2-Aminopyrimidine Derivatives Exhibiting Anion-Ï Interactions: A

2-Aminopyrimidine Derivatives Exhibiting Anion-π Interactions: A Combined Crystallographic and Theoretical Study Angel Garcıá-Raso,*,† Francisca M. Albertı´,† Juan J. Fiol,† Andre´s Tasada,† Miquel Barcelo´-Oliver,† Elies Molins,‡ Carolina Estarellas,† Antonio Frontera,*,† David Quinõnero,† and Pere M. Deya`†

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 5 2363–2376

Department of Chemistry, UniVersitat de les Illes Balears, Crta. de Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain, and Institut de Cie`ncia de Materials de Barcelona (CSIC), Campus de la UAB, E-08193 Cerdanyola (Barcelona), Spain ReceiVed NoVember 11, 2008; ReVised Manuscript ReceiVed January 28, 2009

ABSTRACT: In this manuscript, we report the synthesis and the solid-state characterization of five new compounds based on the 2-aminopyrimidine building block. Some of them exhibit interesting anion-π interactions. In addition, we report a high level ab initio study of anion-π interactions involving 2-methylaminopyrimidine and its dimer. We demonstrate that these compounds are able to interact favorably with anions. The dimer of 2-methylaminopyrimidine interacts with the anion more strongly than the monomer due to cooperativity effects between the noncovalent hydrogen bonding and anion-π interactions. This pattern, that is, coexistence of hydrogen bonding and anion-π bonding, is observed experimentally in the solid state. Introduction In modern chemistry, noncovalent interactions play a pivotal role in many areas. They are important in deciding the conformation of molecules,1 chemical reactions, molecular recognition, and in regulating biochemical processes.2 The specificity and efficiency of these chemical processes are accomplished by taking advantage of intricate combinations of weak intermolecular interactions of various sorts. Noncovalent interactions such as hydrogen bonding, anion-π, cation-π, and π-π interactions, and other weak forces govern the organization of multicomponent supramolecular assemblies.3 A deep understanding of these interactions is of outstanding importance for the rationalization of effects observed in several fields, such as biochemistry and materials science. A quantitative description of these interactions can be performed taking advantage of quantum chemical calculations on model systems.4 Anion-π interactions5 have attracted considerable attention in last five years.6 There is a great deal of experimental7 and theoretical8 work that shows that anion-π interactions play a prominent role in several areas of chemistry, such as molecular recognition9 and transmembrane anion transport.10 Anion coordination is an important and challenging aspect of contemporary supramolecular chemistry. Recent investigations have provided experimental evidence for the usefulness of anion-π interactions in a structurally directing role.11 Moreover, Berryman et al. have reported structural criteria for the design of anion receptors based on the interaction of halides with electron-deficient arenes.12 Recent reviews of Gamez et al. deal with anion-binding involving π-acidic heteroaromatic rings.13 In this manuscript we report the synthesis of 1,3-bis(2pyrimidyl)-1,3-diazapropane (1), 1,4,7,10-tetrakis(2-pyrimidyl)1,4,7,10-tetraazadecane (2), 1,5,8,12-tetrakis(2-pyrimidyl)1,5,8,12-tetraazadodecane (3), and their corresponding nitrate salts 1,3-bis(2-(1-H)-pyrimidyl)-1,3-diazapropane nitrate (4), 1,4,10-tris(2-(1-H)-pyrimidyl)-7-(2-pyrimidyl)-1,4,7,10-tetraazadecane nitrate (5), and 1,5,8,12-tetrakis(2-(1-H)-pyrimidyl)* Corresponding authors. Fax: +34 971 173426; e-mail: [email protected] (A.F.); [email protected] (A.G.R.). † Universitat de les Illes Balears. ‡ Institut de Cie`ncia de Materials de Barcelona (CSIC).

Figure 1. 1,3-Bis(2-pyrimidyl)-1,3-diazapropane (1), 1,4,7,10-tetrakis(2pyrimidyl)-1,4,7,10-tetraazadecane (2), 1,5,8,12-tetrakis(2-pyrimidyl)1,5,8,12-tetraazadodecane (3), 1,3-bis[2-(1-H)-pyrimidyl]-1,3-diazapropane nitrate (4), 1,4,10-tris[2-(1-H)-pyrimidyl]-7-(2-pyrimidyl)1,4,7,10-tetraazadecane nitrate (5), 1,5,8,12-tetrakis[2-(1-H)-pyrimidyl]1,5,8,12-tetraazadodecane nitrate (6).

1,5,8,12-tetraazadodecane nitrate (6) (Figure 1). We have been able to characterize by means of X-ray crystallography compounds 1 and 3-6. We analyze the effect of hydrogen bonding and C-H/π noncovalent interactions on the crystal packing of the neutral molecules 1 and 3. Moreover, we also analyze the influence of the anion on the crystal packing of nitrate salts 4-6, and we compare the solid-state structure of 4 and 6 with the previously reported and related 1,3-bis(2-1-H)-pyrimidyl)1,3-diazaetane nitrate and 1,3-bis(2-1-H)-pyrimidyl)-1,3-diazabutane nitrate.14 In all charged structures relevant anion-π interactions are present and they are responsible for the differences in the crystal packing. We also report a high level ab initio study of the anion-binding affinity of the protonated 2-methylaminopyrimidine (7) via hydrogen bonding and anion-π interactions using ab initio calculations and the molecular interaction potential with polarization (MIPp) method.15 We also analyze how the π-binding affinity of 2-methylaminopyridine

10.1021/cg801245g CCC: $40.75  2009 American Chemical Society Published on Web 02/27/2009

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Garcıá-Raso et al.

