking didn’t cause a dramatically change in energy barrier except the amine addition on C2 carbonyl. The ROP mechanism of NTA is quite similar to NCA and rate-determining steps are also the amine addition.