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

Home , Enantiomeric excess

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.

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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).

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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 found [10].found that that starting starting from from prochiral prochiral compounds, compounds, the enantiomeric the enantiomeric composition composition of the resulting of the compoundsresultingGirad compounds varies found depending that varies starting depending on the from composition prochiralon the composition compounds, of the chiral of catalystthethe enantiomericchiral enantiomers catalyst composition enantiomers [1]. of [1]. the resultingKlussmannKlussmann compounds et et al. al. demonstrated demonstratedvaries depending that that in on the in the casethe composition case of an of aldol an of reaction aldolthe chiral reaction there catalyst is there a relationshipenantiomers is a relationship between[1]. thebetween eutecticKlussmann the composition eutectic et compositional. of demonstrated the amino of acidthe that amino used in the as acid acase catalyst used of anas and aldola catalyst the reaction composition and therethe ofcomposition is the a relationship product of [ 11the ]. between the eutectic composition of the amino acid used as a catalyst and the composition of the Forproduct example, [11]. inFor the example, presence in of the proline presence (~50% of proline eutectic (~50% composition), eutectic thecomposition), aldol reaction the resultsaldol reaction in 50% product [11]. For example, in the presence of proline (~50% eutectic composition), the aldol reaction enantiomericresults in 50% purity, enantiomeric the same purity, result the was same obtained result also was in obtained the presence also in of the less presence than 50% of pure, less than or even 50% results in 50% enantiomeric purity, the same result was obtained also in the presence of less than 50% purerpure, prolineor even enantiomeric purer proline mixtures. enantiomeric Thus, mixtures. the eeEu compositionThus, the eeEu of composition the chiral catalyst of the can chiral determine catalyst pure, or even purer proline enantiomeric mixtures. Thus, the eeEu composition of the chiral catalyst thecan enantiomeric determine the purity enantiomeric of the product purity (Figure of the product4). (Figure 4). can determine the enantiomeric purity of the product (Figure 4).

FigureFigureFigure 4. 4. The4.The The eeffectﬀ effectect ofof of thethe the chiral chiral chiral catalyst catalyst catalyst on on on the thethe enantiomeric enantiomericenantiomeric purity puritypurity of of the the product. product. product.

SubstantiallySubstantiallySubstantially after after after the the completionthe completion completion of theof of reaction,the the reaction,reaction, the reaction thethe reaction mixture mixturemixture contains contains contains the two the the non-racemic two two non non‐ ‐ mixturesracemicracemic ofmixtures themixtures enantiomers of ofthe the enantiomers inenantiomers the same proportionin in thethe samesame as proportionproportion the eutectic asas composition thethe eutecticeutectic of composition thecomposition catalyst, andof of the thethe chiralcatalyst,catalyst, catalyst. and and the the chiral chiral catalyst. catalyst. However,However,However, the the the distribution distribution distribution of of of non-racemic non non‐racemic‐racemic enantiomeric enantiomeric enantiomeric mixtures mixtures [[12] 12[12]] between between two two two phases phases phases is is isalso also also determineddetermineddetermined by by by their their their own own own eutectic eutectic eutectic composition. composition. composition.

3.3. TheThe3. The E ffEffectect Effect of of the ofthe Eutecticthe Eutectic Eutectic Composition Composition Composition of the ofof Racemic thethe RacemicRacemic Compound Compound on the onon thethe Diastereomeric Diastereomeric DiastereomericSeparation Separation Separation WhenWhen a racemic a racemic (or (or non-racemic) non‐racemic) enantiomeric enantiomeric mixture mixture isis reactedreacted with a a single single enantiomer enantiomer of of When a racemic (or non‐racemic) enantiomeric mixture is reacted with a single enantiomer of relatedrelated molecular molecular structure structure but but of of opposite opposite character character (as (as a a resolving resolving agent), the the composition composition of of the the related molecular structure but of opposite character (as a resolving agent), the composition of the enantiomericenantiomeric mixture mixture that that can can be be separated separated from from the the precipitating precipitating diastereomericdiastereomeric salt salt (which (which can can be be enantiomeric mixture that can be separated from the precipitating diastereomeric salt (which can be filtered from the solution) is the same as its own eutectic composition (eeDia‐eeEuRac) [4]. filtered from the solution) is the same as its own eutectic composition (eeDia-eeEuRac)[4]. filtered from the solution) is the same as its own eutectic composition (eeDia‐eeEuRac) [4]. ForFor example, example, after after dissolving dissolving racemic racemic fluor-acetyl-phenylglicinefluor‐acetyl‐phenylglicine (FAPhG (FAPhG)) and and (R (R)‐)-methyl-methyl‐ For example, after dissolving racemic fluor‐acetyl‐phenylglicine (FAPhG) and (R)‐methyl‐ phenylglicinephenylglicine ((R (()-MPhG)R)‐MPhG in) in water, water, the the ( S(,SR,)-diastereomerR)‐diastereomer couldcould bebe separatedseparated by by crystallization crystallization phenylglicine ((R)‐MPhG) in water, the (S,R)‐diastereomer could be separated by crystallization

