Second-Generation Crystalline Sponges with High Isomorphism

Crystallization is typically highly sensitive to even minor structural differences in target molecules. As a result, obtaining crystals of complex compounds often requires extensive trial-and-error experiments for each target molecule. We recently reported a second-generation crystalline sponge (2G-CS), in which a coordination cage is fixed within a crystal lattice. In the 2G-CS, target molecules are first encapsulated within the cage in solution, followed by salt formation with a symmetry-mismatched polyanion, leading to the formation of single crystals suitable for structure analysis. A key feature of this improved method is its high isomorphism, which allows diverse guest molecules to be crystallized under uniform conditions into the same crystal system, clearly distinguishing it from conventional co-crystallization techniques. In our initial report on 2G-CS, however, the isomorphism rate was limited to approximately only 25%. Through careful screening of the polyanion used for salt formation, we successfully increased this rate to around 80%. As a result, this study highlights the development of a truly practical and versatile molecular structure analysis that eliminates the need for trial-and-error crystallization. This claim is supported by approximately 40 case studies, including the analyses of polar, medium-sized, and various complex molecules, most of which are of pharmaceutical interest.