Benzimidazoles and

Toward High-Yielding Supramolecular Synthesis: Directed Assembly of Ditopic Imidazoles/Benzimidazoles and Dicarboxylic Acids into Cocrystals via Selective O-H‚‚‚N Hydrogen Bonds

CRYSTAL GROWTH & DESIGN 2005 VOL. 5, NO. 3 865-873

Christer B. Aakeroÿ,* John Desper, Brian Leonard, and Joaquin F. Urbina Department of Chemistry, Kansas State University, Manhattan, Kansas 66506 Received September 20, 2004;

Revised Manuscript Received November 2, 2004

ABSTRACT: The supramolecular reactions between symmetric ditopic imidazoles/benzimidazoles and a variety of aliphatic and aromatic dicarboxylic acids produced molecular cocrystals 1-8 in high yields. Despite variations in molecular shape and substituent groups on the ditopic bases, each structure contained infinite 1-D molecular chains held together by robust, primary O-H‚‚‚N hydrogen bonds. Secondary C-H‚‚‚O interactions existed within these motifs as well as between neighboring chains, and it seems that intra- and interchain interactions are of equal structural importance based upon an analysis of the metrics displayed by each set of interactions. This study demonstrates that neutral hydrogen-bond interactions between imidazole/benzimidazoles (acting as the acceptor sites) and carboxylic acids (acting as the donor sites) provide sufficient driving force for the directed assembly of a wide range of binary cocrystals. Introduction Understanding the nature of intermolecular interactions is a crucial aspect of crystal engineering,1-3 and the hydrogen bond has been established as the most effective tool for constructing sophisticated assemblies from discrete ionic or molecular building blocks due to its strength and directionality.1,3 A key requirement in the development of strategies for noncovalent synthesis is the availability of reliable supramolecular synthons.4,5 The usefulness of supramolecular synthons is related to the frequency of occurrence of desired intermolecular interactions between molecules under certain reaction conditions. Such reliability can be paralleled to named reactions in organic chemistry where molecular transformations or specific bond-making/breaking events take place under particular reaction conditions with high degrees of certainty. Typically, reliable supramolecular synthons need to be insensitive to subtle changes in molecular shape, substituent groups, and to competition from other intermolecular interactions such as π-π interactions and interactions with solvent molecules. One supramolecular synthon that has been employed frequently in the construction of extended architectures in the solid state is the carboxylic acid‚‚‚pyridine (COOH‚‚‚Py) synthon, Scheme 1. The COOH‚‚‚Py synthon consists of the primary O-H‚‚‚N hydrogen bond and the auxiliary C-H‚‚‚O interaction (although the latter may not always be present). It has been instrumental in the design of oneand two-dimensional supramolecular architectures, such as infinite chains,6 honeycomb layers,7 and sheets,8 utilizing 4,4′-bipyridine and its derivatives as the hydrogen-bond acceptor. Since crystal engineering also seeks a niche in mimicking the sophisticated and delicate systems observed in Nature, it is also necessary to identify synthons built upon chemical moieties compatible with or encountered in biology and biochemistry. As a result, we will focus on the carboxylic acid‚‚‚imidazole (COOH‚‚‚Im) and

Scheme 1. The Carboxylic Acid‚‚‚Pyridine Synthon

carboxylic acid‚‚‚benzimidazole (COOH‚‚‚Bzim) interactions, which have more biological relevance than the COOH‚‚‚Py synthon. Imidazole (Im), benzimidazole (Bzim), and their derivatives are ubiquitous in biological and biochemical structure and function, such as the roles of histidine as a metal ion binding site in metalloenzymes9 and in the catalytic mechanisms of ribonucleases and other phosphoesterases.10 Histidine also plays a part in cytochrome c peroxidase11 as well as in copper transport in humans.12 Im and Bzim derivatives have also found applications in drug design in the forms of antitumor13 and anticancer14 agents. In fact, these derivatives are known to treat a variety of physiological disorders.15 Consequently, the importance of imidazoles and benzimidazoles in biology and biochemistry cannot be overstated. We are interested in exploring the reliability of the COOH‚‚‚Im and COOH‚‚‚Bzim synthons in the presence of potentially disruptive intermolecular interactions such as π-π interactions and interactions with solvent molecules. In addition, we will study the effect of molecular shape and substituent groups on these synthons by altering the geometry involved in the constituent intermolecular interactions (i.e., switching from imidazole to benzimidazole and by replacing the H2 hydrogen atom on the benzimidazol-1-yl moiety with a methyl group). By understanding these scenarios we can develop a library of reliable supramolecular synthons that can, in principle, find applications in more sophisticated biological systems, e.g., cytochrome c peroxi-

