The encapsulation of medium-sized molecules in synthetic hosts remains a major challenge, hindered by both the lack of suitable hosts that combine a large size with high molecular recognition capability and kinetic and thermodynamic barriers to encapsulating bulky molecules in solution. Here, we demonstrate that solid-state mechanochemical grinding of a large M9L6 coordination cage with various medium-sized guests efficiently overcomes these barriers. This simple, solvent-free approach enables the high-yielding formation of inclusion complexes that are inaccessible or form exceedingly slowly under conventional solution conditions. The resulting complexes, featuring synthetic macrocycles and pharmaceuticals, are kinetically persistent in solution for hours to days, allowing for not only their full characterization, including by X-ray crystallography, but also for their subsequent chemical manipulation. The versatility of this method was confirmed with a smaller cage system. This study establishes solid-state grinding as a powerful strategy for accessing metastable host-guest systems, opening new avenues for the structural analysis of challenging molecules and the design of complex, functional supramolecular architectures.
Iizuka et al. (Fri,) studied this question.