Hydrogen Bonding Is Not Everything: Extensive Polymorphism in a

Nov 19, 2009 - and Jonathan W. Steed*. Department of Chemistry, Durham University, South Road, Durham DH1 3LE, United Kingdom. Received October 5 ...
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DOI: 10.1021/cg901224f

Hydrogen Bonding Is Not Everything: Extensive Polymorphism in a System with Conserved Hydrogen Bonded Synthons

2010, Vol. 10 880–886

Katharina Fucke, Naseem Qureshi, Dmitry S. Yufit, Judith A. K. Howard, and Jonathan W. Steed* Department of Chemistry, Durham University, South Road, Durham DH1 3LE, United Kingdom Received October 5, 2009; Revised Manuscript Received October 26, 2009

ABSTRACT: A simple N,N0 -diaryl urea derivative was found to form four different anhydrous crystal forms (I-IV°), which can be crystallized in pure form by several techniques from solution as well as from the melt. These polymorphs were characterized by thermomicroscopy, differential scanning calorimetry, Fourier-transform infrared spectroscopy and single crystal and powder X-ray diffraction. The polymorphs were found to be purely monotropically related with large differences in their heats of fusion (11.1 kJ mol-1 for the least stable form I, 34.5 kJ mol-1 for the most stable form IV°). The crystal structures of all forms show the same conformer for forms I-III and a second conformer in form IV°. However, the hydrogen bonding motifs in all of the polymorphs are the same and thus the compound can be seen as a model for the importance of the entire crystal packing arrangement to the overall energy and stability of the crystal form, as opposed to just a few dominant interactions.

1. Introduction Polymorphism, i.e. the ability to crystallize in different crystal forms, is a widespread phenomenon in low molecular weight organic compounds. It remains a topic of considerable industrial importance in chemistry, particularly in the pharmaceutical industry.1,2 The understanding and subsequent control of polymorphism is crucial for the manufacturing of any chemical compound. However, the prediction of the incidence and packing arrangement of polymorphic compounds still poses a major challenge for current crystal structure calculation methodologies.3,4 This task becomes even more difficult5 when the crystal structure incorporates more than one kind of chemically distinct molecule, i.e. in co-crystals6-8 such as solvates or hydrates, which can themselves show polymorphism, or crystallographically distinct occurrences of the same molecule (Z0 > 19,10). From a crystallographic point of view, two extremes can be distinguished: conformational polymorphs11,12 show a different molecular conformation in different modifications, while in packing polymorphs the molecules pack differently while maintaining the same conformation.13 Conformational isomorphs are a special case of conformational polymorphs where more than one conformation occurs in the same crystal.14 However, conformational polymorphism usually includes a difference in packing, while in packing polymorphs the conformation of the molecules might also differ slightly. Thus, every mixture in between these two extremes is possible and frequently realized. Hence, molecular flexibility is often a driver for the occurrence of polymorphism. Another widespread assumption is that the crystal structure of molecular compounds is mainly dependent on strong intermolecular interactions, particularly intermolecular hydrogen bonds, which have been described as the “most important discriminating cohesive force”.15 This focus on strong interactions underlies the very successful supramolecular synthon approach in which crystal structure design *Corresponding author. E-mail: [email protected]. pubs.acs.org/crystal

