Synthon Competition and Cooperation in Molecular Salts of

Feb 6, 2009 - Competition and cooperation between COO−, OH, NH2, PyNH+, and H2O functional groups for the observed hydrogen bond synthons are examin...
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Synthon Competition and Cooperation in Molecular Salts of Hydroxybenzoic Acids and Aminopyridines Bipul Sarma, Naba K. Nath, Balakrishna R. Bhogala, and Ashwini Nangia* School of Chemistry, UniVersity of Hyderabad, Hyderabad 500 046, India

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 3 1546–1557

ReceiVed October 14, 2008; ReVised Manuscript ReceiVed December 23, 2008

ABSTRACT: Meta- and para-substituted hydroxy-benzoic acids and amino-pyridines were cocrystallized and characterized by X-ray diffraction. Proton transfer from the COOH to pyridyl N acceptor (PyN) occurred in 11 molecular salts (1-11) leading to a PyNH+ · · · -OOC ionic synthon in 10 structures and a PyNH+ · · · OdC hydrogen bond in one structure. Competition and cooperation between COO-, OH, NH2, PyNH+, and H2O functional groups for the observed hydrogen bond synthons are examined in 11 structures, of which 4 are hydrates. The second and third highest occurring synthons are NH2 · · · OH, NH2 · · · -OOC, and OH · · · -OOC in nine, eight, and eight structures, respectively. Hydrogen bonding of water to/from COO-, OH, and NH2 groups is present in hydrates 1, 5, 7, and 9. There are no systematic studies on our knowledge on hydrogen bond competition and interplay when the above four common functional groups are present in the same crystal structure. Synthons in this study are compared with statistics extracted from the Cambridge Structural Database to summarize trends and predict hydrogen bonding in new cocrystal and salt structures. The term molecular salt is suggested for ionic complexes derived from organic acids and bases. Acidity constants of benzoic acids and amino-pyridines were calculated in the gas phase, MeOH, and water using the SPARC program. The ∆pKa rule is found to be inadequate for predicting neutral or ionic O-H · · · N/N+-H · · · O- hydrogen bonds when other polar functional groups are also present in the system. The persistence of PyNH+ · · · -OOC ionic synthons is ascribed to the presence of OH and NH2 groups in the same supramolecular system. ∆pKa values are in the range 1-5 in the gas phase and water but negative in MeOH (-1 to -6), on the whole lower than the pKa difference of >3 that is generally accepted as a condition for proton transfer. Our results are at variance with a recent paper in Cryst. Growth Des. (2008, 8, 4533-4545) wherein neutral COOH · · · NPy heterosynthon occurs with 78% probability when competition in the presence of phenol OH group only was analyzed. Introduction The aim of this study was to understand hydrogen bond motifs when four functional groups are simultaneously present in the supramolecular system: carboxylic acid, pyridine, amine, and hydroxyl. Hydroxybenzoic acids and aminopyridines were selected as readily available compounds for cocrystallization (Figure 1). The identification of supramolecular synthons1 between common functional groups is a first step toward crystal engineering. Strong and specific recognition of the carboxylic acid group with pyridine (acid-pyridine synthon)2 and amine with hydroxyl group (amine-phenol synthon)3 is well studied. These hydrogen bond donor and acceptor groups are complementary and well matched for pairwise bonding4 (Figure 2). The acidic COOH donor bonds to the basic pyridine acceptor and O-H · · · N + N-H · · · O bond combinations satisfy donors and acceptors in amino-phenols. Both acid-pyridine and aminophenol are robust and popular synthons for crystal design when they are present in different crystal structures, that is, two functional groups at a time. We found that the presence of the above four functional groups resulted in proton transfer throughout the series of 11 crystal structures analyzed by X-ray diffraction, in effect making it a synthon analysis study of carboxylate, pyridinium, amine, and hydroxyl functional groups. Apart from structural interest, amino pyridines are bioactive agents that exist in neutral and ionic form at physiological pH (pKa 6-9),5 and hydroxy-benzoic acids, such as gallic acid, are antioxidants and cause apoptosis characterized by DNA fragmentation.6 Results Molecules selected in this study cover the functional groups space of positional isomers (3-HBA, 4-HBA and 3-AP, 4-AP), * To whom correspondence should be addressed. Tel.: +91 40 2313 4854; e-mail: [email protected].

