Solubility, Formation of the Metastable Conglomerate, and Use of a

Aug 6, 2013 - Metastable Conglomerate, and Use of a Nonaqueous Emulsion To. Prepare an Enantiomerically Enriched Product. S. E. Gilks,* R. J. Davey,* ...
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Crystallization of 2‑Chloromandelic Acid: Solubility, Formation of the Metastable Conglomerate, and Use of a Nonaqueous Emulsion To Prepare an Enantiomerically Enriched Product S. E. Gilks,* R. J. Davey,* R. K. Mughal, G. Sadiq, and L. Black School of Chemical Engineering and Analytical Sciences, University of Manchester, The Mill, Sackville Street, Manchester M13 9PL, United Kingdom S Supporting Information *

ABSTRACT: Crystallization of 2-chloromandelic acid (2ClMA) using diverse crystallization techniques yields both stable and metastable racemic compounds and a metastable conglomerate. In this work, solubility data for the system is reported and a robust drown-out method developed for preparation of the conglomerate. UV−vis spectroscopy reveals that in a stirred slurry this conglomerate converts to the stable compound in about 10 min. Attempts to utilize the existence of the conglomerate in a preferential crystallization process proved successful with crystallization from a seeded, tailormade, nonaqueous emulsion, providing a route to a product with significant chiral enrichment of the R enantiomer.

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INTRODUCTION Preferential crystallization is widely used as a means of separating pure enantiomers from racemic solutions. Typically seed crystals of one enantiomer are added to a racemic solution for which crystallization yields a conglomerate rather than a compound.1 Previous studies of the phase behavior and diverse crystallization of R,S-2-chloromandelic acid (2ClMA) have indicated the existence of both a stable racemic compound and a metastable conglomerate.2−4 Lorenz et al.2 demonstrated that the metastable conglomerate may be preferentially crystallized from the melt and also from polar solvents, whereas He et al.3 found that freeze drying an aqueous solution or recrystallization of the crude synthetic material from toluene yielded the metastable conglomerate. More recently, Davey et al. successfully prepared the metastable conglomerate by use of an additive which selectively inhibited crystallization of the stable racemic compound.4 While the appearance of metastable phases is well known in polymorphic systems,5,6 to our knowledge 2ClMA is unusual in exhibiting a metastable conglomerate phase. In this article we return to this system to investigate further the use of solution crystallization as a means of consistently preparing the conglomerate and also explore the possibility of developing a crystallization process for isolating an enantiomerically enriched product. This latter objective follows our previous work on purification by emulsion crystallization,7,8 since a seeded crystallization in an emulsion would offer the possibility of exploiting preferential crystallization to separate the enantiomers despite the metastable nature of the conglomerate. Interestingly, the potential for developing a robust process for crystallization of the metastable conglomerate is supported by our observation that racemic starting material purchased from Sigma Aldrich was the stable © 2013 American Chemical Society

(α form) racemic compound, while that from Alfa Aesar was the conglomerate.

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EXPERIMENTAL SECTION

Materials. (R,S)-2-Chloromandelic acid was supplied by Sigma Aldrich and Alfa Aesar. pXRD and melting point determinations confirmed that the former is received as the stable racemic compound (CSD ref code GUMXAO02, mp 119 °C) and the latter as the conglomerate (CSD refcodes GASCEK (S), and OVIDUT (R), mp 83−86 °C) with small amounts of the (R,S) compound present. The pure R enantiomer, mp 90 °C, was purchased from AK Scientific, Inc. All three materials had a stated purity of 98% and were used as received. For crystallization experiments acetonitrile was obtained from Fisher (99.99%), n-hexane from Fluka (≥98%), toluene (99%) and dodecane (≥99%) from Sigma Aldrich, and diethyl ether (DEE, 99.5% stabilized with 1% ethanol) from BDH Prolebo Chemicals. Distilled water and acetone were used throughout this study for preparation of laboratory glassware and apparatus. The nature of the crystalline phases and the chiral purity of the solid materials were determined by pXRD, DSC, FTIR, and polarimetry. FTIR was performed using an Avatar ESP FTIR spectrometer with Nicolet’s OMNIC v.5.1b software over the range 4000−400 cm−1. Solid and liquid samples were scanned for a period of 32 s with a resolution of 4 cm−1. DSC experiments were performed using either a Mettler Toledo DSC 30 instrument controlled by Mettler TC15 complete with a liquid nitrogen cooling system with data analyzed by STARe software v.610 or a TA DSC Q100 with software universal analysis 2000 v. 4.5A. A start temperature of 30 °C and a heating rate of 2, 5, or 10 °C/min were used up to a final heating temperature of 130 °C. Between 2 and 8 mg of the solid sample was used for the DSC Received: May 1, 2013 Revised: July 31, 2013 Published: August 6, 2013 4323