Table 1. Crystallographic Data for Compounds 1 and 3-6

empirical formula M crystal system space group a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) Dc (mg/m3) Z µ (mm-1) crystal size (mm3) θ for data collection [°] index ranges no. of reflns collected independent reflections data/restraints/params final R indices [I > 2σ(I)] wR2 ) 0.0971 R indices (all data) wR2 ) 0.1066 GOF on F2 largest diff peak/hole (e Å-3)

1

3

4

5

6

C11H18N6O2 266.31 orthorhombic Pbcn 20.886(15) 4.628(3) 13.755(7) 90 90 90 1329.6(15) 1.330 4 0.096 0.50 × 0.47 × 0.08 2.96 to 26.25 0 e h e 25 0eke5 0 e l e 16 1264 1264 1264/3/95 R1 ) 0.0352 wR2 ) 0.1135 R1 ) 0.0899 wR2 ) 0.1286 1.03 0.153 and -0.114

C24H30N12 486.60 triclinic P1j 10.101(5) 10.6020(14) 12.698(3) 93.639(19) 110.5(3) 99.759(19) 1244.1(8) 1.299 2 0.085 0.46 × 0.34 × 0.31 1.73 to 24.97 -11 e h e 11 -12 e k e 12 0 e l e 15 4348 4348 4348/0/445 R1 ) 0.0483 wR2 ) 0.1741 R1 ) 0.1060 wR2 ) 0.2009 0.995 0.136 and -0.133

C11H16N8O6 356.32 monoclinic P121/c1 15.344(8) 25.381(6) 7.956(5) 90 95.21(4) 90 3086(3) 1.534 8 0.127 0.48 × 0.29 × 0.26 1.33 to 24.97 -18 e h e 18 0 e k e 30 0ele9 5423 5423 5423/26/467 R1 ) 0.072 wR2 ) 0.1326 R1 ) 0.1639 wR2 ) 0.1462 1.069 0.482 and -0.293

C22H35N15O12 701.65 monoclinic P121/c1 20.969(12) 11.734(3) 13.139(6) 90 108.40(4) 90 3068(2) 1.519 4 0.125 0.43 × 0.32 × 0.24 1.02 to 24.97 -24 e h e 23 0 e k e 13 0 e l e 15 5379 5379 5379/101/470 R1 ) 0.053 wR2 ) 0.1372 R1 ) 0.0981 wR2 ) 0.1627 1.059 0.501 and -0.193

C24H34N16O12 738.67 triclinic P1j 5.222(4) 11.079(6) 13.943(5) 94.47(4) 97.36(6) 91.11(8) 797.2(8) 1.539 1 0.126 0.42 × 0.21 × 0.12 2.46 to 24.66° -6 e h e 6 -12 e k e 12 0 e l e 16 2619 2619 2619/0/235 R1 ) 0.0592

7 is affected by a variety of factors: (i) participation in hydrogen bonding interaction, (ii) conformation (syn/anti) of its protonated form, and (iii) interaction with its counterion via hydrogen bonding. These situations have been observed in the crystal structures 4-6. The MIPp is a convenient tool for predicting binding properties. It has been successfully used for rationalizing molecular interactions such us hydrogen bonding and ion-π interactions and for predicting molecular reactivity.16 In particular, it has been found useful to predict the binding energy of a variety of π-acidic rings, such as hexafluorobenzene,5c s-triazine,16f s-tetrazine,16g tricyanobenzene,16h isocyanuric acid,7e etc.16i The MIPp partition scheme is an improved generalization of the MEP where three terms contribute to the interaction energy, (i) an electrostatic term identical to the MEP,17 (ii) a classical dispersion-repulsion term,18 and (iii) a polarization term derived from perturbational theory.19 We have found a good agreement between the theoretical calculations and the solid-state structures. Anion-π interactions involving pyrimidine rings have been previously observed.20 Many π-acidic aromatic rings can be found in biomolecules, among them the DNA bases are representative. There is experimental evidence of attractive anion-base interactions, including the sixmembered rings of adenine, guanine, and thymine.21 In addition, these bases participate in hydrogen bonding interactions. Therefore, it is feasible that both interactions coexist in a given biological system. Some of us have recently published that cooperativity effects exist between hydrogen bonding and anion-π interactions. Actually, we have demonstrated that when either an anion or a cation interacts with an aromatic ring establishing a cation/anion-π interaction, the strength of the interaction is modulated if the aromatic ring is involved in hydrogen bonding interactions.22 Experimental Section and Theoretical Methods General Comments. Elemental analyses were carried out using a Carlo-Erba models 1106 and 1108 and Thermo Finningan 1112 microanalysers. Infrared spectra (KBr pellets) were recorded on a Bruker IFS 66. 1H and 13C NMR spectra were obtained with a Bruker AMX

R1 ) 0.2297 0.92 0.26 and -0.242

Scheme 1. Synthetic Route to 1-6

300 spectrometer. Proton and carbon chemical shifts in dimethylsulfoxide (DMSO-d6) were referenced to DMSO-d6 [1H NMR, δ(DMSO) ) 2.47 ppm; 13C NMR, δ(DMSO) ) 40.0 ppm]. All organic and inorganic reagents (Sigma and Aldrich) were used without further purification. Crystal Structure Determination. Suitable crystals of 1, 3, 4, 5, and 6 were selected for X-ray single crystal diffraction experiments and mounted at the tips of glass fibers on an Enraf-Nonius CAD4 diffractometer producing graphite monochromated Mo KR radiation (λ ) 0.71073 Å). After the random search of 25 reflections, the indexation procedure gave rise to the cell parameters. In compounds 4 and 5, cell parameters were transformed to follow the “best choice” criterion for monoclinic structures according to the literature.23 Intensity data were collected in the ω-2θ scan mode and corrected for Lorenz and polarization effects. Absorption correction was performed following the empirical DIFABS24 method. The structural resolution procedure was made using the WinGX package.25 Solving for structure factor phases was performed by SHELXS8626 (6), SIR200227 (1), and SIR200428 (3, 4, and 5) and the full-matrix refinement, by SHELXL97.29 Non-H atoms were refined anisotropically and H-atoms were introduced in calculated positions and refined riding on their parent atoms, except for water molecules in 1 and 5 and protonated compounds 4-6, where the protonation sites were located in difference Fourier maps and refined isotropically. A summary of refinement parameters can also be seen in Table 1. 1,3-Bis(2-pyrimidyl)-1,3-diazapropane (1 · 2H2O). The synthesis of this compound was previously described.14 Suitable crystals for X-ray

2-Aminopyrimidine Derivatives with Anion-π Interactions

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Figure 2. ORTEP drawings of 1 and 3. Displacement ellipsoids are drawn at 50% probability level and H atoms are drawn as circles of arbitrary radii.

