In Prof. Feihe Huang’s research group at Zhejiang University, we focus on discovering supramolecular chemistry for functionalization and applications. We initiated this project on the interdisciplinary research between supramolecular chemistry and crystalline framework materials three years ago. In this project, we raise the concept of “supramolecular docking” and use this strategy to solve the problem of structure determination of alkyl-bearing molecules. To our knowledge, this is the first time a general solution to the problem of solving the X-ray structures of “greasy” molecules is being reported.

Motivation and Key Challenges: Structure determination stands as a cornerstone of chemical research. Arguably, single crystal X-ray diffraction (SCXRD) analysis provides the most accessible and accurate method for structure determination. As the name implies, SCXRD requires crystalline samples. In many instances, this is not problematic. Unfortunately, the applicability of SCXRD is limited in the case of non-crystalline samples, including those that exist as liquids or which tend to form oils or produce polycrystalline phases during single crystal growth. This limitation can be overcome by imposing order on non-crystalline molecular species. In seminal work, Fujita and coworkers reported the so-called crystalline sponge (CS) method for the X-ray diffraction (XRD) structure determination of small molecules with a poor propensity to form single crystals. This strategy relies on the accommodation of an analyte within the pores of metal-linked crystalline interstitial voids via multiple weak interactions and has proved to be a powerful tool for determining the crystal structures of numerous non-crystalline compounds. In 2016, the Yaghi group reported a metal−organic framework (MOF)-based alignment strategy that allowed XRD structural analyses of molecules with ligating groups, such as carboxylates. Powerful as they are, the current CS- and MOF-based structure determination approaches are subject to limitations that affect their applicability. For instance, they have not proved routinely effective for solving the structures of molecules bearing long alkyl chains. Molecules with these motifs are often found in natural products and drugs. They are generally difficult to crystallize and can produce disordered structures even when included into CSs or MOFs. One approach that might overcome this limitation is to order long alkyl chain-containing molecules in solid frameworks via specific host−guest interactions. To our knowledge receptor-bearing materials suitable for this purpose have yet to be reported. Pillar[5]arenes are a well-studied class of supramolecular receptors, which are notable for their ability to form complexes with alkyl chain-containing guests. We thus considered that their integration into MOFs would provide rigid materials endowed with docking sites that, in turn, might allow for the structure ordering and hence SCXRD analysis of target molecules containing long alkyl chains. This study was undertaken as a test of this hypothesis.

Key Findings: In this work, we show that pillar[5]arene-incorporated MOFs can be used to capture alkyl chain-containing molecules in a way that permits their structural analysis via SCXRD. Accordingly, EtP5-MOF-2 was found to act as a particularly effective “supramolecular dock” for this target due to its crystallinity, structural robustness, and strong affinity for long alkyl chain-containing guests. The power of this “supramolecular docking” method is illustrated through the SCXRD-based structure determination of 48 alkyl chain-containing molecules, including a FDA-approved drug, Dojolvi. Moreover, in contrast to the complicated and time-consuming solvent exchange procedures in previous CS- and MOF-based methods, our “supramolecular docking” approach facilitate the rapid incorporation of guest molecules in frameworks within 10 minutes through the fast host-guest molecular recognition process. Leveraging these merits, the crystal structure of an unstable alkene sulfide compound is successfully determined. Notably, in order to confirm the efficacy of our method in determining the structures of unknown compounds, blind experiments are also performed. 14 compounds can be unambiguously determined by our supramolecular docking strategy via SCXRD analysis with the assistance of nuclear magnetic resonance (NMR) spectral and mass spectrometric data without prior knowledge of their structural details. Besides, in certain instances, the SCXRD-based structures of products taken directly from crude reaction mixtures could be obtained. Thus, in both conception and scope, the present approach merges the merits of rational design, efficient sample preparation, broad applicability and successful structural determination for challenging molecules.

The merits of our supramolecular docking method are regard to:

• Broad Applicability: We have tested a total of 63 compounds, including 18 home-made samples and 14 successful blinded samples.
• Successful Structural Determination for Challenging Molecules: We have obtained crystal structures for a range of challenging molecules, encompassing an unstable compound and the highest molecular weight compound measured to date in MOF-based structure determination studies.
• Efficient Sample Preparation: Our method allows for simple and rapid sample preparation within 10 minutes, in contrast to the CS and MOF methods, which typically require over a day.
• Rational Design Emphasis: Our “supramolecular docking” method brings overall order to alkyl chain-containing molecules, which provides conceptual guiding principle for MOF-based structural analysis using a rationally designed and directed “supramolecular strategy”.

Impact: In summary, we report a supramolecular docking strategy designed to address the challenges associated with the structure determination of alkyl chain-containing molecules. Based on the results obtained, we suggest that the present approach may have a role to play in the structural analysis of a wide range of products obtained under typical laboratory conditions (liquid, sticky, solid, or unstable samples and mixtures). Notably, the rational design of a MOF-carrier is always a challenging task in framework-based structure determination. Our “supramolecular docking” method provides a conceptual guiding principle for framework-based structural analysis using a designable and directed “supramolecular host−guest recognition strategy”, significantly advancing the field of structure determination. The current approach still faces potential limitations, particularly in the structure determination of high molecular weight and structurally complex molecules. Future research will focus on incorporating various supramolecular docking hosts into MOFs to facilitate the structure determination of a diverse range of compounds.