NAM-TMS Mechanism of α‑Amino Acid <i>N</i>‑Carboxyanhydride Polymerization: A DFT Study

The normal amine mechanism via the proton-transfer route (NAM-H) is widely accepted for the synthesis of polypeptides with nonionic initiators. Besides proton transfer, the trimethylsilyl (TMS) group transfer process has been found in living/controlled polymerization initiated by <i>N</i>-TMS amine in experiments, but the corresponding mechanism has never been proposed. In this work, we employed density functional theory (DFT) with the solvation model to investigate the details of the TMS-transfer mechanism, defined as NAM-TMS, for the ring-opening polymerization of α-amino acid <i>N</i>-carboxyanhydride. The TMS transfer process of NAM-TMS is thermodynamically more favored than the NAM-H mechanism according to the lower addition energy barrier observed. The rate-determining step (RDS) in NAM-TMS is the decarboxylation step, i.e., the release of CO₂, rather than carbonyl addition in NAM-H because of the low dipole stable precursor enlarged energy gap of decarboxylation. It is the first calculation evidence supporting decarboxylation as RDS in the NAM mechanism

Hydroxyl Group Tolerated Polymerization of N‑Substituted Glycine <i>N</i>‑Thiocarboxyanhydride Mediated by Aminoalcohols: A Simple Way to α‑Hydroxyl-ω-aminotelechelic Polypeptoids

<i>N</i>-Carboxyanhydride (NCA) polymerization cannot tolerate nucleophilic groups that have the ability of initiation, e.g., hydroxyl group. In contrast, <i>N</i>-thiocarboxyanhydride (NTA) is a much more stable monomer to tolerate them. In this contribution, we investigate aminoalcohols including 2-amino-1-ethanol (<b>AE</b>), 3-amino-1-propanol (<b>AP</b>), 4-amino­methylbenzyl alcohol (<b>AMB</b>), 6-amino-1-hexanol (<b>AH</b>), and 12-amino-1-dodecanol (<b>AD</b>) as initiators for ring-opening polymerization of N-substituted glycine <i>N</i>-thiocarboxyanhydride (NNTA) to prepare α-hydroxyl-ω-aminotelechelic water-soluble polypeptoids. Hydroxyl groups of <b>AE</b>, <b>AP</b>, and <b>AMB</b> are activated by hydrogen bonding with amino groups, which results in a mixture of α,ω-diaminotelechelic and α-hydroxyl-ω-amino­telechelic polypeptoids confirmed by ¹H NMR, MALDI-ToF, and SEC measurements. Pure α-hydroxyl-ω-amino­telechelic polypeptoids are synthesized for the first time initiated by <b>AH</b> and <b>AD</b> with controlled molecular weights (1.3–12.4 kg/mol) and low polydispersity indices (<1.30). Hydroxyl groups in <b>AH</b> and <b>AD</b> remain inactive to generate hydrogen bonding due to the long distance from amino groups. Water-soluble polypeptoids with special functional end groups are attractive alternatives of PEG for their nontoxicity and biocompatibility having great potential in biomedical applications

Polymerization of N‑Substituted Glycine <i>N</i>‑Thiocarboxyanhydride through Regioselective Initiation of Cysteamine: A Direct Way toward Thiol-Capped Polypeptoids

Because of the high reactivity, <i>N</i>-carboxyanhydride (NCA) can be initiated by the thiol group. On the contrary, <i>N</i>-thiocarboxy­anhydride (NTA) is more stable and is able to tolerate it. Herein, we apply cysteamine as a regioselective initiator for ring-opening polymerization (ROP) of N-substituted glycine <i>N</i>-thiocarboxy­anhydride (NNTA) to synthesize well-defined thiol-capped polypeptoids. ROPs of sarcosine NTA (Sar-NTA) and <i>N</i>-ethylglycine NTA (NEG-NTA) are well controlled when [M]/[I] ≤ 100 with high yields (>87.5%) producing polypeptoids with designable molecular weights and low polydispersity indices (<1.2). All the polypeptoid chains contain a thiol end group, which is confirmed by NMR analyses, MALDI-ToF MS spectra, and Ellman’s assay. Through radical-mediated thiol–ene reaction with styrene, all the thiol chain ends are transferred to oligostyrene, revealing the convenience of further modification. Benefiting from the thiol–ene click chemistry, thiol-capped polysarcosine (PSar) and poly­(<i>N</i>-ethylglycine) (PNEG) are promising candidates to replace PEG for their nontoxicity and biocompatibility

Spontaneous Amino-yne Click Polymerization: A Powerful Tool toward Regio- and Stereospecific Poly(β-aminoacrylate)s

Efficient synthesis of poly­(enamine)­s has been a great challenge because of their poor stability, poor solubility, and low molecular weights. In this work, a spontaneous amino-yne click polymerization for the efficient preparation of poly­(enamine)­s was established, which could proceed with 100% atom efficiency under very mild conditions without any external catalyst. Through systematic optimization of the reaction conditions, several soluble and thermally stable poly­(β-aminoacrylate)­s with high molecular weights (<i>M</i>_w up to 64400) and well-defined structures were obtained in excellent yields (up to 99%). Moreover, the polymerization can perform in a regio- and stereospecific fashion. Nuclear magnetic resonance spectra analysis revealed that solely anti-Markovnikov additive products with 100% <i>E</i>-isomer were obtained. The reaction mechanism was well demonstrated with the assistance of density functional theory calculations. In addition, by introducing the tetraphenylethene moiety, the resulting polymers exhibit unique aggregation-induced emission characteristics and could be applied in explosives detection and bioimaging. This polyhydroamination is a new type of click polymerization and opens up enormous opportunities for preparing functional polymeric materials