Article Cite This: J. Chem. Eng. Data XXXX, XXX, XXX-XXX
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Melting Behavior and Solubility Equilibria of (R)- and (S)‑Mefenpyrdiethyl in Ethanol/Water Mixtures Anne-K. Kort,*,† Heike Lorenz,† and Andreas Seidel-Morgenstern†,‡ †
Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstrasse 1, Magdeburg 39106, Germany Otto von Guericke University, Universitätsplatz 2, 39106 Magdeburg, Germany
‡
ABSTRACT: Thermodynamic dependencies and information are of prime importance in performing a controlled selective crystallization process to separate, e.g., the enantiomers of chiral compounds. This study is focused on the determination of phase diagrams of a chiral system. The melting behavior and solubility equilibria (SLE) of diethyl-1-(2,4-dichlorophenyl)-5methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate (mefenpyrdiethyl) in various ethanol/water mixtures in the temperature range of (273 to 293) K were analyzed. The obtained results identify mefenpyr-diethyl as a racemic compound-forming system. It has been found that the solubility behavior strongly depends on temperature. In certain concentration ranges, liquid− liquid equilibria (LLE) were detected. Liquid−liquid separation has to be prevented during cooling crystallization processes. The observed LLE phenomena were quantified within this study in polythermal (turbidity) measurements, and the phase diagrams were derived on the basis of the experimental data. With these diagrams, a successful selective crystallization process avoiding oiling out is feasible.
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INTRODUCTION
Besides asymmetric syntheses, a possibility for obtaining pure enantiomers is the separation of racemic mixtures. Different methods are well known, such as the application of chromatography, chiral membranes, and electrophoresis.1−3 Enantioseparation based on crystallization is known to be another easy and low-priced method.4 A special process type is, if applicable, preferential crystallization (PC), where separation is realized by adding seeds of the target enantiomer to a supersaturated solution containing a mixture of enantiomers. Because crystallization of the seeded enantiomer has a higher driving force than crystallization of the counter enantiomer, the target enantiomer is crystallized preferentially.1,5 The advantage of PC is that pure enantiomers can be recovered directly without the addition of a chiral auxiliary. Particular studies on PC in conglomerate-forming and racemic compound-forming chiral systems were published in the last years.6−8 Because PC is performed in the three-phase region of the ternary solubility phase diagram of a chiral system, for nonconglomerates an enrichment of the target enantiomer is necessary.4 The design of such delicate crystallization processes requires a profound knowledge of thermodynamic data of the specific substances.9 This contribution focuses on determining thermodynamic equilibria and phase diagrams of the herbicide safener diethyl-1(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate (Mef) containing one chiral center (Figure 1).10,11 In previous studies by the authors, some initial solubility data for Mef in ethanol/water mixtures were reported.12 It has been found that the solubility (SLE) in an aqueous mixture of ethanol increases with increasing ethanol content. Above a © XXXX American Chemical Society
Figure 1. Chemical structure of mefenpyr-diethyl.
certain concentration, the solubility curve escalates to very high saturation concentrations, indicating a region of liquid−liquid equilibrium (LLE).9 Liquid−liquid phase separation (LLPS), a phenomenon also called oiling out, occurs when components (substances or solvents) of different polarities are involved, and thus a miscibility gap in the liquid state is caused.9,13 In the case of small organic molecules, oiling out often appears for substances possessing a low melting point that are merged with a solvent exhibiting low solubility.14 The knowledge of LLPS is widely applied in organic chemistry for purification processes.15 However, during the crystallization process, oiling out should be avoided because slow crystal growth and uncontrollable crystallization morphology could be evoked or undesired impurities can be included.9,13 Several methods and approaches Received: September 14, 2017 Accepted: November 8, 2017
A
DOI: 10.1021/acs.jced.7b00819 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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to determining LLE regions were reported.13,16−18 In the case of a miscibility gap in the liquid state, a second liquid phase appears by cooling a homogeneous solution, and hence a solute-rich phase and a solute-poor phase coexist. With further cooling, at monotectic temperature (Tm), an additional solid phase is formed and coexists with the two liquid phases. The concentrations of both liquid phases constitute the boundaries of LLE at a certain temperature in the phase diagram.9,19,20 This article aims to characterize chiral Mef in a binary melting phase diagram and in ternary systems with solvents consisting of two different ethanol/water compositions. As a consequence of oiling out, LLE regions in both solvent mixtures are determined and depicted. Phase diagrams representing the SLE and LLE are derived.
