Predicting Cocrystallization Based on Heterodimer Energies: Part II

Article pubs.acs.org/crystal

Predicting Cocrystallization Based on Heterodimer Energies: Part II Marina A. Solomos, Taylor A. Watts, and Jennifer A. Swift* Department of Chemistry, Georgetown University, 37th and O Streets NW, Washington, D.C. 20057-1227, United States S Supporting Information *

ABSTRACT: Many crystal engineering studies employ urea functionalities for their predictable association into onedimensional hydrogen bonded chains. Previously, we showed (Cryst. Growth Des., 2015, 15 (10), 5068−5074) that the urea chain motif usually seen in structures of diphenylureas (PUs) with meta-substituents could be disrupted in several cases by cocrystallization with the strong hydrogen bond acceptor triphenylphosphine oxide (TPPO). Computed differences in the urea···urea and urea···TPPO dimer energies of ∼5.3−6 kcal/ mol were a reasonably accurate indicator for cocrystallization success. The current study attempts to reassess the limits of this computational approach using a larger set of 16 ortho- and para-substituted PUs. Seven of the 10 PU systems predicted to cocrystallize on the basis of dimer energy calculations were experimentally realized, along with an eighth whose difference in homo/heterodimer energies fell below the threshold. The absence of cocrystallization in two of the predicted systems is likely due to preferred urea···substituent hydrogen bonding over both urea···urea and urea···TPPO interactions, a factor that was not considered in the homo/heterodimer energy comparisons. When taken in combination with the previous study, energy predictions were 87% accurate over the 30 systems investigated.

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INTRODUCTION Cocrystallization can be a valuable approach to significantly alter the physical properties of crystalline organic materials. For example, cocrystal forms of drug compounds may exhibit improved stability and/or bioavailability,1−6 and cocrystal forms of energetic materials may have reduced sensitivity.7−9 However, in most cases there is little certainty as to whether a cocrystal will form, let alone whether that form will exhibit improved properties relative to its single component form. The scientific literature is inherently biased toward experimental successes rather than failures (for a variety of obvious reasons). This is unfortunate since the failures seen in cocrystallization can be as instructive as the successes. However, because it is not possible to exhaustively survey all the possible conditions that might lead to cocrystallization in a practical sense, the absence of a cocrystal is not proof that it can never exist. The identification of a cocrystal phase will always depend on its experimental realization. Experimental cocrystal screening processes require extensive, empirical trials.10,11 To minimize the time invested in this important step, a variety of predictive computational tools can help to focus experimental effort on coformers most likely to be successful. This may involve the identification of preferred binding motifs seen across large numbers of compounds,12,13 for example, in the Cambridge Structural Database. Lattice energy calculations,14,15 molecular surface electrostatic potentials,16 surface site interaction points,17 and density functional theory calculations (DFT)18 have also been used for cocrystal prediction. In a previous study,19 we assessed the ability of metasubstituted diphenylurea (mPU) compounds to cocrystallize with triphenylphosphine oxide (TPPO). Our experimental efforts resulted in cocrystals in 9/14 cases. Density functional © XXXX American Chemical Society

theory calculations were subsequently used to rationalize this success rate. We found that when the relative interaction energy between urea···TPPO (heterodimer) and urea···urea (homodimer) pairs was greater than ∼5.3−6 kcal/mol, cocrystals were generally favored. Although the thermodynamics of cocrystals are certainly more complex than the dimer energies alone, the differences in hetero- and homodimer energies strongly correlated with our experimental results. This study did not attempt to clarify whether the steric constraints imposed by the meta-substituents affected the likelihood of cocrystal formation. Whereas in the previous study, computational methods were used to rationalize the experimental results, in the present study, calculations of an expanded set of PUs with ortho- and parasubstituents (oPUs and pPUs) are used to predict cocrystal formation. The compounds have different steric factors than the mPUs, particularly the oPUs, which have more restricted rotation about the amide bond. The energies of 16 different urea···urea and urea···TPPO dimers were calculated at the B3LYP/631G(d,p) level after geometry optimization. Ten of the oPU and pPU systems had interaction energy differences >5.3 kcal/mol, indicating cocrystallization was likely. Seven of the predicted cocrystals were obtained experimentally. One additional cocrystal whose calculated interaction energy difference fell below the threshold was also obtained. Herein, we discuss the validity and limitations of the computational approach and report 12 new cocrystal and pPU structures. Received: June 30, 2017 Revised: August 8, 2017