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Figure 1. Morphology of the racemic compound (a) and the pure, R enantiomer (b) grown from acetonitrile solution. Scale bar 100 μm in each case. (c) Calculated BFDH morphology of the pure enantiomer.

Figure 2. Powder pattern of unground R-2-ClMA enantiomer crystals grown in acetonitrile (red) compared to the calculated pattern (OVIDUT, black). (Top) Packing diagram showing the nature of the (001) layer. experiments. pXRD was performed using a Rigaku miniflex X-ray powder diffractometer at a wavelength of 1.5406 Å controlled by DIFFRACPLUS software and subsequent data analysis using EVA v. 7.0. Measurements covered a 2θ range from 0° to 50° with a step size of 0.03°. UV−vis studies were performed using a Zeiss CLD600 deuterium light source with an attenuated total reflectance 661.872-UVS immersion probe by Hellma with associated quartz glass fiber optic cables. A MCS621 spectrometer cassette with a 14 thermoelectronically controlled housing, covering wavelengths of 320−1080 nm with a resolution of 2.4 nm, was used and controlled by a Zeiss processXplorer and Aspect Plus software v.1.76 with measurement intervals every 60 s. Polarimetry was performed (automatic Intersystems polarimeter AA-100 was used with sensitivity to ±0.002 of a millidegree) on samples and products to ascertain the materials’ optical purity. Sample preparation involved addition of a known amount of material dissolved into a known amount of distilled water (typically 0.25 g in 25 mL) forming a 1% solution which was placed into a 2 dm3 glass polarimeter tube with amended bulb. Observed rotation was recorded in triplicate and an average taken to calculate the specific rotation. Samples and products were observed throughout this study using optical microscopy to determine emulsion stability, particle and drop

sizes, shapes, and possible identification of known crystalline materials. For this purpose a Zeiss Axioplan 2 polarizing light microscope controlled by Linksys software was used. Both pXRD and morphological characterization were compared to their associated calculated powder patterns and linked to their BFDH-predicted morphology using additional Mercury v.2.1 software from the CSD. The solubility of the compound, conglomerate, and pure enantiomer in acetonitrile (Fisher 99.99%) were measured in the temperature range 15−60 °C using a gravimetric method. The solubility of the compound was also measured in pure toluene at 25 °C and diethyl ether (DEE) at 20 °C. Crystallization experiments were performed in racemic acetonitrile solutions (3.45 g/mL) by cooling in a jacketed vessel from 60 °C to RT at 10 °C/min and by evaporation (1.59 g/mL) at room temperature over a 48 h period. In DEE (0.1 g/ mL) crystallizations were performed by evaporation overnight, and some cooling crystallizations were performed from a 10% DEE/ acetonitrile solution. Finally, some crystallizations involved drown-out of 1 mL of acetonitrile solution (0.82 g/mL) into 5 mL of pure toluene or DEE at room temperature. All experiments were done with magnetic stirring. The choice of acetonitrile and dodecane as the dispersed and continuous phases, respectively, in the emulsion was made on the basis of a miscibility screen (performed at the 2 mL scale) of 12 different 4324

