Polymorphic Co-crystals from Polymorphic Co ... - ACS Publications

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Polymorphic Co-crystals from Polymorphic Co-crystal Formers: Competition between Carboxylic Acid···Pyridine and Phenol···Pyridine Hydrogen Bonds Andreas Lemmerer,*,§ Daniel A. Adsmond,*,‡ Catharine Esterhuysen,∥ and Joel Bernstein†,⊥ §

Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, Johannesburg 2050, South Africa Faculty of Science, New York University Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates ⊥ Department of Chemistry, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel ∥ Department of Chemistry and Polymer Science, University of Stellenbosch, Matieland 7602, South Africa ‡ Department of Physical Sciences, Ferris State University, Big Rapids, Michigan 49307, United States †

S Supporting Information *

ABSTRACT: The recent literature has shown an increase in the number of co-crystals reported to be polymorphic, with at least 45 such systems identified thus far. The question of whether cocrystals, defined as any multicomponent neutral molecular complex that forms a crystalline solid, are inherently less prone to polymorphism than the individual components is shown to be untrue in four sets of polymorphic co-crystals. The co-crystal formers in this study, acridine, nicotinamide, 3-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, malonic acid, and pimelic acid, are all polymorphic in their unimolecular states and are shown to be dimorphic in the following combinations: (3-hydroxybenzoic acid)·(acridine) [1(I) and 1(II)], (2,4-dihydroxybenzoic acid)· (nicotinamide) [4(I) and 4(II)], (malonic acid)·(nicotinamide) [5(I) and 5(II)], and (pimelic acid)·(nicotinamide) [6(I) and 6(II)]. These co-crystals are assembled primarily using carboxylic acid and phenol hydrogen bond donors that hydrogen bond to pyridine N or amide carbonyl acceptors. Two different combinations of donors and acceptors are primarily responsible for the formation of polymorphs in 1 and 4, whereas conformational differences within the malonic and pimelic acid molecules lead to different packing arrangements using the same combination of hydrogen bonded interactions in 5 and 6. The 1:2 co-crystal of (3hydroxybenzoic acid)·(acridine)2 (2) displays both the phenol O−H···N hydrogen bond observed in 1(I) and the carboxylic acid O−H···N hydrogen bond observed in 1(II). In addition, a methanol solvate of (2,4-dihydroxybenzoic acid)·(nicotinamide) (3) is reported. DFT calculations show that the carboxylic acid···pyridine hydrogen bond is strongest and one of co-crystallization’s most useful interactions.

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moieties)4 and reduce the potential for multiple crystal forms. While chemical intuition can often be a useful basis for chemical thinking and understanding, in this instance, there is no published statistical basis for the claim of reduced polymorphism in co-crystals.4 On the contrary, the lack of data has been noted: “However, it should be stressed that the amount of data available concerning the extent of polymorphism in co-crystals remains minimal”.5 The aim of this contribution is to attempt to put this issue into focus on the basis of currently available structural data and some new experimental evidence. Co-crystals, defined by Bond6 as a multicomponent molecular complex (including materials that have different unimolecular states, that is, solid, liquid, and gas, at room temperature) associate through a variety of intermolecular interactions, a

INTRODUCTION

Co-crystals have been recognized and studied for over a century (Molekülverbindungen), usually under another description. The latter-day recognition of the potential for preparing new materials, improving the solid-state properties of a specific compound, or creating new intellectual property has sparked renewed and heightened interest in the preparation and utilization of co-crystals, especially in the pharmaceutical industry.1 Polymorphism, which is the existence of multiple solid state forms of a compound, plays a significant role in the pharmaceutical industry.2 One of the hoped for advantages of cocrystals over solids of a single chemical moiety (although salts/ hydrates/solvates have also been included in this group) is that they may be less prone to polymorphic behavior.3 There may be some intuitive justification for this suggestion, since we tend to think that the added complexity (and entropy) of the cocrystallization of two or more components would increase the structural specificity (or self-complementarity of the chemical © XXXX American Chemical Society

Received: April 26, 2013 Revised: July 19, 2013

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dx.doi.org/10.1021/cg4006357 | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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imply that if a carboxylic acid is present along with an alcohol or phenol, the two donors will compete to interact with the pyridine.19b In another study,15b examination of 28 co-crystals in the CSD containing m- or p-hydroxybenzoic acid yielded 19 hydroxybenzoic acid molecules in which both the acid and phenol hydrogen bond to the coformer, 3 in which only the acid forms a hydrogen bond to the conformer, and 7 in which only the phenol forms a hydrogen bond to the coformer. Slight changes in experimental conditions could thus yield co-crystals with either carboxylic acid···pyridine or alcohol/phenol···pyridine interactions, each with a distinctly different form. In this report, two different compounds with both acid and phenol groups were co-crystallized with two different pyridinecontaining materials, one with a single pyridine N (acridine) and one more complex, with both a pyridine and an amide carbonyl (nicotinamide), in order to study the subtle influences on the preparation of polymorphic co-crystals. A second aspect investigated was the effect of utilizing symmetrical molecules with two acid functional groups, which can form a hydrogen bonded synthon with the pyridine and amide groups of nicotinamide (Scheme 1). All compounds selected are known

palette that can extend from very strong hydrogen bonds to very weak interactions.7 A search of the recent literature shows that co-crystals are certainly not immune to the phenomenon of polymorphism, with at least 45 documented systems.8 The most encountered so far is five polymorphs in the (furosemide)· (nicotinamide) system.8ll However, there are also studies in which polymorphism was not observed even in a large screen, specifically noted so by the authors.9 In this report, co-crystal polymorphism is limited to polymorphs that have the same ratios (stoichiometries) of the individual molecules. Stoichiometric variations in co-crystals are a separately observed phenomenon occurring also as solid solutions.10 A systematic approach for designing and rationalizing cocrystals has been made by introducing the concept of supramolecular synthesis, where intermolecular interactions are identified that can reliably bring together two distinct molecules in a process akin to organic covalent synthesis.11 The synthon principle used in organic synthesis has been expanded to define analogous “supramolecular” synthons as “structural units within supermolecules, which can be formed and/or assembled by known or conceivable synthetic operations involving intermolecular interactions”.12 The hydrogen bond is arguably the most important intermolecular interaction, and the synthons formed by utilizing those hydrogen bonds can be between the same (homosynthon) and different functional groups (heterosynthon).13 Examples of complementary homosynthons, also known as homomeric interactions, include carboxylic acids, oximes, pyridones, and amides.14 Heterosynthons, which are the key to making co-crystals, have been found to be more prevalent in co-crystals than homosynthons. Common heteromeric interactions in the literature include carboxylic acid···pyridine, acid···amide, and alcohol···pyridine.15 A method of systematizing the interactions in the organic solid state was developed by the late M. C. Etter, who used mathematical graph theory to devise a system of graph sets for describing the motifs observed in hydrogen bonding patterns. Further refinements in the method have been made by Bernstein and co-workers.16 A set of empirical rules was also derived by Etter, which state that (i) all good proton donors and acceptors are used in hydrogen bonding; (ii) six-membered ring intramolecular hydrogen bonds form in preference to intermolecular hydrogen bonds; and (iii) the best proton donors and acceptors remaining after intramolecular hydrogen-bond formation form intermolecular hydrogen bonds. For the latter rule, where first ranked donors and acceptors should interact preferentially, followed by second ranked donor and acceptor, the ranking of the donors and acceptors is not clear-cut and will be discussed further below. Rule iii is particularly relevant for co-crystals, because one can make good guesses as to which functional groups will interact best to create co-crystals. For example, carboxylic acids and phenols are good hydrogen bond donors, and pyridines and amide carbonyl groups are good hydrogen bond acceptors and, as expected from rule iii, they form one of the most successful hydrogen bonding combinations seen for cocrystal formation.17 There are much empirical data that suggests that both carboxylic acids and phenols will hydrogen bond to pyridines. In isolation, both reliably form supramolecular heterosynthons that can assemble to form co-crystals.18,19 If alcohols and phenols are considered together in one group, the limited empirical data suggest that the acid···pyridine interaction is preferred over the alcohol (or phenol)···pyridine hydrogen bond by a small margin when both are present in the crystallizing solution.20 Considering that the difference is slight, this might

Scheme 1. Co-crystal Components of the Four Polymorphic Co-crystal Systems Reported

polymorphic materials or display temperature dependent phase transitions (see below). As such, they are ideal to show that, under ambient conditions, polymorphs are no more or less likely to be observed in bimolecular co-crystals than in unimolecular crystals.

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EXPERIMENTAL PROCEDURES

Compounds. All reagents and solvents were purchased from commercial sources and used without further purification. B



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Table 1. Crystallographic Data for Co-crystals 1(I), 1(II), and 2 formula Mr temp (K) cryst. size (mm3) cryst syst space group (No.) a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z ρ(calcd) (Mg m−3) μ(Mo Kα) (mm−1) θ range (deg) reflns collected no. unique data [R(int)] no. data with I > 2σ(I) final R (I > 2σ(I)) final wR2 (all data) CCDC ref. code formula Mr temp (K) cryst. size (mm3) cryst syst space group (No.) a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z ρ(calcd) (Mg m−3) μ(Mo Kα) (mm−1) θ range (deg) reflns collected no. unique data [R(int)] no. data with I > 2σ(I) final R (I > 2σ(I)) final wR2 (all data) CCDC ref. code formula Mr temp (K) cryst. size (mm3) cryst syst space group (No.) a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg)

1(I)

1(II)

2

(C7H6O3)·(C13H9N) 317.33 293(2) 0.26 × 0.32 × 0.36 monoclinic P21/n 6.807(1) 9.483(2) 24.016(5) 90 94.459(4) 90 1545.6(5) 4 1.364 0.092 1.70−25.50 7910 2860 [0.0206] 2178 0.0472 0.1471 907120 3

(C7H6O3)·(C13H9N) 317.33 293(2) 0.20 × 0.30 × 0.50 triclinic P1̅ 7.091(2) 9.287(2) 12.972(3) 72.937(5) 75.915(5) 80.609(5) 788.3(3) 2 1.337 0.090 1.68−25.50 4338 2873 [0.0222] 1563 0.0452 0.1356 907121 4(I)

(C7H6O3)2·(C13H9N) 496.54 293(2) 0.34 × 0.40 × 0.50 triclinic P1̅ 10.222(3) 11.687(3) 11.903(3) 110.667(5) 99.266(6) 100.742(6) 1266.8(6) 2 1.302 0.084 1.89−25.50 6962 4621 [0.0261] 2301 0.0484 0.1630 907122 4(II)

(C6H6NO2)·(C7H7O3)·(CH3OH) 308.29 213(2) 0.18 × 0.40 × 0.48 triclinic P1̅ 7.042(6) 7.280(6) 14.536(11) 77.36(2) 80.549(2) 65.51(2) 659.5(9) 2 1.552 0.123 2.88−25.49 4378 2425 [0.0278] 1616 0.0642 0.1944 907123 5(I) 5(II) (C6H6NO2)2·(C3H4O4) 348.32 293(2) 0.24 × 0.26 × 0.50 orthorhombic Pna21 32.783(3) 4.0815(3) 12.4392(7) 90 90 90

(C6H6NO2)2·(C3H4O4) 348.32 293(2) 0.08 × 0.26 × 0.55 monoclinic P21/c 11.804(3) 5.336(1) 25.121(6) 90 94.484(5) 90 C

(C6H6NO2)·(C7H7O3) 276.25 293(2) 0.14 × 0. 52 × 0.64 triclinic P1̅ 5.8411(9) 8.170(1) 13.418(2) 96.617(5) 91.353(4) 94.753(7) 633.5(2) 2 1.448 0.113 1.53−25.50 5949 2338 [0.0294] 1555 0.0416 0.1269 907124 6(I) (C6H6NO2)·(C7H12O4) 282.29 180(2) triclinic P1̅ 5.4425(1) 7.3981(2) 17.9304(6) 99.568(2) 94.075(2) 104.177(2)

(C6H6NO2)·(C7H7O3) 276.25 293(2) 0.26 × 0.26 × 0.56 monoclinic P21/c 12.464(3) 8.286(2) 12.665(3) 90 109.579(5) 90 1232.3(4) 4 1.489 0.116 1.73−25.50 6034 2285 [0.0469] 1353 0.0484 0.1011 907125 6(II) (C6H6NO2)·(C7H12O4) 282.29 293(2) 0.04 × 0.36 × 0.40 orthorhombic Pna21 8.838(3) 31.514(8) 5.252(2) 90 90 90