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DOI: 10.1021/acs.cgd.7b00922 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Bis(p-nitrophenyl)urea (ZURVAL),29 and 1-(p-nitrophenyl)-3-phenylurea (FUWJAJ)30 have been previously reported. For cocrystallization experiments, equimolar amounts of TPPO and oPU or pPU were ground with a mortar and pestle, dissolved in the same range of solvents listed above, and allowed to slowly evaporate at room temperature. In cases where cocrystals were successfully grown, they typically appeared within 2−10 days. Characterization. Optical and hot-stage microscopy (HSM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and single crystal X-ray diffraction (when possible) were used to characterize the solid state materials. Bulk and single crystal samples were analyzed by HSM using an Olympus BX-50 microscope equipped with an HCS302 optical hot-stage (INSTEC, Inc., Boulder, CO) from 25−250 ± 1 °C. Melting points were determined by DSC using a TA Instruments Modulated DSC 2920. Samples were prepared in hermetically sealed aluminum pans and heated at a rate of 5−10 °C/ min. DSC data was analyzed with Universal Analysis software. PXRD data was collected on bulk ground single component and cocrystal samples at room temperature (5−40° in 2θ) on a Rigaku Ultima IV X-ray diffractometer (Cu Kα radiation, 40 kV tube voltage, 44 mA current). PXRD spectra were analyzed using Jade v9.0 software and compared against simulated PXRD patterns of known single component structures. Single crystal diffraction data were collected at 100 or 110 K using a Siemans/Bruker SMART or APEX II Platform CCD diffractometer (Mo Kα radiation = 0.71073 Å). Structures were solved in SHELXS and refined using SHELXL. Non-hydrogen atom positions were determined using direct methods and refined with anisotropic displacement parameters. Hydrogen atom treatment was mixed. Urea hydrogen atom positions were typically determined from the residual electron density, while other protons were placed in ideal positions and refined with a riding model. Twelve cif files for pPU (4), pPU:TPPO (5), and oPU:TPPO (3) have been deposited in the CCDC (1554299− 1554310). Density Functional Theory (DFT) Calculations. Optimized geometries and frequencies for all oPU and pPU monomers, dimers, and o/pPU:TPPO heterodimers were calculated using Gaussian09 at the B3LYP/6-31G(d,p) level.