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(Figure5), where the ee Dia was circa 86.3%, which is in good agreement with the eutectic composition (Figure 5), where the eeDia was circa 86.3%, which is in good agreement with the eutectic composition of the racemic compound (eeEuRac ~88%). of the racemic compound (eeEuRac ~88%).

FigureFigure 5. 5.Diastereomic Diastereomic salt salt formation formation of ( Rof,S )-FAPhG(R,S)‐FAPhG with (Rwith)-MPhG (R)‐MPhG resolving resolving agent—similar agent—similar eutectic compositioneutectic composition of racemic of and racemic diastereomeric and diastereomeric compound. compound.

WhenWhen related related structured structured resolving resolving agents agents were were used, used, the the mean mean of the of the eutectic eutectic compositions compositions of the of examinedthe examined racemic racemic compounds compounds (85.3%) (85.3%) was was in good in good agreement agreement with with the the mean mean of the of the compositions compositions of theof the enantiomeric enantiomeric mixtures mixtures isolated isolated from from the the corresponding corresponding diastereomeric diastereomeric salt salt (85.9%) (85.9%) [4]. [4]. EvenEven ifif therethere is is no no molecular molecular structural structural relationship relationship betweenbetween thethe racemicracemic compoundcompound andand thethe resolvingresolving agent,agent, thethe eutecticeutectic compositioncomposition ofof thethe racemicracemic compoundcompound maymay stillstill bebe decisivedecisive forfor thethe compositioncomposition of of the the diastereomer. diastereomer. ForFor example, example, the the eutectic eutectic composition composition of of the the Flumequine Flumequine intermediate intermediate (FTHQ)(FTHQ) forfor the the racemic racemic basebase corresponds corresponds well well with with the composition the composition of the enantiomericof the enantiomeric mixture isolated mixture from isolated the diastereomer from the obtaineddiastereomer with obtained the (R,R)-DPTA with the resolving (R,R)‐DPTA agent resolving (Figure6 )[agent13]. (Figure 6) [13].

FigureFigure 6. 6. DiastereomericDiastereomeric saltsalt formationformation ofof ((RR,S,S)-FTHQ)‐FTHQ with with half half equivalent equivalent ( (RR,R,R)-DPTA.)‐DPTA.

IfIf the the eutectic eutectic compositions compositions of of the the racemic racemic compound compound were were averaged averaged during during the the 45 45 resolutions resolutions developed by our group (ee ~73%), and the enantiomeric compositions separated from the developed by our group (eeEuaverageEuaverage ~73%), and the enantiomeric compositions separated from the crystalline diastereomeric salt were also averaged (ee ~78%), a good agreement could be crystalline diastereomeric salt were also averaged (eeDiaaverageDiaaverage ~78%), a good agreement could be obtained,obtained, so so ee eeDiaDia ~ ee EuResAg [14].[14 ].

