Balancing Hydrogen-Bond Donors and Acceptors in a Family of

Balancing Hydrogen-Bond Donors and Acceptors in a Family of Bifunctional Aromatic N-Heterocycles Christer B. Aakeröy,*,† Nate Schultheiss,† John Desper,† and Curtis Moore‡ Department of Chemistry, Kansas State UniVersity, 111 Willard Hall, Manhattan, Kansas, and Department of Chemistry, Wichita State UniVersity, 1845 Fairmount, Wichita, Kansas

CRYSTAL GROWTH & DESIGN 2007 VOL. 7, NO. 11 2324–2331

ReceiVed April 17, 2007; ReVised Manuscript ReceiVed August 16, 2007

ABSTRACT: A series of bifunctional pyridine-aminopyrimidine/aminopyridine supramolecular reagents (SRs) have been synthesized through palladium-catalyzed cross-coupling reactions and characterized by single-crystal X-ray crystallography. 3-(2-Amino-4-methylpyrimidin-6-yl)pyridine 1, 4-(2-amino-4-methylpyrimidin-6-yl)pyridine 2, and 4-methoxy-3-(2-amino-4-methylpyrimidin-6-yl)pyridine 3 were synthesized via Suzuki-Miyaura cross-coupling conditions in good yields, whereas 1-(2-amino-4-methylpyrimidin-6-yl)-2-(3-methoxypyridin5-yl)ethyne 4, 1-(2-aminopyrid-5-yl)-2-(pyrid-3-yl)ethyne 5, and 1-(6-amino-3-pyridyl)-2-(4-{benzimidazol-1-yl}phenyl)ethyne 6 were synthesized through conventional Sonogashira cross-coupling conditions. The primary hydrogen-bonding motif in solid-state structures 1–5 is a self-complementary amino-pyrimidine N–H · · · N/N · · · H–N synthon, whereas adjacent molecules in the structure of 6 are connected via aminopyridine-benzimidazole N–H · · · N hydrogen bonds. Secondary anti-amino proton/pyridyl N–H · · · N hydrogen bonds exist in the structures of 1, 2, 4, and 5, thereby establishing a hierarchy of intermolecular interactions in structures with multiple hydrogen-bond donors and acceptors. Introduction The design and construction of di- and tritopic supramolecular reagents (SRs) that can be utilized for establishing intermolecular pattern preferences and a relative ranking of competing supramolecular synthons play an important part when it comes to developing transferable strategies for deliberate assembly of molecular cocrystals.1 Such SRs offer two or more electronically and geometrically different binding sites, which can be probed in systematic structural studies using a series of molecular building blocks substituted with competing chemical functionalities. It has been demonstrated in systematic cocrystallization reactions that a carboxylic acid (or a suitable oxime) prefers to bind to the more basic site in molecules composed of two aromatic N-heterocyclic moieties, i.e., pyridine, imidazole, benzimidazole, indazole. Furthermore, when an aromatic Nheterocycle is combined with a self-complementary functionality such as an amide, an incident carboxylic acid displays a preference for the heterocycle as long as this moiety is sufficiently basic, e.g., pyridine, benzimidazole, imidazole, etc.2 Such SRs can also act as synthetic platforms for the construction of ternary supermolecules with predictable stoichiometry and connectivity.3 Furthermore, they are also synthetically useful in the directed assembly of extended inorganic–organic hybrid materials. The combination of a reliable coordination site, i.e., nitrogen-containing aromatic heterocycle, and a self-complementary hydrogen-bonding moiety can enable the assembly of discrete metal–ligand complexes into one-, two-, or threedimensional networks.4,5 Within crystal engineering, heteromeric synthons are often employed as tools for the construction of predictable supramolecular architectures with reliable connectivities and stoichiometries. Molecules containing self-complementary donor/ acceptor functionalities such as carboxylic acids and carboxamides, Scheme 1, are particularly advantageous because of their hydrogen-bonding strength and versatility.6 However, far fewer strategies have employed molecules appended with aminopy* Corresponding author. E-mail: aakerö[email protected]. † Kansas State University. ‡ Wichita State University.