peak. The DSC device was calibrated regularly in the midtemperature range by applying high purity standard metals (In, Sn, and Pb). For each sample, about 7 mg of a solid substance was weighed in an aluminum crucible (30 μL). Because Mef has a relatively low melting point,10 the starting temperature was set to 253 K. The melting data was observed using a heating rate of 1 K·min−1 until 333 K. For the pure racemate and enantiomer and for the mixture with a composition of xen = 0.6, the analyses were repeated twice. The remaining measurements with different compositions of the enantiomers were performed only once. The solid phases of all samples were identified with X-ray powder diffraction (XRPD; XPert Pro PANalytical) with Cu Kα radiation (2θ range from 3 to 40°) immediately before DSC measurements. Solubility Analysis. Solubility data of pure (S)- and racemic Mef in ethanol/water mixtures containing 100wEtOH = 76 and 65 ethanol, respectively, were already published by the authors.12 In this article, additional data in the ternary system (RS)- and (S)-Mef in the presence of solvent mixtures (ethanol/water 76/24 100w/100w or 65/35 100w/100w) were determined. For this purpose, mixtures of racemate and enantiomer at enantiomeric ratios of between 0.65 and 0.93 were mixed with ethanol/water 76/24 100w/100w and 65/35 100w/100w, respectively. Under isothermal conditions, the samples were stirred for 48 h in a thermostated jacketed vessel. In a preliminary experiment, the equilibration time was estimated to be t = (8 to 9) h. The respective saturation temperatures, in particular between (273 to 303) K, were monitored using a Pt-100 temperature sensor (resolution = 0.1 K, class B). After equilibration, solid/liquid phase separation was performed using a syringe with a filter (pore size = 0.45 μm). The liquid phases were analyzed gravimetrically to obtain saturation concentrations (wsat, mass fraction). In favor of this, the mass of the saturated solution (msat) was weighed (resolution = 0.01 mg) and the solvent was subsequently evaporated at 298 K for 24 h at standard pressure. The mass of the dried substances (mdry) was divided by the total mass of the sample, and the solubility was calculated according to eq 1.
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EXPERIMENTAL SECTION Materials. The materials used for this study and their corresponding purities are summarized in Table 1. Pure Table 1. Source and Purity of the Chemicals Used in This Work chemical mefenpyrdiethyl
ethanol a
CAS number
supplier/source
135590-91-9 (racemic) (R)- or (S)enantiomers 64-17-5
BayerCropScience AG enantioseparation (PHPLC) VWR
mole fraction purity 99.3a 99.9b 99.6a
b
As stated by the supplier. Average purity based on measured compositions of (R)- and (S)-Mef using HPLC.
