Crystallization of the Racemic Compound and Conglomerate of (

DOI: 10.1021/cg100879p

Crystallization of the Racemic Compound and Conglomerate of (RS)-2-Chloromandelic Acid

2010, Vol. 10 5136–5145

Quan He,† Sohrab Rohani,*,‡ Jesse Zhu‡ and Hassan Gomaa‡ †

Department of Chemical Engineering, Ningbo University of Technology, Ningbo 315016, China, and Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, Ontario N6G 4R3, Canada

‡

Received July 2, 2010; Revised Manuscript Received September 7, 2010

ABSTRACT: (RS)-2-Chloromandelic acid is a new example of chiral compounds that can exist as a racemic compound or a conglomerate depending on the crystallization conditions. Two polymorphic racemic compounds and one conglomerate were disclosed and characterized in this work. Commercially available racemic compound Form R can be prepared by crystallization from nonpolar solvents such as toluene. Freeze-drying leads to a conglomerate formation, Form γ. Crystallization from polar solvents always results in a mixture of Form R and Form γ under our experimental conditions. Thermodynamic calculation of the Gibbs free energy of racemic compound formation demonstrates that the conglomerate Form γ is slightly less stable than the racemic compound Form R. The conglomerate has a tendency to transform into racemic compound by a solid-solid transition. Another metastable racemic compound, Form β, was observed as a single crystal grown from methanol. But bulk crystals of Form β were not obtained.

1. Introduction The chiral nature of drugs is a major concern in the pharmaceutical industry, since a pair of enantiomers has different pharmacological activity. Developing a pure enantiomer is of great significance. Crystallization resolution continues to be one of the most efficient and practical techniques to produce enantiopure compounds on an industrial scale.1 Crystallization resolution includes direct crystallization (preferential crystallization or spontaneous resolution)2 and diastereomeric crystallization (classical resolution).3 The direct crystallization can only be applied to conglomerates and consists of crystallizing single enantiomers by seeding a supersaturated racemic solution with the opposite enantiomers alternatively. Both enantiomers can be obtained without introducing any chiral reagent. Obviously, direct crystallization is simpler and more cost-effective than any other methods. It is generally believed that only 5% to 10% of all organic racemates belong to conglomerates and that racemic compounds rather than conglomerates tend to crystallize from a racemic solution. The racemic compound is thermodynamically more stable than the conglomerate.4,5 However, the statistical data attributing a 5-10% probability to conglomerate formation may be statistically biased in the collection of racemate/enantiomer pairs.6 Quite often, the experimental conditions for preparing racemates are not clearly reported. It is difficult to elucidate to what extent the results reflect the thermodynamics of the system or whether kinetic limitations play a role. In addition, just like most organic compounds, the polymorphism is also prevalent in chiral molecules.5,7-12 It is possible that a racemate exists as a racemic compound under one condition but as a conglomerate under another set of conditions. Regarding the design of crystallization resolution, it is of crucial significance to screen all possible polymorphs of racemate and enantiomers, followed by determining the relative stability of racemic compound and conglomerates. It is advantageous to broaden the application of direct crystallization by increasing the probability of conglomerate formation by careful control of the crystallization process. pubs.acs.org/crystal

Published on Web 10/20/2010

Enantiopure (R)-2-chloromandelic acid (hereafter (R)-2ClMA) is an important intermediate for the production of clopidogrel, a widely administered anticoagulant that can reduce the risk of cardiovascular failures in patients with acute coronary syndromes. Many efforts have been made to develop efficient synthesis methods for (R)-2-ClMA.14,15 However, reported preparation methods have drawbacks, such as low yield and high cost of the chiral selectors employed. Therefore, developing a more efficient and cost-effective (R)-2ClMA preparation method is of importance. This system is of particular interest because the melting point of enantiomer (R)-2-ClMA, 118.7 C, is much higher than 89.9 C of (RS)-2-chloromandelic acid (hereafter 2-ClMA), which is an indicator of the conglomerate nature of 2-ClMA.13 However, in our previous work,15commercially available 2-ClMA was proven to be a racemic compound, hereafter noted as racemic compound Form R. In current work, we systematically screened the polymorphs of 2-ClMA with the underlying ambition to find a stable conglomerate for a potential application of direct crystallization to prepare the (R)-2-ClMA. A conglomerate, designated as Form γ, and another racemic compound Form β were found. Three solid phases of 2-ClMA were thoroughly characterized by thermal analysis, X-ray diffraction, and solid-state spectroscopy. The relative thermodynamic stability and the possibility of transformation among R, β, and γ forms were explored. The stability of the conglomerate lies between stable racemic compound Form R and metastable Form β. The favorable stability of the conglomerate enhances the possibility of direct crystallization application. 2. Experimental Section 2.1. Materials. (RS)-2-Chloromandelic acid with 98% absolute purity, (R)-2-chloromandelic acid with 99% e.e. optical purity, and (S)-2-chloromandelic acid with 98% e.e. optical purity were purchased from Aldrich-Sigma Canada (Oakville, ON). All solvents were HPLC grade from Aldrich-Sigma Canada (Oakville, ON) and were used without further purification. r 2010 American Chemical Society

