pyrazole and Salicylic Acid - American Chemical Society

CRYSTAL GROWTH & DESIGN

Cocrystals of 3,5-Dimethyl-1H-pyrazole and Salicylic Acid: Controlled Formation of Trimers via O-H‚‚‚N Hydrogen Bonds† Concepcio´n Rosa M. Marı´a A Ä ngeles M. Rosario Torres,§ Ibon Alkorta,# and Jose´ Elguero# Lo´pez,*,‡

Claramunt,‡

Garcı´a,‡

Elena

2007 VOL. 7, NO. 6 1176-1184

Pinilla,§

Departamento de Quı´mica Orga´ nica y Bio-Orga´ nica, Facultad de Ciencias, UniVersidad Nacional de Educacio´ n a Distancia (UNED), Senda del Rey 9, 28040 Madrid, Spain, Departamento de Quı´mica Inorga´ nica I, Facultad de Ciencias Quı´micas, UniVersidad Complutense de Madrid (UCM), 28040 Madrid, Spain, and Instituto de Quı´mica Me´ dica, Consejo Superior de InVestigaciones Cientı´ficas (CSIC), Juan de la CierVa 3, 28006 Madrid, Spain ReceiVed February 12, 2007; ReVised Manuscript ReceiVed March 20, 2007

ABSTRACT: Solid-state reactions of 3,5-dimethyl-1H-pyrazole (dmpz) and salicylic acid (sa) in different stoichiometries afford two different trimers whose structures have been determined by X-ray diffraction and analyzed by 13C and 15N solid-state nuclear magnetic resonance spectroscopy. GIAO absolute shieldings at the B3LYP/6-311++G** level have been calculated and compared with the experimental chemical shifts. Hydrogen-bond interactions between dmpz and sa provide sufficient driving force to direct molecular recognition and crystal packing. Introduction Since the emergence of crystal engineering in 1988, many achievements have been accomplished in this research field, where an important aspect responsible for its fruition has been the understanding of the nature of intermolecular interactions.1-3 Hydrogen bonding has been established as the most effective tool for constructing sophisticated assemblies because of its strength and directionality.4-6 The development of strategies for noncovalent synthesis is the availability of reliable supramolecular synthons, and in such a way, the patterns formed by carboxylic acidsscyclic dimers and open catemerss7 or by azole derivativesscyclic dimers, trimers, tetramers, and open catemerss8 have been widely investigated (see Scheme 1, the Etter/Bernstein graph set of descriptors are given for each motif).9 Another supramolecular synthon that has been frequently used in the construction of extended architectures in the solid state is the carboxylic acid‚‚‚pyridine heterosynthon (COOH‚‚‚ pyridine) that consists of the primary O-H‚‚‚N hydrogen bond and the auxiliary C-H‚‚‚O weak interaction (see Scheme 2).10 The possibility of hydrogen-bond formation between azoles and carboxylic acids, both donor-acceptor systems of different strengths, offers a broad scope for the study of (COOH‚‚‚azole) interactions, which are of biological and pharmaceutical importance.11 In the case of N-unsubstituted pyrazoles compared to pyridine, the replacement of the weak C-H‚‚‚O interaction by the strong N-H‚‚‚O hydrogen bond should allow us to obtain more stable supramolecular assemblies. We have already published our investigations concerning the structure of the derivatives that resulted from mixing dmpz and five carboxylic acids, 2,4,6-trimethylbenzoic acid, 2,6-dimethylbenzoic acid, p-methoxybenzoic acid, p-chlorobenzoic acid, and 3,5-dimethyl-4-pyrazole carboxylic acid, in a 1:1 ratio. Only 2,4,6-trimethylbenzoic (tmb) and 2,6-dimethylbenzoic (dmb) acids destroy the 3,5-dimethyl-1H-pyrazole trimer to form †

Dedicated to Professor M. Yus on the occasion of his 60th birthday. * Corresponding author. Tel.: 34 91398 7327. Fax: 34 91398 8372. E-mail: [email protected]. ‡ Universidad Nacional de Educacio ´ n a Distancia. § Universidad Complutense de Madrid. # Consejo Superior de Investigaciones Cientı´ficas.

Scheme 1.

Supramolecular Synthons

(a) (dmpz)3 trimer from 3,5-dimethy-1H-pyrazole dmpz; (b) (sa)2 dimer from salicylic acid sa.