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Table 1. continued V (Å3) Z ρ(calcd) (Mg m−3) μ(Mo Kα) (mm−1) θ range (deg) reflns collected no. unique data [R(int)] no. data with I > 2σ(I) final R (I > 2σ(I)) final wR2 (all data) CCDC ref. code

5(I)

5(II)

1664.4(2) 4 1.390 0.110 2.06−25.50 8232 1601 [0.0234] 1386 0.0386 0.1107 907126

1577.5(7) 4 1.467 0.116 1.63−25.50 8720 2942 [0.0322] 1908 0.0384 0.1103 724143

(3-Hydroxybenzoic Acid)·(Acridine) Co-crystals 1(I), 1(II), and 2. Note: All co-crystal stoichiometries list 3-hydroxybenzoic acid followed by acridine. We have grown crystals by slow evaporation of 1:1 and 1:2 solutions of 3-hydroxybenzoic acid and acridine from a variety of solvents at room temperature.21 When mixed solvents were used, the mixture was selected such that the solvent in which the reactants were most soluble had the lower boiling point. As the concentration of the better solvent decreased, the co-crystal precipitated out of solution.22 Five distinctly different 3-hydroxybenzoic acid/acridine co-crystals were obtained from 26 crystallizations using 16 different solvents and solvent mixtures. All products were characterized by FTIR (KBr pellet) and Xray powder diffraction. Three of the co-crystals have been characterized by single-crystal X-ray diffraction and are reported here: a dimorphic 1:1 co-crystal and one 1:2 co-crystal. The 1:1 (form I) co-crystals are obtained by slow evaporation of 1:1 or 1:2 solutions in 1:4 acetone/ toluene or concomitantly with the 1:2 co-crystal from a 1:2 solution in 1:2 acetone/cyclohexane. The 1:1 (form II) co-crystals are obtained from a 1:1 solution in 1:2 acetone/cyclohexane. The 1:2 co-crystal has been the most prolific, appearing in 19 of 26 crystallizations from all but two solvent mixtures. The fourth and fifth co-crystals, a 2:9 hydrate and a 3:2 co-crystal, will be discussed in a future paper on the influence of solvent on the formation of m-hydroxybenzoic acid/acridine cocrystals.21 The structure of the 3:2 co-crystal has also been solved from the powder.21 (2,4-Dihydroxybenzoic acid)·(nicotinamide)·(methanol) 1:1 Co-crystal 3. Nicotinamide (0.100 g, 0.819 mmol) and 2,4dihydroxybenzoic acid (0.120 g, 0.779 mmol) were dissolved in 5 mL of methanol. Large, colorless block crystals that lose methanol upon standing at ambient conditions were formed. (2,4-Dihydroxybenzoic acid)·(nicotinamide) 1:1 co-crystals, 4(I) and 4(II). Nicotinamide (0.100 g, 0.819 mmol) and 2,4dihydroxybenzoic acid (0.120 g, 0.779 mmol) was dissolved in 5 mL of tetrahydrofuran. Plate-like, colorless form 4(I) and block-like, colorless form 4(II) crystals appeared concomitantly. Form 4(II) was also obtained from ethanol, isopropanol, 2-butanone, cyclopentanone, and nitromethane. (Malonic acid)·(nicotinamide)2 1:2 Co-crystals, 5(I) and 5(II). Nicotinamide (0.200 g, 1.64 mmol) and malonic acid (0.085 g, 0.817 mmol) were dissolved in 8 mL of acetonitrile. Plate-like, colorless crystals of both forms 5(I) and 5(II) appeared concomitantly within a few hours. (Pimelic acid)·(nicotinamide) 1:1 Co-crystals, 6(I) and 6(II). The co-crystal of form 6(I) was synthesized by Karki et al.10d and its synthesis is included here. The stoichiometric ratio of acid to nicotinamide was 1:1, and the solvent was a 1:1 mixture of nitromethane and ethanol. Form 6(II) was grown by dissolving a 2:1 mixture of nicotinamide and acid (0.100 g (0.819 mmol) of nicotinamide and 0.065 g (0.405 mmol) pimelic acid) in 5 mL of methanol. Powder X-ray Diffraction. The X-ray data were collected on a Philips 1050 powder diffractometer using Cu Kα1 radiation and a graphite monochromator on diffracted beam, operating at 40 kV, 30 mA on a flat sample holder. X-ray Crystallography. Intensity data were collected on a Bruker SMART 1K CCD23 area detector diffractometer with graphite

6(I) 685.49(3) 2 1.368

6741 2390 2156 0.035 0.092 ref 10d

6(II) 1462.7(9) 4 1.282 0.099 2.39−25.49 7309 1525 [0.0998] 725 0.0909 0.3072 724144

monochromated Mo Kα1 radiation (λ = 0.71073 Å; 50 kV, 30 mA) and performed at T = 293 or 213 K. The collection method involved ωscans of width 0.3°. Data reduction was carried out using the program SAINT+,24 and empirical absorption corrections were made using the program SADABS.24 In all cases, the structures were solved in the WinGX25 suite of programs with direct methods using SHELXS-97.26 Non-hydrogen atoms were first refined isotropically followed by anisotropic refinement by full matrix least-squares calculations based on F2 using SHELXL-97.26 Hydrogen atoms were first located in a difference map and thereafter all CH and OH hydrogen atoms were positioned geometrically and allowed to ride on their respective parent atoms and their isotropic thermal parameters were assigned as 1.2 or 1.5 times those of their parent atoms. Diagrams and publication material were generated using ORTEP-3,27 PLATON,28 and DIAMOND.29 Further crystallographic data are summarized in Table 1. Computational Details. Geometry optimizations were performed with Gaussian 0930 using the BP86 method,31 a density functional theory (DFT) type of calculation with hybrid functionals, and the 631G(d) basis set.32 Single point energies of pairs of molecules were calculated utilizing the M06-2X density functional type of calculation33 with the 6-31+G(d)32 basis set. Basis set superposition errors were corrected using the counterpoise method. 34 The strength of intermolecular interactions [ΔE(int)] was calculated at the M06-2X/631+G(d) counterpoise corrected level of theory by placing pairs of molecules, with hydrogen atom positions optimized, in the same relative orientations as found in the crystal structures and calculating as follows: ΔE(int) = E(dimer) − E(molecule1) − E(molecule2)

(1)

where E(molecule1) and E(molecule2) are the energies of the two molecules involved in the intermolecular interactions. CSD Searches. All searches were done in the CSD version 5.33 database (2012) with Feb, May, and August updates.35

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RESULTS Polymorphic Behavior of 3-Hydroxybenzoic Acid and Acridine and Rationalization of Their Co-crystallization. The hydrogen-bonding behavior of carboxylic acids has been well studied and in the absence of competing groups, carboxylic acids are known to form centrosymmetric R22(8) rings16 in the majority of crystal structures.36 The hydrogen bonding of phenols has also been well studied: they typically hydrogen bond to each other in C(2) chains or in finite R44(8) and R66(12) rings.37 One might expect, then, that if these two typical patterns were conserved, 3-hydroxybenzoic acid would crystallize forming both an R22(8) ring and a C(2) chain. A structure search of the 2012 version of the Cambridge Structural Database (CSD) for 3hydroxybenzoic acid38 (organics only) yielded 29 hits: two 3hydroxybenzoic acid polymorphs, 21 co-crystals, and 6 co-crystal hydrates. The first 3-hydroxybenzoic acid polymorph, BIDLOP, has the expected R22(8) ring and C(2) chain.39 However, in the second polymorph, BIDLOP01, the carboxylic acid proton forms D



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a hydrogen bond to the phenol oxygen forming a C(7) chain, while the phenol proton forms a hydrogen bond to the acid carbonyl in a D hydrogen bond. Together they form, at the second level, an R33(13) ribbon (See Figure 1).40

pyridine acceptor and thus immediately raises the question of the possibility of 3-hydroxybenzoic acid co-crystal polymorphism. Since the same sets of functional groups yield different sets of hydrogen-bond pairings in different crystals, would it not be likely to find a polymorph of the 3-hydroxybenzoic acid/ isonicotinamide co-crystal containing the hydrogen-bond pattern found in the 3-hydroxybenzoic acid/nicotinamide cocrystal (and vice versa)? One can easily imagine aggregates of each pattern in solution. Acridine, which has a good hydrogen-bond acceptor functionality with its pyridine N, is known to be polymorphic as well,41 with the crystal structures of five of the six known polymorphs of acridine appearing in the CSD, form II (ACRDIN01,42 ACRDIN0443), form III (ACRDIN,44a ACDRDIN0744b), form IV (ACRDIN0844b), form VI (ACRDIN0543), and form VII (ACRDIN0643). Only the unit cell constants of form V are reported.45 Form I is in fact the hydrate of acridine, and its crystal structure and history has been described recently.46 Although polymorphic forms II, III, and VII are in the same space group, they clearly afford different packing motifs (Figure 2). Form II shows a regular stacked packing and Form III a

Figure 1. (a) The first polymorph of 3-hydroxybenzoic acid has a ribbon that is formed by the carboxylic acid R22(8) dimer and C(2) hydrogen bonded chains. Both the R22(8) and C(2) are in accord with Etter’s rules. (b) The second polymorph of 3-hydroxybenzoic acid with a carboxylic acid···phenol hydrogen bond forming a C(7) chain and a phenol··· carbonyl discrete hydrogen bond. Combined, they form a ribbon with repeating R33(13) rings. Note: The deposited crystal structure of the second polymorph does not list fractional coordinates for the phenol H atom.

Scheme 2 shows the lack of selectivity between the carboxylic acid proton and the phenol proton of 3-hydroxybenzoic acid in the presence of molecules containing both an amide and a

Figure 2. Partial packing diagrams of four of the polymorphic forms of acridine.

herringbone packing, whereas forms VI and VII exhibit a zigzag or perpendicular arrangement of dimeric and tetrameric units, respectively. Acridine co-crystals are much more numerous than 3hydroxybenzoic co-crystals (39 in the CSD),47 with acridine acting as an acceptor for a variety of hydrogen bonding donors including phenol protons (7),48 carboxylic acid protons (15),49 and amine protons (3),50 halogen bonding donors such as Br and I (6),51 and weaker interactions such as C−H···N, C−H···O, and π-stacking (7).52 It is noteworthy that in two acridine co-crystal systems, there are co-crystals with different stoichiometries for a single co-crystal former. In the co-crystals between acridine and phenothiazine, which have only one acceptor and donor site, respectively, both yellow 3:4 (NIWCEB) and red 1:1 (NIWCIF) co-crystals are formed.53 Both have the same N−H···N hydrogen bonding. The co-crystal system between acridine and pyromellitic dianhydride has both a 1:1 (BIHBUP10) and 2:1

Scheme 2. Hydrogen Bonding Patterns in 3-Hydroxybenzoic Acid Co-crystals with Isonicotinamide (LUNMEM) and Nicotinamide (XAQQIQ)

