Chiral Discrimination in the Structures and Energetics of Association of Stereoisomeric Salts of Mandelic Acid with α-Phenethylamine, Ephedrine, and Pseudoephedrine

A carefully coordinated study of the relations between structure and energetics of association in the crystalline state and solution is reported here. Hydrogen-bonded ion pairs formed from reaction between the enantiomers of mandelic acid, α-phenethylamine, ephedrine, and pseudoephedrine have been studied in dimethyl sulfoxide, dioxane, and water and as solid salts. Single-crystal X-ray analysis, performed on four unique diastereomeric pairs of (±)-ephedrinium and (±)-pseudoephedrinium (±)-mandelates yielded details of the solid-state hydrogen-bonding schemes for all eight diastereomeric salts. 1H NMR spectra (at 300 and 600 MHz) over a wide concentration range were determined and indicated a simple two-state equilibrium between ion pairs and free ions in dimethyl sulfoxide. The dissociation equilibria in dimethyl sulfoxide were examined more quantitatively by conductance and the results treated by the Fuoss-Justice, Fuoss-1977, and Onsager methods to yield calculated dissociation constants, equivalent conductances, and mean activity coefficients over a wide concentration range. Thermochemical properties determined by various techniques were (1) the heat of fusion by differential scanning calorimetry, (2) heats of solution of the crystalline salts to high dilution by isoperibolic batch calorimetry, and (3) heats of protonation and heats of dissociation from thermometric titration of solutions of mandelic acid with the bases. Extensive use was made of cross-chiral checks (e.g., R, R' vs S, S') to prove that observed chiral discrimination factors were real and accurate. Significant chiral discrimination factors were found for all properties of diastereomeric combinations. In several cases the largest differences in thermochemical properties and 1H NMR spectra of diastereomeric pairs could be related reasonably to differences in hydrogen-bonding schemes in their crystals. © 1988, American Chemical Society. All rights reserved.

Duke Scholars

Author Andrew T. McPhail Chemistry