substituents (F, Cl, Me), and OH groups (mono- and dihydroxy). These readily available starting materials were cocrystallized in MeOH to obtain diffraction quality single crystals of 11 molecular salts listed in Figure 1. Four hydrates were obtained without intent but analyzed as part of the same structural family. There are four variants of the acid-pyridine heterosynthon in crystal structures: (i) neutral, two-point; (ii) neutral, single-point; (iii) ionic, two point; and (iv) ionic, single-point (Figure 3).2 The carboxylic acid OH donor is localized on the acid group and pyridine N is the acceptor in neutral synthons. There is auxiliary support from (pyridine)C-H · · · O(carbonyl) interaction to the two-point cyclic motif (i) in the coplanar arrangement of interacting functional groups. The acid-pyridine neutral twopoint synthon has energy of 9.9-10.0 kcal mol-1 and occurrence probability of 90% when competing functional groups are absent.7 Twisting of the acid and pyridine groups across the O-H · · · N hydrogen bond gives motif (ii). When there is a sufficient pKa difference between the COOH and pyridyl groups proton transfer will occur to give an ionic hydrogen bond N+-H · · · O-, which too can exist as two-point or single interaction, (iii) and (iv). The transfer from neutral to ionic hydrogen bond as a continuum of intermediate N · · · H · · · O bond states has been noted.8 The issue of whether the acid-pyridine synthon is neutral or ionic is more than a physical and structural chemistry problem, thanks to the legal and patent implications of pharmaceutical cocrystals and salts.9 Some examples of COOH/COO-, pyridine/PyNH+, aniline, and phenol fragments in the same multicomponent crystal structures are listed in Figure 4.10 These hits were extracted from the Cambridge Structural Database11 (CSD, ConQuest 1.1, November 2007 release, January 2008 update). There is a mix of neutral O-H · · · N and ionic N+-H · · · O- acid-pyridine synthons in these crystal structures. Hydrogen bond recognition and pairing studies when

10.1021/cg801145c CCC: $40.75  2009 American Chemical Society Published on Web 02/06/2009

Molecular Salts of Hydroxybenzoic Acids and Aminopyridines

Crystal Growth & Design, Vol. 9, No. 3, 2009 1547

Figure 1. Hydroxybenzoic acids (HBA) cocrystallized with aminopyridines (AP) and the resulting molecular salts.

Figure 2. Acid · · · pyridine and amine · · · phenol synthons are stabilized by strong hydrogen bond pairing.

Figure 3. Four variants of acid-pyridine H bonding in crystal structures. The interacting groups are coplanar in two point synthon i, iii but the pyridyl ring is twisted out of the COO plane in single interaction ii, iv.

many functional groups (COOH/COO-, Py/PyNH+, OH, and NH2) are present in the same crystal structure are relatively few, and this was a reason for carrying out the present work. The term molecular salt is suggested in situations where both anion and cation are derived from acidic and basic molecules, or electron acceptor and donor species. “Molecular salts” have been referred to in the context of organic nonlinear optical materials,12 pharmaceutical solids,13 and structural chemistry14 (see Supporting Information for more examples). Usage of the word molecular salt is appropriate when both ionic components are neutral organic molecules prior to proton or electron transfer. When one or both components are simple counterions (say Cl-or Na+) then the common word salt is correct; for example, ranitidine hydrochloride, sodium diclofenac, and sodium chloride are all salts. In terms of structural landscape, there are many more hydrogen bond synthon combinations possible in molecular salts because of multiple functional groups on both cation

