A Presumable Mechanism of the Separation

aphy & S r ep og a t r a a t m i o o r n Palovics and Fogassy, J Chromatogr Sep Tech 2017, 8:6

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o DOI: 10.4172/2157-7064.1000391

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Mini Review OpenOpen Access Access A Presumable Mechanism of the Separation of Diastereomeric and Enantiomeric Mixtures Palovics E* and Fogassy E Department of Organic Chemistry and Technology, Budapest University of Thechnology and Economics, Budapest H-1521, P.O.B. 91 Budapest, Hungary

Abstract Homo and heterochiral supramolecular associates with helical structure are formed in the solutions of mixtures of chiral compounds due to their self-disproportionation (SDE). These form homo and heterochiral double helices having eutectic composition. Pure enantiomers are obtained by the distribution of these associates between two immiscible phases.

Keywords: Resolution; Supramolecular associates; Helical structure; composition is the same in each phase. During the crystallization a Eutectic composition; Double helix purer mixture is obtained compared to the starting composition in case of enantiomeric mixtures having conglomerate-like behaviour. Introduction The composition of the crystalline phase depends on the eutectic The chiral compounds, the pure enantiomers are ubiquitous in our composition in the case of enantiomeric mixtures having racemic- everyday life, e.g., fragrances, in vitamins or in medicines. A main part like behaviour, namely, if the starting composition is higher than the of the medicines contains just one of the mirror image pairs, one of the eutectic composition, a purer mixture can be obtained in the crystalline enantiomers, because the biological activity of the two antipodes may phase, while starting out from a lower composition than the eutectic be different or even opposite. So they have different or even opposite composition, the crystallized part will have a near racemic composition. effect on the living organisms, built up by asymmetric molecules, by How do the interactions work? If in the solution of an enantiomeric enantiomers. So, the enantiomeric separations are necessary and mixture homo chiral supramolecular associations are formed by self- inevitable and the demand for pure enantiomers becomes higher and organization and self-disproportionation (SDE), in the crystalline phase higher [1]. we can find the pure (purer) enantiomer. If we change the temperature Even though several new methods and selective synthesis are known in the pharmaceutical practice, the most commonly and economic method remains the resolution, in other words the separation of racemic compounds (1:1 mixture of the two enantiomers), obtained in the chemical synthesis into pure enantiomers using another chiral R* R R* R* R compound, the so called resolving agent. In this case the separation of R* solvent S enantiomeric mixtures are based on the exploitation of the distribution R* R* + R R* R* R* of hetero- and homochiral associates between two phases (most often R* R* time S R* between solid and liquid or vapour phases) [2]. S S R R* R R R S S Results and Discussion R S R* S R* R S R S How does a resolution process work in general? To the solution of racemic compound obtained at the chemical synthesis, which is an SR SR* + RR* ee * * equimolar mixture of mirror-image pairs of enantiomers, is added the EuRac SnRmR SmRnR resolving agent (Scheme 1). In the solution due to the self-organization n>m of enantiomers (SDE), supramolecular associates are formed, and these Scheme 1: The general scheme of the resolution processes. (R and S the pure will be distributed between two phases, according to the conditions, enantiomers, R* the resolving agent). and circumstances of the process. The distribution depends, mainly on the properties of the starting compounds, on the eutectic compositions of the racemic compound (ee ) and the resolving agent (ee ), respectively. The solvent *Corresponding author: Emese Palovics, Department of Organic Chemistry and EuRac EuRes Technology, University of Technology and Economics, Budapest H-1521, P.O.B. applied, and the time of crystallization has a significant effect as well. 91 Budapest, Hungary, Tel: +3614632101; Fax: +3614633648; E-mail: The behaviour of enantiomeric mixtures can be described as [email protected] racemic-like, (about 80%), and conglomerate-like behaviour (about Received December 21, 2017; Accepted December 27, 2017; Published 20%) [3,4] A non-linear correlation can be seen between the purity of December 29, 2017 the crystallized mixture and the initial composition, both the melting Citation: Palovics E, Fogassy E (2017) A Presumable Mechanism of the point diagrams and purity-purity diagrams are specific for a given Separation of Diastereomeric and Enantiomeric Mixtures. J Chromatogr Sep Tech 8: 391. doi: 10.4172/2157-7064.1000391 behaviour [5,6]. Copyright: © 2017 Palovics E, et al. This is an open-access article distributed In both cases a specific composition of enantiomeric mixtures can under the terms of the Creative Commons Attribution License, which permits be observed, the so-called eutectic composition, when the enantiomeric unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

