Cocrystallization: A Solution Chemistry Perspective and the Case of Benzophenone and Diphenylamine K. Chadwick, R. J. Davey,* G. Dent, and R. G. Pritchard The Molecular Materials Centre, School of Chemical Engineering and Analytical Science, SackVille Street, Manchester M 60 1QD, U.K.
CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 4 1990–1999
C. A. Hunter and D. Musumeci Centre for Chemical Molecular Biology, Krebs Institute for Biomolecular Science, Department of Chemistry, UniVersity of Sheffield, Sheffield S3 7HF, U.K. ReceiVed December 1, 2008; ReVised Manuscript ReceiVed December 11, 2008
ABSTRACT: The design and preparation of two component crystalline solids, cocrystals, for potential pharmaceutical applications has been a significant activity in the field of crystal engineering over the past five years. In this contribution, we explore the solution chemistry of one particular system, diphenylamine-benzophenone. In particular, we elucidate the relationships between crystal chemistry, solution chemistry, and phase behavior in both binary and ternary systems. The combined use of FTIR spectroscopy and proton NMR reveals the molecular basis of negative and positive deviations from ideality and provides important insights into the crystal nucleation processes.
1. Introduction While the pharmaceutical utilization of two component crystals in the form of salts1 is well-known, over the past decade, there has been an increasing interest in the extension of such solid forms to include cocrystals.2 In both cases, commercial processes utilize ternary systems for their preparation, with solvent selection and crystallization being key aspects of current technology.3 The discovery of such two component solid forms has largely occurred through a trial and error screening process traditionally involving recrystallization from solvent but increasingly accompanied by grinding techniques.4 Academically, this area is underpinned by developments in materials chemistry which aim to utilize crystallographic data, alongside the more traditional concept of acidity, to develop a rational design methodology for both salt and cocrystal systems.5,6 Curiously, however, this approach has developed with almost total focus on crystallography, while solution chemistry and phase equilibria have been generally neglected. From a physical chemistry perspective this is paradoxical: the aim of much work in this area is to realize de novo design of multicomponent crystalline solids, and although solution based synthesis is ubiquitous the approach totally ignores the nature of the solution. A cursory examination reveals the limitations of such a strategy. For example, to make a cocrystal from two molecular components, one structural prerequisite might be that these two species are capable of forming an intermolecular H-bond. Given the extent of our knowledge of intermolecular forces and crystal packing, this is relatively straightforward to engineer and if required may be supported by state of the art structure prediction methods.7,8 However, to define a process by which such a cocrystal structure might be synthesized by solution crystallization involves finding a set of conditions for which the sum of the chemical potentials of the components in solution is greater than that in the potential solid phases. This is not so straightforward, clearly implies prediction of activity coefficients and ternary solubility data, and is only now beginning to be considered.9,10 * To whom correspondence should be addressed.
In this current contribution, we show how the application of the complementary techniques of vibrational spectroscopy and proton NMR can be used in conjunction with binary and ternary phase equilibria and crystallographic data to investigate the relationship between crystal and solution chemistry in a cocrystal forming system. In the simpler case of the crystallization of single component solid phases from binary systems the use of proton NMR chemical shift data combined with molecular modeling,11,12 FTIR,13 and neutron scattering14 have all shown how relevant aspects of solution chemistry can be understood even for highly concentrated solutions. Among other features these studies have demonstrated that, while in some cases self-association in solution mirrors that in the crystal, this is by no means an essential feature of the crystallization process. We now demonstrate how such insights can be extended to the field of cocrystal formation. As a suitable material for study we have chosen benzophenone (BZP) and diphenylamine (DPA) which form a 1:1 cocrystal from both the binary melt and ternary solutions. The binary BZP-DPA system was previously studied by Lee and Warner in 1933,15 who also discovered that the resulting 1:1 cocrystal was polymorphic. The structure of the stable polymorph was solved in 1972,16 and we have resolved it in this current work in order to define the hydrogen positions.17 The structure of the metastable polymorph has never been solved and in the work reported here we deal only with the stable form.