EXPERIMENTAL SECTION

Materials. All 4-X-isocyanate and 4-X-aniline reagents were obtained from Sigma-Aldrich (97−99%) and used without further purification. All solvents used in synthesis and crystallization experiments were reagent grade or higher and were obtained from SigmaAldrich, Fischer Scientific, and Warner-Graham. 1H NMR data were collected on a 300 MHz Varian Inova Spectrometer in d6-DMSO. Synthesis of Ortho- and Para-Substituted Diphenylureas. Syntheses for 1,3-Bis(o-nitrophenyl)urea (oNPU), 1-(o-nitrophenyl)-3phenylurea (oNHPU), 1,3-Bis(o-cyanophenyl)urea (oCyPU), 1-(ocyanophenyl)-3-phenylurea (oCyHPU), 1,3-Bis(o-chlorophenyl) urea (oClPU), 1-(o-chlorophenyl)-3-phenylurea (oClHPU), 1,3-Bis(otrifluoromethylphenyl)urea (oCF3PU), and 1-(o-trifluorophenyl)-3phenylurea (oCF3HPU) are reported elsewhere.20 Symmetrical and unsymmetrical para-substituted diphenylureas were synthesized according to previously reported methods.21 For each compound, equimolar amounts of 4-X-isocyanate and 4-X-aniline were dissolved in benzene or dichloromethane flushed with nitrogen and stirred at room temperature for 24 h. Gentle heating was often required for full dissolution. After 24 h, the product was vacuum filtered and recrystallized in ethanol or acetonitrile. The products were characterized with 1H NMR and differential scanning calorimetry (DSC). 1,3-Bis(p-nitrophenyl)urea (pNPU). Prepared from 4-nitroaniline and 4-nitrophenyl isocyanate.22 Recrystallization in acetone yielded yellow needles with a broad mp = 264.64−313.65 °C (lit. decompose 323 °C).23 1H NMR (DMSO-d6) δ: 9.69 (s, 2H); 8.21 (m, 4H); 7.72 (m, 4H). 1-(p-Nitrophenyl)-3-phenylurea (pNHPU). Prepared from aniline and 4-nitrophenyl isocyanate. Recrystallization in ethanol yielded colorless needles with a mp = 217.5−225.6 °C (lit. 218−219 °C).24 1 H NMR (DMSO-d6) δ: 9.43 (s, 1 H), 8.91 (s, 1 H), 8.19 (m, 2 H), 7.69 (m, 2 H), 7.48 (m, 2 H), 7.31 (m, 2 H), 7.02 (m, 1 H). 1,3-Bis(p-cyanophenyl)urea (pCyPU). Prepared from 4-aminobenzonitrile and 4-cyanophenyl isocyanate. Recrystallization in ethanol yielded colorless needles with a broad mp = 284.1−293.7 °C (lit. 273 °C).25 1H NMR (DMSO-d6) δ: 9.39 (s, 2H), 7.75 (d, 4H), 7.56 (d, 4H). 1-(p-Cyanophenyl)-3-(phenyl)urea (pCyHPU). Prepared from 4aminobenzonitrile and phenyl isocyanate. Recrystallization in ethanol yielded colorless needles with mp = 204.0−210.4 °C. 1H NMR (DMSOd6) δ: 9.22 (s, 1H), 8.87 (s 1H), 7.73 (d, 2H), 7.63 (d, 2H), 7.46 (d, 2H), 7.30 (t, 2H), 7.00 (m, 1H). 1,3-Bis(p-nitrophenyl)urea (pClPU). Prepared from 4-chloroaniline and 4-chlorophenyl isocyanate. Recrystallization in ethanol yielded colorless needles with a broad mp = 298.8−313.6 °C (lit. 315−319 °C).26 1H NMR (DMSO-d6) δ: 8.84 (s, 2H), 7.47 (m, 4H), 7.33 (m, 4H). 1-(p-Chlorophenyl)-3-(phenyl)urea (pClHPU). Prepared from 4chloroaniline and phenyl isocyanate. Recrystallization in ethanol yielded colorless needles with mp = 232.4−242.5 °C (lit. 240−242 °C).27 1H NMR (DMSO-d6) δ: 8.79 (s, 1H), 8.68 (s, 1H), 7.45 (m, 4H), 7.29 (m, 4H), 6.97 (m, 1H). 1,3-Bis(p-trifluoromethylphenyl)urea (pCF3PU). Prepared from 4trifluoromethylaniline and 4-(trifluoromethyl)phenylisocyanate. Recrystallization in ethanol yielded colorless needles with a broad mp = 234.6−240.7 °C. 1H NMR (DMSO-d6) δ: 9.24 (s, 2H), 7.65 (m, 8H). 1-(p-Trifluoromethylphenyl)-3-(phenyl)urea (pCF3HPU). Prepared from 4-trifluoromethylaniline and phenyl isocyanate. Recrystallization in ethanol yielded colorless needles with mp = 223.9−228.5 °C. 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.80 (s, 1H), 7.63 (m, 4H), 7.47 (m, 2H), 7.29 (t, 2H), 7.00 (m, 1H). Crystal and Cocrystal Growth. Crystallization of pPUs by slow evaporation was attempted from a number of different solvents, including but not limited to acetone, toluene, acetonitrile, ethanol, methanol, benzene, 2-propanol, ethyl acetate, 1:1 hexanes/acetone, 1:1 hexanes/ethyl acetate, and chloroform. Vials containing supersaturated solutions were covered with pierced Parafilm and maintained at room temperature for typically 2−10 days or until precipitate appeared. Crystal structures of 1,3-Bis(p-chlorophenyl)urea (MIXZAV),28 1,3-

