Cocrystal Formation between Chiral Compounds: How Cocrystals

Article pubs.acs.org/crystal

Cocrystal Formation between Chiral Compounds: How Cocrystals Differ from Salts Géraldine Springuel,† Koen Robeyns,† Bernadette Norberg,‡ Johan Wouters,‡ and Tom Leyssens*,† †

Institute of Condensed Matter and Nanosciences, Université Catholique de Louvain, Louvain-La-Neuve, Belgium Unité de Chimie Physique, Théorique et Structurale, Université de Namur, Namur, Belgium

‡

S Supporting Information *

ABSTRACT: A cocrystal screening of a series of chiral target compounds was performed in order to investigate the propensity for two optically active compounds to cocrystallize in an enantiospecific manner. Thirteen novel cocrystal systems were identified, out of which 11 are enantiospecific and two present a diastereomeric cocrystal pair, yielding a total of 15 novel cocrystals. Six of these are structurally characterized in this study. A meticulous search in the Cambridge Structural Database (CSD) has allowed expanding this study. The results led us to the conclusion that enantiospecific cocrystallization seems to be the common rule of thumb, as over 85% of cocrystal systems behave enantiospecifically. Directionality of the hydrogen bonding motifs is likely responsible for the cocrystals’ predilection toward enantiospecificity, while salts are mainly stabilized by less directional electrostatic interactions, leading to the formation of diastereomeric pairs.

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INTRODUCTION Obtaining optically pure compounds remains a constant challenge for the pharmaceutical and agrochemical industry, as in most cases only one of both enantiomers displays desirable activity. Despite significant advances made in asymmetric synthesis, a high proportion of chiral molecules are still synthesized as racemic mixtures, followed by an appropriate resolution.1 A widely used resolution method is crystallization through formation of a diastereomeric salt,2 starting from a racemic basic (or acidic) target compound and adding an enantiopure acidic (or basic) resolving agent. The two diastereomeric salts are not symmetrically related and thus exhibit different physical properties, such as solubility. Under appropriate conditions (amount and nature of solvent, quantity of resolving agent, and temperature), it is possible to crystallize a product with high enantiomeric excess or in the ideal case a single of the two diastereomeric salts.3,4 For chiral resolution of molecules that are not, or not easily, ionizable, cocrystal formation was shown to offer an alternative resolution method.5,6 Although the term cocrystal remains a topic of a semantic debate,7 these compounds can broadly be defined as follows:8 (1) Cocrystals are crystalline structures that contain at least two different compounds that are solid in their pure form under ambient conditions. Hydrates and other solvates are thus excluded. (2) Cocrystals are made from neutral molecular species, and all species have to remain neutral after crystallization. Salts are not considered as cocrystals and vice versa. (3) Cocrystals are crystalline homogeneous phase materials where two or more building compounds are present in a © 2014 American Chemical Society

defined stoichiometric ratio. Solid solutions are thus ruled out. Recent studies show how cocrystal formation using an enantiopure coformer can lead to the selection of a given enantiomer from a racemic mixture.9−16 On the basis of these observations, we developed a chiral resolution technique using solution cocrystallization. Such resolutions were sporadically encountered in the literature,10,14 and they remained trial-anderror based. In our work,5,6 a rationalization for this resolution was given through the development and study of quaternary phase diagrams. To our surprise, the systems identified in this work behaved enantiospecifically, with a chiral coformer forming a cocrystal with only one of the two enantiomers of the target compound. Contrary to salts, a diastereoisomeric cocrystal pair cannot be formed. Although the enantiospecific character is not essential for chiral resolution, the thermodynamic phase diagrams crucial for process development are easier to handle, as the reduced number of solid forms leads to simpler phase diagrams. Furthermore, we showed how, in a single crystallization step, up to 80% of a given enantiomer can be recovered when using an enantiospecific cocrystal system. If such an enantiospecific character could be generalized, resolution through cocrystallization becomes an economically interesting alternative to diasteriomeric salt formation. In this paper, we investigate the propensity for two optically active compounds to cocrystallize in an enantiospecific manner. The methodological approach was based on a bibliographic Received: April 25, 2014 Revised: June 20, 2014 Published: June 27, 2014 3996

dx.doi.org/10.1021/cg500588t | Cryst. Growth Des. 2014, 14, 3996−4004

Crystal Growth & Design

Article

Figure 1. Chemical structures of levetiracetam (S-2-(2-oxopyrrolidin-1-yl)butanamide) (S1), R-2-(2-oxopyrrolidin-1-yl)butanamide) (R1), fasoracetam ((5R)-5-(piperidine-1-carbonyl) pyrrolidin-2-one) (R2), S-oxiracetam (S-2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetamide) (S3), 2R,3R-/ 2S,3S-tartaric acid (R,R/S,S4), R-/S-methylsuccinic acid (R/S5), S-phenylsuccinic acid (S6), R-/S-mandelic acid (R/S7), R-/S-3-phenyllactic acid (R/S8), S-ibuprofen (S9), R-flurbiprofen (R10), R-2-(4-hydrophenoxy)propionic acid (R11), 1R,3S-camphoric acid (R,S12), diprophylline (S-7(2,3-dihydroxy-propyl)theophylline (S13), tautomers of stanozolol ((1S,3aS,3bR,5aS,10aS,10bS,12aS)-1,10a,12a-trimethyl1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-f ]indazol-1-ol) (14), for brevity in designation, the specification of chiral centers is omitted for this compound and is designated 14 instead of S,S,R,S,S,S,S14.

research using the Cambridge Structural Database (CSD)17 and on an experimental cocrystal screening.

