Predicting Cocrystallization Based on Heterodimer Energies: The

Sep 25, 2015 - Predicting Cocrystallization Based on Heterodimer Energies: Part II. Marina A. Solomos , Taylor A. Watts , and Jennifer A. Swift. Cryst...
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Predicting Cocrystallization Based on Heterodimer Energies: The Case of N,N′‑Diphenylureas and Triphenylphosphine Oxide Marina A. Solomos, Cameron Mohammadi, Jessica H. Urbelis, Elizabeth S. Koch, Rochelle Osborne, Claire C. Usala, and Jennifer A. Swift* Department of Chemistry, Georgetown University, 37th and O Streets Northwest, Washington, DC 20057-1227, United States S Supporting Information *

ABSTRACT: Diarylureas frequently assemble into structures with one-dimensional H-bonded chain motifs. Herein, we examine the ability of triphenylphosphine oxide (TPPO) to disrupt the H-bonding motif in 14 different meta-substituted N,N′-diphenylureas (mXPU) and form cocrystals; 1:1 mXPU:TPPO cocrystals were obtained in 9 of 14 cases examined (64% success rate). Cocrystals adopt five different lattice types, all of which show unsymmetrical H-bonded [R12(6)] dimers between the urea hydrogens and the phosphine oxygen. Heterodimer (mXPU···TPPO) and homodimer (mXPU···mXPU) interaction energies, ΔEint, calculated using density functional theory at the B3LYP/6-31G(d,p) level were used to rationalize the experimental results. A clear trend was observed in which cocrystals were experimentally realized only in cases in which the differences in heterodimer versus homodimer energy, ΔΔEint, were greater than ∼5.3−6 kcal/mol. Although calculated interaction energies are a simplified measure of the system thermodynamics, these results suggest that the relative ΔΔEint between heterodimers and homodimers is a good predictor of cocrystal formation in this system.

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INTRODUCTION Cocrystallization is a widely used method for altering the physical properties of organic molecules in desirable ways to improve their performance. This approach has found widespread applications in various industries, including pharmaceuticals,1,2 nutraceuticals,3 and energetic materials.4,5 Experimentally, the search for cocrystals is a trial and error process that requires significant effort. Typically, evaporative and cooling methods from various solvents are pursued, though additional crystallization methods such as those involving the melt, slurries, and/or grinding may also be used. High-throughput technology6 can accelerate the process but is not a standard approach because of the limited availability of such instrumentation. Predictive approaches to cocrystal formation usually rely on the identification of common binding motifs observed across large numbers of crystal structures in the Cambridge Structure Database.7 Lattice energy calculations can also be used in a predictive way,8−11 though as the number of different molecules and their complexity increases, so do the computational resources required. Virtual screening of cocrystals using electrostatic potential maps12,13 or solubility parameters14 have also been used to evaluate potential coformers from a large number of possibilities. This in principle allows experimental efforts to focus on those with the highest likelihood of success. However, even when the thermodynamics favor cocrystal formation, whether the kinetics will favor cocrystals or a physical mixture of each component remains an open question. Unsuccessful cocrystallization experiments are typically not reported or easily searchable (a notable exception is Stahly’s 2007 report,15 citing a 61% success rate in a cocrystal screen of © XXXX American Chemical Society