Published on Web 11/19/2009

is based on the reproducibility of particular robust, reproducible intermolecular interaction motifs.16-19 However, the very robustness of some supramolecular synthons reduces the probability of polymorphism. Indeed, compounds with reproducible, stable intermolecular interaction motifs should tend towards having a single, most stable crystal structure. In the present work, we describe the extensive polymorphism (including conformational polymorphism) of a 1-(3-methylsulfanylphenyl)-3-pyridin-2-ylurea—a compound that exhibits a robust hydrogen bonding motif that is conserved throughout all of the observed polymorphic forms— and show that it is the weak interactions that influence the solid state structure. 2. Experimental Section 2.1. Materials. Compound 1 was prepared as previously described.20 2.2. Crystallization Techniques. Evaporation experiments were conducted by preparation of a slightly saturated solution at ambient temperature and subsequent evaporation from a watch glass at ambient conditions. Fast cooling was performed by preparing a hot saturated solution and quench cooling it in an ice water bath, while slow cooling allowed the hot saturated solution to slowly cool down to room temperature. Precipitation was conducted using a hot saturated solution and at least double the volume of precooled (ice water bath) antisolvent. All crystalline material obtained was filtered and stored as dry powder for further analysis. 2.3. Thermomicroscopy. Hot-stage microscopic investigations were performed on an Olympus BX51 microscope (Olympus, Southend-on-Sea, U.K.) equipped with a Linkam THMS600 hot stage operated with a TMS94 controller (Linkam Scientific Instruments Ltd., Tadworth, U.K.). Photomicrographs were taken with a JVC KY-F75U digital camera with 4.3 Megapixel operated with the KY-LINK 2.0 software (JVC, London, U.K.). 2.4. Powder and Single Crystal X-ray Diffraction. Single crystals suitable for structure determination were selected, soaked in perfluoropolyether oil, and mounted on a glass fiber. Crystallographic measurements were carried out at 120 K using a Bruker SMART CCD 6000 single crystal diffractometer equipped with an open flow N2 Cryostream (Oxford Cryostream) device using graphite monochromated Mo KR radiation (λ = 0.71073 A˚). For data reduction, the SAINT suite was used, and the structures were solved with r 2009 American Chemical Society

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SHELXS21 and refined with SHELXL.21 All non-hydrogen atoms were treated anisotropically, and the hydrogen atoms were located from the Fourier maps and refined isotropically. Powder X-ray diffraction patterns were recorded using a D5000 diffractometer (Bruker, Coventry, U.K.) in Bragg-Brentano geometry with Cu KR radiation (λ=1.54056), a graphite monochromator, 20 mm variable Soller slits, and a scintillation counter detector. The X-ray tube was operated at 40 kV and 40 mA, while the sample was prepared on a low background silicone slide sample holder as a dry powder. 2.5. ATR Infrared Spectroscopy. Fourier transform infrared spectra were recorded with a Perkin-Elmer Spectrum 100 ATR instrument (Perkin-Elmer, Norwalk, CT). For each spectrum, 64 scans were conducted over a spectral range of 4000 to 600 cm-1 with a resolution of 4 cm-1. The analysis was carried out with the Spectrum Express 1.01 software. 2.6. Differential Scanning Calorimetry. Differential scanning calorimetry (DSC) was performed with a Pyris 1 (Perkin-Elmer, Norwalk, CT). Approximately 1-3 mg of sample was accurately weighed (AD-6 ultra microbalance, Perkin-Elmer, Norwalk, CT) into sealed Al-Pans and submitted to a ramp scan in the range from 25 to 160 °C. Dry helium was used as the purge gas (purge: 20 mL min-1). The instrument was calibrated for temperature and energy in the respective temperature range with pure indium (purity 99.999%, mp 156.6 °C, heat of fusion 28.45 J g-1).

3. Results and Discussion The simple N,N0 -diaryl urea derivative 1 (Scheme 1) was prepared as part of our ongoing work on ion-pair binding ligands with juxtaposed metal ion binding and anion binding functionality.20,22-24 As part of our studies on this system, we have undertaken structural and solution phase studies on a range of metal salts of 1. Our attempts to prepare diffraction quality single crystals of metal complexes of 1 also resulted in a number of crystalline samples that did not prove to contain metals. X-ray crystallographic analysis of these samples showed them to consist purely of the unreacted ligand, 1. Remarkably, however, these studies also showed that this simple, relatively inflexible urea derivative exists in at least four pure polymorphs (termed forms I-IV°). While not as many as the “most polymorphic” organic compound, 40 methylchalcone with reported 13 crystal forms,25 the isolation of so many different polymorphs is relatively rare, and hence, we undertook a systematic study of this system. Scheme 1. Molecular Structure of Compound 1-(3-Methylsulfanylphenyl)-3-pyridin-2-ylurea (1)