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Alfa Aesar. R-Flurbiprofen (R10), R-2-(4-hydroxyphenoxy)propionic acid (R11), and 1R,3S-camphoric acid (R,S12) were purchased from Sigma-Aldrich. R-/S-Methylsuccinic acid (R/S5) and stanozolol ((1S,3aS,3bR,5aS,10aS,10bS,12aS)-1,10a,12a-trimethyl1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-f ]indazol-1-ol) (14) were purchased from TCI Europe N.V. These materials were used as received, without further purification, except for fasoracetam that was recrystallized from DMSO to remove impurities. R-2-(2-Oxopyrrolidin-1-yl)butanamide (R1) cannot be purchased and was therefore obtained from the racemic compound. A solution containing a molar percentage in RS-2-(2oxopyrrolidin-1-yl)butanamide, R7 and acetonitril of respectively 4.36, 6.63, and 89 mol % was kept at −10 °C and seeded with R1:R7 cocrystal. Under these conditions, the R1:R7 cocrystal is recovered, as it is the most stable phase in suspension.6 After filtration, R1 was separated from R7 with reverse HPLC system Waters Alliance 2690 equipped with a PDA detector (Waters 2998). A Waters Atlantis T3 column (4.6 mm × 50 mm × 3.5 μm) has been used with a dilution solvent of CH3CN/H2O 50/50 v/v. It should be mentioned that stoichiometrically diverse cocrystals can exist or that cocrystal phases in solution based screening experiments due to incongruent behavior. However, as at least five equimolar identification experiments were performed using multiple solvents, the

EXPERIMENTAL SECTION

Starting Materials. In this study a set of chiral active pharmaceutical ingredients (APIs), containing carboxylic acid, amide, or alcohol functional groups were chosen from the literature as listed in Figure 1. Ideally, coformers are selected using a synthon-based approach in which particular functional groups are prone to form intermolecular synthons typically encountered in cocrystals.8,18−23 Therefore, coformers were also selected based on the presence of carboxylic acid, amide, or alcohol functional groups in order to promote acid−acid or amide−amide homosynthons, as well as acidamide, alcohol-amide, or alcohol-acid heterosynthons. Levetiracetam (S-2-(2-oxopyrrolidin-1-yl)butanamide) (S1) was purchased from Xiamen Top Health Biochem Tech. Co., Ltd. Fasoracetam ((5R)-5-(piperidine-1-carbonyl) pyrrolidin-2-one) (R2) and diprophylline (S-7-(2,3-dihydroxy-propyl)theophylline (S13) were purchased from Jinan Haohua Industry Co., Ltd. S-Oxiracetam (S-2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetamide) (S3) was purchased from Angene. 2R,3R-/2S,3S-Tartaric acid (R,R/S,S4), R-/S-mandelic acid (R/S7), S-ibuprofen (S9), and S-3-phenyllactic acid (S8) were purchased from Acros Organics. R3̅-Phenyllactic acid (R8) was purchased from Fluka. S-Phenylsuccinic acid (S6) was purchased from 3997



