Supramolecular docking structure determination of alkyl-bearing molecules

Abstract

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.