4.4. TheThe EEffectﬀect of of the the Resolving Resolving Agent Agent (Enantiomeric (Enantiomeric Mixture) Mixture) on on the the Diastereomeric Diastereomeric Separation Separation SinceSince the the eutectic eutectic composition composition of of the the enantiomeric enantiomeric mixtures mixtures of the of racemicthe racemic resolving resolving agent agent can also can determine the ee value when separated with the appropriate unrelated molecular structured resolving also determine Diathe eeDia value when separated with the appropriate unrelated molecular structured agent, the average of the resolving agents (ee ) used in previous resolutions was determined resolving agent, the average of the resolvingEuResAg agents (eeEuResAg) used in previous resolutions was (ee ~78%) that also showed good accordance (ee ~80%). Thus, the enantiomeric determinedEuResAgaverage (eeEuResAgaverage ~78%) that also showed good accordanceDiaaverage (eeDiaaverage ~80%). Thus, the compositionenantiomeric of composition the crystalline of precipitatingthe crystalline diastereomeric precipitating diastereomeric salts can also be salts determined can also bybe thedetermined eutectic compositionby the eutectic of thecomposition enantiomeric of the mixtures enantiomeric of the single mixtures enantiomeric of the single resolving enantiomeric agent, i.e., resolving eeDia ~ agent, eeRac or ~ ee . i.e., eeEuResAgDia ~ eeRac or ~ eeEuResAg. Ee ~ ee is understandable, since both enantiomers are present during crystallization, thus the EeDiaDia ~ eeRacRac is understandable, since both enantiomers are present during crystallization, thus etheﬀect effect of the of eutectic the eutectic composition composition prevails. prevails. The chiral (enantiomeric mixture) catalyst may also enforce (eeEuKat) its effect, e.g., in aldol reactions [11]. How can a single enantiomeric resolving agent (eeEuResAg) enforce its effect?

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The chiral (enantiomeric mixture) catalyst may also enforce (eeEuKat) its effect, e.g., in aldol ChemistryChemistry 2020 2020, 2, ,2 x, x 5 5 reactions [11]. How can a single enantiomeric resolving agent (eeEuResAg) enforce its effect? Single enantiomers are present under different conditions as two conformers. For example, two conformersSingleSingle enantiomers enantiomers of enantiomers are are present present of benzothiazepineunder under different different co derivativesconditionsnditions as as participate two two confor conformers. inmers. the For crystal For example, example, structure, two two imitatingconformersconformers the of conformersof enantiomersenantiomers of the ofof more benzothiazepinebenzothiazepine stable racemic de crystallinederivativesrivatives structure participateparticipate ((S,S inin)-HMB thethe crystalcrystal and ( S,R structure,structure,)-HMB) (Figureimitatingimitating7)[ the15 the, 16conformers conformers]. of of the the more more stable stable racemic racemic crystalline crystalline structure structure (( ((S,SS,S)-HMB)‐HMB and and ( S,R(S,R)-HMB))‐HMB) (Figure(Figure 7) 7) [15,16]. [15,16].

FigureFigure 7. 7. Imitative Imitative benzothiazepine benzothiazepine derivates. derivates.

OneOne of ofof the thethe enantiomers enantiomersenantiomers ((R )-TOF) ((((RR)-TOF))‐TOF) of a benzodiazepine ofof a a benzodiazepinebenzodiazepine derivative derivativederivative (Toﬁzopam (Tofizopam(Tofizopam TOF) in chloroform TOF)TOF) inin atchloroformchloroform room temperature at at room room temperature includingtemperature 100% including including of the major100% 100% of conformer of the the major major converts conformer conformer into converts aconverts mixture into into of 77.9%a amixture mixture major of of and77.9%77.9% 21.8% major major minor and and conformer21.8% 21.8% minor minor in 48conformer conformer h. However, in in 48 48 racemic h. h. However, However, Toﬁsopam racemic racemic immediately Tofisopam Tofisopam forms immediately immediately two conformers forms forms upontwotwo conformers conformers dissolution upon (Figureupon diss dissolution8)[olution17]. (Figure (Figure 8) 8) [17]. [17].

FigureFigure 8. 8. The The conversion conversion of of the the conformers conformers of of ( R(R)-TOF)-TOF.)‐TOF. .