E



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(BIWVUY) adduct.54 The former has C−H···O hydrogen bonds whereas the latter makes use of C−H···N hydrogen bonds. In the only acridine co-crystal structure containing a partner molecule with both alcohol and carboxylic acid moieties (OVUFUH), the acridine forms a hydrogen bond with the carboxylic acid proton, leaving the alcohol to hydrogen bond to the acid carbonyl. Interestingly, in the 5-methylbenzene-1,3-diol 4,4′-bipyridine hemikis(acridine) ternary co-crystal (UBUJUY), both of the phenolic protons hydrogen bond to the two bipyridine nitrogens leaving the acridine with no corresponding hydrogen bond donor. On the basis of the published structures of 3-hydroxybenzoic acid, one can predict that since it is a ditopic hydrogen-bond donor compound it may potentially form co-crystals with appropriately selected monoacceptor compounds such as acridine. In addition, it could potentially hydrogen bond to the acridine through the carboxylic acid (Figure S1a, Supporting Information) or the phenol (Figure S1b, Supporting Information) to form 1:1 complexes, or both the carboxylic acid and phenol protons could hydrogen bond to acridine to yield a 1:2 complex (Figure S1c, Supporting Information). One might expect that solutions containing the compounds in a 1:1 ratio would preferentially yield 1:1 co-crystals while solutions containing twice the molar concentration of acridine would preferentially yield the 1:2 co-crystals. One might also invoke the best donor/best acceptor rules to predict that 3-hydroxybenzoic acid would preferentially hydrogen bond to the best acceptor present through its best donor, the carboxylic acid proton. The two donors of 3-hydroxybenzoic acid differ greatly in their pKa’s with the carboxylic acid proton having a pKa1 of 4.08 which is 6 orders of magnitude more acidic than the phenol proton (pKa2 = 9.92).55 Hydrogen-bond donating ability has been roughly correlated with pKa for protons bonded to the same heteroatom, and with a difference in magnitude of 106, the carboxylic acid is identified as the better of the two donors by this method. It should be noted that electrostatic potentials have also been used to quantify donating and accepting abilities and can contradict or substantiate the intuitive arguments based on pKa’s.56 Polymorphic Behavior of Nicotinamide, 2,4-Dihydroxybenzoic Acid, Malonic Acid, and Pimelic Acid and Rationalization of Their Co-crystallization. Nicotinamide has been reported to exist in four polymorphic forms, obtained by recrystallizing the commercially available form I (melting point 126−128 °C) from the melt and obtaining a mixture of three forms II (112−117), III (107−111) and IV (101−103).57 Form I is the stable one, and the remaining three are all metastable to it. Until recently only one crystal structure had been obtained in a number of structure determinations (Figure S2, Supporting Information), which was assumed to be form I (NICOAM, NICOAM01, NICOAM02, NICOAM03);58a,b however the structure of a metastable form has now been identified,58c which appears to correspond to form III, based on its melting point. In form I, the anti NH of nicotinamide forms C(4) hydrogen bonded chains with the carbonyl O. Adjacent chains are connected in a 2D network through C(6) chains formed by a hydrogen bond from the syn-H to the pyridine N. Form III has four symmetry independent nicotinamide molecules. In all four molecules, the roles of syn and anti protons are reversed from their roles in form I. It is the syn NH that forms a hydrogen bond to the amide carbonyl in all four molecules of form III resulting in R22(8) rings for three of the four.58c The four anti NH protons hydrogen bond to pyridine nitrogens joining sets of four molecules in R44(24) rings.

The three carboxylic acids used here in the co-crystallization experiments with nicotinamide all exist in either multiple temperature dependent phases (malonic and pimelic acid) or are polymorphic (2,4-dihydroxybenzoic acid). 2,4-dihydroxybenzoic acid has three polymorphs. The first form was described in 1956 by Giacomello and co-workers, but only unit cell data and no structural details were reported (ZZZEEU);59 it is most likely a hemihydrate.60 Subsequently, a new form was reported in 2007 by Parkin and co-workers (ZZZEEU07).61 They were unable to grow crystals of the form reported by Giacomello but instead found an anhydrous form, crystallized from acetone. This form consists of hydrogen bonded R22(8) dimers of the carboxylic acid groups and an intramolecular S(6) hydrogen bond of the phenol in the 2-position. Adjacent dimers are connected by an O−H···O bond from the phenol in the 4-position to the O atom of the phenol in the 2-position (Figure S2, Supporting Information). A second anhydrous polymorph form, published in 2011, exhibits the same hydrogen-bonding patterns as form II but with a puckering of the hydrogen-bonded sheets.60 Malonic acid and pimelic acid exhibit multiple temperature dependent phase transitions before their melting points.62 Both exist in three phases, α, β, and γ. Only the detailed crystal structure of the α phase of malonic acid is known (MALNAC02)63 and its crystal packing consists of 1-D chains of dimeric R22(8) carboxylic acid hydrogen bonds (Figure S2, Supporting Information). The single crystal structures of the α (PIMELA05)64 and γ (PIMELA03)65 forms of pimelic acid have been determined (Figure S2, Supporting Information). Both forms consist of R22(8) dimers and form 1-D chains. The differences between the two forms is seen in the conformations of the carboxylic acid end groups, being different from each other in the α form (torsion angles O3−C7−C6−C5 7.6(1)° and O1−C1−C2−C3 −143.2(1)°) and identical to each other in the γ form (O1− C1−C2−C3 19.84°). There is extensive literature regarding the co-crystals of carboxylic acids and pyridine-containing molecules such as nicotinamide.66 Nicotinamide was selected for co-crystallization with our didonor molecules because it has two good acceptor atoms, a pyridine N and carbonyl O. It also has two amide protons, as does its related isomer isonicotinamide.67 A search of the CSD for co-crystals containing nicotinamide and a carboxylic acid yielded 42 structures.68 The most commonly observed hydrogen bonding motif, where the carboxylic acid forms a hydrogen bond to the pyridine N and the amide forms an R22(8) dimer with itself, is found in the majority (33/42) of structures. In a few cases in which an alternative hydrogen bonding donor exists, the carboxylic acid and amide form a heteromeric R22(8) dimer (seen in 17/42 structures). In a third motif, the amide forms a C(4) chain while the carboxylic acid forms a hydrogen bond to the pyridine (7/42 structures). Nicotinamide is featured as a co-crystal former in the most polymorphic co-crystal system to date, with five polymorphs.8ll In the particular case of dicarboxylic acid/nicotinamide cocrystals, there are two predicted patterns of aggregation,10d illustrated for the case of malonic acid and nicotinamide in Figure S3a, Supporting Information. The first is a 1:1 motif where diacid molecules alternate with nicotinamide molecules in a hydrogenbonded chain with one acid group hydrogen bonding to a pyridine nitrogen and the other forming an R22(8) heterodimer with the amide. The second is a 1:2 motif where both carboxylic acids (best donors) hydrogen bond to the pyridine nitrogens (best acceptors) leaving the amides to hydrogen bond to each other in a homomeric R22(8) ring (Figure S3b, Supporting F



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Information). Pimelic acid has been used in numerous cocrystallization experiments and shows evidence of polymorphic behavior. For example, three polymorphs of the (pimelic acid)· (4,4′-bipyiridine) co-crystal (XOLHUC, XOLHUC01, and XOLHUC02) have been reported.8p The co-crystal of pimelic acid with hexamethylenetetramine, meanwhile, has two phase transitions between liquid nitrogen and its melting point (IJETOG, IJETOG01, IJETOG02).8h Thus, there is a precedent for attempting to co-crystallize nicotinamide and pimelic acid in order to test for polymorphism. To date, there are no reported polymorphic co-crystals involving malonic acid. 2,4-Dihydroxybenzoic acid is a tritopic hydrogen-bond donor compound because it has three hydrogen bond donors, a carboxylic acid and two phenol protons. However, because the phenol group at the 2 position is expected to preferentially form an S(6) intramolecular hydrogen bond (following Etter’s rule ii) to one of the O atoms of the carboxylic acid, the compound behaves as a ditopic donor for co-crystallization.16a The two remaining donors on the 2,4-dihydroxybenzoic acid have the same two possibilities for interacting with the two acceptors of nicotinamide as seen in Scheme 2 for the 3-hydroxybenzoic acid co-crystals. As described previously in the diacid/nicotinamide paragraph, a 1:1 pattern could form where didonor molecules alternate with nicotinamide molecules in a hydrogen-bonded chain (Figure S4a, Supporting Information). Here, though, there are two possibilities for didonor orientation. The acid could hydrogen bond to the pyridine, while the phenol forms a hydrogen bond to the amide or vice versa. A second possibility is a 1:2 motif where both the acid and the phenol (the two best donors) hydrogen bond to the pyridine nitrogens (best acceptors) leaving the amides to hydrogen bond to each other in a homomeric R 22 (8) ring (Figure S4b, Supporting Information).69 Crystal Structure of 1:1 (3-Hydroxybenzoic acid)· (acridine) Co-crystal, Form 1(I). The asymmetric unit consists of one molecule each of 3-hydroxybenzoic acid and acridine, both on general positions (Figure 3a). C−O bond lengths of 1.231(2) and 1.273(2) Å in the carboxylic acid group indicate that proton transfer has not occurred. The carboxylic acid of the 3-hydroxybenzoic acid forms a hydrogen bond with a neighboring acridine molecule (O···N distance 2.552(2) Å), while the phenol forms a hydrogen bond to the acid carbonyl of the screw-related molecule forming C(7) chains (O···O distance 2.650(2) Å) (Figure 4a; Table S1, Supporting Information). The acridine molecule borders the C(7) chains, thus creating 1-D ribbons extending along the crystallographic b-axis. C−H···O hydrogen bonds join atom H12 of acridine with the phenolic oxygen O3 and H14 of acridine with the acid carbonyl O2. The carboxylic acid···pyridine hydrogen bond is joined by two C− H···O hydrogen bonds between H9 and H19 of the acridine and O1 of the acid (C···O distances 3.390(3) and 3.494(3) Å, C−H··· O angles 125° and 123°, respectively). Inversion-related acridine molecules associate by face-to-face π-stacking along the a-axis (Cg···Cg, 3.581(1) Å). Crystal Structure of 1:1 (3-Hydroxybenzoic Acid)· (Acridine) Co-crystal, Form 1(II). The asymmetric unit consists of one molecule each of 3-hydroxybenzoic acid and acridine, both on general positions (Figure 3b). The phenolic proton of 3-hydroxybenzoic acid forms a hydrogen bond to neighboring acridine molecules, while inversion-related carboxylic acid groups hydrogen-bond together forming R22(8) rings resulting in a hydrogen-bonded tetramer. The tetramers are bonded to one another via a C−H···O hydrogen bond between

Figure 3. Ortep diagrams of the asymmetric units of the three co-crystals of 3-hydroxybenzoic acid and acridine in a 1:1 ratio, (a) 1(I) and (b) 1(II), and (c) a 1:2 ratio. Hydrogen bonds are indicated by dashed lines.

H17 of acridine and the phenolic oxygen to form a 1-D ribbon (Figure 4b, Table S1, Supporting Information). Inversion-related acridine molecules associate by π-stacking along the a-axis (Cg··· Cg, 3.609(2) Å). Crystal Structure of 1:2 (3-Hydroxybenzoic Acid)· (Acridine)2 Co-crystal (2). The asymmetric unit consists of one molecule of 3-hydroxybenzoic acid and two molecules of acridine, all on general positions (Figure 3c). Again, C−O bond lengths for the carboxylic acid group of 1.206(3) and 1.313(3) Å indicate that proton transfer has not occurred. Both the carboxylic acid proton and the phenol proton of the 3hydroxybenzoic acid form O−H···N hydrogen bonds with G



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Figure 5. The hydrogen bonding patterns in 2.

nicotinamide, and a methanol solvent molecule, all on general positions (Figure 6a). C−O bond lengths of 1.193(3) and

Figure 4. Different hydrogen bonded ribbons due to the different associations between the hydrogen bond donors and acceptors in (a) form 1(I) of the 1:1 co-crystal between 3-hydroxybenzoic acid and acridine and (b) form 1(II).

neighboring acridine molecules forming a hydrogen-bonded trimer. The carboxylic acid forms a hydrogen bond to an acridine molecule (acridine 1) with an O···N distance of 2.627(2) Å and an O−H···N angle of 169°. The phenolic proton hydrogen bonds to an acridine molecule (acridine 2) (O···N distance = 2.747(2) Å, O−H···N angle = 174°). Inversion-related trimers are joined by R22(8) rings connecting the aromatic proton between the acid and phenol groups to the phenolic oxygen of the neighboring molecule (C···O distance is 3.499(3) Å; C−H···O angle is 165°). In addition, the pairs of inversion-related trimers associate through parallel π-stacking of the acridines at each end of the trimer. Each acridine pair stacks with another inversion-related acridine pair forming stacks of four acridine molecules throughout. The inversion-related pairs receive further stabilization from the O−H···N and C−H···O hydrogen bonds previously mentioned, which join two acridines in an R44(18) ring. These trimers extend along the [101] direction to form 1-D ribbons (Figure 5, Table S1, Supporting Information). An additional C−H···O hydrogen bond (C···O distance = 3.457(3) Å, C−H···O angle = 146°) is formed between atom H14 of acridine 1 and the carbonyl oxygen (O2) of an inversion-related 3-hydroxybenzoic acid molecule. A third C−H···O hydrogen bond (C···O distance = 3.736(3) Å, C−H···O angle = 154°) is formed between H17 of acridine 1 and the carbonyl of an inversion-related 3-hydroxybenzoic molecule. Crystal Structure of 1:1 (2,4-Dihydroxybenzoic Acid)· (Nicotinamide)·(Methanol) Co-crystal (3). The asymmetric unit consists of a molecule of 2,4-dihydroxybenzoic acid, one

Figure 6. Ortep diagrams of the asymmetric units of the three co-crystals of 2,4-dihydroxybenzoic acid and acridine: (a) with methanol solvate, 3, (b) 4(I), and (c) 4(II). Hydrogen bonds are indicated by dotted lines. The disorder of the OH group in the 2-position is shown in panel c.

