N-(6-Methoxypyridin-2-yl)-1-(pyridin-2-ylmethyl)-1H-pyrazole-3-carboxamide: crystal structure and Hirshfeld surface analysis

The title molecule adopts the shape of the letter L as the dihedral angle between the pyridyl rings is 78.37 (5)°. Linear supramolecular chains are found in the crystal mediated by weak carbonyl-C=O⋯π(triazolyl) interactions.


Chemical context
Amide bond formation involving acid-amine coupling is an important synthetic tool for the manufacture of pharmaceuticals and fine chemicals (Schuele et al., 2008). The use of a variety of acid-amine coupling agents, most commonly carbodiimides and onium salts such as phosphonium as well as ammonium salts, for amide bond synthesis has been reviewed (Al-Warhi et al. 2012;Urich et al., 2014). In this context, n-propanephosphonic acid anhydride (T3P) has proved to be an excellent reagent for amide or peptide bond formation. The synthesis of amide bonds utilizing T3P offers high yields, low epimerization and avoids the use of hazardous additives such as explosive hydroxybenzotriazole (HOBt). Further, reactions occur with high yields and lead to the easy removal of the byproducts with a simple work-up, overall resulting in the formation of high-quality product. In addition, it is noted that the T3P reagent is non-toxic and non-allergenic (Joullie & Lassen, 2010;Fennie & Roth, 2016). Moreover, amine bond formation between pyrazole and pyrimidine ring systems can lead to the formation of biologically accepted ingredients such as AM251 (Xi et al., 2006), as a CB1 cannabinoid receptor antagonist, and Meclinertant (SR48692; Liu et al., 2017), a neurotensinreceptor (NTS) antagonist. The combination of such moieties can also lead to molecules with anti-tuberculosis, anti-cancer, anti-bacterial and anti-fungal activities (Fustero et al., 2009;Pal et al., 2012;Dar & Shamsuzzaman, 2015;Sapra et al., 2016). As part of our studies in this area, acid-amine coupling between heterocycles such as pyrazole ISSN 2056-9890 and pyridine using efficient coupling reagents such as T3P was performed; herein, the crystal and molecular structures of (I) are described along with an analysis of its calculated Hirshfeld surface.

Structural commentary
The molecular structure of (I), Fig. 1, comprises an almost planar bi-substituted pyrazolyl ring with the r.m.s. deviation of the fitted atoms being 0.0023 Å . Connected to the ring at the N2 position is a methyl-2-pyridyl residue with the dihedral angle between the five-and six-membered rings being 77.68 (5) , indicating an almost orthogonal relationship. A substituted amide (C10/N4/O1) group is connected at the C3position, which is approximately co-planar with the pyrazolyl ring, forming a dihedral angle of 3.5 (3) . The dihedral angle between the amide atoms and the appended N5-pyridyl ring is 4.4 (3) , indicating a co-planar relationship. The dihedral angle between the pyridyl rings in (I) of 78.37 (5) indicates that the molecule has an approximate L-shape. The amide-N4-H4N atom is flanked on either side by the pyrazolyl-N1 and pyridyl-N5 atoms and in the same way, the amide-O1 atom accepts a weak intramolecular interaction from the C15-H15 grouping; see Table 1 for geometric data characterizing these interactions. Finally, the methoxy group is approximately co-planar with the pyridyl ring to which it is attached, as seen in the C16-O2-C12-N5 torsion angle of 4.2 (3) .

Supramolecular features
The molecular packing of (I) is largely devoid of structuredirecting interactions as the key amide atoms are involved in intramolecular contacts. The only identified directional interaction less than van der Waals separations (Spek, 2009) is a carbonyl-C10 O2Á Á Á(triazolyl) contact, Table 1. As illustrated in Fig. 2a, these lead to linear supramolecular chains aligned along the b-axis direction. The supramolecular chains pack without specific interactions between them, Fig. 2b.

Hirshfeld surface analysis
The Hirshfeld surfaces calculated for (I) were performed in accord with recent studies (Jotani et al., 2016) and provide additional information on the influence of short interatomic contacts influential in the molecular packing. On the Hirshfeld  Table 1 Intra-and intermolecular interactions (Å , ) for (I).
Cg1 is the centroid of the N1/N2/C1-C3 ring.   The molecular structure of (I), showing displacement ellipsoids at the 50% probability level.

