Hydrogen-Bond Directed Structural Selectivity in Asymmetric Heterocyclic Cations Christer B.
Aakero¨y,*,‡
Kelly
Beffert,#
John
Desper,‡
and Eric
Elisabeth‡
Department of Chemistry, Kansas State University, Manhattan, Kansas, 66506, and Department of Natural Sciences, Carrol College, Helena, Montana 59625
CRYSTAL GROWTH & DESIGN 2003 VOL. 3, NO. 5 837-846
Received May 1, 2003
ABSTRACT: The notion that the best hydrogen-bond donor preferentially interacts with the best hydrogen-bond acceptor has been explored in the synthesis and structural characterization of 12 salts based on asymmetric 2-aminopyrimidinium cations: 2-amino-4-methoxy-6-methylpyrimidinium 2-fluorobenzoate, 2-amino-4-methoxy-6methylpyrimidinium 3-chlorobenzoate, 2-amino-4-methoxy-6-methylpyrimidinium 3-nitrobenzoate, 2-amino-4-methoxy-6-methylpyrimidinium benzoate, 2-amino-4-methoxy-6-methylpyrimidinium 3-N,N ′(dimethyl)aminobenzoate, 2-amino-4-methoxy-6-methylpyrimidinium methylene-hydrogensuccinate hydrate, bis(2-amino-4-methylpyrimidinium) fumarate, 2-amino-4-methylpyrimidinium 3-fluorobenzoate, 2-amino-4-methylpyrimidinium nitrate, 2-amino4-methylpyrimidinium 3-chlorobenzoate, 2-amino-4-methylpyrimidinium 2-methyl-hydrogenmaleate, and 2-amino4-chloro-6-methylpyrimidinium 3,5-dinitrobenzoate toluene0.4. In each structure, the -COO- acceptor consistently seeks out the -N-H+ donor generating the most important intermolecular interaction throughout this family of compounds. This exclusive recognition process can tolerate the presence of several other hydrogen-bond donors, which makes it a reliable structure-directing tool. Introduction Ever since Wo¨hler observed the transformation of ammonium cyanate to urea, organic chemists have devised a vast number of reactions allowing more and more complicated molecules to be made using elaborate synthetic processes.1 Today, we are capable of making extraordinary molecules that rival some of nature’s best efforts when it comes to structural complexity and chemical reactivity.2 Successful covalent synthesis relies on an extensive framework of practical guidelines based upon reliable and reproducible links between molecular structure, reactivity, and reaction pathways that have been established through systematic studies of innumerable organic reactions. For example, functional groups can be organized into classes depending upon the way in which they activate/deactivate specific chemical reactions, and they can even be ranked within those classes according to the extent to which they influence such reactions. In contrast, supramolecular synthesis,3 a new but rapidly expanding area of science concerned with the construction and properties of discrete and extended assemblies of molecules has yet to reach anywhere near the same level of sophistication.4,5 Even though many elegant supramolecular systems have been designed and constructed,6 effective supramolecular synthesis remains a very difficult proposition as the available synthetic tool-box contains relatively weak and illdefined intermolecular interactions. To develop reliable supramolecular synthetic strategies, it is necessary to acquire a thorough understanding of the balance between competing intermolecular interactions and of the ensuing supramolecular structural consequences. A functional tenet of hydrogen-bond driven supramolecular synthesis is derived from the common observation ‡ #
Kansas State University. Carrol College.
