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Design and Synthesis of Ternary Cocrystals Using Carboxyphenols and Two Complementary Acceptor Compounds Published as part of the Crystal Growth & Design Margaret C. (Peggy) Etter Memorial virtual special issue Daniel A. Adsmond,*,† Abhijeet S. Sinha,§ U. B. Rao Khandavilli,§ Anita R. Maguire,‡ and Simon E. Lawrence§ †

Ferris State University, Department of Physical Sciences, Big Rapids, Michigan 49307, United States Department of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork, Ireland ‡ Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork, Ireland §

S Supporting Information *

ABSTRACT: A strategy combining a ditopic hydrogen-bond donor with two different hydrogen-bond acceptor molecules is proposed for the assembly of simple trimeric building blocks used in the construction of ternary cocrystals. The crystallization of each of three different low symmetry carboxyphenols (3-hydroxybenzoic acid, 6-hydroxy-2-naphthoic acid, and ferulic acid) with acridine and 2-amino-4,6dimethylpyrimidine yielded ternary cocrystals where the three components are joined by phenol-pyridine and carboxylic acidamidine synthons. The use of pKa values, beta values, and synthon histories in the selection of the acceptor compounds is discussed. Significant challenges to the growth of the desired ternary products from solution were presented by competing crystalline phases, including the individual components, a variety of binary phases, salts, and hydrates. Molecular electrostatic potentials were used to analyze the donating and accepting abilities of the competing synthons.

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INTRODUCTION In 1990 Margaret (Peggy) Etter published a set of hydrogen bond rules describing the trends in hydrogen bond connectivity that are observed in crystal structures of organic compounds.1 The rules, built on her observations as well as those of others,2−5 were developed to be used as guidelines for predicting the solidstate hydrogen bond connectivity of molecules having multiple donors and acceptors. More importantly, because of the strong orienting effect that hydrogen bonds have on the molecules involved, the rules could be applied in the design of molecules that would orient themselves in a predetermined way, exerting control over the long-range order of molecules in the crystal. The most often quoted of Etter’s rules: “If possible all hydrogen bond donors and acceptors will be used,” and “the best donor will hydrogen bond to the best acceptor” shaped the thinking of the students in the Etter group, as well as the thinking of generations of crystal engineers to follow. It should be noted here that these “rules” are not infallible, and as pointed out by Steiner,6 the best donor/best acceptor rule might better be described as a “tendency”. As a result of the application of these two rules, a wide range of binary cocrystals were designed and synthesized in the Etter group.7−13 The cocrystal design relied on two different compounds, one containing the best hydrogen-bond donor of the pair and the other containing the best acceptor as illustrated © XXXX American Chemical Society

in Scheme 1. If the association between the two different molecules in the aggregate is strong enough to survive the crystallization process, a binary cocrystal results. Scheme 1 shows two examples of binary aggregates that fit this design model. In Scheme 1. Binary Aggregate Design (Top) with Representative Examples (Bottom)

Received: July 8, 2015 Revised: November 13, 2015

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DOI: 10.1021/acs.cgd.5b00957 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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the first example, the carboxylic acid hydrogen atom preferentially hydrogen bonds to the pyridine nitrogen atom, the best of three possible acceptors, joining the two molecules in a hydrogen-bonded pair. In the second example the best donor, the acid moiety, hydrogen bonds to the best acceptor, the pyrimidine nitrogen atom. Although this acid−pyrimidine attraction is reinforced by a second weaker hydrogen bond between the amine hydrogen atom and the acid carbonyl, creating a bidentate hydrogen bond interaction between the two molecules, the aggregate formation is predicted solely on the attraction between the best donor and best acceptor. The pyrimidine nitrogen and the ortho amino group together constitute an amidine group which is known to hydrogen bond to the complementary carboxylic acid forming an eightmembered ring. The eight-membered hydrogen-bonded ring observed in Scheme 1 is also seen in a variety of other functional group pairings including carboxylic acid, primary amide, and amidine homodimers as well as acid−primary amide heterodimers. Upon observing such recurring patterns of hydrogen-bond connectivity between and within molecules in crystals, Etter set out to develop a method that would precisely describe the connectivity seen in the patterns. Her development of graph set terminology1 and refinement by Bernstein and co-workers14,15 has given the scientific community a common language with which to discuss and compare: (a) hydrogen bonding between complementary functional groups; (b) intramolecular hydrogen bonding; and (c) the larger hydrogen bond patterns seen in crystals. The R22(8) graph set used to describe the carboxylic acid-amidine hydrogen bond connectivity in Scheme 1 is now ubiquitous in its usage. Design of Ternary Cocrystals. During the years following Etter’s work, the hydrogen bond rules were applied successfully in the design of a wide variety of binary cocrystals. In 2001 Aakeröy, building on the knowledge gained from this binary work, applied the best donor/best acceptor rule in the design and synthesis of a set of ternary cocrystals, pulling three different compounds into the same crystal.16 From a minimalist perspective, the simplest fundamental building block of a hydrogen-bonded ternary cocrystal is a trimer of unlike molecules connected by two different hydrogen bond interactions. This trimer may be assembled by one of the three different strategies depicted in Scheme 2. Strategy 1 requires the

