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Effect of the Enantiomeric Ratio of Eutectics on the Results and Products of the Reactions Proceeding with the Participation Of

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Effect of the Enantiomeric Ratio of Eutectics on the Results and Products of the Reactions Proceeding with the Participation Of Perspective Effect of the Enantiomeric Ratio of Eutectics on the Results and Products of the Reactions Proceeding with the Participation of Enantiomers and Enantiomeric Mixtures Emese Pálovics *, Dorottya Fruzsina Bánhegyi and Elemér Fogassy Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; [email protected] (D.F.B.); [email protected] (E.F.) * Correspondence: [email protected]; Tel.: +36-1-4632101 Received: 3 August 2020; Accepted: 14 September 2020; Published: 21 September 2020 Abstract: This perspective is focused on the main parameters determining the results of crystallization of enantiomers or enantiomeric mixtures. It was shown that the ratio of supramolecular and helical associations depends on the eutectic composition of the corresponding enantiomeric mixture. The M and P ratios together with the self-disproportionation (SDE) of enantiomers define the reaction of the racemic compound with the resolving agent. Eventually, each chiral molecule reacts with at least two conformers with different degrees of M and P helicity. The combined effect of the configuration, charge distribution, constituent atoms, bonds, flexibility, and asymmetry of the molecules influencing their behavior was also summarized. Keywords: chiral molecules; enantiomeric separation; self-disproportionation of enantiomers; supramolecular associations; helical structure; eutectic composition 1. Introduction The preparation of asymmetric (chiral) compounds (enantiomers) is one of the main goals of research, industry and medicine. The preparation of a given enantiomer is possible in several ways, for example by selective synthesis, which requires the separation of the chiral catalyst or the enantiomers of the racemic compound, and in which case a resolving agent (like a chiral catalyst) may be required. In this case, we are confronted with the non-linear behavior [1] as well as the self-organization [2] of chiral compounds and their M and P helicity [3]. In our work [4,5] we proved that the result of non-linear processes of enantiomers, enantiomeric mixtures, and mixtures of diastereomers, taking into account the solvent and the crystallization time, depends on the eutectic ratio of the enantiomeric mixtures of the participating chiral compounds. By this eutectic composition, the enantiomeric ratio (eeEu) corresponding to the eutectic points of the “binary melting point phase diagrams” of the enantiomeric mixtures (Figure1) is meant. Chemistry 2020, 2, 787–795; doi:10.3390/chemistry2030051 www.mdpi.com/journal/chemistry Chemistry 2020, 2 788 Chemistry 2020, 2, x 2 Chemistry 2020, 2, x 2 Figure 1. Melting point phase diagrams of a racemate forming (A) and of aa conglomerateconglomerate formingforming Figure 1. Melting point phase diagrams of a racemate forming (A) and of a conglomerate forming enantiomeric mixture (B).). enantiomeric mixture (B). Binary melting point point phase phase diagrams diagrams were were described described by by Roseboom Roseboom [6] [6 based] based on on the the behavior behavior of ofenantiomeric enantiomericBinary melting mixtures. mixtures. point Important phase Important diagrams evidence evidence were was described was that that the the by distribution Roseboom distribution [6] of of based enantiomeric on the behavior mixtures of betweenenantiomeric two (solid,mixtures. liquid) Important phases is evidence non-linear.non‐linear. was The that racemate the distribution forming enantiomeric of enantiomeric mixtures mixtures [[7]7] are between two (solid, liquid) phases is non‐linear. The racemate forming enantiomeric mixtures [7] are estimated to be aboutabout 80%80% ofof enantiomericenantiomeric mixtures.mixtures. Besides eeeeEu,, the the melting point values of thethe singleestimated enantiomers to be about and 80% of the of racemic racemicenantiomeric compositioncomposition mixtures. areare ofBesidesof prominentprominent eeEu, the importance.importance. melting point values of the singleIn enantiomers general, these and preferred of the racemic values composition also appear are on of thethe prominent solubilitysolubility importance. ternaryternary phasephase diagramsdiagrams when crystallizingIn general, from these solutions preferred of mixtures mixturesvalues also ofof chiralappearchiral compounds.compounds. on the solubility For practical ternary phasereasons, diagrams the result when of crystallizationcrystallizing from (ee) fromsolutions a solution of mixtures of a given of concentration chiral compounds. of enantiomeric For practical mixture reasons, is plotted the result against of crystallization (ee) from a solution of a given concentration of enantiomeric mixture is plotted against the starting enantiomeric mixture compositioncomposition (ee(ee00) (Figure2 2).). the starting enantiomeric mixture composition (ee0) (Figure 2). (A) (B) (A) (B) Figure 2. The ee0‐ee separation diagrams of a racemate (A) and of a conglomerate (B) enantiomeric Figuremixture 2.2. of The a given ee0‐-eeee concentration. separation diagrams of a racemate (A) and of aa conglomerateconglomerate ((BB)) enantiomericenantiomeric mixture of a given concentration. 