64 compounds), but from a predictive standpoint, this is unfortunate because the failures can often be just as instructive as the successes. Herein, we report on our efforts to form cocrystals between the strong H-bond acceptor triphenylphospine oxide and a family of meta-substituted ureas (mPUs). meta-substituted diphenylureas (mPUs) have previously been studied for their biological activity,16−18 their nonlinear optical properties,19,20 and their propensity to form polymorphs.21−23 Most (but not all) diphenylureas form one-dimensional (1D) hydrogen-bonded chains between self-complementary urea groups. Previous work24−26 has shown that this H-bonding motif can be interrupted by other strong H-bond donors or acceptors in some cases. For example, the compound 1,3-bis(mnitrophenyl)urea was identified by Etter25 to be especially prone to cocrystallization, forming 14 different 1:1 cocrystals with 2-butanone, tetrahydrofuran, dimethyl sulfoxide, triphenylphopshine oxide (TPPO), etc. Other ureas such as 1,3-bis(m-trifluorotolyl)urea also formed cocrystals, though 1,3-bis(m-tolyl)urea and 1,3-bis(phenyl)urea did not. She rationalized that the presence of electron-withdrawing substituents in the meta position destabilized the urea chain, making cocrystallization more likely. In the study presented here, we assess the ability of 14 mPUs to form 1:1 cocrystals with TPPO. Nine were successful (64%), adopting isomorphous lattices in some cases. All cocrystals share a similar dimer binding motif between urea and phosphine oxide Received: July 21, 2015 Revised: August 30, 2015

A

DOI: 10.1021/acs.cgd.5b01039 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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GIMSEA10. bReported in ref 23.

syn−syn 22.86, −2.11

temp (K) space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å3) Z R Rw conformation torsion angles (deg)

a

mClHPU mCyHPU

C14H11N3O: C18H15OP 100 P1̅ 9.684(2) 11.821(3) 12.795(3) 78.034(3) 80.629(3) 68.109(3) 1323.6(5) 2 0.0392 0.0990 anti 168.25, 25.06 C13H11N3O3: C18H15OP 100 P1̅ 9.7475(12) 11.6042(14) 13.0180(15) 77.883(2) 80.275(2) 69.372(2) 1340.1(3) 2 0.0423 0.0998 anti −172.29, −23.68

mNHPU mCyMePU

C15H13N3O: C18H15OP 100 P21/c 14.9370(9) 9.9094(6) 18.6942(13) 90 102.306(3) 90 2703.5(3) 4 0.0365 0.0917 syn−anti 6.13, −179.34 C14H13N3O3: C18H15OP 100 P21/c 11.5017(6) 16.7140(9) 15.4037(8) 90 111.476(1) 90 2755.6(3) 4 0.0360 0.0994 anti−syn 170.76, −31.59

mNMePU mCF3PU

C15H10N4O: C18H15OP 100 P21/c 14.978(2) 10.0785(14) 18.541(3) 90 103.338(1) 90 2723.4(7) 4 0.0418 0.1321 anti−syn −176.92, −7.02 C13H10N4O5: C18H15OP RT P1̅ 12.340(10) 15.136(6) 8.311(6) 101.93(4) 91.22(6) 110.97(4) 1414.46 2 0.035

mClPU mCyPUb

Table 1. Crystallographic Data for 1:1 mPU:TPPO Cocrystals B

C15H10N2OF6: C18H15OP 100 P1̅ 9.0796(12) 11.9729(15) 14.6290(18) 66.121(1) 81.015(1) 83.584(1) 1434.3(3) 2 0.0372 0.0989 anti−syn −165.75, 16.74

