Chiral discrimination of dicarboxylic acids with Cinchona alkaloids

Abstract

This thesis is aimed at the investigation of the chiral discrimination process during diastereomeric salt formation, when selected cinchona alkaloids are exposed to racemic mixtures of tartaric acid derivatives. This research is based on the use of (+)‐cinchonine, (‐)‐cinchonidine, (‐)‐quinidine and (+)‐ quinine, which served as chiral bases, in order to resolve racemates of O,O'‐dibenzoyl‐tartaric acid (DBTA) and O,O'‐di‐p‐toluoyl‐tartaric acid (DTTA). Cinchona alkaloids were selected because of their abilities to form salts with the targeted acids. DBTA and DTTA are commonly used resolving agents to separate racemic bases via diastereomeric salt formation, and they are also commercially available and affordable chiral acids. Results were obtained from all combination but only the experiments with cinchonidine were included in this thesis, namely [CIND+][L‐DBTA‐], 2[CIND+][D‐DBTA2‐], [CIND+][LDTTA‐] and 2[CIND+][D‐DTTA2‐]∙2DMSO∙0.7H2O. Experimental analytical techniques, such as thermal analysis, powder X‐ray diffraction, and single crystal X‐ray diffraction were used to analyze the harvested diastereomeric salts. A correlation of molecular parameters derived from the structures and an investigation of the mechanism, which drives the resolution process were discussed. The thesis also summarizes the findings on 8 inclusion compounds of (‒)‐O,O'‐dibenzoyl‐(2R,3R)‐tartaric acid (L‐DBTA) and (‒)‐O,O'‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid (L‐DTTA) or their racemic mixtures, (rac)‐ DBTA and (rac)‐DTTA, with DMSO and water: (rac)‐DBTA∙H2O, (rac)‐DBTA∙DMSO, L‐DBTA∙H2O, LDBTA∙ DMSO, (rac)‐DTTA∙H2O, (rac)‐DTTA∙DMSO, L‐DTTA∙H2O, and L‐DTTA∙DMSO. The discussed inclusion compounds were obtained serendipitously, as a product of the pre‐screening of suitable solvents to dissolve both the acids and the cinchona alkaloids during the discrimination experiments. Only few crystal structures of solvates of these two tartaric acid derivatives are known up to now, and fewer of these structures do exist when both the racemic and the enantiopure acid encapsulates the same solvent. The synthesis and structural analysis of these inclusion compounds contribute to the pool of available crystal structures when comparing chiral vs. achiral crystal forms of the same compounds.