Looking into the Quest for Stereoselective Ring-Opening Polymerization of Racemic Lactide with Chiral Organocatalysts

A model for stereoselective ring-opening polymerization (ROP) of racemic lactide (rac-LA) catalyzed by chiral thiourea-based organocatalysts is presented based on density functional theory (DFT) calculations. The model reveals the complex mechanism of the process, highlighting (a) multiple mechanistic pathways, (b) enantioselective activation of monomer reactive faces (re for RR-LA and si for SS-LA), and (c) shifts in the rate-determining steps from the nucleophilic addition to the ring opening step depending on monomer chirality. The interplay between enantiomorphic site control and chain-end control is also sorted out, demonstrating good agreement with experimental stereoselectivity. Furthermore, the model is extended to chiral thiourea-based bifunctional catalysts, providing insights into the enhanced stereochemical outcomes observed in the ROP of rac-LA.