Figure 3. Left: ORTEP representation of the hydrogen bonding network in 1. Displacement ellipsoids are drawn at 50% probability level and H atoms are drawn as circles of arbitrary radii. Right: Stick representation of 1, where the C-H/π interactions are highlighted. Distances in Å. Table 2. Distances (Å) and Angles (°) for Hydrogen Bonds in 1 and 3a D-H · · · A N(2)-H(2) · · · N(3)#1 O(1)-H(1) · · · N(1) O(1)-H(2) · · · O(1)#2 D-H · · · A N(2)-H(2) · · · N(1′)#3 N(2′)-H(2′)#3 · · · N(1)

Compound 1 d(H · · · A) 2.28 1.99 1.80 Compound 3 d(H · · · A) 2.09 2.07

d(D · · · A)

∠(DHA)

3.13 2.89 2.78

171 166 173

d(D · · · A)

∠(DHA)

3.06 3.03

172 173

a Symmetry transformations used to generate equivalent atoms in 1: #1 -x, -y, -z; #2 -x + 1/2, y - 1/2, z; in 3 #3 -x, -y + 1, -z + 1.

diffraction were obtained by means of recrystallization in boiling water of 1 in 50% yield. 1,4,7,10-Tetrakis(2-pyrimidyl)-1,4,7,10-tetraazadecane (2). A suspension of 2-chloropyrimidine (1.10 g, 9.60 mmol) in n-butanol (20 mL) and triethylamine (3 mL) was refluxed with 1,4,7,19-tetrazadecane (triethylenetetramine) (0.30 g, 2.05 mmol) during 24 h. The resulting solid was filtered off and washed with cold water and acetone to remove the impurities of triethylammonium hydrochloride that contaminate the crude materials. White microcrystals were obtained by recrystallization in boiling ethanol. Yield 34%. Mp 208-210°; Anal. Calcd. (%) for 2 (C22H26N12, 458.52): C, 57.63; H, 5.72; N, 36.66. Found (%): C, 57.59;

H, 5.73; N, 36.79. Selected IR bands (cm-1): ν(N-H), 3256 (s); [ν(ring) + δ(NH)], 1612 (vs), 1582 (vs). 1H NMR, ([d6]DMSO): δ ) 8.23 [br d, 4H, H(10)/H(12)], 8.14 [br d, 4H, H(4)/H(6)], 7.14 [br t, 2H, N-H], 6.54 [br t, 2H, H(11)], 6.50 [br t, 2H, H(5)], 3.71 [s, 4H, H(15)], 3.62 [br t, 4H, H(14)] ppm. The addition of a few drops of D2O allows one to assign the corresponding signal to H(13): 3.36 [br t, 4H, H(13)] ppm. The very low solubility of this product in common deuterated solvents made it impossible to obtain the 13C NMR spectrum. 1,5,8,12-Tetrakis(2-pyrimidyl)-1,5,8,12-tetraazadodecane (3). A suspension of 2-chloropyrimidine (1.10 g, 9.60 mmol) in n-butanol (20 mL) and triethylamine (3 mL) was refluxed with N,N′-bis-(3-aminopropyl)-ethylendiamine (0.33 g, 1.89 mmol) during 24 h. The resulting solid was filtered off and washed with cold water and acetone to remove the impurities of triethylammonium hydrochloride that contaminate the crude materials. A crystalline material can be obtained by recrystallization from ethanol in 30% yield. Mp 156-158°. Anal. Calcd. (%) for 3 (C24H30N12, 486.58): C, 59.24; H, 6.21; N, 34.54. Found (%): C, 59.20; H, 6.19; N, 34.50. Selected IR bands (cm-1): ν(N-H), 3269 (s); [ν(ring) + δ(NH)], 1604 (vs), 1584 (vs). 1H NMR, ([D6]DMSO): δ ) 8.24 [d, J ) 4.8 Hz, 4 H, H(10)/H(10′)/H(12)/H(12′)], 8.20 [d, J ) 4.8 Hz, 4 H, H(4)/H(6)], 7.06 [br t, 2 H, N-H], 6.51 [t, J ) 4.8, 4 H, H(5)/H(11)], 3.68 [s, 4 H, H(16)], 3.53 [br t, Jest ) 7.2 Hz, 4 H, H(15)], 3.26 [br q, Jest ) 7.2 Hz, 4 H, H(13)], 1.77 [br q, 4 H, H(14), Jest ) 7.2 Hz] ppm. 13C NMR ([D6]DMSO): δ ) 162.7 [C(2)], 161.5 [C(8)], 158.3 [C(4)/C(6)], 158.2 [C(10)/C(12)], 110.2 [C(5)], 109.8 [C(11)], 45.8 [C(15)], 45.3 [C(16)], 38.8 [C(13)], 27.8 [C(14)] ppm.

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Figure 4. ORTEP representation of the X-ray structure of 3. Displacement ellipsoids are drawn at 50% probability level and H atoms are drawn as circles of arbitrary radii. Distances in Å.