Scheme 2. Carboxylic Acid‚‚‚Pyridine Synthon

new supramolecular structures, the tetramers of Scheme 3. The other carboxylic acids gave rise to physical mixtures of the individual components. We related it to the much higher acidities of the first two, whose experimental pKas are 3.45 for 2,4,6-trimethylbenzoic acid and 3.35 for 2,6-dimethylbenzoic acid.12 To assess the utility of these synthons, we present here our studies on the supramolecular reactions between 3,5-dimethyl1H-pyrazole (dmpz) and salicylic acid (sa). Various techniques could be used to achieve this aim and, in addition to the traditional method involving mixing the two components in a solvent followed by evaporation (slow crystallization), we propose to attempt the preparation of such complexes through the mechanochemical approach, which involves mixing the two components in a mortar with a pestle with or without solvent

10.1021/cg0701527 CCC: $37.00 © 2007 American Chemical Society Published on Web 05/12/2007

Cocrystals of 3,5-Dimethyl-1H-pyrazole and Salicylic Acid

Crystal Growth & Design, Vol. 7, No. 6, 2007 1177

Scheme 3. Tetramers of 2,4,6-Trimethylbenzoic Acid (tmb) and 2,6-Dimethylbenzoic Acid (dmb) with dmpz

drops. The mechanochemical method is more efficient, costeffective, and ecologically more sound and provides fascinating and unexpected results. Previous works have shown that it is possible to form different cocrystals depending on the method of preparation and the stoichiometry used.13-15

Figure 1. ORTEP plot of 1 with ellipsoids at the 40% probability level showing the HBs.

Experimental Section Materials and Preparation of Cocrystals. 3,5-Dimethyl-1Hpyrazole (99%, mp: 105-108 °C) and salicylic acid (99%, mp: 158161 °C) were commercially available and used without further purification. Differential Scanning Calorimetry. The DSC analyses were carried out using a Seiko DSC 220C instrument. The samples were placed into an aluminum DSC pan and the weights accurately recorded. The pan was covered with a lid and then crimped. The samples cells were heated from -19 to 160 °C using nitrogen at a rate of 5 °C/min. Indium was used as the calibration standard. Synthesis of the Trimers. The trimers were prepared in two different ways: (i) both components were mixed in an agate mortar with 2 drops of chloroform and ground with a pestle for 10 min until a homogeneous mixture was obtained, (ii) the compounds were dissolved in ethanol (5 mL), the solvent was removed in a vacuum, and an oil was then obtained that solidified in the refrigerator. In all cases, the stoichiometry was checked by 1H NMR solution spectroscopy. For trimer 1, a mixture of dmpz (48.0 mg, 0.5 mmol) and sa (138.1 mg, 1 mmol) was used. Mp: 78.6 °C. For trimer 2, a mixture of dmpz (96.1 mg, 1 mmol) and sa (69.1 mg, 0.5 mmol) was employed. Mp: 76.3 °C. When we prepared the stoichiometric 1:1 mixture of both components, we observed by solid-state NMR the sum of the spectra of both trimers, 1 and 2 (Scheme 4). X-ray Data Collection and Structure Refinement. Colorless prismatic single crystals of supramolecular entities 1 and 2 suitable for X-ray diffraction experiments were successfully grown from dichloromethane/petroleum ether (bp: 60-80 °C) at 10 °C. Data collection was carried out at room temperature on a Bruker Smart CCD diffractometer using graphite-monochromated Mo-KR radiation (λ ) 0.71073 Å) operating at 50 kV and 20 mA. In both cases, data were collected over a hemisphere of the reciprocal space by combination of three exposure sets, each exposure was of 20 s covered 0.3° in ω. The first 50 frames were recollected at the end of the data collection to monitor crystal decay after X-ray exposition, and a 10% decay was observed for 2. A summary of the fundamental crystal and refinement data are given in Table 1. The structures were solved by direct methods and conventional Fourier techniques. The refinement was done by fullmatrix least-square procedures on F2 (SHELXL-97).16a All non-hydrogen atoms were refined anisotropically. In both cases, all hydrogen atoms were calculated at geometrical positions and refined as riding on the respective carbon atoms. The hydrogen atoms bonded to N or O atoms were found in a difference Fourier synthesis (2θ ) 35 for 2) and their coordinates and thermal parameters fixed, except the H3 for 2, for which the coordinates were refined. Largest peaks and holes in the final difference map were 0.159 and -0.150 e Å-3 for 1 and 0.214 and -0.311 e Å-3 for 2. Final R (Rw) values were 0.0402 (0.0892) for 1 and 0.0566 (0.1819) for 2.

