Absolute Configuration of Small Molecules by Co‐Crystallization

Abstract

The most reliable method to determine the absolute configuration of chiral molecules is X‐ray crystallography, but small molecules can be difficult to crystallize. We report rapid co‐crystallization of tetraaryladamantanes with small molecules as different as n‐decane to nicotine to produce crystals for X‐ray analysis and the assignment of absolute configuration when the molecules are chiral. A screen of 52 diverse compounds gave inclusion in co‐crystals for 88 % of all cases and a high‐resolution structure in 77 % of cases. Furthermore, starting from three milligrams of analyte, a combination of NMR spectroscopy and X‐ray crystallography produced a full structure in less than three days using an adamantane crystallization chaperone that encapsulates the analyte at room temperature.

Determining the Relative Configuration of Propargyl Cyclopropanes by Co-Crystallization

“…Template for SYNTHESIS © Thieme Stuttgart • New York 2020-10-07 page explain why molecules structurally different from each other (and the many other guest molecules studied earlier) 5-9 can be encapsulated in EnOCs, using chaperones like TBro. As in our study on determining absolute configuration by cocrystallization, 5 the current approach does not require screening for solvents or special crystallization conditions and produced the final results in less than 48 h. We have yet to determine whether crystallization can be performed without heating, as in the SCC method reported earlier. 5 The results of entries 1-4 of Table 1 were obtained with one racemic mixture (cis or trans), as obtained after chromatographic purification.…”

“…4 Recently, we reported a one-step thermal crystallization method for determining the absolute configuration of small molecules by co-crystallization. 5 This method uses tetraaryladamantane tetra-or octaethers as chaperones.…”

“…10 Thermal cocrystallization is rapid, does not require screening for suitable solvents, and produced well diffracting co-crystals for the majority of over 50 liquid compounds tested. 5 This prompted to ask whether co-crystallization can also be used to determine relative configuration for compounds prepared in non-enantioselective synthetic processes. Racemic mixtures are usually more difficult to crystallize than pure compounds of a single stereochemical configuration.…”

“…250 g/mol. 5 This tetrabromide is also a good co-crystallization agent for lipophilic compounds that may not interact strongly enough with octaether chaperones to form crystalline inclusion complexes. 5,6 All conventional crystallization experiments for racemic cisand trans-cyclopropanes 1 and 2 had failed when we initiated our experiments, indicating that the analytes have little tendency to crystallize by themselves.…”

“…5 This tetrabromide is also a good co-crystallization agent for lipophilic compounds that may not interact strongly enough with octaether chaperones to form crystalline inclusion complexes. 5,6 All conventional crystallization experiments for racemic cisand trans-cyclopropanes 1 and 2 had failed when we initiated our experiments, indicating that the analytes have little tendency to crystallize by themselves. Co-crystallization was induced by treating 30 µL of HPLC-purified, racemic 1 with 5 mg TBro, heating to 70 °C in a glass vial placed on the surface of a heater/stirrer until a clear solution formed, and allowing crystallization to occur by switching off the hot plate.…”