Crystalline Mate Assists Structural Elucidation and Offline LC‐SCXRD Analysis of Flavonoid Glycosides via Synergistic π–π Stacking and C–H···O Interactions

Single-crystal X-ray diffraction (SCXRD) is a key technique for the structural determination of organic molecules. However, natural flavonoid glycosides are difficult to crystallize due to their large volume, flexible glycosidic bonds, and limited solubility. Herein, a novel methylthio-modified palladium(II)-based metal-organic macrocycle (PdS-MOM) was designed and synthesized as a crystalline mate that exhibits an excellent structural match for flavonoid glycosides. PdS-MOM can efficiently accommodate flavonoid glycosides with different sugar chains and substituents in its open cavity and stably anchor their aglycone and sugar moieties through a synergistic strategy of π-π stacking and C-H···O interactions, respectively. Such stabilization not only promotes co-crystallization and enables high-precision structural elucidation by subsequent SCXRD analysis, but also provides conclusive evidence of the important roles of weak interactions in supramolecular assembly. Furthermore, besides the successful application to the structural analysis of thirteen different complex flavonoid glycosides, including monoglycosides, diglycosides, and triglycosides via three binding modes, PdS-MOM facilitates direct structural elucidation of isoflavone glycosides from crude plant extracts by offline LC-SCXRD. These synergistic noncovalent interactions demonstrate that PdS-MOM exhibits broad substrate compatibility and excellent potential for structural elucidation of complex flavonoid glycosides.