2. Experimental Procedures The two component BZP-DPA phase diagram was taken from the original work of Lee and Warner,15 while the ternary phase diagrams in methanol and toluene were determined using the methodology described in ref 18. Commercial BZP (R form) and DPA (triclinic form) were both ex Aldrich (purity 99%). The Raman data for solid forms and melts (two component liquids) was acquired with a J. Y. Horiba LabRam, Confocal Raman Microscope (Labspec v.4 18-06 software) with a resolution of 1 cm-1 and sample temperature control provided via a Linkam hot stage. FTIR data (resolution 2 cm-1) for solutions was acquired using a Mettler Toledo ReactIR 4000 ATR FTIR spectrometer (ReatcIR software v. 2.21) and
10.1021/cg8013078 CCC: $40.75 2009 American Chemical Society Published on Web 02/12/2009
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Figure 1. The 1H NMR proton labeling scheme for BZP and DPA showing torsion angles that were allowed to vary during conformational searches. for solids using a ThermoNicolet Avatar 360 ESP FTIR with Golden Gate ATR attachment (Omnic software). NMR data was acquired with a Bruker AMX400 400 MHz spectrometer (XWin-NMR software). 1H NMR dilution experiments were carried out by preparing an initial 3 mL sample of each compound at a known concentration: 10.98 M (supersaturated) in CD3OD and 2.78 M in toluene-d8 for BZP, 2.99 M in CD3OD and 2.95 M in toluened8 for DPA. 1H NMR titrations were carried out for complexation of DPA and BZP in CD3OD and in toluene-d8 and these yielded accurate limiting complexation-induced changes (Supporting Information) in chemical shift for both molecules. Host stock solutions were prepared having 0.29 M DPA and 0.30 M BZP in CD3OD and 0.10 M DPA and 0.10 M BZP in toluene-d8. Guest stock solutions were prepared containing BZP (2.99 M) with DPA (0.29 M) in CD3OD, DPA (2.99 M) with BZP (0.30 M) in CD3OD, BZP (3.11 M) with DPA (0.10 M) in toluene-d8, and DPA (3.05 M) with BZP (0.10 M) in toluene-d8. The 1H NMR spectrum of the host solution was recorded before and after successive addition of aliquots of guest solution. For all the measured data, purpose-written nonlinear curve fitting software was used to fit the data to the appropriate binding isotherm. The selfassociation constants are all relatively low and, in most cases, only 20-30% of the binding isotherm was accessible so the absolute values maybe subject to error.10 However, the limiting changes in chemical shift are not affected. Structure determinations were carried out using the SHIFTY software described in detail elsewhere.19 Briefly, molecules were built in XED 2.8 using standard bond lengths and angles and were energy minimized.20 A genetic algorithm optimized the conformation of the complex so that the calculated ∆∂ values (∆∂ is the limiting complexation-induced change in chemical shift on dimerization) matched the experimental values as closely as possible. The conformational search allowed intermolecular translations of ( 5 Å and intermolecular rotations of ( 180° as well as intramolecular torsional changes of ( 180° for the bonds highlighted in Figure 1. The experimental ∆∂ values were allowed to scale by a factor Kf, between 0.1 and 10. In each case, 20 different calculations (8 h on a DELL-Linux cluster with 12 dual processor INTEL Pentium IV 3.0 GHz nodes) using random starting points were carried out. All structures with rmsd between the experimental and calculated ∆∂ values less than 0.01 ppm were collected.
3. Solid-State Chemistry of the Components and Cocrystal 3.1. Crystal Structures. Benzophenone has two known crystal structures, a stable orthorhombic R form (BPHENO12), the starting material in this study, and a metastable monoclinic β form (BPHENO11). In both forms the carbonyl oxygen is weakly H-bonded to ring hydrogens (2.617, 2.617, and 2.682 Å in R and creating a chain along [101] in β) and the aromatic rings are involved in π stacking and face-edge contacts. The triclinic form of diphenylamine (QQQBVP02) has eight molecules in the asymmetric unit, with the amine group located in two different environments, one involving two N-H · · · ring close contacts (2.80 Å) and the other only one ring contact, (2.78 Å). The rings interact via edge-to-face interactions (typically 2.85 Å), and there is π stacking between the asymmetric units. The unit cell parameters of a second polymorph of DPA have been reported (QQQBVP01), but the full structure is unknown. The crystal structure of the cocrystal (BZPPAM,17) is based on a centrosymmetric tetramer in which two benzophenone and
Figure 2. The centrosymmetric tetramer in the cocrystal.
