Advances in crystallization chaperones based on a host-guest system for structural determination of difficult-to-crystallize molecules

Abstract

Determining the precise atomic structure and absolute configuration of unknown compounds is a crucial goal in chemistry. Over the past few decades, several techniques for structural determination have been developed and refined, including nuclear magnetic resonance, mass spectrometry, infrared spectroscopy, and so on. However, these methods have limitations, particularly in the identification of complex structures, especially those with multiple chiral centers. Single crystal X-ray diffraction (SCXRD) is regarded as the most reliable technique for determining the absolute configuration of a compound. The primary prerequisite for the use of SCXRD is the successful cultivation of high-quality single crystals. Unfortunately, many organic molecules present significant challenges here, as growing suitable crystals can be a time-consuming and labor-intensive process, especially for compounds that are oily at room temperature or are inherently difficult to crystallize. This review will first examine traditional crystallization methods and the challenges they present. It will then shift focus on innovative crystallization strategies that exploit supramolecular host-guest interactions to determine the structures of various guest molecules. The host molecules discussed will include metal-organic frameworks, hydrogen-bonded organic frameworks, tetraaryladamantanes, macrocycles, and other novel crystalline chaperones with effective co-crystallization capabilities. Looking forward, this review highlights the potential of integrating artificial intelligence and machine learning to improve the efficiency and accuracy of single crystal growth and structural analysis. This review can serve as a valuable reference for the development and rational design of novel co-crystals.