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Table 1. Solid Forms of 2-ClMA Racemate and Enantiomer source Form R Form β Form γ En-I

commercially available single crystal from methanol, no bulk crystals obtained from freeze-drying and melt crystallization commercially available

racemic type

melting point (C)

enthalpy of fusion (kJ/mol)

racemic compound racemic compound

89.9 ( 0.5 N/A

23.1 ( 1.0

conglomerate, corresponding to En-I enantiomer (R)-2-ClMA

85.0 ( 0.5 118.7 ( 0.5

21.4 ( 1.0 24.9 ( 1.0

2.2. Characterization Methods. X-ray and XRPD Powder Diffraction. The XRPD spectra were collected on a Rigaku-Miniflex benchtop X-ray powder diffractometer (Carlsbad, CA) using Cu KR (λ = 1.54059 A˚) radiation obtained at 30 kV and 15 mA. The scans were run from 5.0 to 40.0 2θ, increasing at a step size of 0.05 2θ with a counting time of 2 s for each step. The diffractograms were processed using JADE 7.0 Software. Calibration was performed using a silicon standard. Raman Spectroscopy. Solid-state Raman spectra were recorded with a Raman RXN1-785 spectrometer (Kaiser Optical Systems Inc., Ann Arbor, MI) equipped with a diode laser (784.5 nm) and a fiber optic probe. The software used was iCRaman v2.0. Calibration of the Raman shift was performed using cyclohexane, the factory-set Raman shift standard. The Raman shift range was 3245 to 100 cm-1, and spectral resolution was 10 cm-1. The collection time was set to 30 s, and samples were collected three times. Differential Scanning Calorimeter (DSC). The melting point and enthalpy of fusion were measured with a Mettler Toledo DSC 822e differential scanning calorimeter (Greifensee, Switzerland). Accurately weighed samples (3-12 mg) were prepared in a covered aluminum crucible having pierced lids to allow escape of volatiles. The sensors and samples were under nitrogen purge during the experiments. The temperature calibration was carried out using the melting point of highly pure indium in the medium temperature range. Heating rates of 1, 3, 5, and 10 C/min were tested, and the best heating rate was selected. Hot Stage Microscopy (HSM). The melting behavior and thermal transition of solid samples were visually investigated with a Linkam LTS350 hot stage equipped with a Linkam TNS 94 programmable heater, a Linkam LNP cooler, and a ZEISS microscope. The heating temperature range is from 25 C to 120 C with a heating rate of 5 C/min. X-ray Single Crystal Diffraction. Single crystals of Form R of 2-ClMA were grown from a toluene solution by slow evaporation at 4 C. The data were collected at 295 K on a 2D detector (Bruker Smart 6000 CCD) and a 3-circle diffractometer (Bruker D8) using Cu KR radiation (λ = 1.54184 A˚). The structures were solved with direct methods using the SHELXS-97 program and refined on F2’s by full-matrix least-squares with a SHELXL-97 program. Single crystals of Form β of 2-ClMA were grown from concentrated methanol solution by slow evaporation at room temperature. A translucent colorless chiplike crystal was mounted on a glass fiber, and data were collected at low temperature, 150 K, on a Nonius kappa-CCD area detector diffractometer with COLLECT using monochromatic Mo KR radiation (λ = 0.71073 A˚). The structures were solved with direct methods using the SHELXS-97 program and refined on F2’s by full-matrix least-squares with the SHELXL-97 program. 2.3. Crystallization by Freeze-Drying. Form R of 2-ClMA dissolved in water was sublimated to afford solid by freeze-drying technology on a benchtop manifold freeze drier, Thermo Electron Corporation Modulyod-115 (San Diego, CA). The operating temperature was -54 C, and the pressure was 0.2 mbar. 2.4. Solution Crystallization. Form R was achieved by crystallizing from nonpolar solvents as discussed in the literature.16 2-ClMA (1.8 g) was suspended in 50 mL of toluene and heated to 60 C to afford a clear solution. The solution was cooled to 18 C with a linear cooling rate of 10 C/h. The resulting solid was characterized and was proven to be Form R. 2-ClMA Form R was dissolved in polar solvents such as water, ethanol, methanol, and 2-propanol. The solution was put in a fume hood to evaporate the solvent completely at 22 and 45 C, respectively. The resulting solid was proven to be a mixture of Form R and Form γ. The solution was put in the fridge to evaporate solvent slowly at 4 C.