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3.1. Crystallization of the Polymorphs and Thermomicroscopy. All four polymorphs were initially discovered by crystallization from solution in the presence of different metal salts (Table 1). However, they were found to also form by solution crystallization in the absence of metal salts, as well as from the melt. Form I can be crystallized from THF solutions by adding silver triflate in equimolar ratios and letting the solvent evaporate. This form was also obtained by evaporation of a low saturated methanol solution and in mixtures with other polymorphs by evaporation from ethanol, 2-butanol, and acetonitrile. The crystals grow as elongated prisms mostly as bunches with one nucleation center. Additionally, the crystals seem to grow as aggregates of smaller prisms, as can be seen as fraying (i.e. disintegrating into thinner strands) when a more focused stress, e.g. cutting, is applied. Under the microscope, the crystals are bright and colorless without phenomena such as cracking or pseudomorphosis, which would indicate a prior phase transition. Between crossed polarizers, they are brightly multicolored, which is most likely due to low thickness. Upon heating, no thermal event can be detected until 139 °C, at which temperature the crystals melt incongruently. The crystal form present thereafter melts at 154 °C and represents form IV°, as was verified by IR spectroscopy. Above this temperature, no crystal growth could be detected. Form II crystallizes from evaporation of THF solution in the presence of an equimolar amount of silver triflate, when the solution is more concentrated than that resulting in form I. Form II was also obtained by evaporation of DCM and fast cooling of methanol solutions. The crystals grow as elongated prisms, but unlike form I, the crystallites are mostly separated. The crystals grown from DCM were smaller than those obtained in the other experiments and mostly grew spherulitically, which is most likely due to the fast evaporation of the solvent and thus faster crystallization. Under the microscope, the crystals are bright and colorless and show no signs of prior phase transition such as cracking or pseudomorphosis. Placed between crossed polarizers, the crystals show mostly white interference. Only a few crystals are multicolored due to their small thickness. Upon heating, the crystals show no thermal event up to 145 °C, at which temperature the whole sample melts. Immediately after melting, a new crystal form grows into the melt as broad rays, subsequently melting at 154 °C and thus representing form IV°. Above this temperature, no further crystal growth could be detected. Form III crystallizes from THF/ethanol/water mixtures in the presence of silver nitrate by solvent evaporation. It can

Table 1. Crystallization Conditions for the Different Modifications of 1 form I

form II

solvent salt solvent for salt evaporation time

THF AgCF3SO3 THF 10 days

THF AgCF3SO3 THF 15 days

solvent technique

methanol fea

nucleation temperature

135 °C room temperature

form IV° THF AgMeCO2 H2O/EtOH (1:1) 10 days any sc,c sed >144 °C

Fast evaporation (rim of watchglass). b Fast cooling (rim of watchglass). c Slow cooling. d Slow evaporation (center of watchglass).

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Figure 1. Photomicrographs of the polymorphs grown from the melt (a = forms I and III, b = form II, c = form IV°).