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likelihood of not having identified a possible alternative form is unlikely. Screening Experiment. The experimental cocrystal screening procedure was performed as follows. In a first stage, solvent-drop grinding (10 μL of methanol) was performed using an equimolar mixture of starting materials. Samples were ground in a RETSCH mixer mill MM 400 for 90 min with a beating frequency of 30 Hz. The resulting powders were characterized using X-ray powder diffraction. Upon cocrystal identification, attempts were made to obtain a single crystal of suitable size and quality for single crystal X-ray diffraction measurements. As mechanochemistry can occur during solvent-drop grinding, solution proton nuclear magnetic resonance (1H NMR) analyses were preformed upon grinding to eliminate those cases where such transformations occurred. As solid-state grinding is not a guarantee for cocrystal formation, additional experiments were performed when one out of two enantiomers yielded a cocrystal but not the other. Therefore, a second step consisted of performing solvent evaporation and slurrying experiments. Solvent evaporation experiments were performed both in methanol and acetone from an equimolar mixture of completely dissolved starting materials. Slurrying experiments were performed in both dichloromethane and ethyl acetate starting from an equimolar mixture of suspended starting material and allowing a 48 h isothermal hold at room temperature. The resulting powders were filtered (when needed) and characterized by X-ray powder diffraction. Overall, this implies that when a system is counted as enantiospecific, a total of five experiments were performed to show that this was effectively the case. Because R1 was at our disposal in a small quantity, this compound was only used to show the enantiospecificity for systems 1/9 and 1/10. X-ray Powder Diffraction (XRPD). X-ray diffraction (XRD) measurements were performed with a Siemens D5000 difractometer equipped with a Cu X-ray source operating at 40 kV and 40 mA and a secondary monochromator allowing the selection of the Kα radiation of Cu (λ = 1.5418 Å). A scanning range of 2θ values from 2° to 72° at a scan rate of 0.6° min−1 was applied. Single Crystal X-ray Diffraction (SCXRD). Single crystal X-ray diffraction was performed on a Gemini Ultra R system (4-circle kappa platform, Ruby CCD detector) using Cu Kα radiation (λ = 1.54056 Å)/ or on a MAR345 detector using monochromated Mo Kα radiation (λ = 0.71073 Å) (Xenocs Fox3D mirror) produced by a Rigaku UltraX 18 generator. The structures were solved by direct methods with SHELXS-97 and then refined on |F2| using SHELXL-97/or SHELXL2014. Non-hydrogen atoms were anisotropically refined and the hydrogen atoms (not implicated in H-bonds) in the riding mode with isotropic temperature factors fixed at 1.2 times U(eq) of the parent atoms (1.5 times for methyl groups). Hydrogen atoms implicated in H-bonds were localized in the Fourier difference maps (ΔF). Nuclear Magnetic Resonance (NMR). 1H NMR spectra were recorded on Bruker 300 MHz Avance II spectrometer. 1H NMR chemical shifts are reported relative to CD3OD (4.87 ppm). Search in the Cambridge Structural Database. A search in the CSD (version 5.34, updated to May 2013) using the ConQuest program (version 1.15) was performed to retrieve crystalline structures of cocrystals containing only chiral molecules. To do so, the query was limited to include only Sohncke (or chiral) space groups with at least two residues and enclosing only elements from the list below. Furthermore, at least two asymmetric carbons were requested as a search criterion. Allowed atoms were selected from the list H, B, C, N, O, F, Si, P, S, Cl, Se, Br, and I, as other atoms are not frequently encountered in small organic molecules of pharmaceutical interest. In coherence with the cocrystal definition we adopted, charged molecules, as well as solvates and hydrates, were excluded. A total of 253 structures were retrieved and investigated in detail. The crystal packing and hydrogen bond interactions were visualized with the Mercury software (version 2.3).

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RESULTS Cambridge Structural Database Search. Over 250 structures were retrieved based on our CSD search containing multicomponent structures between optically active compounds. However, most of them do not correspond with the cocrystal definition stated above. After elimination of solvates, stochiometrically not well-defined structures, and/or structures with proton transfer between molecular partners, only 52 systems12−16,24−46 from the initial hit list were found relevant to this study. These structures were then classified into three categories: (1) Enantiospecific systems (only one of two enantiomers forms a cocrystal with an enantiopure coformer). (2) Diastereomeric systems (both enantiomers form a cocrystal with an enantiopure coformer). (3) Systems for which the enantiospecific behavior is not proven nor the existence of a diastereomeric cocrystal pair clearly established. A system was only classified enantiospecific, if the original work clearly stated this, or when optically pure compound was retrieved in a pure form from the racemic starting material. Doing so, 8 out of the 52 systems were placed in the last caterogy,41,46−49 as information in the literature is insufficient to classify this system into one of the two first categories. Astonishingly, 38 out of the remaining 44 systems12−16,24−40 belong to the first category of “enantiospecific systems”. A mere six systems36,41−45 show formation of “diastereomeric systems”. In conclusion, the CSD search implies that in 86% of cases (38/ 44), chiral compounds cocrystallize in an enantiospecific manner. Experimental Screen. As mentioned this study was complemented with an experimental cocrystal screen. Liquidassisted grinding is a method recognized as powerful, timeefficient, and cost-effective for the identification of novel cocrystals.50−52 However, as this method does not always lead to cocrystal formation, an enantiospecific system was only presumed after no less than four additional solvent mediated experiments were performed as mentioned in the experimental details to clearly show the cocrystal between the mismatching pair of partners did not exist. The 19 compounds, 5 of which are enantiomerically related, selected for this screen are summarized in Figure 1. As chiral coformers, compounds 1, 4, 5, 7, and 8 were selected as both enantiomers are available and required for the purpose of this work. All combinations between the compounds of interest and the coformers were tested, and results are summarized in Table 1. Fifteen hitherto unknown cocrystals were identified and classified into 13 systems. Eleven systems showed enantiospecific cocrystal formation, whereas two diastereomeric systems (four novel cocrystals) were obtained (Table 1). Two cocrystals (S1/S,S4 and S1/S7) were already published in previous work. They were part of the CSD search and have been taken into account in the CSD’s percentage of enantiospecific systems. Nevertheless, they were added in Table 1 for completeness. On the basis of this table, formation of a diasteriomeric pair does not seem linked to the nature of the compounds, as both compounds forming diastereomeric systems (i.e., levetiracetam (S1), stanozolol (14) and methylsuccinic acid (5)) are also involved in several enantiospecific systems. The reason why cocrystals behave enantiospecifically, rather than diasteriomerically, should therefore not be attributed to the nature or the structure of molecules but rather to the combination of a given 3998



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For the remaining cocrystals, for which we were not able to grow single crystals large enough, the cocrystal identification was performed by PXRD patterns comparison: only when the pattern of the final sample did not match with either of the initial compounds nor any alternative form of these (solvates, polymorphs, ...), the formation of a new crystal form is expected. The exact superposition of the pattern of the ground sample with ones of the initial compounds indicates that no new solid form was formed. An example is given in Figure 2 for the enantiospecific cocrystal system S13/R,R4; S13/S,S4. Efforts are ongoing to identify the missing crystal structures of Table 1.