carbonyl) with two different carboxylic acid compounds (the monotopic donors).16 Although both the donor compounds were carboxylic acids, the two donor molecules were differentiated from each other by appended functional groups imposing a significant difference in their pKa values. As predicted, the acid with the lowest pKa preferentially hydrogen-bonded to the pyridine nitrogen atom, while the acid with the highest pKa hydrogen-bonded to the primary amide carbonyl. A dozen ternary cocrystals employing the acid-pyridine and acid-primary amide synthons in the isonicotinamide system have been synthesized and crystallographically characterized. Aakeröy subsequently published a second set of ternary cocrystals based on Strategy 1 where the ditopic acceptor was an asymmetric bisheterocycle.17 Again, as predicted, the more acidic of the two carboxylic acids in the ternary cocrystal hydrogen bonded to the more basic heterocycle. Desiraju18,19 and Nangia20 have employed high symmetry compounds in the successful design and synthesis of ternary cocrystals constructed from essential aggregates of 5−13 molecules. We were interested in the ability of simple ditopic donors to form ternary cocrystals with appropriately complementary acceptors as outlined in Strategy 2. While not implying any value of ternary cocrystals in drug formulation, we were particularly interested in carboxylic acids and phenols as donors due to their high frequency of appearance in active pharmaceutical ingredients (APIs) and thus selected a set of carboxyphenols to form ternary cocrystals with a pair of suitable acceptor compounds (Scheme 3). In order to increase the relevance of this work to a larger range of compounds we selected carboxyphenols without particularly high symmetry. Scheme 3. Strategy 2 Using a Carboxyphenol for the Design of Ternary Cocrystals

Selection of Coformers. The challenge remaining before us was to select two different acceptor molecules each that would selectively hydrogen bond to one of the two donors while avoiding synthon crossover.21 This selection process was informed by an ongoing investigation of the hydrogen bond preferences of ditopic donor compounds and coformer candidates.22,23 One of the challenges of applying the best donor/best acceptor rule in the selection of functional groups is the actual ranking of the donating and accepting abilities. Historically this has been accomplished through employing a combination of pKa values, β values,24 and results from competition experiments.1 pKa values provide a rough guide to hydrogen-bond donating and accepting abilities, but have been shown to have limited value outside of comparing donors or acceptors within a specific functional group.25 The acidity of carboxylic acids is roughly a million times greater than the acidity of phenols raising little doubt in the 1980s as to which was the better donor of the two. Recently, however, molecular electrostatic potential surface (MEPs) calculations have been used to determine the hydrogen bond propensity parameters (αi and βj values) of specific compounds, which have demonstrated that the donating abilities of phenols and carboxylic acids are actually quite similar, with MEPs often identifying the phenol as the better donor in carboxyphenols.25 Previous work has shown that both carboxylic acids and phenols preferentially hydrogen bond to pyridine nitrogen

Scheme 2. Ternary Aggregate Design

central molecule to be a ditopic acceptor and each of the end molecules to be hydrogen bond donors. Strategy 2 requires the central molecule to be a ditopic donor and each of the end molecules to be acceptors. Strategy 3 requires the central molecule to contain both a donor and an acceptor while one of the end molecules is a donor and the other an acceptor. Aakerö y’s 2001 design followed Strategy 1, coupling isonicotinamide (a ditopic acceptor compound having two good acceptors: a pyridine nitrogen atom and an amide B



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atoms.6,26 Cocrystallization of carboxyphenols with acridine23 has yielded cocrystals where (a) only the carboxylic acid hydrogen bonds to the pyridine nitrogen atom; (b) only the phenol hydrogen bonds to the pyridine nitrogen atom; and (c) both carboxylic acid and phenol hydrogen bond to the pyridine nitrogen atom. With no clear preference for the acid-pyridine synthon over the phenol-pyridine synthon or vice versa, we sought to resolve this ambivalence by taking advantage of the ability of carboxylic acids to act as both donors and acceptors in hydrogen bonding. We reasoned that synthon fidelity might be maintained by crystallizing a carboxyphenol with (a) a strongly accepting pyridine derivative for the best donor, the phenol; and (b) a slightly less basic amidine compound that would not only accept from the carboxylic acid but also donate through an amine to the carbonyl to selectively form a bidentate hydrogen bond interaction with the carboxylic acid. Upon selecting the two synthons to be employed, we turned our attention to aminopyrimidines as possible amidine acceptors. The ability of 2-aminopyrimidines to form cocrystals with carboxylic acids, driven by the best donor (the carboxylic acid) best acceptor (pyrimidine nitrogen atom) attraction was studied in the Etter group in the late 1980s.9,27 It was predicted that evaporation of solutions containing a carboxylic acid and a 2aminopyrimidine, both known to form R22(8) homodimers, would yield cocrystals with the acid and pyrimidine molecules joined by R22(8) heterodimers. The experiments yielded 1:1 cocrystals, displaying aggregates of four molecules connected by two of the predicted acid-amidine heterodimers and an amidine homodimer, as well as 1:2 cocrystals displaying aggregates of three molecules connected by two acid-amidine heterodimers (Figure 1).

Table 1. Influence of 2-Aminopyrimidine Substituents on Basicity and on Carboxylic Acid-Amidine R22(8) Heterodimer Formation 1 2 3 4 5 6 7 8 a

A

B

C

pKaa

supramolecular yield (%)

CH3 CH3 H H CH3 H H Cl

H H H NH2 H Br NO2 H

CH3 H H H Cl H H Cl

4.4 3.6 2.8 2.8 2.2 0.5 −1.5 −4.8

7/7 (100) 7/7 (100) 10/10 (100) 3/3 (100) 7/7 (100) 1/9 (11) 0/3 (0) 0/6 (0)