also be grown by very fast crystallization from any solvent by fast cooling or evaporation under reduced pressure. The habit is like forms I and II prismatic with one preferred axis of growth and mostly spherulitic. Being rather brittle, the crystals can be ground to a powder by applying low mechanical stress, e.g. shearing between two coverslips. Under the microscope, the crystals appear bright and colorless without any signs of a prior phase transition. Between crossed polarizers, they show white interference. Up to 142 °C, no thermal event could be detected, while at that temperature all the crystals melt. Only slight recrystallization could be detected upon further heating, and the obtained crystals then melt at 154 °C, representing form IV°. Form IV° itself can be crystallized from THF/ethanol/ water mixtures in the presence of equimolar ratios of silver acetate. It also grows from any solvent using slow crystallization methods such as slow cooling or slow evaporation. It also transforms any other polymorph in suspension, thus being the most stable form at ambient conditions. Form IV° grows as large elongated prisms which are of white to yellow-white color. Under the microscope, the crystals are bright and show no cracks or pseudomorphosis, indicating no prior phase transition has taken place. The interference color between crossed polarizers is bright white. Upon heating, no thermal event can be detected until the equilibrium melting point of 154 °C. Compound 1 melts undecomposed, thus allowing the preparation of a supercooled melt by quenching the melt on the cold benchtop. Only slight crystallization of small needles in spherulites can be detected immediately after quenching, while storing the supercooled melt for four hours at ambient conditions effected more nucleation, mostly on the surfaces of the amorphous material as well as on scratches on the microscopic slide. Heating the supercooled melt shows strong nucleation of small plates with gray-blue and yellow interference colors, which grow spherulitically into the amorphous material. These crystals were determined to be form III by IR spectroscopy. Upon further heating, the crystals show no transition up to their melting point of 135 °C. Immediately after, larger partially bent prisms with bright interference grow into the melt. IR spectroscopy established this form to be form II. At 144 °C, the crystals melt and the very slow growth of a third form as broad rays, with multicolored interference, can be observed. Its equilibrium melting point was determined to be 152 °C, and IR spectroscopy verified it to be form IV°. Upon slow cooling of the melt at a rate of about 20 K min-1 and stressing the sample mechanically, two different crystal forms grow below 90 °C. One is form III, as determined by IR spectroscopy, which grows as rays of fine needles with multicolored interference; the other, form I as determined by IR spectroscopy, grows as rays of thin prisms with yellow interference (Figure 1). Upon heating, form III grows into form I above 80 °C,

Figure 2. DSC thermograms of the four polymorphs.

while the sample afterwards shows the same behavior as described for pure form III. 3.2. Differential Scanning Calorimetry. The DSC traces of all four polymorphs are presented in Figure 2. Form I shows no thermal event up to its melting point at 137 °C. This melting event is rather low in energy and immediately followed by a recrystallization exotherm, and it is most likely that these two events overlap considerably. This assumption is based on the thermomicroscopic results, as it was observed that form I melts incongruently and recrystallizes immediately to form IV°. The DSC thermogram shows recrystallization to form II rather than form IV°, which most likely is triggered by the aluminum surface of the DSC pan. Form II then melts at 143 °C, as is also detected in the thermogram of pure form II. Immediately after the melting event, form IV° recrystallizes, as detected as an exothermic event in both DSC traces. Form III also shows no thermal event up to its melting point at 138 °C and recrystallizes immediately after to form IV°. Like in the case of form I, the melting endotherm is extraordinarily low in enthalpy, indicating the overlap of melting and recrystallization. Form IV° does not show any thermal event up to its melting point at 153 °C, while above that temperature the melt is stable and does not recrystallize. In order to obtain proper enthalpies of fusion for the incongruently melting forms I and III, as well as for form II, although its melting endotherm is well resolved from the recrystallization exotherm, samples of all three forms were measured at higher heating rates. The best results were obtained at 75 K min-1, at which rate the events are well resolved and the melting endotherms of the different forms do not overlap. In addition, at this heating rate the highest enthalpies of fusion were found (Table 2). The behavior of 1 during successive heating/cooling cycles is presented in Figure 3. The initial material is form IV°, and

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Figure 3. DSC thermogram of the form IV° heating and cooling cycle. Table 2. Physicochemical Data for the Polymorphs: Tfus, Melting Point; TM, Thermomicroscopy; ΔHfus, Enthalpy of Fusion; All Values with (95% Confidence Interval form

I

II

III

Tfus (°C) TM 138-141 144 140 DSC (onset) 136.96 ( 0.05 143.8 ( 0.4 137.6 ( 0.1 ΔHfus (kJ mol-1) 11.1 ( 0.7 26.3 ( 1.9 23 ( 3 order of thermodynamic stability at 25 °C 4 2 3

