A facile glovebox-free strategy to significantly accelerate the syntheses of well-defined polypeptides by N-carboxyanhydride (NCA) ring opening polymerizations

Abstract

A facile N₂ flow-accelerated N-carboxyanhydride ring opening polymerization (NCA ROP) is demonstrated, herein, with rigorous kinetic studies to evaluate the methodology in detail. By using n-hexylamine as initiator and γ-benzyl-L-glutamate N-carboxyanhydride (BLG-NCA) as monomer, the NCA ROP via a normal amine mechanism (NAM) reached 90% conversion in 2 h under N₂ flow at room temperature in a fume hood, much shorter than the time required for the same polymerization conducted in a glove box (14 h). The efficient removal of CO₂ from the reaction by N₂ flow drove the carbamic acid-amine equilibrium toward the formation of active nucleophilic amino termini and promoted polymerization. The detailed kinetic studies of the polymerization with different feed ratios and N₂ flow rates were conducted, demonstrating the living feature of the NCA ROP and the tuning of the polymerization rate by simply changing the flow rate of N₂. Maintenance of the reactivity of the amino ω-chain terminus and control during a subsequent polymerization were confirmed by performing chain extension reactions. The N₂ flow method provides a new straightforward strategy to synthesize well-defined polypeptides with predictable molecular weights and narrow molecular weight distributions (PDI < 1.19).

Keywords: NCA; Nitrogen flow; ring opening polymerization.

Figure 1

(a) ¹H NMR spectrum of PBLG₄₆. (b) The GPC trace of PBLG₄₆.

Figure 2

(a). The kinetics studies of n-hexylamine initiated BLG-NCA ROP at room temperature with BLG-NCA/I ratio of 100:1. The initial BLG-NCA concentration was 50 mg/mL (0.19 M). The N₂ flow rates were 0 mL/min (green line), 100 mL/min (black line) and 250 mL/min (red line). (b). NCA ROP terminated at selected monomer conversion with flow rate of 100 mL/min.

Scheme 1

NCA ROP under N2 flow via normal amine mechanism.