Versatile Dual-Chiral Covalent Organic Framework Microspheres Synthesized at Room Temperature for Chromatographic Separation and Raman Detection of Chiral Polar Compounds

Abstract Chiral separation and detection remain challenging areas in analytical science. Herein, we report a mild and rapid preparation of versatile dual-chiral covalent organic framework (D-CCOF) microspheres that can be directly employed as both a chiral stationary phase and a Raman substrate for the chiral separation and detection of polar chiral compounds. Based on the rapid synthesis of three-component COF microspheres at room temperature, uniform D-CCOF microspheres were prepared through two-step mild post-modification, including an ultraviolet-assisted thiol−ene click reaction for precise chiral site modification. The integration of two chiral functional groups (thiolated β-cyclodextrin and glutathione) into the skeleton of COF with low energy consumption provided abundant chiral sites. When employed as a chiral stationary phase in HPLC, D-CCOF demonstrated enantioseparation performance for hydroxyl-containing drug intermediates that was superior to that of single-chiral COFs and comparable to that of commercial chiral columns. D-CCOF was also used as a Raman chiral substrate for the detection of six carboxyl-containing chiral metabolites by monitoring the intensity ratio variations of two characteristic Raman bands at ∼1133 and ∼1146 cm−1. Furthermore, it demonstrated the potential for chiral qualitative analysis in complex matrices. Molecular simulations revealed that the interactions between the two chiral groups on the dual-chiral COF and the enantiomers are dominated by hydrogen bonds and van der Waals interactions and that the synergistic effect of the dual chiral groups contributes to chiral recognition. This work offers a green and facile route to the rapid synthesis of dual-chiral COF microspheres and illustrates the potential of this dual-chirality design for both chromatographic enantioseparation and Raman-based chiral detection.