1.273(3) Å for the carboxylic acid group show that proton transfer has not occurred. 2,4-Dihydroxybenzoic acid has an intramolecular hydrogen bond, from the phenol O4 in the 2 position to the carbonyl O2 of the acid group. There is an intermolecular hydrogen bond between the carboxylic acid of the 2,4-dihydroxbenzoic acid and the pyridine N of the nicotinamide, while two nicotinamide molecules form a homodimer through the syn H of the amide. The anti H forms a hydrogen bond to the phenol oxygen (O4), while the methanol forms a hydrogen bond to the carbonyl of the amide group (O5). The combination of these intermolecular hydrogen bonds leads to a complex 3-D hydrogen bonded network (Figure 7, Table S2, Supporting Information). Four weaker C−H···O interactions further stabilize the structure. The phenol in the 2-position (O4) does not act as a hydrogen bond acceptor. H



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groups, forms a centrosymmetric R22(8) dimer to the alcohol oxygen O3 (C···O distance = 3.568(2) Å, C−H···O angle = 151°), and H11 forms a hydrogen bond to the carboxylic acid oxygen O1 (C···O distance = 3.361(2) Å, C−H···O angle = 151°). The latter hydrogen bond forms a centrosymmetric R44(14) ring together with the O−H···O hydrogen bond of the heterodimer mentioned previously. The 2-D hydrogen bonded sheets stack in a parallel manner on top of each other, with a separation of 3.383(1) Å. There are no π-stacking interactions because all of the aromatic rings are offset from each other. Crystal Structure of 1:1 (2,4-Dihydroxybenzoic Acid)· (Nicotinamide) Co-crystal Form 4(II). The asymmetric unit is the same as that in 4(I) and consists of one molecule each of 2,4dihydroxybenzoic acid and nicotinamide, both on general positions (Figure 6c). C−O bond lengths of 1.225(2) and 1.315(2) Å for the carboxylic acid group show that proton transfer has not occurred. The phenol group on the 2-position of 2,4-dihydroxybenzoic acid molecule is disordered over both the 2 and 6 positions on the phenyl ring with refined occupancies of 50%. In both cases, the disordered OH forms an intramolecular S(6) hydrogen bond to the closest O atom of the carboxylic acid group. The hydrogen bonding interactions of the amide group of the nicotinamide are unlike any of the other nicotinamide cocrystals reported in this study or the previously published nicotinamide co-crystals. Instead of forming a homomeric dimer with itself or a heteromeric dimer with the carboxylic acid molecule, it forms a C22(6) chain through N−H···O and O−H··· O hydrogen bonds between the anti H on the amide on the nicotinamide and the phenol H in the 4-position on the 2,4dihydroxybenzoic acid molecules. The chain extends along the c axis (Figure 8b, Table S2, Supporting Information). 2,4Dihydroxybenzoic acid molecules hydrogen bond to the chain of nicotinamide molecules through the carboxylic acid H to the pyridine N1 atom and through an N−H···O hydrogen bond from the syn H on the amide to the carbonyl O2. This generates a complex 3-D hydrogen bonded pattern. There are two C−H···O interactions. The phenol O4 in the 2-position does not act as a hydrogen bond acceptor. Crystal Structure of 1:2 (Malonic Acid)·(Nicotinamide) Co-crystal Form 5(I). The asymmetric unit consists of one molecule of malonic acid and two molecules of nicotinamide, all on general positions (Figure 9a). C−O bond lengths of 1.196(4) and 1.306(4) Å and of 1.210(4) and 1.291(4) Å for the two carboxylic acid groups show that proton transfer has not occurred. The crystal structure consists of a 3-D hydrogen bonded network, generated through two carboxylic acid··· pyridine interactions, the amide homomeric dimer, and amide···carbonyl hydrogen bonds from the amide to the malonic acid (Figure 10a, Table S3, Supporting Information). There is one C−H···O interaction. While this work was in progress, this structure was reported concurrently by Karki et al.,10d and the relevance of this paper will be discussed in more detail below. Crystal Structure of 1:2 (Malonic Acid)·(Nicotinamide) Co-crystal Form 5(II). The contents of the asymmetric unit are the same as 5(I) (Figure 9b), but the spatial arrangement is clearly different. C−O bond lengths of the two carboxylic acid groups of 1.212(2) and 1.291(2) Å and of 1.216(2) and 1.308(3) Å show that proton transfer has not occurred. The crystal structure consists of a 3-D hydrogen bonded network, generated through two carboxylic acid···pyridine interactions, the nicotinamide homomeric dimer, and amide···carbonyl hydrogen bonds from the amide to the malonic acid (Figure 10b, Table S3, Supporting Information). The carboxylic acid proton H3 is in

Figure 7. The pattern of hydrogen bonded interactions in 3.

Crystal Structure of 1:1 (2,4-Dihydroxybenzoic Acid)· (Nicotinamide) Co-crystal Form 4(I). Because the methanol solvate formed from methanol, we used an aprotic solvent that would not hydrogen bond to the phenol group as in 3, and thus tetrahydrofuran was chosen as the solvent for 4(I). The asymmetric unit consists of one molecule each of 2,4dihydroxybenzoic acid and nicotinamide, both on general positions (Figure 6b). C−O bond lengths for the carboxylic acid group of 1.237(2) and 1.316(2) Å show that proton transfer has not occurred. The phenol forms a hydrogen bond through H4 to the best acceptor, the pyridine N, whereas the amide and carboxylic acid groups form a R22(8) heterodimer, resulting in a 1D chain along the c-axis. The chains assemble into 2-D sheets through two C−H···O interactions along the a-axis (Figure 8a, Table S2, Supporting Information). H3, ortho to the two phenol

Figure 8. (a) In form 4(I), 2-D sheets are formed, whereas (b) in 4(II), a more complex 3-D pattern is observed, part of which is shown. Note the uncommon carboxylic acid···amide heterodimer in 4(I), while in 4(II), the more common carboxylic acid···pyridine heterosynthon is seen. I



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Figure 10. The packing of the two polymorphic co-crystals of nicotinamide with malonic acid 5(I) (a) and 5(II) (b). Both have the carboxylic acid···pyridine hydrogen bond and the amide···amide homodimer but have very different packing architectures.

Figure 9. The asymmetric units of the polymorphic co-crystals 5(I) and 5(II). The stoichiometries of the two are identical, but the conformations of the malonic acid molecules differ. The conformation of form I has both carboxylic protons syn, whereas form II has one syn and one anti.

the anti position, a rarely observed conformation of carboxylic acids (see below). Since the strong hydrogen bonding interactions are identical to form I, the conformational change from the syn to the anti position is the major structural difference between the two forms. This form II also features a much larger number of C−H···O interactions than form I. Crystal Structure of 1:1 (Pimelic Acid)·(Nicotinamide) Co-crystal Form 6(I). As noted above, this structure was reported by Karki et al.10d while this work was in progress. The asymmetric unit consists of one molecule of pimelic acid and one molecule of nicotinamide, both on general positions (Figure 11a). C−O bond lengths of 1.204(2) and 1.334(2) Å and of 1.221(2) and 1.311(2) Å of the two carboxylic acid groups show that proton transfer has not occurred. The crystal structure consists of 1-D ribbons, generated through one carboxylic acid··· pyridine interaction, an acid···amide R22(8) heterodimer, and a R24(8) tetramer70 formed by two amide and two acid groups (Figure 12a, Table S3, Supporting Information). Crystal Structure of 1:1 (Pimelic Acid)·(Nicotinamide) Co-crystal Form 6(II). The asymmetric unit consists of one molecule of pimelic acid and one molecule of nicotinamide, both on general positions (Figure 11b). C−O bond lengths of 1.196(4) and 1.306(4) Å and of 1.210(4) and 1.291(4) Å for the two carboxylic acid groups show that proton transfer has not occurred. The crystal structure consists of a 2-D hydrogen bonded sheet, generated through one carboxylic acid···pyridine interaction, an acid···amide R22(8) heterodimer, and amide· R22(8)··carbonyl hydrogen bonds from the amide to the pimelic acid (Figure 12b, Table S3, Supporting Information). There are two weak C−H···O interactions.

Figure 11. The asymmetric units of the polymorphic co-crystals 5(I) and 5(II). The stoichiometries of the two are identical, but the conformations of the pimelic acid molecules differ.

Calculation of Hydrogen Bond Strength. The strength of all the primary hydrogen bonds observed in the crystal structures of 1(I) to 6(II) were calculated at the M06-2X/6-31+G(d,p) level of theory, with basis set superposition error taken into account by utilizing counterpoise corrections. Pairs of molecules involved in hydrogen bonds were utilized for the calculations, with the hydrogen atom positions optimized at the BP86/631G(d) level of theory prior to single point calculations at the M06-2X/6-31+G(d,p) level. The results are listed in Table 2. J



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distance that appears to play the greatest role in the hydrogen bond strength with the shortest O···N distances corresponding to the strongest hydrogen bonds (see Table 2). It is nevertheless clear from Table 2 that this is not the only factor involved. For instance, in co-crystal 4(II), the second conformation of the disordered 2,4-dihydroxybenzoic acid molecule forms an amide to carboxylic acid N−H···O hydrogen bond that is almost 8 kJ mol−1 stronger than the first despite the fact that the O···N distances are identical. Closer inspection of the two structures shows that the greater stabilization of the second conformation is likely due to the donor O−H group also accepting an intramolecular hydrogen bond, that is, cooperative effects may also be involved in adding stabilization. It is also possible that weak C−H···O or C−H···N hydrogen bonds may assist in further stabilizing coplanar molecules, although perhaps at the expense of additional repulsion, which may lengthen the O···N distance. The next strongest attractions after the carboxylic acid··· pyridine hydrogen bonds are the three phenol···pyridine hydrogen bonds. Their energies are similar to those of the weaker carboxylic acid···pyridine hydrogen bonds. This knowledge coupled with the fact that the phenol is the only other donor that hydrogen bonds to the pyridine nitrogen “best acceptor” in this set of structures supports the contention that the phenol is the second best hydrogen bond donor. Following this line of thinking identifies the amide protons as the weakest of the three donor types seen here. Table 2 provides stabilization energies for amide protons hydrogen bonding to three different acceptors: four amide carbonyls, eight acid carbonyls, and four phenol oxygens. The average interaction energies for these three acceptor types are −34.2, −24.6, and −16.6 a kJ mol−1 supporting the following ranking of accepting abilities: amide carbonyl > acid carbonyl > phenol. The fact that no acid OHs act as acceptors in this set of structures supports the following overall ranking of acceptors: pyridine nitrogen > amide carbonyl > acid carbonyl > phenol oxygen > acid OH. The 3-Hydroxybenzoic Acid/Acridine System. The cocrystallization attempts between 3-hydroxybenzoic acid and acridine resulted in five distinct co-crystals, three of which are discussed here and shown in Figure 13. The polymorphic co-crystals with 1:1 stoichiometric ratios are polymorphs arising from the two hydrogen bonding interactions postulated in the Introduction. The carboxylic acid···pyridine hydrogen bond seen in 1(I) was expected because it follows Etter’s empirical rules representing the combination of the best donor/acceptor hydrogen bonding pair, followed by the combination of the second best donor−acceptor pair. The hydrogen-bond connectivity seen in 1(II) however makes use of the phenol···pyridine hydrogen bond, in contradiction to Etter’s rules (if pKa’s are used for ranking the donors.) The formation of this polymorph however should not be seen as a direct failure of Etter’s rule, because it has the archetypical carboxylic acid dimer, which is a well-known hydrogen bonding feature of carboxylic acids in the solid state, being the preferred hydrogen bonding interaction in carboxylic acids.71 If a particular solvent favored the homomeric aggregation of the carboxylic acid dimer over the heteromeric carboxylic acid···pyridine interaction, the relative concentration of available phenol donors would be increased favoring the phenol···pyridine hydrogen bond. In fact, even though the two forms have completely different hydrogen bonding interactions, the architecture of the two co-crystals is similar. Both have the 3-hydroxybenzoic acid molecule in the

Figure 12. The packing of the two polymorphic co-crystals of nicotinamide with pimelic acid 6(I) (a) and 6(II) (b). Both have the carboxylic acid···pyridine hydrogen bond and the acid···amide heterodimer but have very different packing architectures.