pKa values calculated using pyridinium ion Hammett equation.30

pyrazine, or triazine yielded 174 hits. Of these, 168 (97%) were acid/amidine cocrystals and 161 (93%) contained an R22(8) acid/ amidine heterodimer. A search for structures containing both a phenol and an ortho-aminopyridine, pyrimidine, pyrazine, or triazine, however, yielded only 26 structures with 39 crystallographically independent hydroxyl groups. Without the benefit of the bidentate hydrogen-bond interaction with the amidine only 16 of the 39 phenolic protons (41%) hydrogen-bonded to an aromatic nitrogen atom. Interestingly, all 16 of these were components of a phenol-amidine cocrystal. We found only one crystal structure that contained all four of the chosen donor and acceptor groups with no other competing groups. The 1:1 cocrystal of p-hydroxybenzoic acid and 2-amino-4-methyl-6-(3pyridyl)pyrimidine displayed both of the predicted acid-amidine and phenol-pyridine synthons.32 When comparing our two chosen acceptor moieties, pyridine and 2-aminopyrimidine, there is no definitive answer to the question of whether carboxylic acids preferentially bind to 2aminopyrimidines over pyridines, with the accepting ability of each being closely related to the electronic effects of neighboring substituents. The question has been directly addressed by two different authors. In 2001, Lynch and McClenaghan synthesized 2-amino-4-(4-pyridyl)pyrimidine and cocrystallized it with paminobenzoic acid.33 Their experiment yielded a 1:1 cocrystal where the carboxylic acid hydrogen-bonded to the pyridine, leaving the 2-aminopyrimidine sites to form a chain of R22(8) homodimers. In 2006, Aakeröy et al. synthesized three different supramolecular reactants each containing a 2-aminopyrimidine moiety and a pyridine moiety.32 Upon cocrystallizing these three reactants with a variety of aromatic carboxylic acids, they obtained nine 1:1 cocrystals in which the carboxylic acid hydrogen-bonded only to the aminopyrimidine, thus completely rejecting the pyridine moiety. Despite the observed uncertainty in the fidelity of the phenolpyridine and carboxylic acid-amidine synthons in each other’s presence, based on their strong independent histories we chose to crystallize three asymmetric carboxyphenols [3-hydroxybenzoic acid (HBA), 6-hydroxy-2-naphthoic acid (HNA), and ferulic acid (FA), Figure 2] from solutions containing both acridine (ACR) and 2-amino-4,6-dimethylpyrimidine (ADMP) in an attempt to obtain ternary cocrystals containing the proposed aggregate shown in Scheme 4. The amidine group, being activated by the methyl groups, was predicted to form a strong bidentate hydrogen-bond interaction with the acid while the phenol, the best donor, would preferentially bind to the acridine nitrogen atom, the best acceptor. The resulting products were analyzed via NMR spectroscopy, DSC, and single crystal X-ray

Figure 1. Hydrogen bonding seen in 1:1 (left) and 1:2 (right) 2aminopyrimidine/carboxylic acid cocrystals.

The work,27 pairing 8 different 2-aminopyrimidines with up to 10 different carboxylic acids (pKa range 1.2−4.5) demonstrated the utility of the acid-amidine synthon as well as the sensitivity of the amidine’s accepting ability to the electronic effects of the neighboring substituents. It was shown that electron-withdrawing groups could reduce the accepting ability of the pyrimidine nitrogen atom to the point where it was no longer a better acceptor than the acid carbonyl, thereby inhibiting cocrystal formation. As seen in Table 1, the 2-aminopyrimidines having pKa values of 2.2 or higher gave a 100% supramolecular yield of acid/pyrimidine cocrystal, while those with pKa values of −1.5 or lower gave a 0% supramolecular yield. With compound 5, the ability to differentiate between the two amidine binding sites was demonstrated, activating one with an ortho methyl group and deactivating the other with an ortho chloro group. More recently others have studied the hydrogen-bonding between carboxylic acids and aminopyrimidines.28,29 A search of the CSD (version 5.36)31 for structures containing both a carboxylic acid and an ortho-aminopyridine, pyrimidine, C