EXPERIMENTAL SECTION

Materials. All 3-X-isocyanate and 3-Y-aniline reagents and triphenylphosphine oxide (TPPO) 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 Sigma-Aldrich, Fischer Scientific, or WarnerGraham. 1H nuclear magnetic resonance (NMR) data were collected on a 300 MHz Varian Inova spectrometer in d6-dimethyl sulfoxide (d6-DMSO). Melting points were determined by differential scanning calorimetry (DSC) using a TA Instruments Modulated DSC 2920 instrument. Samples were prepared in hermetically sealed aluminum pans using 2−10 mg of crystalline sample. All runs were performed at a heating rate of 5−10 °C/min. DSC data were analyzed with Universal Analysis software. Synthesis of meta-Substituted Diphenylureas. Symmetrical and unsymmetrical diphenylureas were synthesized according to previously reported methods.25 For each compound, equimolar amounts of 3-X-isocyanate and 3-Y-aniline were dissolved in benzene flushed with nitrogen and left to stir at room temperature (RT) for 24 h. Gentle heating was often required for full dissolution. After 24 h, the product was isolated using vacuum filtration and recrystallized in ethanol or acetonitrile. Product synthesis was confirmed by 1H NMR and DSC. 1,3-Bis(m-trifluoromethylphenyl)urea (mCF3PU). mCF3PU was prepared from 3-trifluoromethylaniline and 3-(trifluoromethyl)phenylisocyanate. Recrystallization in ethanol yielded white needles with a mp of 199−202 °C (Lit.25 200.0−201.0 °C). 1H NMR (DMSO-d6): δ 9.13 (s, 2H), 7.98 (s, 2H), 7.57 (d, 2H), 7.49 (t, 2H), 7.30 (d, 2H). 1,3-Bis(phenyl)urea (PU). PU was prepared from aniline and phenylisocyanate. Recrystallization in acetonitrile yielded material with a mp of 239−240 °C (Lit.27 239.8−240.6 °C). 1H NMR (DMSO-d6): δ 8.64 (s, 2H), 7.45 (m, 4H), 7.27 (m, 4H), 6.96 (m, 2H). 1-(m-Nitrophenyl)-3-(m-tolyl)urea (mNMePU). mNMePU was prepared from 3-nitrophenyl isocyanate and m-toluidine. Recrystallization in ethanol yielded yellow needles with a mp of 191−195 °C (Lit.28 187 °C, Lit.29 194 °C). 1H NMR (DMSO-d6): δ 9.15 (s, 1H), 8.71 (s, 1H), 8.53 (s, 1H), 7.79 (m, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 7.30 (s, 1H), 7.21 (d, 1H), 7.14 (dd, 1H), 6.79 (d, 1H), 2.25 (s, 3H). 1-(m-Cyanophenyl)-3-(m-tolyl)urea (mCyMePU). mCyMePU was prepared from 3-cyanophenyl isocyanate and m-toluidine. Recrystallization in ethanol yielded beige needles with a mp of 199−205 °C. 1H NMR (DMSO-d6): δ 8.95 (s, 1H), 8.70 (s, 1H), 7.94 (m, 1H), 7.62 (m, 1H), 7.45 (m, 1H), 7.38 (m, 1H), 7.27 (m, 1H), 7.16 (m, 2H), 6.78 (d, 1H), 2.28 (s, 3H). 1-(m-Nitrophenyl)-3-phenylurea (mNHPU). mNHPU was prepared from phenylisocyanate and 3-nitroaniline. Recrystallization in ethanol yielded yellow needles with a mp of 208−210 °C. 1H NMR

mNPUa

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formula

functionalities. The successes and failures are rationalized on the basis of dimer energies of urea−TPPO and urea−urea pairs calculated at the B3LYP/6-31G(d,p) level. Calculations indicate that dimer formation is always thermodynamically favored; however, a clear trend is observed in which only those with the largest differences in dimer energies resulted in cocrystals.

C13H10N2OCl2: C18H15OP 100 P1̅ 8.5430(11) 12.8679(16) 14.3027(18) 66.316(1) 74.600(1) 71.094(1) 1345.5(3) 2 0.0287 0.0817 anti−syn 172.86, 3.28

Figure 1. Different conformations of meta-substituted diphenylureas.

C13H11N2OCl: C18H15OP 100 P1̅ 9.7142(9) 11.6676(11) 12.9154(12) 77.063(1) 80.745(1) 68.912(1) 1326.0(2) 2 0.0384 0.1007 anti −170.29, −24.15