J Chromatogr Sep Tech, an open access journal ISSN: 2157-7064 Volume 8 • Issue 6 • 1000391 Citation: Palovics E, Fogassy E (2017) A Presumable Mechanism of the Separation of Diastereomeric and Enantiomeric Mixtures. J Chromatogr Sep Tech 8: 391. doi: 10.4172/2157-7064.1000391

Page 2 of 5 the heterochiral associations become more stable and less soluble, so molecule has a code in its structure (its eutectic composition), which the crystalline phase will contain an enantiomeric mixture with near influences the configuration and the helicity of the macromolecule racemic composition (Scheme 2). formed. It is remarkable, that even though this chiral molecule has 8 isomers, just one of them takes part in the building up of this If in the solution only one of enantiomers is present, it was macromolecule [8]. demonstrated, that the homo chiral self-organized supramolecular associates can have plus (P) and minus (M) helicity. For example, in the In case of resolution processes small chiral molecules, the racemic case of Threonine (a chiral proteinogenic amino acid), which crystallizes compounds tend to form homo- and heterochiral associations due to as a conglomerate, the deposited aggregates show an obvious right and their self-organization, and these groups have helical structures, where left-handed configuration. It was observed at the same time, that in the P and M helices are formed in a definite amount encoded by their own R configuration the P helical structure is present in 85% amount, while code. These helices tend to form homo and heterochiral double helices in the S configuration the M helical structure was formed in crystalline which will be distributed between two phases (Scheme 5). phase in the same amount. This ratio between P and M helical structures The homochiral helices can be transformed to helices, having is almost the same as the ee of the enantiomeric mixture of Threonine Eu eutectic composition. The heterochiral double helices racemic crystals (Scheme 3) [7]. are precipitated, if the starting enantiomeric ratio does not exceed the A similar right and left-handed configuration was observed in case eutectic composition (Scheme 6). of mirror-image pairs during the crystallization of quartz. In this case Due the resolution processes the resolving agent, with its P and M the ratio of P and M helical structures is equal because it is a helical but double helices can react with the antiparallel P and M heterochiral double achiral molecule (Scheme 4). helices of racemic compound. The composition of the diastereomer in A similar antiparallel double helical structure was also observed crystalline phase can be influenced by the applied solvent (Scheme 7). when non-covalent associates were formed by interactions of chiral If the kinetic control of crystallization is determined by the eutectic molecules. The structure of DNA, which plays a decisive role in composition of the racemic mixture, then the thermodynamic control the inheritance of living organisms, is antiparallel double helix may be determined by the eutectic composition of the resolving agent. supramolecular structure. The backbone of this macromolecule is Or contrarily, if the latter determines the kinetic control, then the an enantiomer, the phosphate of deoxyribose monomer. This chiral thermodynamic control is determined by the eutectic composition of the racemic mixture. From different solvents, not the same diastereomers precipitate, S S S most probably due to the different solubility of the double helix S S S structures, however, their stoichiometry is decisively determined by Homochiral the eutectic composition of the racemic compound. It is an adequate R SDE R R example the resolution of Flumequine intermediate in different solvents R (Scheme 8) [9]. R R In the case of the resolution of FTHQ with DPTA, during the Conglomerate crystallization from ethyl acetate, both the kinetic and thermodynamic control is determined by the eutectic composition of the racemic S S compound. Although in the case of the thermodynamic control instead R R R S S R S of the faster crystallizing diastereomer salt, the other one, of poorer R S Heterochiral R S R solubility precipitates, the stoichiometry is determined by the eutectic S R SDE S R composition of the racemic FTHQ. Racemate Three weeks of crystallization gives the evidence, that in this case Scheme 2: The distribution of enantiomeric mixture into homo- and heterochiral undoubtedly the ee code of the racemic compound determines the supramolecular associations. EU