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RESULTS AND DISCUSSION Symmetrically substituted compounds used in this study are named as oXPU or pXPU, where X corresponds to the substituent (N = nitro, Cy = cyano, CF3 = trifluoromethyl, Cl = chloro) and o/p refer to ortho- or para-substitution. Monosubstituted compounds are named as oXHPU or pXHPU. Predictions Based on Homo- and Heterodimer Energies. oPU monomers and homodimers were geometry optimized starting from planar conformations with the orthosubstituents initially oriented opposite the carbonyl group. This is consistent with the conformations of oPUs observed in their single crystal structures, though it does not guarantee the same conformation would be observed in cocrystals. pPU monomers and homodimers were also geometry optimized from initially planar conformations. PU homodimers and PU:TPPO heterodimers were geometry optimized from initial positions, which allow urea···urea or urea···phosphine oxide hydrogen bonding to occur (Figure 1). Interaction energies (ΔEint) were calculated according to eq 1 ΔE int = EAB − (EA + E B)

(1)

where EA and EB are the optimized energies of the individual monomers and EAB is the optimized energy of the dimer. When calculating ΔEint for the homodimers, EA = EB. The difference in interaction energies (ΔΔEint) was determined from eq 2. ΔΔE int = ΔE int(heterodimer) − ΔE int(homodimer) B

(2)

DOI: 10.1021/acs.cgd.7b00922 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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2. For a complete list of intermolecular hydrogen bond distances and angles in these structures, see Table S1. Each of the eight cocrystals identified in this work exhibited hydrogen bonding between the urea amide and the oxygen of TPPO. Seven of the eight cocrystal structures (pNHPU, pCyPU, pCF3PU, pCF3HPU, oCyHPU, oCF3HPU) had the expected [R12(6)] motif31 with intermolecular PO···H−N bond lengths ranging from 1.840 to 2.170 Å and PO···H angles from 126.19 to 160.96° (Figure 2). The oNHPU:TPPO structure was slightly different than the others since one of the amide protons forms an intramolecular hydrogen bond to the ortho-NO2 substituent (N−H···O, 1.980 Å). The one remaining amide hydrogen bonds to TPPO (N−H···O, 1.840 Å), but the orientation between heterodimer components is quite skewed with a PO···H angle of 173.62°. We presume this is due to the steric demands of the osubstituent and the large energetic penalty that would be associated with breaking the intramolecular hydrogen bond. Steric effects and large rotational barriers about the amide bond in oPUs are likely factors in why none of the disubstituted oPUs readily cocrystallized with TPPO.20 Among the eight cocrystals reported here, only p NHPU:TPPO and pCyHPU:TPPO were isostructural. Notably, these are also the only structures that belong to a chiral space group from the 17 PU:TPPO cocrystals that have been prepared to date. The packing consists of alternating sheets of urea and TPPO molecules stacked along the c-axis. In Figure 3, TPPO molecules are depicted in blue to more easily visualize the layered packing arrangement. Urea molecules adopt nearly planar conformations, in good agreement with the calculated energy minima. oCyHPU:TPPO and pCF3PU:TPPO adopt topologically similar layered packing motifs, though alternating urea and TPPO molecules stack along the a-axis in the former and the [011] axis in the latter. oCF3HPU:TPPO also adopts a layered motif; however, the layers are less discrete with π−π interactions between the two component layers (Figure 4). In oCF3HPU:TPPO, face−face dimers exist between the p-CF3 phenyl ring and one phenyl ring of the TPPO (center···center distance of 3.90 Å). The phenyl ring in oCF3HPU aligns edge-face in relation to the other rings of TPPO. In pCF3PU:TPPO, π−π face−face dimers between a pCF3PU and TPPO (center···center distance of 3.85 Å) are seen. A second face−face interaction is seen between rings of neighboring pCF3PU molecules (center···center distance of 3.93 Å). Unexpected topologies were observed for pCyPU:TPPO and oNHPU:TPPO. pCyPU:TPPO was isolated as a hemisolvate, with half a benzene molecule in the asymmetric unit. The structure lacks discrete layers of the two components. Rather, the phenyl rings of the TPPO molecules align to create a pore-like void in the structure, essentially a hydrophobic channel along the b-axis, which is occupied by benzene molecules. oNHPU:TPPO is also unique, consisting of an infinite checkerboard of oNHPU and TPPO molecules when viewed down the [101] axis. Accuracy of Cocrystal Predictions. The results of our cocrystallization attempts are summarized in Figure 5. Based on the 30 systems now investigated, the thermodynamic barrier (ΔΔEint) for cocrystallization narrows to −5.38 and −5.34 kcal/ mol (Figure 5). This barrier successfully predicted the outcome in 26/30 (87%) of the systems investigated. However, 4/26 systems still did not cocrystallize or crystallize as expected based on ΔΔEint values. We were initially most surprised that pNPU failed to cocrystallize since it had the largest ΔΔEint in Table 1. From