Table 1. Overview of Screening Experiments, Highlighting New Solid Forms Identifieda

√ = new solid form identified by XRPD; √√ = new solid form identified by XRPD and crystal structure determined by SCXRD; × = highlighting of no new solid form identified by XRPD; empty cell = no new solid form identified; black cell = no experiment have been done; gray cell = previously published structure. a

pair of molecules. Our experimental screen also confirms that in about 85% (11/13) of the systems an enantiospecific behavior is observed between chiral cocrystal partners, a similar number as observed above for the CSD search. Structural Analysis. To fully understand enantiospecific cocrystal formation, a more profound analysis of crystal structures is necessary. We set out to identify crystals of suitable size and quality for single crystal X-ray diffraction on the newly identified cocrystals. Six cocrystals could be found large enough for single crystal analysis: S1/S5, S1/R5, S1/S9, R2/S,S4, 14/R5, and 14/S5. The main crystallographic parameters for each are displayed in Table 2. All simulated diffractograms derived from the single crystal structure match the experimental XRPD diffractograms obtained after grinding.

Figure 2. PXRD patterns of R,R4 or S,S4 (blue), S13 (black), ground product between R,R4 and S13 (pink) leading to an exact superposition of the R,R4 and S13 patterns, and ground product between S,S4 and S13 (red), which is not a superposition of the S,S4 and S13 patterns, indicating the formation of a new crystal form.

Crystal Structure Analysis of R2/S,S4 (2:1). The R2/S,S4 cocrystal crystallizes in P21 space group with two R2 and one S,S4 molecule in the asymmetric unit. The expected acid-amide

Table 2. Main Crystallographic Data for Cocrystals S1/S5, S1/R5, R2/S,S4, S1/S9, 14/R5, and 14/S5 cocrystals

S1/S5 (1:1)

S1/R5 (1:1)

structural formula

(C8H14N2O2) (C5H8O4) 302.32 monoclinic P21 12.0408(8) 5.9067(3) 12.1169(8) 113.961(8) 787.505 2 1.275 0.0411(0.0584) 0.0885(0.0966) 2859 194/1 1.023 0.134/−0.134

(C8H14N2O2) (C5H8O4) 302.32 monoclinic P21 5.9628(4) 11.5797(8) 22.5983(18) 95.615(8) 1552.87 4 1.293 0.0485(0.0602) 0.1162(0.1243) 5301 383/1 1.024 0.183/−0.379

formula weight (g/mol) crystal system space group a (Å) b (Å) c (Å) β (deg) V (Å3) Z ρcalc (g/cm3) R1 (all) wR2 (all) Nrefl Nparm/Nrest GOF (S) min/max res dens (e·Å−3)

R2/S,S4 (2:1) 2(C10H16N2O2) (C4H6O6) 542.59 monoclinic P21 10.7203(7) 9.3534(4) 14.3581(11) 110.236(8) 1350.84 2 1.334 0.0372(0.0447) 0.0892(0.0951) 4748 383/1 0.956 0.116/−0.122 3999

S1/S9 (1:1) (C8H14N2O2) (C13H18O2) 376.50 orthorhombic P212121 7.351(2) 9.780(3) 29.993(5) 90 2156.28 4 1.16 0.0837(0.0883) 0.234(0.2366) 3456 253/0 1.056 0.281/−0.311

14/R5 (1:2) (C21H32N2O) 2(C5H8O4) 592.71 orthorhombic P212121 7.2659(1) 10.3858(3) 42.1865(10) 90 3183.49 4 1.237 0.0323(0.0336) 0.0829(0.0845) 5618 412/0 1.039 0.167/−0.19

14/S5 (1:1) (C21H32N2O) (C5H8O4) 460.60 monoclinic P21 6.8807(1) 11.0656(2) 16.4085(3) 96.713(2) 1240.76 2 1.233 0.0298(0.0312) 0.0774(0.0792) 4361 342/1 1.039 0.121/−0.113



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heterosynthon, described in graph set notation53 as [R22(8)], is present and is formed between the pyrrolidone amide of R2 and the carboxylic acid of S,S4. Both amide oxygens of R2 and both hydroxyl groups of S,S4 are involved in a dimeric [R22(12)] motif (Figure 3a). On the whole, the cocrystal

Figure 4. (a) The lamellar structure of S1/S9 is a juxtaposition of 20membered rings [R44(20)] involving three S1 and one S9. View along the c-axis. (b) Lamellas are held together by hydrophobic interactions. Hydrophobic groups are represented in ball and stick style. View along the a-axis.

Figure 3. (a) The structure of R2/S,S4 is composed of acid-amide heterosynthons [R22(8)] and 12-membered rings [R22(12)]. (b) The lamellar structure can be seen as a ladder wherein each rung is composed of S,S4 (ball and stick style) and two R2 (capped stick style). View along the c-axis.