two diphenylamine molecules are held together by a combination of -CdO · · · H-N- hydrogen bonds (O · · · H distance 1.92 Å) and face-to-edge phenyl ring contacts (2.93-3.02 Å) shown in Figure 2. Overall, the conformations of the molecules differ only slightly between the structures. In the case of benzophenone, for example, the dihedral angle between the phenyl rings is 64.6 and 53.75° in R and β forms, respectively, compared to its value of 58.5° in the cocrystal. In diphenylamine, the eight molecules in the asymmetric unit each have unique values lying between 37 and 49°,21 while in the cocrystal it is 45.6°. 3.2. Solid-State Infrared and Raman Spectra. The solidstate Raman spectrum of DPA has two peaks at 3388 and 3411 cm-1, reflecting the two crystal environments of the amine functionality discussed above. In the cocrystal there is only a single N-H environment at the lower wavenumber of 3371 cm-1, as a consequence of the N-H · · · OdC hydrogen bond. The corresponding IR frequencies are 3407 and 3383 cm-1 in pure DPA and 3370 cm-1 in the cocrystal. The carbonyl stretch in R BZP occurs at 1653 cm-1 in the Raman (1656 in β22), falling to 1645 cm-1 in the cocrystal, again as a result of the hydrogen bond. In the infrared, these occur at 1651 and 1645 cm-1, respectively, typical for conjugation effects seen in carbonyl groups attached to unsaturated ring systems. The spectral regions from 900-1000 cm-1 and around 1600 cm-1 correspond to vibrations of the phenyl rings, the associated -C-H stretches and ring breathing modes. These latter occur at 1599 and 1603 cm-1 in BZP and 1610 cm-1 in DPA and yield a triplet (1577, 1594, and 1609 cm-1) in the cocrystal which is essentially the sum of the components but with reversed relative intensities resulting from the new H-bonded crystal environment. The -C-H and ring deformation modes occur at 990, 1002, 1006, 1033 cm-1 in BZP; 989, 997, 1004, 1035 cm-1 in DPA and 982, 991, 1000, 1029 cm-1 in the cocrystal. These similarities reflect the complex combination of edge-face and π stacking interactions that exist in all three structures. Overall we note that these assignments are consistent with previous IR analyses of Naumov et al.23 for DPA and Nyquist et al. who reported 1657 cm-1 as the carbonyl stretch for BZP in a 2% DMSO solution.24 It is noted that overall the spectral changes induced through the formation of the cocrystal are small. In particular both the -CdO and -N-H stretches fall only approximately 8 cm-1 on the formation of the intermolecular hydrogen bond in the cocrystal. This is presumably the result of the rather small difference between the formal H-bond in the cocrystal and the sum of the weaker -C-H · · · O and -CH · · · N interactions in the pure components.
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Figure 3. The measured and ideal binary phase diagrams (liquidus curve only) of the two component BZP/DPA system, constructed using data from ref 15. 1 and 2 indicate the two eutectics.
4. Phase Equilibria Of key importance in linking solution and crystal chemistry is the availability of phase equilibria data defining the stability domains of the single and two component crystalline phases. This section reports the measured phase diagrams and compares these with calculated ideal phase behavior as a means of gaining initial insight into the extent and nature of the intermolecular association in melts and solutions of BZP and DPA. 4.1. The Binary Phase Diagram. The binary phase diagram for BZP and DPA15 is reproduced here in Figure 3. The melting points (Tm) and enthalpies of fusion (∆Hf) of R-BZP and DPA are known to be 321.15 and 326.15 K and 18.19 and 18.5 kJ mol-1, respectively.25 The enthalpy (∆Hfc) and temperature (Tmc) of fusion of the cocrystal were determined in this study (DSC) to be 35.8 kJ mol-1 and 39.9 °C, in good agreement with previous reports of 32.3 kJ mol-1,26 and 40.2 °C.15 Using these values together with the Schro¨der-Van Laar and Prigogine-Defay,27 the ideal binary phase diagram for BZP, DPA, and the cocrystal has been constructed and overlaid on the experimental data in Figure 3. This ideal curve provides a reference state against which to compare the real two component liquid. For example, it is observed that for compositions in the vicinity of the eutectic points, the system deviates significantly from ideal behavior. As the eutectic points are approached from either pure starting component, the mutual solubilities of BZP and DPA are greater than predicted for an ideal mixture, suggesting that BZP and DPA molecules undergo heteroassociation giving a negative deviation from ideality in the melt phase. On the cocrystal side of the eutectics, however, the same heteroassociation reduces the solubility (positive deviation) of the cocrystal relative to ideality. An indication of the extent of these deviations and hence the extent of hetero assembly are given by the activity coefficients (referred to the pure molten liquids) calculated for any temperature from the ratio xideal/ xmeasured. Overall these deviations are small; at the ideal DPA rich eutectic temperature, the activity coefficients are 0.95 and 1.11, while for the equivalent BZP rich eutectic, they are 0.96 and 1.04. 4.2. The Ternary Phase Diagram. The ternary phase behavior of BZP and DPA measured at 25 °C in methanol and toluene (three data points only) is shown in Figure 4. The measured solubilities of the pure components and the cocrystal
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Figure 4. The measured and ideal ternary phase diagrams (liquidus curve only) of BZP-DPA (mole fraction basis) in methanol and toluene (three points only) Solubility values of pure phases and cocrystal: in toluene-BZP: 9.24 M (x ) 0.496); DPA: 8.36 M (x ) 0.471); cocrystal (per mol of cocrystal): 10.38 M (x ) 0.525); cocrystal ternary composition in mole fraction BZP 0.244; DPA 0.244; MeOH 0.512, and in methanol-BZP: 5.72 M (x ) 0.188); DPA: 4.84 M (x ) 0.0.164); cocrystal (per mol of cocrystal): 11.78 M (x ) 0.323); cocrystal ternary composition in mole fraction BZP 0.345; DPA 0.345; MeOH 0.310.
