Water-resistant and temperature-tolerant ring-opening polymerization of <italic>N</italic>-carboxyanhydrides in hydrophobic deep eutectic solvents

Hydrophobic deep eutectic solvents are introduced as a reaction medium for overcoming the moisture sensitivity of N-carboxyanhydride ring-opening polymerization. Systematic screening identified [camphor][decanoic acid] as an optimal solvent, enabling decagram-scale synthesis of poly(γ-benzyl-L-glutamate) under open-air conditions. The reaction reached 95% conversion in 50 min at 25 °C, and the degree of polymerization closely matched the feed ratios with low dispersity (Đ = ~1.3). This polymerization also tolerated 80% humidity, water addition, and temperatures up to 85 °C, at which it reached completion within 4 min. The [camphor][decanoic acid] system was compatible with diverse initiators and various amino acid N-carboxyanhydride monomers (Ala, Leu, Bn-His, Tr-Gln, Cbz-Lys, Bn-Cys, and Phe), further supporting the synthesis of block polypeptide copolymers via sequential monomer addition. Additionally, the chirality of DES also has a significant effect on the polymerization rate. These findings establish hydrophobic deep eutectic solvent as a practical, scalable, and water-resistant platform for controlled polypeptide synthesis and offer a general strategy for other water-sensitive reactions.