Mechanism of Alternating Poly(lactic-co-glycolic acid) Formation by Polymerization of (S)- and (R)-3-Methyl Glycolide Using an Enantiopure Aluminum Complex

The mechanism(s) of alternating PLGA synthesis by ring-opening polymerization of (S)- and (R)-3-methyl glycolide promoted by enantiopure aluminum complexes have been rationalized by density functional theory (DFT) calculations. The high regioselectivity of the (S)-MeG polymerization is obtained by repetitive ring opening at the glycolyl site by the (R)-catalyst whereas a lower regioselectivity is predicted by the ROP of (R)-MeG. The behavior of the two monomers is rationalized by unveiling the active site fluxionality of the enantiopure catalyst, identifying the rate-limiting steps that encode a preference at the glycolyl site versus the lactyl site, and revealing selection of the opposite monomer enantioface. The microstructure of the PLGA copolymers is predicted by considering the influence of the configuration of the last inserted unit. The identification of the preferred mechanistic paths may allow for a targeted catalyst design to enhance control of the polymer microstructures.