are given in the caption to Figure 4 in terms of molarity, M, mole fraction, x, and for the cocrystals as ternary compositions. In order to calculate the ideal phase diagram, the Schro¨der-Van Laar and Prigogine-Defay relations27 have again been used, the former to calculate the ideal solubility of the pure components in toluene and methanol and the latter (following Rastogi28) to calculate xA and xB, the compositions of BZP and DPA in the solutions in equilibrium with the cocrystal. This is possible since, at constant temperature, the product of the mole fractions (i.e., the sum of the chemical potentials) of the components is equal to a constant, k. Hence, xAxB ) k where k ) 0.1245 at 25 °C. The melting points in these systems all lie within 20 °C of room temperature so that heat capacity corrections to the enthalpic terms have been ignored. It is clear that the solubilities of all three solid phases are lower than their ideal values, indicating positive deviations from Raoult’s Law and implying that solute aggregation occurs in all the solutions. Over all compositions, the deviation from ideality is larger in methanol than in toluene, as might be expected given the aromatic nature of both toluene and the solutes. The activity coefficients, relative to pure liquid phases, are 3.1, 3.2, and 1.5 for BZP, DPA, and the cocrystal in methanol and 1.2, 1.1, and 1.02 in toluene.
5. Spectroscopy of Liquid Phases In this section vibrational and NMR spectroscopies have been used to study intermolecular interactions in key regions of the phase diagrams in order to relate the phase behavior to the solution and crystal chemistry. 5.1. Binary Compositions. Intermolecular interactions in the two component liquid system were characterized by Raman spectra, recorded for five BZP-DPA compositions (mol% in order of decreasing BZP)-pure BZP, 75.5:24.5 (close to eutectic 2), 50:50 (cocrystal composition), 29:71 (close to eutectic 1), and pure DPA. These were selected in an attempt to assess changes in intermolecular interactions occurring as the phase diagram was traversed from one pure component to the other via the cocrystal region. Measurements were made at 35 °C for pure BZP and DPA and 30 °C for the mixtures so that the liquids were supersaturated in all cases. Given the Raman data described
Cocrystallization: Case of Benzophenone and Diphenylamine
above for the crystalline phases, four spectral regions were chosen for study: 980-1040 cm-1 and 1580-1630 cm-1 corresponding to the phenyl ring deformation and stretching vibrations, 3300-3450 cm-1 the -N-H stretching region and 1650-1680 cm-1, the -CdO asymmetric stretching vibration. The onset of heteroassociation in the mixtures was evidenced through the -N-H and -CdO asymmetric stretches as well as the ring associated frequencies. Moving across the binary phase diagram from pure liquid DPA to pure liquid BZP the N-H stretch remained constant at 3402 up to 29 mol% BZP but fell to 3390 cm-1 in the equimolar melt (cf 3371 cm-1 in the cocrystal). The carbonyl stretch on the other hand appeared at 1657 cm-1 (cf 1653 cm-1 in the cocrystal) in the presence of 71% DPA, rising to 1660 cm-1 in both the cocrystal composition and pure molten BZP. Similar small changes were seen in the ring associated frequencies the C-H stretch in DPA, for example, shifts from 1610 to 1613 cm-1 as the BZP concentration increases. Overall, these spectral changes are small, mirroring those discussed in section 3 between pure crystalline phases and the cocrystal. They are consistent with intermolecular interactions which in pure liquid BZP and DPA comprise combinations of weak -CdO · · · H-C-, C · · · H-N-, ring-ring, face to edge, and stacking contacts but which in the mixtures involve new specific heterointeractions in the form of a -CdO · · · H-N- hydrogen bond, as well as ring-ring associations. These changes can be clearly associated with the deviations from ideality discussed in section 4.1. 5.2. The Ternary System. NMR and FTIR experiments were performed at 25 °C in toluene and methanolic solutions of both the pure components and at the 1:1 BZP/DPA stoichiometry. Benzophenone Solutions. The 1H NMR data (measured up to 8 M in methanol-d4 and 2.2 M in toluene-d8) revealed that the BZP protons underwent concentration-dependent changes in chemical shift, which could be fitted to dimerization isotherms (Supporting Information). The self-association constants are on the order of 0.1 to 1 M-1, and saturation of the dimer state is never achieved. In methanol, large negative changes in chemical shift were observed for all three protons (A, B, and C in Figure 1), and this is characteristic of aromatic interactions in a dimer. In toluene, the complexation-induced changes in chemical shift are smaller, and the positive values observed for B and C suggest that there may be -C-H · · · OdC- hydrogen bonding interactions in the dimer. Figure 5 shows possible 3D structures of the dimers in the deuterated solvents as determined by SHIFTY using the limiting complexation-induced changes in chemical shift. For each iteration of SHIFTY a blue and green dimer pair is created as seen in Figure 5, whose calculated proton shifts were an excellent fit with the measured data but which failed to converge to a unique dimer, a large number of equivalent structures being obtained. This result reflects either a genuine diversity in dimer configurations or insufficient experimental data (i.e., only proton three signals) to constrain the calculated structures. The IR spectra over a similar concentration range to the NMR of 1.43, 2.86, and 5.72 M (mole fractions 0.055, 0.11, and 0.219) BZP in methanol are shown in Figure 6. At low concentrations the carbonyl stretching band is a doublet, 1652 and 1660 cm-1, indicating the existence of two different BZP species. The relative intensity of the two bands changes with increasing concentration, the 1660 cm-1 band dominating at saturation. Comparison of the position of this band with that in crystalline, molten, and dilute DMSO solutions of BZP (respectively 1651, 1660, and 1657 cm-1) suggests that it be assigned to carbonyl groups involved in weak -CdO · · · H-C- interactions with other