Scheme 1. Series of Self-Complementary Hydrogen-Bonding Moieties; Carboxylic Acid, Amide, Amino-Pyrimidine, and Amino-Pyridine

Scheme 2. Series of Bifunctional Pyridine/Amino-Pyrimidine and Pyridine/Amino-Pyridine SRs Suitable for the Construction of Ternary Cocrystals and/or Extended Coordination Complexes

rimidine7 or aminopyridine8 groups, Scheme 1, as supramolecular building blocks, although they too possess selfcomplementary hydrogen-bonding moieties capable of linking individual molecules together. In this study, we describe the synthesis and solid-state characterization of six ditopic pyridine/amino-pyrimidine or pyridine/ amino-pyridine SRs, Scheme 2. Each SR contains two distinctly different binding sites, e.g., pyridine and amino-pyridine or amino-

10.1021/cg070373c CCC: $37.00  2007 American Chemical Society Published on Web 10/19/2007

Balancing Hydrogen-Bond Donors and Acceptors in N-Heterocycles

Crystal Growth & Design, Vol. 7, No. 11, 2007 2325

Table 1. Crystallographic Data for 1–6 and 2a

formula fw equipment cryst syst color, habit space group, Z a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) T (K) density (g/cm3) X-ray wavelength µ (mm-1) θmin (deg) θmax (deg) no. of reflns collected no. of independent reflns no. of reflns observed threshold exp R1 (observed) wR2 (all)

1

2

2a

3

4

5

6

(C10H10N4) 186.2 SMART 1000 triclinic amber prism j 2 P1, 6.9426(4) 7.2048(5) 9.3201(6) 92.459(4) 91.380(4) 107.319(4) 444.31(5) 203(2) 1.392 0.71073 0.090 2.19 27.86 3137 1937 1457 >2σ(I) 0.0500 0.1613

(C10H10N4) 186.22 SMART APEX orthorhombic yellow prism P2(1)2(1)2(1), 2 5.5629(4) 7.4679(6) 22.1080(18) 90 90 90 918.44(12) 100(2) 1.347 0.71073 0.087 1.84 28.29 8151 1333 1272 >2σ(I) 0.0365 0.1022

(C10H10N4) 186.22 SMART APEX monoclinic clear block P2(1)/c, 16 12.7944(9) 12.9712(9) 23.1035(15) 90 90.246(4) 90 3834.2(5) 293(2) 1.290 0.71073 0.083 1.57 26.58 81780 7976 5056 >2σ(I) 0.1079 0.3066

(C11H12N4O) 216.25 SMART APEX orthorhombic colorless prism Pbca, 8 11.6093 7.2822(7) 24.604(2) 90 90 90 2080.0(3) 173(2) 1.381 0.71073 0.094 2.41 28.28 14559 2469 1266 >2σ(I) 0.0566 0.1490

(C13H12N4O)(CH2Cl2)0.5 282.73 SMART APEX triclinic colorless plate j 2 P1, 7.2432(8) 7.7893(8) 12.6950(13) 107.292(2) 91.059(2) 98.566(2) 674.75(12) 100(2) 1.392 0.71073 0.282 1.68 29.98 7714 3831 2885 >2σ(I) 0.0677 0.1922

(C12H9N3) 195.22 SMART APEX monoclinic yellow block P2(1)/c, 4 8.6286(6) 15.3249(10) 8.1780(6) 90 115.5070(10) 90 976.00(12) 100(2) 1.329 0.71073 0.083 2.62 30.02 11007 2834 2389 >2σ(I) 0.0563 0.1887

(C21H16N4) 324.38 SMART 1000 triclinic amber plate j 2 P1, 5.132(2) 10.542(4) 15.457(6) 83.343(19) 89.94(3) 88.14(3) 830.1(6) 173(2) 1.298 0.71073 0.079 1.33 27.08 5700 3484 972 >2σ(I) 0.0881 0.2667

