Construction Platform for Preparation of Chiral COF@Silica Core-Shell Stationary Phase via Ugi and Click Reactions for HPLC Enantioseparation.

Chiral covalent organic frameworks (CCOFs) have potential application in enantioseparation due to their advantages, such as large surface area, abundant chiral recognition sites, and good chemical stability in organic solvents. However, due to the lack of essential active groups in COFs structures, it is challenging to introduce chiral ligands, which poses a challenge to the preparation and promotion of CCOFs. In this study, a strategy was developed to prepare CCOF@SiO2 core-shell microspheres for enantioseparation using the Ugi and click reactions. Imine-linked COF@SiO2 core-shell microspheres were synthesized in situ by using nonporous silica microspheres as the core and TAPB-DMTP-COF as the COF shell. This shell was formed by covalently conjugating 1,3,5-tris(4-aminophenyl)benzene (TAPB) and 2,5-dimethoxyterephthalaldehyde (DMTP). The carbon-carbon double bond was introduced into the COF framework through the Ugi multicomponent reaction in the presence of 4-pentenoic acid and cyclohexene isocyanate. The olefin-linked Ugi-COF@SiO2 microspheres were then reacted with thiolated chiral ligands such as β-CD-SH, captopril, and l-cysteine to produce CCOF@SiO2 core-shell microspheres via the "thiol-ene" click reaction. These CCOF@SiO2 microspheres were used as stationary phases to separate various racemic compounds in the normal phase and reversed-phase liquid chromatography modes. The columns with different chiral ligands showed excellent chiral recognition and separation capabilities for chiral compounds with good reproducibility. The successful applications highlight the potential of using the Ugi and "thiol-ene" click reactions to incorporate double bond active groups and different chiral ligands into the imine-linked COFs framework. This study's proposed strategy is versatile and offers a broad platform for the preparation and applications of CCOFs in enantioseparation.