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Figure 5. Structures of benzophenone dimers determined using Shifty (a) in deuterated toluene and (b) in deuterated methanol. Overlays of all structures that are consistent with the 1H NMR chemical shift data are shown, along with a representative structure and the structure of a dimer from the X-ray crystal structure for comparison. For the aromatic interactions highlighted, the distance d1 and interplanar angles in the X-ray crystal structures (4.6-4.9 Å, 35°-66°) fall within the range found in the Shifty structures (3.4-7.3 Å, 4°-89°).
BZP molecules. The band at 1652 cm-1 being more intense at low concentration may then be considered to result from BZP molecules solvated by methanol through a stronger -CdO · · · H-Ohydrogen bond. This appears as a shoulder in saturated solutions suggesting the existence of both solvated and self-aggregated solute molecules, with an excess of the latter. This dominance of self-associated species is consistent with the positive deviations from ideality observed in the solubility data, while the solvation by methanol is consistent with the NMR dimer in Figure 5b which exposes a free carbonyl to the environment. Figure 6 further shows that solution concentration has no effect on the position of the asymmetric ring stretching (1590 cm-1) bands in the IR spectra of BZP in methanol. However, the ring and C-H deformation bands (not shown) do exhibit shifts with increasing concentration from 776 to 760 cm-1 and 704 to 695 cm-1 toward their positions in the IR spectrum of a benzophenone melt suggesting the existence of ring-ring contacts in solution, again in agreement with the NMR data. In contrast, the IR spectra of 0.49, 0.99, and 1.48 mol L-1 (mole fraction 0.05, 0.099, and 0.198) toluene solutions of BZP (not shown) exhibit a single carbonyl stretching band at 1664 cm-1 shifting to 1662 cm-1, with increasing concentration, toward its value in a benzophenone saturated methanol solution, the melt and in R BZP (1660 and 1651 cm-1). In contrast to methanol, where the solvent and solute have significantly different interactions with the carbonyl oxygen, in toluene there will be little discrimination since weak -C-H · · · OdC- interactions will be involved throughout. Thus, the shift to lower wave numbers with increasing concentration of BZP suggests that solute-solvent interactions are displaced by self-associated
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Figure 6. The effect of concentration on the carbonyl, ring stretching, and deformation bands in the IR spectrum of benzophenone in methanol.
Figure 7. Changes in chemical shift observed for DPA in 1H NMR dilution experiments (a) in CD3OD (b) in toluene-d8 (proton E black, D red, F blue, G green). The lines are the best fit to a dimerization isotherm, except for proton G in CD3OD where best fit to a dimer plus tetramer isotherm is shown.
BZP molecules as in the melt. This conclusion is confirmed by the asymmetric ring stretching vibration which shifts toward its position in the benzophenone melt from 1604 cm-1 at 0.48 mol L-1 to 1602 cm-1 at 1.48 mol L-1. Other ring stretching vibrations and the ring and C-H deformation bands remained unchanged. These FTIR results suggest that both solvent systems comprise a mixture of solvated and self-associated solute molecules. Such complexity of dimer species offers a further reason for the inability of SHIFTY to converge to a unique dimer. The positive deviations from ideality in the two solvents are revealed to result from changes in the balance of selfassociation versus solvation. The greater deviation in the case of methanol is presumably due to the tendency for methanol itself to self-associate, leading to enhanced segregation of BZP. Diphenylamine Solutions. For DPA in toluene, the experimental changes in 1H NMR chemical shift (up to 2.2 M in both solvents) for all of the protons could be fitted to a dimerization isotherm (Figure 7). The self-association constant is on the order
0.1 to 1 M-1. Proton G showed a positive change in chemical shift, which is indicative of H-bonding interaction in the dimer, and very small changes in chemical shift were observed for all of the other signals. In methanol, quite different behavior was observed. In this case, the chemical shift of proton G initially increased with concentration, suggesting the formation of a H-bond, but at higher concentrations, the chemical shift decreased again (Figure 7). This biphasic behavior indicates two distinct self-association processes, dimerization followed by higher order aggregation. The simplest isotherm that gave a good fit to the data was a three state model allowing for equilibrium between monomer, dimer and tetramer. For protons D, E, and F, negative changes in chemical shift are observed which are indicative of aromatic interactions, and these appear to be important in both phases of the dilution experiment. Thus formation of the dimer involves H-bonding of the NH groups as well as aromatic interactions, and further aggregation of the dimer is probably dominated by aromatic interactions.