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(s, 6H), 6.32 (br s, 1H), 6.39 (br s, 2H), 7.13−7.24 (m, 2H), 7.75 (d, J = 8.6, 1H), 7.87 (dd, J = 8.6, 1.4, 1H), 7.96 (d, J = 8.6, 1H), 8.47 (s, 1H). 1:1:1 Acridine/3-Hydroxybenzoic acid/2-Amino-4,6-dimethylpyrimidine, ACR·HBA·ADMP. ACR (144 mg, 0.80 mmol) was dissolved in a 1:4 acetone/toluene mixture (4 mL). HBA (110 mg, 0.80 mmol) and ADMP (98 mg, 0.80 mmol) were dissolved together in acetonitrile (22 mL). The two solutions were combined, filtered into a 50 mL beaker, and covered by parafilm with a small hole present. After being left to evaporate for 20 days at room temperature, light orange plates were removed from the remaining 0.5 mL of solution and identified by 1H NMR as containing a 1:1:1 molar ratio of ACR, HBA, and ADMP. Melting point: 120−123 °C; 1H NMR: δH (300 MHz, DMSO-d6) 2.16 (s, 6H), 6.33 (br s, 3H), 6.99 (dd, J = 7.90, 2.30, 1H), 7.24−7.42 (m, 3H), 7.63 (t, J = 7.6, 2H), 7.87 (t, J = 7.6, 2H), 8.13−8.23 (m, 4H), 9.13 (s, 1H). Note: When repeated a second time on exactly the same scale with identical conditions, the experiment yielded after 20 days of slow evaporation at room temperature a mixture of light orange plates and dark reddish brown plates which were removed from the remaining 0.5 mL of solution. Upon sorting, the orange plates were identified by 1H NMR as containing a 1:1 molar ratio of HBA and ADMP, and the dark reddish brown plates were identified by 1H NMR as containing a 2:1 molar ratio of ACR and HBA. When repeated a third time, doubling the scale, light orange plates were removed from the 0.5 mL of solution that remained after 20 days of evaporation and identified by 1H NMR as containing a 1:1:1 molar ratio of ACR, HBA, and ADMP identical to that obtained in the original experiment. In a fourth experiment, brown blobs were obtained from a 3:1 v/v solution of ethanol/water and identified by 1 H NMR as containing a 2:1 molar ratio of ACR and HBA. In a fifth experiment orange plates were obtained from acetonitrile and identified by 1H NMR as containing a 2:1 molar ratio of ACR and HBA. 1:1:1 Acridine/6-Hydroxy-2-naphthoic acid/2-Amino-4,6-dimethylpyrimidine, ACR·HNA·ADMP. ACR (72 mg, 0.40 mmol) was dissolved in acetonitrile (2 mL); HNA (69 mg, 0.40 mmol) was dissolved in acetonitrile (6 mL); and ADMP (49 mg, 0.40 mmol) was dissolved in acetonitrile (8 mL). The three solutions were combined in a 20 mL sample vial and covered with foil in which a small hole had been punctured. After being left to evaporate at room temperature for 24 h, burnt orange plates were removed from the remaining 13 mL of solution and identified by 1H NMR as containing a 1:1:1 molar ratio of ACR, HNA, and ADMP. Melting point: 164−166 °C; 1H NMR: δH (300 MHz, DMSO-d6) 2.16 (s, 6H), 6.31 (br s, 1H), 6.35 (br s, 2H), 7.13− 7.22 (m, 2H), 7.63 (t, J = 7.7, 2H), 7.75 (d, J = 8.7, 1H), 7.80−7.91 (m, 3H), 7.95 (d, J = 8.6, 1H), 8.18 (d, J = 8.8, 4H), 8.47 (s, 1H), 9.11 (s, 1H). 1:2:1 Acridine/Ferulic acid/2-Amino-4,6-dimethylpyrimidine Acetonitrile Solvate, AC·FA·ADMP·MeCN. ACR (72 mg, 0.40 mmol) was dissolved in acetonitrile (2 mL); FA (78 mg, 0.40 mmol) was dissolved in acetonitrile (4 mL); and ADMP (49 mg, 0.40 mmol) was dissolved in acetonitrile (8 mL). The three solutions were combined in a 20 mL sample vial and covered by foil with a small hole present. After being left to evaporate for 4 days at room temperature, orange plates were removed from the remaining 12 mL of solution and identified by 1H NMR as containing a 1:2:1:1 molar ratio of ACR, FA, ADMP, and acetonitrile. Melting point: 112−115 °C; 1H NMR: δH (300 MHz, DMSO-d6) 2.07 (s, 3H), 2.16 (s, 6H), 3.82 (s, 6H), 6.32 (s, 3H), 6.37 (d, J = 16.1, 2H), 6.80 (d, J = 8.3, 2H), 7.09 (dd, J = 8.3, 1.8, 2H), 7.28 (d, J = 1.8, 2H), 7.50 (d, J = 16.1, 2H), 7.63 (t, J = 7.7, 2H), 7.87 (t, J = 7.7, 2H), 8.12−8.24 (m, 4H), 9.12 (s, 1H), 9.56 (s, 1H). Crystallography. Single crystal X-ray data was collected on a Bruker APEX II DUO diffractometer or on a Bruker X2S diffractometer, using graphite monochromatic Mo Kα (λ = 0.7107 Å) radiation, as previously described.34 The structures were solved using direct methods and refined on F2. Analysis was undertaken with the SHELX suite of programs35,36 and diagrams were prepared with Mercury 3.6.37 All nonhydrogen atoms were located and refined with anisotropic thermal parameters. Hydrogen atoms were either placed in calculated positions or they were located and refined with isotropic thermal parameters. For ACR·FA·ADMP·MeCN, the crystal exhibited disorder for one of the hydrogen atoms, and the occupancy was allowed to refine. The detailed

Figure 2. Carboxylic acids (top) investigated for ternary cocrystal formation with acridine and 2-amino-4,6-dimethylpyrimidine (bottom).

Scheme 4. Proposed Carboxyphenol Ternary Design with Selected Ditopic Donor and Acceptor Compound Structures

diffraction. The observed motifs in the single crystal structures were compared with results predicted by calculated MEPs.

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EXPERIMENTAL SECTION

Materials and Methods. The compounds utilized in this study were obtained from Sigma-Aldrich and used as received. Solvents were obtained from commercial sources and distilled before use. Nuclear Magnetic Resonance (NMR) Spectroscopy. 1H NMR spectra were recorded at 20 °C on a BRUKER AVANCE 300 MHz spectrometer using DMSO-d6 as solvent. Chemical shifts are given in ppm relative to tetramethylsilane (TMS) as an internal standard. Coupling constants (J) are given in hertz (Hz). Differential Scanning Calorimetry (DSC). Thermal analysis was recorded on a TI DSC Q1000 instrument. Samples (2−6 mg) were crimped in nonhermetic aluminum pans and scanned from 30 to 250 °C at a heating rate of 5 °C min−1 under a continuously purged dry nitrogen atmosphere. Molecular Electrostatic Potential Calculations. Charge calculations were performed using Spartan’14 (Wave function, Inc., Irvine, CA). All molecules were geometry optimized using DFT B3LYP/631+G* ab initio calculations, with the maxima and minima in the electrostatic potential surface (0.002 e au−1 isosurface) determined using a positive point charge in vacuum as a probe. CSD Searches. All searches were done in the CSD version 5.36 database (2015). Solution Crystallization. 6-Hydroxy-2-naphthoic Acid, HNA. HNA (50.0 mg, 0.27 mmol) was dissolved in methanol (5 mL). The solution was covered by foil with a small pinhole present and left to stand on the bench until crystals appeared. Colorless plate-shaped crystals suitable for single crystal X-ray diffraction were harvested from the methanol solution after 2 days. Melting point: 244−246 °C. 1:1 6-Hydroxy-2-naphthoic acid/2-Amino-4,6-dimethylpyrimidine, HNA·ADMP. ACR (288 mg, 1.6 mmol) was dissolved in acetonitrile (8 mL); HNA (276 mg, 1.6 mmol) was dissolved in acetonitrile (24 mL); and ADMP (196 mg, 1.6 mmol) was dissolved in acetonitrile (32 mL). The three solutions were combined, placed in a 100 mL beaker, covered by foil with a small pinhole present, and left to evaporate. After the solutions were left to stand at room temperature for 40 h, large clumps of orange plates were removed from the remaining 58 mL of solution. The plates were identified by 1H NMR as containing a 1:1:1 molar ratio of ACR, HNA, and ADMP. After being left to stand at room temperature for an additional 9 days of evaporation, thick orange plates were removed from the remaining 9 mL of solution and identified by 1H NMR as containing a 1:1 ratio molar ratio of HNA and ADMP. Melting point: 172−174 °C; 1H NMR: δH (300 MHz, DMSO-d6) 2.16 D