Figure 1. XRPD patterns of solid forms of the racemate. The obtained crystal was also a mixture of Form R and Form γ. Batch cooling crystallization was conducted as follows: 20 g of 2-ClMA was dissolved in 10 mL of water and was heated to 45 C. The clear solution was cooled to 4 C naturally to afford white crystals, which was Form R mixed with a small amount of Form γ.

3. Results and Discussion 3.1. Characterization and Identification of Solid Forms of 2-ClMA. The commercially available racemic compound Form R was recrystallized using different strategies to seek the possible conglomerate formation. The resulting solids were characterized by thermal analysis, Raman spectroscopy, and XRPD. Form R can be obtained by crystallization from toluene as described in section 2.4. The calculated X-ray diffraction pattern based on the single crystal structure was in good agreement with the experimentally measured pattern of bulk R form shown in the Supporting Information. Form β is a metastable racemic compound. Single crystals of β form were grown in methanol by very slow evaporation at room temperature, and crystal data were collected at -123 C, but crystals became opaque quickly and transformed to other forms. No bulk crystals of Form β were isolated due to its unstable nature. But the form was observed from melt crystallization. Form γ is a conglomerate obtained by freeze-drying. Commercially available enantiomer was designated as En-I, which corresponded to conglomerate γ, as they presented the same XRPD pattern and Raman spectra. Unfortunately, we failed to grow quality single crystals of En-I. For all forms reported here, there were no mass losses observed under the TGA thermal analysis, indicating that these forms are anhydrous or nonsolvated. For the clarification in the following sections, the physical properties of solid forms of racemate and enantiomer are summarized in Table 1. XRPD patterns are illustrated in Figure 1, and distinguished characteristic peaks are listed in Table 2. Raman spectra are depicted in Figure 2, and characteristic Raman shifts are summarized in Table 3.

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Table 2. XRPD Peaks of Solid Forms characteristic peaks 2θ/deg Form R Form β Form γ

9.99 6.30 6.56

14.06 12.65 13.18

14.59 14.8 16.28

16.17 17.08 18.56

22.52 19.12 19.84

24.96 22.06 23.04

27.58 23.69 26.54

30.18 27.52 29.08

37.52 36.68 35.42

Figure 4. Raman spectra of crystals obtained from freeze-drying. Figure 2. Raman spectra of racemic compound Form R and Form γ.

Figure 3. XRPD patterns of crystals obtained from freeze-drying. Table 3. Raman Shift of Solid Forms characteristic Raman shift/cm-1 Form R 199.8 280.4 530.1 641.3 858.5 1448.8 1639.8 Form γ 149.7 524.6 537.4 659.9 853.1 863.1 169.42

3.2. Crystallization by Freeze-Drying. 2-ClMA Form R dissolved in water was subject to freeze-drying to afford the solid phase. The resulting solid was characterized by DSC, XRPD, and Raman spectroscopy. DSC showed only one melting peak; no other thermal events were observed. The melting point of 85.5 C and the fusion enthalpy of 21.5 kJ/ mol were determined by DSC. Figure 3 shows the XRPD pattern of solid from freeze-drying compared with those of racemic compound Form R and enantiomer En-I. The same pattern as that of commercially available Form En-I implies the conglomerate nature of the solid. The Raman spectra were also similar, as shown in Figure 4. We further calculated the theoretical melting point of conglomerate on the basis of the melting point and fusion enthalpy of (R)-2-ClMA En-I by the Schroder-van Laar equation.4 The calculated conglomerate melting point of 86.1 C was consistent with the experimental value of 85.5 C, which further verified the

Figure 5. XRPD patterns of solid crystallized from the melt of Form R.