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DISCUSSION By variation of the crystallization conditions, it was possible to obtain a number of polymorphic co-crystals with the differences characterized by differing hydrogen bonding patterns and conformations: two co-crystals of 3-hydroxybenzoic acid with acridine and two each of 2,4-dihydroxybenzoic, malonic, and pimelic acids with nicotinamide. In all cases, significantly different C−O distances in the carboxylic acid group indicated that proton transfer had not taken place, confirming the crystals as co-crystals of neutral entitites rather than salts. There are a number of factors that play a role in the formation of polymorphs; we will focus on the influence of hydrogen bonding strength and hydrogen bond donor−acceptor rankings on the co-crystal polymorphs obtained here, as well as conformational changes. Hydrogen Bonding Energies. It is clear from the calculations (Table 2) that the strongest hydrogen bonds in this set of structures are the set of 11 hydrogen bonds between carboxylic acids and pyridine nitrogens. This implies that the acid groups are the best donors in this set of structures, while the pyridine moieties are the best acceptors. This provides a quantitative justification for the earlier empirical observation that the carboxylic acid···pyridine hydrogen bond is a reliable supramolecular synthon,20 with an occurrence probability of more than 90%. Nevertheless, the calculations also indicate that the carboxylic acid···pyridine hydrogen bond varies widely in strength, as can be seen from Table 2, with interaction energies between −70.8 and −46.3 kJ mol−1. The homomeric amide··· amide hydrogen-bonded dimers, on the other hand, are stabilized by almost equal amounts in the different co-crystals. This indicates something of the relative nature of these two synthons: whereas the formation of the amide···amide hydrogen-bonded ring leads to a fairly rigid conformation in most crystal structures [see 3, 5(I), and 5(II)], the carboxylic acid can form a hydrogen bond with the pyridine moiety in a large range of possible orientations, as evidenced by the crystal structures reported here. The carboxylic acid group varies from being coplanar with the pyridine ring [as in 3, 4(II), 5(I), 6(I), and 6(II)] to nearly perpendicular to it [as in 1(I), 2, and 5(II)]. Moreover, the conformational flexibility of the synthon means that the O···N distance can also vary over a substantial range, and it is this K



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Table 2. Interaction Energies and Donor···Acceptor Distances of Intermolecular Hydrogen Bonds (kJ mol−1) Calculated at the M06-2X/6-31+G(d,p) Level of Theorya acceptor 1 pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine carbonyl (acid) carbonyl (nicotinamide) carbonyl (nicotinamide) carbonyl (nicotinamide)

acceptor 2

donor 1

donor 2

crystal

interaction E (kJ mol−1)

O/N···O/N distance (Å)

−70.8 −64.0 −63.1 −62.5 −61.1 −59.3 −58.9 −55.9 −54.6 −51.9 −46.3 −53.0 −50.3 −43.5 −110.2 (−55.1) −42.1 −41.3 −82.3b

2.552(2) 2.569(4) 2.566(3) 2.616(2) 2.590(4) 2.575(2) 2.604(2) 2.627(2) 2.616(2) 2.701(1) 2.637(11) 2.747(2) 2.725(2) 2.720(2) 2.649(2) 2.648(2) 2.648(2) 2.605(1) O···O 2.905(1) N···O 2.580(2) O···O 2.891(2) N···O 2.607(10) O···O 2.912(12) N···O 2.641(4) 2.788(3) 2.929(4) and 2.938(3) 2.896(2) 2.962(2) 2.650(2) 2.525(3) 2.905(1) 2.921(2) 2.936(11) 2.956(4) 2.925(4) 3.039(2) 2.818(2) 2.818(2) 2.954(2) 2.967(4) 3.056(2) 3.056(2)

carbonyl (acid)

acid acid acid acid acid acid acid acid acid acid acid phenol phenol phenol acid phenol phenol acid

amide

1(I) 5(I) 3 4(II)b 5(I) 5(II) 5(II) 2 4(II)a 6(I) 6(II) 2 1(II) 4(I) 1(II) 4(II)b 4(II)a 6(I)

carbonyl (nicotinamide)

carbonyl (acid)

acid

amide

4(I)

−80.7b

carbonyl (nicotinamide)

carbonyl (acid)

acid

amide (H1S)

6(II)

−75.2b

3 3 5(I) 5(II) 5(II) 1(I) 3 6(I) 5(II) 6(II) 5(I) 5(I) 5(II) 4(II)bc 4(II)ac 4(I) 3 4(II)bc 4(II)ac

−27.0 −69.9 (−35.0) −69.6 (−34.8) −69.0 (−34.5) −65.3 (−32.7) −28.8 −25.1 −33.8 −29.4 −27.5 −26.9 −26.2 −20.9 −19.9 −12.3 −20.5 −15.7 −15.2 −15.2

carbonyl (nicotinamide) carbonyl (nicotinamide) carbonyl (nicotinamide) carbonyl (nicotinamide) carbonyl (nicotinamide) carbonyl (acid) alcohol carbonyl (acid) carbonyl (acid) carbonyl (acid) carbonyl (acid) carbonyl (acid) carbonyl (acid) carbonyl (acid) carbonyl (acid) phenol phenol phenol phenol

carbonyl (acid)

carbonyl (nicotinamide) carbonyl (nicotinamide) carbonyl (nicotinamide) carbonyl (nicotinamide)

methanol amide amide amide amide phenol phenol amide amide amide (H1A) amide amide amide amide amide amide amide amide amide

acid

amide amide amide amide

a

For homomeric dimers forming rings of hydrogen bonds, the interaction energy per hydrogen bond is given in parentheses as half the total interaction energy. The two disorder models of the 2,4-hydroxybenzoic acid in 4(II) are indicated as 4(II)a and 4(II)b, respectively, where 4(II)a contains the 2,4-hydroxybenzoic acid with the OH group syn to the carbonyl of the carboxylic acid group. bThe total interaction energy includes contributions from the N−H···O and O−H···O interactions. cCalculated for the two parts of the disorder of the OH group in the 2-position.

center of the ribbon, and the acridine molecule forming the edge of the ribbon. This is due to acridine being a monofunctional hydrogen bonding molecule and hence a natural terminator. The ribbons are then cojoined via dimeric π-stacking interactions as seen in the polymorphs III and VI of acridine. Co-crystal 2, which is a 1:2 co-crystal, is the most frequently observed co-crystal and crystallizes out of most solutions, regardless of the starting stoichiometry of the two reagents. It has two features that make it appear to be the most stable co-crystal. First, both donors hydrogen bond to the best available acceptor increasing the average strength of the hydrogen bonds in the structure. It has the carboxylic acid···pyridine pair (best donor/

Figure 13. The crystal habits of the polymorphs and stoichiometric cocrystals with acridine and 3-hydroxybenzoic acid.

L



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The Polymorphic Co-crystals with Nicotinamide. The crystal form system of co-crystals between the molecule 2,4dihydroxybenzoic acid and nicotinamide has a methanol solvate and two unsolvated polymorphic modifications. The plate-like crystals of form 4(I) reflect the sheet-like packing of the cocrystal whereas the blocks of form 4(II) have a 3-D packing with very different hydrogen bonding interactions (Figure 14). In all three cases, the best donor bonds to one of the two best acceptors and the second best donor bonds to the other acceptor or the solvent.

acceptor), and due to the 1:2 stoichiometry, a second acridine molecule can act as an acceptor for the second best donor, the phenol. Second, the packing of the acridine molecules in the cocrystal resembles the packing observed in four of the acridine polymorphs, especially acridine VII. Co-crystal 2 and acridine VII have tetrameric units of acridine molecules that are π-stacked on top of each other. The other polymorphs of acridine have similar stacks of two or four units. As such, the creation of cocrystal 2 may be viewed as an insertion of the 3-hydroxybenzoic molecule into or between the tetrameric framework of acridine VII in the crystallization solution creating new linkages between the tetramers that adjust to generate a new closely packed structure. Hydrogen Bonding Strengths in the 3-Hydroxybenzoic Acid/Acridine System. As discussed earlier, it was expected that in the case of the co-crystals of 3-hydroxybenzoic acid and acridine, either the carboxylic acid or the phenol OH, or both, would hydrogen bond with the N of the acridine. We see that all three of these possibilities are obtained [1(I), 1(II), and 2, respectively] depending on the crystallization conditions. DFT calculations at the M06-2X/6-31+G(d,p) level of theory (basis set superposition error is taken into account by utilizing counterpoise corrections) indicate that the carboxylic acid forms the strongest hydrogen bond to the acridine in 1(I) (70.8 kJ mol−1, see Table 2), whereas in 2 it forms a weaker interaction of 55.9 kJ mol−1. Both these interactions are stronger than the phenol···acridine hydrogen bonds, which are still relatively strong interactions at 50.3 and 53.0 kJ mol−1 in 1(II) and 2, respectively. In 1(I) and 1(II), the OH group not utilized in hydrogen bonding to the acridine then forms additional hydrogen bonds to the carboxyl group of the acid. In 1(I), this O−H···OC interaction is surprisingly weak (28.8 kJ mol−1); however in 1(II) a typical R22(8) carboxylic acid dimer forms an extremely strong interaction of 110.2 kJ mol−1, corresponding to two hydrogen bonds each approximately 55.1 kJ mol−1 in strength. The hydrogen bonding thus stabilizes the 3hydroxybenzoic acid by 128.4, 160.5, and 108 kJ mol−1 in 1(I), 1(II), and 2, respectively. Furthermore, calculating the total stabilization of each molecule by determining its interaction energy with all neighboring molecules within a distance of 4.5 Å (Supporting Information, Tables S4a−j, interaction energies to molecules beyond 4.0 Å are less than 1 kJ mol−1) shows that although strong hydrogen bonds are formed in every polymorph, these contribute only about two-thirds of the interaction energy experienced by the 3-hydroxybenzoic acid molecule and less than 36% to the stabilization of the acridine. A variety of interactions, mostly weak, contribute to the stabilization of the polymorphs; however it was found that the π-stacking interactions that exist between the acridine molecules in all three polymorphs are similar in strength to the hydrogen-bonding interactions [43.0 and 40.9 kJ mol−1 in 1(I), 36.9 and 43.7 kJ mol−1 in 1(II), and 42.4, 34.6, 31.7, and 34.6 kJ mol−1 for the two molecules in 2, respectively]. These interactions are therefore similar in all polymorphs; however, it should be borne in mind that both of the acridine molecules in the asymmetric unit of 2 are involved in π-stacking interactions, which means that 2 contains more stabilizing interactions than either 1(I) or 1(II) (see Supporting Information, Tables S4a−c). This thus suggests that 2 is the most stable polymorph, while if all interactions are taken into account, 1(I) is expected to be the least stable. This agrees with the experimental results, where 2 is the most commonly observed polymorph.

Figure 14. The crystal habits of the polymorphic co-crystals of nicotinamide with 2,4-dihydroxybenzoic acid.