Figure 1. Hydrogen bonding in (left) homodimers and (right) heterodimers.

In the previous mPU:TPPO cocrystallization study, the only binary solutions that successfully yielded cocrystals had calculated ΔΔEint < −5.34 to −6.07 kcal/mol.19 Based on this threshold and the calculated energies in Table 1, we predicted Table 1. Calculated Homodimer (PU···PU) and Heterodimer (PU···TPPO) Energies and the Difference between Them PU

ΔEint (homodimer) (kcal/mol)

ΔEint (heterodimer) (kcal/mol)

ΔΔEint (kcal/mol)

pNPUa pCyPUa pNHPU pCyHPU pCF3PU pClPU pCF3HPU oCyPUa oNHPU oCyHPUa pClHPU oClHPU oCF3HPU oClPU oNPUa oCF3PU

−9.19 −9.60 −9.53 −10.11 −10.68 −11.10 −11.10 −10.03 −8.44 −10.94 −11.52 −9.43 −11.53 −6.86 −5.25 −11.16

−21.01 −20.42 −18.42 −18.34 −18.90 −17.58 −17.50 −15.97 −13.95 −16.33 −16.82 −14.57 −16.36 −11.34 −8.98 −13.69

−11.82 −10.82 −8.89 −8.24 −8.22 −6.48 −6.40 −5.94 −5.51 −5.38 −5.31 −5.14 −4.83 −4.48 −3.73 −2.53

a

Urea···urea hydrogen bonded chain not observed in singlecomponent PU crystals.

that ten of the oPU and pPU systems in the current study should cocrystallize with TPPO. These are pNPU, pNHPU, pCyPU, pCyHPU, pCF3PU, pClPU, pCF3HPU, oCyPU, oNHPU, and oCyHPU. Calculated heterodimer geometries appear in Figure S1. Calculated heterodimers that were not observed appear qualitatively similar. The relative energies suggest some interesting differences in pPU and oPUs due to steric effects. The difference in hetero- and homodimer energies was smaller for almost all oPUs compared to pPU, a trend that is most likely due to TPPO’s inability to approach the urea hydrogens without altering the urea torsion angles. While rotation about the amide bond in oPUs is not strictly prohibited, the increase in conformational energy is considerably higher than for analogous rotations in mPUs or pPUs.20 Cocrystals. Cocrystallization of 1:1 mixtures of TPPO and all PUs was attempted from multiple solvents. Eight of the 16 systems yielded 1:1 cocrystals, including seven of the cocrystals predicted by energy calculations (pCyPU, pCyHPU, pCF3PU, pCF3HPU, pNHPU, oNHPU, oCyHPU) and one that was not (oCF3HPU). The X-ray data for all cocrystals are given in Table C