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Figure 3. (a) Racemic compound (GUMXAO02), and (b) pure S enantiomer (GASCEK). polar and nonpolar pairs and the fact that 2ClMA is soluble in acetonitrile and insoluble in dodecane. The extremely high aqueous solubility of 2ClMA ruled out the use of water-in-oil emulsions on a cost basis since they would have consumed too much 2ClMA. Emulsion crystallizations were performed in 25 mL of a stirred (overhead, two-bladed propeller, 700 rpm) acetonitrile solution/ dodecane (volume ratio 10:90) nonaqueous emulsion stabilized using 1% (of total system mass) Span80. 2ClMA was predissolved in acetonitrile to give a solution saturated at 60 °C (4.55 g/mL), and 2.5 mL of this solution was emulsified into 22.5 mL of dodecane at 60 °C, into which the surfactant was predissolved and formed the continuous phase. In order to effect preferential crystallization of the R enantiomer some of these emulsions were seeded (in the continuous phase) at levels up to 100% (based on the total mass of 2CMA in the system). Thus, for example, a typical experiment performed at 100% seeding level was comprised of 22.5 mL of dodecane, 2.5 mL of saturated acetonitrile solution, 11.4 g of racemic 2ClMA, and 11.4 g of R seeds. These crystallizations were carried out over varying total time periods from 0.5 to 24 h with a final cooling temperature of 54 °C. In some cases sampling of the solid phase at 30 min intervals was performed. Products were filtered under vacuum, and excess dodecane adhering to the crystalline filtrates was removed by washing with warm (40 °C) hexane. A limited number of experiments were carried out in which a racemic melt was emulsified in dodecane at 90 °C. A 2.5 g amount of molten 2ClMA was added dropwise to 22.5 mL of dodecane with 1% Span80 predissolved. Solid products were characterized by combinations of optical microscopy, pXRD, and DSC. Enantiomeric excess (ee) values were calculated using the measured optical rotation data and taking into account the contribution of the added seeding level.

appearing as elongated prisms. Figure 1 shows typical crystals growing from acetonitrile. The plate-like appearance of the pure enantiomer is evident, and Figure 2 shows the pXRD pattern of an unground sample of these crystals in which the preferred orientation is striking and corresponds very well with the BFDH morphology prediction (Figure 1c), which suggests the appearance of (001) plates. The inset in Figure 2 shows the correspondence between these slow-growing (001) faces and the weak edge to edge contacts between the phenyl rings. On the basis of these observations it was relatively easy to characterize the products of crystallization from racemic solutions initially though microscopic observation of the crystal morphology and more definitively using pXRD and melting point determination. Crystal Structures. Figure 3a and 3b shows the essential intermolecular H-bonding arrangements in the crystal packings of the racemic compound and the pure enantiomer. In the racemic compound the carboxylic acid groups are involved in centrosymmetric hydrogen-bonded dimers with one carbonyl having an extra −OH contact. In the pure enantiomer there are no such dimers; instead, one acid group is H bonded to carbonyl and hydroxyl groups on an adjacent molecule (R22(10)), while a second acid group forms a bifurcated contact with the hydroxyl on an adjacent molecule. These differences are reflected in the fingerprint region of the state solid FTIR spectra9 shown in Figure 4D and 4E. In the pure enantiomer (Figure 4D), the carbonyl absorbance around 1700 cm−1 is split as expected given the two significantly different environments. In the racemic compound the environment of both carbonyls is dominated by the presence of the dimer, leading to a single peak at 1700 cm−1 as well as the rather broad absorbance centered at 900 cm−1 typical of the out of plane O−H wag within the carboxyl dimer. Solubility. Figure 5 shows the solubility data measured in acetonitrile. Initial estimates of the solubility of the conglomerate as being twice that of the pure enantiomer1 gave the red line in Figure 5, suggesting the conglomerate to be less soluble than the racemic compound. From crystallization studies (see below and ref 4) it was known that the conglomerate transformed to the compound and hence that it must be the more soluble of the two. One data point measured at 25 °C confirmed this, but it was evident that the

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RESULTS Characterization of Solid Forms. The R,S compound and conglomerate were distinguished by combined use of melting point determination and pXRD. Previous studies2 report the melting points of pure enantiomer and compound to be 118.7− 119.2 and 89.9−90.2 °C, respectively, while the conglomerate melts in the range 83−85.5 °C. Lorenz et al.2 additionally demonstrated the use of pXRD in discriminating the pure enantiomer, stable compound, and metastable polymorph of the compound (CSD ref code GUMXAO, mp 72−76 °C). Of course, since the conglomerate is an equimolar mixture of pure enantiomers, its identification requires both pXRD and melting point determinations. Additionally, it was found that the crystal morphology of pure R crystals differed significantly from that of the stable compound, the former being plate-like and the latter 4325