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ring interactions between diphenylamine molecules. The shift in the C-H deformation bands from 695 to 693 cm-1 (689 cm-1 in the melt) confirms this interpretation, and given the NMR result implies that with rising concentration the -N-H · · · Nbased dimers further associate via ring-ring interactions.
Figure 8. Structures of diphenylamine dimers determined using Shifty (a) in deuterated toluene and (b) in deuterated methanol. Overlays of all structures that are consistent with the 1H NMR chemical shift data are shown, along with a representative structure and the structure of a dimer from the X-ray crystal structure for comparison. For the potential H-bond highlighted in (a), the N-N distance d2 in the X-ray crystal structure (4.6 Å) falls within the range found in the Shifty structures (3.0-9.4 Å). For the aromatic interactions highlighted, the distance d1 and interplanar angles in the X-ray crystal structures (4.7-4.9 Å, 7°-86°) fall close to the range found in the Shifty structures (4.3-7.8 Å, 14°-89°).
The DPA structures derived from the SHIFTY runs (Figure 8) are somewhat better defined by the NMR data than for BZP with all the calculated dimers in both solvents featuring -NH · · · N-H- interactions. These results clearly show how selfassembly underpins the positive deviations seen in the ternary phase diagram, with molecular aggregation being much more extensive in methanol solutions. Solutions of diphenylamine in methanol could not be studied by FTIR as key stretching vibrations were masked by solvent. In toluene, however, spectra were recorded for 0.49, 0.99, and 1.48 M diphenylamine, (mole fraction 0.05, 0.099, and 0.198). At low concentrations the N-H stretching vibration (not shown) occurred at 3405 cm-1. As the concentration of the solution was increased the band maximum shifted toward 3397 cm-1, its position in the pure melt (cf 3388 cm-1 in crystalline DPA). This is consistent with the NMR result, again suggesting selfaggregation through the amine group. As with benzophenone, the IR data also provide insight into the solvent-solute interactions, not revealed by NMR. For example, in toluene the asymmetric ring stretching band (Figure 9) of a 0.49 mol L-1 comprises two overlapped bands at 1596 and 1602 cm-1. The band at 1596 cm-1 increased in intensity and moved to 1594 cm-1 (1590 in the melt) as the solution concentration increased, while the relative intensity of the second band at 1602 cm-1 decreased. The latter is consistent with solvation of the aromatic rings by toluene the former with phenyl
Equimolar Solutions. The NMR titration data, measured up to 2.5 M in each solvent, were analyzed, using the self-association constants and dimerization-induced changes in chemical shift obtained from the dilution experiments to account for the presence of the BZP and DPA dimers as well as the 1:1 DPA/BZP complex.29 The 1:1 association constants were determined to be 0.4 M-1 in toluene and 0.2 M-1 in methanol. The speciation plots in Figures 10 and 11 show that both homodimers and the 1:1 complex are all present in significant amounts during the titration. It is worth noting that while the 1:1 heterodimer exists up to levels of 40% in both solutions, the behavior is quite different in the two solvents: a very large increase in chemical shift is observed for the amine proton G of DPA in toluene (green in Figure 11c) which is indicative of the formation of an H-bond to the BZP carbonyl oxygen, but there is no evidence of such H-bonding in methanol (Figure 10). All of the other protons show large negative changes in chemical shift that are indicative of aromatic interactions in both solvents. These data were again used, in conjunction with SHIFTY, to determine possible three-dimensional structures of the complex. There is excellent agreement obtained between the experimental and calculated chemical shifts (see Supporting Information) and the three-dimensional structures are seen in Figure 12. In deuterated methanol (Figure 12a) all the calculated structures of the BZP/DPA complex show interactions between the phenyl rings. Given the polar nature of methanol this result, arising presumably from the solvation of the polar amine and carbonyl groups, is not unexpected. As discussed in section 3.1 and inset into Figure 12a such