enantiomers (99.9%) were separated out of the racemic compound by the use of preparative high-performance liquid chromatography (PHPLC; column material, ChiralCel OJ; mobile phase, n-heptane/ethanol/methanol (85/7.5/7.5 v/v/ v); flow 75 mL−1). The purity of each enantiomer was determined using analytical HPLC (column, ChiralCel OJ-RH; mobile phase, n-heptane/ethanol/methanol (85/7.5/7.5 v/v/ v); flow, 0.8 mL−1). The relative errors were ±0.05%. Water was filtered and deionized by applying Milli-Q (resistivity = 18.2 MΩ·cm). For SLE and LLE experiments, two different solvent compositions of ethanol/water containing 100wEtOH = 76 or 65 were used. Determination of Melting Behavior. For the investigation of melting data, samples of pure racemate or enantiomer, respectively, and various prepared mixtures of both components at different enantiomeric ratios (xen) of 0.55 to 0.97 were analyzed. Because the recrystallization of Mef is inhibited after solvent evaporation, the use of a solvent to prepare molecularly dispersed mixtures of racemate and enantiomer was not suitable. Thus, in mixtures, the substances were only partially dissolved in ethanol and ground during evaporation of the solvent at 278 K for 5 min. Melting analyses were performed using differential scanning calorimetry (DSC 131, Setaram, Diepholz) evaluating the occurring melting peak to determine the melting temperature (Tliq) from the peak onset and the corresponding enthalpy of fusion (ΔHliq) from the peak area. When analyzing mixtures of racemate and enantiomer, the onset of the eutectic peak specifies the eutectic temperature (Teu). The corresponding liquidus temperature (Tliq) is defined by the peak maximum of the second (melting)
⎛ mdry ⎞ wsat = ⎜ ⎟ ⎝ msat ⎠
(1)
The solubility for each enantiomeric ratio (0.65, 0.8, and 0.93) at the defined temperatures was investigated in triplicate so that an average of the measured data was calculated. The measurements for each sample were repeated twice. To determine the composition of (R)- and (S)-enantiomers (xen) of the liquid phase, HPLC was applied, and the solid phases were analyzed by XRPD (as described above). The methods used to measure SLE are seen as conventional standard methods that have been validated frequently for other systems.9,21,22 Identification of LLE. During solubility analysis under certain conditions, oiling out was observed. Because the occurrence of this phenomenon should be avoided during a controlled crystallization process, the boundaries of LLE are of great importance and were studied as follows: Polythermal (turbidity) measurements of LLE were performed in multireactor systems Crystal16 and Crystalline (Technobis, Netherlands). Small-scale samples of racemate, enantiomer, and mixtures of both were added to ethanol/water mixtures containing 100wEtOH = 76 and 65, respectively, within B
DOI: 10.1021/acs.jced.7b00819 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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a certain concentration range (100w = (3.5 to 90), v = (1 to 3) mL). The samples were first heated to get a homogeneous mixture, cooled until turbidity occurred (Tbegin, cloud point), and subsequently reheated to a clear solution (Tend, clear point) using a cooling/heating rate of 0.5 K·min−1. Selected samples were also analyzed by applying a cooling/heating rate of 0.1K· min−1 to ensure that the results are not affected by cooling that is too rapid. The observed deviations were in a range equal to that of other uncertainties during polythermal LLE measurements. The LLPS temperature of every sample was listed and defined as a function of concentration at the LLE boundary. During polythermal solubility measurements (SLE), the temperatures of nucleation and dissolution are different, i.e., metastable zone width (MSZW), whereas in the case of LLE the measured boundary temperatures during cooling and heating should be similar because the rate of formation of the oily droplets is faster than crystal nucleation.23 Thus, an indication of LLE is given if the temperatures observed when turbidity occurs and disappears are in the same range (Tbegin ≈ Tend). For each enantiomeric ratio with a defined concentration in both solvent mixtures of ethanol/water, the LLPS temperatures were investigated at least twice, respectively. Standard uncertainties are regarded as a deviation of three measurements for the respective sample. Typically, the LLE region is defined by a binodal. Thus, a certain temperature, namely, the upper critical solution temperature (UCST), is the highest temperature at which the two liquid phases can exist.24 Tm was determined by the stepwise cooling (cooling rate 0.05 K·min−1, intervals of 1 K) of samples of a defined concentration until the temperature, at which the formation of the solid phase started, was reached. Types of existing phases (solid or liquid) were optically identified by a microscopic camera in the crystalline device or visually.
Table 2. Experimental Liquidus and Solidus Temperatures, Tliq and Teu, of (RS)-, (S)-Mef, and Prepared Mixtures and Melting Enthalpy, ΔHliq for (RS)- and (S)-Mef, under 101 kPaa xen
Tliq/K
0.5 0.55 0.6 0.6 0.7 0.75 0.9 0.97 1.0
322.3 322.2 320.9 321.9 319.4 317.6
Teu/K
ΔHliq/kJ ·mol−1 18.4
299.3 300.2 299.2 299.7 300.5 300.7
302.6 303.6
24.6
a
Standard uncertainties are u(x) = 0.002, u(T) = 0.3K, u(P) = 1 kPa, and u(ΔHliq) = 0.47 kJ mol−1.