and anion species compared to salts in which hydrogen bonding modes with the counterion are simpler and easier to predict. The site of protonation (on organic base) or deprotonation (of organic acid) is well defined for salts but often the main intent of structural study in case of molecular salts. We suggest the term molecular salt (instead of salt) for ionic compounds assembled from organic acids and bases in this study as well as several others in the recent literature.2,8 The term cocrystal has been debated,15 but we use it to mean neutral multicomponent systems. Crystal structures 1-10 contain the ionic (Py)N+H · · · O-(carboxylate) synthon, whereas 11 is sustained by (Py)N+-H · · · O(acid) hydrogen bond (Figure 5). The proton is transferred from COOH to PyN in all cases. Two-point ionic synthon (iii) is present in six structures (2, 3, 4, 6, 7, 8), and a single ionic H bond (motif iv) occurs in four structures (1, 5, 9, 10). Whether the COOH and pyridine groups are neutral or ionized was ascertained by C-O, CdO bond distances and C-N-C, C-N+-C angles. For example, bond distances of 1.30, 1.20 Å and angles of 117-118° indicate a neutral synthon, whereas an intermediate distance of 1.25 Å and a slightly obtuse angle of 120-121° mean an ionized pyridinium state.8,16 The C-O distance parameter is restated as ∆r < 0.03 Å for ionic COO- and ∆r > 0.08 Å for neutral COOH.9 Similarly, C-O · · · N-C torsion angles of ∼ 3.75.22 This is also referred to as the “rule of 2”; that is, the difference in dissociation constants of acid and base should be >2 for proton transfer.13 Predicting the location of the H atom in the solid-state from acid/base strength or pKa differences is difficult and uncertain. (1) A hydrogen bond is the sharing of H atom between two electronegative atoms, whereas pKa defines the ability of the proton to be transferred from acid to base. Thus pKa values, which are measured specific to a given solvent, have limited predictive ability about the location of the H atom in the crystal structure. Dissociation constants can differ by up to 4-5 orders

Discussion The issue of proton transfer in carboxylic acid · · · pyridine synthon to give PyNH+ · · · -OOC (O-H · · · N f N+-H · · · O-) is a classical problem.21 There is a resurgence in this topic, thanks to advances in X-ray and neutron diffraction8,16 and also because both neutral and salt forms of cocrystals are useful in the pharmaceutical industry for different reasons.9 A rule of thumb is that proton transfer will occur from acid to base when the difference in pKa between the conjugate acid of the base and the carboxylic acid is >3.75, and neutral complex will form when ∆pKa < 3.75, the so-called “rule of 3”.21 With additional structural data on acid · · · pyridine cocrystals and salts the crucial pKa range of -2.5 to + 2.5, in which many organic acids and

Table 2. FT-IR Stretching Frequencies (KBr, cm-1) in 1-11 molecular salt

1

2

3

4

5

6

7

8

9

10

11

COO-, C-O νas, νs

1644 1379

1611 1377

1636 1372

1617 1372

1655 1375

1616 1493

1628 1367

1634 1380

1626 1365

1618 1381

1601 1375 1748

COOH, CdO νs

Molecular Salts of Hydroxybenzoic Acids and Aminopyridines

Crystal Growth & Design, Vol. 9, No. 3, 2009 1551

Figure 9. Synthons in 3-APH+ · 3,5-DiHBA- (4) are PyNH+ · · · -OOC, NH2 · · · -OOC, NH2 · · · OH, and OH · · · -OOC hydrogen bonds.

Figure 10. Synthons in 4-APH+ · 3-F-4-HBA- hydrate (5) are PyNH+ · · · -OOC, NH2 · · · -OOC, NH2 · · · OH, H2O · · · -OOC and OH · · · H2O.

Figure 8. (a) 1D tape of 3-HBA- along the b-axis. (b) OH · · · NH2 · · · -OOC groups involved in a hydrogen-bonded tetramer motif with 4-APH+, which is different from 2 having 3-APH+ and 4-HBA- ions. (c) Overall packing in 3. (d) Square network constructed by H bonds at the nodes and phenyl ring spacers as the connectors. The four H bonds at the nodes are (pyridinium)N+-H · · · O-(carboxylate), (aniline)N-H · · · O(carboxylate), (phenol)O-H · · · O-(carboxylate), and (aniline)N-H · · · O(phenol).

of magnitude by change from water to MeOH medium;23 for example, AcOH pKa is 4.76 in water and 9.63 in MeOH. In effect, salt formation is certain with an organic base (e.g., ephedrine pKa is 9.74 in water and 8.69 in MeOH) when crystallized in aqueous medium but not in MeOH.14 (2) The

nature of the crystalline solid which precipitates from an equilibrium mixture of H-bonded aggregates in solution will depend on many factors such as pH, solvent polarity, temperature, concentration, rate of cooling, supersaturation, crystal nucleation, growth morphology, etc. The crystallized solid is the species at supersaturation from among many others present in solution under the given conditions. Ionic species are generally less soluble in organic solvents and hence more likely to precipitate compared to neutral aggregates, even though they are present only in a minor amount (say 2 σ(I)] wR2 (all) goodness-of-fit T (K)

