Structure determination of difficult-to-crystallize organic molecules by co-crystallization of a phosphorylated macrocycle

Abstract

Single crystal X-ray diffraction (SCXRD) is the preeminent method for determining organic molecular structures with atomic precision. However, its effectiveness depends on the successful growth of single crystals of organic molecules under investigation, which sometimes is a major challenge, particularly for organic molecules that are difficult to crystallize under ambient conditions. Here, we report the macrocycle F[3]A1-[P(O)Ph]₃, which has a suitably sized and rigid cavity, as a crystallization chaperone with good crystallization properties for the structural analysis of difficult-to-crystallize organic molecules. A diverse set of thirty-seven organic guest molecules with different structures and sizes are co-crystallized with the crystallization chaperone F[3]A1-[P(O)Ph]₃. Significantly, F[3]A1-[P(O)Ph]₃ exhibits a high level of adaptability as a crystallization chaperone, demonstrating the ability to select different binding modes based on the structure of the trapped guest molecule during the co-crystallization process. Furthermore, F[3]A1-[P(O)Ph]₃ is successfully used to overcome the crystallization challenges posed by the traditionally “uncrystallizable” drug molecule dithianon, and its co-crystal structure with dithianon is successfully obtained. This work may provide an alternative macrocyclic crystallization chaperone for determining the structures of organic molecules based on co-crystallization using SCXRD technology.