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Table 2. Crystallographic Data for the Compounds formula MW crystal system space group, Z a, Å b, Å c, Å α, deg β, deg γ, deg V, Å3 Dc, g cm−3 μ, mm−1 2θ range, deg T, K total reflns unique reflns Rint obs reflns, I > 2σ(I) no. parameters no. restraints R1 [I > 2σ(I)] wR2 [all data] S ρmax, ρmin, e Å−3

HNA

HNA·ADMP

ACR·HBA·ADMP

ACR·HNA·ADMP

ACR·FA·ADMP·MeCN

C11H8O3 188.17 monoclinic P21/c, 4 6.1320(8) 19.149(3) 7.2335(10) 90 98.561(5) 90 839.9(2) 1.488 0.109 3.04−26.66 300.(2) 9938 1608 0.045 1144 135 0 0.047 0.139 1.03 0.20, −0.30

C17H17N3O3 311.33 monoclinic C2/c, 8 24.0092(15) 6.0153(4) 21.0514(14) 90 90.304(2) 90 3040.3(3) 1.360 0.095 3.39−25.67 300.(2) 30185 2883 0.042 2296 226 3 0.040 0.115 1.03 0.19, −0.19

C26H24N4O3 440.49 triclinic P1̅, 2 7.789(3) 9.702(4) 16.315(6) 82.933(10) 78.236(9) 69.530(9) 1129.0(8) 1.296 0.087 1.28−26.42 296.(2) 33295 4594 0.046 3177 317 2 0.040 0.118 1.02 0.23, −0.14

C30H26N4O3 490.55 triclinic P1̅, 2 8.5585(16) 9.4171(19) 16.709(3) 101.307(5) 98.623(4) 103.864(4) 1254.3(4) 1.299 0.086 1.27−26.41 296.(2) 38569 5106 0.032 4188 352 0 0.044 0.132 1.04 0.25, −0.28

C41H41N5O8 731.79 triclinic P1̅, 2 9.4332(9) 14.5275(13) 14.5316(13) 105.050(3) 91.418(3) 93.175(3) 1918.6(3) 1.267 0.089 1.45−25.71 300.(2) 39868 7259 0.031 5195 523 17 0.047 0.139 1.05 0.22, −0.20

Table 3. Key Hydrogen Bond Parameters compound HNA HNA·ADMP

ACR·HBA·ADMP

ACR·HNA·ADMP

ACR·FA·ADMP·MeCN

interaction

(D−H), Å

d (H···A), Å

d (D···A), Å

(D−H···A), deg

O12−H12···O13 O14−H14···O13 O14−H14···O12 N17−H17···O12 N21−H21A···O13 N21−H21B···O13 O8−H8···N13 O10−H10···N33 N17−H17A···N11 N17−H17B···O9 O13−H13···N15 O14−H14···N37 N21−H21A···O12 N21−H21B···N17 O11−H11···N29 O14−H14···O12 O14−H14···N51 O24−H24···N31 O28−H28···O10 N29−H29···O11 N35−H35A···O25 N35−H35B···O10

0.92(3) 0.92(3) 0.843(16) 0.932(12) 0.909(2) 0.915(13) 0.828(5) 0.825(5) 0.90(2) 0.88(2) 0.97(3) 0.93(3) 0.87(2) 0.84(2) 0.849(19) 0.854(17) 0.854(17) 0.869(17) 0.865(17) 0.90(2) 0.90(2) 0.89(2)

1.83(3) 1.97(3) 2.009(16) 1.783(13) 2.005(19) 1.870(14) 1.805(6) 1.971(7) 2.17(2) 2.22(2) 1.70(3) 1.88(3) 2.05(2) 2.21(2) 1.72(2) 2.22(3) 2.08(2) 1.810(17) 1.804(18) 1.69(2) 1.98(2) 2.00(2)

2.7097(18) 2.8662(19) 2.8363(17) 2.7124(15) 2.8294(17) 2.7858(17) 2.6263(19) 2.787(2) 3.064(2) 3.090(2) 2.6681(16) 2.7891(17) 2.9011(18) 3.052(2) 2.5795(19) 2.674(2) 2.775(2) 2.674(2) 2.669(2) 2.5795(19) 2.876(2) 2.885(2)

158.(3) 162.(2) 167.(2) 174.8(17) 150.1(16) 179.8(19) 171.(2) 170.(3) 177.5(17) 169.1(18) 175.(2) 165.(2) 168.8(17) 175.3(17) 171.(4) 113.(2) 138.(3) 173.(3) 180.(3) 168.(3) 170.(2) 174.7(18)

crystallographic data and structure refinement parameters for these compounds are summarized in Table 2, and the key hydrogen bond parameters for the crystal structures are provided in Table 3.

with the exception of HNA. Having determined the crystal structure of HNA, the next step was to obtain binary cocrystals containing the desired connectivity between a carboxyphenol and each of the two coformers. We synthesized and solved the structure of the 1:1 HNA·ADMP salt to complement the three previously published carboxyphenol/acridine binary cocrystals, two of 1:1 stoichiometry and one of 1:2 stoichiometry.23 Finally we synthesized and solved the structures of the three ternary cocrystals.

