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.