Mechanistic Insights into the Ring-Opening Polymerization of Cyclic Esters Catalyzed by Phosphonium Carboxybetaines and Catalyst Design

Aliphatic polyesters, widely used in biomedicine due to their biocompatibility and biodegradability, are typically synthesized via the ring-opening polymerization (ROP) of cyclic esters. Although traditional metal catalysts are highly active, their biological toxicity limits their applications. Organocatalysts, particularly natural organic molecules, offer safer alternatives. We explored the ROP mechanisms of cyclic esters (<i>L</i>-Lactide (<i>L</i>-LA), <i>ε</i>-caprolactone (<i>ε</i>-CL), and <i>δ</i>-valerolactone (<i>δ</i>-VL)) catalyzed by phosphonium carboxybetaines (PCBs, (PhR)₃P⁺(CH₂)₂COO^-, R = H(PCB), F(PCB-F) and OMe(PCB-OMe)) through density functional theory (DFT) computations. The DFT results revealed that the ROP of cyclic esters follows a bifunctional-cooperative activation mechanism, wherein the phosphonium moiety (Ph₃P⁺(CH₂)₂) activates the monomer via an extensive hydrogen-bonding interaction network, and the carboxylate (COO^-) serves as a proton acceptor to enhance the nucleophilicity of the initiator phenylpropanol (PPA). In contrast, unsubstituted PCB exhibited the lowest energy barrier, being consistent with the highest catalytic activity among PCB derivatives observed experimentally. Moreover, a series of novel PCB derivatives (Ph₃P⁺(CH₂)_nCOO^-, n = 3-6 (PCB1-PCB4)) were designed by regulating the carbon spacer length, and their catalytic performances were computationally tested. The designed catalyst PCB2 (Ph₃P⁺(CH₂)₄COO^-) exhibited higher activity for the ROP of <i>L</i>-LA, attributed to providing sufficient flexibility to minimize deformation while improving proton-accepting capability. Similarly, PCB2 also demonstrated superior catalytic activity for <i>δ</i>-VL and the more challenging <i>ε</i>-CL monomer. This work not only clarifies the intrinsic catalytic nature of these zwitterionic organocatalysts, but also provides an effective strategy for the rational design of high-performance, metal-free catalysts for the synthesis of sustainable polyesters.