How far can an unstable racemic compound affect the performances of preferential crystallization? Example with (R) and (S)-α-methylbenzylamine chloroacetate†

Abstract

It is shown that the yield of preferential crystallization can be dramatically lowered by the presence of an unstable racemic compound. Indeed, the title racemic mixture crystallizes as a stable conglomerate whatever the temperature but the yield of the preferential crystallization is far from what could be expected on the basis of the thermodynamics limits only. Various experiments show that the secondary nucleation is no obstacle to a high yield. Thus, the difficulties result rather from homochiral crystal growth in a quasi racemic solution.

At several (hkl) crystal–solution interfaces, the magnitude of {E _P/N^hkl } ratios (energy of homochiral interactions/energy of heterochiral interactions) is supposed to depart only slightly from 1. For this subset of (hkl) orientations with low E _P/N^hkl , racemic compound-like interactions at the solid–solution interfaces are suspected to slow down the rate of crystal growth to the extent that, as soon as the counter enantiomer is predominant in the mother liquor, they could bring the entrainment effect to an end. A close-to-1 {E_P/N^hkl } subset is revealed by the possibility of isolating this unstable racemic compound, whose determined structure is compared with that of the enantiomer. In addition to diffusion parameters which favour the racemic compound, the syndiotactic arrangement of the molecules along the strongest periodic bond chain is found to give a kinetic advantage to the unstable racemic compound over the conglomerate in crystal growth rate. In the time consuming screening for derivatives which form a conglomerate, various routine tests, based on the predominance of kinetic effects, are recommended to detect such unstable racemic compounds so that early indications can be gained in the development of a racemic mixture’s resolution process by preferential crystallization.