4-[(Benzylamino)carbonyl]-1-methylpyridinium bromide hemihydrate: X-ray diffraction study and Hirshfeld surface analysis

The ability of 4-[(benzylamino)carbonyl]-1-methylpyridinium bromide salt to form hydrates was studied. Hirshfeld surfaces analysis was performed for identification of intermolecular interactions.

The hemihydrate of 4-[(benzylamino)carbonyl]-1-methylpyridinium bromide, C 14 H 15 N 2 O + ÁBr À Á0.5H 2 O, was studied by single-crystal and powder X-ray diffraction methods. In the asymmetric unit, two organic cations of similar conformation, two bromide anions and one water molecule are present. In the crystal, N-HÁ Á ÁBr hydrogen bonds link the cations and anions. The formation of a set of intermolecular C-HÁ Á ÁBr and C-HÁ Á Á interactions result in double chains extending parallel to [011]. A Hirshfeld surface analysis showed high contributions of HÁ Á ÁH and CÁ Á ÁH/HÁ Á ÁC short contacts to the total Hirshfeld surfaces of the cations.

Chemical context
The 4-[(benzylamino)carbonyl]-1-methylpyridinium cation (Am + ) has been shown to possess antiviral activity (Buhtiarova et al., 2003;Frolov et al., 2004;Boltz et al., 2018;te Velthuis et al., 2021). Being charged due to quartenization of the pyridine N atom, this type of cation is more stable than its protonated analogue formed by H-atom transition in the form of an acid-base pair. Halogenide anions can be used as simple counter-ions of the organic cation. In fact, the iodide salt of 4-[(benzylamino)carbonyl]-1-methylpyridinium (AmI) is known as a multimodal antiviral drug and has been studied by singlecrystal X-ray diffraction, powder diffraction, IR spectroscopy, and DSC methods (Drebushchak et al., 2017). The search for polymorphic modifications, hydrates or solvates is of great importance for the pharmaceutical industry to improve the quality of a drug and to protect intellectual property. However, polymorphic screening performed for the AmI salt did not reveal any other crystalline form.

Structural commentary
The asymmetric unit contains two molecules of the cation (denoted A and B), two bromide anions (A and B) and one water molecule (Fig. 1). The positive charge of the cation is located at the quaternized nitrogen atom of the pyridine ring.
The carbamide group is slightly non-coplanar with the plane of the aromatic ring, as shown by the N2-C7-C4-C3 torsion angles given in Table 1. The non-planarity is caused by steric repulsion between the two constituents as revealed by the amide H2Á Á ÁH3 pyridine and amide H2Á Á ÁC3 pyridine short contacts (Table 1) as compared to the van der Waals radii sums (Zefirov, 1997) of 2.34 and 2.87 Å , respectively. The cations A and B have similar conformations of the benzyl substituent (Fig. 2). The phenyl fragment of the benzyl substituent is located in an Àac position in relation to the C7-N2 bond and is twisted in relation to the carbamide fragment in both cations A and B, as seen in the C7-N2-C8-C9 and N2-C8-C9-C10 torsion angles (Table 1).

Figure 2
Molecular overlay plot of cations A and B.

Hirshfeld surface analysis
Intermolecular interactions were analysed using Hirshfeld surface analysis and two-dimensional fingerprint plots by using CrystalExplorer17 (Turner et al., 2017). The Hirshfeld surfaces were calculated separately for cations A and B using a standard high surface resolution, mapped over d norm (Fig. 4). The red spots corresponding to contacts that are shorter than the van der Waals radii sum of the closest atoms are observed at the hydrogen atom of the amino group and at some phenyl and methyl hydrogen atoms. The two-dimensional fingerprint plots showed the absence of strong hydrogen bonds in the structure under study. To compare intermolecular interactions of different types in a more quantitative way, their contributions to the total Hirshfeld surfaces were analysed (Fig. 5). The main contribution is provided by HÁ Á ÁH short contacts ( Fig. 5g,h). The contribution of CÁ Á ÁH/HÁ Á ÁC short contacts is also significant (Fig. 5i,j). The BrÁ Á ÁH/HÁ Á ÁBr and OÁ Á ÁH/ HÁ Á ÁO interactions contribute to the total Hirshfeld surface in the same way (Fig. 5c,d and 5e,f).

Database survey
A search of the Cambridge Structural Database (Version 5.42, update of November 2020; Groom et al., 2016) revealed the structure of the anhydrous AmI salt with an equimolar cation:iodine ratio (refcode BEBFIA; Drebushchak et al., 2017). A comparison of the molecular conformation of the cation showed its flexibility due to rotation about the N-Csp 3 and Csp 3 -C aryl bonds.

Powder diffraction characterization
An X-ray powder diffraction pattern of the title compound was registered using a Siemens D500 powder diffractometer (Cu K radiation, Bragg-Brentano geometry, curved graphite monochromator on the counter arm, 4 < 2 < 60 , D2 = 0.02 ). A Rietveld refinement ( Fig. 6) on the basis of the obtained pattern was carried out with FullProf and WinPLOTR (Rodriguez-Carvajal & Roisnel, 1998) using data of an external standard (NIST SRM1976) for the calculation of the instrumental profile function and the single-crystal data as the structure model for refinement. The main results of the Rietveld refinement are shown in Table 3. On the basis of the Rietveld refinement, the experimental powder X-ray diffraction pattern coincides with the theoretical one calculated from the X-ray single crystal study. Contributions of interactions of different types to the total Hirshfeld surface of cations A and B in the crystal structure of AmBr hemihydrate. Table 3 Experimental data of the X-ray powder diffraction study performed at 293 K.

Figure 4
Hirshfeld surfaces mapped over d norm for cations A (left) and B (right) in the crystal structure of AmBr hemihydrate.

Figure 6
Final Rietveld plots for the title compound. Observed data points are indicated by red circles, the best-fit profile (black upper trace) and the difference pattern (blue lower trace) are shown as solid lines. The vertical green bars correspond to the Bragg reflections. 700 ml of water were loaded into a glass flask. The mixture was stirred for 72 h, and the resulting precipitate was filtered off. The solvent was evaporated under reduced pressure. To the precipitate were added 300 ml of acetonitrile and refluxed for 2 h. The reaction then was spontaneously cooled to a temperature of 303 K and the precipitate filtered off and rinsed on the filter with 50 ml of cooled acetonitrile. The product was dried at 313 K for 12 h. Yield: 14 g of 4-[(benzylamino)carbonyl]-1-methylpyridinium bromide (28%); colourless crystals.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. All of the hydrogen atoms were placed in calculated positions and treated as riding with C-H = 0.96 Å , U iso (H) = 1.5U eq for methyl groups and with C ar -H = 0.93 Å , C sp 2 -H = 0.97 Å , U iso (H) = 1.2U eq for all other hydrogen atoms. CrysAlis PRO (Rigaku OD, 2021); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: Mercury (Macrae et al., 2020); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009). 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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Br1A 0.68503 (10