Nina Tulashie Honors Portfolio

Nina Tulashie\u27s honors portfolio captured in May 2022

The Potential of Chiral Solvents in Enantioselective Crystallization

The objective of this thesis is to evaluate the potential of applying chiral solvents for crystallization-based resolution of racemates. In general, it can be expected that a chiral solvent can discriminate two enantiomers by creating some weak interactions between the solvent and the substrate molecules forming diastereomeric complexes with different physical properties. This may lead to either asymmetry in the solubility phase diagrams or selective kinetic effects which can be employed for resolution purposes. To evaluate the prospect of using chiral solvents for crystallization based enantioseparation and to evaluate the potential of this approach, systematic experimental work is required. The chosen model systems studied experimentally in this work are two pharmaceutically interesting substances (mandelic acid and N-methylephedrine) which belong to the compound and conglomerate forming systems, respectively. Three different types of chiral solvents were studied: a “classical” chiral solvents, a chiral ionic liquids and a tailor-made chiral solvents

Potential of chiral solvents for chiral discrimination in crystallization processes

Usually, it is expected that a chiral solvent can discriminate two enantiomers by creating some weak interactions between the solvent and the substrate molecules forming diastereomers which have different physical properties. This may lead to asymmetry in the solubility phase diagrams and can be employed for resolution purposes [1]. Based on these expectations much work has been done in the past in this field with limited outcome. However, recently Gausepohl et al. reported a first example of an enantioselective asymmetric synthesis using a chiral ionic liquid as a reaction medium [2]. In this work, we will report results obtained by studying the potential of chiral solvents in enantioselective crystallization on the example of two chiral systems. The selected systems are the compound forming system mandelic acid and the conglomerate forming system N-methylephedrine. In the case of mandelic acid, we performed a comprehensive resolution study based on the preliminary metastable zone width results for primary nucleation, which show that the (R)-mandelic acid is inhibited with the (S)-ethyl lactate as chiral solvent in the measured range. For N-methylephedrine the effect of the chiral solvent on the ternary solubility phase diagram, on the metastable zone width and on a possible resolution with chiral solvents will be outlined. Further, first results concerning the application of a chiral ionic liquid as an example of a non-classical chiral solvent will be shown for selective crystallization of enantiomers. [1] J. Jacques, A. Collet, S. H. Wilen, Enantiomers, Racemates, and Resolutions, Krieger Publishing, Florida, 1994. [2] R. Gausepohl, P. Buskens, J. Kleinen, A. Bruckmann, C. W. Lehmann, J. Klankermayer, W. Leitner, Highly Enantioselective Aza-Baylis-Hillman Reaction in a Chiral Reaction Medium, Angew. Chem. Int. Ed., 2006, 45, 3689-3692

Potential of Chiral Solvents for Enantioselective Crystallization. 2. Evaluation of Kinetic Effects

In part 1 of this work, the potential of chiral solvents in enantioseparation was studied for two pharmaceutical substances with regard to thermodynamics (Cryst. Growth Des. 2008, 8, 3408−3414). Unfortunately, no measurable chiral recognition in terms of the solubility equilibria was observed between the chiral solvents and the chiral systems investigated. In this part 2, studies are directed toward the potential of chiral solvents in enantioseparation based on differences in crystallization kinetics. For the case study performed, mandelic acid as a racemic compound forming system has been chosen. The crystallization kinetics (metastable zone width data with regard to primary nucleation) determined for mandelic acid in the chiral solvents (S)-ethyl lactate and (2R,3R)-diethyl tartrate are shown and discussed. On that basis successful preferential nucleation/crystallization experiments allowed for racemate resolution. To explain the observed results solvation enthalpy data obtained from dissolution enthalpy measurements are considered. Copyright © 2009 American Chemical Society [accessed March 17, 2009

Solid−Liquid Equilibria of N-Methylephedrine Enantiomers and Their Mixtures in Three Chiral Solvents Distinguished by Chain Length

Solubility equilibria of the chiral N-methylephedrine species in three chiral solvents, (S)-methyl lactate, (S)-propyl lactate, and (S)-butyl lactate, have systematically been studied. Solubility measurements were performed for enantiomeric compositions ranging from 1:1 mixtures to the pure enantiomer and at temperatures between (273 and 298) K. The influence of increasing chain length of the chiral solvents on solubility has been evaluated. copyright American Chemical Society [accessed November 19th, 2010

Solubility of Mandelic Acid Enantiomers and Their Mixtures in Three Chiral Solvents

A systematic study of the ternary solubility phase diagrams of chiral mandelic acid species in the chiral solvents (S)-methyl lactate, (S)-propyl lactate, and (S)-butyl lactate has been carried out. Solubility measurements were performed for different enantiomeric compositions in a temperature range between (273 and 318) K. Experimental results indicated no proof of solubility differences of the enantiomers in all three chiral solvents used. Hence, increasing chain length of the chiral solvents has no influence on chiral recognition. Besides, the eutectic composition in the chiral system in the presence of the solvent as a significant parameter for enantioseparation was determined for all the chiral solvents investigated. Also, the activity coefficients were derived for all three chiral solvents applied. copyright 2010 American Chemical Society [accessed November 18th, 2010

Theoretical and Experimental Study on Residue Curve Maps of Propyl Acetate Synthesis Reaction

Residue curve maps of propyl acetate synthesis reaction in the batch reactive distillation process are studied. In order to adapt the model equations of residue curve maps to a practicable heating policy, the theoretical analysis and experimental measurements in this paper are carried out isothermally instead of the autonomous heat policy first introduced by Venimadhavan et al. (1994). The chemical equilibrium constant of this reaction is determined by experiments to be 20 within the temperature range 80 °C ~ 110 °C. Using this equilibrium constant, the RCMs predicted by simulation are in good agreement with the experimental measurements. The results show that there is an unstable node branch emerging from the propyl acetate-water edge, moving toward the chemical equilibrium surface with the increasing Damköhler number (Da), and eventually reaches the quaternary reactive azeotrope when Da approaches infinity. Residue curves are measured with initial compositions around the unstable node, and thus the results verify the existence of this reactive azeotrope. Further bifurcation analysis shows that different heat policies will influence the singular points and topology of kinetically controlled RCMs, but not the cases when Da = 0 or Da approaches infinity. © 2005 Elsevier B.V. All rights reserved. [accessed 2013 November 27th