Separability of diastereomer salt pairs of 1-phenylethylamine with enantiomeric 2-substituted phenylacetic acids by fractional crystallization, and its relation to physical and phase properties

Abstract

The separations of three pairs of the title diastereomer salts by crystallization have been investigated, as examples of the ‘classical’ resolution of enantiomers via conversion to diastereomers. All three fractional crystallizations occurred relatively slowly, and appeared to be thermodynamically controlled with the outcomes corresponding with the key features of the phase diagrams. In one case, X = CH 3, the salts–solvent ternaries exhibited eutonic behaviour, and the direction of isomeric enrichment changed markedly on passing through the eutonic composition. These salts also formed solid solutions on crystallization, but high separation factors were nevertheless recorded. In another example, X = OH, the ternaries indicated near-ideal solubility behaviour of the salt mixtures, and the separations by crystallization again corresponded. The stability and solubility ordering of the diastereomer pair X = CH 3 in the crystallization temperature range 5–50 °C were determined by the temperature-dependent entropic contribution to the free energy. Our results show that the use of simple surrogate parameters, such as the difference in the enthalpies of formation of the two salts, cannot be used as a reliable guide to their separability by crystallization. More rapid crystallizations are likely to be additionally influenced by kinetic factors, and their investigation is planned in future work.