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The Stoichiometry, Structure and Possible Formation of Crystalline Diastereomeric Salts

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The Stoichiometry, Structure and Possible Formation of Crystalline Diastereomeric Salts S S symmetry Article The Stoichiometry, Structure and Possible Formation of Crystalline Diastereomeric Salts Dorottya Fruzsina Bánhegyi and Emese Pálovics * Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; [email protected] * Correspondence: [email protected] Abstract: Knowing the eutectic composition of the binary melting point phase diagrams of the diastereomeric salts formed during the given resolution, the achievable F (F = eeDia*Y) value can be calculated. The same value can also be calculated and predicted by knowing the eutectic compositions of the binary melting point phase diagrams of enantiomeric mixtures of the racemic compound or the resolving agent. An explanation was sought as to why and how the crystalline precipitated diastereomeric salt—formed in the solution between a racemic compound and the corresponding resolving agent—may be formed. According to our idea, the self-disproportionation of enantiomers (SDE) has a decisive role when the enantiomers form two nonequal ratios of conformers in solution. The self-organized enantiomers form supramolecular associations having M and P helicity, and double helices are formed. Between these double spirals, with the formation of new double spirals, a dynamic equilibrium is achieved and the salt crystallizes. During this process between acids and bases, chelate structures may also be formed. Acids appear to have a crucial impact on these structures. It is assumed that the behavior of each chiral molecule is determined by its own code. This code validates the combined effect of constituent atoms, bonds, spatial structure, charge distribution, flexibility and complementarity. Citation: Bánhegyi, D.F.; Pálovics, E. The Stoichiometry, Structure and Keywords: predictable resolution; supramolecular associations; helical structure; eutectic Possible Formation of Crystalline composition Diastereomeric Salts. Symmetry 2021, 13, 667. https://doi.org/10.3390/ sym13040667 Academic Editor: Takashiro Akitsu 1. Introduction When a racemic mixture (SR) reacts in a solution with a suitable chiral compound (R*), Received: 25 March 2021 depending on the solvent, one of the diastereomers precipitates (e.g., crystalline SR*) and Accepted: 9 April 2021 the other remains in solution (RR* solution). The multiplication of the purity (eeDia) and Published: 13 April 2021 yield (Y) of the enantiomeric mixture, which is isolated from the precipitated diastereomer, gives the selectivity (F = eeDia*Y). F corresponds to the enantiomeric ratio of the mixture Publisher’s Note: MDPI stays neutral (in addition to the racemic ratio). with regard to jurisdictional claims in When the binary melting point phase diagram of the racemic mixture is constructed, published maps and institutional affil- a relationship between the eutectic composition (eeEu) and the results can be observed iations. (Figure1)[1]. We have also shown experimentally [1] that under certain conditions the purity of the enantiomeric mixtures separable from the precipitated diastereomeric salt is approximately equal to the eutectic composition of the enantiomeric mixtures of the racemic compound or Copyright: © 2021 by the authors. the eutectic composition of the enantiomeric mixtures of the resolving agent (eeDia~eeEuRac Licensee MDPI, Basel, Switzerland. or eeDia~eeEuRes). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Symmetry 2021, 13, 667. https://doi.org/10.3390/sym13040667 https://www.mdpi.com/journal/symmetry Symmetry 2021, 13, x FOR PEER REVIEW 2 of 13 Symmetry 2021, 13, 667 2 of 12 = ∙∙10 1−2 = ∙= 1− . ≈ FigureFigure 1.1.Binary Binary melting melting point point phase phase diagram diagram of diastereomeric of diastereomeric mixtures and mixtures stoichiometry and of stoichiometry of diastereomers (eeeuRac: ee of an enantiomer at the eutectic composition of the racemic compound; diastereomers (eeeuRac: ee of an enantiomer at the eutectic composition of the racemic compound; eeeuRes: ee of the resolving agent enantiomer (R) at the eutectic composition; eeDia: ee of the enan- eeeuRes: ee of the resolving agent enantiomer (R) at the eutectic composition; eeDia: ee of the enantio- tiomer of the original racemic compound at the eutectic composition of the diastereoisomeric salt). mer of the original racemic compound at the eutectic composition of the diastereoisomeric salt). The enantiomers—whose separation possibilities are summarized in this article—have been usedWe have for the also synthesis shown of active experimentally pharmaceutical ingredients[1] that under (Jumex, certain