The calculated XRD patters were obtained using the program LAZY PULVERIX.16b The X-ray powder diffraction was made at room temperature using a Panalytical X’PERT PRO R1. NMR Parameters. Solid-state 13C (100.73 MHz) and 15N (40.60 MHz) CPMAS NMR spectra were obtained on a Bruker WB 400 spectrometer at 300 K using a 4 mm DVT probehead. Samples were carefully packed in 4 mm diameter cylindrical zirconia rotors with Kel-F end-caps. Operating conditions involved 3.2 µs 90° 1H pulses and a decoupling field strength of 78.1 kHz by TPPM sequence. The NQS (non-quaternary suppression) technique17 was employed to observe only the quaternary C atoms. 13C spectra were originally referenced to a glycine sample and then the chemical shifts were recalculated to the Me4Si (for the carbonyl atom δ (glycine) ) 176.1 ppm) and 15N spectra to 15NH4Cl and then converted to nitromethane scale using the relationship δ15N(nitromethane) ) δ15N(ammonium chloride) - 338.1 ppm. The typical acquisition parameters for 13 C CPMAS were spectral width, 40 kHz; recycle delay, 60 s; acquisition time, 30 ms; contact time, 2 ms; and spin rate, 12 kHz. For 15N CPMAS, the parameters were spectral width, 40 kHz; recycle delay, 60 s; acquisition time, 35 ms; contact time, 7 ms; and spin rate, 6 kHz. GIAO Calculations. Geometries of trimers 1, 2, and 3 were fully optimized initially at the B3LYP/6-31G* computational level,18-20 and in a second step at the B3LYP/6-311++G**21 level as implemented in the Gaussian 03 program.22 Harmonic frequency calculations23 verified the nature of the stationery points as minima (all real frequencies). Absolute shieldings of compounds 1 and 2 have been calculated over the fully optimized geometries within the GIAO approximation24 at the B3LYP/6-311++G** level.

Results and Discussion The 3,5-dimethyl-1H-pyrazole (dmpz) is a useful supramolecular reagent which in combination with salicylic acid (sa) produces cocrystals in a high supramolecular yield. After various experiments, we have been able to obtain two trimers, 1 and 2, by using different dmpz:sa stoichiometries (Scheme 4). Even as the structures of these aggregates can be understood from the molecular constituents in a straightforward manner, the nature of carboxylic acid‚‚‚pyrazole synthon, neutral or ionic, is difficult to anticipate. From their ∆pKa (pKa conjugate acid of pyrazole base-pKa carboxylic acid) value of 1.09 (pKa of dmpz 4.06 and pKa of sa 2.97), an intermediate O-H‚‚‚N/ O-‚‚‚H-N+ hydrogen-bond character would be expected.25,26 We will demonstrate by analyzing the crystal structures and using 13C and 15N CPMAS NMR that there coexist neutral

1178 Crystal Growth & Design, Vol. 7, No. 6, 2007 Scheme 4.

Lo´pez et al.

Supramolecular Synthesis of Aggregates 1 and 2

Table 1. Crystal Data and Structure Refinement for Trimers 1 and 2 1 empirical formula fw wavelength (Å) cryst syst space group a (Å) b (Å) c (Å) β (deg) V (Å3) Z density (calcd) (mg/m3) absorp coeff (mm-1) F(000) θ range (deg) for data collection index ranges

C19H20N2O6 372.37 0.71073 orthorhombic Pna2(1) 9.375(1) 19.717(3) 9.866(1)

C17H22N4O3 330.30 0.71073 monoclinic P2(1)/c 7.751(8) 10.954(1) 20.72(2) 92.30(2) 1762(3) 4 0.245 0.087 704 2.96 to 25 -9 e h e 9, -13 e k e 13, -19 e l e 24 13155 3084[R(int) ) 0.1224] 0.0566 (1253 obs. reflns) 0.1819

1823.7(4) 4 1.356 0.102 784 2.1 to 25.0 -10 e h e 11, -23 e k e 23, -10 e l e 11 13420 2850 [R(int) ) 0.1158] 0.0402 (1077 obs. reflns) 0.0893

no. of reflns collected no. of independent reflns Ra [I > 2σ(I)] RwF b (all data) a

2

∑||Fo| - |Fc||/∑|Fo|. b {∑[w(Fo2 - Fc2)2]/∑[w(Fo2)2]}1/2. Table 2. Hydrogen-Bond Parameters in the Crystal Structures of 1 and 2 trimer

