Mechanism of enantiomeric resolution

Abstract

Selected racemic mixtures were resolved using the four Cinchona alkaloids; cinchonine (CINC), cinchonidine (CIND), quinine (QUIN) and quinidine (QUID) in a series of solvents. The resultant crystalline products were analyzed with the ultimate objective of establishing the mechanism of enantiomeric resolution. The effect of the choice of solvent on the chiral resolution outcome was also investigated. Several racemates were used in the study but only the following five gave rise to suitable crystalline material; citronellic acid (3.1), malic acid (3.2), trans-9,10-dihydro-9,10ethanoanthracene-11,12-dicarboxylic acid (3.3), 9,10-dihydro-9,10-ethanoanthracene-11carboxylic acid (3.4) and 2-chloropropanoic acid (3.5). Crystals were obtained from the slow evaporation of mixtures of the racemate and the resolving agent in a 1:1 ratio. The desolvation temperatures and melting points of the crystalline materials were determined using differential scanning calorimetry (DSC). The mass loss percentages of the incorporated solvents were obtained from thermogravimetry (TGA). Single crystal X-ray diffraction was used to determine the crystal structures. The crystal packing and hydrogen bond data of the resultant salts were analyzed. In selected cases, FT-IR spectroscopy was used to confirm salt formation by determining the carboxylate frequencies. The CrystalExplorer program was employed to determine the intermolecular interactions involved in stabilising the molecular packing. The Cahn-Ingold-Prelog system was used to establish the configurations of the isolated enantiomers, based on the known configurations of the resolving agents. Suitable crystals resulted from slow evaporation of solutions from the following solvents; acetone, acetonitrile mixed with water, methanol, pentanol, toluene, and water. Fourteen diastereomeric salts and their crystal structures were obtained in the study. These include eleven crystal structures where one enantiomer was preferred; P1 (S-3.1-)(CIND+)•H2O, P2 (D-3.2)(CINC+)•2H2O, P3 (L-3.2-)(CIND+)•2H2O, P4 (R,R-3.3-)(CINC+)•ACE, P5 (R,R-3.3)(CIND+), P6 (S,S-3.3-)(QUID+)•2MeOH, P7 (R,R-3.3-)(QUIN+)•2MeOH, P8 (S,S-3.3)(CINC+)•H2O, P9 (R-3.4-)(QUIN+)•MeOH, P10 (R-3.4-)(QUID+) and P11 (S-3.5)(QUIN+)•H2O. Mixtures of enantiomers were also found in three crystal structures involving 3.5, P12 (0.4S-3.5-)(QUID+)•H2O, P13 (0.8S-3.5-)(CINC+)•H2O and P14 (0.6S-3.5)(CIND+)•H2O. Attempts to obtain more material of P5 and P10 resulted in powders, P5a and P10a. All of the salts were obtained in a 1:1 ratio with transfer of protons from the carboxylic acids to the bases and some of the salts were solvated. The crystal structures were dominated by N―H∙∙∙O, O―H∙∙∙O and O―H∙∙∙N hydrogen bonds and weak hydrogen bonds in the form of C―H∙∙∙O interactions. The close contacts were established by the CrystalExplorer program as O∙∙∙H, H∙∙∙H, C∙∙∙H, N∙∙∙H and Cl∙∙∙H (in the case of 3.5).