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RESULTS AND DISCUSSION Upon completion of the design and coformer selection phases of the work, we set out to analyze the hydrogen-bond connectivity of our selected ditopic donor and acceptor molecules. Crystal structures of the individual components were previously known, E



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The hydrogen bonding seen in the previously published ACR· HBA binary cocrystal structures (Figure 5) demonstrates the promiscuity of HBA in the presence of ACR. In the 1:1, Form I ACR·HBA cocrystal the carboxylic acid hydrogen bonds to the acridine, while the phenol hydrogen bonds to the acid carbonyl.23 In the 1:1, Form II ACR·HBA cocrystal the phenol hydrogen bonds to the acridine while the carboxylic acids form a R22(8) homodimer. Finally, in the 2:1 ACR·HBA cocrystal both donors hydrogen bond to the acridine. With the introduction of ADMP to the mixture, we expected to selectively bind the carboxylic acid in an R22(8) heterodimer with the amidine, while the phenol selectively hydrogen bonded to the acridine nitrogen atom. The anticipated ternary cocrystal ACR·HBA·ADMP would be in competition with a minimum of 15 other known crystalline forms: six polymorphs of ACR,38−43 two polymorphs of HBA,44 ADMP,45 ADMP hydrate,46 the three ACR·HBA binary cocrystals shown in Figure 5,23 along with a 2:3 ACR·HBA binary cocrystal,23 and a 9:2 ACR·HBA binary cocrystal hydrate.23 The crystal structure of ACR·HBA·ADMP contains one molecule each of ACR, HBA, and ADMP in the asymmetric unit. The phenolic OH of HBA hydrogen bonds to the acridine nitrogen atom, while the carboxyl group of HBA hydrogen bonds to one of the amidine groups of ADMP, forming an R22(8) heterodimer connecting the three molecules into a trimeric supermolecule (Figure 6, top). The free amidine groups of ADMP hydrogen bond to each other around a crystallographic inversion center forming an R22(8) amidine homodimer connecting the two trimeric supermolecules into a centrosymmetric hexameric supermolecule. The two ADMP and two HBA molecules in the center of the hexamer occupy the same plane, while the ACR molecules on the ends are tilted up and down, giving the hexamer a zigzag conformation. Inversion-related ACR molecules π stack in columns throughout the structure, while HBA alternates with ADMP molecules in π stacks (Figure 6, bottom). The crystal structure of ACR·HNA·ADMP contains one molecule each of ACR, HNA, and ADMP in the asymmetric unit. The hydrogen-bond connectivity in ACR·HNA·ADMP is the same as that seen in ACR·HBA·ADMP; i.e., the phenolic O−H of HBA hydrogen bonds to the ACR nitrogen atom, while the carboxyl group of HBA hydrogen bonds to one of the amidine groups of ADMP through an R22(8) heterodimer (Figure 7, top).

The crystal structure of HNA has one molecule per asymmetric unit. The carboxylic acids hydrogen bond to each other in an R22(8) ring (Figure 3). The phenol OH hydrogen bonds to the anti-lone pair of the acid carbonyl.

Figure 3. Capped dimer seen in the crystal structure of HNA.

The crystal structure of HNA·ADMP contains one molecule each of HNA and ADMP. The acid has proton transferred to the pyrimidine forming a pyrimidinium ion, which no longer acts as a hydrogen-bond acceptor, and a carboxylate, which acts as an acceptor for all four protons in the structure (Figure 4). An R22(8)

Figure 4. Hydrogen bonding seen in the crystal structure of HNA· ADMP.

heteromeric ring joins the pyrimidinium ion to the carboxylate ion. Pairs of inversion related R22(8) rings are connected by amino-carboxylate hydrogen bonds forming an R24(8) motif. The phenol OH also hydrogen bonds to a carboxylate oxygen atom.

Figure 5. Hydrogen bonding seen in 1:1 ACR·HBA Form I (top left), 1:1 ACR·HBA Form II (top right), and 2:1 ACR·HBA (bottom).23 F



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pairs to form a step-like pattern throughout the structure, while HNA molecules alternate with ADMP molecules in stacks (Figure 7, bottom). The crystal structure of ACR·FA·ADMP·MeCN contains one molecule each of ACR and ADMP, two molecules of FA, and one molecule of acetonitrile in the asymmetric unit. The phenolic OH of one of the FA molecules hydrogen bonds to the ACR nitrogen atom, while the carboxyl group of the same FA molecule hydrogen bonds to one of the amidine groups of ADMP through an R22(8) heterodimer (Figure 8, top). There is ∼50:50 disorder in the position of the hydrogen atom associated with the pyrimidine nitrogen atom and the carboxylic acid of the FA molecule which is hydrogen bonding to the acridine. Thus, the basic acridine/carboxyphenol/pyrimidine trimer is the same as that seen in the two other ternary systems discussed above. The carboxyl group of the second FA forms an R22(8) heterodimer with the second amidine group of the ADMP molecule extending the trimeric supermolecule into a tetramer. The tetramers are then connected to each other through two hydrogen bonds between the phenolic OH of the second FA molecule and the anti-lone pair of the carboxyl of the first FA forming an R46(28) ring around a crystallographic inversion center. The six molecules forming the central ring of the resultant octamer are coplanar, while the two terminal ACR molecules are bent out of the plane. The acetonitrile molecule is connected to the FA methoxy group through a C−H···N hydrogen bond (C13− H13B···N54, 3.135 Å, 104.78°). Pairs of inversion related ACR molecules interact through π stacking of the terminal rings (Figure 8, bottom). Molecular Electrostatic Potentials. The calculated molecular electrostatic potentials (MEPs) of all five reactants, along with their corresponding α and β values (Figure 9),47 may be used to rank competing donors and acceptors in our ternary systems. Figure 9 shows that in two of the three carboxyphenols (HBA and HNA) the phenolic OH is the better of the two hydrogen bond donors with the difference in electrostatic potential between the phenol and acid being more significant in HNA (50 kJ/mol) than in HBA (14 kJ/mol). This difference can be accounted for by the resonance between the phenolic OH and the carboxyl group in HNA. In FA, the presence of the electron donating methoxy group ortho to the phenolic substituent on the benzene ring reduces the charge on the phenolic moiety so that it is a weaker donor than the carboxylic acid proton, with a difference in surface potential of 27 kJ/mol. The better of the two coformer hydrogen-bond acceptors, according to the MEPs, is the acridine nitrogen atom with a β value of 5.8 as compared to a β value of 5.3 for the pyrimidine nitrogen atom; however, the difference in surface potential between the two is relatively small (8 kJ/mol). There are two questions we wanted to address with the MEP values we calculated. First of all, do the MEP values predict the specific hydrogen bond connectivity that is observed in the ternary products? Second, do the calculations show a net stabilization of the donor−acceptor pairings relative to the reactant pairings upon formation of the ternary product pairings? The first question requires no further calculations, just simple pairings of appropriately ranked donors and acceptors. According to the MEP values and hydrogen bond propensity parameters, the rankings of the four donors in the HBA ternary system are phenol > carboxylic acid > amine (two), while the acceptor rankings are pyridine > pyrimidine (two) > acid carbonyl > phenol. Pairing of the best donor in the system with the best acceptor, followed by the second best donor and the

