A Size-Matching Strategy to Differentiate Flexible Conformers for the Discovery of Novel Cages with Twin Cavities

Considerable efforts have been made to characterize the meaningful conformers that a molecule can adopt, which is of great significance for understanding the structure-property correlation in the fileds of molecular biology, drug discovery, catalysis, materials science, etc. It is however challenging to differentiate and make use of the flexible conformers in solution, as they often experience rapid interconversion due to low isomerization barrier. We herein present a novel yet simple size-matching strategy for conformation identification. As a proof of concept, we rationally designed a three-dimensional model compound, namely hexaformyl molecule 1 exhibiting two types of conformers, i.e. Conformer-1 and -2 with different cleft positions and sizes. Aided by DFT calculations, we selected two triamino conformation capturers (denoted CC). Small-sized CC-1 selectively captured Conformer-1 by matching its cleft size, while large-sized CC-2 was able to match and capture both conformers. It therefore allowed facile differentiation of the two conformations by conventional NMR and X-ray analyses. These two erstwhile inverconverting and indistinguishable conformational isomers were made use of, leading to the discovery of two novel configurational isomers, namely two novel cage-like compounds with twin cavities, one exhibiting a sandglass-shaped and another with a dumbbell form, which we coined diphane.