Article

DOI: 10.1021/acs.cgd.5b01039 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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(DMSO-d6): δ 9.21 (s, 2H), 8.84 (s, 1H), 8.57 (s, 1H), 7.83 (d, 2H), 7.53 (m, 3H), 7.30 (t, 1H), 6.99 (t, 1H). 1-(m-Cyanophenyl)-3-phenylurea (mCyHPU). mCyHPU was prepared from 3-cyanophenyl isocyanate and aniline. Recrystallization in ethanol yielded beige needles with a mp of 190−195 °C. 1H NMR (DMSO-d6): δ 9.016 (s, 2H), 8.835 (s, 1H), 7.987 (s, 1H), 7.687 (d, 2H), 7.471 (m, 3H), 7.30 (t, 1H), 7.00 (t, 1H). 1-(m-Chlorophenyl)-3-phenylurea (mClHPU). mClHPU was prepared from 3-chlorophenyl isocyante and aniline. Recrystallization in ethanol yielded thin white needles with a mp of 184−190 °C. 1 H NMR (DMSO-d6): δ 8.881 (s, 2H), 8.746 (s, 1H), 7.72 (s, 1H), 7.46 (d, 2H), 7.29 (m, 3H), 7.00 (t, 1H), 6.89 (t, 1H). Synthesis and characterization data for 1,3-Bis(m-cyanophenyl)urea (mCyPU) and 1,3-bis(m-nitrophenyl)urea (mNPU) appear in refs 23 and 30, respectively. Synthesis and characterization data for 1,3-bis(m-chlorophenyl)urea (mClPU) and the other halogenated analogues mBrPU, mMePU, mClMePU, and mBrMePU appear in ref 22. Preparation and Identification of Cocrystals. Cocrystallization experiments were performed using solvent-mediated solid-state grinding. Equimolar amounts (5 mmol) of mXPU and TPPO were ground using a glass mortar and pestle and a few drops of a mutually miscible solvent (ethanol, acetone, acetonitrile, etc.). Samples were then transferred to 1 dram glass vials (Fischer Scientific), and an additional 2−3 mL of solvent was added while the samples were gently heated to promote dissolution. A range of single and binary solvents (acetone, toluene, acetonitrile, ethanol, methanol, benzene, 2-propanol, heptane, ethyl acetate, 1:1 dichloromethane:acetone, 1:1 toluene:acetone, 1:1 acetone:acetonitrile, and 1:1 ethanol:acetonitrile) were used. Vials were then covered with pierced Parafilm to encourage slow solvent evaporation and maintained at room temperature for 2−10 days. All samples were subsequently analyzed by optical microscopy, DSC, and powder X-ray diffraction (PXRD) to identify new phases. An Olympus BX-50 polarizing microscope fitted with an HCS302 optical hot-stage (INSTEC, Inc., Boulder, CO) was used to observe melting transitions in bulk and single-crystal samples. The hot-stage was calibrated against several standards with known melting points. The standard deviation up to 250° is ±1°. PXRD data were collected

on bulk ground samples of cocrystal products 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 version 9.0 and compared against simulated PXRD patterns of known single-component structures. Single-Crystal X-ray Structure Determination. Cocrystal structure determination was accomplished using Siemans/Bruker SMART or APEX II Platform CCD diffractometers (Mo Kα radiation at 0.71073 Å) at 100 K. Intensity data was corrected for absorption and decay in SADABS.31 Structures were determined in SHELXS and refined using SHELXL.32 Non-hydrogen atoms were solved using direct methods and refined with anisotropic displacement parameters. Hydrogen treatment was mixed. Urea hydrogen atom positions were typically determined from the residual electron density, while some other protons were placed in ideal positions and refined with a riding model. The cocrystals used for structural determination were grown from the following conditions: 1:1 mClPU:TPPO, 1:1 mCyMePU:TPPO, and 1:1 mClHPU:TPPO were from acetone; 1:1 mCF3PU:TPPO was a clear block grown from methanol; 1:1 mNMePU:TPPO was a yellow prism grown from ethyl acetate/hexane; 1:1 mNHPU:TPPO was a yellow block grown from toluene; and 1:1 mCyHPU:TPPO was a clear block grown from a mixed acetone/hexane solution. Density Functional Theory (DFT) Calculations. Optimized geometries and frequencies for all mPU monomers, dimers, and mPU:TPPO heterodimers were calculated using GAUSSIAN09 at the B3LYP/6-31G(d,p) level. All possible conformations of mPU monomers were subjected to optimization to identify the relative energies of the syn−syn, syn−anti, anti−syn, and anti−anti conformations (of meta substituents relative to the urea carbonyl). In cases in which cocrystal structures were unavailable, heterodimers were created from the lowestenergy conformations of mPU and TPPO and then geometry-optimized. In cases in which cocrystals formed, heterodimer conformations were geometry-optimized starting from the single-crystal structure. Interaction dimer energies (ΔEint) were calculated according to eq 1