pyrimidine that can be utilized for preparing ternary cocrystals or higher-dimensional inorganic–organic hybrid materials. Experimental Section All chemicals, unless otherwise noted, were purchased from Aldrich and used without further purification. The catalyst, bis(triphenylphosphine)palladium(II) dichloride, was purchased from Strem chemicals. Trimethylsilylacetylene was purchased from GFS chemicals. 4-Pyridylboronic acid was purchased from COMBI-BLOCKS and used as is. Detailed synthetic procedures for 1, 3, 4, and 5 have been published previously.9 Column chromatography was carried out on silica gel (150 Å pore size) from Analtech Inc. Melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a Varian Unity plus 400 or 200 MHz spectrometer in CDCl3. Compounds were prepared for infrared spectroscopic (IR) analysis as a mixture in KBr and analyzed on a Nicolet Protégé 460. Electrospray Ionization–Ion Trap–Mass Spectrometry (ESI-IT-MS) was carried out on a Bruker Daltonics Esquire 3000 Plus. Synthesis of 4-(2-Amino-4-methylpyrimidin-6-yl)pyridine, 2. A mixture of 2-amino-4-chloro-6-methylpyrimidine (1.20 g, 8.39 mmol), 4-pyridylboronic acid (1.14 g, 9.27 mmol), sodium carbonate (0.500 g, 6.03 mmol), and bis(triphenylphosphine)palladium(II) dichloride (180 mg, 0.256 mmol, 2.5 mol %) was added to a round bottom flask. Acetonitrile (50 mL) and water (50 mL) were added, and dinitrogen was bubbled through the resultant mixture for 10 min. A condenser was attached and the mixture was heated at 80 °C under a dinitrogen atmosphere. The reaction was monitored by TLC and allowed to cool to room temperature upon completion (48 h). The solution was then diluted with ethyl acetate (150 mL), washed with water (3 × 100 mL), and then washed with saturated aqueous sodium chloride (1 × 100 mL). The organic layer was separated and dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the residue chromatographed on silica with ethyl acetate as the eluant. The product was isolated as a light yellow/white solid. The product was then recrystallized from an ethanol/chloroform mixture as colorless plateshaped crystals (1.1 g, 71%). M.p. 179–181 °C. 1H NMR (δH; 400 MHz, CDCl3): 8.74 (dd, J ) 4.4 Hz, J ) 2 Hz, 2H), 7.84 (dd, J ) 4.4 Hz, J ) 2 Hz, 2H), 6.97 (s, 1H), 5.18 (s, 2H), 2.45 (s, 3H). 13C NMR (δC; 200 MHz, CDCl3): 169.6, 163.4, 162.7, 150.5, 144.7, 121.0, 107.5, 24.2. IR (KBr pellet): V 3318, 3151, 1581, 1376 cm-1. ESI–IT–MS m/z 187 ([2 + H]+). Synthesis of 1-(6-Amino-3-pyridyl)-2-(4-{benzimidazol-1-yl}phenyl)ethyne, 6. A mixture of 4-[benzimidazol-1-yl)methyl]-bromobenzene (500 mg, 1.74 mmol), 2-amino-5-ethynylpyridine (220 mg, 1.91 mmol), copper(I) iodide (0.012 g, 0.06 mmol), triphenylphosphine