Scheme 1. Relative Basicity of the Two Aromatic Nitrogen Atoms in 2-Aminopyrimidine Can Be Modulated through the Appropriate Use of Electron-Donating (ED) and/or Electron-Accepting (EA) Substituents
that the best hydrogen-bond donor preferentially interacts with the best hydrogen-bond acceptor.7 It has also been shown through systematic structural studies that it is possible to carefully manipulate the way in which molecules recognize and bind by “tuning” the strengths of site-specific complementary hydrogen-bond functionalities.8 This idea provided the key to the directed assembly of binary cocrystals through the use of an efficient supramolecular reagent, isonicotinamide,9 and the subsequent unparalleled supramolecular design of ternary supermolecules with predictable connectivity and stoichiometry.10 In this paper, we present a systematic structural study of organic salts based upon asymmetrically substituted 2-aminopyrimidine to examine the reliability of relatively simple and modular assembly concepts with a view to developing more robust and practical supramolecular synthetic strategies. In asymmetrically substituted 2-aminopyrimidine, the two nitrogen atoms in the ring display somewhat different basicity due to the uneven electronic influence of the substituent, Scheme 1. Consequently, the two selfcomplementary binding sites (N-H‚‚‚N/N‚‚‚H-N) have different hydrogen-bond accepting abilities, and they could, in principle, be utilized in the synthesis of ternary supermolecules through preferential interactions with other molecules, e.g., two carboxylic acids with different pKa values.
10.1021/cg030021f CCC: $25.00 © 2003 American Chemical Society Published on Web 08/12/2003
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Aakero¨y et al. Table 1.
compound formula moiety empirical form molecular weight color, habit crystal system space group, Z a, Å b, Å c, Å R, degree β, degree γ, degree volume, Å3 density, g/cm3 temperature, K X-ray wavelength µ, mm-1 Θmin, deg Θmax, deg reflections: collected independent obsd, I >2σ (I) R1 (observed) wR2 (all)
1
2
3
4
5
6
(C6H10N3O) (C7H4F1O2) C13H14FN3O3 279.27 colorless prism monoclinic P2(1)/n, 4 9.5236(16) 14.810(3) 9.5336(16)
(C6H10N3O) (C7H4NO4) C13H14N4O5 306.28 colorless plate triclinic P1 h, 4 7.2119(14) 12.846(3) 16.565(3) 111.624(4) 92.302(5) 95.926(5) 1414.0(5) 1.439 203(2) Mo KR 0.113 1.72 28.24 10943
(C6H10N3O) (C7H5O2) C13H15N3O3 261.28 colorless prism triclinic P1 h, 2 7.236(4) 7.573(4) 11.440(6) 84.090(12) 83.983(13) 83.300(14) 616.5(6) 1.407 203(2) Mo KR 0.102 1.80 28.24 5376
(C6H10N3O) (C9H10NO2) C15H20N4O3 304.35 colorless prism triclinic P1 h, 2 7.5172(15) 7.8631(16) 14.655(3) 86.887(4) 81.203(4) 63.750(5) 767.7(3) 1.317 203(2) Mo KR 0.094 1.41 28.27 5468
(C6H10N3O) (C5H5O4)(H2O) C11H17N3O6 287.28 colorless prism monoclinic P2(1)/c, 4 14.4929(12) 7.4645(7) 13.7233(12)
1318.5(4) 1.407 203(2) Mo KR 0.111 1.37 28.29 9927
(C6H10N3O) (C7H4ClO2) C13H14ClN3O3 295.72 colorless prism triclinic P1 h, 2 7.3009(16) 7.9904(17) 12.903(3) 96.996(5) 96.619(5) 113.439(4) 674.3(3) 1.456 203(2) Mo KR 0.294 1.62 28.26 5043
1391.3(2) 1.371 203(2) Mo KR 0.112 1.5 27.1 10018
3046 2285 0.0561 0.1635
3016 2275 0.0596 0.2055
6286 3675 0.0430 0.1146
2741 1950 0.0447 0.1292
3404 2386 0.049 0.1557
2772 1968 0.0452 0.1363
101.319(4)
compound
7
8
10
11
12
formula moiety
(C5H8N3)2 (C4H2 O4)
(C5H7N3) (C7H5O2F)
(C5H8N3) (NO3)
(C5H8N4) (C7H4O2Cl)
(C5H8N3) (C5H5O4)
empirical formula molecular weight color, habit crystal system space group; Z a, Å b, Å c, Å R, degree β, degree γ, degree volume, Å3 density, g/cm3 temperature, K X-ray wavelength µ, mm-1 Θmin, deg Θmax, deg reflections: collected independent observed, I >2σ (I) R1 (observed) wR2 (all)
