Covalently Preorganized (Thio)Urea-Alkoxide Organocatalysts Enable Controlled Synthesis of High-Molecular-Weight Polyglycolide.

Polyglycolide (PGA) is a leading biodegradable polyester, but controlled access to high-molecular-weight PGA remains challenging. Here, we introduce a covalent preorganization strategy that merges H-bond-mediated monomer activation and alkoxide-based chain propagation within a single molecular scaffold. Systematic variation of the H-bond donor, substituent electronics, tether length, and counter cation identifies the thiourea-based sodium alkoxide Cat. 7 as an optimal catalyst/initiator. Under mild conditions, Cat. 7 enables rapid and selective ring-opening polymerization of glycolide, affording PGA with number-average molecular weights up to 222.4 kDa (dispersity of 1.57, turnover number of 11 600, and turnover frequency of 483 h-1). Crystallographic, kinetic, spectroscopic, and computational studies support an intramolecular cooperative mechanism. The resulting high-molecular-weight PGA exhibits high crystallinity and tensile strength, highlighting (thio)urea-alkoxide covalent integration as a powerful strategy for the precision synthesis of high-performance biodegradable polyesters.