IV° 153 150.7 ( 0.3 34.5 ( 1.3 1

the first heating curve shows, as expected, no thermal event up to the melting point of this modification. Upon cooling the melt at 10 K min-1, the crystallization of form II, as determined by IR spectroscopy, can be detected as an exothermic event in the range from 90 to 78 °C. Upon second heating, another small exotherm can be detected in the range from 70 to 83 °C, which indicates that the crystallization upon cooling was not complete. Nevertheless, the modification nucleating in this lower temperature range is form III, as observed by hot-stage microscopy, resulting in a mixture of forms II and III present in the DSC pan. Upon further heating, the corresponding melting endotherms of both forms can be detected in the range from 120 to 145 °C. The crystallinity of form III seems to be lower than that of the samples obtained from solution growth, since the maximum of the melting peak is lowered by 5 °C (onset at 132.6 °C) to that presented in Table 2. However, these results are consistent with the results of the thermomicroscopy with respect to the presence of form III, while the nucleation of form II is again most likely triggered by the aluminum surface of the DSC pan. 3.3. Thermodynamic Stability of the Modifications. Since this system forms four polymorphs, there is a total of six possible polymorphic pairs ((n - 1)n/2 = 6, where n = 4), which can either be enantiotropic or monotropic. From the DSC measurements, the melting points and enthalpies of fusion for all four polymorphs could be detected (Table 2). Since no transitions could be measured, only the heat of fusion rule by Burger and Ramberger26 can be applied stating that if in a polymorphic pair the form with the higher melting temperature shows the higher enthalpy of fusion, the pair is monotropically related, while a polymorphic pair with the higher melting modification having the lower enthalpy of fusion is enantiotropically related. This rule implies that form IV° is monotropically related to all of the other modifications, since this form shows the highest melting point as well as the highest melting enthalpy.

Figure 4. Semi-schematic energy/temperature diagram of the four polymorphs.

Thus, this form is unambiguously the thermodynamically stable polymorph over the whole temperature range. This fact is also verified by the crystallization behavior of form IV°, since it is the product of every slow crystallization experiment and most likely results from the transformation of any polymorph which might nucleate initially, thus following the Ostwald rule of stages.27 The second highest enthalpy of fusion can be found for form II, which additionally shows the second highest melting temperature. Consequently, this form is also related monotropically to all other forms. Form III shows the third highest melting point with the third highest enthalpy of fusion and is thus also monotropically related to the other modifications. Finally, therefore, form I has to be related monotropically to all other forms as well, and this is proven by this form having the lowest melting point and the lowest enthalpy of fusion as detected by DSC measurements. The measured thermodynamic data allows us to draw a semi-schematic energy/temperature diagram26,28 (Figure 4), in which the relative thermodynamic stability of all of the modifications can be visualized in the temperature range from 0 K to their melting points. This diagram shows that none of the G-isobars of the modifications intersect and thus all polymorphs are monotropically related. Theoretically, a transition from any of the less stable forms to the more stable ones can occur at any temperature. However, since all polymorphs are stable if stored out of solution, and no transitions can be detected by DSC measurements, the transformations have to be kinetically hindered. 3.4. Infrared Spectroscopy. The IR spectra of all four polymorphs are presented in Figure 5. The forms are very closely related and show only minor differences in the spectra, which nevertheless allow them to be unambiguously identified. At higher wavenumbers, all spectra show two N-H vibrations at 3372 and 3210 cm-1, of which the higher one is assigned to the urea NH connected to the phenyl ring. At lower wavenumbers, the C-H stretch vibrations occur. In this upper range of the spectrum, the four forms do not differ sufficiently to distinguish them. At about 1700 cm-1, the

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Figure 6. Overlay of the four polymorphs (I-red, form II-blue, form III-yellow, form IV°-green).