Table 6. Distribution of Neutral and Ionic Variants of Acid · · · Pyridine Synthona

(C5H7N2) · (C9H9O3) 260.29 monoclinic P21/c 11.5274(12) 11.9967(12) 10.7001(11) 90 111.328(2) 90 1378.4(2) 1.254 0.089 1.90-26.02 4 -14 to 14 -14 to 14 --13 to 13 13952 2326 2721 0.0467 0.1214 1.098 298

-2.08 -5.86 -1.90 -5.35 -1.30 -5.08 -1.07 -4.85 -1.87 -5.65 -5.35

(C5H7N2) · (C9H9O3) · (H2O) 278.30 monoclinic P21/c 8.7720(9) 12.1664(12) 14.0288(14) 90 104.823(2) 90 1447.4(3) 1.277 0.094 2.25-26.01 4 -10 to 10 -14 to 15 -17 to 17 14306 1989 2849 0.0493 0.1358 0.954 298

4.40 1.45 4.63 1.77 4.76 1.81 4.82 1.87 4.26 1.31 1.77

(C5H7N2) · (C7H4O3Cl) 266.68 monoclinic P21/n 11.9368(15) 8.3774(11) 12.6509(17) 90 109.183(2) 90 1194.8(3) 1.482 0.321 2.04-25.00 4 -12 to 14 -9 to 9 -15 to 15 7750 1570 2094 0.0466 0.1120 1.017 100

4.38 1.44 4.61 1.76 4.73 1.79 4.80 1.86 4.24 1.30 1.76

(C5H7N2) · (C7H4O3Cl) · 2(H2O) 302.71 triclinic P1j 7.9596(10) 9.2141(12) 10.1006(13) 83.020(2) 78.551(2) 88.151(1) 720.64(16) 1.395 0.285 2.07-25.00 2 -9 to 9 -10 to 10 -12 to 11 6953 1644 2527 0.0900 0.2083 1.183 298

4-HBA and 4-AP (1) 4-HBA and 3-AP (2) 3-HBA and 4-AP (3) 3,5-DiHBA and 3-AP (4) 3-F-4-HBA and 4-AP (5) 3-F-4-HBA and 3-AP (6) 3-Cl-4-HBA and 4-AP (7) 3-Cl-4-HBA and 3-AP (8) 3,5-DiMe-4-HBA and 4-AP (9) 3,5-DiMe-4-HBA and 3-AP (10) 3,5-DiHBA and 3-AP (11)

(C5H7N2) · (C7H4O3F) 250.23 monoclinic P21/c 12.0905(16) 9.0847(12) 12.0905(16) 90.00 118.30 90.00 1169.2(3) 1.421 0.114 1.91-25.00 4 -14 to 14 -10 to 10 -14 to 10 4916 1687 2032 0.0435 0.1218 1.041 298

∆pKa (methanol)

(C5H7N2) · (C7H4O3F) · (H2O) 268.24 monoclinic P21/c 7.1711(7) 12.8232(13) 13.2749(14) 90.00 95.314(2) 90.00 1215.5(2) 1.466 0.121 2.21-26.02 4 -8 to 8 -15 to 15 -16 to 16 7888 2011 2380 0.0589 0.1426 1.148 298

∆pKa (water)

(C5H7N2) · (C7H5O4) 248.24 monoclinic P21/n 9.6416(15) 10.5167(16) 11.7845(19) 90.00 105.398(2) 90.00 1152.0(3) 1.431 0.109 2.64-25.99 4 -10 to 8 -12 to 2 -13 to 14 2761 1287 1738 0.0457 0.1133 1.004 100

∆pKa (gas phase)

empirical formula

molecular components

(C5H7N2) · (C7H5O3) 232.24 monoclinic P21/c 8.5521(8) 12.7834(12) 10.7993(11) 90.00 111.6490(10) 90.00 1097.35(18) 1.406 0.103 2.56-25.00 4 -10 to 10 -15 to 15 -12 to 12 12031 1792 1924 0.0348 0.0924 1.081 100