form was a conglomerate. The thermal and spectroscopic evidence demonstrated that freeze-drying leads to a conglomerate formation. The newly found form is designated as conglomerate Form γ. 3.3. Melt Crystallization. Recrystallization from a melt is a well-known method to detect polymorphs.17,18 Upon cooling the melt of Form R from 100 C to room temperature, metastable racemic compound β form and conglomerate Form γ were observed. The crystallization from the melt of Form R was tracked by an ad-hoc experimental procedure. The powder samples were placed on the XRPD slide and melted in an oven. The melt was moved to the XRPD machine, and the diffraction patterns were monitored as a function of time. Each XRPD run took 23 min. The initial melt exhibited several peaks immediately upon cooling for about 10 min, showing the occurrence of crystallization. After 23 min, there emerged more strong peaks in the second run, as shown in Figure 5. Interestingly, some of these peaks decreased in their intensity, some peaks kept growing, and even some new peaks appeared with time, indicating crystallization and transformation of more than one phase. Carefully

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examining the changes of these peaks demonstrated that the strong peaks at 2θ such as 6.29, 12.68, 17.20, 19.05, and 25.49 can be attributed to the β form. These characteristic peaks kept decreasing with time and finally vanished. Peaks related to enantiomer En-I such as those at 6.57, 13.15, 16.26, 19.88, 23.05, 26.59, and 35.45 emerged gradually, and their intensities increased. After 8 days, all the characteristic peaks of En-I grew, and the intensities of these peaks were comparable to those of enantiomer En-I. Therefore, we concluded that resulting crystals from the melt of racemic compound R form were conglomerate Form γ. A phase transition occurred from metastable racemic compound Form β to conglomerate Form γ. Thermal analysis of the solid from melt is shown in Figure 6. In accordance with the XRPD patterns in Figure 5, after the first XRPD run (23 min), a small piece of sample from the XRPD sampler was taken and run on the DSC. The broad peak shown in Figure 6 demonstrates the melting behavior and possible phase transition of the metastable phase crystallized from the melt. After 3 days, the DSC curve of the samples exhibited one peak, indicating that most solid had transformed into Form γ.

Figure 6. DSC traces of solid crystallized from melt at different times.

Figure 7. Hot stage micrographs of Form R.


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After 8 days, solid from the melt completely converted into conglomerate γ, and the values of the melting point and heat of fusion were close to those of the conglomerate obtained from freeze-drying. In order to further verify the observation, a hot stage microscope (HSM) was employed to visually observe the thermal events happening during heating and cooling. The racemic compound R form was heated under a HSM with a heating rate of 5 C/min. The photomicrographs are displayed in Figure 7. Image a shows the powder samples of R form at 25 C. When heated to 88 C, a small move of crystals was observed. At 89 C, shown in Figure 7b, the crystals started to melt and the edge became round; then quickly the crystals melted completely to form big liquid droplets at 92 C, shown in Figure 7c and d. The observed melting behavior was exactly the same as the onset and end-set temperatures of the melting point measured by DSC. Upon cooling, crystallization did not happen immediately due to the smooth surface of the microscope slide. It was difficult to detect the crystallization of Form β and the phase transition to conglomerate Form γ. However, after 1 day, reheating the crystals on the microscope slide provided some clues to help identify the polymorphic behavior. As shown in Figure 8b, when the crystals on the slide were reheated, several blocks of crystals started to melt at 70 C and turned completely into liquid at 75 C, which should correspond to the melt of metastable phase Form β. Most blocks did not change upon heating from 70 to 75 C. At 83 C, crystals started to move and melt into big liquid drops below 88 C, as shown in Figure 8d. Although we were not able to clearly capture the phase transition upon crystallization, the observation of reheating the crystals from the melt under HSM suggested that two phases coexisted in the solid crystallized from the melt. The results were consistent with the DSC traces shown in Figure 6.

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Figure 8. Hot stage micrographs of reheating solid crystallized from the melt.