D-H‚‚‚A

d(D-H) (Å)

d(H‚‚‚A) (Å)

d(D‚‚‚A) (Å)

∠(DHA) (deg)

1

N1-H1‚‚‚O21 N1-H1‚‚‚O12 O11-H11‚‚‚O12 O22-H22‚‚‚N2 O31-H31‚‚‚O21 O32 H32 O22 O1-H1‚‚‚N22 O3-H3‚‚‚O2 N11-H11‚‚‚O2 N12-H12‚‚‚N21 C42-H42A‚‚‚O2′a

0.99 0.99 0.87 0.93 0.90 0.93 1.28 1.03(4) 1.30 1.22 0.93

1.98 2.24 1.68 1.74 1.83 1.75 1.37 1.57(4) 1.47 1.49 2.95

2.815(6) 2.941(5) 2.526(5) 2.665(5) 2.585(4) 2.535(4) 2.598(4) 2.528(4) 2.738(4) 2.710(4) 3.336(5)

140.0 126.0 166.1 179.3 139.7 140.7 157.7 153(3) 163.8 175.4 106.3

2

a

Symmetry transformation used (-x + 1, -y + 1, -z + 1). Table 3. Torsion Angles for Trimers 1 and 2a 1 planes C11C21C31C41C51C61 (1) O11C71O21 (2) C12C22C32C42C52C62 (3) O11C71O21 (4) N1N2C3C4C5 (5)

a

2 dihedral angles 1/2 3.89 3/4 9.84 1/3 2.90 1/5 3.12 3/5 4.32

planes C1C2C3C4C5C6 (1) O1C7O2(2) N11N21C31C41C51 (3) N12N22C32C42C52 (4)

dihedral angles 1/2 5.64 1/3 33.0 1/4 4.2 3/4 15.0

In both compounds, the COO group of the salicylic molecules is almost coplanar with respect to the benzene ring.

)O‚‚‚H-N and )O‚‚‚H-O with ionic O-‚‚‚H-N+ intermolecular hydrogen bonds in both trimers and there is no dynamic solid-state proton transfer (SSPT) in either of them. Energy and GIAO absolute shieldings calculations will support these conclusions. Crystal Structures. The structure of aggregate 1 shows the presence in the asymmetric unit (Figure 1) of two molecules of sa C7H6O3 and one molecule of dmpz C5H8N2 bonded through

hydrogen bonds forming a trimer that involves two supramolecular synthons [R22(7) and R22(6)] in an almost planar disposition. Hydrogen-bond lengths and angles are listed in Table 2. Torsion angles are gathered in Table 3. The C72O12 and C72-O22 distances are 1.262(6) and 1.285(5) Å and their closeness is an indication of bond delocalization, but C71O11 and C71-O21 are quite different, with values of 1.323(5) and 1.240(5) Å, respectively (Table 6).

Cocrystals of 3,5-Dimethyl-1H-pyrazole and Salicylic Acid Table 4.

Chemical Shifts in Solid State -NH-

-Nd

(dmpz)3 dmpz‚TFAA

-170.6 -187.4 [-16.8]

(dmpz)2(tmb)2

-182.8 [-12.2]

(dmpz)2(dmb)2

-172.6 [-2.0] -188.7 [-18.1] -176.9 [-6.3] -176.9 [-6.3]

-97.7 -180.0 -180.8 [-82.7]a -113.9 [-16.2] -116.8 [-19.1] -159.3 [-61.6] -173.4 [-75.7] -175.3 [-77.6] -112.6 [-14.9]

compd

1 (dmpz)(sa)2 2 (dmpz)2(sa)

a

15N

Crystal Growth & Design, Vol. 7, No. 6, 2007 1179

Protonation chemical shift effects are in brackets. Table 5. Absolute Energies in Hartrees of Trimers 1-3 and Difference in Energy between 2 and 3 in kJ mol-1 trimer

B3LYP/6-311++G**

1 2 3 2-3

-1297.37896 +1106.10111 +1106.09796 8.3

Figure 2. Trimer units 1 along the b-axis.