(0.050 g, 0.191 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.050 g, 0.71 mmol) was added to a round-bottom flask. Tetrahydrofuran (15 mL) and triethylamine (15 mL) were added, and dinitrogen was bubbled through the resultant mixture for 10 min. A condenser was attached and the mixture heated at 65 °C under a dinitrogen atmosphere. The reaction was monitored by TLC and allowed to cool to room temperature upon completion (48 h). The solution was then diluted with ethyl acetate (100 mL), washed with water (3 × 100 mL), and washed with saturated aqueous sodium chloride (1 × 100 mL). The organic layer was separated and dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the residue chromatographed on silica with ethyl acetate as the eluant. The product was recrystallized from pouring a chloroform mixture into hexanes, producing an off-white solid (390 mg, 70%). M.p. 234–236 °C. 1H NMR (δH; 200 MHz, CDCl3): 8.26 (d, J ) 1.8 Hz, 1H), 7.96 (s, 1H), 7.87–7.82 (m, 1H), 7.54 (dd, J ) 8.8 Hz, J ) 2.2 Hz, 1H), 7.46 (d, J ) 8.4 Hz, 2H), 7.32–7.25 (m, 3H), 7.14 (d, J ) 8.4 Hz, 2H), 6.46 (d, J ) 8.4 Hz, 1H), 5.37 (s, 2H), 4.6 (s, 2H). 13C NMR (δC; 200 MHz, CDCl3): 157.5, 151.6, 144.0, 143.2, 141.3, 140.4, 135.2, 133.8, 132.0, 127.0, 123.5, 123.2, 122.4, 120.5, 110.0, 109.6, 107.9, 89.1, 48.6. IR (KBr pellet): V 3445, 3299, 3168, 2217, 1616, 1596, 1514, 1494, 1392, 742 cm-1. ESI–IT–MS m/z 197 ([6 + H]+). Crystal Growth. Crystals suitable for single-crystal X-ray diffraction of 1 were grown by slow evaporation from a saturated ethanol solution at room temperature. Crystals of 2 were grown by slow evaporation from a saturated ethanol solution at room temperature. Crystals of 2a were obtained by slow evaporation from a saturated ethyl acetate solution in an attempt to form cocrystals of 2 (10 mg, 0.05 mmol) and benzoic acid (7.0 mg, 0.6 mmol). Crystals of 3 were grown by slow evaporation from a saturated ethanol solution at room temperature. Crystals of 4 were grown by slow evaporation from a saturated dichloromethane solution at room temperature. Crystals of 5 were grown by slow evaporation from a saturated chloroform solution at room temperature. Crystals of 6 were grown by slow evaporation from a saturated ethanol solution at room temperature. X-ray Crystallography. Data sets were collected on Bruker CCD systems at low temperature using MoKR radiation. Data were collected using SMART.10 Initial cell constants were found by small, widely separated “matrix” runs. An entire hemisphere of reciprocal space was collected. 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 data set. Integration was performed with SAINT,11 using this improved unit cell as a starting point. Precise unit-cell constants were calculated in SAINT from the final merged data set. Lorenz and polarization corrections were

2326 Crystal Growth & Design, Vol. 7, No. 11, 2007

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Figure 1. Thermal ellipsoid plots and labeling schemes for 1–6 and 2a. Thermal ellipsoids are displayed at a 50% probability level. Solvent molecule is left out for 4. applied. Absorption corrections were not applied. Data were reduced with SHELXTL.12 The structures were solved in all cases by direct methods without incident. Unless otherwise noted, hydrogen atoms were assigned to idealized positions and allowed to ride. All nonhydrogen atoms were given anisotropic thermal parameters. Additional relevant experimental crystallographic data are shown in Table 1, and thermal ellipsoids and numbering schemes for all structures are given in Figure 1. In 1, Coordinates for the NH2 protons (H12A&B) were allowed to refine. In 2, the compound crystallized in the noncentrosymmetric

orthorhombic space group P212121. Friedel opposites were merged; no attempt was made to determine handedness of the lattice. Coordinates for the NH2 protons (H12A&B) were allowed to refine. In 2a, the compound crystallized in the monoclinic crystal system and exhibited pseudomerohedral twinning emulating the orthorhombic lattice; β ) 90.246°, refined batch scale factor 0.157(1). The NH2 protons (H12A&B) were placed in calculated positions and were allowed to ride. In 3, coordinates for the NH2 protons (H12A&B) were allowed to refine. 4 The NH2 protons (H12A&B) were placed in calculated



Figure 2. 1D strand formed through multiple N–H · · · N hydrogen bonds in the crystal structure of 1.

Figure 3. 1D buckled strand in the structure of 2 formed through self-complementary amino-pyrimidine N–H · · · N hydrogen bonds.

Figure 4. Extended architecture of polymorph 2a. positions and allowed to ride. A dichloromethane molecule was located in the difference Fourier in close proximity to an inversion center; anisotropic refinement with half-occupancy and geometry restraints was uneventful. In 5, coordinates for the NH2 protons (H12A&B) were allowed to refine. In 6, the NH2 protons (H12A&B) were placed in calculated positions and allowed to ride. Powder XRD data were collected on a Bruker/Nonius D8 ADVANCE diffractometer with Bragg–Brentano geometry. A step size of 0.04° and a step time of 5 s

per step were used. Data was obtained over 5–30° 2θ ranges. Data were then processed using EVA v.8.0.13

Results The crystal structure of 1 contains one molecule in the asymmetric unit, with the two heterocyclic rings almost coplanar. Adjacent molecules are organized into a flat 1D strand


Christer et al.