Figure 5. Stick representation of the C-H/π interactions responsible of the dimer formation in 3. Distances in Å. 1,3-Bis[2-(1-H)-pyrimidyl]-1,3-diazapropane Nitrate (4). The previously described 1,3-bis(2-pyrimidyl)-1,3-diazapropane 1 (0.1 g, 0.4 mmol) was dissolved in HNO3 (0.33 M, 3 mL) and slightly heated to favor the dissolution for 15 min and then filtered. Suitable crystals for X-ray diffraction were only obtained when the solvent had almost evaporated after a month. Yield 60%. Mp 138-140° (d). Anal. Calcd. (%) for 4 (C11H16N8O6, 356.30): C, 37.08; H, 4.53; N, 31.45. Found (%): C, 37.08; H, 4.54; N, 31.75. Selected IR bands (cm-1): ν(N-H), 3251 (m br); [ν(ring) + δ(NH)], 1663 (vs), 1617 (vs), νasym(NO3) 1384 (vs br). 1H NMR, ([D6]DMSO): δ ) 8.48 [d, J ) 5.1 Hz, 4 H, H(4)/ H(6)], 6.82 [t, J ) 5.1 Hz, 2 H, H(5)], 3.39 [t, J ) 6.9 Hz, 4 H, H(7)], 1.83 [br quint, Jest ) 6.9 Hz, 4 H, H(8)] ppm. 13C NMR ([D6]DMSO): δ ) 157.9 broad peak [C(2)], 157.6 [C(4)/C(6)], 110.3 [C(5)], 39.04 [C(7)], 28.2 [C(8)] ppm. 1,4,10-Tris[2-(1-H)-pyrimidyl]-7-(2-pyrimidyl)-1,4,7,10-tetraazadecane Nitrate Trihydrate (5 · 3H2O). The previously described 1,4,7,10-tetrakis(2-pyrimidyl)-1,4,7,10-tetraazadecane 2 (0.1 g, 0.22 mmol) was dissolved in HNO3 (0.33 M, 3 mL). The solution was heated under reflux for 15 min and then filtered. After 15 days crystals suitable for X-ray studies were obtained in 30% yield. Mp 146-148° (d). Anal. Calcd. (%) for 5 (C22H35N15O12, 738.63): C, 37.66; H, 5.03; N, 29.95. Found (%): C, 38.03; H, 4.73; N, 29.95. Selected IR bands (cm-1): ν(N-H), 3227 (br); [ν(ring) + δ(NH)], 1631 (vs br); νasym(NO3), 1383 (vs br). 1H NMR, ([D6]DMSO): δ ) 8.46 [d, J ) 5.1 Hz, 4 H, H(4)/ H(6)], 8.27 [d, J ) 5.1 Hz, 4 H, H(10)/H(12)], 6.85 [t, J ) 5.1 Hz, 2 H, H(11)], 6.63 [t, J ) 5.1 Hz, 2 H, H(5)], 3.57 [br m, 4H, H(13)]. The addition of a few drops of D2O allows to assign the corresponding signals to H(14) and H(15): 3.68 [br m, 4H, H(14)], 3.70 [s, 4 H, H(15)] ppm. 13C NMR ([D6]DMSO): δ 160.7 [C(8)], 158.3 [C(4)/C(6)/C(10)/

C(12)], 157.2 [C(2)], 110.6 [C(5)/C(11)], 47.0 [C(14) or C(15)], 46.1 [C(14) or C(15)] ppm. 1,5,8,12-Tetrakis[2-(1-H)-pyrimidyl]-1,5,8,12-tetraazadodecane Nitrate (6). The previously described 1,5,8,12-tetrakis(2-pyrimidyl)1,5,8,12-tetraazadodecane 3 (0.1 g, 0.2 mmol) was dissolved in HNO3 (1 M, 5 mL). The solution was heated under reflux for 15 min and then filtered. After three days crystals suitable for X-ray studies were obtained in 80% yield. Mp 128-130 °C (d). Anal. Calcd. (%) for 6 (C24H34N16O12,738.63): C, 39.03; H, 4.64; N, 30.34. Found (%): C, 39.19; H, 4.61; N, 30.49. Selected IR bands (cm-1): ν(N-H), 3252 (m br); [ν(ring) + δ(NH)], 1657 (vs), 1612 (vs); νasym(NO3), 1382 (vs br). 1H NMR, ([D6]DMSO): δ ) 8.52 [d, J ) 5.1 Hz, 4 H, H(10)/ H(12)], 8.32 [d, J ) 5.1 Hz, 4 H, H(4)/H(6)], 6.87 [t, J ) 5.1 Hz, 2 H, H(11)], 6.63 [t, J ) 5.1 Hz, 2 H, H(5)], 3.74 [s, 5H, H(16)], 3.60 [br t, 2H, Jest ) 6.6 Hz, H(15)], 3.34 [br t, Jest ) 6.6 Hz, 4 H, H(13)], 1.84 [br m, Jest ) 6.6 Hz, 4 H, H(14)] ppm. 13C NMR ([D6]DMSO): δ ) 160.2 [C(8)], 158.2 [C(4)/C(6)/C(10)/C(12)], 156.4 [C(2)], 110.1 [C(5)/ C(11)], 45.7 [C(15)], 45.3 [C(16)], 27.0 [C(14)] ppm. Structural Characterization of the Compounds. All compounds have been characterized by usual spectroscopic techniques (FT-IR, 1H and 13C NMR) and elemental analyses (EA). In particular, vibrational spectra of pyrimidine and 2-aminopyrimidine is well-known, and it has been studied experimentally30 and theoretically.31 We focus on the assignment of the following bands: (i) a marked intense band in the higher-frequency range at approx. 3250 cm-1, assigned to a stretching vibration to the exocyclic nitrogen ν(NH); (ii) very intense bands close to 1600 and 1580 cm-1 respectively, assigned to the coupled NH scissoring, δ(NH), and ring double bond [ν(CdC) + ν(CdN)] stretching vibrations. The protonation of the pyrimidine ring gives rise