Figure 6. R22(8) dimer and discrete motifs joining the three components together in the ternary ACR·HBA·ADMP system (top) and the columnar stacks (bottom).

Figure 7. R22(8) dimer and discrete motifs joining the three components together in the ternary ACR·HNA·ADMP system (top) and the stacked acridine pairs and offset pyrimidine planes (bottom).

The free amidine groups of ADMP hydrogen bond to each other around a crystallographic inversion center forming an R22(8) amidine homodimer. The two trimeric supermolecules are connected into a centrosymmetric hexameric supermolecule by an R22(8) homodimer formed by the free amidine groups. Pairs of HNA and ADMP joined by an R22(8) heterodimer occupy the same plane, while the two ADMP molecules joined by the R22(8) homodimer are parallel, but in planes slightly offset from each other. Similar to the ACR·HBA·ADMP cocrystal, the ACR molecules on the ends are tilted up and down, giving the hexamer a zigzag conformation. Pairs of stacked inversion-related ACR molecules partially overlap with neighboring inversion-related G



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Figure 8. R22(8) dimer and discrete motifs joining the three components together in the ternary ACR·FA·ADMP·MeCN system (top) and stacked acridine pairs (bottom). Note the disorder has been omitted for clarity.

Figure 9. Calculated MEPs and hydrogen bond propensity parameters (αi and βj) for the entire set of ternary components.

second best acceptor etc. predicts phenol-pyridine, carboxylic acid-pyrimidine, amine-pyrimidine, and amine-carbonyl hydrogen bonds, matching exactly the hydrogen-bond connectivity that was predicted and observed in ACR·HBA·ADMP.

In the HNA system the donor ranking is the same as that seen in HBA (phenol > carboxylic acid > amine), but the acceptor ranking (pyridine > acid carbonyl > pyrimidine > phenol) is different. The HNA carbonyl is a better acceptor than the H



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Table 4. Energy Comparisons between the Reactant Homodimers and the Product Heterodimers

paired the best donor in the system with the best acceptor, the second best donor with the second best acceptor, etc.47 A comparison of the sum of the donor−acceptor pair energies in the potential cocrystal with the sum of the energies of the donor−acceptor pairs in the individual components provides a rough estimate of the total stabilization of a binary cocrystal. Hunter has concluded from his work that when a binary cocrystal is favored by more than 11 kJ/mol over the two pure solids, the probability of obtaining a cocrystal is better than 50%. We applied Hunter’s method to our three ternary systems by comparing the sum of the pairwise stabilization energies of the four donor−acceptor pairs in the reactant crystal structures with the sum of the pairwise stabilization energies in the ternary product structures. The calculations (see Supporting Information) show that both ACR·HBA·ADMP and ACR·FA·ADMP, which are stabilized by 12 and 20 kJ/mol, respectively, have a high probability of forming with respect to the reactants. ACR· HNA·ADMP however is stabilized by less than 1 kJ/mol with respect to the reactants so would not necessarily be predicted to form. It should also be noted that we have ignored all possible CH---O and CH---N hydrogen bonds in these calculations, including the known CH---N hydrogen bond between FA and acetonitrile and the reported trifurcated CH---O hydrogen bond in the reactant FA. The significant stabilization (12.0 kJ/mol) in the HBA system is not surprising because in forming ACR·HBA·ADMP, the two best donors shift from hydrogen bonding to the third and fourth best acceptors in the system (the acid carbonyl and the phenol oxygen) to the first and second best acceptors (the pyridine and the pyrimidine). In the HNA system, where the two best donors were both originally hydrogen bonding to the acid carbonyl second best overall acceptor, one switches to the best acceptor while the other switches to the third best acceptor in the ternary cocrystal, providing no significant overall stabilization. In the FA system there would seem to be little driving force toward cocrystallization with either of the coformers, neither one of them having a better acceptor than the original carboxyphenol carbonyl. However, in the reactant (FA) the phenol hydrogen bonds to the acid hydroxyl, the fifth best overall acceptor, providing only a fraction of the stabilization contributed by the phenol hydrogen bonding in the free HBA and HNA.