Figure 5. 1D strand in 3 formed through multiple N–H · · · N and N–H · · · O hydrogen bonds.

Figure 6. 1D strands formed through multiple N–H · · · N hydrogen bonds of ligand 4.

Figure 7. Extended 2D architecture of 5 formed through multiple N–H · · · N hydrogen bonds.

through multiple N–H · · · N hydrogen bonds. The aminopyrimidine moiety forms self-complementary N–H · · · N hydrogen bonds (N12 · · · N11, 3.1013(17) Å), whereas the remaining anti-amino proton forms a N–H · · · N hydrogen bond with the pyridyl nitrogen atom (N12 · · · N21, 3.0450(17) Å), Figure 2. The crystal structure of 2 also contains one molecule within the asymmetric unit. The two heterocyclic rings are arranged in a coplanar manner, and adjacent molecules form corrugated 1D strands through self-complementary amino-pyrimidine N–H · · · N (N12 · · · N11, 3.052(2) and N12 · · · N13, 3.1222(19) Å) hydrogen bonds, Figure 3. As both hydrogen atoms of the amino group are now engaged, the pyridyl moiety is left without any strong hydrogen-bond donors.

A polymorph of 4-(2-amino-4-methylpyrimidin-6-yl)pyridine, 2a contains four molecules within the asymmetric unit. Multiple N–H · · · N hydrogen bonds extend the architecture into a 2-D sheet, Figure 4. The N–H · · · N hydrogen bonds include a pairwise self-complementary amino-pyrimidine/amino-pyrimidine (N12–2 · · · N11–1, 3.042(4), N12–1 · · · N11–2, 3.067(4) Å) motif, two different amine/pyridine (N12–1 · · · N21–3, 3.033(4), N12–2 · · · N21–4, 3.008(5) Å), and two different amine/pyrimidine (N12–3 · · · N11–4, 3.047(4), N12–3 · · · N21–1, 3.013(5) Å) interactions. The crystal structure of 3 contains one molecule within the asymmetric unit, with the two rings almost coplanar. Neighboring ligands form a dimeric unit through self-complementary



Figure 8. 1D chain in 6 formed through N–H · · · N hydrogen bonds.

Figure 9. Simulated powder XRD patterns for 2 and 2a.

amino-pyrimidine N–H · · · N/N · · · H–N (N12 · · · N11, 3.047(3) Å) hydrogen bonds, Figure 5. The motif is extended into a 2-D sheet through N–H · · · O hydrogen bonds between the anti-amino proton and the oxygen atom of the methoxy group with a N12–O26 distance of 3.062(3) Å. The crystal structure of 4 contains 0.5 dichloromethane molecules in the asymmetric unit in addition to the desired product. The supramolecular network in 4 is very similar to that observed in the crystal structure of 1, Figure 6. The aminopyrimidine moiety forms self-complementary N–H · · · N hydrogen bonds (N12 · · · N11, 3.086(2) Å), producing a dimer that is further extended by secondary N–H · · · N hydrogen bonds from the anti-amino proton to the pyridyl nitrogen atom (N12 · · · N21, 2.993(2) Å) in a head-to-tail arrangement. In the crystal structure of 5, the parent molecules are arranged into a 2D sheet through multiple N–H · · · N hydrogen bonds. The amino-pyridine moiety forms self-complementary N–H · · · N hydrogen bonds (N12 · · · N11, 3.0522(9) Å) with a neighboring ligand producing a dimeric unit, which is further extended by secondary N–H · · · N hydrogen bonds from the anti-amino proton to the pyridyl nitrogen atom (N12 · · · N21, 3.1183(9) Å), Figure 7. The crystal structure of 6 contains one molecule within the asymmetric unit. The supramolecular architecture shows parallel 1D strands constructed via amino-pyrimidine/benzimidazole N–H · · · N (N12 · · · N33, 3.004(7) Å and N12 · · · N33, 3.440(7) Å) hydrogen bonds, Figure 8. Within this arrange-

Figure 10. Experimental powder XRD pattern of 2 grown from ethyl acetate.

ment, the pyridine moiety is not participating in hydrogen bonding. Discussion Bifunctional pyridine/amino-pyrimidine (py-pym) SRs 1–3 were synthesized in good yields following the conventional


Christer et al.