C14H18N6O4 334.34 colorless prism triclinic P1 h; 1 6.2558(8) 7.3155(10) 9.3364(13) 89.447(3) 86.094(3) 64.687(3) 385.26(9) 1.441 203(2) Mo KR 0.109 2.19 28.2 3008
C12H12FN3O2 249.25 amber plate monoclinic P2(1)/c; 4 6.2800(9) 26.396(4) 7.0265(12)
C12H12ClN3O2 265.7 amber prism monoclinic P2(1); 4 9.707(5) 10.570(5) 11.711(6)
1153.9(3) 1.435 203(2) Mo KR 0.111 1.54 28.2 8827
C5H8N4O3 172.15 yellow prism triclinic P1 h; 2 5.557(2) 7.207(3) 9.654(5) 98.482(8) 93.749(8) 96.733(9) 378.4(3) 1.511 203(2) Mo KR 0.126 2.14 28.27 2477
1200.5(10) 1.47 203(2) Mo KR 0.316 1.74 28.22 9444
C10H13N3O4 239.23 amber prism triclinic P1 h; 4 7.458(2) 11.023(3) 13.888(4) 89.945(6) 98.513(5) 100.482(5) 1109.9(5) 1.432 203(2) Mo KR 0.112 1.48 28.28 7856
(C5H7N3Cl) (C7H3N2O6) (C7 H8)0.4 C14.80H13.20ClN5O6 392.55 colorless prism triclinic P1 h; 2 7.0639(4) 11.1904(7) 11.2136(6) 101.709(4) 97.381(4) 101.663(4) 836.66(8) 1.558 203(2) Mo KR 0.275 1.91 28.27 6423
1720 1423 0.0379 0.1138
2645 2139 0.0453 0.1325
1632 980 0.0453 0.1161
4181 2536 0.0472 0.1319
4883 3491 0.0438 0.1182
3760 2317 0.062 0.1905
97.836(4)
9
110.424(2)
However, before asymmetrically substituted 2-aminpyrimidine can be reliably employed in the directed assembly of ternary supermolecules, it is necessary to obtain answers to two questions that may also have important consequences for hydrogen-bond driven supramolecular synthesis in general. First, does molecular structure consistently translate to predictable acid-base behavior despite the fact that the difference between the two sites is very small? Second, if one of the nitrogen atoms in the ring is protonated, the resulting N-H+ moiety becomes a very powerful hydrogen-bond donor which, according to the best donor/best acceptor strategy, should make it prone to forming strong hydrogenbonds with the best hydrogen-bond acceptor (a suitable anionic moiety). The question is, will an asymmetric 2-aminopyrimidinium cation consistently engage in
92.537(10)
hydrogen bonds that can be rationalized via a modular view of intermolecular interactions that allows for sitespecific manipulation of individual binding sites? To answer these questions, we present the syntheses and crystal structures of 2-amino-4-methoxy-6-methylpyrimidinium 2-fluorobenzoate 1, 2-amino-4-methoxy6-methylpyrimidinium 3-chlorobenzoate 2, 2-amino-4methoxy-6-methylpyrimidinium 3-nitrobenzoate 3, 2amino-4-methoxy-6-methylpyrimidinium benzoate 4, 2-amino-4-methoxy-6-methylpyrimidinium 3-N,N′-(dimethyl)aminobenzoate 5, 2-amino-4-methoxy-6-methylpyrimidinium methylene-hydrogensuccinate hydrate 6, bis(2-amino-4-methylpyrimidinium) fumarate 7, 2-amino4-methylpyrimidinium 3-fluorobenzoate 8, 2-amino-4methylpyrimidinium nitrate 9, 2-amino-4-methylpyrimidinium 3-chlorobenzoate 10, 2-amino-4-methyl-
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Table 2. Melting Points for 1-12a compound
mp (°C)
2-amino-4-methoxy-6-methylpyrimidinium 2-fluorobenzoate 2-amino-4-methoxy-6-methylpyrimidinium 3-chlorobenzoate 2-amino-4-methoxy-6-methylpyrimidinium 3-nitrobenzoate 2-amino-4-methoxy-6-methylpyrimidinium benzoate 2-amino-4-methoxy-6-methylpyrimidinium 3-N′N′-(dimethyl)aminobenzoate 2-amino-4-methoxy-6-methylpyrimidinium methylene hydrogensuccinate bis(2-amino-4-methylpyrimidinium) fumarate 2-amino-4-methylpyrimidinium 3-fluorobenzoate 2-amino-4-methylpyrimidinium nitrate 2-amino-4-methylpyrimidinium 3-chlorobenzoate 2-amino-4-methylpyrimidinium methyl-hydrogenmaleate 2-amino-4-chloro-6-methylpyrimidinium 3,5-dinitrobenzoate
150-152 135-138 179-182 163-169 199-204 118-128 230 (d) 64-66 105 (d) 95-96 215-218 190-192
a 2-Amino-4-methoxy-6-methylpyrimidine (mp 156-158 °C); 2-amino-4-methylpyrimidine (mp. 158-160 °C); 2-amino-4-chloro6-methylpyrimidine (mp 168-171 °C).