ItIt cancan can bebe be interpretedinterpreted interpreted thatthat that the the the two two two conformers conformers conformers of of theof the the single single single enantiomer enantiomer enantiomer are are are formed formed formed immediately immediately immediately in theinin the presencethe presence presence of anotherof of another another chiral chiral chiral molecule. molecule. molecule. TheThe single single enantiomeric enantiomeric resolving resolving agent agent is is also also involved involved in in the the crystalline crystalline structure structure of of the the diastereomericdiastereomeric salt—formedsalt—formed salt—formed withwith with thethe the enantiomer enantiomer of of the the racemic racemic compound—with compound—with its its two two conformers conformers (in(in(in aa a ratioratio ratio ofof of 4141/59), 41/59),/59), e.g.,e.g., e.g., whenwhen when reactingreacting reacting (1-hydroxy-2-cyclopentenyl)acetic(1-hydroxy-2-cyclopentenyl)acetic (1‐hydroxy‐2‐cyclopentenyl)acetic acid acid (PGL) (PGL) with with racemicracemic racemic phenylethylaminephenylethylamine (PhEA)(PhE (PhEA)A) (Figure(Figure (Figure9 9))[ 9) 18[18]. [18].]. Thus, under the conditions of the crystallization of the diastereomeric salt, eeDia depends on either the eutectic composition of the racemic compound (eeEuRac) or the eutectic composition of the enantiomeric mixtures of the single enantiomeric resolving agent (eeEuResAg) reacting with its two conformers. However, this means that the ratio of the conformers depends on the eutectic composition. Koshima described that the enantiomers of sodium ammonium tartrate from Pasteur’s enantiomeric separation (1848) are formed by crystallization of M and P helical double-helix associations (mirror-image crystals containing pure enantiomers) from the conglomerate forming racemic solution [19,20].

FigureFigure 9. 9. Diastereomeric Diastereomeric salt salt formation formation with with both both conformers. conformers.

Thus,Thus, under under the the conditions conditions of of the the crystallization crystallization of of the the diastereomeric diastereomeric salt, salt, ee eeDiaDia depends depends on on eithereither the the eutectic eutectic composition composition of of the the racemic racemic compound compound (ee (eeEuRacEuRac) )or or the the eutectic eutectic composition composition of of the the

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Single enantiomers are present under different conditions as two conformers. For example, two conformers of enantiomers of benzothiazepine derivatives participate in the crystal structure, imitating the conformers of the more stable racemic crystalline structure ((S,S)‐HMB and (S,R)‐HMB) (Figure 7) [15,16].

Figure 7. Imitative benzothiazepine derivates.

One of the enantiomers ((R)‐TOF) of a benzodiazepine derivative (Tofizopam TOF) in chloroform at room temperature including 100% of the major conformer converts into a mixture of 77.9% major and 21.8% minor conformer in 48 h. However, racemic Tofisopam immediately forms two conformers upon dissolution (Figure 8) [17].

Figure 8. The conversion of the conformers of (R)‐TOF.

It can be interpreted that the two conformers of the single enantiomer are formed immediately in the presence of another chiral molecule. The single enantiomeric resolving agent is also involved in the crystalline structure of the diastereomeric salt—formed with the enantiomer of the racemic compound—with its two conformers (inChemistry a ratio2020 of, 241/59), e.g., when reacting (1‐hydroxy‐2‐cyclopentenyl)acetic acid (PGL) with racemic792 phenylethylamine (PhEA) (Figure 9) [18]. Chemistry 2020, 2, x 6

enantiomeric mixtures of the single enantiomeric resolving agent (eeEuResAg) reacting with its two conformers. However, this means that the ratio of the conformers depends on the eutectic composition. Koshima described that the enantiomers of sodium ammonium tartrate from Pasteur’s enantiomeric separation (1848) are formed by crystallization of M and P helical double‐helix associations (mirror‐image crystals containing pure enantiomers) from the conglomerate forming

racemic solution [19,20]. Figure 9. DiastereomericDiastereomeric salt salt formation formation with both conformers.

5.5. Solvent Solvent and and Time Time Dependence Dependence of Diastereomericof Diastereomeric Mixture Mixture Separation Separation by the by E fftheect ofEffect the of the Thus, under the conditions of the crystallization of the diastereomeric salt, eeDia depends on EutecticEutectic Composition Composition either the eutectic composition of the racemic compound (eeEuRac) or the eutectic composition of the TheThe following following are are examples examples of the of etheffect effect of the of eutectic the eutectic of the racemic of the compoundracemic compound and the resolving and the agentresolving in di fferentagent solventsin different with disolventsfferent crystallization with different times crystallization [5,12,21–23]. Thetimes diastereomers [5,12,21–23]. were The separateddiastereomers in each were case separated based on in their each distribution case based between on their thedistribution two phases. between the two phases.