Crystal Structure Analysis of S1/S5 (1:1). The combination S1/S5 is part of a diastereomeric cocrystal pair. The S1/S5 cocrystal crystallizes in a monoclinic system with space group P21. The asymmetric unit contains one molecule of S1 and one of molecule S5. The acid-amide heterosynthon [R22(8)] is formed between the amide group of S1 and the carboxylic acid group of S5. The whole cocrystal structure exhibits a layered structure, with layers lying in the bc plane. A layer is composed of chains of alternating S1 and S5 molecules, linked by the acidamide heterosynthon and a dimer (D) between the proton of the remaining carboxylic acid group of S5 and the pyrrolidone oxygen of S1 (Figure 5a). These chains are connected to each other via [C22(8)] motifs, hereby constituting a layer (Figure 5b). Crystal Structure Analysis of S1/R5 (1:1). The S1/R5 cocrystal crystallizes in a monoclinic space group P21. The asymmetric unit contains two molecules S1 and two molecules R5. As for its diastereomeric counterpart, the acid-amide heterosynthon [R22(8)] is formed between the amide group of S1 and the carboxylic acid group of R5. An additional 20membered ring [R44(20)] is composed of two S1 and two R5

exhibits a lamellar structure along the b-axis, that can be seen as a ladder wherein each rung is composed of two R2 linked to a S,S4 by two acid-amide heterosynthons (Figure 3b). The 12membered ring [R22(12)] serves up to join the rungs to form the ladder. Ladders are kept together by hydrophobic interactions. Crystal Structure Analysis of S1/S9 (1:1). Contrary to the R2/S,S4 cocrystal, the acid-amide heterosynthon is not present in the S1/S9 cocrystal. The lamellar structure is composed of a juxtaposition along the a-axis of ring motifs [R44(20)] involving three molecules of S1 and one S9 molecule (Figure 4a). The molecules of S1 lie in the middle of the lamella, flanked by molecules of S9. Under this layout, all hydrophobic isobutyl, methyl, ethyl, and pyrrolidone groups are oriented outward, which allows lamellas to be held together by hydrophobic interactions (Figure 4b). It should be noted that each molecule of S1 is involved in three different [R44(20)] motifs. 4000



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Figure 5. (a) Structure of S1/S5 cocrystal including acid-amide heterosynthons [R22(8)], chain motifs [C22(8)], and a dimer [D]. View along the b-axis. (b) View along the a-axis with highlighting of the chain motif [C22(8)] in blue.

Figure 6. (a) Structure of S1/R5 cocrystal including acid-amide heterosynthons [R22(8)] and a 20-membered ring [R44(20)]. View along the a-axis. (b) View along the c-axis with highlighting of the herringbone motif.

(Figure 6a) . The whole structure exhibits a herringbone motif stacked one on top of the other along the a-axis (Figure 6b). Under this arrangement, all hydrophobic methyl, ethyl, and pyrrolidone groups are oriented outward, which allows herringbone motifs to be held together by hydrophobic interactions. Crystal Structure Analysis of 14/R5 (1:2). The cocrystal 14/ R5 belongs to the second diastereomeric system. This latter crystallizes in an orthorhombic space group P212121 with one molecule of 14 and two molecules of R5 in the asymmetric unit. The structure exhibits two types of H-bonding ring motifs: a 10-membered ring [R23(10)] involving the hydroxyl group of 14 and two carboxylic acid groups of two R5, and a 11membered ring [R33(11)] involving nitrogen atoms of pyrazole of 14 and two carboxylic acid groups of two R5 (Figure 7). On the whole, the cocrystal 14/R5 displays a layered structure, with layers lying in the ab plane. The center of a layer is constituted of π-stacking of 14 and sandwiched between R5 molecules (via [R23(10)] and [R33(11)] motifs mentioned above). It must be emphasized that no direct hydrogen bonding is observed between molecules of 14. Crystal Structure Analysis of 14/S5 (1:1). The diastereomeric counterpart (14/S5) does not have strong similarities with the 14/R5 structure described above, as the cocrystal crystallizes in a monoclinic space group P21 with a 1:1 stoichiometric ratio. Two carboxylic acid groups coming from two molecules of S5 form a ring motif [R34(13)] with hydroxyl group and nitrogen atoms of pyrazole of two entities of 14, as shown in Figure 8a. This sole ring motif is repeated along the aand c-axis, leading to the formation of a planar structure. These layers stack one onto another in the direction of the b-axis

(Figure 8b). This structure no longer shows a sandwich arrangement in contrast to its diastereoisomeric counterpart, although a layered structure is once again observed. Compound 14 shows little conformational flexibility due to the embedded rings, but it can exist in two tautomeric forms. The initial compound was identified by XRPD as polymorph 2,54 wherein only tautomer B is present in the structure (Figure 1). Strikingly, only tautomer A is present in the cocrystal structures described herein.

