Abstract
SummarySingle-crystal X-ray diffraction analysis (SCXRD) constitutes a universal approach for the elucidation of molecular structure and the study of crystalline forms. However, the discovery of viable crystallization conditions remains both experimentally challenging and resource intensive in both time and the quantity of analyte(s). We report a robot-assisted, high-throughput method for the crystallization of organic-soluble small molecules in which we employ only micrograms of analyte per experiment. This allows hundreds of crystallization conditions to be screened in parallel with minimal overall sample requirements. Crystals suitable for SCXRD are grown from nanoliter droplets of a solution of analyte in organic solvent(s), each of which is encapsulated within an inert oil to control the rate of solvent loss. This encapsulated nanodroplet crystallization methodology can also be used to search for new crystal forms, as exemplified through both our discovery of a new (13th) polymorph of the olanzapine precursor ROY and SCXRD analysis of the “uncrystallizable” agrochemical dithianon.
Highlights
Single-crystal X-ray diffraction (SCXRD) allows for the direct analysis of crystalline small molecules, providing structural information with sub-Angstrom resolution,[1] de novo absolute stereochemistry assignment,[2] and detailed information on intermolecular interactions and structural packing motifs
Preliminary Oil-Encapsulated Nanodroplet Crystallizations Nanoscale crystallizations are typically incompatible with the use of analyte solutions containing a high percentage of organic solvents because rapid solvent evaporation leads to deposition of the analyte as amorphous material
The rate of evaporative loss is proportional to the air-liquid interface surface area and is rapid in terms of percentage volume for a nanoliter-scale droplet
Summary
Single-crystal X-ray diffraction (SCXRD) allows for the direct analysis of crystalline small molecules, providing structural information with sub-Angstrom resolution,[1] de novo absolute stereochemistry assignment (via anomalous dispersion),[2] and detailed information on intermolecular interactions and structural packing motifs. We discuss our use of high-throughput crystallization techniques as a general method for the growth of single crystals of organic-soluble small molecules on the nanoscale.
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