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previously3 based on thermochemical data. The ratio, α, of the solubility of conglomerate to pure enantiomer is 2.43 in acetonitrile, well in excess of the ideal value of 2, suggesting that not only do the two enantiomers not experience R−S interactions in solution but that they are in fact solvated. This conclusion is borne out by the FTIR spectra (Figure 4B and 4C) of pure enantiomer and racemate solutions which in both cases show the 2ClMA carbonyl stretch close to 1750 cm−1 (cf ∼1700 cm−1 in the solid phases). This equivalence indicates no specific intermolecular H bonds between R and S molecules but rather solvation of the carboxylic acid group, presumably via interactions of acetonitrile with the acid hydroxyl group, leaving the carbonyl experiencing only weak van der Waals contacts. Crystallization Experiments. In racemic acetonitrile solutions, whether from cooling or evaporative crystallization, the only form observed was the stable racemic compound, see Figure 1a. In drown-out experiments using toluene as the drown-out solvent, the mixture went cloudy almost directly upon addition of the acetonitrile solution. The precipitate was filtered within 30 s and identified as the stable racemic compound in 7 out of 10 repeats of this experiment. The conglomerate formed in only three cases. In experiments in which the precipitate was left to stir for times longer than about 30 s the product was always the stable racemic compound. Using DEE as the drown-out solvent there was no immediate precipitate upon mixing; instead, crystals appeared after the solution was left stirring and evaporating over a 12 h period. During this time the viscosity of the solution increased, and when most of the DEE had evaporated the conglomerate formed. Of 10 repeats all gave the conglomerate. Microscope observation on a drop of this solution afforded the possibility of direct observation of the transition from conglomerate to racemic compound as seen in Figure 8 in which the central group of plate-like crystals of the pure enantiomer can be seen dissolving at the expense of the growing crystals of the stable compound. Observations of the speed of crystallization in these drownouts appear to be reasonable when considering that the solubility of the compound in toluene is 0.0084 g/g toluene and in DEE 0.738 g/g diethyl ether. Drown-out in toluene thus produces much larger supersaturations and hence faster crystallization than in DEE. Cooling crystallization of a racemic solution from acetonitrile with 10% DEE added gave, first, the conglomerate at 23 °C and, on further cooling, rapid transformation to the compound. Given that an identical experiment in pure acetonitrile always gave the compound this does implicate DEE as having a specific role in formation of the conglomerate. Emulsion Crystallization. Given that the melting points of the conglomerate and the stable racemic compound lie between 83 and 90 °C and that crystallization of the conglomerate from the melt has been observed previously it seemed feasible to perform initial crystallization experiments by emulsifying molten racemate in dodecane. Experiments were performed both on a microscope slide and in the jacketed vessel. In both cases it was clear that crystallization took place within the drops, initially as the conglomerate with subsequent conversion to the stable compound. Given that the locus of crystallization was within the drops rather than in the continuous phase, this technique was not explored further as a purification method.

Figure 4. FTIR spectra of 2-chloromandelic solids and solutions: (A) acetonitrile solvent; (B) R-2ClMA pure enantiomer in acetonitrile solution (0.235 g/mL, RT); (C) RS-2ClMA compound in acetonitrile solution (0.671 g/mL, RT); (D) R-2ClMA pure enantiomer solid; (E) RS-2ClMA compound solid.

Figure 5. Solubility of 2-chloromandelic acid as a function of temperature: Pure, R enantiomer is in green, stable compound in blue, conglomerate as black points, and estimated conglomerate in red.

transformation occurred rather quickly and hence that this point may be subject to significant error. In order to check this, one experiment was performed at 15 °C in which the solution composition of a stirred slurry of conglomerate was monitored with time using the UV−vis probe. The results of this experiment are in Figure 6, which shows the evolution of concentration with time. During the first 700 s the concentration rises as conglomerate is added to the acetonitrile and dissolves. At about 800 s the solution concentration reaches the solubility of the conglomerate, and further additions of solid conglomerate create a slurry. This is followed by rapid conversion of the conglomerate to the racemic compound and hence a fall in solution composition to the solubility of the compound. As seen in Figure 6 these data are in good agreement with the solubility values measured at 15 and 25 °C by gravimetric analysis. Thus, it is confirmed that the conglomerate is more soluble than the compound and that the lifetime of the conglomerate is on the order of 10 min at 15 °C. Figure 7 takes the data points at 25 °C and displays them, together with previously reported data4 in ethyl acetate, in a schematic ternary phase diagram. The logarithmic ratio of the mole fraction ln(Xconglomerate/Xracemic compound) = 0.18 in ethyl acetate and 0.11 in acetonitrile, suggesting a free energy difference between the forms of 0.3−0.5 kJ/mol, which is in good agreement with the value of 0.3 kJ/mol calculated 4326