Table 5. ∆pKa [) pKa (BH+ - AH)] for 1-11 in Different Media

(C5H7N2) · (C7H5O4) · (C7H6O4) 402.35 orthorhombic Pccn 21.8769(11) 11.7814(6) 14.6796(7) 90 90 90 3783.5(3) 1.413 0.112 1.86-26.04 8 -26 to 26 -14 to 14 -17 to 18 36836 2969 3691 0.0864 0.1691 1.211 298

Molecular Salts of Hydroxybenzoic Acids and Aminopyridines

1556 Crystal Growth & Design, Vol. 9, No. 3, 2009 4-Aminopyridinium 3-chloro-4-hydroxybenzoate hydrate (7) (4APH+ · 3-Cl-4-HBA-- hydrate, 1:1:2): Mp 165-168 °C. Water release at 111-114 °C. 1 H NMR (DMSO-d6): δ 8.21 (br, 1H), 8.03 (d, J ) 4, 2H), 7.93 (d, J ) 8, 1H), 7.23 (d, J ) 8, 1H), 6.72 (d, J ) 4, 2H), 6.53 (s, 1H), 6.29 (br s, 2H). 3-Aminopyridinium 3-chloro-4-hydroxybenzoate (8) (3-APH+ · 3-Cl4-HBA-, 1:1): Mp 150-152 °C. 1 H NMR (DMSO-d6): δ 7.92 (br s, 1H), 7.83 (s, 1H), 7.72-7.74 (m, 2H), 6.99-7.04 (m, 3H), 6.89 (d, J ) 8, 1H), 5.24 (br s, 2H). 4-Aminopyridinium 3,5-dimethyl-4-hydroxybenzoate hydrate (9) (4APH+ · 3,5-DiMe-4-HBA- hydrate, 1:1:1): Mp 170-172 °C. Water release at 115-118 °C. 1 H NMR (DMSO-d6): δ 8.04 (d, J ) 8, 2H), 7.60 (s, 2H), 6.81 (d, J ) 8, 2H), 2.24 (s, 6H). 3-Aminopyridinium 3,5-dimethyl-4-hydroxybenzoate (10) (3-APH+• 3,5-DiMe-4-HBA-, 1:1): Mp 164-168 °C. 1 H NMR (DMSO-d6): δ 9.00 (br s, 1H), 7.91 (s, 1H), 7.70 (d, J ) 4, 1H), 7.52 (s, 2H), 6.96 (dd, J ) 4,4, 1H), 6.88 (dd, J ) 8,1, 1H), 5.23 (br s, 2H), 2.17 (s, 6H). 3-Aminopyridinium 3,5-dihydroxybenzoate (3,5-dihydroxybenzoic acid) (11) (3-APH+ · 3,5-DiHBA- · 3,5-DiHBA, 1:1:1): Mp 204-206 °C. 1 H NMR (DMSO-d6): δ 12.48 (br s, 1H), 9.78 (br s, 4H), 7.93 (br s, 1H), 7.72 (br s, 1H), 7.00 (br s, 1H), 6.87 (br s, 1H), 6.78 (s, 4H), 6.57 (s, 2H), 5.23 (br s, 2H). X-ray Crystallography. Reflections were collected on Bruker SMART CCD diffractometer. Mo KR (λ ) 0.71073 Å) radiation was used to collect X-ray reflections on all crystals (1-11). Data reduction was performed using Bruker SAINT software.31 Structures were solved and refined using SHELXL-9732 with anisotropic displacement parameters for non-H atoms (Table 7). Hydrogen atoms on O and N atoms were experimentally located in all crystal structures. All C-H atoms were fixed geometrically. A check of the final CIF file using PLATON33 did not show any missed symmetry. All N-H and O-H hydrogens were located in difference electron density maps. Packing diagrams were prepared in X-Seed.34 Cambridge Structural Database Searches. The CSD version 5.29,11 ConQuest 1.10, November 2007 release, January 2008 update was used in all searches and crystal structures were visualized in Mercury 2.0. Only organic crystal structures with R < 0.10, no error and not polymeric were retrieved from the database. The lower R-factor structure was retained for duplicate Refcodes. A subdatabase of cocrystals having O-H · · · N or N+-H · · · O- hydrogen bond intermolecular contact within the van der Waals sum was created. Structures having intermediate proton transfer state were retrieved from the neutral acid-pyridine cocrystals set by sorting O-H and N-H distances such that O-H > 1.1 Å in O · · · H · · · N hydrogen bond.