The XRPD patterns and thermal analysis described above demonstrated that the solid crystallized from the melt was a mixture of Form β and Form γ. Form β was a metastable phase; it converted completely into Form γ after 8 days. The results were in accordance with Ostwald’s rule,19 stating that the least stable phase preferably crystallizes first and subsequently converts into the more stable form. 3.4. Solution Crystallization. Form R was recrystallized from polar solvents such as water, methanol, ethanol, and 2-propanol, as described in section 2.4. The resulting solid from ethanol, water, and methanol presented complicated XRPD peaks. They mainly showed the pattern of racemic compound Form R. But there were several peaks at 2θ angles such as 6.59, 18.59, and 29.11, coinciding with the characteristic peaks of conglomerate Form γ. The representative XRPD of solid from ethanol is shown in Figure 9. XRPD peaks implied that the resulting solid could be a mixture of racemic compound Form R and conglomerate Form γ. Raman spectra giving the consistent trend with XRPD are not presented here. DSC curves provided further evidence as depicted in Figure 10(2). There is a small endothermal curve located about 85 C before the major melting peak of Form R, which should correspond to the melting of Form γ. The HSM investigation clearly demonstrated two melting behaviors and ruled out the possibility that the crystals from ethanol were a new form. In contrast, the XRPD of solids crystallized from 2-propanol exhibited the same pattern as that of Form R, and no characteristic peaks of Form γ were observed. The melting point of 89.5 C was in agreement with that of Form R (89.9 C) shown in Figure 10(3). However, the heat of fusion was lower than that of Form R. After grinding, the heat of fusion increased and became closer to that of Form R, which meant that the solids crystallized from 2-propanol were contaminated by very small amounts of Form γ, which was not detectable in XRPD patterns.

Figure 9. XRPD patterns of solid crystallized from ethanol.

Figure 10. DSC traces of solid crystallized from polar solvents.

The above experimental results demonstrated a trend that recrystallization of Form R from a nonpolar solvent such as toluene and hexane led to the original racemic compound R

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Figure 11. DSC traces of crystals from ethanol before and after annealing.

form, whereas that from polar solvents such as methanol and ethanol resulted in a mixture of mainly Form R with some Form γ. The exact crystallization conditions for the formation of pure conglomerate or pure racemic compound from polar solvents were not found under our experimental scope. The mixture of conglomerate and racemic compound has also been observed in several reported chiral systems.5,20,21 In the present work, we found that conglomerate-racemic compound formation was strongly dependent on solvent polarity, whereas other researchers have observed temperature as the determining factor.8,10,12,22 3.5. Solid Phase Transformation of Conglomerate and Racemic Compound. As we found in section 3.4, crystallization of 2-ClMA from polar solvents resulted in a mixture of Form R and a small amount of Form γ. When grinding was applied on the mixture, Form γ tended to transform into Form R. The ground mixture was maintained at room temperature for 2 years and completely converted into Form R. A DSC trace of the crystals showed one sharp peak at 90.1 C, and XRPD exhibited the same pattern as that of Form R. These observations suggest that conglomerate Form γ was a metastable phase and transformed into stable phase racemic compound R form. The transition took place very slowly without additional energy. In order to further investigate the relationship between racemic compound Form R and conglomerate Form γ, the solid phase transformation (SPT) between two forms was investigated by annealing solids at different temperatures. The grinding was not employed due to the potential decrease in crystallinity and the introduction of a large number of defects in the structure.23,24 The solventmediated transition was not included in the study. The solid crystallized from ethanol was subject to annealing at 70 and 80 C prior to the melting of Form γ. At 80 C, it took 45 min for the small amount of Form γ to completely transform. At 70 C, it took 175 min. The characterization of crystals before and after annealing by XRPD peaks and Raman spectra clearly showed the disappearance of the characteristic peaks of Form γ. Thermal analysis by DSC was consistent with results from XRPD and Raman spectroscopy. As shown in Figure 11, the initial solid from ethanol presented a broad peak in the DSC thermogram, indicating a solid mixture feature. After grinding, the conglomerate showed the eutectic melting peak and the racemic compound presented the melting peak. After annealing at 70 and 80 C, conglomerate Form γ was converted into racemic compound completely. DSC traces showed only one endothermal peak that coincided with the melting point of Form R. The melting


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Figure 12. XRPD of Form γ annealing at 80 C.

Figure 13. DSC traces of Form γ annealing at 80 C.