fraction of the enantiomer; R is the gas constant; Tliq,en and Tliq,rac are the melting temperatures of the enantiomer and the racemic compound, respectively; and ΔHliq,en and ΔHliq,rac are the corresponding melting enthalpies of enantiomer and racemic compound, respectively.1 ln xen =
ΔHliq,en ⎛ 1 1 ⎞⎟ ⎜⎜ − R ⎝ Tliq,en Tliq ⎟⎠
ln 4xen(1 − xen) =
2ΔHliq,rac ⎛ 1 1 ⎞⎟ ⎜⎜ − R Tliq ⎟⎠ ⎝ Tliq,rac
(2)
(3)
The experimental detection of Teu and Tliq is challenging in the range of xen = (0.8 to 0.99) because the eutectic peak and the final melting effect are strongly merged. As can be seen in Figure 2, the intersection temperature of Schroeder−van Laar and Prigogine−Defay equations agrees well with the measured eutectic temperatures of all prepared mixtures. Thus, the use of simplified versions of the Schroeder−van Laar and Prigogine− Defay equations offers a good approximation for the determination of the melting behavior in the system (RS)and (S)-Mef. For that reason, the eutectic composition was estimated by the intersection of Schroeder−van Laar and Prigogine−Defay equations using the melting data (ΔHliq, Tliq) of the racemate and enantiomer, respectively, revealing a value of xeu = 0.93 at Teu = 300.7 K. SLE: Solubility Data in the Ternary System. Solubility results of the Mef racemate and enantiomer12 as well as of defined mixtures in solvent mixtures of ethanol/water containing 100wEtOH = 76 and 65 (Table 3) are visualized in typical equilateral ternary phase diagrams (TPD) in Figure 3. Each data point in the diagram represents a mixture composed of the three components [(R)-Mef, (S)-Mef, and the respective solvent mixture] at a certain temperature. Thus, a solubility isotherm can be drawn in the ternary phase diagram connecting all points belonging to one temperature. It is clear from the data that solubility increases with increasing temperature. Thus, crystallization can be performed by cooling. The strong temperature dependency of solubility in the analyzed temperature range is expressed in the TPDs by growing concentration distances between the saturation isotherms. As can be seen from the TPDs in Figure 3, in both applied solvent mixtures, solubility increases from the racemate or from the enantiomer to eutectic composition, respectively. Hence,
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RESULTS AND DISCUSSION SLE: Melting Data. The binary phase diagram of (RS)- and (S)-Mef (Figure 2) shows the typical behavior of a racemic
Figure 2. Binary melt phase diagram on the basis of DSC measurements from pure racemate and enantiomer of Mef and prepared mixtures thereof. Black and gray lines were calculated with eqs 2 and 3 (see the text); ○, liquidus temperatures; ●, points on solidus line; Teu, eutectic temperature.
compound-forming system and exhibits a eutectic composition at xeu ≈ 0.93. In Table 2, the results of DSC measurements are summarized. The calculated liquidus lines, using simplified Schroeder−van Laar and Prigogine−Defay eqs (eqs 2 and 3), are in good agreement with the liquidus temperature measured for the prepared mixtures. In eqs 2 and 3 xen is the mole C
DOI: 10.1021/acs.jced.7b00819 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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LLE: Boundaries of Oiling-Out Region. LLE boundaries were ascertained for different concentrations in ethanol/water mixtures containing 100wEtOH = 76 and 65 ethanol and different enantiomeric ratios, respectively, using polythermal temperature profiles. The results are given in Tables 4 and 5 and are illustrated in quasi-binary phase diagrams in Figures 4 and 5, respectively. As can be seen from the data, the phase boundaries of the miscibility gap are found at higher temperature in the presence of increasing water content. Beginning at low concentrations, the phase-splitting temperature in both ethanol/water mixtures increases with the increase in concentration, showing a binodal (Figures 4 and 5). Hence, all analyzed samples show strong concentration dependencies exhibiting a temperature maximum at a certain enantiomeric ratio, the upper critical solution temperature (UCST). Afterward, with further increases in concentration, the phase-splitting temperature decreases again, and thus the binodal ends at Tm. For samples containing the racemic compound, the monotectic temperature (Tm) was higher (∼303 K) than the corresponding temperature for the enantiomer (∼298 K). The measured solubility line (gray solid line) and the hypothetical binodal (black solid line) of LLE for each system are depicted in one diagram (Figures 4 and 5). Additionally, the respective calculated liquidus line (general eq 2) and the melting temperatures of each component (racemate/enantiomer) and of the corresponding solvent mixture25 (Tsolvent ) liq are shown. However, because of the presence of LLE and thus the nonideality of Mef in aqueous ethanol mixtures, the simplified Schroeder−van Laar equation for the prediction of solubility is not applicable. For both solvent compositions, the ideal boiling temperature line was calculated using the Clausius−Clapeyron equation connected with Raoult’s law (eq 4) and is additionally given in Figures 4 and 5 (dashed gray line). In eq 4, Tsolvent is the boiling temperature of the respective b solvent mixture and ΔHvap is the enthalpy of vaporization.