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DISCUSSION To understand the propensity behind enantiospecific cocrystal formation, one needs to consider hydrogen bonding interactions, which are the main interactions responsible for cocrystal formation. Directionality of hydrogen bonds is widely accepted by the scientific community.23 This directionality results from hydrogen bonding an anisotropic intermolecular potential that separates it from ionic bonds, which are expected to be isotropic. In general, the donor H-bond tends to point at the acceptor electron pair, forming a linear bond. However, secondary interactions, such as electrostatic potential of molecules, hydrophobic, or π-stacking interactions, could force the H-bond away from linearity. Cocrystal formation is not solely guided by the hydrogen-bonding capability of both entities, but overall steric effects, and less strong van der Waals interactions are also important factors in the cocrystal formation.23,55 The main challenge is to understand how a change in chirality can perturb the hydrogen bonding motif in a particular system strongly enough so that only one cocrystal pair can be 4001



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Figure 7. Packing organization of the layered structure of 14/R5 cocrystal. The 14 entities stay in the center of a sandwich arrangement and the R5 stay outward. This structure includes two rings: [R23(10)] and [R33(11)]. View along the a-axis.

Computational crystal structure prediction (CSP) is a developing method for the calculation of approximate lattice energy landscapes for solid components. Over recent years, efforts were made to improve computational methods and to transfer this to predicted structures of salts and cocrystals. As lattice energy indicates stability of a structure, it is possible to predict the most stable cocrystal or salt in a fixed stoichiometry. This calculated structure is only likely to be formed if the lattice energy is lower than the sum of its components’ lattice energies, as represented schematically in Figure 9. In general, cocrystals rarely show considerable stabilization energies, with the stabilization free enthalpy of formation hardly surpassing 10 kJ mol−1.56,58−61 This is supported by typical cocrystal lattice energies (of about −200 kJ mol−1), which are comparable to those of the isolated components.57 In contrast, the lattice energies of salts are far greater than the sum of their isolated components, reflecting the stronger ionic hydrogen bonds in salts. Typical lattice energies for salts are on the order of −600 kJ mol−1,61,62 in strong contrast to the value of −200 kJ mol−1 mentioned above for cocrystals. These low stabilization energies also explain the reduced success rate obtained during typical cocrystal screens. Furthermore, this implies that small changes in structure, such as the changes observed when changing chirality, can render cocrystal formation unfavorable. Typically, a change in chirality, will lead to stronger steric interactions and loss of stabilizing secondary interactions such as π-stacking interactions and van der Waals interactions. These latter seem to be of the same order of magnitude as the total cocrystal stabilization energy (a few kJ mol−1), and loss of these explains why a cocrystal can be formed with one enantiomer, but not with the other, even if similar hydrogen bonding patterns are plausible. Accordingly, a similar structure for the two diastereomers seems unlikely. As shown by the structure of the diasteriomeric cocrystal pair described in this contribution,

Figure 8. (a) The structure of 14/S5 is composed of 13-membered rings [R34(13)] involving two 14 and two S5. View along the b-axis. (b) Layers are stacked one to another in the direction of the b-axis. View along the a-axis.

formed instead of a diasteriomeric pair. A recent contribution,56 focusing on structural aspects as well as theoretical simulation of lattice energies, gives a plausible explanation to the enantiospecific character of cocrystal systems. In this contribution, cocrystal formation is shown not only to depend on strong hydrogen bonding motifs but also on weaker secondary interactions, mentioned above. Considering the low stabilization free enthalpy of cocrystal formation (on the order of kJ mol−1) these secondary interactions cannot be neglected when studying cocrystal stability. 4002



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Figure 9. Schema illustrating lattice energies of isolated components (about −100 kJ mol−1), the sum of components’ lattice energy, lattice energy of cocrystal formation (about −200 kJ mol−1), and lattice energy of salt formation (about −600 kJ mol−1). If the lattice energy of cocrystal formation is higher than the sum of its components (dotted line), then no cocrystal formation can occur (unless a mestable cocrystal could be formed).

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an overall rearrangement of the hydrogen bonding motifs seems required, in order to display two energetically favored diasteriomers.

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CONCLUSION In this contribution, we investigated the propensity toward enantiospecific cocrystal formation. Contrary to salts for which formation of a diastereomeric salt pair seems to be the general rule, cocrystal systems nearly always behave enantiospecifically. An experimental cocrystal screen combined with an extensive CSD search shows how for about 85% of cocrystal systems, an enantiospecific behavior is encountered. This particularity of cocrystal systems can be explained by the relatively low stabilization energies of these systems (a few kJ mol−1), which make them extremely sensitive to changes in steric interactions, and/or losses in stabilizing secondary interactions typically encountered when one changes the chirality of one of the components.

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ASSOCIATED CONTENT

S Supporting Information *

Additional images of cocrystals. This material is available free of charge via the Internet at http://pubs.acs.org/. The structures have been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition numbers for S1/S5 #977387, S1/R5 # 998777, R2/S,S4 #9977388, 14/S5 #977389, 14/R5 #977390, and S1/S9 #977391.