5.1.5.1. Role Role of of the the Solvent—The Solvent—The E Effectffect of of the the Eutectic Eutectic Composition Composition BesideBeside thethe effect effect of of the the eutectic eutectic composition, composition, the role the roleof the of applied the applied solvent solvent can also can be observed. also be observed.For example, For in example, case of inthe case resolution of the resolutionof the intermediate of the intermediate of Flumequin of Flumequin (FTHQ) with (FTHQ) di‐p‐toluyl with ‐ di-(Rp,-toluyl-(R)‐tartaricR, Racid)-tartaric (DPTA), acid the (DPTA), composition the composition of the precipitated of the precipitateddiastereomer diastereomer could be influenced could be by influencedthe modification by the of modification the solvent. ofAt the the solvent. same time, At in the both same presented time, in solvents both presented the enantiomeric solvents ratio the enantiomericof the FTHQ ratio enantiomer, of the FTHQ separated enantiomer, from separated its DPTA from‐salt, its DPTA-salt,corresponded corresponded well to the well eutectic to the eutecticcomposition composition of the FTHQ of the enantiomeric FTHQ enantiomeric mixture mixture (eeEuFTHQ (ee ~EuFTHQ eeDia) (Figure~ eeDia 10)) (Figure [24]. 10)[24].

FigureFigure 10. 10.The The composition composition of of the the diasteromer diasteromer can can be be influenced influenced and and predetermined predetermined by by the the variation variation ofof the the solvent. solvent. 5.2. Role of the Crystallization Time—The Effect of Kinetic and Thermodynamic Control on the 5.2. Role of the Crystallization Time—The Effect of Kinetic and Thermodynamic Control on the Eutectic Eutectic Composition Composition In case of the presented resolution, the effect of time could also be observed. Although, In case of the presented resolution, the effect of time could also be observed. Although, by by prolonging the crystallization time, the composition of the precipitated diastereomer changed. prolonging the crystallization time, the composition of the precipitated diastereomer changed. In In both cases of kinetic and thermodynamic control, the eutectic composition of the racemic compound both cases of kinetic and thermodynamic control, the eutectic composition of the racemic compound (eeEuRac) is determinant in the formation of the stoichiometry of the diastereomer (Figure 11)[13]. Thus, (eeEuRac) is determinant in the formation of the stoichiometry of the diastereomer (Figure 11) [13]. the eutectic composition of the racemic compound participates in the formation of the diastereomeric Thus, the eutectic composition of the racemic compound participates in the formation of the salt (eeEuRac ~ eeDia). diastereomeric salt (eeEuRac ~ eeDia).

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FigureFigureFigure 11. 11. 11.The The The enantiomeric enantiomeric enantiomeric mixture, mixture, mixture, taking taking part part in in in the the the formation formationformation of of the the diastereomer diastereomer diastereomer present present present in in the in the the Figure 11. The enantiomeric mixture, taking part in the formation of the diastereomer present in the crystallinecrystallinecrystalline phase, phase, phase, alters alters alters in in in the the the function function function ofof of thethe the crystallization crystallization time. time. time. crystalline phase, alters in the function of the crystallization time. 5.3. When the ee ~ ee /Determinant Role of the Kinetic Control 5.3.5.3. When When the the eeEuResAg eeEuResAgEuResAg ~ ~ee eeDiaDia/Determinant/Determinant Role Role of of the the Kinetic Kinetic Control Control 5.3. When the eeEuResAg ~ eeDia/Determinant Role of the Kinetic Control InIn theIn the the followings, followings, followings, two two two resolutions resolutions resolutions conﬁrmingconfirming confirming the thethe memory memorymemory of of the the the resolving resolving resolving agent agent agent are are are presented. presented. presented. In the followings, two resolutions confirming the memory of the resolving agent are presented. InIn theIn the the ﬁrst first first one, one, one, the the the resolving resolving resolving agent agent agent determines determines determines the the kinetic kinetic control control control (Figure (Figure(Figure 12) 1212) [25].)[ [25].25 ]. In the first one, the resolving agent determines the kinetic control (Figure 12) [25].

FigureFigureFigure 12. 12. 12.The The The kinetickinetic kinetic control control is is is determined determined determined by byby the the resolving resolving agent. agent. agent. Figure 12. The kinetic control is determined by the resolving agent.