10.1021/cg049682i CCC: $30.25 © 2005 American Chemical Society Published on Web 12/24/2004

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Crystal Growth & Design, Vol. 5, No. 3, 2005

Scheme 2. N-Substituted Imidazoles and Benzimidazoles Denoting Labeled Nitrogen Atoms

dase11 and CGS 14796C,17 in order to better understand the nature and roles of relevant intermolecular interactions. When carboxylic acids interact with Im and Bzim the solid-state outcome is often an organic salt, not a cocrystal, as a result of proton transfer.16 A cocrystal can form, however, if a carboxylic acid interacts with an imidazol-1-yl or benzimidazol-1-yl moiety as noted in the crystal structure of 1,4-bis[(imidazol-1-yl)methyl]cyclohexane:succinic acid, a 1:1 cocrystal (CGS 14796C, an active nonsteroidal aromatase inhibitor).17 An O-H ‚‚‚N hydrogen bond is formed between the carboxylic acid group on succinic acid and the imidazol-1-yl nitrogen atom. In this study, we will test the limits and limitations of COOH‚‚‚Im/COOH‚‚‚Bzim interactions through a systematic structural study of eight molecular cocrystals composed of dicarboxylic acids and symmetric ditopic bis-imidazol-1-yl/bis-benzimidazol-1-yl compounds; 1,4bis[(imidazol-1-yl)methyl]benzene:trans-3-hexenedioic acid (1), 1,4-bis[(imidazol-1-yl)methyl]benzene:fumaric acid (2), 1,4-bis[(imidazol-1-yl)methyl]benzene:succinic acid (3), 1,4-bis[(imidazol-1-yl)methyl]benzene:isophthalic acid (4), 1,4-bis[(benzimidazol-1-yl)methyl]benzene:fumaric acid (5), 1,4-bis[(benzimidazol-1-yl)methyl]benzene:isophthalic acid:EtOH0.5 (6), 1,4-bis[(benzimidazol-1-yl)methyl]benzene:5-aminoisophthalic acid: EtOH0.5 (7), and 1,4-bis[(2-methylbenzimidazol-1yl)methyl]benzene:trans-3-hexenedioic acid (8). N-Substituted symmetric ditopic imidazoles and benzimidazoles can be prepared by substituting the N1 atom on the Im and Bzim moieties with an alkyl group, Scheme 2. We will also investigate the nature of the C-H‚‚‚O interaction that can arise from the COOH‚‚‚Im and COOH‚‚‚Bzim synthons. Since a O-H‚‚‚N hydrogen bond would involve the best hydrogen-bond donor (the acidic OH group of the carboxylic acid) and the best hydrogen-bond acceptor (the heterocyclic nitrogen atom), we can expect this hydrogen bond to be the primary intermolecular force. In cocrystals of carboxylic acids and 4,4′-bipyridine, the secondary C-H‚‚‚O interaction also arises from the C-H group on the C2 carbon of 4,4′bipyridine and the carbonyl oxygen atom of the carboxylic acid. However, since 4,4′-bipyridine is symmetric about the nitrogen atoms, the ortho-C-H groups are equivalent. This is not the case in the COOH‚‚‚Im and COOH‚‚‚Bzim synthons because the ortho-C-H groups possess different acidities. Thus, our study will allow us to establish if the carbonyl oxygen atom on the acid shows a preference for the more acidic of the two C-H options,18 Scheme 3. Experimental Section Syntheses.19 The syntheses of the imidazol-1-yl/benzimidazol-1-yl compounds are presented elsewhere.20 Melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected.

Aakeroÿ et al. Scheme 3. The (a) COOH‚‚‚Im and (b) COOH‚‚‚Bzim Synthons Indicating the Best and Second-Best Hydrogen-Bond Donor/Acceptor Couples