point of 89.6 C and heat of fusion of 22.3 kJ/mol were both slightly lower than those of commercial racemic compound (mp 89.9 C, ΔHf = 23.1 kJ/mol). The reason is that the solid phase transition must be accompanied by a destruction and reconstruction process. The intermediate amorphous phase, solid solution, and disordered component may degrade the melting point and enthalpy of fusion.25,26 Conglomerate Form γ from freeze-drying was also subject to annealing at 80 C. After 18 h, most solids had transformed into Form R, and there was still a small amount of γ form left, and after 24 h, the solid transition was completed, as shown in Figures 12 and 13. To further verify the transformation of the conglomerateracemic compound, equivalent molar amounts of (R)-2ClMA and (S)-2-ClMA enantiomers were mechanically mixed to form an artificial conglomerate. The mixture was ground slightly and then was continuously vibrated under vortex. Every 24 h interval, a sample was taken out to be characterized by DSC, XRPD, and Raman spectroscopy. The melting point of the artificially mixed conglomerate was the same as the melting point of Form γ from freeze-drying at the beginning. After 2 days of mixing under vortex, some of the conglomerate gradually transformed to Form R and the mixture presented two thermal peaks in DSC. The XRPD peaks also showed the occurrence of a solid transition from conglomerate Form γ to racemic compound R. However, under vortex, after 15 days, there were still small characteristic peaks of Form γ in the XRPD profile and the transition was not competed. We left the mixture in a zipped plastic bag at room temperature in the lab. After 2 years, revisiting the conglomerate mixture, it had converted into racemic compound completely. The DSC traces and XRPD patterns

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Figure 14. Stability relationship among polymorphs of 2-ClMA. Table 4. Crystal Structure Data of Racemic Compound Forms R and β empirical formula formula weight (g/mol) temperature (K) wavelength (A˚) crystal system space group a (A˚) b (A˚) c (A˚) R (deg) β (deg) γ (deg) V (A˚3) Dcalc (g/cm3) Z crystal size (mm) reflections collected independent reflections goodness-of-fit on F2 final R indices (I > 2σ(I)) R indices (all data)

Form R

Form β

C8H7ClO3 186.59 295 1.54178 triclinic P1 a = 9.0874 (19) b = 9.805 (2) c = 10.830 (2) R = 66.066 (14) β = 74.371 (14) γ = 85.606 (14) 848.8 (2) 1. 46 4 0.4 0.2 0.06 8497 3006 1.033 R1 = 0.0502 wR2 = 0.1315 R1 = 0.0561 wR2 = 0.1414

C8H7ClO3 186.59 150 0.71073 monoclinic P21/c 14.1961(7) 8.0521(4) 14.4453(5) 90 99.177(3) 90 1630.08(13) 1.521 8 0.28 0.25 0.05 19332 2886 1.080 R1 = 0.0454 wR2 = 0.1126 R1 = 0.0562 wR2 = 0.1184

showed the same patterns as those of commercial racemic compound Form R. The conglomerate obtained by mixing R and S was also tested by annealing at 80 C, where the behavior of the solid transition was similar to that of conglomerate from freeze-drying. In summary, Form β appears to be the least stable form under present experimental conditions, which can transform into conglomerate Form γ easily, as we observed in melt crystallization. Form γ has reasonable stability and can convert slowly to racemic compound Form R at room temperature. However, it converts quickly to Form R with heating at a temperature below the melting point of Form γ. To our knowledge, the heating-induced transformation of a conglomerate to a racemic compound or the reverse, in solid state, is not a very common phenomenon, but the results are consistent with those of a few similar cases reported.8,10,27,28 The stability relationship among three forms was derived from the experimental observation and illustrated in Figure 14. 3.6. Crystal Structures of Racemic Compound Form r and Form β. The stability between racemic compound Form R and Form β cannot be compared from a thermodynamic viewpoint due to a lack of thermal data of Form β. The comparison of their crystal structures will provide evidence for the relative stability. The single crystal structures of racemic compound forms R and β were obtained. The crystallographic data are summarized in Table 4. The hydrogen-bonding geometry is listed in Table 5. Detailed geometric parameters

Figure 15. Two pairs of R and S molecules packing in a unit cell of Form R.

Figure 16. Atomic-numbering molecular structure of Form R. Table 5. Hydrogen-Bonding Geometry of 2-ClMA (d in A˚ and Angle in deg) D-H 3 3 3 A

d(D-H) d(H 3 3 3 A) d(D 3 3 3 A) — (DHA)

Form Ra O1A-H4 3 3 3 O3B #1 O1B-H6 3 3 3 O1A #2 O2B-H12 3 3 3 O3B#3 O2A-H16 3 3 3 O3A#4

0.779 0.814 0.788 0.905

2.136 2.025 1.883 1.740

2.880 2.836 2.671 2.640

160.06 174.47 177.77 173.13

Form βb O(19)-H(19A) 3 3 3 O(39)#1 O(21)-H(21A) 3 3 3 O(22)#2 O(39)-H(39A) 3 3 3 O(42)#3 O(41)-H(41A) 3 3 3 O(19)