ΔE int = EAB − (EA + E B)

(1)

Figure 2. Dimers observed in 1:1 mPU:TPPO cocrystals. All O···H−N distances fall within the range of 1.97−2.22 Å (O···N range of 2.80−2.99 Å). Cocrystals within the same box adopt isomorphous 3D packing motifs. C

DOI: 10.1021/acs.cgd.5b01039 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Figure 4. Packing diagram of (top) mNMePU:TPPO (form IV) viewed down the c-axis (discrete layers of urea and TPPO alternate along the a-axis) and (bottom) mNPU:TPPO (form V) viewed down the b-axis (alternating nitophenyl and phenyl rings face−face stack along the c-axis).

compounds are named mXPU, where X denotes the substituent (N = nitro, Cy = cyano, CF3 = trifluoromethyl, Me = methyl, Br = bromine, and Cl = chlorine). Unsymmetrically substituted compounds are named mXYPU, where X is the substituent with the higher molecular weight. A low rotational barrier about the amide bond allows the molecule to exist in multiple conformations, generically described as anti−anti, anti−syn, syn−anti, and syn−syn based on the relative orientation of the meta subsitutents and the carbonyl group (Figure 1). Monosubstituted compounds are named mXHPU and can adopt syn or anti conformations. The unsubstituted parent is PU. Efforts to cocrystallize 14 different mPUs with TPPO resulted in nine new 1:1 cocrystal phases (with mNPU, mCyPU, mClPU, mCF3PU, mNMePU, mCyMePU, mNHPU, mCyHPU, and mClHPU). The X-ray data for all cocrystals are listed in Table 1. Two of these structures have been previously reported: mNPU:TPPO by Etter25 and mCyPU:TPPO23 as part of a more recent polymorphism study. Repeated attempts to cocrystallize PU, mMePU, mClMePU, mBrMePU, and mBrPU with TPPO using a variety of methods were unsuccessful.

Figure 3. Packing diagram of (top) mNHPU:TPPO (form I) viewed down the b-axis (discrete layers of urea and TPPO alternate along the a-axis), (middle) mClPU:TPPO (form II) viewed down the a-axis (urea and TPPO form in discrete (011) layers), and (bottom) mCyMePU:TPPO (form III) viewed down the b-axis (layers of urea and TPPO alternate along the c-axis). Urea molecules are colored red and TPPO molecules black to better visualize the topologies. where EAB is the optimized energy of the dimer and EA and EB are the optimized energies of the individual monomers. When ΔEint is calculated for the mPU homodimers, EA = EB. The differences in interaction energies were calculated according to eq 2.

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ΔΔE int = ΔE int(heterodimer) − ΔE int(mPU homodimer)

(2)

RESULTS AND DISCUSSION Fourteen different mPUs were synthesized and purified according to established procedures.25 Symmetrically substituted D

DOI: 10.1021/acs.cgd.5b01039 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Figure 5. Interaction energy differences between mPU dimers and heterodimers in 1:1 mPU:TPPO for the 14 compounds investigated. Only systems in which ΔΔEint > 5.3−6 kcal/mol yielded actual cocrystals.