OH O O OH (S) (R) H3C (R) OH HO (S) CH3 NH2 NH2

S S R R

S S R R R S S R

S S R R

P M P M

SM > SP RP > RM M/P~85/15 P/M~85/15 Scheme 3: The macroscopic helicity of threonine aggregates reveals their Scheme 4: The right and left-handed configuration observed in case of quartz predominant molecular chirality. crystals.

J Chromatogr Sep Tech, an open access journal ISSN: 2157-7064 Volume 8 • Issue 6 • 1000390 Citation: Palovics E, Fogassy E (2017) A Presumable Mechanism of the Separation of Diastereomeric and Enantiomeric Mixtures. J Chromatogr Sep Tech 8: 391. doi: 10.4172/2157-7064.1000391

Page 3 of 5

S S R R S S R R "Cryst"

I. II. PSS/MRR

a MSS/PRR S S R R -Conglomerates the crystals are each others mirror images

PSS PRR MSS MRR - in the case of racemates if ee0> eeEu Racemic Double Helix PRR > MRR Solution Homo MSS > PSS

b S R S R

P M P M fast crystallization SR-Crystal

Racemic Helices Racemate

Solution ee0 < eeEu Can be cyrstals of mirror images

PSR MSR Fast cystallization can occur only if the structure is Racemic Double Helix ready in the solution Racemate Solution

Scheme 5: Formation of double helices from the chiral helices.

S S R R R S S R R S R S P A R R R R SS R S A L S S L E L

P M P M PREu MREu PS MS Eu Eu PSREu MSREu

Racemic Helices Racemic Eutectic Helices Racemic Double Helix Solution Solution Solution

Fast crystallization

SR-Crystal

Racemate

ee0 < eeEu Can be crystals of mirror images Scheme 6: Transformation of helices into helices having eutectic composition.

S R R R S R

R S Time R Solvent A

S R A S R R R N T PR0R* PSR* I R>S eeDia S>R R P R Cryst. Solution A + R S A S L L R R S R R R E L PSREu MSREu PR*R* > MR*R* ee EuRes R S Racemic Double Helix S Resolving Agent Solvent B Time Solution Solution

MS0R MRR* eeDia S>R R>S Cryst. Solution Scheme 7: Transformations due the resolution processes.

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C C C C ee: F ee: 59 0.5 e. (R,R)-DPTA 0.5 e. (R,R)-DPTA 48 : 70 : 91 . . F: 0 41 Me EtAc F: 0 44 RS S R R R ee racem c E 90 i FT eeE 90 RS eeE 40

Scheme 8: Solvent dependency of the resolution of Flumequine intermediate.

C C C C ee: F ee: 41 0.5 e. (R ,R )-DPTA 0.5 e. (R,R ) -DPTA 48 : 92 : 91 . , . F: 0 38 EtAc 3 ees EtAc, 5 minutes F: 0 44 thermodynamic R R inetic control control ee 90 racemic FT ee 90 E E S S 7 3 7 3 RS eeE 40

Scheme 9: The kinetic and thermodynamic control is determined by the eutectic composition of racemic compound.

Scheme 10: A solvent-depended resolution when the stoichiometry of diastereomers is determined by the eutectic composition of resolving agent.