The trimers 1 are situated in a columnar disposition parallel to a-axis and are independent entities as the distances to the neighboring ones are higher than the van der Waals radii sum. Crystal packing is shown in Figure 2. In the case of aggregate 2, the crystal structure confirms the presence of one molecule of sa and two molecules of dmpz bonded through hydrogen bonds in the asymmetric unit involving an R33(10) supramolecular synthon (Figure 3), not completely planar (Table 3). The hydrogen-bond parameters are collected in Table 2. Bond distances C7-O1 and C7-O2 are 1.247(4) and 1.268(4) Å, respectively, pointing to some delocalization as encountered in trimer 1. The individual trimers 2 are connected through weak interactions, C42-H42A‚‚‚O2′, with the centrosymmetric trimers (Table 2 and Figure 4) giving rise to dimers. The experimental powder X-ray diffraction patterns of the samples obtained by mechanochemical synthesis are identical to the calculated powder diffraction patterns in both compounds. Figures 5 and 6 show the corresponding superimposed calculated XRD and PXRD patterns for 1 and 2. NMR Results. The 13C and 15N NMR data of 3,5-dimethyl1H-pyrazole dmpz in the solid state at 200 K have been previously reported by us as being C-3 147.4, C-4 104.6, C-5 139.1, Me-3 12.6, Me-5 10.5, N-1 -170.6, and N-2 -97.7 ppm. The chemical shifts of 3,5-dimethylpyrazolium tetrafluoroborate in the solid state are C-3 146.9 [-0.5], C-4 105.6 [+1.0], C-5

Figure 3. ORTEP plot of 2 with ellipsoids at the 40% probability level showing the HBs.

145.6 [+6.5], Me-3 10.8 [-1.8], Me-5 10.1 [-0.4], N-1 -187.4 [-16.8], and N-2 -180.0/-180.8 [-82.7] ppm, with the values in brackets corresponding to the protonation chemical shift effects.12 For salicylic acid (sa), we also registered its 13C CPMAS spectrum at 300 K with the following results: COOH 176.05, C-1 118.27, C-2 162.04, C-3 111.92, C-4 138.44, C-5 121.03, and C-6 133.06 ppm. Deprotonation of the carboxylic group in benzoic acids affects mainly the chemical shifts of C-1, which

Table 6. Geometries of Trimers 1-2 Concerning Non-Hydrogen Atoms compd

distance (Å)

angles (deg)

X-ray (Å)

X-ray (deg)

calcd (Å)

calcd (deg)

ratio R:β

1

C72-O12 C72-O22 C71-O21 C71-O11 N2-C3 N1-C5 C7-O1 C7-O2 N22-C32 N12-C52 N21-C31 N11-C51

C12-C72-O12 C12-C72-O22 C11-C71-O21 C11-C71-O11 N1-N2-C3 N2-N1-C5 C1-C7-O1 C1-C7-O2 N12-N22-C32 N22-N12-C52 N11-N21-C31 N21-N11-C51

1.262 1.285 1.240 1.324 1.340 1.346 1.247 1.268 1.332 1.333 1.329 1.344

121.9 116.9 123.5 115.0 107.8 109.3 118.3 117.9 108.5 108.4 106.1 110.8

1.232 1.325 1.240 1.323 1.335 1.352 1.244 1.309 1.337 1.352 1.335 1.354

124.0 115.5 122.6 115.2 106.4 111.8 121.6 115.4 106.0 111.8 105.4 112.6

70:30 30:70 100:0 100:0 70:30 30:70 50:50 50:50 60:40 40:60 90:10 10:90

2

% charge 60 anion 0 0 60 cation 100 anion 80 cation 20 cation

avg (Å)

avg (deg)

1.260 [0.002] 1.291 [-0.006] 1.240 [0.000] 1.323 [0.001] 1.340 [0.000] 1.347 [0.001] 1.277 [-0.030] 1.277 [-0.009] 1.309 [0.023] 1.343 [-0.010] 1.337 [-0.008] 1.352 [-0.008]

121.4 [0.5] 118.0 [-1.1] 122.6 [0.9] 115.2 [-0.2] 108.0 [-0.2] 110.2 [-0.9] 118.5 [-0.2] 118.5 [-0.6] 109.5 [-1.0] 108.3 [0.1] 106.1 [0.0] 111.9 [-1.1]

1180 Crystal Growth & Design, Vol. 7, No. 6, 2007

Figure 4. View along the b-axis showing the formation of dimers between units of 2.

Lo´pez et al.

Figure 7. 13C CPMAS NMR spectra of trimer 1: (a) CPMAS and (b) NQS sequence.

Figure 8. 13C CPMAS NMR spectra of trimer 2: (a) CPMAS and (b) NQS sequence.

Figure 5. Experimental powder diffraction (black) and calculated powder diffraction (red) patterns for 1.