Cocrystal Structures. The nine cocrystals obtained share a similar R12(6) binding motif between urea and PO groups (Figure 2). All O···H−N distances fall within the range of 1.97−2.22 Å (O···N range of 2.80−2.99 Å). The two O···H−N bonds in the dimers are inequivalent in all cocrystal structures, including the mXPUs that have identical meta substituents. In the unsymmetrical mXYPU and monosubstituted mXHPU, the O···H−N bonds on the side adjacent to the aromatic ring bearing the more electron-withdrawing substituent are slightly shorter (by 0.01−0.20 Å) except in mNMePU:TPPO, where the O···H−N bond is 0.06 Å shorter on the tolyl group side. The three monosubstituted ureas adopt anti conformations. All of the disubstituted ureas adopt syn−anti conformations except for mNPU:TPPO, in which the urea is syn−syn. The dimer units assemble into five different three-dimensional (3D) structure types. The three monosubstituted compounds, mNHPU:TPPO, mCyHPU:TPPO, and mClHPU:TPPO, are isomorphous (form I). mClPU:TPPO and mCF3PU:TPPO are isomorphous (form II), as are mCyPU:TPPO and mCyMePU:TPPO (form III). Figure 3 shows representative packing motifs of forms I−III with urea (red) and TPPO (black) molecules color-coded to more easily visualize the topologies. In the three monosubstituted urea cocrystals that adopt form I, alternating discrete sheets of urea and TPPO stack along the a-axis (viewed down b-axis). In the urea layer, the C−X dipoles of adjacent molecules are antiparallel because of the presence of an inversion center between them. In the TPPO layer, two of the three phenyl rings assemble face to face and edge to face into 1D π-stacked chains that parallel the c-axis. H-bond dimers link the two types of layers. mClPU:TPPO and mCF3PU:TPPO adopt form II and are characterized by alternating (011) layers of urea and TPPO (viewed down the a-axis). Molecules within the urea layer assemble as dimers in which the m-chorophenyl or m-trifluoromethyl phenyl π systems align to form face−face dimers. Each molecule within a (011) TPPO layer has four nearest neighbors. Face−face interactions exist between one set of neighbors and edge−face interactions among the other three.

As in form I, the urea and TPPO layers are linked by H-bonded dimers. In structure form III, layers of urea and TPPO alternate along the c-axis (viewed down the b-axis). In the urea layer of mCyMePU:TPPO, the cyanophenyl rings of adjacent molecules form face−face π dimers with a 3.7 Å separation, whereas the tolyl units have an offset geometry separated by 4.3 Å. The phenyl−phenyl interactions in the TPPO layer adopt orientations that are neither pure face−face nor pure edge−face and also appear to be somewhat less densely packed than in forms I and II. mNMePU:TPPO (form IV) and mNPU:TPPO (form V) each have unique structures (Figure 4). In mNMePU:TPPO, more highly corrugated layers of alternating TPPO and mNMePU molecules can be seen when viewed down the c-axis. This packing may occur as a way to better project the tolyl substituents into the nonpolar pockets made by the triphenyl groups of TPPO. In contrast, the nitrophenyl substituents orient toward the more polar phosphine oxide side of TPPO. In mNPU:TPPO, layers of mNPU and TPPO are stacked along the a-axis. However, compared to all other cocrystal structures obtained, this one stands out as being unique for two reasons. The conformation of mNPU is different from that of all other disubstituted ureas investigated in the study, and it is the only one in which an infinite 1D face−face stack of aromatic groups is observed (c-axis, with rings spaced 4.15 Å apart). Homodimer versus Heterodimer Energies. We sought to rationalize the successes and failures in our cocrystallization efforts by comparing the interaction energies of urea:TPPO (ΔEint‑AB) heterodimers and urea homodimers (ΔEint‑AA). Calculations at the B3LYP/6-31G(d,p) level showed a clear trend across the 14 systems examined (Figure 5). The difference in heterodimer and homodimer energies, denoted as ΔΔEint, was negative in all cases, and the magnitude of ΔΔEint was greatest in the nine ureas that formed cocrystals. The barrier for successful versus unsuccessful cocrystal formation falls somewhere between −6.07 kcal/mol (mClPU) and −5.34 kcal/mol (mClMePU). These numbers are cited as a E