0.84 0.84 0.84 0.84

2.12 1.83 2.05 1.82

2.958(3) 2.669(2) 2.894(3) 2.649(2)

172.4 177.1 179.5 169.2

a Symmetry transformations used to generate equivalent atoms: (#1) x, y þ 1, z; (#2) -x þ 1, -y þ 1, -z þ 1; (#3) -x, -y, -z þ 1; (#4) -x þ 1, -y þ 2, -z. b Symmetry transformations used to generate equivalent atoms: (#1) x, -y þ 1/2, z þ 1/2; (#2) -x þ 1, -y þ 2, -z þ 1; (#3) -x þ 1, y - 1/2, -z þ 1/2.

such as bond lengths and angles are summarized in the Supporting Information. In Form R crystals, there are four molecules in a unit cell, as shown in Figure 15. The atomic-numbering molecule is depicted in Figure 16. The hydrogen bond plays a key role in determining crystal packing. 2-Chloromandelic acid has three potential sites for hydrogen-bonding interactions. O2A and O3A of the carboxylic group form two hydrogen bonds with O2A and O3A of another heterochiral molecule in a hand in hand manner, as shown in Figure 17, to form a cyclic dimer hydrogen-bonding motif. Another cyclic dimer

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Figure 19. Two pairs of R and S molecules packing in a unit cell of Form β. Figure 17. Hydrogen-bonding motifs in a crystal structure of Form R.

Figure 20. Atomic-numbering molecular structure of Form β. Figure 18. Crystal packing in a crystal structure of Form R.

hydrogen-bonding motif is formed between O2B and O3B of the carboxylic acid and O2B and O3B of another molecule in the same manner. One cyclic dimer is linked with another dimer by a hydrogen bond, O1BH6 3 3 3 O1A, between the hydroxyl oxygen of one molecule and the hydroxy hydrogen of another adjacent molecule. The O1AH4 also forms a bond with the oxygen of the carbonyl part of O3B. Thus, a twodimensional hydrogen-bonding network vertical to the b-axis is formed. The interlinked two dimers construct building blocks to extend in three-dimensional space. The cyclic dimer hydrogen bonds link four oxygen atoms and form a plane; the phenyl rings are oriented to the opposite sides of the plane and nearly vertical to the plane. The angles of the phenyl planes and two cyclic dimer hydrogen-bonding planes are 78.56 and 75.11, respectively. All the phenyl rings are nearly vertical to one another to form a T-shaped intercrossing crystal structure. The crystal packing is illustrated in Figure 18. Form β has eight molecules in the crystal unit cell, as shown in Figure 19. The atomic-numbering molecule is shown in Figure 20. The two chiral molecules each show different patterns of hydrogen-bonding. The carboxylic acid consisting of O21 and O22 forms hydrogen bonds with a symmetry related molecule of itself to form a cyclic dimer

hydrogen-bonding motif. This closes off the option extending the hydrogen-bonding network. However, the second carboxylic acid molecule (O41-H and O42) forms two hydrogen bonds which serve to extend the hydrogen network along the b-axis and the c-axis. The carbonyl part (O42) of the carboxylic acid interacts with the hydroxy (O39-H) of a symmetry related molecule. The alcohol part (O41-H) of the carboxylic acid forms a hydrogen bond with the hydroxyl oxygen (O19) of an adjacent molecule. Finally, the hydroxy (O19-H) continues with a hydrogen bond to the hydroxyl oxygen (O39). The cyclic dimer hydrogen bonds linked to four oxygen atoms form a plane, and the related phenyl rings are oriented in opposite sides of the plane and nearly vertical to the plane. The angle of the phenyl plane and the cyclic dimer hydrogen-bonding plane is 83.48. The hydrogenbonding pattern is depicted in Figure 21. The molecular packing mode is shown in Figure 22. The crystallographic relationships among the molecules in Forms R and β differ significantly. In Form R, molecules form two kinds of cyclic dimer hydrogen-bonding motif, and the two dimers are linked by additional hydrogen bonds. In Form β, only one kind of cyclic dimer hydrogen-bonding motif is observed. The other molecules are connected with the dimer molecules by hydrogen bonds formed between carboxylic groups and hydroxyl groups. The hydrogen-bonding interaction between carboxylic acid has been thoroughly investigated

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on the basis of thermal properties of solid forms to evaluate the relative stability of the two forms. To calculate the difference in thermodynamic stability between racemic compound and conglomerate, Li and Grant et al.13 introduced the Gibbs free energy of the reaction of racemic compound formation from enantiomers. The free energy can be calculated from eq 1:13 ΔG Trac, f ¼ -

ðTrac;f - TR;f ÞΔHR;f - Trac;f R lnð2Þ TR;f if ðTR;f > Trac;f Þ

Figure 21. Hydrogen-bonding motif in crystal structure of Form β.