D-HÁ
surfaces mapped over d norm in Fig. 3, the presence of diminutive red spots near the pyrazole-N1, methyl-H16B, pyridyl-N3 and pyridyl-H5 atoms are indicative of short interatomic NÁ Á ÁH/HÁ Á ÁN contacts (Table 2). In addition, the presence of diminutive red spots near the carbonyl-O1 and pyridyl-H6 atoms on the surface connect the molecules through short interatomic OÁ Á ÁH/HÁ Á ÁO contacts (Table 2) are highlighted through black dashed lines in Fig. 3a. The faint-red spots appearing near the pyridyl-C5, C6 and C8 atoms and the pyrazolyl-H1 atom in Fig. 3b represent the short interatomic CÁ Á ÁC and CÁ Á ÁH/HÁ Á ÁC contacts (Table 3) between these atoms. The intermolecular C OÁ Á Á contacts connecting the molecules along the b-axis direction are illustrated in Fig. 3c. The weak intermolecular interactions described above are also viewed as the blue and red regions near the respective atoms on the Hirshfeld surfaces mapped over the calculated electrostatic potential shown in Fig. 4.
The overall two-dimensional fingerprint plot for (I), Fig. 5a, and those delineated into HÁ Á ÁH, NÁ Á ÁH/HÁ Á ÁN, OÁ Á ÁH/ HÁ Á ÁO, CÁ Á ÁH/HÁ Á ÁC and CÁ Á ÁC contacts (McKinnon et al., 2007) are illustrated in Fig. 5b-f, respectively, and the percentage contributions from the different interatomic contacts to the Hirshfeld surface are summarized in Table 3. The greatest, i.e. 46.4%, contribution to the Hirshfeld surfaces are from HÁ Á ÁH contacts and indicates the significance of dispersive forces on the molecular packing as the interatomic distances involving these contacts are greater than the sum of van der Waals radii. The short interatomic OÁ Á ÁH/HÁ Á ÁO and CÁ Á ÁH/HÁ Á ÁC contacts in the crystal structure of (I) are characterized as the pair of thin needle-like and forceps-like tips at d e + d i $ 2.5 Å and 2.7 Å , respectively, in the corresponding delineated fingerprint plots Fig. 5c and e. The pair of spikes with the tips at d e + d i $ 2.6 Å and the regions of green points aligned in the fingerprint plot delineated into NÁ Á ÁH/HÁ Á ÁN contacts, Fig. 5d, are indicative of short NÁ Á ÁH interatomic contacts (Table 2). In the fingerprint plot delineated into CÁ Á ÁC contacts, Fig. 5f, the presence of points at d e + d i < 3.4 Å , i.e. less than the sum of van der Waals radii, are due to short interatomic C5Á Á ÁC8 contacts involving pyridyl-carbon atoms (Fig. 3b)
Contact Distance Symmetry operation 3.380 (3) x, 1 + y, z Figure 4 Two views of the Hirshfeld surface mapped over the electrostatic potential in the range À0.080 to +0.044 a.u. The red and blue regions represent negative and positive electrostatic potentials, respectively.
surfaces (Table 2) in the crystal arise from the presence of the intermolecular C OÁ Á Á contacts. The interatomic NÁ Á ÁN contacts show no significant contribution to the packing of (I).

Synthesis and crystallization
1H-Pyrazole-4-carboxylic acid (0.0446 mol) was treated with diisopropylethyl amine (0.0669 mol) and 1-propane phosphonic acid (T3P) (0.0669 mol) in dimethyl formamide (10 ml) at 273 K for 15 min. Then, 6-methoxypyridin-2-amine (0.0490 mol) was added at 273 K. The reaction mixture was heated at 353 K for 3 h. After completion of the reaction, the product was extracted with ethyl acetate and the excess solvent was removed under vacuum. The product was recrystallized using methanol as solvent to yield 1-(6-methoxypyridin-2-ylmethyl)-1H-pyrazole-4-carboxylic acid. This product (0.0246 mol) and 2-(chloromethyl)pyridine (0.0295 mol) were dissolved in acetone (10 ml), potassium carbonate (0.0369) was added and the reaction mixture was heated at 329 K for 5 h. After completion of the reaction, the product was extracted with ethyl acetate twice (5 ml) and the extract was concentrated under vacuum. The product was washed with diethyl ether (3 ml) and recrystallized from methanol solution to obtain the title compound, (I), as colourless blocks in 88% yield.

N-(6-Methoxypyridin-2-yl)-1-(pyridin-2-ylmethyl)-1H-pyrazole-3-carboxamide
Crystal data Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.