DOI: 10.1021/acs.cgd.5b01039 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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useful relative guide and not as an absolute measure of the system thermodynamics. The actual energy difference must be lower, because a comparison of dimer energies does not take into account the lattice energy of TPPO or the effect of H-bond cooperativity in mPUs. Given that most mPUs crystallize with infinite H-bonded urea chain motifs, we sought to assess the magnitude of cooperative effects to verify that homodimer formation was a reasonably accurate measure of H-bond strength in these systems. Using mClPU as a test system, the interaction energies for 1D H-bonded assemblies of two to nine molecules were calculated. The interaction energy per monomer unit was found to plateau at the heptamer, with an overall difference of −1.73 kcal/mol between the dimer and nonamer configurations. This small value suggests that chain length cooperativity would lower the absolute ΔΔEint threshold needed for successful cocrystallization by not more than a few kilocalories per mole, though it would not alter the observed trend. Differences in ΔΔEint also reflect differences in the distribution of species within the growth solution. The more negative the ΔΔEint value, the larger the Keq of the following equilibrium.

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file file file file file

for for for for for

mClPU:TPPO (CIF) mMeHPU:TPPO (CIF) mNHPU:TPPO (CIF) mNMePU:TPPO (CIF) mCyHPU:TPPO (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support provided by the National Science Foundation via Grants CHE-0851581 (REU), CHE0959546 (MRI), and CHE-1337975 (MRI). We additionally thank Miklos Kertesz and Kelly Tran for helpful discussions regarding DFT calculations.

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[mPU] + [TPPO] ⇌ [mPU:TPPO]

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A rough estimate is that Keq changes by a factor of 10 for every 1.4 kcal/mol at room temperature.33 For example, a ΔΔEint of −1.4 kcal/mol suggests a 10:1 heterodimer:monomer ratio; a ΔΔEint of −2.8 kcal/mol suggests a 100:1 heterodimer:monomer ratio, etc. We do not know whether cocrystals grow by the attachment of preformed heterodimers or monomers, but if heterodimers are the preferred building block, this could also limit the cocrystal growth kinetics in systems with low ΔΔEint values. While the ΔΔEint values in all 14 systems suggest heterodimer formation in the growth solution is favored, it is possible that if both cooperativity and the lattice energy of TPPO were more rigorously considered in the total energy, heterodimers may not be favored in some of the systems that failed to cocrystallize.

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CONCLUSIONS Hydrogen bonding between urea groups is a common motif used in many crystal engineering and supramolecular studies. Herein, we have shown that in 9 of 14 cases this reliable motif can be disrupted by the presence of the H-bond acceptor triphenylphosphine oxide, resulting in 1:1 cocrystals, all showing a similar PO···N−H dimer binding motif. The ability of a given meta-substituted diphenylurea to cocrystallize with TPPO depends strongly on the electronic nature of the meta substitutent; e.g., mClPU cocrystallized with TPPO, but mMePU did not, despite the similar steric requirements of Cl and Me groups. Calculated differences in the heterodimer and homodimer interaction energies showed a clear trend that accurately predicts the 64% success rate of our cocrystallization efforts. We are currently assessing whether differences in dimer energies are a good predictor for diphenylureas with other substitution patterns, such as those in which steric factors may play a more pronounced role.

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Cif Cif Cif Cif Cif

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b01039. Cif file for mCF3PU:TPPO (CIF) Cif file for mClHPU:TPPO (CIF) F

DOI: 10.1021/acs.cgd.5b01039 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

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DOI: 10.1021/acs.cgd.5b01039 Cryst. Growth Des. XXXX, XXX, XXX−XXX