Table 3. Experimental Isothermal Solubilities (Mass Fraction) in the Ternary Systems (S)/(R)-Mef and Ethanol/ Water Mixtures (76/24 100w/100w or 65/35 100w/100w) at T = (273 to 303) K under 101 kPa, in Which ± Characterizes the Average and the Deviationa T/K
xen
100w76/24
100w65/35
303 301 298
0.5 0.5 0.1 0.5 1.0 0.93 0.8 0.65 0.5 1.0 0.5 1.0 0.93 0.8 0.65 0.5 0.5 1.0 0.93 0.8 0.65 0.5
31.5 ± 0.13
29.3 ± 0.21 9.5 ± 0.06 10.05 ± 0.08 7.66 ± 0.19 9.43b 9.89 ± 0.04 7.15 ± 0.13 5.56 ± 0.29 4.37b 7.41b 3.34b 5.47b 6.36 ± 0.11 4.76 ± 0.04 3.12 ± 0.06 2.66b 2.22b 2.35b 2.38 ± 0.07 1.93 ± 0.14 1.49 ± 0.05 1.13b
293
288 283
278 273
24.4 ± 0.16 12.4 ± 0.05 13.46b 23.51 ± 0.24 15.84 ± 0.09 10.92 ± 0.03 9.59b 9.78b 6.94b 8.21b 7.72 ± 0.01 5.47 ± 1.28 5.25 ± 0.07 6.07b 3.56b 6.98b 6.84 ± 0.02 3.76 ± 0.04 3.17 ± 0.02 2.40b
a Standard uncertainties are u(x) = 0.002, u(T) = 0.1 K, u(P) = 1 kPa, and u(w) = 0.0008. bData taken from ref 12.
Mef is crystallizing in the selected solvent mixtures in a racemic compound-forming system with the same eutectic composition in the chiral system as in melt phase analyses (xeu ≈ 0.93). There were no differences observed comparing the eutectic compositions in ethanol/water 76/24 100w/100w and 65/35 100w/100w in the temperature range of (273 to 293) K. Thus, with regard to the eutectic composition for crystallization-based enantioseparation, the choice of solvent is insignificant. However, the difference in solubility in the two ethanol/ water mixtures is remarkable in the mentioned temperature range. At higher temperatures (T ≥ 293 K), the ternary system gets more complex, and thus the differences are even more considerable, an issue discussed below.