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REFERENCES

(1) Nogradi, M.; Palovics, E.; Schindler, J. Tetrahedron: Asymmetry 2008, 19 (5), 519−536. (2) Siedlecka, R. Tetrahedron 2013, 69, 6331−6363. (3) Querniard, F.; Linol, J.; Cartigny, Y.; Coquerel, G. J. Therm. Anal. Calorim. 2007, 90 (2), 359−365. (4) Marchand, P.; Lefèbvre, L.; Querniard, F.; Cardinaël, P.; Perez, G.; Cournioux, J.-J.; Coquerel, G. Tetrahedron: Asymmetry 2004, 15, 2455−2465. (5) Springuel, G.; Leyssens, T. Cryst. Growth Des. 2012, 12, 3374− 3378. (6) Springuel, G.; Collard, L.; Leyssens, T. CrystEngComm 2013, 15, 7951−7958. (7) Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney, M. L.; Choudhury, A. R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.; Duggirala, N.; Ghogale, P. P.; Ghosh, S.; Goswami, P. K.; Goud, N. R.; Jetti, R. R. K. R.; Karpinski, P.; Kaushik, P.; Kumar, D.; Kumar, V.; Moulton, B.; Mukherjee, A.; Mukherjee, G.; Myerson, A. S.; Puri, V.; Ramanan, A.; Rajamannar, T.; Reddy, C. M.; Rodriguez-Hornedo, N.; Rogers, R. D.; Guru Row, T. N.; Sanphui, P.; Shan, N.; Shete, G.; Singh, A.; Sun, C. C.; Swift, J. A.; Thaimattam, R.; Thakur, T. S.; Thaper, R. K.; Thomas, S. P.; Tothadi, S.; Vangala, V. R.; Variankaval, N.; Vishweshwar, P.; Weyna, D. R.; Zaworotko, M. J. Cryst. Growth Des. 2012, 12, 2147−2152. (8) Aakeröy, C. B.; Salmon, D. J. CrystEngComm 2005, 7 (72), 439− 448. (9) Thorey, P.; Bombicz, P.; Szilágyi, I. M.; Molnár, P.; Bánsághi, G.; Székely, E.; Simándi, B.; Párkányi, L.; Pokol, G.; Madarász, J. Thermochim. Acta 2010, 497, 129−136. (10) Kassai, C.; Juvancz, Z.; Balint, J.; Fogassy, E.; Kozma, D. Tetrahedron 2000, 56, 8355−8359. (11) Caira, M. R.; Nassimbeni, L. R.; Scott, J. L.; Wildervanck, A. F. J. Chem. Crystallogr. 1996, 26 (2), 117−122. (12) Springuel, G.; Norberg, B.; Robeyns, K.; Wouters, J.; Leyssens, T. Cryst. Growth Des. 2012, 12 (1), 475−484. (13) Roy, B. N.; Singh, G. P.; Srivastava, D.; Jadhavn, H. S.; Saini, M. B.; Aher, U. P. Org. Process Res. Dev. 2009, 13 (3), 450−455. (14) Nemak, K.; Acs, M.; Jaszay, Z. M.; Kozma, D.; Fogassy, E. Tetrahedron 1996, 52 (5), 1637−1642. (15) Takata, N.; Shiraki, K.; Takano, R.; Hayashi, Y.; Terada, K. Cryst. Growth Des. 2008, 8 (8), 3032−3037. (16) Hu, X.; Shan, Z.; Li, W. J. Fluorine Chem. 2010, 131, 505−509. (17) Bruno, I. J.; Cole, J. C.; Edgington, P. R.; Kessler, M.; Macrae, C. F.; McCabe, P.; Pearson, J.; Taylor, R. Acta Crystallogr., Sect. B: Struct. Sci. 2002, 58, 389−397. (18) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311− 2327. (19) Vangala, V. R.; Chow, P. S.; Tan, R. B. H. Cryst. Growth Des. 2012, 12 (12), 5925−5938.

AUTHOR INFORMATION

Corresponding Author

*Tel: +32 10 47 2811. Fax: +32 10 47 27 07. E-mail: Tom. [email protected]. Web: http://www.uclouvain.be/ leyssens-group. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank the UCL (FSR) and FNRS (PDR T009913F) for financial support, and Dr. A.Tilborg for fruitful discussion. 4003



