A State of Independents: Rationalizing the High Z' Crystal Structures of Shikimate Esters.

Z' is a parameter used to denote the number of symmetry-independent molecules in the asymmetric unit of a crystal structure. High Z' (>1) crystal structures are relatively uncommon and are thought to arise through competition between intermolecular interactions of similar strength. As such high Z' crystal structures are challenging to predict and new examples are valuable in improving understanding in the field. Herein, we report the X-ray crystal structures of a series of shikimate esters, the asymmetric units of which exhibit high Z' values. Of special interest is the crystal structure of methyl shikimate, the asymmetric unit of which comprises 12 independent molecules; Z' = 12. This uncommonly large Z' value arises through a combination of factors, including the intrinsic homochirality of the molecule, the conformational inflexibility of the cyclohexene ring, the presence of multiple hydrogen bonding motifs, and both the cis- and trans-conformers of the ester moiety. Comparison of the X-ray crystal structures of shikimic acid, methyl shikimate, ethyl shikimate, and iso-propyl shikimate suggests that instances of high Z' in this series correlate with specific hydrogen bonding motifs influenced by the steric bulk of the ester. The results of this study provide important insights into factors that influence the formation of organic crystal structures where the value of Z' is greater than 1.

Encapsulated Nanodroplet Crystallization of Organic-Soluble Small Molecules.

Single-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.