Precision Synthesis of Polysarcosine via Controlled Ring-Opening Polymerization of N-Carboxyanhydride: Fast Kinetics, Ultrahigh Molecular Weight, and Mechanistic Insights

Abstract

The rapid and controlled synthesis of highmolecular-weight (HMW) polysarcosine (pSar), a potential polyethylene glycol (PEG) alternative, via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is rare and challenging. Here, we report the well-controlled ROP of sarcosine NCA (Sar-NCA) that is catalyzed by various carboxylic acids, which accelerate the polymerization rate up to 50 times, and enables the robust synthesis of pSar with an unprecedented ultrahigh molecular weight (UHMW) up to 586 kDa (DP ∼ 8200) and exceptionally narrow dispersity (D̵ ) below 1.05. Mechanistic experiments and density functional theory calculations together elucidate the role of carboxylic acid as a bifunctional catalyst that significantly facilitates proton transfer processes and avoids charge separation and suggest the ring opening of NCA, rather than decarboxylation, as the rate-determining step. UHMW pSar demonstrates improved thermal and mechanical properties over the low-molecular-weight counterparts. This work provides a simple yet highly efficient approach to UHMW pSar and generates a new fundamental understanding useful not only for the ROP of Sar-NCA but also for other NCAs.

Enhanced rate of sarcosine N-carboxyanhydride polymerisation from a lysine dendrimer macroinitiator driven by neighbouring H-bonding effects

“…who have demonstrated that organic carboxylic acids act as useful catalysts for PSar polymerisation capable of producing very high molecular weight polymers in a controlled way. 13 It has also been shown that the synthesis of poly(peptides) from NCAs can be catalysed by their own macromolecular structure. For example, the Cheng group have demonstrated that the polymerisation rate for poly(γ-benzyl- l -glutamate) (PBLG) is accelerated following the formation of α-helical chains in dichloromethane (DCM).…”

Controlled Synthesis of Crystalline and Helical N-Alkyl Poly(l-alanine)

“…Different initiators and catalysts, including ammonium hydrochloride, , Ni/Co-based organometallic catalysts, rare earth catalysts, lithium hexamethyldisilazide, , hexamethyldisilazane, trimethylsilyl sulfide, fluorinated alcohols, urea, crown ether, carboxylates, etc., have been reported to achieve the rapid and controlled ROPs of NCAs/NTAs and NNCAs/NNTAs. In recent years, the controlled ROPs of NCAs/NTAs and NNCAs/NNTAs catalyzed by organic acids have also been reported. − The studies of N-substituted polypeptides have nevertheless been rarely reported due to the difficulty of their synthesis. The primary-initiated ROPs and solid-phase synthesis failed to efficiently synthesize N-substituted polypeptides due to the steric hindrance added by the disubstitution. ,− Our group recently reported, for the first time, the rapid and controlled ROPs of N -methyl-α-amino acids N -carboxyanhydrides (αNNCAs) using acetic acid (AA) as the catalyst and primary amine as the initiator .…”

“…The primary-initiated ROPs and solid-phase synthesis failed to efficiently synthesize N-substituted polypeptides due to the steric hindrance added by the disubstitution. ,− Our group recently reported, for the first time, the rapid and controlled ROPs of N -methyl-α-amino acids N -carboxyanhydrides (αNNCAs) using acetic acid (AA) as the catalyst and primary amine as the initiator . The AA was shown to play multiple roles in the ROPs: , (1) activates the monomers via hydrogen bonding interaction; (2) facilitates nucleophilic addition–elimination by proton exchange; (3) facilitates the release of CO 2 ; and (4) forms acid–base equilibrium at the propagation center. This method allowed us to obtain a series of N -methyl polypeptides with diverse structures, controlled molecular weights ( M n ), and narrow distributions.…”