Figure 5. ATR spectra of forms I-IV°. Table 3. Crystal Data and Structure Refinement for Modifications I-IV° form formula formula weight (g mol-1) crystal system space group cell dimensions (A˚) a b c cell angles (deg) R β γ volume (A˚3) Z0 Z Fcalc (g cm-3)

I

II

III

IV°

C13H13N3OS C13H13N3OS C13H13N3OS C13H13N3OS 259.32 259.32 259.32 259.32 monoclinic C2/c

monoclinic P21/n

orthorhombic monoclinic Pca21 P21/n

26.8102(7) 5.4333(2) 17.7090(5)

5.4862(3) 13.9388(8) 16.1959(9)

17.2320(14) 5.4830(4) 26.478(2)

11.5968(4) 5.3174(2) 20.2774(8)

90 107.09(2) 90 2465.8(2) 1 8 1.397

90 93.59(2) 90 1236.1(1) 1 4 1.393

90 90 90 2501.7(3) 2 8 1.377

90 93.45(2) 90 1248.75(8) 1 4 1.379

carbonyl stretch vibration appears. In this peak, form I can be identified, since this modification shows a significant shift to higher wavenumbers (form I, 1702 cm-1; other forms, 1686 - 1691 cm-1). Considering this shift, form I should have significantly weaker hydrogen bonding involving the carbonyl function than the other forms (although surprisingly the structural data indicates that this form also has the shortest hydrogen bonds, vide infra). The stretch vibrations of the aromatic rings are quite characteristic of form IV°. While forms I-III show three peaks in this range from 1630 to 1540 cm-1, form IV° reveals four peaks with significantly shifted positions. Thus, the packing of the terminal ring substituents should differ substantially in the crystal form IV° while it is most likely similar in forms I, II, and III. Form II can be identified by a separate weak vibration at 1271 cm-1, which does not occur as a separate peak in any of the other forms. This band is hard to interpret, since multiple functional groups show low order and combined vibrations in this range. The range from 991 to 975 cm-1 is characteristic for form III, since this form is the only polymorph to show a doublet in this range. Again, the precise interpretation of these vibrations is impossible due to multiple overlapping peaks. Another range proves interesting to identify the different forms: from 1275 to 1220 cm-1 (urea symmetric stretch vibrations) all polymorphs show a slightly different pattern of peak positions and intensities of the multiplet.

Figure 7. Hydrogen bonded dimer found in the crystal forms (here form I).

3.5. Crystal Structures. The X-ray crystal structures of all polymorphs were determined. The crystal data is listed in Table 3. Overall, the different polymorphs show similar conformations, which leaves the molecules almost planar (Figure 6). The most striking difference can be detected between form IV° and the other modifications. In form IV° the 3-methylsulfanyl-phenyl-group is rotated 180° around the C-NH bond and the methylsulfanyl substituent adopts an anti conformation with respect to the rest of the molecule whereas it is syn in forms I, II, and III. Form IV° is thus a conformational polymorph of the other forms. Forms I, II, and III also reveal slight conformational differences, which are mainly the out-ofplane twist of the phenyl moiety as well as the methylsulfanyl substituent (none of the structures is completely planar). However, these slight differences would not normally be considered to represent conformational polymorphism. In all four crystal structures, the molecules form dimers linking one NH group of the urea moiety to the carbonyl group of the second molecule to give an R22 (8) motif.29 The second NH group is involved in an intramolecular hydrogen bond to the pyridyl moiety of S(6) type (Figure 7). Remarkably this hydrogen bonding scheme is identical in all of the modifications. However, the lengths of these bonds differ slightly between the modifications. Form I has the shortest N 3 3 3 O distance with 2.813(2) A˚, followed by form IV° with 2.826(2) A˚. Forms II (2.828(2) A˚) and III (2.829(6) A˚ for one molecule, 2.878(6) A˚ for the other, since Z0 = 2) have the longest N 3 3 3 O distances. This result contradicts the widespread assumption that shorter hydrogen bonds are stronger, since the most stable modification IV° reveals only the second shortest N 3 3 3 O distance, while the shortest interaction can be detected for the most unstable modification. Therefore, the hydrogen bonding cannot be the prominent factor contributing to the difference in stability and energy found by thermal analysis.