Figure 6. View of the crystal packing of compounds 1 and 3 (a ) 2, b ) 2, c ) 2) along the b axis. to a displacement to higher frequencies to the bands at approx. 1650-1615 cm-1 assigned to the CdN+ stretching and H-N+-H scissoring, with CdC stretching. This displacement is attributed to a more localized π-electron system in the protonated pyrimidine ring.30a Moreover, a broadening of the higher-frequency bands (3300-2500 cm-1) is in agreement with the presence of hydrogen bond interactions. Finally, the appearance of a broad intense band, corresponding to N-O asymmetric stretching mode, νasym(NO3-), at around 1380 cm-1 is in agreement with the presence of nitrate in the structure of compounds

4-6.32 Additional 1H and 13C NMR spectra have been obtained, including 2D-NMR experiments (COSY and HMBC) for compounds 3, 5, and 6 to obtain an unequivocal assignation of the bands. Because of the low solubility of 2 and 5 in DMSO-d6, the assignment of the proton signals has been done by comparison to the well-characterized compounds 3 and 6. All IR and NMR spectra (1H-, 13C-, 1H,1H-COSY, and 1H,13C-HMBC) are included in Supporting Information. Computational Details. The geometries of all compounds studied in this work were fully optimized using the RI-MP2/6-31++G** level

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Figure 7. Top: ORTEP representation of the X-ray structure of 4. Bottom: XAXWUP and XAXWOJ X-ray structures, shown for comparison purposes. Displacement ellipsoids are drawn at 50% probability level and H atoms are drawn as circles of arbitrary radii.

of theory within the program TURBOMOLE version 5.10.33 The RIMP2 method34 applied to the study of cation-π and anion-π interactions is considerably faster than the MP2 and the interaction energies and equilibrium distances are almost identical for both methods.35 The binding energies were calculated with correction for the basis set superposition error (BSSE) by using the Boys-Bernardi counterpoise technique.36 This methodology (RI-MP2) has been successfully used for the computation of stacking energies of DNA bases37 and the study of a variety of intermolecular interactions, such as N-H · · · π interactions38 and dihydrogen with aromatic systems.39 Moreover, there are several works that have successfully used RI-MP2 calculation to study several issues regarding nucleic acid bases, that is, stacking,37,40 hydrogen bonding,41 tautomers,42 and complexation with metal ions.43 The optimization of the complexes has been performed without imposing symmetry constrains unless otherwise noted. Calculation of the MIPp energies of compunds 7-10 interacting with O- was performed using the RI-MP2/6-31++G** geometries and the HF wave function computed by means of the Gaussian 03 package.44 The MIPp

calculations were computed by means of the MOPETE-98 program.45 The ionic van de Waals parameters for O- were taken from the literature.46

Results and Discussion Synthesis. Compounds 1-3 were easily prepared in moderated yield (22-50%) from the reaction between 2-chloropyrimidine and the corresponding polyamine (see Scheme 1) at reflux conditions in a BuOH/Et3N mixture. Crystals suitable for X-ray diffraction could only be obtained for 1 and 3, by means of recrystallization in boiling water and ethanol, respectively. On the other hand, the corresponding nitrate salts 4-6 were obtained from 1-3 in diluted HNO3. Suitable crystals for X-ray crystallography appear after several days (30-80% yield); see Scheme 1. X-ray Structures 1 and 3. The ORTEP drawings of neutral compounds 1 and 3 are represented in Figure 2. In these two

2-Aminopyrimidine Derivatives with Anion-π Interactions Table 3. Distances (Å) and Angles (°) for Hydrogen Bonds in 4, 5, 6, XAXWUP and XAXWOJa D-H · · · A

d(H · · · A)

d(D · · · A)

∠(DHA)

2.77 2.78 2.77 2.91 2.78 2.75 3.11 3.12

171 170 162 171 176 172 168 164

2.92 2.72

162 174

2.79 2.85

170 171

2.72 2.98 2.79 2.65 3.02 2.82 2.76 2.89 2.83 2.84 2.85 3.24

162 168 171 162 166 178 173 173 174 176 164 141

2.72 2.88 2.63

169 161 143

Compound 4 N(2)-H(2) · · · O(51) N(1)-H(1) · · · O(52) N(12)-H(12) · · · O(43) N(11)-H(11) · · · O(42) N(1′)-H(1′) · · · O(23)#1 N(11′)-H(11′) · · · O(31) N(12′)-H(12′) · · · N(3′) N(2′)-H(2′) · · · N(13′)

1.92 1.76 1.94 1.92 1.79 1.80 2.27 2.29 Compound XAXWUP

N(2)-H(2) · · · O(3) N(3)-H(3) · · · O(1)

2.09 1.87 Compound XAXWOJ

N(2)-H(2) · · · O(2) N(1)-H(1) · · · O(1)

1.94 1.99 Compound 5

N(3)-H(3) · · · O(2W) N(2)-H(2) · · · O(53) N(11)-H(11) · · · N(23) N(33)-H(33) · · · O(1W) N(32)-H(32) · · · O(51) O(1W)-H(1W1) · · · N(21) O(1W)-H(1W2) · · · O(3W) O(2W)-H(2W1) · · · N(13) O(2W)-H(2W2) · · · O(42) O(3W)-H(3W1) · · · O(61)#1 O(3W)-H(3W2) · · · O(62) O(3W)-H(3W2) · · · O(63)