Figure 9. Calculated geometry (no PT) of trimer 1 showing the HBs.

Figure 6. Experimental powder diffraction (black) and calculated powder diffraction (red) patterns for 2.

moves approximately +10 ppm, and C-2, approximately -6 ppm (without an OH); COO- is approximately +5 ppm shifted with respect to the COOH chemical shift value.12 In Table 4 are gathered the 15N CPMAS NMR chemical shifts of the two trimers 1 and 2 and the results have been compared with those of dmpz in neutral and acid media (trifluoroacetic acid, TFAA), as well as those obtained for tetramers (dmpz)2(tmb)2 and (dmpz)2(dmb)2 (Scheme 5). The analysis of the data shows that in 1 the dmpz is protonated by the salicylic acid in the formation of the synthon R22(7). However, in 2, one dmpz

Figure 10. Geometries (no PT) of trimers 2 (left) and 3 (right) showing the HBs.

becomes protonated with migration of the carboxylic OH proton, but the second dmpz remains neutral and completes the trimeric aggregate through neutral hydrogen bonds. The 13C CPMAS spectra of trimers 1 and 2 are reproduced in Figures 7 and 8 and the complete assignment of the signals is depicted in Scheme 5, confirming all the conclusions drawn

Cocrystals of 3,5-Dimethyl-1H-pyrazole and Salicylic Acid Scheme 5.

13C

Scheme 6.

Crystal Growth & Design, Vol. 7, No. 6, 2007 1181

and 15N (in bold) CPMAS NMR Chemical Shift Assignments for Trimers 1 and 2 (An, N, and C are design anionic, neutral, and cationic monomers, respectively)

Proton Transfer in Aggregates 1-3

from the 15N CPMAS NMR on the neutral and ionic hydrogenbonding network. Theoretical Calculations. It is necessary to realize that as far as proton transfer is concerned, the situation of trimers 1 and 2 is different (Scheme 6). In complex 1, a triple proton transfer affords an identical structure (degenerate tautomerism), a condition necessary but not sufficient to observe dynamic solid-state proton transfer (SSPT). The SSPT is not observed, probably because the structure is highly distorted with a partly protonated pyrazole. In complex 2, a triple proton transfer results in structure 3, which differs from 2 in the O-H‚‚‚O HB: in 2, the acceptor O atom belongs to the carbonyl group, whereas in 3, it belongs to the OH group. On going from 3 to 2, it is necessary to rotate the phenol, something that cannot happen in the solid state. We have calculated the geometries of the three compounds (Figures 9 and 10): those of 1 and 2 are similar to those determined for 1 and 2 by X-ray crystallography for the nonhydrogen atoms and the HB connectivities, but they strongly differ in the position of the O-H and N-H hydrogen atoms. We have reported in Table 5 the total energies associated with these trimers. The experimental structure 2 is more stable than 3, but the difference is only 8.3 kJ mol-1. Comparison of Experimental and Calculated Geometries (Table 6 and Scheme 7). As we have already commented, the main difference between the calculated structures and the

experimental ones is that the calculated structures represent the molecules without any proton transfer. It is well-known that in the absence of any field (solvent, crystal), the hydrogen atom involved in an HB between neutral molecules A-H‚‚‚B is not transferred (A-‚‚‚H-B+).27 Because the H atoms bonded to the heteroatoms (A or B) are difficult to locate (see the Experimental Section), we have used bond distances and bond angles involving the nonhydrogen atoms most sensitive to HBs (Table 6). We have assumed that proton transfer between salicylic acid and 3,5dimethyl-1H-pyrazole resulted in a combination of the geometries calculated theoretically for the neutral molecules (Scheme 7). As the total charge must be 0, if a proton is trasferred, the same amount of negative and positive charges must be in the monomers. To assume that a pyrazolium cation has a geometry similar to that resulting from averaging both tautomers of a NHpyrazole is consistent with statistical studies of pyrazoles and pyrazolium salts.28 The approximation is less good in the case of salicylic acid because of the intramolecular O-H‚‚‚OdC bond.

In any case, the best compromise we have found is reported in Table 6 and Scheme 7. Note that a pyrazolium cation (100% protonated) is a 50:50 mixture of R and β tautomers, whereas a neutral pyrazole (0% protonated) is a 100:0 mixture of both tautomers. For other situations, charge ) 200 - 2(% tautomer R). For instance, a pyrazole 80% protonated corresponds to 60% tautomer R and 40% tautomer β.