pyrimidinium 2-methyl-hydrogenmaleate 11, and 2amino-4-chloro-6-methylpyrimidinium 3,5-dinitrobenzoate toluene0.4 12. Experimental Section Syntheses. Stoichiometric amounts (1:1 molar equivalents) of the two reagents were dissolved separately in warm ethanol. The solutions were combined and the resulting mixture was allowed to cool to room temperature. Crystals formed upon slow evaporation (anywhere from hours to days) of the solvent. X-ray Crystallography. Crystalline samples of 1-12 were placed in inert oil, mounted on a glass pin, and transferred to the cold gas stream of the diffractometer. X-ray data were collected on a Bruker SMART 1000 four-circle CCD diffractometer using a fine-focus Mo-KR tube (λ ) 0.71073 Å). Data were collected using SMART.11 Initial cell constants were found by small and 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 from the entire dataset. Integration was performed with SAINT12 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.13 The structures were solved in all cases by direct methods. In general, hydrogen atoms were assigned to idealized positions and were allowed to ride with fixed thermal parameters [uij ) 1.2Uij(eq) for the atom to which they are bonded]. Where possible, the coordinates of hydrogen-bonding hydrogen atoms were allowed to refine. Heavy atoms, other than those of the guests, were refined with anisotropic thermal parameters. Table 1 provides crystallographic details for 1-12, and the molecular geometries and numbering scheme are shown in Figure 1a-l.
Results Thermal analyses, Table 2, of 1-12 revealed that only one new crystalline phase appeared for each reaction and it was consistent with the structure as determined by single-crystal X-ray diffractions11 of the products
contained salts in a 1:1 cation-anion ratio, whereas one compound, bis(2-amino-4-methylpyrimidinium) fumarate, displayed a 2:1 cation-anion ratio. Two compounds were solvated (water in the case of 6 and toluene in the case of 12), but in neither structure did the solvent molecule disrupt the primary hydrogen-bond motifs. In the series of compounds presented here, four compounds have melting points below, three between, and four above the melting points of their constituents (the nitrate salt is not included). There is not even any consistency within salts containing the same cation, Table 2. As is often noted when comparing the melting points of molecular cocrystals or organic salts with the melting points of their individual components, it is rare to find trends or identifiable connections between structure and thermal behavior; despite huge advances in computational chemistry and the dramatic increase in structural data, the melting point of a simple organic solid remains a highly unpredictable property.14 The 1H NMR solution results show that the ratio of cation to anion is consistent with the ratios observed in the solid state. IR spectroscopy confirmed that protontransfer had taken place in every single reaction, no molecular cocrystals were formed, and that each compound contains a carboxylate moiety. This is in agreement with the structural evidence that shows that a proton has been transferred from the acid to the base leading to a charge-assisted hydrogen bond between the two components. The structural analysis of 1-12 demonstrates that, in the overwhelming majority of cases, the most basic nitrogen atom accepts a proton from the acid resulting in a monocationic species, Figure 1a-l. The only exception to this behavior is found in 11, where one of the two