Crystal structure and Hirshfeld surface analysis of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-N-(pyridin-2-ylmethyl)benzamide

The title N-(pyridin-2-ylmethyl)benzamide derivative, crystallizes with two independent molecules (A and B) in the asymmetric unit, which differ essentially in the orientation of the pyridine ring with respect to the benzene ring, with the two rings being inclined to each other by 53.3 (2) and 72.9 (2)° in molecules A and B, respectively.


Structural commentary
The asymmetric unit of the title compound contains two crystallographically independent molecules (A and B; Fig. 1). ISSN 2056-9890 The overall conformation of the A and B molecules differs in the orientation of the pyridine ring with respect to the benzene ring, as shown in the molecular overlap figure [Fig. 2; inverted molecule B (black) on molecule A (red), with an r.m.s. deviation of 0.641 Å ]. The dihedral angle between the benzamide ring and the pyridine ring is 53.3 (2) in molecule A and 72.9 (2) in molecule B. The cyclopropane ring makes a dihedral angle of 57.7 (5) with the benzene ring in molecule A and 58.7 (4) in molecule B. The sum of the bond angles around atom N1 (359.9 ) is in accordance with sp 2 hybridization in both molecules. The bond lengths and bond angles in both molecules are comparable with those reported for a similar compound, 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide (Viertelhaus et al., 2013), that crystallizes with three independent molecules in the asymmetric unit.

Supramolecular features
In the crystal, the A and B molecules are linked by C-HÁ Á ÁO and C-HÁ Á Á interactions (Table 1 and Fig. 1), forming A-B units, which are in turn linked by N-HÁ Á ÁO hydrogen bonds, forming chains propagating along the c-axis direction (Table 1 and Fig. 3). The chains are linked by C-HÁ Á ÁO, C-HÁ Á ÁN and C-HÁ Á ÁF hydrogen bonds, forming layers lying parallel to the ac plane (Table 1 and  Structural overlay of inverted molecule B (black) on molecule A (red). Hydrogen atoms have been omitted for clarity. Table 1 Hydrogen-bond geometry (Å , ).

Figure 3
A partial view along the b axis of the crystal packing of the title compound (colour code: molecule A blue, molecule B red). The N-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds (Table 1) are shown as dashed lines and, for clarity, only the H atoms involved in these interactions have been included.

Figure 1
The molecular structure of the title compound, showing the atomic labelling and the displacement ellipsoids drawn at 30% probability level. Hydrogen bonds (Table 1) are shown as dashed lines.

Figure 4
The crystal packing of the title compound, viewed along the b axis. The hydrogen bonds (Table 1)  action links the layers to form a supramolecular threedimensional structure (Fig. 5).

Database survey
A search of the Cambridge Structural Database (CSD, Version 4.0, last update May 2019; Groom et al., 2016) for the (cyclopropylmethoxy)benzene skeleton gave twelve hits for nine structures. Only three molecules resemble the title compound. The most similar is 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide (CSD refcode PEDWOM; Viertelhaus et al., 2013). It is known as Roflumilast (trade names Daxas, Daliresp), a drug that has anti-inflammatory properties and is used in the treatment of chronic obstructive pulmonary disease (Hohlfeld et al., 2008). The authors (Viertelhaus et al., 2013) have made a variable temperature study of this compound (CSD entries PEDWOM at 100 K, PEDWOM01 at 343 K, PEDWOM02/PEDWOM03 at 298 K) in relation to a reversible single-crystal to singlecrystal phase transition at 323 K. The compound crystallizes in the monoclinic P2 1 /n space group with three independent molecules in the asymmetric unit. The high temperature phase at 343 K also crystallizes in space group P2 1 /n but with only one molecule in the asymmetric unit, the length of the b axis being reduced by around a third. Here, the compound has a disordered difluoromethoxy group. The overall conformations of the molecules in all four entries (PEDWOM at 100 K, PEDWOM01 at 343 K, PEDWOM02/PEDWOM03 at 298 K) are very similar. Considering the low-temperature phase PEDWOM only, in each molecule the benzene and pyridine rings are positioned almost perpendicular to each other, with dihedral angles of 88.38 (14), 89.34 (14) and 84.72 (14) , compared to 53.3 (2) and 72.9 (2) for molecules A and B, respectively, in the title compound. In PEDWOM the cyclopropane ring makes dihedral angles of 55.43 (3), 49.6 (3) and 50.9 (3) with the corresponding benzene ring. These dihedral angles are very similar to those observed in the title structure [57.7 (5) in molecule A and 58.7 (4) in molecule B]. In the second compound, methyl 3-(cyclopropylmethoxy)-4-hydroxybenzoate (DUSXOF; Hou et al., 2010), the cyclopropane ring is inclined to the benzene ring by 63.34 (10) , while in the third compound, methyl 3,4-bis(cyclopropylmethoxy)benzoate (URAWEQ; Cheng et al., 2011), this dihedral angle is smaller at 45.49 (11) .

Synthesis and crystallization
A mixture of 4-(difluoromethyl)-3-hydroxybenzoic acid (2 mmol), (chloromethyl)cyclopropane (2 mmol) and 2picolylamine (3 mmol) with PPh 3 (0.2 mmol) in methanol were heated first to 393 K for 2 h in the presence of the inexpensive ionic liquid tetrabutylammonium bromide (TBAB). The reaction was monitored by TLC, and on completion the reaction mixture was allowed to cool to room temperature, then filtered to remove the insoluble solids. The filtered solid was then washed with dichloromethane. Excess solvents were removed under reduced pressure and the obtained crude product was purified by crystallization using 1:1 ratio of chloroform and methanol. Colourless block-like crystals were obtained after two days.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The NH H atoms were located in difference-Fourier maps and refined freely. The C-bound H atoms were positioned geometrically (C-H = 0.93-0.98 Å ) and allowed to ride on their parent atoms, with U iso (H) =1.5U eq (C-methyl) and 1.2U eq (C) for other H atoms. The absolute structure of the molecules in the crystal are unknown; the Flack parameter refined to 0.6 (3).

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-N-(pyridin-2-ylmethyl)\ benzamide
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.