1,4-Bis[(imidazol-1-yl)methyl]benzene:Trans-3-hexenedioic Acid, 1. 1,4-Bis[(imidazol-1-yl)methyl]benzene (0.050 g, 0.18 mmol) was dissolved in 1 mL of methanol. To this solution was added an ethanolic solution containing trans-3hexenedioic acid (0.030 g, 0.18 mmol). Colorless prisms were obtained after one week of slow evaporation of the solvent. mp 171-176 °C; IR (KBr pellet) ν 2450 cm-1, 1928 cm-1 (OH‚‚‚N, br), 1700 cm-1 (CdO, s). 1,4-Bis[(imidazol-1-yl)methyl]benzene:Fumaric Acid, 2. 1,4-Bis[(imidazol-1-yl)methyl]benzene (0.050 g, 0.18 mmol) was dissolved in 1 mL of methanol. To this solution was added fumaric acid (0.020 g, 0.18 mmol) in ethanol. Colorless prisms were afforded after one week of slow evaporation of the solvent. mp 175-178 °C; IR (KBr pellet) ν 2472 cm-1, 1931 cm-1 (OH‚‚‚N, br), 1695 cm-1 (CdO, s). 1,4-Bis[(imidazol-1-yl)methyl]benzene:Succinic Acid, 3. 1,4-Bis[(imidazol-1-yl)methyl]benzene (0.050 g, 0.18 mmol) was dissolved in 1 mL of methanol. An ethanolic solution of succinic acid (0.020 g, 0.18 mmol) was added to this solution. Colorless prisms were obtained after one week upon evaporation of the solvent. mp 159-161 °C; IR (KBr pellet) ν 2423 cm-1, 1952 cm-1 (O-H‚‚‚N, br), 1700 cm-1 (CdO, s). 1,4-Bis[(imidazol-1-yl)methyl]benzene:Isophthalic Acid, 4. 1,4-Bis[(imidazol-1-yl)methyl]benzene (0.050 g, 0.18 mmol) was dissolved in 1 mL of methanol. To this solution was added isophthalic acid (0.030 g, 0.18 mmol) in ethanol. Colorless prisms were afforded after one week of slow evaporation of the solvent. mp 174-178 °C; IR (KBr pellet) ν 2448 cm-1, 1927 cm-1 (O-H‚‚‚N, br), 1691 cm-1 (CdO, s). 1,4-Bis[(benzimidazol-1-yl)methyl]benzene:Fumaric Acid, 5. 1,4-Bis[(benzimidazol-1-yl)methyl]benzene (0.050 g, 0.15 mmol) was dissolved in 1 mL of ethanol. To this solution was added an ethanolic solution containing fumaric acid (0.020 g, 0.15 mmol). Orange plates were afforded after 24 h of slow evaporation of the solvent. mp 234-238 °C (decomp.); IR (KBr pellet) ν 2450 cm-1, 1917 cm-1 (O-H‚‚‚N, br), 1700 cm-1 (Cd O, s). 1,4-Bis[(benzimidazol-1-yl)methyl]benzene:Isophthalic acid:EtOH0.5, 6. 1,4-Bis[(benzimidazol-1-yl)methyl]benzene (0.050 g, 0.15 mmol) was dissolved in 1 mL of ethanol. To this solution was added an ethanolic solution containing isophthalic acid (0.030 g, 0.15 mmol). Orange prisms were obtained after two weeks of slow evaporation of the solvent. mp 177-180 °C; IR (KBr pellet) ν 2494 cm-1, 1918 cm-1 (O-H‚‚‚N, br), 1696 cm-1 (CdO, s). 1,4-Bis[(benzimidazol-1-yl)methyl]benzene:5-Aminoisophthalic Acid:EtOH0.5, 7. 1,4-Bis[(benzimidazol-1-yl)methyl]benzene (0.050 g, 0.15 mmol) was dissolved in 1 mL of ethanol. To this solution was added a solution containing 5-aminoisophthalic acid (0.030 g, 0.15 mmol) in ethanol. Orange plates were afforded after two weeks of slow evaporation of the solvent. mp 230-234 °C; IR (KBr pellet) ν 2438 cm-1, 1917 cm-1 (O-H‚‚‚N, br), 1700 cm-1 (CdO, s). 1,4-Bis[(2-methylbenzimidazol-1-yl)methyl]benzene: Trans-3-hexenedioic Acid, 8. 1,4-Bis[(2-methylbenzimidazol-1-yl)methyl]benzene (0.020 g, 0.050 mmol) was dissolved in 1 mL of ethanol. To this solution was added trans-3hexenedioic acid (0.010 g, 0.050 mmol) in ethanol. Colorless plates were obtained after 2 days of slow evaporation of the

Directed Assembly of Binary Cocrystals

Crystal Growth & Design, Vol. 5, No. 3, 2005 867 Table 1. Crystallographic Data for 5-8

compound

1

2

3

4

formula moiety empirical formula molecular weight color, habit crystal system space group, Z A, Å B, Å C, Å R, deg β, deg γ, deg volume, Å3 density, g/cm3 temperature, K X-ray wavelength µ,mm-1 θmin, deg θmax, deg reflections collected independent observed threshold expression R1 (observed) wR2 (all)

(C14H14N4) (C6H8O4) C20H22N4O4 382.42 colorless prism monoclinic P2(1)/n, 2 6.3599(9) 9.7320(14) 15.357(2) 90 94.874(3) 90 947.1(2) 1.341 203(2) 0.71073 0.095 2.48 28.23