a dimer is replicated in the crystal structure as a BZP-DPA dimer held by face-edge interactions of the phenyl rings. In deuterated toluene, Figure 12b, the converse occurs with possible complexes held together through hydrogen bonding, -N-H · · · OdC-. Again as discussed in section 3.1 and shown in Figure 12b, an equivalent hydrogen bonded dimer also exists in the crystal structure. Overall these data suggest that although the BZP/DPA dimer is not necessarily the most populous species (Figures 10 and 11), in both solvents similarities exist between this solution phase complex and structural synthons, with the solvent dictating the precise nature of the self-assembled solution species. The IR spectra of 2.94, 5.89, and 11.78 M (mole fraction of each component 0.096, 0.192, and 0.385) equimolar DPA-BZP methanol solutions showed that with increasing concentration the asymmetric ring stretch moved from 1598 to 1592 cm-1, and the C-H deformation bands moved toward their positions in the equimolar melt. This supports the enhanced ring-ring interactions between BZP and DPA seen in the NMR data. As with pure BZP solutions (Figure 6), the IR spectrum of the 2.94 mol L-1 equimolar solution (Figure 13) shows two carbonyl stretching bands at 1652 and 1660 cm-1. At concentrations comparable to pure benzophenone and to those used in the NMR experiments (2 M) these can be assigned as before to solvated and unsolvated species. However, at higher concentrations it is apparent that there is insufficient methanol to solvate all the carbonyl groups (methanol out numbered 2:1) and consequently the two bands merge at around 1652 cm-1, to give a single carbonyl peak between its position in the cocrystal and in the equimolar melt. Thus, the dimers present and revealed
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Figure 9. The effect of concentration on the phenyl ring vibrations in the IR spectrum of diphenylamine in toluene.
Figure 10. Changes in 1H NMR chemical shift and associated speciation profiles observed in CD3OD for, (a) and (b), titration of DPA into BZP (proton A black, B red, C blue) and, (c) and (d), BZP into DPA (proton E black, D red, F blue, G green). The lines in (a) and (c) are the best fit to a 1:1 binding isotherm allowing for dimerization of both components. In the speciation profiles, (b) BZP black, DPA black dotted, DPA dimer red dotted, BZP · DPA blue; (d) DPA black, BZP black dotted, BZP dimer red dotted, BZP · DPA blue).
in the NMR are solvated at low concentrations but begin to selfaggregate though hydrogen bonds in the highly concentrated solutions.
IR spectra of 2.6, 5.2, and 10.3 M (mole fraction 0.178, 0.356, and 0.713) equimolar BZP/DPA toluene solutions are shown in Figure 14. At a solution concentration of 2.6 M the carbonyl
Cocrystallization: Case of Benzophenone and Diphenylamine
Crystal Growth & Design, Vol. 9, No. 4, 2009 1997
Figure 11. Changes in 1H NMR chemical shift and associated speciation profiles observed, (a) and (b), in toluene-d8 for titration of DPA into BZP (proton A black, B red, C blue) and, (c) and (d) BZP into DPA (proton E black, D red, F blue, G green). The lines in (a) and (c) are the best fit to a 1:1 binding isotherm allowing for dimerization of both components. In the speciation profiles (b) BZP black, DPA black dotted, DPA dimer red dotted, BZP · DPA blue and (d) DPA black, BZP black dotted, BZP dimer red dotted, BZP · DPA blue.
band occurred at 1664 cm-1. As the concentration was increased up to the saturation point (10.39 M) the band shifted to 1656 cm-1, the same value as that for an equimolar melt (cf. 1645 cm-1 in the cocrystal). This is the same behavior observed for benzophenone in concentrated equimolar methanol solutions. Therefore, it is suggested that, in agreement with the NMR data, hydrogen bonded BZP/DPA dimers exist in concentrated equimolar toluene solutions. Further evidence supporting this hypothesis was found when analyzing the effect of concentration on the amine (N-H) stretching band. The amine band was observed to shift from 3401 to 3378 cm-1 as the concentration of the solution was increased from 2.6 to 10.39 ML-1. This shift is toward the position of the amine band in the cocrystal, again indicating the formation of hydrogen bonded benzophenone-diphenylamine dimers in concentrated equimolar toluene solutions.