1.76 2.13 1.66 1.74 2.17 1.99 1.88 2.01 2.00 1.96 1.99 2.50 Compound 6

N(1)-H(1) · · · O(21) N(2)-H(2) · · · O(22) N(11)-H(11) · · · O(31)

1.87 2.05 1.89

a

Symmetry transformations used to generate equivalent atoms in 4 #1 -x, y - 1/2, -z - 1/2. Symmetry transformations used to generate equivalent atoms in 5: 1 -x + 1, -y + 2, -z.

structures intramolecular interactions are not observed, and, curiously, the pyrimidine rings do not participate in intermolecular π-π stacking interactions in the crystal packing. However, there are other interesting intermolecular noncovalent interactions that determine the crystal packing. In 1, the crystal packing is governed by a combination of hydrogen bonds and C-H/π interactions, which are shown in Figure 3. In this structure, the molecule self-assembles through double N-H · · · N/ N · · · H-N bonds to form ribbons (see bond distances and angles in Table 2), that are connected via C-H/π interactions (3.05 Å) to give the 3D network. Moreover, additional H-bonds between the nitrogen atom of the pyrimidine ring, that does not participate in the N-H · · · N system, and water molecules are also present. These general features, that is, no stacking, double N-H · · · N hydrogen bonds, and C-H/π interactions also characterize other previously described structures formed with two 2-aminopyrimidine rings linked by different polymethylenic chains.14 In compound 1, the disposition of the pyrimidine rings belonging to the same molecule, is almost orthogonal (79.7°). In general the length of the linker affects significantly this relative disposition. The noncovalent interactions of 3 that are present in the solid state are shown in Figures 4 and 5. Since only two of the four aminopyridine moieties of 3 have a hydrogen atom available in the amino group, the hydrogen bonding network is formed involving these rings. In a similar way to 1, this molecule selfassembles through two double N-H · · · N/N · · · H-N bonds with the participation of two aminopyrimidine rings to form ribbons.


Moreover, C-H/π interactions (observed distances 2.88 and 3.16 Å) are established between two neighboring units forming dimeric aggregates (Figure 5). The dimers are formed via four C-H/π interactions and generate the unit cell of this crystal structure. As aforementioned, structures 1 and 3 grow by means of tandems of H-bonds in the same plane and CH/π interactions among different planes (Figure 6). All noncovalent interactions are in the range of the expected geometric values available in the bibliography.47 X-ray Structures of Nitrate Salts 4-6. The ORTEP drawing of compound 4 is shown in Figure 7 (top). Two related structures previously published are also presented for comparison purposes. The only difference among them is the length of the polymethylenic chain that links the two pyrimidine rings: 1,6-bis[2(1-H)-pyrimidyl]-1,6-diazabutane nitrate (XAXWUP) and 1,4bis[2-(1-H)-pyrimidyl]-1,4-diazaethane nitrate (XAXWOJ). Two different conformations of the aminopyrimidine group are present in 4. A syn-orientation between one exocyclic nitrogen (NH) and the corresponding protonated pyrimidine nitrogen allows a strong interaction with a NO3- anion via two hydrogen bonds, which is similar to the interactions observed in XAXWUP and XAXWOJ structures. An anti-orientation in the other aminopyrimidine moiety in 4 is ideal for the formation of the double N-H · · · N/N · · · H-N intermolecular bonds between two aminopyrimidine rings, as has already been described for neutral 1 and 3 compounds. In these rings, the interaction with the nitrate anion is established via one N-H · · · O-N hydrogen bonding interaction (see bond distances and angles in Table 3). A possible explanation for this different behavior compared to XAXWUP and XAXWOJ could be related to an odd number of carbon atoms linking both amino groups in 4, that influences the relative orientation of the aminopyrimidine moieties and, consequently, the possibility of formation of the double N-H · · · N/N · · · H-N intermolecular bonds. To verify this hypothesis we have tried to obtain crystals of the nitrate salt of the already synthesized the 1,3-bis(2-pyrimidyl)-1,3-diazapentane compound.14 Unfortunately, to date all attempts to obtain crystals suitable for X-ray crystallography have been unsuccessful. In addition to the hydrogen bonding interactions present in 4, the solid-state structure reveals interesting anion-π interactions, as can be observed in Figure 8. It is worth mentioning that the anion-π interaction is formed between the nitrate anion and the pyrimidine ring that is establishing double N-H · · · N/ N · · · H-N bonds (Table 3). This result is in agreement with previous theoretical findings, which demonstrate that the anion-π interaction is reinforced if the arene is simultaneously forming hydrogen bonding as acceptor as in 4. Further on in the present manuscript, we investigate and discuss the cooperativity of both interactions theoretically using a model of this system (see below). The ORTEP drawing of compound 5 is represented in Figure 9. A peculiar characteristic of this compound is that only three pyrimidine rings are protonated. As a matter of fact, one protonated pyrimidine ring interacts with the neutral pyrimidine moiety by means of a nonsymmetrical hydrogen bond. This interesting hydrogen bond has been analyzed according to the Steiner’s classification rules.47a The N(11)-H (1.134 Å), N(25) · · · H (1.663 Å), and N(11) · · · N(25) (2.785 Å) bond lengths (Figure 9) suggest a moderate (mostly electrostatic) hydrogen bond. However, the strong directionality of the hydrogen bond suggested by the N(11)-H-(N(25) (170.35°), C(16)-N(11)-C(12) (118.92°), and C(24)-N(25)-C(22) (116.77°) angles and the lengthening of N(11)-H bond (0.125

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Figure 8. ORTEP representation of the X-ray structure of 4. Some hydrogen atoms have been omitted for clarity. Displacement ellipsoids are drawn at 50% probability level and H atoms are drawn as circles of arbitrary radii. Distances in Å. The symmetry transformation used to generate the equivalent O23#1 atom is -x + 1, -y + 2, -z and the O41#2 atom is -x, -y + 2, -z.

