Supramolecular docking structure determination of alkyl-bearing molecules

Numerous natural products and drugs contain flexible alkyl chains. The resulting conformational motion can create challenges in obtaining single crystals and thus determining their molecular structures by single-crystal X-ray diffraction (SCXRD)1–11. Here we demonstrate that by using pillar[5]arene-incorporated metal–organic frameworks (MOFs) and taking advantage of pillar[5]arene−alkyl chain host−guest recognition12–15, it is possible to reduce this motion and bring order to alkyl-chain-containing molecules as the result of docking within accessible pillar[5]arene units present in an overall MOF. This has allowed the single-crystal structures of 48 alkyl-chain-containing molecules, including 6 natural products, 2 approved drugs and 18 custom-made compounds collected from 16 research groups, to be determined using standard SCXRD instrumentation. The structures of alkyl-chain-containing molecules derived from crude reaction products can also be determined directly by SCXRD analyses without further purification. The simplicity, high efficiency and apparent generality of the present pillar[5]arene-incorporated MOF-based supramolecular docking approach suggest that it could emerge as a new tool for the analyses of natural products and drugs that might not be amenable to traditional SCXRD-based structure determination. A metal–organic framework (MOF)–pillar[5]arene hybrid can bind small molecules with long alkyl chains, such that single-crystal structures of the host–guest complexes can be obtained and therefore small molecular structures determined.