DOI: 10.1021/acs.cgd.7b00922 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Table 2. Crystallographic Data for 1:1 PU:TPPO Cocrystals with o/p Substituentsa urea growth solvent habit formula temp (K) space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z Rw R

pNHPU

pCyHPU

pCF3HPU

pCyPUb

pCF3PU

toluene

toluene

benzene

benzene

benzene

prism C31H26N3O4P 100 P212121

prism C32H26N3O2P 100 P212121

plate C32H26F3N2O2P 100 P1̅

plate C33H25F6N2O2P 100 P1̅

8.9079(5) 15.1290(8) 19.5918(11) 90 90 90 2640.34 4 0.0881 0.0387

9.2105(2) 15.5477(3) 18.6380(3) 90 90 90 2669 4 0.0634 0.0246

9.3828(7) 10.8486(8 14.4419(11) 70.363(2) 76.647(2) 78.122(2) 1333.87 2 0.0945 0.0369

9.2449(6) 10.6637(6) 15.0842(9) 78.273(2) 82.222(2) 88.163(2) 1442.62 2 0.0833 0.0340

oNHPU

oCyHPU

oCF3HPU

toluene

acetone/hexane

plate C36H28N4O2P 100 C2/c

ethyl acetate/ hexane prism C31H26N3O4P 110 P21/n

plate C32H26N3O2P 100 P1̅

plate C32H26F3N2O2P 100 P21/c

23.4860(13) 17.0082(13) 16.4758(10) 90 114.566(2) 90 5985.61 8 0.0927 0.0356

15.3698(6) 11.3061(4) 16.8337(7) 90 114.406(4) 90 2663.84 4 0.0998 0.0412

9.7488(3) 11.9024(4) 12.5824(4) 79.788(2) 81.358(2) 66.7270(10) 1314.74 2 0.1024 0.0394

14.0110(15) 10.9306(12) 17.981(2) 90 97.419(5) 90 2730.71 4 0.1349 0.0427

a

N = nitro. Cl = chloro. CF3 = trifluoromethyl. Cy = cyano/nitrile. H = hydrogen. bStructure is a hemisolvate with 0.5 benzene for every pair of PU and TPPO molecules.

Figure 2. Heterodimers observed in 1:1 PU:TPPO cocrystals. pNHPU:TPPO and pCyHPU:TPPO dimers are isostructural.

Our inability to cocrystallize oCyPU and TPPO likely stems from the unanticipated chemical instability of oCyPU. Although oCyPU crystallizes under some conditions, prolonged time in solution can lead to an unexpected rearrangement product.32 We suspect that the oCyPU lifetime in solution may not be compatible with the time scale required for cocrystallization to occur. The inability to cocrystallize pClPU and TPPO (not predicted) and the realization of oCF3HPU:TPPO (not predicted) serve to remind us that cocrystal prediction methods, especially the simple ones used here, are not infallible.

the advantage of hindsight, we surmise that at least part of why the difference in homodimer (urea···urea) and heterodimer (urea···TPPO) energies is not a good predictor for cocrystallization in all cases may be because the comparison does not account for the strongest hydrogen bonds. The structure of pNPU (refcode: ZURVAL) does not exhibit the typical [R12(6)] urea bonding motif, instead the dominant intermolecular hydrogen bonding is between NO2···urea groups. Crystal structures of four pPU dimers were determined in the course of this work: pCyPU, pCF3PU, pCyHPU, and pClHPU (Table 3, Figure S2). Structures for pNHPU (FUWJAJ) and pClPU (MIXZAV) have been previously reported. The single component structures of pCyPU and oCyHPU also lack a urea chain bonding motif. While this did not prevent pCyPU:TPPO and oCyHPU:TPPO cocrystals from forming, it may be that urea···nitrile and urea···TPPO interactions are more similar in energy, whereas urea···nitro bonding is stronger than both.

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CONCLUSIONS We have shown that interaction energy differences between hetero- and homodimers are good predictors of oPU or pPU (and previously mPU) cocrystal formation with the hydrogen bond acceptor TPPO. In all eight cocrystals reported herein, P O···N−H hydrogen bonding was identified across a variety of three-dimensional lattice packing arrangements. This computaD

DOI: 10.1021/acs.cgd.7b00922 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Figure 3. (top) View down the b-axis of pNHPU:TPPO and pCyHPU:TPPO and (bottom) view down the a-axis of oCyHPU:TPPO and pCF3HPU:TPPO. TPPO molecules are colored blue for clarity.