Å, with respect to the standard reference value of 1.009 Å47a) is basically in agreement with a strong interaction (mostly covalent).48 Therefore, this hydrogen bond can be classified as a moderately strong hydrogen bond, with a certain covalent contribution. It is worth mentioning that the position of the hydrogen atom involved in this hydrogen bond has been obtained from the X-ray analysis of the diffraction data. An interesting aspect of this structure is that one nitrate anion forms two hydrogen bonds with two amino groups and several nonconventional N-O · · · H-C hydrogen bonds with ethylene groups. The distances of these bonds range from 2.50 to 2.85 Å; see Figure 9. Curiously, the protonated nitrogen atoms of two pyrimidine rings do not interact with the counterions (nitrate anions), instead they interact with water molecules. This fact is related to a syn-orientation of the aminopyrimidine moieties as has been already described for compound 4. This prevents the possibility of nitrate anion to interact with the protonated aminopyrimidine forming two strong N-O · · · H-N hydrogen bonds. Therefore, this spatial disposition of the groups favors the interaction of the nitrate anions with the pyrimidine rings via anion-π interactions (as is shown in Figure 9, bottom) because the N+-H groups are not available. The anionic oxygen atom to ring centroid distances range from 3.24 to 3.53 Å. This crystal structure is a clear example of the importance of anion-π interactions, which have a remarkable influence on the crystal packing. Lastly, the ORTEP drawing of compound 6 is represented in Figure 10. This tetraprotonated structure presents two different types of nitrate anions. One type forms only one N-H · · · O-N hydrogen bond with a protonated pyrimidine, as in compound 4, and the other type establishes two N-H · · · O-N hydrogen bonds with the protonated aminopyrimidine moiety. The latter also forms an anion-π interaction with the pyrimidine ring that interacts with the anion via one hydrogen bond. This recognition pattern has been previously noticed by us in 1,3-bis(2-(1-H)pyrimidyl)-1,3-diazaetane nitrate and 1,3-bis(2-(1-H)-pyrimidyl)1,3-diazabutane nitrate. In these two compounds, this pattern was responsible for the crystal growth in one direction (Figure

11). In 6 this pattern is found in the unit cell, and it also contributes to the crystal growth. Finally, C-H · · · O interactions are also very important for the crystal packing of these protonated structures (Figure 12). Thus, in the crystal packing of compound 4, C-H · · · O interactions (distances from 2.38 to 2.68 Å; angles from 140 to 180°) extend the network to give a zigzag arrangement. In compound 5, the 3D structure is formed by an A-B arrangement where the nitrate anions that interact with lateral aminopyrimidine moieties (highlighted in Figure 13, left) are placed in a hydrophilic channel present in each layer. The other nitrate anions and water molecules present in the structure (Table 3) establish multiple hydrogen bonds and C-H · · · O interactions connecting different layers (distances from 2.42 to 2.56 Å and angles from 120 to 150°). Lastly, in compound 6 nitrate anions are placed between layers establishing C-H · · · O interactions (2.40-2.42 Å; 124-164°) connecting them (Figure 13, right). Also observed are the previously mentioned NH · · · O hydrogen bonds and anion-π interactions. All observed angles and bond distances are within the normal range for these types of interactions.47a,49 Energetic Analysis. We have fully optimized compounds 7-13 at the RI-MP2/6-31++G** level in order to study their energetic affinity toward nitrate; see Figure 14. In addition compounds 11-13 are useful to analyze the combination of hydrogen bonding and anion-π interactions observed in the X-ray structures of compounds 4-6. We have used the dimers of 2-methylaminopyrimidine 8 and 10 as models of the double N-H · · · N hydrogen bonding interaction present in the X-ray structure of 4. The former allows us to study the effect of the double hydrogen bond on the π-binding ability of neutral 2-methylaminopyrimidine and the latter allows us to study the effect on a charged system. In Table 4 we summarize the results obtained from the MIPp study. Some very interesting points emerge from the analysis of the energetic data. First, the total interaction (Et) of neutral 2-aminopyrimidine 7 with a negatively charged oxygen atom is favorable (-3.90 kcal/mol) due to the ion-induced polarization component (Ep). The electrostatic term



Figure 9. ORTEP representation of the X-ray structure of 5. Displacement ellipsoids are drawn at 50% probability level and H atoms are drawn as circles of arbitrary radii. At the bottom representations, where the anion-π interactions are illustrated, some hydrogen atoms have been omitted for clarity. Distances in Å.

(Ee) is positive, indicating that the pyrimidine ring with an electron donating amino group substituent is not π-acidic enough to warrant a favorable electrostatic interaction. Second, we have previously studied the interplay between anion-π and hydrogen bonding interactions.22 We have demonstrated that the anion-π interaction is reinforced when the aromatic ring participates in hydrogen bonding interactions as acceptor and that the contrary occurs when it acts as donor. We have also demonstrated that these cooperativity effects are due to electrostatic effects. A very interesting behavior has been observed in 8 (2-methylaminopyrimidine dimer), where a double donor/acceptor N-H · · · N hydrogen bonding interaction is present. The MIPp partition scheme indicates that the electrostatic term (Ee) is more positive in 8 than in 7, indicating that double N-H · · · N hydrogen bonds do not favor electrostatically the anion-π interaction. However, the total interaction energy (Et) is more favorable in 8 than in 7, due to the polarization term, which is 1.7 kcal/mol more

negative in 8 than in 7. Therefore, the π-binding affinity toward anions is enhanced in the dimer with respect to the monomer and this enhancement is not due to electrostatic effects. Third, the almost isoenergetic data obtained for 9a and 9b point out that the relative orientation of the protonated nitrogen atom with the methyl group does not influence the interaction energy. Again, an interesting finding is observed in 10. In this case we study the influence of the double donor/acceptor N-H · · · N hydrogen bonding interaction on the binding ability of a protonated pyrimidine. It can be observed that the total interaction energy is more negative in 10 than in 9, demonstrating that the double hydrogen bonding has a positive influence on the anion-π interaction. As in 8, this behavior is due to ioninduced polarization effects that are able to compensate the electrostatic term, which is more positive in 10 than in 9 (see Table 4). This result is in agreement with the anion-π interaction observed in the X-ray structure of 4, where the nitrate anion

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Figure 10. ORTEP representations of the X-ray structure of 6. Displacement ellipsoids are drawn at 50% probability level and H atoms are drawn as circles of arbitrary radii. Distances in Å.