Table 2. Hydrogen-Bond Geometries for 1–6 and 2a compd

D–H · · · H

d(D–H) (Å)

d(H · · · A) (Å)

d(D · · · A) (Å)

∠(DHA) (deg)

a

N(12)–H(12A) · · · N(21)#1 N(12)–H(12B) · · · N(11)#2 N(12)–H(12A) · · · N(11)# N(12)–H(12B) · · · N(13)#2 N(121)–H(12B1) · · · N(112) N(121)–H(12A1) · · · N(213) N(122)–H(12B2) · · · N(111) N(122)–H(12A2) · · · N(214) N(123)–H(12A3) · · · N(211)#1 N(123)–H(12B3) · · · N(114)#2 N(12)–H(12A) · · · O(26)#1 N(12)–H(12B) · · · N(11)#2 N(12)–H(12A) · · · N(21)#1 N(12)–H(12B) · · · N(11)#2 N(12)–H(12A) · · · N(21)#1 N(12)–H(12B) · · · N(11)#2 N(12)–H(12B) · · · N(33)#1

0.892(18) 0.897(18) 10.93(2) 0.85(2) 0.86 0.86 0.86 0.86 0.86 0.86 0.97(3) 0.88(3) 0.88 0.88 0.872(9) 0.883(10) 0.88

2.154(19) 2.206(19) 2.17(2) 2.29(2) 2.23 2.20 2.20 2.18 2.19 2.22 2.10(3) 2.17(3) 2.12 2.21 2.248(10) 2.170(10) 2.17

3.0450(17) 3.1013(17) 3.052(2) 3.1222(19) 3.067(4) 3.033(4) 3.042(4) 3.008(5) 3.013(5) 3.047(4) 3.062(3) 3.047(3) 2.993(2) 3.086(2) 3.1183(10) 3.0522(9) 3.004(7)

176.4(15) 175.3(14) 159.3(18) 166.0(19) 164.4 161.8 168.2 162.6 160.3 160.9 170(2) 77(3) 171.5 172.7 175.8(8) 178.0(8) 156.8

1

b

2

2ac

3d 4e 5f 6g

a #1 -x + 2, -y + 1, -z + 1; #2 -x + 1, -y + 1, -z. b #1 -x, y + 1/2, -z + 1/2; #2 -x, y - 1/2, -z + 1/2. c #1 x - 1, y, z; #2 x - 1, y, z + 1. d #1 - x, y - 1/2, -z + 1/2; #2 -x, -y, -z + 1. e #1 -x + 2, -y + 2, -z + 1; #2 -x + 1, -y + 1, -z. f #1 x + 1, -y + 1/2, z + 3/2; #2 -x + 2, -y + 1, -z + 3. g #1 x - 1, y, z - 1.

palladium-catalyzed Suzuki-Miyaura cross-coupling conditions, whereas ethynyl-spaced pyridine/amino-pyrimidine and pyridine/ amino-pyridine SRs 4–6 were synthesized in moderate to good yields through the palladium-catalzyed Sonogashira crosscoupling reaction. Two different polymorphs of 4-(2-amino-4-methylpyrimidin6-yl)pyridine were found in the course of this study. Form I, 2, was obtained through recrystallization from ethanol, whereas Form II, 2a, was obtained as a byproduct of a cocrystallization reaction with benzoic acid in ethyl acetate, and consequently, we wanted to try to establish whether the solvent or the presence of benzoic acid was responsible for the production of 2a. Therefore, we recrystallized 2 from ethyl acetate and compared the resulting powder diffraction pattern with simulated powder patterns of 2 and 2a, Figure 9. The powder pattern of the sample grown from ethyl acetate, Figure 10, proved to be a very close match with Form I of 4-(2amino-4-methylpyrimidin-6-yl)pyridine, which was obtained upon recrystallization from ethanol. Thus, we can conclude that the solvent choice is unlikely to discriminate between Form I and Form II; instead the presence of benzoic acid in stoichiometric quantities is more likely to induce precipitation of Form II. Although we have yet to come across other polymorphs of 1–6, through simple recrystallization experiments, we are currently examining if carboxylic acids are capable of producing polymorphs of other members of this family of compounds. An overview of the crystal structures reported herein does provide information that can assist in identifying patterns of behavior and structural preferences for molecules that contain combinations of pyridine, pyrimidine, and amino-moieties. First of all, it is worth remembering that each compound, 1–4, contains two conventional hydrogen-bond donors and three conventional hydrogen-bond acceptors, which, in theory, could leave one of the latter sites vacant. In 5 and 6, on the other hand, the number of donors and acceptors is balanced at two each. Each molecule has a NH2 substituent next to a heterocyclic nitrogen atom, which provides the necessary geometric and electronic opportunities for the formation of a self-complementary N–H · · · N/N · · · H–N synthon. In fact, such an R22 (8) motif is observed in six of the seven structures, making it the primary intermolecular interaction. The only exception, 7, contains a benzimidazole moiety, which is considerably more basic than the alternative site, a pyridine ring. Consequently, the benzimidazole site is so competitive as a hydrogen-bond acceptor that