ΔT =
R(Tbsolvent)2 x ΔH vap
(4)
The required data are taken from the Dortmund Data Bank, H2O −1 Explorer version 2013 (ΔHEtOH vap = 38.6 kJ·mol ; ΔHvap = 40.7 −1 76/24 65/35 kJ·mol ; Tb = 351.5 K; Tb = 352.5 K). Ethanol/Water 76/24 100w/100w. As can be seen from the data, the binodal spans 40−50% of the quasi-binary phase diagrams in the ethanol/water mixture containing 100wEtOH =
Figure 3. Ternary phase diagram of chiral Mef in ethanol/water mixture 76/24 100w/100w (left, upper 30%) and in ethanol/water mixture 65/35 100w/100w (right, upper 10%) with solubility isotherms; lines are guides to the eye: blue −⧫−, 273 K; ●, 278 K; brown −●−, 283 K; red ●, 288 K; and blue −●−, 293 K. D
DOI: 10.1021/acs.jced.7b00819 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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Table 4. Experimental Polythermal LLPS Temperatures as a Function of the Enantiomeric Ratio and Mass Fraction of (S)-/(R)-Mef in Ethanol/Water 76/24 100w/100w under 101 kPaa,b
Table 5. Experimental Polythermal LLPS Temperatures as a Function of the Enantiomeric Ratio and Mass Fraction of (S)-/(R)-Mef in Ethanol/Water 65/35 100w/100w under 101 kPaa,b
xen
100w
Tbegin/K
Tend/K
xen
100w
Tbegin/K
Tend/K
1.0
90.0 85.0 80.0 71.5 63.6 57.7 52.6 49.2 38.5 25.5 9.9 68.5 60.7 56.5 54.5 49.2 39.7 25.8 9.9 64.8 60.9 58.6 50.8 43.3 35.7 20.2 9.8 68.1 63.2 58.3 50.3 45.8 40.1 28.2 15.0 8.0 90.0 85.0 80.0 73.0 69.0 65.0 61.9 47.3 46.5 33.8 9.6 8.7
304.4 305.8 308.1 312.5 310.5 298.0 295.6 295.0 291.3 282.0 258.4 315.0 310.1 297.0 296.5 293.4 292.0 291.0 n.d. 312.2 306.2 n.d. 296.3 292.5 294.0 280 n.d. 310.1 305.5 306.2 604.5 291.6 294.9 290.8 n.d. 290.9 305.5 306.2 308.4 312.9 305.0 306.0 303.5 292.5 295.0 290.5 n.d. 293.1
305.6 306.4 308.0 311.9 309.9 298.5 295.4 294.4 290.7 281.0 258.5 314.6 309.9 298.5 296.0 293.0 292.6 n.d. 255.0 312.0 304.2 299.5 296.2 292.0 292.1 283.5 255.0 310.2 303.9 306.0 303.2 291.5 293.3 289.8 285.5 289.2 304.8 307.8 308.0 310.5 303.3 305.5 302.4 290.9 293.3 291.5 286.9 290.6
1.0
90.0 85.0 80.0 70.0 49.8 39.9 24.8 10.4 4.97 3.55 72.2 48.7 38.9 24.2 10.1 5.05 3.49 72.4 47.8 37.9 24.6 9.92 5.13 3.59 71.6 47.8 37.0 25.4 9.96 4.93 3.62 90.0 85.0 80.0 73.2 50.8 43.4 40.8 24.6 20.6 4.97 3.52
304.4 323.2 329.4 355.0 351.5 n.d. 317.5 283.0 257.4 255 355.5 348.3 330.0 316.4 293.4 257.5 254.4 355.0 348.0 n.d. 318.5 295.4 257.3 254.2 355.0 348.0 334.5 319.3 297.5 257.4 254.9 304.3 320.5 323.7 355.0 349.5 349 343.1 318.5 314.9 257.5 255.1
307.9 323.3 328.7 n.d. n.d. 329.2 316.8 285.4 257.9 254.3 n.d. n.d. 328.1 316.3 291.1 257.9 254 n.d. n.d. 330.9 318.6 294.5 258 255 n.d. n.d. 333.5 318.6 297.1 258 254.8 305.5 321.3 324.6 n.d. n.d. 349.4 342.7 319.5 315.6 258 254.1
0.93
0.8
0.65
0.5
0.93
0.8
0.65
0.5
a Standard uncertainties are u(x) = 0.002, u(w) = 0.0005, u(T) = 5 K, and u(P) = 1 kPa. bItalic data represents the assumed VLE region; xen, enantiomeric ratio; w, mass fraction; Tbegin, temperature at which turbidity appears (by cooling); and Tend, temperature at which turbidity disappears (by heating).
a
Standard uncertainties are u(x) = 0.002, u(w) = 0.0005, u(T) = 5 K, and u(P) = 1 kPa. bItalic data represents the UCST region (upper critical solution temperature); xen, enantiomeric ratio; w; mass fraction; Tbegin, temperature at which turbidity appears (by cooling); Tend, temperature at which turbidity disappears (by heating).