The hydrogen bonding of the solvated co-crystal 3 follows Etter's second rule: There is an S(6) intramolecular hydrogen bond, favored over intermolecular hydrogen bonds. Thereafter, the best donor/best acceptor functional groups remain to form intermolecular hydrogen bonds. The carboxylic acid proton on O1, as best donor, forms a hydrogen bond to the pyridine N2 of the nicotinamide, the best acceptor. Solvent molecules often have an important role in filling a void, and it is unpredictable how it will incorporate or associate with hydrogen bonds. In this case, the second best donor, the phenol H in the 4-position, forms a hydrogen bond to the oxygen of the methanol, which in turn forms a hydrogen bond to the second best acceptor, the carbonyl O on the amide group. The third best acceptor/donor pair is the hydrogen bond between the amide group to form the homomeric R22(8) dimers. In the first polymorph of the unsolvated co-crystals, co-crystal 4(I), the best donor forms a hydrogen bond to the second best acceptor to form the heteromeric acid···amide R22(8) dimers. The second best donor, the phenol H, forms a hydrogen bond now to the best acceptor (pyridine) instead of the solvent molecule. The second polymorph, co-crystal 4(II), is an example of a system that follows exactly Etter’s rule of hydrogen bonding. After dispensing with the formation of the intramolecular S(6) hydrogen bond, the best donor bonds to the best acceptor (carboxylic acid··· pyridine) and the second best donor bonds to the second best acceptor (phenol···carbonyl oxygen(amide)), a reversal of what was seen in 4(I). The third best donors, the two amide protons, bond to the third best acceptor, the carbonyl O on the carboxylic acid, and the fourth best acceptor, the phenol O. This form 4(II) has been observed in most crystallization attempts from various solvents. Malonic Acid/Nicotinamide and Pimelic Acid/Nicotinamide Co-crystals. The co-crystals 5(I) and 5(II) and 6(I) and 6(II) are examples of conformational polymorphs. The structures of malonic acid/nicotinamide and pimelic acid/ nicotinamide co-crystals were recently published in an extensive study of alkyldicarboxylic acids from oxalic to sebacic acid with nicotinamide,10d in fact at about the same time that the structures in this report were determined. However, those structures are M



Article

for bezafibrate (72.4 kJ mol−1). The lower energy of the syn planar conformation means that it is far more common, with the anti conformation primarily observed when the OH engages in an intramolecular hydrogen bond.77 In the CSD, there are 2 out of 23 crystal structures containing malonic acid that have the one carboxylic acid group syn and the other anti.78 The presence of the anti-conformer in 5(II), in the absence of any intramolecular hydrogen bonds, suggests that this conformation is stabilized by intermolecular interactions. Form 6(II) of the (pimelic acid)·(nicotinamide) co-crystal was grown from a methanol solution, whereas form 6(I) was grown from a methanol/chloroform solution as described above.10d Both forms have the same carboxylic acid···pyridine and carboxylic acid···amide R22(8) hydrogen bonding interactions that link the two molecules into 1-D chains, but 6(II) has discrete amide···carbonyl hydrogen bonds that link the chains into 2-D sheets. Form 6(I) instead has an R24(8) carboxylic acid···amide ring that connects the chains into tapes. Forms 6(I) and 6(II) differ primarily in the conformation of their pimelic acid molecules. Form 6(I) has an all-trans planar conformation of the hydrocarbon chain, and the two carboxylic acid groups are in the same plane as the chain (C11−C12−C13−O5 178.2(1)°; C9−C8−C7−O2 −9.5(2)°). Form 6(II) again has an all-trans planar conformation of the hydrocarbon chain with one of the carboxylic acid groups coplanar (C5−C6−C7−O3 −167(1)°). The second carboxylic acid group is however twisted out of the plane with the C3−C2−C1−O1 torsion angle being 73(2)°. Hence, the two polymorphs of the (pimelic acid)·(nicotinamide) co-crystal differ both in their conformations and in their detailed hydrogen-bonding interactions, in contrast to the two polymorphs of malonic acid/nicotinamide, which differ only in the conformations of the malonic acid molecules. Recently, the same two polymorphs of nicotinamide with pimelic acid were studied by Aitipamula et al., who found that 6(II) is the metastable polymorph at room temperature and transforms to 6(I) during extended grinding slurry experiments.79 Hydrogen Bonding Strengths in the Polymorphic Nicotinamide Co-crystals. Turning again to the 2,4dihydroxybenzoic acid·nicotinamide co-crystals [3 with methanol, 4(I) and 4(II)], we see that there is a greater variety of hydrogen bonding possibilities, with the most likely hydrogen bond, as defined by Etter,16a between the OH group at the 2position of the 2,4-dihydroxybenzoic acid and the carboxylic acid being observed in every case, as expected. The remaining phenol and carboxylic acid OH are then free to hydrogen bond either with the pyridine N or amide O of the nicotinamide, each other, or even the solvate methanol in 3. All these possibilities are observed in the co-crystals studied here, other than the homomeric phenol···phenol or carboxylic acid···carboxylic acid hydrogen bonding. Since malonic and pimelic acid both contain two identical functional groups, the hydrogen bonding options are fewer in 5(I), 5(II), 6(I), or 6(II): the carboxylic acid OH can either bond to the pyridine N or amide O of the nicotinamide. Similar to the case of 2,4-dihydroxybenzoic acid, the formation of a homomeric hydrogen-bonded ring is not observed. The strength of the acid OH···N pyridine synthon is confirmed by the fact that it is found in all four of these co-crystals, while the next strongest hydrogen bond, the heteromeric acid···amide hydrogen bonded ring, is present in 6(I) and 6(II). In contrast to the co-crystals 1(I), 1(II), and 2, where there are limited possibilities for forming hydrogen bonds to the acridine, nicotinamide can form a wide range of hydrogen bonds itself,

different modifications from the ones reported here and are labeled (malonic acid)·(nicotinamide)2 form 5(I) and (pimelic acid)·(nicotinamide) form 6(I). Co-crystal 5(I) grew concomitantly72 with form 5(II) out of a warm acetonitrile solution (Figure 15a). Both forms have the same plate-like morphology

Figure 15. (a) The crystal habits of the polymorphs of nicotinamide with malonic acid. (b) The transition from form 5(II) to form 5(I) at 64 °C, suggesting an enantiotropic relationship.

and were thought to be identical. However, form 5(II) crystals had clear faces, were much harder, and were selected preferentially over the (then unknown) form 5(I) crystals, which had striated faces and were deemed of an inferior diffraction quality. However, the measured PXRD did not match up with the calculated pattern of form II, with extra peaks appearing at 2θ = 17.9°, 24.3°, and 30.9° (Figure S6, Supporting Information). Thereafter, a striated crystal of form 5(I) was selected, and the structure was determined. The form 5(I) and form 5(II) crystals were visually separated (there were only about ten crystals of the latter), and a measured PXRD pattern of pure form 5(I) then matched up perfectly with the calculated pattern (See Figure S6, Supporting Information). As yet, we have not been able to regrow crystals of form 5(II) and obtain a phase pure sample, a situation reminiscent of that described for disappearing polymorphs.73 Form I melts at 106 °C. Form II undergoes a phase transition at 64 °C into form I and then melts at 106 °C (Figure 15b). Both forms have the same set of strong hydrogen bonding interactions but differ in one crucial feature. Co-crystal 5(I) has both carboxylic acid protons in the syn conformation, whereas 5(II) has one acid in the anti conformation. It is well-known that the syn-conformation of the OH group of COOH is far more stable than the anti conformation, by 2−4 kcal/mol.36a,74 A calculation of the change in energy upon rotation of the H3 atom around the C3−O3 bond in malonic acid at the B3LYP/6-31+G(d,p) level of theory (given in Figure S5 in the Supporting Information) shows that the syn conformation is 22.4 kJ mol−1 lower in energy than the anti conformation. This is similar to what was found for acetic acid of 28.9 or 21.3 kJ mol−175 but less than the 40.6 kJ mol−1 that we have previously calculated for bezafibrate.76 The barrier to rotation of 60.5 kJ mol−1 is also slightly less than that calculated N



Article

details of the hydrogen-bond connectivities as described by the graph sets. The differences between the polymorphs of the coformers we have used here range from completely different hydrogen-bond connectivities to differences only in molecular conformation to different packing arrangements of conformationally rigid molecules. All types of variations used have resulted in polymorphic co-crystals. It appears from our survey of the Cambridge Crystallographic Database and from the polymorphic co-crystals we have discovered in our laboratory that indeed cocrystallization is not the “cure” for the polymorphism of individual molecules as has been suggested.

with the formation of a resonance-assisted homomeric amide dimer providing on average 69(2) kJ mol−1 (standard deviation given in parentheses) stabilization to the co-crystals containing this moiety (with two hydrogen bonds per ring motif). Despite this potentially large amount of stabilization, the amide dimer motif is observed only in three of the co-crystals [3, 5(I), and 5(II)]. Thus the amide dimer motif is not as common within this subset of co-crystals as the amide to carboxylic acid N−H···O interactions, which are found in co-crystals 4(II), 5(I), 5(II), 6(I), and 6(II), even though they are slightly weaker and more variable, on average 25(7) kJ mol−1, varying from 33.8 kJ mol−1 in 6(I) to a mere 12.3 kJ mol−1 in conformation a of 4(II). Similarly, the resonance-assisted amide···carboxylic acid hydrogen-bonded rings found in 4(I), 6(I), and 6(II) are even stronger [average 79(4) kJ mol−1] than the homomeric amide dimer but are less common. The homomeric carboxylic acid···carboxylic acid hydrogen bonding motif is not observed at all, despite the fact that this interaction is even stronger than the homomeric amide dimer. This may be a reflection of the restrictions imposed on the formation of hydrogen bonded rings, where coplanarity is a conformational requirement, as opposed to acyclic N−H···O hydrogen bonds, which can take on any orientation to allow optimal packing arrangements. Electrostatic Surface Potentials: A Final Comment on Rankings of Donors and Acceptors. We have used literature examples and pKa’s to make sense of the donor and acceptor strengths of our hydrogen bonding functional groups and to rationalize what we expect and observe in our four pairs of cocrystals. Electrostatic surface potentials (ESPs), which can be accurately calculated once the crystal structure is known, have also been used to rank hydrogen-bond donating and accepting abilities and can, in principle, disagree with the pKa argument.56

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ASSOCIATED CONTENT

S Supporting Information *

Crystallographic information files (cif) for all compounds except 6(I), PXRD patterns, hydrogen bonding tables, and details of all calculations for intermolecular interactions. This information is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*(A.L.) E-mail: [email protected]. Fax: +27 11 717 6749. Tel: +27 11 717 6711. (D.A.A.) E-mail: DanAdsmond@ ferris.edu. Fax: (231) 591-2618. Tel: (231) 591-5867. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported in part by Grant 2004118 from the United States-Israel Binational Science Foundation (Jerusalem). A.L. thanks the South African National Research Foundation for a postdoctoral scholarship (Grant SFP2007070400002) and Oppenheimer Memorial Trust and the Molecular Sciences Institute for funding. C.E. thanks the South African National Research Foundation for funding and the Centre for High Performance Computing of South Africa for computational time. D.A. thanks Ferris State University for both sabbatical and research grant support.

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CONCLUSION In this paper, we have described four polymorphic co-crystal systems arising from polymorphic coformers. Two of the systems involve hydroxybenzoic acids, previously shown to be promiscuous in their hydrogen bonding with acceptor molecules. In 1(I) the acid group of m-hydroxybenzoic acid forms a hydrogen bond to the acridine nitrogen, while in 1(II), the phenol forms a hydrogen bond to the acridine nitrogen. In 4(I), the acid group of 2,4-dihydroxybenzoic acid forms a hydrogen bond to the amide of nicotinamide and the 4-hydroxy group forms a hydrogen bond to the pyridine nitrogen. In its polymorph, 4(II), the exact opposite hydrogen-bond pairing occurs. While these observations raise the question whether there is any significant difference in donor strength between the carboxylic acids and the phenols, support is gained for the ranking of the carboxylic acid as the better acceptor from our calculations, which show that nine of the eleven carboxylic acid···pyridine hydrogen bonds observed in these structures are stronger than all three of the phenol···pyridine hydrogen bonds seen here. In the other two systems, dicarboxylic acid/nicotinamide cocrystals provide examples of co-crystal polymorphs with little or no difference in hydrogen-bond connectivity. In both 5(I) and 5(II), malonic acid forms 1:2 co-crystals with nicotinamide where the carboxylic acids hydrogen bond to the pyridine nitrogens leaving the amide groups to form an R22(8) dimer. In both 6(I) and 6(II), pimelic acid forms 1:1 co-crystals with nicotinamide where one acid group forms a hydrogen bond to the pyridine nitrogen and the other forms an R22(8) ring with the amide group. Structural differences between the two polymorphs are observed in the molecular conformations and in the finer

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DEDICATION We dedicate this work to Prof. Mino R. Caira for his work on the polymorphism and co-crystallization of drug compounds. REFERENCES