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Figure 6. Solution compositions versus time (black squares) for a conglomerate slurry in acetonitrile at 15 °C performed to obtain its solubility and conversion time to the compound. Also shown for reference are the solubility of 2ClMA conglomerate at 15 °C (black triangle), solubility of 2ClMA conglomerate at 25 °C (red square), solubility of RS-2ClMA compound at 15 °C (green square), solubility of RS-2ClMA compound at 25 °C (purple square), solubility of R-2ClMA at 15 °C (blue square), and solubility of R-2ClMA 25 °C (orange square).

The appearance of the conglomerate in this situation further suggested that seeding such emulsions with pure R enantiomer may offer a route to an enantiomerically enriched product. The R enantiomer would be transported from the drops through the continuous phase to drive the growth of the R seeds, while the emulsion drops would become enriched in S enantiomer but due to their decreased size be reluctant to nucleate.7 Hence, a number of emulsion crystallizations were performed in which the seeding level was increased up to a maximum of 100% R based on the total R,S composition of the emulsion. As expected from the unseeded experiments, such emulsions, when run for times in excess of 2 h, always yielded a product which was a mixture of the initial seeds together with the stable racemic compound. However, again based on the behavior of the unseeded emulsions it was judged that if the emulsion was allowed to crystallize for only 30 min, growth of the R seeds may occur without nucleation of the stable or metastable compound occurring. In this case the solid product would exhibit some enantiomeric enrichment which might be expected to increase with the seeding level. The results of these 30 min experiments confirmed that the emulsion droplets did not crystallize and that all the crystallization took place in the continuous phase as evidenced by the final size of the crystals being at least an order of magnitude larger than the emulsion drops. Figure 10 shows both the initial seeded emulsion and the crystallized product 30 min later which appears to have a morphology consistent with pure enantiomer. Polarimetry confirmed that indeed an excess of the R enantiomer had been achieved. Enantiomeric excess data are shown in Table 1 and indicate that almost 40% enantiomeric excess of R (taking into account the seeding level) is possible in this system, despite the metastability of the conglomerate and the tendency of the

Figure 7. Schematic ternary diagram for 2-ClMA in ethyl acetate (small squares ref 3) and acetonitrile (large squares, nb, eutectics not measured) (mole fraction).

In acetonitrile/dodecane emulsions solution drops sizes were typically in the range 50−100 μm and crystallization took place on cooling the emulsion from 60 to 54 °C. In nonseeded emulsions crystals were observed (Figure 9) to form within the continuous phase and not in the emulsion drops. pXRD and DSC indicated that after 2 min the product comprised a mixture of conglomerate and the metastable polymorph of the compound (GUMXAO) and that this situation continued for up to 1 h. By 90 min the metastable compound had disappeared in favor of a mixture of the conglomerate and the stable compound. The final product after 2 h was the stable compound. This transformation sequence, metastable compound (β) to metastable conglomerate to stable compound (α), appears to be in agreement with previous work on racemic melts.3 4327

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Figure 8. Solution-mediated transition from conglomerate to compound in an acetonitrile/DEE mixture. These photos cover a 30 min time period at RT. Scale bar is 100 μm.

Table 1. Enantiomeric Excess Data for Products of Seeded Emulsion Crystallizationsa wt of seed added (wt %)

yield of R (%)

ee of R in product (%)

5 10 20 100

3 8 23 46

4 6 18 38

a

The wt % of seed added is based on the total amount of 2ClMA in the system. Calculated yield is based on the total amount of R present in the product after subtraction of that arising from the seeds. Enantiomeric excess was calculated in the standard way.1

system to form the racemic compound. As the amount of seed added increased, yields of R recovered were between 2.8% and 46%.