5.4.5.4.5.4. When When When the the the ee eeEuResAg eeEuResAgEuResAg ~~ ~ee eeeeDiaDia/Thermodynamic/Thermodynamic/Thermodynamic Control Control Control is is Decisive is Decisive Decisive 5.4. When the eeEuResAg ~ eeDia/Thermodynamic Control is Decisive InIn theIn the secondthe secondsecond case, case,case, the thermodynamic thethe thermodynamicthermodynamic control controlcontrol (Figure (Figure (Figure13) is vindicated 13)13) isis vindicatedvindicated by the eutectic byby thethe composition eutecticeutectic In the second case, the thermodynamic control (Figure 13) is vindicated by the eutectic ofcomposition thecomposition enantiomeric of of the the mixtures enantiomeric enantiomeric of the mixtures mixtures racemic of of compound the the racemic racemic [ 25compound compound]. [25]. [25]. composition of the enantiomeric mixtures of the racemic compound [25].

FigureFigure 13. 13. The The thermodynamic thermodynamic control control is is determined determined by by the the racemic racemic compound. compound. FigureFigure 13. 13.The The thermodynamic thermodynamic control control is is determined determined by the racemic compound. compound. 6.6. Conclusions Conclusions 6. Conclusions6. Conclusions BasedBased on on others others [19,20,26] [19,20,26] and and our our own own experiments experiments [27,28], [27,28], during during the the crystallization crystallization of of BasedBased on otherson others [19,20 [19,20,26],26] and ourand own our experiments own experiments [27,28], [27,28], during theduring crystallization the crystallization of molecules, of molecules,molecules, the the formation formation of of mirror mirror crystals crystals from from solutions solutions of of achiral achiral and and chiral chiral molecules molecules should should be be themolecules, formation ofthe mirror formation crystals of mirror from solutionscrystals from of achiral solutions and of chiral achiral molecules and chiral should molecules be interpreted should be as interpretedinterpreted asas behavingbehaving asas codedcoded robots.robots. InIn eacheach case,case, theythey formform supramolecularsupramolecular andand helicalhelical behavinginterpreted as coded as behaving robots. Inas eachcoded case, robots. they In form each supramolecular case, they form and supramolecular helical associations and helical in their associationsassociations in in their their solutions. solutions. In In the the case case of of achiral achiral molecules, molecules, the the associates associates with with M M and and P P helicity helicity solutions.associations In the in case their of solutions. achiral molecules, In the case the of associatesachiral molecules, with M andthe associates P helicity with are formed M and inP helicity the same areare formed formed in in the the same same amount amount (M~P). (M~P). However, However, for for chiral chiral molecules, molecules, the the M M and and P P helicity helicity associates associates amountare formed (M~P). in However,the same amount for chiral (M~P). molecules, However, the for M chiral and Pmolecules, helicity associates the M and areP helicity a function associates of the areare a afunction function of of the the eutectic eutectic composition composition of of the the corresponding corresponding enantiomeric enantiomeric mixture, mixture, where where M M ≠ ≠ P.P. eutecticare a compositionfunction of the of eutectic the corresponding composition enantiomeric of the corresponding mixture, enantiomeric where M , mixture,P. where M ≠ P. TheseThese M M and and P P ratios, ratios, in in addition addition to to the the self self‐disproportionation‐disproportionation of of enantiomers enantiomers (SDE) (SDE) [29–33], [29–33], TheseThese M M and and P ratios,P ratios, in in addition addition to to the the self-disproportionation self‐disproportionation of of enantiomers enantiomers (SDE) (SDE) [29–33], [29–33 ], validatevalidate their their effect effect when when the the racemic racemic compound compound is is reacted reacted with with the the resolving resolving agent, agent, and and this this is is why why validatevalidate their their eﬀ ecteffect when when the the racemic racemic compound compound is is reacted reacted withwith the resolving agent, agent, and and this this is is why why

Chemistry 2020, 2 794 the eutectic composition of the racemic compound or the resolving agent occurs in the crystalline diastereomeric salt, depending on which eutectic composition is predominant under the given circumstances. Thus, each chiral molecule reacts with at least two conformers with different degrees of M and P helicity. The code of behavior of molecules validates the combined effect of their configuration, charge distribution, constituent atoms, bonds, flexibility, and asymmetry.

Author Contributions: E.P., D.F.B. and E.F. wrote the paper together, and it is based on the own experimental results. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by the National Research, Development and Innovation Office-NKFIH through OTKA grants 124180 Conflicts of Interest: The authors declare no conflict of interest.

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