24 100w/100w (Figure 4, left) shows at concentrations higher than 100w = 75 that the temperatures at which LLE occurs are decreasing. The phase diagram of the enantiomer looks similar. The calculated liquidus lines of the racemate and the enantiomer deviate significantly from the measured solubility data according to the appearance of the liquid−liquid miscibility gap. Ethanol/Water 65/35 100w/100w. Figure 5 shows the beginning of LLPS at concentrations of 100w = 10−20 and
76 (Figure 4). The UCST for the racemic compound and enantiomer is found around 100w = 72 at 312 K (Table 4). The phase diagram of the racemic compound in ethanol/water 76/ E
DOI: 10.1021/acs.jced.7b00819 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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Figure 4. Quasi-binary phase diagrams for the racemic compound (left) and the enantiomer (right) in ethanol/water mixture 76/24 100w/100w indicating the LLE region. ○, isothermal solubility data, with the gray line being a guide to the eye; gray ●, melting temperature of the racemate/ enantiomer; ●, melting temperature of the ethanol/water solvent mixture; ×, polythermal LLE data, with the black solid line being a guide to the eye for an assumed binodal and the dashed black line belonging to metastable LLE; dotted line, calculated ideal solubility line using the simplified Schroeder−van Laar equation, with the dashed gray line being the calculated ideal boiling temperature (eq 4).
Figure 5. Quasi-binary phase diagrams for the racemic compound (left) and the enantiomer (right) in ethanol/water mixture 65/35 100w/100w indicating the LLE region. ○, isothermal solubility data, with the gray line being a guide to the eye; gray ●, melting temperature of the racemate/ enantiomer; ●, melting temperature of the ethanol/water solvent mixture; ×, polythermal LLE data, with the black solid line being a guide to the eye for the assumed binodal and the dashed black line belonging to metastable LLE; red ×, polythermal LLE data with a lower uncertainty; dotted line, calculated ideal solubility line using simplified the Schroeder−van Laar equation, with the dashed gray line being the calculated ideal boiling temperature (eq 4).
ending at 100w ≈ 90. The possible UCST in this solvent mixture obviously appears at much higher temperatures than in the ethanol/water 100wEtOH = 76 solvent mixture (cf. Figures 4 and 5). Furthermore, the LLPS temperature for concentrations in the range of 100w = (40 to 70) is close to the boiling temperature of the applied solvent mixture (Figure 5). Thus, in the phase diagram the additional vapor−liquid phase equilibria (VLE) may overlap with the LLE. This assumption is experimentally supported by the observation of bubbles during the measurement of these points. Hence, the phase diagram gets more complex and the solvent composition might also change at temperatures higher than 350 K. This correlates to the dent in the curve observed. Thus, the LLE data in the mentioned solvent mixture is uncertain in the range between 100w = (40 to 70). The VLE is difficult to quantify experimentally for the reason that only a small amount of substance was available and also the determination was beyond the scope of this work. However, as can be seen from the obtained LLE data, at Tm the LLE region spans about 70% of the diagrams by applying an ethanol/water mixture with 100wEtOH = 65. Although the solubility data was determined between T = (273 to 303) K for both solvent mixtures, the presence of LLE could be detected at temperatures of less than 293 K, e.g., at ∼283 K and even at ∼253 K, when analyzing samples with smaller concentrations of 100w = (10 to 30) (ethanol/water
76/24 100w/100w) and 100w = (3 to 10) (ethanol/water 65/ 35 100w/100w). These data obviously characterize metastable LLE accessible in polythermal measurements (Figures 4 and 5). Using the data obtained, the construction of a 3D-TPD with temperature as the perpendicular axis is feasible. Figure 6 shows eight different surfaces of two-phase equilibria for the solvent mixture ethanol/water 76/24 100w/100w. In particular, seven SLE surfaces (three within the upper liquidus surface, three within the lower liquidus surface, one of the solvent) and one LLE surface (black) that completely separates the lower (red) from the upper (blue) liquidus surfaces. Different mixtures of racemate and enantiomer in the same concentration ranges in each solvent composition show similar temperatures where LLE occurs. Thus, the ratio of (R)- and (S)-enantiomers does not affect the boundary temperatures significantly, and in the ternary system, the two coexisting liquid phases within the miscibility gap do not show any enantioselectivity.14 Enantiomer Separation. In prospective studies, enantioseparation by crystallization is projected to be designed and examined for feasibility. Because Mef is crystallizing as a racemic compound-forming system, an enrichment of the target enantiomer is required to use preferential crystallization and operate in the three-phase region of the SLE part of the ternary phase diagram.4 Starting with enantiomeric compositions below the eutectic composition xeu (sub-eutectic), a hyper-eutectic composition of the target enantiomer in the liquid phase can be F