Figure 4. (top) oCF3HPU:TPPO and pCF3PU:TPPO viewed down the b-axis. (bottom) pCyPU:TPPO viewed down the c-axis, and oNHPU:TPPO viewed down the [101] direction. TPPO molecules are colored blue for clarity.

none crystallized in multiple forms.33 This stands in contrast to both TPPO (refcode: TPEPHO) and many of the individual PUs, which readily exhibit concomitant polymorphism. Comparison of the packing fractions of PU:TPPO and PU (when known) show a roughly equal number of cases where the density of cocrystal > PU and PU > cocrystal. In nearly all cases, the density of cocrystal > TPPO, which may bias cocrystal formation. Though it is not possible to quantify these secondary effects, we offer them for consideration to others who may wish

tional method had an overall accuracy of 87% in predicting the outcome of 26/30 cocrystallization experiments. The systems that did not crystallize or cocrystallize as expected help to better define the limits of this theoretical approach, in some cases pointing out the presence of stronger interactions that were not accounted for in the hetero/homodimer comparison. We also can not discount the possibility that other factors may be at play in these systems. Though we did not explicitly search for polymorphism in the cocrystals, we note that in our experience, E

DOI: 10.1021/acs.cgd.7b00922 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Figure 5. Interaction energy differences between ortho-, meta-, and para-substituted PU dimers and PU:TPPO heterodimers for all 30 systems reported here and in ref 19. The calculated ΔΔEint barrier for cocrystal formation is represented by a dashed line. Dark blue = 1:1 cocrystals reported here. Light blue = 1:1 cocrystals previously reported. Gray = no cocrystal obtained.

Table 3. Crystallographic Data for pPU Structures urea

pCyPU

pCyHPU

pClHPU

pCF3PU

growth solvent habit formula temp (K) space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z R Rw torsion angles (deg)

ethanol needle C15H10N4O 100 Pca21 28.426(14) 3.7557(19) 11.494(6) 90 90 90 1227.1(11) 4 0.0343 0.0853 179.06, 179.58

ethanol needle C14H11N3O 100 P1̅ 4.5748(11) 11.650(2) 12.002(3) 113.916(13) 90.649(16) 92.275(16) 584.0(2) 2 0.0581 0.1631 134.53, 141.23 (Cy)

ethanol needle C13H11ClN2O 100 Cc 25.6910(18) 4.6079(4) 9.8961(6) 90 101.178(5) 90 1172.31(16) 4 0.0393 0.1058 126.78, 133.30 (Cl)

toluene prism C15H10F6N2O 100 Fdd2 13.5863(11) 43.809(4) 4.6862(4) 90 90 90 2789.2(4) 8 0.0482 0.1162 139.68, 139.68

charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

to extend this predictive approach to other cocrystals with different types of hetero/homodimer interactions.

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ASSOCIATED CONTENT

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* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.7b00922. Table of X-ray parameters for all reported single component structures pCyPU, pCyHPU, pCF 3PU, pClHPU (PDF)

AUTHOR INFORMATION

Corresponding Author

* E-mail: [email protected]. ORCID

Jennifer A. Swift: 0000-0002-8011-781X

Accession Codes

Notes

CCDC 1554299−1554310 contain the supplementary crystallographic data for this paper. These data can be obtained free of

The authors declare no competing financial interest. F

DOI: 10.1021/acs.cgd.7b00922 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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ACKNOWLEDGMENTS The authors are grateful for financial support provided by the National Science Foundation under awards CHE-1156788 (REU), CHE-0959546 (MRI), and CHE-1337975 (MRI). M.A.S. thanks the ARCS Foundation for a predoctoral fellowship. We additionally thank Jeffery Bertke (Georgetown University) for his help with some structure refinements and Maxime Siegler (Johns Hopkins University) for his assistance with data collection and refinement of oNHPU:TPPO.

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DOI: 10.1021/acs.cgd.7b00922 Cryst. Growth Des. XXXX, XXX, XXX−XXX