Trimer 1 has one neutral sa molecule and a pair sa-dmpz with 60% of the proton transferred, i.e., the H of the HB is disordered between O22 (40%) and N2 (60%). On the other hand, trimer 2 corresponds to a pure salicylic anion (100%), a pyrazolium cation (80% protonated), and another dmpz (20% protonated), i.e., the H of the HB is disordered between N12 (80%) and N21 (20%). Comparison of Experimental and Calculated NMR Shieldings (Tables 7 and 8). We have calculated the absolute shielding for all the atoms of structures 1-2. The calculated shieldings correspond to neutral complexes, whereas the experimental chemical shifts

1182 Crystal Growth & Design, Vol. 7, No. 6, 2007 Scheme 7.

Lo´pez et al.

PT in the Complexes (using X-ray structure atom numbering)

Table 7. Experimental 13C Chemical Shifts (solid state, δ (ppm)) and Calculated Absolute Shieldings (gas phase, σ (ppm)) of Trimers 1 and 2

Me Me

Me Me

Me Me a

atom

δ13C

σ13C

predicted

exp - predicted

1 C12 C22 C32 C42 C52 C62 C72 C11 C21 C31 C41 C51 C61 C71 C3 C4 C5 C6 C7 2 C1 C2 C3 C4 C5 C6 C7 C32 C42 C52 C62 C72 C31 C41 C51 C61 C71

117.5 162.3 117.7 135.5 120.9 130.4 175.7 113.5 162.3 117.3 135.5 117.7 130.4 173.5 144.7 108.0 143.1 11.1 11.3 120.1 161.8 117.3 132.5 117.3 131.1 174.0 145.8 106.2 143.7 11.4 10.3 147.6 104.1 140.9 14.0 10.3

63.63 12.86 60.00 41.75 59.82 44.50 5.47 65.47 11.07 60.87 41.50 60.36 45.33 2.60 29.92 73.00 37.02 169.78 171.72 65.54 10.87 60.76 41.44 60.66 45.46 3.66 28.36 73.57 36.83 170.12 171.57 27.93 74.25 37.16 168.25 171.97

114.4 162.3 117.8 135.0 118.8 132.5 169.3 112.7a 164.0a 117.0a 135.3a 117.5a 131.7a 172.0a 146.2 105.6 139.5 12.4 14.2 112.6 164.2 117.1 135.3 117.2 131.5 171.0 147.7 105.0 139.7 13.9 12.6 148.1 104.4 139.4 15.7 12.2

3.1 0.0 -0.1 0.5 2.1 -2.1 6.4 0.8 -1.7 0.3 0.2 0.2 -1.2 1.5 -1.5 2.4 3.6 -1.3 -2.9 7.5 -2.4 0.2 -2.8 0.1 -0.4 3.0 -1.9 1.2 4.0 -2.5 -2.3 -0.5 -0.3 1.5 -1.7 -1.9

Fitted

correspond to structures where a partial proton transfer has occurred (see preceding section, Scheme 7). To determine the extent of proton transfer between the three monomers (Schemes 5 and 7) in compounds 1 and 2, we will

Table 8. Experimental 15N Chemical Shifts (solid State, δ Ppm) and Calculated Absolute Shieldings (gas Phase, σ Ppm) of Trimers 1 and 2

1 2

atom

δ15N

σ15N

predicted

exp - predicted

N1 (NH) N2 (-Nd) N12 (NH) N22 (-Nd) N11 (NH) N21 (-Nd)

-188.7 -173.4 -176.9 -175.3 -176.9 -112.6

39.43 -32.31 34.13 -53.02 30.71 -40.72

-181.4 -115.5 -176.5 -107.8 -173.4 -96.5

-7.3 -57.9 -0.4 -67.5 -3.5 -16.1

compare the calculated σ (ppm) with the experimental δ (ppm) of these compounds. Besides we have added the following compounds calculated at the same level: TMS (δ13C ) 0.00, σ13C ) 184.75); NH3 (δ15N ) -382.0, σ15N ) 261.57); MeNO2 (δ15N ) 0.00, σ15N ) -154.43),28 pyrrole (δ15N ) -234.1, σ15N ) 92.43),12 pyrazole N1 (δ15N ) -190.3, σ15N ) 38.69),12 pyrazolium cation (δ15N ) -194.2, σ15N ) 60.95).12 13C NMR. With eight points (TMS plus the seven carbons of sa N of 1), eq 1 is obtained

