Expanding the Chemical Space of Analytes in the 2G Crystalline Sponge Method: Size-Compensation Strategy for the Structural Analysis of Low-Polarity Small Molecules.

The second-generation crystalline sponge (2G-CS) is a novel type of crystalline sponge that incorporates hollow cages as molecular recognition modules within its crystalline framework. This advanced CS technology provides a versatile structural analysis technique applicable to a broad range of guest molecules, regardless of polarity, with molecular weights ranging from 300 to 1500. However, the method often fails when analyzing rather low-polarity small molecules (MW 200-300) due to an "unfavorable chemical space," where the host cavities are too large to facilitate sufficient host-guest interactions. Here we overcome this limitation by establishing a size-compensation strategy based on cage-mediated pair-selective bimolecular recognition. By co-encapsulating a target analyte with a shape-complementary "modulator" (e.g., phenanthrene), we precisely tailor the cavity environment without the need for chemical modification of the host. This adaptive approach enabled the x-ray structural determination of 24 of 30 low-polarity C15 analytes, predominantly sesquiterpenoids, including absolute configuration determination for selected chiral analytes. This work translates a decades-old molecular recognition phenomenon into a practical approach to crystallographic structure determination of low-polarity sesquiterpenoids.