Article

(20) Weyna, D. R.; Shattock, T.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2009, 9 (2), 1106−1123. (21) Thakuria, R.; Delori, A.; Jones, W.; Lipert, M. P.; Roy, L.; Rodriguez-Hornedo, N. Int. J. Pharmaceut. 2013, 453 (1), 101−125. (22) Adalder, T. K.; Sankolli, R.; Dastidar, P. Cryst. Growth Des. 2012, 12, 2533−2542. (23) Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2003, 3 (5), 783−790. (24) Toda, F.; Tanaka, K.; Kido, M. Chem. Lett. 1988, 513−516. (25) Ikemoto, T.; Nagata, T.; Yamano, M.; Ito, T.; Mizuno, Y.; Tomimatsu, K. Tetrahedron Lett. 2004, 45, 7757−7760. (26) Gao, J.-M.; Liu, W.-T.; Li, M.-L.; Liu, H.-W.; Zhang, X.-C.; Li, Z.-X. J. Mol. Struct. 2008, 892, 466−469. (27) Yamagishi, M.; Yamada, Y.; Ozaki, K.-I.; Da-te, T.; Okamura, K.; Suzuki, M.; Matsumoto, K. J. Org. Chem. 1992, 57, 1568−1571. (28) Toda, F.; Tanaka, K.; Marks, D.; Goldberg, I. J. Org. Chem. 1991, 58, 7332−7335. (29) Nassimbeni, L. R.; Niven, M. L.; Tanaka, K.; Toda, F. J. Crystallogr. Spec. Res. 1991, 21 (4), 451−457. (30) Kaku, H.; Takaoka, S.; Tsunoda, T. Tetrahedron 2002, 58, 3401−3407. (31) Brunner, H.; Pieronczyk, W.; Schonhammer, B.; Streng, K.; Bernal, I.; Korp, U. J. Chem. Ber. 1981, 114 (3), 1137−1149. (32) Tanaka, K.; Takenaka, H.; Caira, M. R. Tetrahedron: Asymmetry 2006, 17, 2216−2219. (33) Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 646−649. (34) Müller, S.; Afraz, M. C.; de Gelder, R.; Ariaans, G. J. A.; Kaptein, B.; Broxterman, Q. B.; Bruggink, A. Eur. J. Org. Chem. 2005, 1082− 1096. (35) Urbanczyk-Lipkowska, Z.; Fukuda, N.; Tanaka, K. Tetrahedron: Asymmetry 2007, 18, 1254−1256. (36) Fantin, G.; Fogagnolo, M.; Bortolini, O.; et al. New J. Chem. 2004, 28, 1295−1300. (37) Toda, F.; Tanaka, K.; Infantes, L.; Foces-Foces, C.; Claramunt, R. M.; Elguero, J. J. Chem. Soc., Chem. Comm. 1995, 1453−1454. (38) Chandramohan, K.; Ravikumar, K. J. Chem. Crystallogr. 1999, 29 (1), 121−125. (39) Toda, F.; Sato, A.; Tanaka, K.; Mak, T. C. W. Chem. Lett. 1989, 873−876. (40) Pinkerton, A. A.; Carrupt, P.-A.; Claret, F.; Vogel, P. Acta Crystallogr. 1993, C49, 1632−1636. (41) Ribeiro, N.; Saigo, K. Tetrahedron: Asymmetry 2009, 20, 2704− 2708. (42) Aakeröy, C. B.; Cooke, T. I.; Nieuwenhuyzen, M. Supramol. Chem. 1996, 7:2, 153−156. (43) Eddleston, M. D.; Arhangelskis, M.; Friscic, T.; Jones, W. ChemComm. 2012, 48, 11340−11342. (44) Koscho, M. E.; Spence, P. L.; Pirkle, W. H. Tetrahedron: Asymmetry 2005, 16, 3147−3153. (45) Zimmerman, H. E.; Alabugin, I. V.; Smolenskaya, V. N. Tetrahedron 2000, 56, 6821−6831. (46) Beckmann, U.; Brooker, S. Acta Crystallogr. Sect. C 2006, 62 (11), o653−o655. (47) Furuya, T.; Fujita, S.; Fujikura, T. Anal. Sci. 1989, 5, 489−490. (48) Venugopal, M.; Elango, S.; Parthiban, A. Tetrahedron: Asymmetry 2004, 15, 3427−3431. (49) Milton Harris, J.; Sedaghat-Herati, M. R.; McManus, S. P. J. Org. Chem. 1988, 53, 3894−3896. (50) Friscic, T.; Fabian, L.; Burley, J. C.; Jones, W.; Motherwell, W. D. S. Chem. Commun. 2006, 5009−5011. (51) Friscic, T.; Jones, W. Cryst. Growth Des. 2009, 9 (3), 1621− 1637. (52) Delori, A.; Friscic, T.; Jones, W. CrystEngComm 2012, 14, 2350−2362. (53) Etter, M. C.; MacDonald, J. C. Acta Crystallogr. 1990, B46, 256−262. (54) Karpinska, J.; Erxleben, A.; McArdle, P. Cryst. Growth Des. 2011, 11, 2829−2838.

(55) Baures, P. W.; Rush, J. R.; Wiznycia, A. V.; Desper, J.; Helfrich, B. A.; Beatty, A. M. Cryst. Growth Des. 2002, 2 (6), 635−664. (56) Habgood, M. Cryst. Growth Des. 2013, 13, 4549−4558. (57) Isolated components typically show lattice energies of −100 kJ mol−1. The −200 kJ mol−1 lattice energy typically observed for 1:1 cocrystals compares to this value, as the cocrystal contains double the amount of molecules. (58) Issa, N.; Karamertzanis, P. G.; Welch, G. W. A.; Price, S. L. Cryst. Growth Des. 2009, 9 (1), 442−453. (59) Habgood, M.; Price, S. L. Cryst. Growth Des. 2010, 10, 3263− 3272. (60) Habgood, M.; Deij, M. A.; Mazurek, J.; Price, S. L.; ter Horst, J. H. Cryst. Growth Des. 2010, 10, 903−912. (61) Mohamed, S.; Tocher, D. A.; Price, S. L. Int. J. Pharm. 2011, 418, 187−198. (62) Karamertzanis, P. G.; Price, S. L. J. Phys. Chem. B 2005, 109, 17134−17150.

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Cocrystal Formation between Chiral Compounds: How Cocrystals

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