Acknowledgment. We thank the CSIR (01(2079)/06/EMRII) for research funding. CSIR provided fellowship to B.S. and UGC fellowship to B.R.B., N.K.N. is acknowledged. DST (IRPHA) funded the CCD X-ray diffractometer, and UGC is thanked for the UPE program. We thank an unknown referee for critical comments and valuable suggestions. Supporting Information Available: Crystallographic information file; hydrogen bond parameters in molecular salts 1-11, CSD refcodes list, and TGA/DSC plots. This material is available free of charge via the Internet at http://pubs.acs.org.

Sarma et al.

(3)

(4) (5) (6) (7) (8)

(9) (10)

(11) (12) (13) (14) (15)

References (1) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311. (2) Bhogala, B. R.; Vishweshwar, P.; Nangia, A. Cryst. Growth Des. 2002, 2, 325. Bhogala, B. R.; Basavoju, S.; Nangia, A. Cryst. Growth Des. 2005, 5, 1683. Shan, N.; Bond, A. D.; Jones, W. New J. Chem. 2003, 27, 365. Walsh, R. D. B.; Bradner, M. W.; Fleischman, S.; Morales, L. A.; Moulton, B.; Rodrı´guez-Hornedo, N.; Zaworotko, M. J. Chem. Commun. 2003, 186. Bhogala, B. R.; Nangia, A. Cryst. Growth Des. ¨ .; Zaworotko, M. J. Chem. Commun. 2004, 2003, 3, 547. Almarsson, O 1889. Aakero¨y, C. B.; Salmon, D. J. CrystEngComm 2005, 7, 439. Sharma, C. V. K.; Broker, G. A.; Szulczewski, G. J.; Rogers, R. D. Chem. Commun. 2000, 1023. Tomura, M.; Yamashita, Y. Chem. Lett.

(16) (17) (18) (19) (20)