unique cations in the crystal structure is protonated at the most basic site, N(1), whereas the other cation is protonated at N(3), the less basic nitrogen atom in the ring.15 Overall, it is clear that a relatively simple change in molecular structure (achieved through the predictable electronic influence of an electron donating/accepting substituent) leads to a highly specific change in chemical reactivity, Scheme 2. In the next phase of this investigation, the focus moves from molecular structure and behavior to the supramolecularsis there a straightforward connection between molecular reactivity and supramolecular assembly in this series of compounds? The six organic salts containing the 2-amino-4-methoxy-6-methylpyrimidinium cation all display exactly the same primary intermolecular interactions: N-H‚‚‚O-, N-H‚‚‚O-, and N-H+‚‚‚O-, Table 3 (all hydrogen-bond angles and distances are within expected values based upon existing structures). The combination of these charge-assisted hydrogen bonds results in the discrete tetrameric core consisting of the two ion-pairs that is present in 1-6, Figure 1a-f. Not even the presence of a water molecule in the lattice of 6 is enough to disrupt this motif, Figure 2. Once the asymmetric 2-aminopyrimidine is transformed into a cation, it contains a very powerful hydrogen-bond donor, the aromatic N-H+ moiety. The question is, does this binding site preferentially interact with the best hydrogen-bond acceptor even though each acid-base system contains a multitude of plausible
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Structural Selectivity in Heterocyclic Cations
Crystal Growth & Design, Vol. 3, No. 5, 2003 841
Figure 1. (a-l) Primary hydrogen-bond interactions in 1-12.
hydrogen-bond acceptors? As it turns out, the N-H+ moiety in all 12 structures consistently rejects all possible competing sites in favor of a negatively charged carboxylate moiety (in the case of the organic salts) or an oxoanion (in the case of the nitrate salt). The primary hydrogen-bond interaction in each case is a chargeassisted N-H+‚‚‚O- hydrogen bond that, invariably, is shorter (average N+‚‚‚O- distance is ca. 2.63 Å) than
the corresponding N-H‚‚‚O- interactions (average N‚‚‚Odistance ca. 2.90 Å) in this series of structures. Consequently, the best donor/best acceptor concept remains intact in this family of compounds despite significant variations in the chemical nature of the individual components, both cations and anions. The key supramolecular synthons in 1-6 also appears in the remaining structures, 7-12; the complementary,
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Table 3. Hydrogen-Bond Geometries for 1-12 D-H 1 2 3
4 5 6
7 8 9 10
11
12
0.87 0.87 0.87 0.82(3) 0.64(4) 0.69(4) 0.958(16) 0.965(16) 0.920(17) 0.864(18) 0.889(18) 0.932(17) 0.993(16) 0.912(18) 0.926(17) 0.979(17) 0.937(19) 0.90(2) 0.976(19) 0.90(2) 0.94(2) 1.30(3) 0.80(3) 0.72(3) 0.82(3) 0.64(4) 0.69(4) 1.209(18) 0.947(19) 0.833(19) 1.01(2) 0.99(2) 0.82(2) 1.03(4) 0.89(4) 0.87 0.87 0.87 0.87 1.009(17) 0.915(18) 0.910(16) 0.897(18) 0.907(18) 0.925(19) 1.01(2) 1.071(19) 1.04 1.01 0.93
1.77 2.00 2.01 1.74(4) 2.26(4) 2.26(4) 1.715(16) 1.698(16) 1.857(17) 1.982(18) 1.974(18) 1.847(17) 1.643(16) 1.887(18) 1.942(16) 1.636(18) 1.841(19) 1.99(2) 1.76(2) 1.87(2) 1.93(2) 1.36(3) 1.97(3) 1.97(3) 1.74(4) 2.26(4) 2.26(4) 1.359(18) 1.85(2) 2.18(2) 1.72(2) 1.84(2) 2.20(2) 1.55(5) 1.73(4) 2.11 2.07 1.99 1.90 1.667(17) 1.987(19) 1.737(17) 1.963(19) 2.078(19) 2.014(19) 1.43(2) 1.360(19) 1.58 1.83 2.15
H‚‚‚A
D‚‚‚A
