Impact of Monomer Purity on the Acid-Catalyzed ROP of Sarcosine N-Carboxyanhydrides: A Comparative Study of Phosgene-Free Synthetic Routes toward High-Molecular-Weight Polysarcosine.

Polysarcosine (pSar) is an attractive alternative to poly(ethylene glycol) for a broad range of bioapplications. However, the preparation of high-molecular-weight pSar remains limited by challenges associated with the synthesis and purity of sarcosine N-carboxyanhydride (Sar-NCA). Here, we report a phosgene-free oxalyl chloride/silyl-mediated synthesis of highly pure Sar-NCA and compare it with a PCl3-based route. The oxalyl chloride method consistently produced pure Sar-NCA with minimal residual sarcosine content, enabling controlled benzoic acid-catalyzed ring-opening polymerization. PSar with Mn up to 186 kDa and narrow dispersity (Đ = 1.08) was obtained under ambient conditions. In contrast, residual impurities in PCl3-derived Sar-NCA promoted competing initiation pathways and reduced polymerization control. SEC-MALS analysis in aqueous media further enabled the determination of the solution properties of pSar over a broad range of molecular weights. These results establish the oxalyl chloride method as a robust, scalable strategy for preparing high-purity Sar-NCA and well-defined, high-molecular-weight pSar.