it forms a bifurcated interaction with two different NH2 protons (from different molecules) simultaneously. In 6, where the two donors have comparable basicity, each site forms a N–H · · · N hydrogen bond, leaving no strong hydrogen-bonding moiety vacant. The remaining question is then what determines the intermolecular preference for the anti-proton in the NH2 moiety in structures involving 1–4, because in each case, the final N–H donor has a choice of two aromatic N-heterocyclic acceptors. The basicity of each remaining site can be quantified through electrostatic potential surface calculations, which offer readily available information about the relative differences in charge in the vicinity of all atoms within a molecule, and such data may provide a better indicator than pKa values for ranking relative hydrogen-bonding abilities of a series of related chemical moieties.14 AM1-based calculations of the electrostatic potential surfaces of 1–4 indicate that the nitrogen atoms in all molecules display relatively small differences in their electrostatic minima, which should, in principle, make them equally attractive to a N–H donor, because electrostatic interactions play a major role in hydrogen-bond interactions. This interpretation is also borne out by the structures involving 1–4, because the remaining N–H donors do not display a clear preference for either pyridine- or pyrimidine nitrogen atom; both sites are left vacant an almost equal number of times. We have previously shown SRs 1 and 4 to be reliable molecules in the construction of inorganic–organic coordination polymers where the pyridine moiety coordinates to the metal center and further extension of the overall network is achieved through the robust self-complementary amino-pyrimidine/aminopyrimidine synthon.9a,9c More recently, preliminary organicbased studies have been achieved with SRs 1, 3, and 4, in which a variety of aromatic monocarboxylic acids were allowed to react with each SR, resulting in 1:1 binary cocrystals constructed through amino-pyrimidine/carboxylic acid synthons.9b The next phase of this work will focus on the deliberate assembly of ternary cocrystals with desirable stoichiometry and connectivity. Acknowledgment. We thank the NSF (Grant CHE-0316479) and Kansas State University for financial support. Supporting Information Available: Crystallographic data in CIF format are available for all the crystal structures. This material is available free of charge via the Internet at http://pubs.acs.org.