(C14H14N4) (C8H6O4) C22H20N4O4 404.42 colorless prism monoclinic C2/c, 4 28.229(4) 6.9743(10) 10.8784(15) 90 111.248(3) 90 1996.1(5) 1.346 203(2) 0.71073 0.095 1.55 28.28

6970 2200 1561 >2σ(I) 0.0534 0.1332

6268 1954 1591 >2σ(I) 0.0484 0.1228

6042 1917 1620 >2σ(I) 0.0397 0.1083

7250 2307 1700 >2σ(I) 0.0479 0.1237

5

6

7

8

formula moiety

compound

(C22H18N4) (C4H4O4) C26H22N4O4 454.48 orange plate monoclinic C2/c, 4 19.6454(17) 11.7257(11) 10.0116(8) 90 108.704(2) 90 2184.4(3) 1.382 203(2) 0.71073 0.095 2.05 28.18

(C22H18N4) (C8H7NO4) (C2H5O)0.5 C31H27.5N5O4.5 542.08 orange plate triclinic P-1, 2 7.5488(4) 12.6754(6) 14.4453(8) 97.729(3) 91.058(4) 105.310(3) 1318.91(12) 1.365 203(2) 0.71073 0.094 1.42 28.31

(C24H22N4) (C6H8O4)

empirical formula molecular weight color, habit crystal system space group, Z A, Å B, Å C, Å R, deg β, deg γ, deg volume, Å3 density, g/cm3 temperature, K X-ray wavelength µ,mm-1 θmin, deg θmax, deg reflections collected independent observed threshold expression R1 (observed) wR2 (all)

(C22H18N4) (C8H6O4) (C2H5O)0.5 C31H26.5N4O4.5 527.06 orange prism triclinic P-1, 2 7.2994(5) 12.8648(10) 14.6528(11) 81.721(2) 89.530(2) 74.090(2) 1308.77(17) 1.337 203(2) 0.71073 0.091 1.41 27.1

C30H30N4O4 510.58 colorless plate triclinic P-1, 1 8.3455(19) 9.0921(19) 9.858(2) 77.825(14) 75.061(15) 66.352(9) 657.1(3) 1.29 203(2) 0.71073 0.087 2.15 28.23

7892 2515 1833 >2σ(I) 0.0439 0.1265

8877 5333 4168 >2σ(I) 0.0487 0.1425

10106 5914 4185 >2σ(I) 0.0460 0.1264

4931 2969 1606 >2σ(I) 0.0467 0.1132

solvent. mp 215-220 °C; IR (KBr pellet) ν 2525 cm-1, 1918 cm-1 (O-H‚‚‚N, br), 1700 cm-1 (CdO, s). X-ray Crystallography. X-ray data were collected on a Bruker SMART 1000 four-circle CCD diffractometer using a fine-focus molybdenum KR tube. Data were collected using SMART.21 Initial cell constants were found by small widely separated “matrix” runs. Preliminary Laue´ symmetry was determined from axial images. Generally, an entire hemisphere of reciprocal space was collected regardless of Laue´ symmetry. Scan speed and scan width were chosen based on scattering power and peak rocking curves. Unit cell constants and orientation matrix were improved by least-squares refinement of reflections thresholded from the entire dataset. Integration was performed with SAINT,22 using this improved unit cell as a starting point. Precise unit cell constants were calculated in SAINT from the final merged dataset. Lorenz and polarization corrections were applied, but

data were generally not corrected for absorption. Laue´ symmetry, space group, and unit cell contents were found with XPREP. Data were reduced with SHELXTL.23 The structures were solved in all cases by direct methods without incident. In general, hydrogens were assigned to idealized positions and were allowed to ride. Where possible, the coordinates of hydrogen-bonding hydrogens were allowed to refine. Heavy atoms, other than those of the guests, were refined with anisotropic thermal parameters. Relevant crystallographic data for 1-8 are given in Table 1 and the relevant hydrogenbond parameters are provided in Table 2. (1) The carboxylic acid hydrogen and the imidazole C-2 hydrogen were allowed to refine; all other hydrogens were located at calculated positions. (2) The carboxylic acid hydrogens and the imidazole C-5 hydrogen were allowed to refine; all other hydrogens were located at calculated positions.

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Aakeroÿ et al.

Table 2. Hydrogen-Bond Geometries for 1-8 compound

D-H‚‚‚A

D-H/Å

H‚‚‚A/Å

D‚‚‚A/Å

Benzimidazoles and

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