prostaglandins, conditions the purity of aspartame, Chlorocid, antibiotics). During the resolution of these compounds, further theinsights enantiomeric have been added mixtures to our previous separable knowledge. from the precipitated diastereomeric salt is approxi- mately equal to the eutectic composition of the enantiomeric mixtures of the racemic com- 2. The Stoichiometry of the Crystalline Diastereomeric Salt May Be Determined by poundthe Eutectic or Compositionthe eutectic of composition Either the Racemic of the Compound enantiomeric or the Resolving mixtures Agent of the resolving agent (eeDiaBased~eeEuRac on our or owneeDia [2~ee–4] andEuRes others’). experimental results regarding the self- dispropor- tionationThe of enantiomers—whose enantiomers (SDE) [5–16], weseparation were looking possibili for an explanationties are ofsummarized the possible in this article— havemechanism been forused the for distribution the synthesis of the enantiomericof active pharmaceutical diastereomeric mixtures ingredients between (Jumex, prostaglan- solid–liquid phases. dins,However, aspartame, there wasChlorocid, no explanation antibiotics). of how it Duri is possibleng the to formresolution the eutectic of these com- compounds, fur- therposition insights of the singlehave enantiomerbeen added resolving to our agent previous from the knowledge. enantiomers of the racemic compound present. We believe that this is only possible if at least two reactive conform- ers of the single enantiomer resolving agent react with the enantiomers of the racemic 2.compound. The Stoichiometry of the Crystalline Diastereomeric Salt May Be Determined by the EutecticIt was demonstrated Composition that two of typesEither of the conformers Racemic are involvedCompound in the or crystalline the Resolving Agent structureBased of the on enantiomers, our own roughly [2–4] mimickingand others’ the stabilityexperi ofmental the corresponding results regarding racemic the self-dispro- structure [17]. Racemic tofizopam tends to form an 82:18 (major/minor) conformer ra- portionationtio immediately of in enantiomers chloroform solution. (SDE) The [5–16], single we enantiomer were looking is also capable for an of explanation this of the pos- siblephenomenon, mechanism but it takes for the 48 h distribution if its enantiomeric of the pair en is notantiomeric present [18 ].diastereomeric mixtures between solid–liquidIt was also phases. shown that in the crystal structure of the diastereomeric salt, the resolving agent (sodium salt of cis-2-hydroxycyclopent-4-enyl acetic acid (CPN) intermediate of the prostaglandinHowever, F2α synthesis)there was participates no explanation with two conformers of how it in is a possible ratio of 59:41 to and form thus the eutectic compo- sitionachieves of high the purity single of theenantiomer corresponding resolving enantiomer agent from from the racemic the enantiomers compound in the of the racemic com- pounddiastereomer present. (Figure We2)[ 19believe]. that this is only possible if at least two reactive conformers of the single enantiomer resolving agent react with the enantiomers of the racemic com- pound. It was demonstrated that two types of conformers are involved in the crystalline structure of the enantiomers, roughly mimicking the stability of the corresponding race- mic structure [17]. Racemic tofizopam tends to form an 82:18 (major/minor) conformer ratio immediately in chloroform solution. The single enantiomer is also capable of this phenomenon, but it takes 48 h if its enantiomeric pair is not present. [18]. It was also shown that in the crystal structure of the diastereomeric salt, the resolving agent (sodium salt of cis-2-hydroxycyclopent-4-enyl acetic acid (CPN) intermediate of the prostaglandin F2α synthesis) participates with two conformers in a ratio of 59:41 and thus achieves high purity of the corresponding enantiomer from the racemic compound in the diastereomer (Figure 2) [19]. Symmetry 2021, 13, x FOR PEER REVIEW 3 of 13 Symmetry 2021, 13, 667 3 of 12 Figure 2. Separation of 1-phenylethan-1-amine hydrochloride (PhEA) enantiomers by the sodium salt of (1S,5R)-CPN Figure 2. Separationand perspective of 1-phenyletha view of the asymmetricn-1-amine unit hydrochloride in the (R)-PhEA. (PhEA)(1S-5R)- enantiomersCPN salt aggregate. by the Thick sodium lines indicatesalt of ( major1S,5R)-CPN and perspective (conformerview of the A with asymmetric 59% population) unit whilein the thin (R lines)-PhEA. the minor(1S-5R (conformer)-CPN salt B with aggregate. 41% population) Thick orientationlines indicate in the major (con- former A withhydroxycyclopentenyl 59% population) part while of the anion. thin lines the minor (conformer B with 41% population) orientation in the hy- droxycyclopentenyl part of the anion.
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