δ13C ) (174.4 ( 0.6) - (0.944 ( 0.007) σ13C, n ) 8, r2 ) 0.9996 (1) Equation 1 allows us to predict the 13C chemical shifts of all the carbon atoms of neutral trimers 1 and 2 (Scheme 7 and Table 7). We must notice from Table 7 three preliminary points: (i) even in the fitted values there are differences that amount to ( 1.6 ppm; (ii) in the solid state, there are some effects that specifically affect the methyl groups,29 thus the effect on these groups must be considered with caution; (iii) besides protonation effects, there are HB effects that perturbate the chemical shifts.30 The most sensitive carbon to protonation in dmpz is C5 (C3 in 1; C51 and C52 in 2). Taking into account an effect of +6.5 ppm for 100% protonation (vide supra) and 0.0 ppm for 0% protonation, the effects of +3.6 ppm for 1 and +4.0 ppm and +1.5 ppm for 2 (Table 7) correspond to 55% (X-ray 60%), 61% (X-ray 80%), and 23% (X-ray 20%). For sa, the most sensitive is Cipso with values of +10 ppm (anion) and 0 ppm (neutral

Cocrystals of 3,5-Dimethyl-1H-pyrazole and Salicylic Acid

sa); the effects observed in Table 7 are 3.1 ppm (C12 1, 31% of anion, X-ray 60% anion), 0.8 ppm (C11 1, 8% anion, X-ray 0% anion), and 7.5 ppm (C1 2, 75% anion, X-ray 100% anion). Taking into account all the approximations, we deduce proportions from 13C NMR results that are consistent with those calculated from X-ray data (Scheme 7). 15N NMR. With the five points corresponding to those in the literature (MeNO2, NH3, pyrrole, pyrazole, pyrazolium)12,31 we have calculated eq 2.

δ15N ) -(145.2 ( 3.8) (0.92 ( 0.03) σ13C, n ) 5, r2 ) 0.998 (2) We have used this equation to predict the chemical shifts of compounds 1 and 2 (no proton transfer) and to calculate the protonation effects (compounds 1 and 2) reported in Scheme 7 (Table 8). The effects on the NH are weak and cannot be used, but those on -Nd (N2, N22, N21) are important and quite regular (Table 8). Taking into account that ∆d (exp - predicted) is 0 for 0% protonation and -82.7 ppm (vide supra) for 100% protonation, the effects of Table 8 correspond to: 1 (-57.9 ppm, 70% protonation, X-ray 60%), 2 (-67.5 ppm, 82% protonation, X-ray 80%), and 2 (-16.1 ppm, 19% protonation, X-ray 20%). Conclusions (1) We have demonstrated that the controlled supramolecular reaction of 3,5-dimethyl-1H-pyrazole (dmpz) and salicylic acid (sa) affords two trimers: 1 [(dmpz)(sa)2], which contains two supramolecular synthons R22(7) and R22(6) and 2 [(dmpz)2(sa)], with an R33(10) motif, both involving neutral dO‚‚‚H-N and O-H‚‚‚, and ionic O-‚‚‚H-N+ hydrogen bonds. (2) A confirmation by PXRD analysis that the solids obtained from the two synthetic ways, mechanochemical and solutionevaporation (slow crystallization), and the single crystal are the same compound, was achieved for both trimers 1 and 2. The same conclusion arose from the analysis of the CPMAS NMR spectra of each solid. (3) The complementary X-ray diffraction analysis and CPMAS NMR studies has permitted us to establish the complete hydrogen-bonding network, supported by calculated geometries and GIAO absolute shieldings calculations. (4) These structures show static proton disorder (static because narrow signals are observed in CPMAS NMR) involving one of the sa and the dmpz of 1 (60% of proton transferred, 3,5dimethylpyrazolium salicylate) and both dmpz of 2. Acknowledgment. This work has been financed by the MEC/DGI of Spain (CTQ2006-02586). M.A.G. is indebted to MEC, UNED, and BRUKER ESPAN ˜ OLA S.A. for a postdoctoral contract. Supporting Information Available: Crystallographic information in CIF and PDF format. Solid-state reactions of 3,5-dimethyl-1Hpyrazole (dmpz) and salicylic acid (sa) in different stoichiometries afford two different trimers whose structures have been determined and analyzed. Hydrogen-bond interactions between dmpz and sa provide sufficient driving force to direct molecular recognition and crystal packing. This material is available free of charge via the Internet at http://pubs.acs.org.

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CG0701527