(1) (a) Almarsson, Ö .; Zaworotko, M. J. Chem.Commun. 2004, 1889− 1896. (b) Stahly, G. P. Cryst. Growth Des. 2007, 7, 1007−1026. (c) Trask, A. V. Mol. Pharmaceutics 2007, 4, 301−309. (d) Shan, N.; Zaworotko, M. J. Drug Discovery Today 2008, 13, 440−446. (e) Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369−1371. (f) Weyna, D. R.; Shattock, T.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2009, 9, 1106−1123. (g) Walsh, R. D. B.; Bradner, M. W.; Fleischmann, S.; Morales, L. A.; Moulton, B.; Rodríguez-Hornedo, N.; Zaworotko, M. J. Chem. Commun. 2003, 186−187. (h) Aakeröy, C. B.; Forbes, S.; Desper, J. J. Am. Chem. Soc. 2009, 131, 17048−17049. (i) Sekhon, B. S. Ars Pharm. 2009, 50, 99−117. (j) Jones, W.; Motherweel, W. D. A.; Trask, A. V. MRS Bull. 2006, 31, 875−879. (k) Mirza, S.; Miroshnyk, I.; Heinämäki, J.; Yliruusi, J. Dosis 2008, 24, 90−96. (l) Brittain, H. G. Cryst. Growth Des. 2012, 12, 1046−1054. (m) Brittain, H. G. Cryst. Growth Des. 2012, 12, 5823−5832. (n) Pfeiffer, P. Organische Molekuulverbindungen; Verlag von Ferdinand Enke: Stuttgart, Germany, 1927. (o) For a review of earlier literature, see Herbstein, F. H. Perspectives in Structural Chemistry; Dunitz, J. D., Ibers, O



Article

J., Eds.; John Wiley & Sons: New York, 1971; Vol. 4, pp 166−395; especially references 4−26 therein. (2) (a) Bernstein, J. Polymorphism in Molecular Crystals; Oxford Science Publications: Oxford, 2002. (b) Ahn, S.; Guo, F.; Kariuki, B. M.; Harris, K. D. M. J. Am. Chem. Soc. 2006, 128, 8441−8452. (c) Llinàs, A.; Goodman, J. M. Drug Discovery Today 2008, 13, 198−210. (d) Bernstein, J. Cryst. Growth Des. 2011, 11, 632−650. (3) (a) “This heterosynthon will provide a different set of molecules to answer the frequently-asked billion dollar question in pharmaceutical R&D: do API co-crystals tend to be less polymorphic than pure compounds?” Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369−1371. (b) “Indeed, to our knowledge there have not yet been any examples of ‘supramolecular isomerism’ in co-crystals. If these observations hold true over a broader range of compounds it would suggest that co-crystals represent a desirable class of compound from the perspectives of both design and phase stability.” Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95, 499− 516. (4) “This question will not have a direct answer, because to prove the absence of polymorphism is tantamount to ‘proving the negative’. But if one considers the argument that compounds have a lower degree of selfcomplementarity than complementarity to a rationally selected cocrystal former, one might suspect that a compound polymorphic in the pure state could display a decreased tendency to polymorphism as a cocrystal relative to the pure phase.” Almarsson, Ö .; Zaworotko, M. J. Chem. Commun. 2004, 1889−1896. (5) Vishweshwar, P.; McMahon, J. A.; Peterson, M. L.; Hickey, M. B.; Shattock, T. R.; Zaworotko, M. J. Chem. Commun. 2005, 4601−4603. (6) Bond, A. D. CrystEngComm 2007, 9, 833−834. (7) (a) Aakeröy, C. B.; Beatty, A. M. Aust. J. Chem. 2001, 54, 409−421. (b) Aakeröy, C. B.; Salmon, D. J. CrystEngComm 2005, 7, 439−448. (8) (a) Haller, T. M.; Rheingold, A. L.; Brill, T. B. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1983, 39, 1559−1563. (b) Hostettler, M.; Birkedal, H.; Gardon, M.; Chapuis, G.; Schwarzenbach, D.; Bonin, M. Acta Crystallogr., Sect. B: Struct. Sci. 1999, 55, 448−458. (c) Ahn, S.; Kariuki, B. M.; Harris, K. D. M. Cryst Growth Des. 2001, 1, 107−111. (d) Gardon, M.; Schönleber, A.; Chapuis, G.; Hostettler, M.; Bonin, M. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2001, 57, 936−938. (e) Koshima, H.; Miyauchi, M. Cryst. Growth Des. 2001, 1, 355−357. (f) Farrell, D. M. M.; Ferguson, G.; Lough, A. J.; Glidewell, C. Acta Crystallogr., Sect. B: Struct. Sci. 2002, 58, 530−544. (g) Bowes, F. F.; Ferguson, G.; Lough, A. J.; Glidewell, C. Acta Crystallogr., Sect. B: Struct. Sci. 2003, 59, 277−286. (h) Gardon, M.; Pinheiro, C. B.; Chapuis, G. Acta Crystallogr., Sect. B: Struct. Sci. 2003, 59, 527−536. (i) Pinheiro, C. B.; Gardon, M.; Chapuis, G. Acta Crystallogr., Sect. B: Struct. Sci. 2003, 59, 414−427. (j) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Chem. Commun. 2004, 890−891. (k) Trask, A. V.; van de Streek, J.; Motherwell, W. D. S.; Jones, W. Cryst. Growth Des. 2005, 5, 2233− 2241. (l) Shattock, T. R.; Vishweshwar, P.; Wang, Z.; Zaworotko, M. J. Cryst. Growth Des. 2005, 5, 2046−2049. (m) Bis, J. A.; Vishweshwar, P.; Middleton, R. A.; Zaworotko, M. J. Cryst. Growth Des. 2006, 6, 1048− 1053. (n) Drebushchak, T. N.; Mikheilenko, M. A.; Boldyreva, E. V.; Shakhtshneider, T. P. Acta Crystallogr., Sect E: Struct. Rep. 2006, 62, o2669−o2671. (o) Drebushchak, T. N.; Mikheilenko, M. A.; Boldyreva, E. V.; Shakhtshneider, T. P. Acta Crystallogr., Sect E: Struct. Rep. 2006, 62, o2707−o2709. (p) Sreekanth, B. R.; Vishweshwar, P.; Vyas, K. Chem. Commun. 2007, 2375−2377. (q) Wang, J.; Ding, L.; Yang, C. CrystEngComm 2007, 9, 591−594. (r) Childs, S. L.; Hardcastle, K. I. CrystEngComm 2007, 9, 364−367. (s) Drebushchak, T. N.; Mikhailenko, M. A.; Drebushchak, V. A.; Boldyreva, E. V. Struct. Chem. 2007, 18, 449−456. (t) Gryl, M.; Krawczuk, A.; Stadnicka, K. Acta Crystallogr., Sect. B: Struct. Sci. 2008, 64, 623−632. (u) Braga, D.; Palladino, G.; Polito, M.; Rubini, K.; Grepioni, F.; Chierotti, M. R.; Gobetto, R. Chem.Eur. J. 2008, 14, 10149−10159. (v) Porter, W. W.; Elie, S. C.; Matzger, A. J. Cryst. Growth Des. 2008, 8, 14−16. (w) ter Horst, J. H.; Cains, P. W. Cryst. Growth Des. 2008, 8, 2537−2542. (x) Skovsgaard, S.; Bond, A. A. CrystEngComm 2009, 11, 444−453. (y) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2009, 11, 889−895. (z) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm

2009, 11, 1823−1827. (aa) Raatikainen, K.; Rissanen, K. CrystEngComm 2009, 11, 750−752. (bb) Du, M.; Jiang, X.-J.; Tan, X.; Zhang, Z.-H.; Cai, H. CrystEngComm 2009, 11, 454−462. (cc) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. Cryst. Growth Des. 2010, 10, 2229−2238. (dd) Schultheiss, N.; Bethune, S.; Hench, J.-O. CrystEngComm 2010, 12, 2436−2442. (ee) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2010, 12, 3691−3697. (ff) Ye, H.-Y.; Ge, J.-Z.; Chen, F.; Xiong, R.-G. CrystEngComm 2010, 12, 1705−1708. (gg) Yu, Z. Q.; Chow, P. S.; Tan, R. B. H.; Ang, W. H. Cryst. Growth Des. 2011, 11, 4525−4532. (hh) Halasz, I.; Rubčić, M.; Užarević, K.; Dilović, I.; Meštrović, E. New J. Chem. 2011, 35, 24−27. (ii) Thomas, L. H.; Craig, G. A.; Gutmann, M. J.; Parkin, A.; Shankland, K.; Wilson, C. C. CrystEngComm 2011, 13, 3349−3354. (jj) Schultheiss, N.; Roe, M.; Boerrigter, X. M. CrystEngComm 2011, 13, 611−619. (kk) Bortel, G.; Pekker, S.; Kovats, É. Cryst. Growth Des. 2011, 11, 865−874. (ll) Ueto, T.; Takata, N.; Muroyama, N.; Nedu, A.; Sasaki, A.; Tanida, S.; Terada, K. Cryst. Growth Des. 2012, 12, 485−494. (mm) Lemmerer, A.; Bernstein, J.; Kahlenberg, V. Acta Crystallogr., Sect. E: Struct. Rep. 2012, 68, o190. (nn) Limwikrant, W.; Nagai, A.; Hagiwara, Y.; Higashi, K.; Yamamoto, K.; Moribe, K. Int. J. Pharm. 2012, 431, 237−240. (oo) Kaur, R.; Row, T. N. G. Cryst. Growth Des. 2012, 12, 2744−2747. (pp) Zhang, S.-W.; Guzei, I. A.; de Villiers, M. M.; Yu, L.; Krzyzaniak, J. F. Cryst. Growth. Des. 2012, 12, 4090−4097. (qq) Lemmerer, A.; Fernandes, M. A. New J. Chem. 2012, 36, 2242−2252. (9) (a) Martí-Rujas, J.; Kariuki, B. M.; Hughes, C. E.; Morte-Ródenas, A.; Guo, F.; Glavcheva-Laleva, Z.; Taştemür, K.; Ooi, L.; Yeo, L.; Harris, K. D. M. New J. Chem. 2011, 35, 1515−1521. (b) Abourahma, H.; Cocuzza, D. S.; Melendez, J.; Urban, J. M. CrystEngComm 2011, 13, 6442−6450. (10) (a) Oliviera, M. A.; Peterson, M. L.; Klein, D. Cryst. Growth Des. 2008, 8, 4487−4493. (b) Sarma, B.; Reddy, L. S.; Nangia, A. Cryst. Growth Des. 2008, 8, 4546−4552. (c) Babu, N. J.; Reddy, L. S.; Aitipamula, S.; Nangia, A. Chem.Asian J. 2008, 3, 1122−1133. (d) Karki, S.; Frišcǐ ć, T.; Jones, W. CrystEngComm 2009, 11, 470−481. (e) Seaton, C. C.; Parkin, A.; Wilson, C. C.; Blagden, N. Cryst Growth Des. 2009, 9, 47−56. (f) Jayasankar, A.; Reddy, L. S.; Bethune, S. J.; Rodríguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 889−897. (g) Trask, A. V.; van de Streek, J.; Motherwell, W. D. S.; Jones, W. Cryst. Growth Des. 2005, 5, 2233−2241. (11) Aakeröy, C. B.; Desper, J.; Elisabeth, E.; Helfrich, B. A.; Levin, B.; Urbina, J. F. Z. Kristallogr. 2005, 220, 325−332. (12) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311−2327. (13) McMahon, J. A.; Bis, J. A.; Vishweshar, P.; Shattock, T. R.; McLaughlin, O. L.; Zaworotko, M. J. Z. Kristallogr. 2005, 220, 340−350. (14) Aakeröy, C. B.; Schultheiss, N. Assembly of Molecular Solids via Non-covalent Interactions. In Making Crystals by Design; Braga, D., Grepioni, F., Eds.; Wiley-VCH: Weinheim, Germany, 2007; pp 209− 240. (15) (a) McMahon, J. A.; Bis, J. A.; Vishweshar, P.; Shattock, T. R.; McLaughlin, O. L.; Zaworotko, M. J. Z. Kristallogr. 2005, 220, 340−350. (b) Lemmerer, A.; Adsmond, D. A.; Bernstein, J. Cryst. Growth Des. 2011, 11, 2011−2019. (16) (a) Etter, M. C. Acc. Chem. Res. 1990, 23, 120−126. (b) Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr., Sect. B: Struct. Sci. 1990, 46, 256−262. (c) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem., Int. Ed. Engl. 1995, 34, 1555−1573. (17) (a) Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. J. Am. Chem. Soc. 2002, 124, 14425−14432. (18) Examples of acid···pyridine are (a) Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem., Int. Ed. 2001, 40, 3240−3242. (b) Bhogala, B. R.; Basavoju, S.; Nangia, A. CrystEngComm 2005, 7, 551−562. (c) Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. Cryst. Growth Des. 2003, 3, 159−165. (d) Lemmerer, A.; Báthori, N. B.; Bourne, S. A. Acta Crystallogr. Sect., B: Struct. Sci. 2008, 64, 780−790. (e) Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2003, 3, 783−790. (f) Oliveira, M. A.; Peterson, M. L.; Klein, D. Cryst. Growth Des. 2008, 8, 4487−4493. (19) Examples of alcohol···pyridine are (a) Sarma, B.; Reddy, L. S.; Nangia, A. Cryst Growth Des. 2008, 8, 4546−4552. (b) Vishweshwar, P.; P