pyrimidine, which means that after the phenol-pyridine pairing, the carboxylic acid is predicted to hydrogen bond to the best remaining acceptor, the acid carbonyl, maintaining the acid homodimer at the exclusion of the pyrimidine molecule. The numbers predict the formation of an ACR·HNA binary cocrystal, but not the ternary cocrystal. In the FA system, as mentioned above, the order of the two best donors is reversed. (carboxylic acid > phenol > amine). With an acceptor ranking of acid carbonyl > pyridine > pyrimidine, the best donor, the carboxylic acid will preferentially hydrogen bond to the acid carbonyl maintaining the acid homodimer and excluding the aminopyrimidine from the cocrystal. The phenol, then, is predicted to hydrogen bond to the pyridine nitrogen and the amines to the pyrimidine, again predicting the formation of an ACR·HNA binary cocrystal and not the ternary cocrystal. Thus, the answer to the first question is that the MEP values successfully predicted the exact hydrogen-bond connectivity observed in ACR·HBA·ADMP but suggest ternary cocrystal formation is not possible in the HNA and FA systems, which favor self-association of the carboxylic acid. The similarity of the MEP values for the pyridine, pyrimidine, and acid carbonyl, as close as 4 kJ/mol in some instances, highlights the difficulties in predicting the hierarchy of donor−acceptor pairings in these ternary systems. However, it is remarkable that the synthon fidelity was maintained despite the range of relative donating abilities of the phenol and the carboxylic acid. In HBA the phenol proton MEP was greater than acid proton MEP by 14 kJ; in HNA the phenol proton MEP was greater by 50 kJ/mol; and in FA the phenol proton MEP was less than the carboxylic acid proton MEP by 27 kJ/mol. The “kinetic chelate effect”48−50 of the bidentate hydrogen bonding of the acid-amidine dimer seems to have a greater influence on the experimental outcome than the actual relative donating abilities of the phenol and acid. Assessment of the overall stabilization upon rearrangement of the donor−acceptor pairings from reactant to product requires examination of the exact hydrogen bonding of the reactants as well as that in the ternary product. The stabilization energy for a particular hydrogen bond may be estimated by multiplying the α value of the potential donor by the β value of the potential acceptor. Upon examining a pair of potential reactants Hunter I



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more effective predictors of the donor−acceptor pairings than the MEP values. Whether this is a system-specific observation, or more general for hydrogen-bonded ternary cocrystals, is an intriguing question for the future. We continue to be guided in our cocrystal design by Margaret (Peggy) Etter’s best donor− best acceptor rule while continually being challenged by the task of the actual ranking of donating and accepting abilities.

Consequently a large stabilization is contributed when the phenols switch from the acid hydroxyl to the pyridine nitrogen and acid carbonyl, both of which are much better acceptors than the acid hydroxyl. While these results seem to point to a significant stabilization contributed in two of the three ternary cocrystals, Hunter cautions that αi and βj calculations are subject to significant error as demonstrated by comparisons with experimental measurements. We have separated the components of the above calculations that apply directly to the formation of the acid-amidine heterodimer and have presented them in Table 4. It is intriguing that the calculations show that the acid-amidine heterodimer in general appears to be disfavored with respect to the acid and amidine homodimers. Similar calculations by Hunter show an acid carbonyl beta value of 5.0, an amide carbonyl beta value of 8.0, and a carboxylic acid-amide heterodimer stabilization of 4 kJ/mol. Our acid carbonyl beta values range from 4.8 to 6.0, while the beta value calculated for the pyrimidine nitrogen atom of ADMP is in the middle of this range at 5.3. This relatively low value for ADMP seems inconsistent with the observation that 161 out of 174 structures (93%) in the CSD that contain both an acid and an amidine display an acid-amidine heterodimer.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b00957. 1 H NMR data, DSC data, and additional figures (PDF) Accession Codes

CCDC 1409796−1409800 contains the supplementary crystallographic data for this paper. These data can be obtained free of 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.

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AUTHOR INFORMATION

Corresponding Author

CONCLUSIONS In conclusion, we have applied a simple design strategy combining a ditopic donor with two acceptor molecules to synthesize ternary cocrystals. We chose to work with low symmetry carboxyphenols because of the prevalence of carboxylic acids and phenols in pharmaceutical materials. In selecting suitable coformers, we first identified a pair of synthons that had a relatively high likelihood of maintaining fidelity in each other’s presence and then selected the specific acceptor compounds based on their hydrogen bond histories and their relative accepting abilities. A significant feature was the requirement to select solvents in which all three components had similar solubility as the basis for beginning the synthetic work. We quickly discovered that the competition between the various donor/acceptor pairs that complicates the aggregation in binary solutions becomes an even greater issue in ternary systems which may yield, in addition to the desired ternary cocrystal, pure crystals of any of the three components, or binary cocrystals containing two of the three components, often in more than one possible stoichiometric ratio. The crystalline product obtained is the result of a complicated interplay between kinetics and thermodynamics. Thus, we found that a single experiment often yields more than one product and analysis often requires careful sorting of a mixed batch of crystals. With the large number of possible products that could be obtained from a single experiment and the variety of intermolecular forces that contribute to each, the task of synthesizing ternary cocrystals is not trivial. Indeed, for these systems the use of phase diagrams to assist with the isolation of pure material is further complicated by the large design space that would need to be explored. In these experiments, success was achieved by careful adjustment of the composition of the solvent mixture to bring the relative solubility of all three components in line with each other. Our understanding of the role of specific hydrogen bond pairings in producing the acquired ternary cocrystals was assisted by analysis of the hydrogen bond motifs observed in the reactants and in binary cocrystals, as well as by MEP calculations applied to the specific hydrogen bond pairings. For our ternary systems, the hydrogen bond histories of the selected synthons seem to be

*E-mail: [email protected]. Phone: (231) 591-5867. Fax: (231) 591-2545. Funding

This publication has emanated from research conducted with the financial support of Science Foundation Ireland under Grant Numbers 12/RC/2275 and 05/PICA/B802/EC07, and UCC 2013 Strategic Research Fund as well as support from Ferris State University, Research and Professional Development Grants. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS D.A. thanks Ferris State University for sabbatical support. We are grateful to Denis Lynch and Daniel McCarthy for assistance with the NMR data collection and processing.

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REFERENCES

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