2001, 532. Shan, N.; Batchelor, E.; Jones, W. Tetrahedron Lett. 2002, 43, 8721. Olenik, B.; Smolka, T.; Boese, R.; Sustmann, R. Cryst. Growth Des. 2003, 3, 183. Bond, A. D. Chem. Commun. 2003, 250. Varughese, S.; Pedireddi, V. R. Chem. Eur. J. 2006, 12, 1597. Du, M.; Zhang, Z. H.; Zhao, X. J.; Cai, H. Cryst. Growth Des. 2006, 6, 114. Grossel, C. M.; Dwyer, A. N.; Hursthouse, M. B.; Orton, J. B. CrystEngComm 2006, 8, 123. Bhogala, B. R.; Nangia, A. New J. Chem. 2008, 32, 800. Santra, R.; Ghosh, N.; Biradha, K. New J. Chem. 2008, 32, 1673. Ermer, O.; Eling, A. J. Chem. Soc., Perkin Trans. 2 1994, 925. Hanessian, S.; Simard, M.; Roelens, S. J. Am. Chem. Soc. 1995, 117, 7630. Allen, F. H.; Hoy, V. J.; Howard, J. A. K.; Thalladi, V. R.; Desiraju, G. R.; Wilson, C. C.; McIntyre, G. J. J. Am. Chem. Soc. 1997, 119, 3477. Vangala, V. R.; Bhogala, B. R.; Dey, A.; Desiraju, G. R.; Broder, C. K.; Smith, P. S.; Mondal, R.; Howard, J. A. K.; Wilson, C. C. J. Am. Chem. Soc. 2003, 125, 14495. Hanessian, S.; Saladino, R.; Margarita, R.; Simard, M. Chem. Eur. J. 1999, 5, 2169. Dey, A.; Desiraju, G. R.; Mondal, R.; Howard, J. A. K. Chem. Commun. 2004, 2528. Etter, M. C. Acc. Chem. Res. 1990, 23, 120. Etter, M. C. J. Phys. Chem. 1991, 95, 4601. Caballero, N. A.; Melendez, F. J.; Mun˜oz-Caro, C.; Nin˜o, A. Biophys. Chem. 2006, 124, 155, and references cited therein. . Kawase, M.; Motohashi, N.; Kurihara, T.; Inagaki, M.; Satoh, K.; Sakagami, H. Anticancer Res. 1998, 18, 1069, and references therein. . Vishweshwar, P.; Nangia, A.; Lynch, V. M. J. Org. Chem. 2002, 67, 556. Vishweshwar, P.; Nangia, N.; Lynch, V. M. Cryst. Growth Des. 2003, 3, 783. Boenigk, D.; Mootz, D. J. Am. Chem. Soc. 1988, 110, 2135. Cowan, J. A.; Howard, J. A. K.; McIntyre, G. J.; Lo, S. M.-F.; Williams, I. D. Acta Crystallogr. 2003, B59, 794. Steiner, T.; Majerz, I.; Wilson, C. C. Angew. Chem., Int. Ed. 2001, 40, 2651. Parkin, A.; Harte, S. M.; Goeta, A. E.; Wilson, C. C. New. J. Chem. 2004, 28, 718. Aakero¨y, C. B.; Hussain, I.; Desper, J. Cryst. Growth Des. 2006, 6, 474. Schmidtmann, M.; Wilson, C. C. CrystEngComm 2008, 10, 177. Childs, S. L.; Hardcastle, K. I. Cryst. Growth Des. 2007, 7, 1291. Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharmaceutics 2007, 4, 323. Smith, G.; Wermuth, U. D.; Healy, P. C.; White, J. M. Aust. J. Chem. 2003, 56, 707. [AJECEX]Smith, G.; Wermuth, U. D.; White, J. M. Acta Crystallogr. 2004, C60, o575[EYIWIS]Meng, X.-G.; Zhao, C.S.; Wang, L.; Liu, C.-L. Acta Crystallogr. 2007, C63, o667[GIMSIF, GIMSOL]Li, S.-L.; Ma, J.-F.; Ping, G.-J. Acta Crystallogr. 2006, C62, o1173[KEFZAX]Yang, D.-J.; Qu, S.-H. Acta Crystallogr. 2006, C62, o5127[KERFUJ]Lynch, D. E.; Smith, D.; Freney, D.; Byriel, K. A.; Kennard, C. H. L. Aust. J. Chem. 1994, 47, 1097. [LEWRUA]Smith, G.; Wermuth, U. D.; Bott, R. C.; White, J. M.; Willis, A. C. Aust. J. Chem. 2001, 54, 165. [MIPRIM, MIPROS]Braverman, M. A.; LaDuca, R. L. Acta Crystallogr. 2007, E63, o3167[RIGWUA]Gellert, R. W.; Hsu, I.-N. Acta Crystallogr. 1988, C44, 311. [SLCADB10]Wang, Z.-L.;Xie,J.-G.;Wei,L.-H.ActaCrystallogr.2007,E63,o1579[TEZXIG]Kobayashi, N.; Naito, T.; Inabe, T. Bull. Chem. Soc. Jpn. 2003, 76, 1351. [BAXZAC]Karle, I.; Gilardi, R. D.; Rao, C. C.; Muraleedharan, K. M.; Ranganathan, S. J. Chem. Cryst. 2003, 33, 727. [OMIHIB]Bertolasi, V.; Gilli, P.; Ferretti, V.; Gilli, G. Acta Crystallogr. 2001, B57, 591. [RALDUD, RALFAL]. . (a) Allen, F. H. Acta Crystallogr. 2002, B58, 380. (b) Cambridge Structural Database, ConQuest 1.10, November 2007 release,January 2008 update. www.ccdc.cam.ac.uk. Coe, B. J.; Harris, J. A.; Brunschwig, B. S.; Garin, J.; Orduna, J. J. Am. Chem. Soc. 2005, 127, 3284. Black, S. N.; Collier, E. A.; Davey, R. J.; Roberts, R. J. J. Pharma Sci. 2007, 96, 1053. McKay, S. E.; Wheeler, K. A.; Blackstock, S. C. CrystEngComm 2006, 8, 129. Desiraju, G. R. CrystEngComm 2003, 5, 466. Dunitz, J. D. CrystEngComm 2003, 5, 506. Bond, A. D. CrystEngComm 2007, 9, 833. Vishweshwar, P.; Jagadeesh Babu, N.; Nangia, A.; Mason, S. A.; Puschmann, H.; Mondal, R.; Howard, J. A. K. J. Phys. Chem. A 2004, 108, 9406. Silverstein, R. M., Webster, F. X. Spectrometric Identification of Organic Compounds, 6th ed.; John Wiley & Sons: Singapore, 2004. Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N. L. Angew. Chem., Int. Ed. Engl. 1995, 34, 1555. Rafilovich, M.; Bernstein, J.; Hickey, M. B.; Tauber, M. Cryst. Growth Des. 2007, 7, 1777. Wenger, M.; Bernstein, J. Cryst. Growth Des. 2008, 8, 1595. Sarma, B.; Reddy, L. S.; Nangia, A. Cryst. Growth Des. 2008, 8, 4546, and references cited therein (Special Issue on Cocrystals) .

