Covalent organic frameworks-bridged bis(β-cyclodextrin) chiral stationary phases for enhanced liquid chromatographic enantioseparation.

Cyclodextrin-based covalent organic frameworks (CD-COFs) have emerged as promising chiral stationary phases (CSPs) for chromatographic enantioseparation. In conventional chiral liquid chromatography, bridged bis(β-cyclodextrin) structures are known for enhancing enantioselectivity by their cooperative interactions. Inspired by this concept, a COF-bridged bis(β-cyclodextrin) architecture was rationally constructed via a thiol-yne click strategy and immobilized onto silica microspheres to obtain a novel chiral stationary phase (2D COF-CSP-1). The resulting material demonstrated significantly incrased enantioseparation performance toward dansylated proteinogenic amino acids (DNS-AAs) under hydrophilic interaction liquid chromatography (HILIC) elution mode. A total of 16 DNS-AAs were successfully resolved, in which 12 achieved baseline separation within 30 min. Notably, high resolution values were obtained for valine (5.02), isoleucine (4.35), and leucine (3.79), indicating excellent enantiorecognition for structurally similar DNS-AAs. Comparative studies with a single-cyclodextrin-functionalized COF confirmed that the present bridged bis(β-cyclodextrin) played an important role in enhancing enantiorecognition. Density functional theory (DFT) calculations revealed that chiral recognition was dominated by cooperative multipoint interactions within the confined COF channels rather than classical inclusion complexation, and high differentiated host-guest interactions were observed with the bridged structure. In summary, this work demonstrated that engineering spatially confined and cooperative chiral microenvironments within COF frameworks represented an efficient strategy for constructing high-performance chiral stationary phases.