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Figure 8. Packing schemes of the four polymorphs (H-bonds of the red molecules are directed into the plane).

Form I shows stacks of the dimers along the b axis, which are tilted by 36.6° from the b direction (Figure 8). The stacks themselves are connected through the 21 screw axis, giving the herringbone structure in the projection of the a plane. Form II contains stacks along the a axis. The dimers are tilted by 37.37° from the stacking direction along b and 53.68° along c. Thus, the dimers are not aligned along any of the cell axes, other than form I. Form IV° also shows a simple herringbone stacking with the stack direction along b and the dimers tilted by 40.65° along a and 11.7° along c. In addition, the dimers are turned 90° in the stacks compared to forms I and II, which results in a CH 3 3 3 π short contact between the stacks. Despite the similarity of the packing, these three forms are not isostructural. Form III also packs in stacks connected in a herringbone manner. However, along c the a glide plane results in a mismatch in the stacks of two adjacent layers. Thus, in one layer the dimers tilt by þ36.86° from the stack axis, and in the

next they tilt by -36.86°, resulting in a more complicated packing compared to the other modifications. Interestingly, although form IV° is the thermodynamically stable polymorph at all temperatures, it has the second lowest calculated density. The overlay of the experimental powder diffraction patterns with the calculated ones (Figure 9) shows good correlation of the crystal structures with the bulk material. We note that the bulk material of form I contains a significant percentage of form II (peak at 8.4° 2θ), which can be explained by the growth of both forms from methanol only. Form II contains traces of form IV° (peak at 14.9° 2θ), which might have nucleated during the crystallization experiment as well as during harvesting. Since all modifications exhibit an elongated prismatic habit, the powder patterns reveal preferred orientation, although the samples were ground in order to avoid this. This orientation effect can be especially detected in form IV° in the range 14-16° 2θ. The calculated

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Charles Wallace Trust Pakistan, and Dr. Wali Muhammad Trust for partial funding. Supporting Information Available: The crystal structures of all four polymorphs are available free of charge via the Internet at http://pubs.acs.org/.

References

Figure 9. Powder X-ray patterns of forms I-IV° (black) in overlay with the calculated patterns (gray).

pattern shows three peaks in this range while the experimental only reveals one well-defined peak with another as a shoulder toward lower diffraction angles. Additionally, a slight shift of the calculated peak position to higher angles can be observed which is due to the temperature difference between the single crystal measurements (120 K) and the experimental powder patterns, which were recorded at room temperature. 4. Conclusion Compound 1 forms four different anhydrous crystal forms (I-IV°), which can be crystallized by several techniques. It was found that forms I and II only crystallize without another polymorph from methanol solution or in the presence of inorganic salts. Thermoanalysis shows that all modifications melt without a previous transition, and applying the heat of fusion rule26 proves this system to be completely monotropic. The crystal structures show that the molecule forms one intramolecular and two intermolecular hydrogen bonds to give S(6) and dimeric R22 (8) graph set synthons in all four structures. However, the packing arrangements differ strikingly, and since the hydrogen-bonding arrangement is the same for all four forms, the differences in energy measured by thermoanalytical methods can only be caused by the different packing arrangements involving combinations of the weaker interactions, of which the CH 3 3 3 S and CH 3 3 3 π contacts are the most prominent. Thus, this system is a clear example in which the presence of robust, reproducible hydrogen bonded synthons does not lead to any control or predictability of polymorphic forms. It is also interesting to note that the form with Z0 > 1 is not the least stable form30-32 and that the most stable form is of relatively low density. Acknowledgment. We thank the EPSRC, Durham University, the Higher Education Commission of Pakistan,

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