Figure 11. ORTEP representation of the X-ray structure of 6, XAXWOJ, and XAXWUP. Displacement ellipsoids are drawn at 50% probability level and H atoms are drawn as circles of arbitrary radii. Some hydrogen atoms have been omitted for clarity. Distances are in Å.

interacts with the pyrimidine ring which establishes the double hydrogen bonding interactions; see Figure 8. In Figure 15 we represent the geometric features of RI-MP2/ 6-31++G** optimized complexes 11-13. We also represent some partial views of crystal structures where these recognition

patterns are found. By comparison of the geometric features of complexes 11-13 to the X-ray structures, a remarkable agreement is found between the optimized and experimental structures regarding the relative disposition of the molecules, giving reliability to the theoretical level and indicating that they are



Figure 12. View of the crystal packing of compound 4 (a ) 2, b ) 2, c ) 2) along the c axis.

Figure 13. View of the crystal packing of compound 5 (a ) 1, b ) 2, c ) 2) along the c axis and compound 6 (a ) 2, b ) 2, c ) 2) along the a axis.

Figure 14. 2-Methylaminopyrimidine derivatives and complexes 7-13.

strong binding motifs of the solid state structures. It can be observed that the equilibrium distances are larger in the experimental structures because the anions participate in additional interactions with neighboring molecules. The binding energy of all complexes is very favorable, and the one computed

for 11 is about 5 kcal/mol more stable than 12 due to the double N-H · · · O bond with one nitrate anion. It is also remarkable that the optimization of the dimer of 12 (complex 13) yields the geometry represented in Figure 15 in the gas phase, where two nitrate anions interact with the aromatic ring via anion-π

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Figure 15. RI-MP2/6-31++G** optimized complexes 11-13 and their complexation energies. Detail of several crystal structures showing the recognition pattern studied theoretically. Distances are shown in Å. Table 4. Contributions to the Total Interaction Energy (kcal/mol) Calculated with MIPp for 7-10 Interacting with O- at 3.2 (Å) from the Center of the Ring compound

Ee

Ep

Evw

Et

7 8 9a 9b 10a

4.15 5.70 -76.81 -76.82 -75.30

-7.30 -9.07 -5.96 -5.95 -8.91

-0.75 -0.83 -0.68 -0.43 -0.90

-3.90 -4.21 -83.45 -83.20 -85.11

a The MIPp interaction energy has been computed at 3.2 Å from the center of the charged ring.

interactions and the other two anions participate in hydrogen bonding interactions with the N+-H group. Concluding Remaks We have reported the synthesis and X-ray characterization of several bis(2-aminopyrimidine) and tetrakis(2-aminopyrimidine) derivatives. The neutral systems present a combination

Chart 1. Structure and IUPAC Atomic Numbering of 2-Aminopyrimidine

of hydrogen bonds and C-H/π interactions that are responsible for the crystal packing. For the charged systems, we have observed that a combination of hydrogen bonding and anion-π interactions determine the crystal packing. For charged bis(2aminopyrimidine) derivatives, the number of carbon atoms that connect both aminopyrimidine moieties is related to the presence or absence of double intermolecular N-H · · · N hydrogen bonds between two aminopyrimidine rings. In one compound (5), the N+-H groups of the pyrimidine ring form hydrogen bonds with water molecules present in the crystal structure. In this case


the interaction of the anion with the aromatic ring is established basically via anion-π and C-H · · · O interactions. The results derived from the theoretical study reveal that the participation of the aromatic ring in hydrogen bonding interactions reinforces the concurrent anion-π interaction. This fact agrees with the experimental results obtained for compound 4. An unexpected result regarding this issue is that this enhancement is due to polarization effects induced by the anion, since the electrostatic effects operate in opposition to the global stabilization of the system. In addition, the geometries of the optimized complexes 11-13 remarkably agree with the X-ray structures, indicating that the location of the anion over the aromatic ring is not fortuitous. Instead, the combination of hydrogen bonding and anion-π interactions between the nitrate and the protonated 2-aminopyrimidine ring is an strong binding motif that should be taken into account in molecular recognition. Acknowledgment. We thank the DGICYT of Spain (projects CTQ2008-00841/BQU and CTQ2006-09339/BQU) and the Direccio´ General de Recerca, Desenvolupament Tecnolo`gic i Innovacio´ del Govern Balear (Accions Especials, 2004) for financial support. We thank the CESCA for computational facilities. F.M.A. and M.B.O. acknowledge respective grants of Conselleria d’Economia, Hisenda i Innovacio´ (Govern de les Illes Balears). Supporting Information Available: The Supporting Information for this paper includes the full citation for ref 44 Cartesian coordinates of RI-MP2/6-31++G** optimized structures 7-13 and crystallographic information files (cif) of new compounds 1, 3 and 4-6, and experimental spectra used for the characterization of the compounds. This material is available free of charge via the Internet at http:// pubs.acs.org. CCDC-708493, CCDC-708494, CCDC-708495, CCDC708496 and CCDC-708497 contain the crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographyc Data Centre via www.ccdc.cam.ac.uk/data_request/ cif.

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