Molecular Salts of Hydroxybenzoic Acids and Aminopyridines (21) Johnson, S. L.; Rumon, K. A. J. Phys. Chem. 1965, 69, 74. (22) Bhogala, B. R.; Basavoju, S.; Nangia, A. CrystEngComm 2005, 7, 551. (23) Rived, F.; Rose´s, M.; Bosch, E. Anal. Chim. Acta 1998, 374, 309. (24) (a) Takasuka, M.; Nakai, H.; Shiro, M. J. Chem. Soc., Perkin Trans. 1982, 2, 1061. (b) CSD refcodes BIXGIY, BIXGIY02, BIXGIY03, BIXGIY04. (25) Babu, N. J.; Reddy, L. S.; Aitipamula, S.; Nangia, A. Chem Asian J. 2008, 3, 1122. (26) Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 8342. (27) Krishna Murthy, H. M.; Vijayan, M. Acta Crystallogr. 1979, B35, 262. (28) The SPARC program (ibmlc2.chem.uga.edu/sparc/) uses computational algorithms based on fundamental chemical structure theory to estimate a variety of reactivity parameters. For some recent papers using the SPARC program for pKa calculations, see Erdemgil, F. Z.; S¸anli, S.; ¨ zkan, G.; Barbosa, J.; Guiteras, J.; Beltra´n, J. L. Talanta 2007, 72, O 489. Hilal, S. H.; Karickhoff, S. W.; Carreira, L. A. Quant. Struct. Act. Rel. 1995, 14, 348. Hilal, S. H.; Carreira, L. A.; Karickhoff, S. W. Talanta 1996, 43, 607. Hilal, S. H.; Carreira, L. A.; Melton, C.; Baughman, G.; Karickhoff, S. W. J. Phys. Org. Chem. 1994, 7, 122.

Crystal Growth & Design, Vol. 9, No. 3, 2009 1557 (29) Shattock, T. R.; Arora, K. K.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2008, 8, 4533. (30) Stahl, P. H.; Wermuth, C. G., Eds.; Handbook of Pharmaceutical Salts. Properties, Selection and Use; Wiley-VCH: Chichester, 2002. Gould, ¨ .; P. L. Int. J. Pharm. 1986, 33, 201. Morissette, S. L.; Almarsson, O Peterson, M. L.; Remenar, J. F.; Read, M. J.; Lemmo, A. V.; Ellis, S.; Cima, M. J.; Gardner, C. R. AdV. Drug DeliVery ReV. 2004, 46, 275. Banerjee, R.; Bhatt, P. M.; Ravindra, N. V.; Desiraju, G. R. Cryst. Growth Des. 2005, 5, 2299. (31) SADABS, Program for Empirical Absorption Correction of Area Detector Data; Sheldrick, G. M. University of Go¨ttingen: Germany, 1997. (32) Sheldrick, G. M. SHELXS-97 and SHELXL-97, Programs for the Solution and Refinement of Crystal Structures; University of Go¨ttingen: Germany, 1997. (33) (a) Spek, A. L. PLATON, A Multipurpose Crystallographic Tool; Utrecht University: Utrecht, Netherland, 2002. Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7. (34) Barbour, L. J. X-Seed, Graphical Interface to SHELX-97 and POVRay; University of Missouri-Columbia: Columbia, MO, 1999.

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