Exploration of the polymorphic solid-state landscape of an amide-linked organic cage using computation and automation

Organic cages can possess complex, functionalised internal cavities that make them promising candidates for synthetic enzyme mimics. Conformationally flexible but chemically robust structures are needed for adaptable guest binding and catalysis, but these rapidly exchanging systems are difficult to resolve in solution. Here, we use inexpensive calculations and high-throughput crystallisation experiments to identify accessible cage conformations for a recently reported organic cage by ‘locking’ them in the solid state. The conformers identified exhibit a range of distances between the carboxylic acid groups in the internal cavity, suggesting adaptability towards binding a wide array of target guest molecules. The complexity of the observed crystal structures goes beyond what is possible with state-of-the-art crystal structure prediction.