2. Separation of Non‐Racemic Enantiomeric Mixtures—Eutectic Composition 2. Separation of Non Non-Racemic‐Racemic Enantiomeric Mixtures—Eutectic Composition The eeee0‐-eeee diagrams also showshow thethe eeeeEu (at thethe intersectionintersection ofof thethe 4545° line).line). From thethe eeee0 The ee00‐ee diagrams also show the eeEuEu (at the intersection of the 45°◦ line). From the ee00 precipitates thethe portionportion closeclose toto thethe racemicracemic ratioratio ofof thethe enantiomericenantiomeric mixturemixture below below ee eeEu, while above precipitates the portion close to the racemic ratio of the enantiomeric mixture below eeEuEu, while above it thethe enantiomeric enantiomeric excess excess of of the the mixture. mixture. In essence, In essence, the latter the latter is also is the also case the for case conglomerate for conglomerate forming formingit the enantiomeric mixtures. Thus, excess a singleof the enantiomermixture. In canessence, only bethe obtained latter is fromalso thea mixture case for of conglomerateenantiomeric mixtures.forming mixtures. Thus, a Thus, single a enantiomer single enantiomer can only can be only obtained be obtained from a from mixture a mixture of enantiomeric of enantiomeric purity greaterpurity greater than ee than, e.g., eeEu by, e.g., crystallization. by crystallization. However, However, if the eutectic if the point eutectic of the point enantiomeric of the enantiomeric mixture is purity greater Euthan eeEu, e.g., by crystallization. However, if the eutectic point of the enantiomeric mixture is high, a lower eeEu can be achieved with its derivative formed with an achiral compound. high, a lower eeEu can be achieved with its derivative formed with an achiral compound. For example, Formixture example, is high, in thea lower case eeof Euibuprofen, can be achieved with a mixturewith its ofderivative sodium saltsformed with with the an same achiral ratio, compound. the single inFor the example, case of ibuprofen,in the case withof ibuprofen, a mixture with of sodium a mixture salts of with sodium the salts same with ratio, the the same single ratio, enantiomeric the single separationenantiomeric [8] separation can start from [8] can a lower start eefromcomposition a lower eeEu (Figurecomposition3). (Figure 3). enantiomeric separation [8] can start fromEu a lower eeEu composition (Figure 3). Chemistry 2020, 2, x 3 Chemistry 2020, 2 789 Chemistry 2020, 2, x 3 Figure 3. Phase diagram (ee0‐ee) of the enantiomeric mixture of ibuprofen and ibuprofen‐Na salt. FigureFigure 3. Phase 3. Phase diagram diagram (ee (ee0-ee)0‐ee) of of the the enantiomeric enantiomeric mixture mixture ofof ibuprofenibuprofen and and ibuprofen ibuprofen-Na‐Na salt. salt. In the first separation of enantiomers, Pasteur used the fractional crystallization of the conglomerateIn theIn firstthe separationformingfirst separation sodium of enantiomers, ofammonium enantiomers, Pasteur salt usedofPasteur tartaric the fractionalused acid the (racemic crystallizationfractional tartaric crystallization ofacid) the conglomerate[9] instead of the of formingtheconglomerate direct sodium separation ammonium forming of the sodium racemate salt of ammonium tartaric forming acid salt (racemictartaric of tartaric acid tartaric enantiomers. acid acid) (racemic [9] instead tartaric of theacid) direct [9] instead separation of of thetheKlussmann racemate direct separation forming et al. of tartaricshowed the racemate acid that enantiomers. formingin case tartaricof amino acid acidenantiomers. enantiomeric mixtures, besides the applicationKlussmannKlussmann of additives, et al. et showed al. e.g., showed crystallizing that inthat case in of fromcase amino aof solvent acidamino enantiomeric using acid dicarboxylicenantiomeric mixtures, acids, mixtures, besides a eutectic the besides application different the offrom additives,application the eutectic e.g., of additives, crystallizing composition e.g., fromcrystallizing on the a solvent binary from using melting a solvent dicarboxylic point using phase dicarboxylic acids, diagram a eutectic acids, appears a di eutecticfferent on differentthe from ee the0‐ee eutecticdiagramfrom composition the[10]. eutectic oncomposition the binary on melting the binary point melting phase diagrampoint phase appears diagram on the appears ee0-ee on diagram the ee0 [‐10ee]. diagramGiradGirad
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