Scheme 11: A time-depended resolution when the stoichiometry of diastereomers is determined by the eutectic composition of one of starting compounds.

Page 5 of 5 stoichiometry of the crystallization instead of DPTA (Scheme 9) [10]. 2. Faigl F, Fogassy E, Nogradi M, Palovics E, Schindler J (2010) Separation of non-racemic mixtures of enantiomers: an essential part of optical resolution. The solvent-dependency can also be observed at the resolution of Org Biomol Chem 8: 947-959. racemic Amlodipine (AML) by (R,R)-tartaric acid (TA) (Scheme 10) 3. Palovics E, Szeleczky ZS, Fodi B, Faigl F, Fogassy E (2014) Prediction of but in this case the stoichiometry of diastereoisomers is determined by the efficiency of diastereoisomer separation on the basis of the behaviour of the eutectic composition of the resolving agent [11-13]. enantiomeric mixtures. RSC Advances 4: 21254-21261. 4. Jacques J, Wilen SH, Collet A (1981) Enantiomers, racemates and resolution. When kinetic control is applied, the results are determined by John Wiley & Sons Inc., New York, USA. the eutectic composition of the racemic compound. On the contrary, 5. Kozma D, Fogassy E (2002) Optical resolutions via diastereomeric salt on thermodynamic control, the determining factor is the eutectic formation. CRC Press, London. composition of the resolving agent (Scheme 11) [14]. 6. Roozeboom HWB (1899) Z Phys Chem 28: 494.

Conclusion 7. Fogassy E, Maria A, Faigl F (1981) Selective reactions of enantiomeric- mixtures. Tetrah Lett 22: 3093-3096. Like DNA in the living organisms reproduces itself, as a result of its code, form supramolecular associates having double helical structure, 8. Viedma C, McBride JM, Kahr B, Cintas P (2013) Enantiomer-Specific Oriented Attachment: Formation of Macroscopic Homochiral Crystal Aggregates from a so it is capable to reproduce itself and to catalyse the processes, in Racemic System. Angew Chem Int Ed 52: 10545-10548. the resolution processes are also observed a self-reproduction of supramolecular associates having helical structure which tend to 9. Watson JD (1965) Molecular Biology of the gene. In: Levinthal C (ed.), WA Benjamin Inc., New York and Amsterdam, p: 494. reproduce themselves. 10. Balint J, Egri G, Kiss V, Gajary A, Juvancz Z, et al. (2002) Unusual phenomena While the self-reproduction of racemic compounds is encoded during the resolution of 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (FTHQ): by its eutectic composition, the resolving agent pursues to reproduce thermodynamic-kinetic control. Tetrahedron: Asymmetry 12: 3435-3439. itself from the enantiomers of racemic compound but in the ratio of its 11. Song SB, Cho IH, Youn YS, Lim DK (2013) Method for the Seperation of (S)-(- eutectic composition. )-Amlodipine from Racemic Amlodipine. Acknowledgments 12. Gharpure MM, Bhawal BM, Ranade PV, Deshmukh RD, Mehta SR (2005) Process for Producing Enantiomer of Amlodipine in High Optical Purity. The authors are grateful for the financial support of the Hungarian Scientific Research Found (OTKA Grant number K 104769 for E. Fogassy). 13. Palovics E, Faigl F, Fogassy E (2012) Advances in Crystallization Processes. In: Yitzhak M (ed.), InTech Chapters, pp: 1-37.

References 14. Palovics E, Schindler J, Faigl F, Fogassy E (2012) Comprehensive Chirality. In: 1. Soloshonok VA (2006) Remarkable Amplification of the Self-Disproportionation Physical Separations. Erick C, Hisashi Y (eds.), pp: 91-95. of Enantiomers on Achiral-Phase Chromatography Columns. Angewandte Chemie International 45: 766-769.

J Chromatogr Sep Tech, an open access journal ISSN: 2157-7064 Volume 8 • Issue 6 • 1000390