6. Discussion and Conclusion These data reveal the nature of the intermolecular interactions in two and three component liquid systems that yield a cocrystal. The utility and success of employing complementary state of the art spectroscopic techniques is evident. In the BZP/DPA system the links between solution structure, phase equilibria, and crystal structure are now clear. Deviations from ideality seen in the phase diagrams have been successfully linked to
molecular aggregation. In the binary BZP-DPA system negative deviations from ideality in the pure component regions are accompanied by the onset of -CdO · · · H-N- hydrogen bonding and changes in ring-ring contacts which then persist into the cocrystal region. In the ternary system, the additional application of proton NMR enables a much more comprehensive view of the solution species to be gained. Positive deviations from ideality across the whole compositional range are indicative of molecular self-association, this being more significant in methanol than in toluene. Spectroscopy revealed important solvent induced changes with methanol acting to solvate polar groups and encourage dimersiation via ring-ring interactions while toluene induces dimerization through H-bonded contacts and solvates the ring systems. In the case of DPA the NMR data clearly indicate the existence of higher order aggregates. As seen in Figure 12, in both solvents, solutions having the 1:1 cocrystal stoichiometry contain dimer species for which an equivalent dimer is present in the crystal structure. Thus, overall, there remains no doubt that the solution and solid-state chemistry act in a concerted way, with the synthons present in the solid reflecting elements of the solution chemistry. Further examination of these data sheds light on the process of crystal nucleation and in particular on links between kinetics and structure. For example, the dual role played by the solvent in stabilizing certain intermolecular contacts while simulta-
1998 Crystal Growth & Design, Vol. 9, No. 4, 2009
Chadwick et al.
Figure 14. The effect of concentration on the carbonyl band of benzophenone in equimolar toluene solutions.
Figure 12. Structures of the benzophenone-diphenylamine complex determined using Shifty (a) in deuterated methanol and (b) in in deuterated toluene. Overlays of all structures that are consistent with the 1H NMR chemical shift data are shown, along with a representative structure and the structure of a complex from the X-ray crystal structure for comparison. For the H-bond highlighted in (b), the distance d3 in the X-ray crystal structure (1.9 Å) falls within the range found in the Shifty structures (1.3-2.6 Å). For the aromatic interactions highlighted, the distance d1 and interplanar angles in the X-ray crystal structures (4.8-7.1 Å, 22°-44°) fall within the range found in the Shifty structures (3.8-8.8 Å, 12°-90°).
Figure 13. The effect of concentration on the carbonyl band of benzophenone in equimolar methanol solutions.
neously solvating the solute aggregates is very evident; in the case of BZP, methanol solvates the polar carbonyl groups thereby forcing ring-ring contacts between solute molecules while toluene does the reverse leading to -C-H · · · OdC-
interactions between BZP molecules. For both solvents while Figure 5 shows how the BZP solution dimer is related to that from the crystal structure it is clear that increases in concentration and extended aggregation leading to nucleation must be accompanied by desolvation, a process likely to be associated with a higher energetic penalty for methanol than for toluene. DPA solutions provide further such insights. Here, as seen in Figure 6, both toluene and methanol yield a -N-H · · · N-H hydrogen bonded dimer which indeed matches that in the crystal structure. However, NMR of methanolic solutions provides evidence of higher-order assembly processes involving aromatic interactions between dimers, while the IR data in toluene again confirms the importance of desolvation in the extension of selfassembly to higher-order species. In equimolar solutions, the comparison of dimers in Figure 12 shows an excellent agreement between solution and solidstate structures and the spectroscopy again reveals how in methanol further aggregation takes place by H-bonding of dimers. Overall, of course it is now patently obvious that more than one self-assembled solution species can lead to a single crystal structure with ring-ring and hydrogen bonding contacts playing equally important roles in directing the structural outcome. The speciation profiles of Figures 10 and 11, however, show a further feature of interest. In all solutions it is apparent that the population of species includes not only the BZP:DPA dimer but also the homodimers and the monomer species. Interestingly, the heterodimer is not necessarily the most populous; Figure 10b, for example, reveals that for titration of DPA into CD3OD/ BZP solutions the heterodimer is in fact the least populated while in other cases it is at best only 15% more populous than the homodimer. The implication here is that while the solution and crystal chemistry are indeed synchronized, in some cases nucleation kinetics may be limited by the solution speciation while in others by the need to assemble a particular crystal packing. The relatively low stability of the BZP/DPA dimer together with the unexpected stability (no nucleation at supersaturations of 700% unless stirred with magnetic stirrer) of all 1:1 supersaturated melts and solutions indicates that in this case the availability of appropriate solution species is rate limiting. Acknowledgment. K.C. and R.J.D. wish to thank GlaxoSmithKline for support through a CASE studentship and Dr. Leo Lue for helpful discussions.
Cocrystallization: Case of Benzophenone and Diphenylamine Supporting Information Available: Tables of intermolecular interactions of selected dimers and complexes; tables of complexationinduced changes in chemical shift; figures of chemical shift changes. This material is available free of charge via the Internet at http:// pubs.acs.org.
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ln x ) ln xAxB ) ln
(
∆H f 1 1 R Tm T
xA∗ xB∗ +
(
)
∆H Cf 1 1 R Tm T C
(1)
)
(2)
The mole fractions of the components at the melting point of the co-crystal are x*A ) xB* ) 0.5 and therefore eq 2 becomes
(
∆H Cf 1 1 ln xAxB ) ln 0.25 + R Tm T C
)
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CG8013078
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