Organocatalyzed ring-opening polymerization of meso-lactide reveals competing mechanisms of stereocontrol

• Revealing the mechanism(s) for stereoselective lactide ring opening polymerization by organocatalysts. • Factors inducing meso -desymmetrization catalysis. • Synergic action of enantiomorphic and chain end controls. • Non covalent interactions inducing stereoselective polymerization. • Role of the monomer enantioface in ring opening polymerization of lactide. The mechanism for the ring-opening polymerization (ROP) of meso -lactide (LA) promoted by the chiral thiourea-amine organocatalyst has been elucidated through density functional theory (DFT) calculations. A comprehensive description of the process was obtained by accounting for the distinct reactivity of the two ring-opening sites of meso -LA with the carbonyl group adjacent to the ( R ) or ( S ) stereogenic atoms and the two monomer enantiofaces ( re vs si ). This mechanistic complexity gives rise to multiple competing pathways with comparable activation barriers, in line with the experimental P m value of 0.62, which indicates the formation of a weakly syndiotactic polylactic acid (PLA). Compared to the ROP of rac -LA ( P m = 0.90), the reduced selectivity is attributed to a weaker and less cooperative (antagonistic) interplay between enantiomorphic site (ESM) and chain-end (CEM) control models, leading to diminished energetic discrimination among the competing pathways.