Figure 22. Crystal packing in crystal structure of Form β.

by many researchers.29,30 There are two major types of hydrogenbonding motifs observed, namely cyclic dimer and catemer motifs. The cyclic dimer is the most abundant hydrogenbonding motif and indicates that this dimer corresponds to the lowest energy.31 Form R with two cyclic dimer structures should be energetically favorable compared to Form β. In addition, the hydrogen bond distances of Form R are shorter than those of Form β, as shown in Table 5. Therefore, we can conclude that Form R is more stable than Form β. This is consistent with our experimental observations showing that Form β crystallized first from the melt and transformed to other forms quickly. The crystal structure investigation provided positive support with respect to hydrogen bond interactions. 3.7. Relative Stability between Racemic Compound and Conglomerate. We were not able to solve the crystal structure of the enantiomer despite many attempts to get quality single crystals. Therefore, investigating the stability difference between racemic compound Form R and conglomerate Form γ based on crystal structure comparison was not possible. Instead we employ the thermodynamic calculations

ð1Þ

, where ΔGTrac,f is the Gibbs free energy of racemic compound formation, ΔHrac,f and ΔHR,f are the fusion enthalpy of racemate and enantiomer, respectively, in kcal/mol, R is the universal gas constant, Trac,f is the melting point of racemate in K, and TR,f is the melting point of enantiomer in K. The free energy of 2-ClMA racemic compound formation is -0.058 kcal/mol using eq 1. The free energy is a small negative number, indicating that the formation of racemic compound is thermodynamically slightly preferred. The thermodynamic calculations support the fact that 2-ClMA exists as racemic compound or conglomerate depending on the crystallization conditions. To achieve resolution of this kind of racemate by direct crystallization, the kinetic factors and solvent type will be very important to the possible formation of conglomerate. 3.8. Potential Application of Direct Crystallization. The present work demonstrates that 2-ClMA is an example of a racemate that can exist either as a racemic compound or as a conglomerate, depending on the crystallization conditions. The complexity encountered in the present system concerning crystallization of the conglomerate or racemic compound provides a good opportunity to study the general features of conglomerate formation and direct crystallization application. The conglomerate can be formed under certain crystallization conditions, which implies that the probability of conglomerate formation among organic chiral compounds could be higher than 5-10%, as generally believed. However, the chance of direct crystallization application may not increase correspondingly. In the present work, we observed another metastable racemic compound of 2-ClMA. The existence of the metastable form could influence the application of direct crystallization. The observation also partially explains the fact that only 30% of conglomerates can be separated by direct crystallization. The reason may lie in the fact that spontaneous nucleation of metastable racemic compound may undermine the resolution efficiency under separation conditions. Further investigation on the effect of the polarity of the solvent and the kinetic factors on the crystallization of conglomerate from solution is necessary. It is also highly desirable to explore the potential influence of metastable racemic compound on direct crystallization performance. 4. Conclusions The polymorphs of 2-chloromandelic acid were explored by melt crystallization, solution crystallization, and freeze-drying crystallization with emphasis on enhancing the probability of conglomerate formation. Freeze-drying led to a conglomerate formation. In nonpolar solvents, 2-ClMA preferably

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crystallized as a stable racemic compound, whereas crystallization in polar solvents resulted in a mixture of racemic compound and conglomerate. The stability of conglomerate Form γ lies between stable racemic compound Form R and metastable racemic compound Form β. The conglomerate had the tendency to transform into racemic compound by solid-solid transition. The solid phase transition kinetics is slow. With additional energy, it can quickly transform into stable racemic compound. Thermodynamic calculations of Gibbs free energy of racemic compound formation provided evidence for the close stability between the conglomerate and the stable racemic compound. Acknowledgment. This work was supported by NSERC Strategic Grants and the Ningbo Nature Science Fund. Supporting Information Available: Calculated and experimentally measured XRPD pattern of 2-ClMA Form R, and tables of bond lengths, bond angles, and torsion angles of 2-ClMA Forms R and β. This material is available free of charge via the Internet at http://pubs.acs.org.

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Crystallization of the Racemic Compound and Conglomerate of (

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