References (1) (a) Aakeröy, C. B. Acta Crystallogr., Sect. B 1997, 53, 569. (b) Aakeröy, C. B.; Salmon, D. J. CrystEngComm 2005, 7, 439. (c) Aakeröy, C. B.; Schultheiss, N. In Making Crystals by DesignsFrom Molecules to Molecular Materials, Methods, Techniques, Applications; Grepioni, F., Braga, D., Eds.; Wiley-VCH: Weinheim, Germany, 2007. (d) Aakeröy, C. B.; Desper, J.; Elisabeth, E.; Helfrich, B.; Levin, B.; Urbina, J. F. Z. Kristallogr. 2005, 220, 325. (e) Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. J. Am. Chem. Soc. 2002, 124, 14425. (2) (a) Aakeröy, C. B.; Salmon, D. J.; Smith, M. M.; Desper, J Cryst. Growth Des. 2006, 6, 1033. (b) Aakeröy, C. B.; Desper, J.; Urbina, J. F. Cryst. Growth Des. 2005, 5, 1283. (c) Aakeröy, C. B.; Desper, J.; Urbina, J. F. Chem. Commun. 2005, 2820. (d) Aakeröy, C. B.; Desper, J.; Scott, B. M. T. Chem. Commun. 2006, 1445. (e) Aakeröy, C. B.; Beatty, A. M.; Lorimer, K. Mol. Cryst. Liq. Cryst. 2006, 456, 163. (3) Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem., Int. Ed. 2001, 40, 3240. (4) (a) Bose, D.; Banerjee, J.; Rahaman, S. H.; Mostafa, G.; Fun, H.-K.; Bailey Walsh, R. D.; Zaworotko, M. J.; Ghosh, B. K. Polyhedron 2004, 23, 2045. (b) Burchell, T. J.; Eisler, D. J.; Puddephatt, R. J. Inorg. Chem. 2004, 43, 5550. (c) Aakeröy, C. B.; Beatty, A. M.; Leinen, D. S. Angew. Chem., Int. Ed. 1999, 38, 1815. (d) Aakeröy, C. B.; Beatty, A. M.; Lorimer, K. R. Dalton Trans. 2000, 3869. (5) (a) Aakeröy, C. B.; Beatty, A. M.; Desper, J.; O’Shea, M.; ValdésMartinez, J. Dalton Trans. 2003, 20, 3956. (b) Bera, J. K.; Vo, T.-T.; Walton, R. A.; Dunbar, K. R. Polyhedron 2003, 22, 3009. (c) Aakeröy, C. B.; Desper, J.; Valdés-Martinez, J. CrystEngComm 2004, 6, 413. (d) Bhogala, B. R.; Thallapally, P. K.; Nangia, A. Cryst. Growth Des. 2004, 4, 215.

Crystal Growth & Design, Vol. 7, No. 11, 2007 2331 (6) (a) Bhogala, B. R.; Vishweshwar, P.; Nangia, A. Cryst. Growth. Des. 2002, 2, 325. (b) Bhogala, B. R.; Nangia, A. Cryst. Growth. Des. 2003, 3, 547. (c) Shattock, T. R.; Vishweshwar, P.; Wang, Z.; Zaworotko, M. J. Cryst. Growth. Des. 2005, 5, 2046. (d) Reddy, L. S.; Badu, N. J.; Nangia, A. Chem. Commun. 2006, 1369. (7) (a) Simundza, G.; Sakore, T. D.; Subell, H. M. J. Mol. Biol. 1970, 48, 263. (b) Lynch, D. E.; Smith, D.; Freney, D.; Byriel, K. A.; Kennard, L. H. L. Aust. J. Chem. 1994, 47, 1097. (c) Etter, M. C.; Adsmond, D. A.; Britton, D. Acta Crystallogr., Sect. C 1990, 46, 933. (d) Aakeröy, C. B.; Beffert, K.; Desper, J.; Elisabeth, E. Cryst. Growth Des. 2003, 3, 837. (8) (a) Bielawski, C.; Chen, Y.-S.; Zhang, P.; Prest, P.-J.; Moore, J. S. Chem. Commun. 1998, 1313. (b) Bis, J. A.; Zaworotko, M. J. Cryst. Growth Des. 2005, 5, 1165. (c) Kushima, H.; Miyamoto, H.; Yagi, I.; Uosaki, K. Mol. Cryst. Liq. Cryst. 2004, 414, 77. (9) (a) Aakeröy, C. B.; Schultheiss, N.; Desper, J. Inorg. Chem. 2005, 44, 4983. (b) Aakeröy, C. B.; Schultheiss, N.; Desper, J.; Moore, C. New J. Chem. 2006, 30, 1452. (c) Aakeröy, C. B.; Schultheiss, N.; Desper, J. Dalton Trans. 2006, 13, 1627. (10) SMART, version 5.060; Bruker Analytical X-ray Systems: Madison, WI, 1997–1999. (11) SMART, version 6.02; Bruker Analytical X-ray Systems: Madison, WI, 1997–1999. (12) SHELXTL, version 5.10; Bruker Analytical X-ray Systems: Madison, WI, 1997. (13) EVA, version 8.0; Bruker AXS Gmbh: Karlsruhe, Germany, 1997– 2002. (14) (a) Hunter, C. A. Angew. Chem., Int. Ed. 2004, 43, 5310. (b) Henry, M. Hosseini, M. W. New J. Chem. 2004, 28, 897.

CG070373C

Balancing Hydrogen-Bond Donors and Acceptors in a Family of

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