DOI: 10.1021/acs.jced.7b00819 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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mixtures in the analyzed temperature range between (273 and 293) K. However, because oiling out occurs, the process window for crystallization is limited. The LLE regions span up to 40% to 70% of the phase diagrams with a measured monotectic temperature Tm at 303 K (racemate) and at 298 K (enantiomer). The binodal for ethanol/water 76/24 100w/100w is not as pronounced as that for ethanol/water 65/35 100w/100w. The determination of LLE in the ethanol/water mixture containing 100wEtOH = 65 leads to the recognition of regions where the VLE could not be neglegted anymore. The achieved overview of the position of LLE regions in the phase diagram allows us to plan crystallization experiments for enantiomer separation. To avoid oiling out during the process, crystallization should be conducted at temperatures lower than the determined monotectic temperature (below 303 K) by applying moderate saturation concentrations. For further optimization, the crystallization window, related to MSZW and LLE, still needs to be investigated more precisely, which is proposed for further work.
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Figure 6. Three-dimensional (quasi-)ternary phase diagram of chiral Mef in ethanol/water 76/24 100w/100w. ●, polythermal LLE data; red ●, isothermal solubility data; blue ●, melting temperatures in the chiral system; green line, Tm (lines are a guide to the eye); black curve, binodal of enantiomers and racemate (lines are a guide to the eye). Data on the (R) side of the diagram are inverse to the data on the (S) side.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Anne-K. Kort: 0000-0002-0356-4771 Andreas Seidel-Morgenstern: 0000-0001-7658-7643
reached by preferential crystallization of the racemic compound. Using the mother liquor of hyper-eutectic composition, the target enantiomer can be crystallized preferentially after adding seeds of the target species. In previous studies, a hypereutectic enrichment of the target enantiomer in the liquid phase by preferential crystallization of the counter species (racemate) and the subsequent preferential crystallization of the target enantiomer were successfully demonstrated for another chiral agrochemical.8 Because the eutectic composition of Mef with xeu ≈ 0.93 is very close to that of the pure enantiomer, preferential crystallization of the racemic compound is supposed to provide a composition of xen ≥ 0.93 in the liquid phase. Therewith, the mother liquor already possesses the target enantiomer in high excess, and after drying, solid Mef with a high enantiomeric purity is provided.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors thank Professor E. Gesing and Bayer CropScience AG for providing mefenpyr-diethyl and Jacqueline Kaufmann and Stephanie Leuchtenberg from our MPI group for help with DSC and XRPD analyses.
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REFERENCES
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CONCLUSIONS Chiral Mef was found to crystallize as a racemic compoundforming system. With a eutectic composition of 0.93 in the melt phase (Teu ≈ 300 K), it has relatively low melting temperatures between 303 K (enantiomer) and 322 K (racemate). Predictions using the simplified equations of Schroeder−van Laar and Prigogine−Defay (eqs 2 and 3) are in good agreement with the measured melting data. During solubility measurements, ethanol was identified as a good solvent and water was identified as a suitable antisolvent. Comparing the solvent mixtures ethanol/water containing 100wEtOH = 76 and 65, there is a pronounced increase in the saturation concentration with higher ethanol contents. Because the solubility increases significantly with rising temperature, cooling crystallization is seen as an attractive option for a separation process, by, e.g., exploiting preferential crystallization. The mentioned eutectic composition (xeu = 0.93) is not changing in the presence of the two aqueous ethanol solvent G
DOI: 10.1021/acs.jced.7b00819 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.jced.7b00819 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