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CONCLUSION AND DISCUSSION In agreement with previous reports, both solubility and crystallization data have confirmed the metastability of the conglomerate relative to the stable compound. A combination of solubility measurements, in-line UV−vis monitoring, and FTIR spectroscopy showed that racemic solutions deviate significantly from ideality due to solvation of the 2ClMA carboxyl group. In attempting to find a link between solution chemistry and crystallization it might be tempting to surmise that the existence of the conglomerate owes something to this solvation and the fact that R and S molecules are not associated in solution. This might then lead to the kinetically driven nucleation of pure enantiomer crystals rather than the compound, even in racemic solutions. However, one has to proceed with caution since exactly the same solution chemistry is true for the parent compound, mandelic acid in which there is no conglomerate and only the racemic compound is ever seen.10 In attempts to define a conventional solution crystallization process for isolation of the conglomerate it has been found that,

Figure 9. Product of an unseeded emulsion showing uncrystallized emulsion drops and crystals (racemic compound) in the continuous phase. Scale bar is 50 μm.

Figure 10. Seeded emulsion (a) after addition of seeds; (b) crystallized product in which the plates are pure enantiomer and the rod is α-racemic compound. Scale bar (a) 50 (b) 100 μm.

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despite previous reports2 that the synthetic route based on toluene as a solvent yields the conglomerate, a drown-out crystallization using toluene as the major component did not lead to consistent outcomes: the conglomerate appeared in only 30% of trials. On the other hand, when DEE was used as part of the solvent system the conglomerate could be obtained consistently. Attempts to capitalize on the existence of the metastable conglomerate proved successful within the emulsion environment. Here, crystallization of the pure enantiomer in the continuous phase was encouraged by seeding with R crystals and provided the overall crystallization time was kept within 30 min crystallization of the drops (and hence the compound) could be avoided. Enantiomeric excesses of up to 38% could be achieved with up to 46% of the original acid recovered.

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ASSOCIATED CONTENT

S Supporting Information *

pXRD patterns for each experiment and data points for Figures 5, 6, and 7. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS S.E.G. and R.J.D. acknowledge financial support from SanofiAventis which funded this research. ABBREVIATIONS 2ClMA, R,S-2-chloromandelic acid; pXRD, powder X-ray diffraction; CSD, Cambridge Structural Database; DEE, diethyl ether; DSC, differential scanning calorimetry; FTIR, Fourier transform infrared spectroscopy; UV−vis, ultraviolet visible; BFDH, Bravais, Friedel, Donnay, and Harker; RT, room temperature; mp, melting point

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REFERENCES

(1) Jacques, J.; Collett, A.; Wilen, S. H. Enantiomers, Racemates and Resolutions; John Wiley and Sons: New York, 1994. (2) Lorenz, H.; Von Langermann, J.; Sadiq, G.; Seaton, C. C.; Davey, R. J. Cryst. Growth Des. 2011, 11, 1549−1556. (3) He, Q.; Rohani, S.; Zhu, J.; Gomaa, H. Cryst. Growth Des. 2010, 10, 5136−5145. (4) Davey, R. J.; Sadiq, G.; Back, K.; Wilkinson, L.; Seaton, C. C. Chem. Commun. 2012, 48, 1976−1978. (5) Davey, R. J.; Blagden, N.; Potts, G. D.; Docherty, R. J. Am. Chem. Soc. 1997, 119, 1767−1772. (6) Weissbuch, I.; Zbaida, D.; Addadi, L.; Leiserowitz, L.; Lahav, M. J. Am. Chem. Soc. 1987, 109, 1869−1871. (7) Davey, R. J.; Garside, J.; Hilton, A. M.; McEwan, D.; Morrison, J. W. Nature 1995, 375, 664−666. (8) Chadwick, K.; Davey, R. J.; Mughal, R. Org. Process Res. Dev. 2009, 13, 1284−1290. (9) He, Q.; Gomaa, H.; Jennings, M.; Rohani, S. J. Pharm, Sci. 2009, 98, 1835−1844. (10) Mughal, R. K.; Davey, R. J.; Blagden, N. Cryst. Growth Des. 2007, 7, 218−224.

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