Article

Nangia, A.; Lynch, V. M. CrystEngComm 2003, 5, 164−168. (c) Huang, K.-S.; Britton, D.; Etter, M. C.; Byrn, S. R. J. Mater. Chem. 1997, 7, 713− 720. (d) Bourne, S. A.; Nassimbeni, L. R.; Toda, F. J. Chem. Soc., Perkin Trans. 2 1991, 1335−1341. (e) Lough, A. J.; Gregson, R. M.; Ferguson, G.; Glidewell, C. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1999, 55, 1890−1892. (f) Bourne, S. A.; Corin, K. C.; Nassimbeni, L. R.; Toda, F. Cryst. Growth Des. 2005, 5, 379−382. (g) Nassimbeni, L. R.; Su, H.; Weber, E.; Skobridis, K. Cryst. Growth Des. 2004, 4, 85−88. (h) Olenik, B.; Boese, R.; Sustmann, R. Cryst. Growth Des. 2003, 3, 175−181. (20) Shattock, T. R.; Arora, K. K.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2008, 8, 4533−4545. (21) Adsmond, D.; Lapidus, S. In preparation. (22) Nehm, S. J.; Rodríguez-Spong, B.; Rodríguez-Hornedo, N. Cryst. Growth Des. 2006, 6, 592−600. (23) Bruker, SMART-NT, version 5.050; Bruker AXS Inc., Madison, Wisconsin, USA, 1999. (24) Bruker SAINT+, version 6.02 (includes XPREP and SADABS); Bruker AXS Inc., Madison, Wisconsin, USA, 1999. (25) Farrugia, L. J. WinGX. J. Appl. Crystallogr. 1999, 32, 837−838. (26) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112−122. (27) Farrugia, L. J. ORTEP-3. J. Appl. Cryst. 1997, 30, 565. (28) Spek, A. L Acta Crystallogr., Sect. D: Struct. Biol. 2009, 65, 148− 155. (29) Brandenburg, K. Diamond, version 2.1e.; Crystal Impact GbR, Bonn, Germany, 1999. (30) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision A.02; Gaussian, Inc.: Wallingford, CT, 2009. (31) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 1372−1377. (b) Lee, C. T.; Yang, W. T.; Parr, R. G. Phys. Rev. B 1988, 37, 785−789. (c) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623−11627. (32) (a) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257−2261. (b) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213−222. (33) (a) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 215−241. (b) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157−167. (34) (a) Ransil, B. J. J. Chem. Phys. 1961, 34, 2109−2118. (b) Boys, S. F.; Bernardi, F. Mol. Phys. 1970, 19, 553−566. (35) Version 5.33: Allen, F. H. Acta Crystallogr., Sect. B: Struct. Sci. 2002, 58, 380−388. (36) (a) Leiserowitz, L. Acta Crystallogr., Sect. B: Struct. Sci. 1976, 32, 775−802. (b) Das, D.; Desiraju, G. R. Chem.Asian J. 2006, 1−2, 231− 244. (c) Das, D.; Desiraju, G. R. CrystEngComm 2006, 8, 674−679. (37) (a) Brock, C. P.; Duncan, L. L. Chem. Mater. 1994, 6, 1307−1312. (b) Taylor, R.; Macrae, C. F. Acta Crystallogr., Sect. B: Struct. Sci. 2001, 57, 815−827. (38) Search Criteria: 3-hydroxybenzoic acid molecule. Filters: 3D coordinates determined, only organics. 35 hits reduced to 29 by eliminating salts. (39) Gridunova, G. V.; Furmanova, N. G.; Struchkov, Yu. T.; Ezhova, Z. I.; Grigoreva, L. P.; Chayanov, B. A. Crystallogr. Rep. 1982, 27, 267− 272.

(40) Desiraju, G. R. Acc. Chem. Res. 1996, 29, 441−449. Note: C−H··· O are defined as those with C···O distances in the range 3.00−4.00 Å, C−H···O angle greater than 110°, and H···O cutoff of 2.80 Å. (41) Schur, E.; Bernstein, J. 2013, manuscript in preparation. (42) Phillips, D. C. Acta Crystallogr. 1956, 9, 237−250. (43) Mei, X.; Wolf, C. Cryst. Growth Des. 2004, 4, 1099−1103. (44) (a) Phillips, D. C.; Ahmed, F. R.; Barnes, W. H. Acta Crystallogr. 1960, 13, 365−377. (b) Braga, D.; Grepioni, F.; Maini, L.; Mazzeo, P. P.; Rubini, K. Thermochim. Acta 2010, 507−508, 1−8. (45) Herbstein, F. H.; Schmidt, G. M. J. Acta Crystallogr. 1955, 8, 399− 405. (46) Schur, E.; Bernstein, J.; Lemmerer, A.; Vainer, R. Acta Crystallogr., Sect. E: Struct. Rep. 2011, 67, o2761. (47) Search Criteria: acridine molecule. Filters: 3D coordinates determined, only organics. 69 hits reduced to 50 by eliminating salts. (48) MEFJEM, MOFYAI, MORVOF, EWAPOI, EWAPUO, RAGSID, UBUJUY. (49) GADHUP, GAHFAX, GAHFIF, NOTKIQ, NOVSIA, NOVSIA01, NOVSOG, NOVSUM, NOVTAT, QALDUE, RAHGUC, RAHHAJ, TIDFER, TIDFUH, OVUFUH. (50) MUDSAF, NIWCEB, NIWCIF. (51) ANUPOP, QARGIZ, VOMHEL, VOMHIP, XOHWOH, XOHWUN. (52) ACRTMA, BIHBUP10, BIWVUY, CEJTAM, ERADUW, KARKAP01, RUJKUR. (53) Koshima, H.; Wang, Y.; Matsuura, T.; Miyahara, I.; Mizutani, H.; Hirotsu, K.; Asahi, T.; Masuhara, H. J. Chem. Soc., Perkin Trans. 2 1997, 2033−2038. (54) (a) Binder, W.; Karl, N. Acta Crystallogr., Sect. B: Struct. Sci. 1982, 38, 2919−2921. (b) Binder, W.; Karl, N. Acta Crystallogr., Sect. B: Struct. Sci. 1982, 38, 2915−2916. (55) http://www.zirchrom.com/organic.htm. (56) (a) Hunter, C. A. Angew. Chem., Int. Ed. 2004, 43, 5310−5324. (b) Aakeröy, C. B.; Desper, J. C.; Smith, M. M. Chem. Commun. 2007, 3936−3938. (c) Aakeröy, C. B.; Epa, K. Top. Curr. Chem. 2011, DOI: 10.1007/128_2011_155. (57) Hino, T.; Ford, J. L.; Powell, M. W. Therm. Acta 2001, 374, 85− 92. (58) (a) NICOAM01, NICOAM02, and NICOAM03: Bright, W. B.; King, G. S. D. Acta Crystallogr. 1954, 7, 283−288. (b) NICOAM: Miwa, Y.; Mizuno, T.; Tsuchida, K.; Taga, T.; Iwata, Y. Acta Crystallogr., Sect. B: Struct. Sci. 1999, 55, 78−84. (c) NICOAM04: Li, J.; Bourne, S. A.; Caira, M. Chem. Commun. 2011, 47, 1530−1532. (59) Giacomello, G.; Liquori, A. M.; Ripamonti, A. Nature 1956, 177, 944−945. (60) Braun, D. E.; Karamertzanis, P. G.; Arlin, J.-B.; Florence, A. J.; Kahlenberg, V.; Tocher, D. A.; Griesser, U. J.; Price, S. L. Cryst. Growth Des. 2011, 11, 210−220. (61) Parkin, A.; Adam, M.; Cooper, R. I.; Middlemiss, D. S.; Wilson, C. C Acta Crystallogr., Sect. B: Struct. Sci. 2007, 63, 303−308. (62) McMullan, R. K.; Klooster, W. T.; Weber, H.-P. Acta Crystallogr. Sect B: Struct. Sci. 2008, 64, 230−239. (63) Jaganathan, N. R.; Rajan, S. S.; Subramanian, E. J. Chem. Crystallogr. 1994, 24, 75−78. (64) Thalladi, R. R.; Nusse, M.; Boese, R. J. Am. Chem. Soc. 2000, 122, 9227−9236. (65) Gopalan, R. S.; Kumaradhas, P.; Kulkarni, G. U.; Rao, C. N. R. J. Mol. Struct. 2000, 521, 97−106. (66) (a) Berry, D. J.; Seaton, C. C.; Clegg, W.; Harrington, R. W.; Coles, S. J.; Horton, P. N.; Hursthouse, M. B.; Storey, R.; Jones, W.; Frišcǐ ć, T.; Blagden, N. Cryst. Growth Des. 2008, 8, 1697−1712. (b) Amai, M.; Kamijo, M.; Nagase, H.; Endo, T.; Ueda, H. Anal. Sci.: XRay Struct. Anal. Online 2001, 21, x9−x10. (c) Amai, M.; Kamijo, M.; Nagase, H.; Ogawaw, N.; Endo, T.; Ueda, H. Anal. Sci.: X-Ray Struct. Anal. Online 2006, 22, x121−x122. (d) Amai, M.; Endo, T.; Nagase, H.; Ueda, H.; Nakagaki, M. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1998, 54, 1367−1369. (e) Chakrabarty, D.; Nagase, H.; Kamijo, M.; Endo, T.; Ueda, H. Anal. Sci.: X-Ray Struct. Anal. Online 2006, 22, x27− x28. (f) Fleischman, S. G.; Kuduva, S. S.; McMahon, J. A.; Moulton, B.; Q



Article

Walsh, R. D. B.; Rodriguez-Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des. 2003, 3, 909−919. (g) Lemmerer, A.; Bernstein, J. CrystEngComm 2010, 12, 2029−2033. (67) Báthori, N. B.; Lemmerer, A.; Venter, G. A.; Bourne, S. A.; Caira, M. R. Cryst. Growth Des. 2011, 11, 75−87. (68) Search Criteria: nicotinamide molecule. Filters: 3D coordinates determined, only organics, no ions. 67 hits reduced to 62 by removing duplicate entries and a fourth covalent bond to the pyridine N. Entries with carboxylic acid coformers were then separated out further (42). (69) Wang, Z.-L.; Wei, L.-H.; Li, M.-X. Acta Crystallogr., Sect. E: Struct. Rep. 2006, 62, o3031−o3032. (70) Bernstein, J.; Novoa, J. J.; Boese, R.; Cirkel, S. A. Chem.-Eur. J. 2010, 16, 9047−9055. (71) Allen, F. H.; Motherwell, W. D. S.; Raithby, P. R.; Shields, G. P.; Taylor, R. New J. Chem. 1999, 23, 25−34. (72) Bernstein, J.; Davey, R. J.; Henck, J.-O. Angew. Chem., Int. Ed. 1999, 38, 3440−3461. (73) Dunitz, J. D.; Bernstein, J. Acc. Chem. Res. 1995, 28, 193−200. (74) (a) Li, Y.; Houk, K. N. J. Am. Chem. Soc. 1989, 111, 405−4507. (b) Montzka, T. A.; Swaminathan, S.; Firestone, R. A. J. Phys. Chem. 1994, 98, 13171−13176. (75) Sato, H.; Hirata, F. J. Mol. Struct.: Theochem 1999, 461−462, 113− 120. (76) Lemmerer, A.; Báthori, N. B.; Esterhuysen, C.; Bourne, S. A.; Caira, M. R. Cryst. Growth Des. 2009, 9, 2646−2655. (77) Of compounds (6270 out of 7235) containing a COOH group, 86% have the OH in syn. Search criteria: Fragments containing a COOH group where the OC−O−H torsion angle had a value between −40° and 40°, corresponding to a syn conformation. Filters: 3D coordinated determined, R-factor < 0.075, not disorder, no error, no ions, no powder structures, only organics. (78) MZMUE, URMALN: torsion angle CC−O−H −40° to 40° and 41−319°. Filters: 3D coordinates determined, not disordered, no errors, no ions, no powder structures, only organics. (79) Aitipamula, S.; Wong, A. B. H.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2012, 14, 8193−8198.

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