3-Methyl-1-{(E)-[1-(4-methylpyridin-2-yl)ethylidene]amino}thiourea: crystal structure and Hirshfeld surface analysis

The title molecule is twisted, with the dihedral angles between the imine core (C3N) and thiourea and methylpyridyl residues being 20.25 (8) and 7.60 (9)°, respectively. In the crystal, corrugated supramolecular layers in the bc plane are mediated by amine-N—H⋯N(pyridyl) and thioamide-N—H⋯S(thione) hydrogen bonds.


Chemical context
Thiosemicarbazones (TSCs) are thiourea derivatives that form versatile ligands containing mixed hard-soft, nitrogen-sulfur donor atoms. TSC and its derivatives have attracted considerable attention due to their promising biological applications, especially in the realm of anti-tumour (Hussein et al., 2015), anti-viral (Easmon et al., 1992), anti-malarial (Kumar et al., 2014), anti-fungal (Lobana et al., 2017), anti-bacterial (Khan & Asiri, 2018) and anti-parasitic (Njogu & Chibale, 2013) activities. Their biological potential has been found to be enhanced by the addition of alkyl groups at the terminal N-position (Liberta and West, 1992). In fact, a thiosemicarbazone drug, methisazone (N-methylisatin -thiosemicarbazone) was reported as an anti-viral agent by McNeill in 1972(McNeill, 1972 and field trials for methisazone as a prophylactic agent against smallpox were carried out in West Pakistan between 1964and 1970(Heiner et al., 1971. More recently, phase I and phase II clinical trials were conducted for triapine (3-aminopyridinecarbaldehyde thiosemicarbazone) in untreated patients with advanced-stage cervical cancer where triapine showed an inhibition of ribonucleotide reductase and thus enhanced the radiochemosensitivity by prolonging DNA repair time (Kunos & Sherertz, 2014). With this interest and as a part of on-going investigations on a series of thiosemicarbazone Schiff bases and their transition metal complexes, the title compound, namely the N-methyl thiosemicarbazone derived from 2-acetyl-4-methyl pyridine, (I), was synthesized. Herein, its crystal and molecular structures along with an analysis of its Hirshfeld surface and fingerprint plots are reported.

Structural commentary
The molecular structure of (I), Fig. 1, comprises three distinct almost planar residues, namely the thiourea (C1,N1,N2,S1), central imine (C3,C4,C5,N3) and methylpyridyl (N4,C5-C10) residues, coincidentally each with the r.m.s. deviation of the respective fitted atoms being 0.0066 Å . Twists in the molecule are apparent about the N2-N3 and C3-C5 bonds as seen in the values of the C1-N2-N3-C3 and C4-C3-C5-C9 torsion angles of À167.44 (13) and 171.34 (13) , respectively. This is reflected in the dihedral angles between the mean planes through the central and each of the thiourea and methylpyridyl residues of 20.25 (8) and 7.60 (9) , respectively; the dihedral angle between the outer planes is 13.62 (7) . The configuration about the C3 N3 imine bond [1.2872 (19) Å ] is E. The molecule in (I) features an anti-disposition of the amine-N-H atoms, which facilitates the formation of an intramolecular amine-N1-HÁ Á ÁN3(imine) hydrogen bond to close an S(5) loop, Table 1. The methyl groups lie to opposite sides of the molecule and can also be described as being anti to one another.

Supramolecular features
The most prominent feature of the molecular packing is the formation of eight-membered thioamide {Á Á ÁHNCS} 2 synthons owing to the formation of thioamide-N2-HÁ Á ÁS1(thione) hydrogen bonds between centrosymmetrically related molecules, Table 1. These serve to link zigzag (glide symmetry) supramolecular chains, along the c-axis direction and  Table 1 Hydrogen-bond geometry (Å , ).

Figure 2
Molecular packing in (I): (a) a view of the supramolecular layer propagating normal to the a-axis direction sustained by thioamide-N-HÁ Á ÁS(thione) and amine-N-HÁ Á ÁN(pyridyl) hydrogen bonds shown as orange and blue dashed lines, respectively. Non-participating hydrogen atoms have been omitted for reasons of clarity, and (b) a view of the unitcell contents shown in projection down the c axis. One layer is highlighted in space-filling mode to emphasize the jagged topology.

Figure 1
The molecular structure of (I) showing the atom-labelling scheme and displacement ellipsoids at the 70% probability level.
sustained by amine-N1-HÁ Á ÁN4(pyridyl) hydrogen bonds, into a supramolecular layer propagating in the bc plane, Fig. 2a. Additional stabilization of the layers is afforded by methyl-C-HÁ Á Á(pyridyl) interactions, Table 1. Layers stack along the a axis without directional interactions between them, Fig. 2b.

Analysis of the Hirshfeld surfaces
The Hirshfeld surface calculations were performed according to recent work on a related organic molecule (Tan et al., 2017) and serve to provide more detailed information on the influence of intermolecular interactions in the crystal. The dominant N-HÁ Á ÁS and N-HÁ Á ÁN hydrogen-bonding interactions in the structure of (I) are viewed as bright-red spots near the respective donor and acceptor atoms on the Hirshfeld surfaces mapped over d norm shown in Fig. 3. The diminutive red spots near the pyridyl-N4 and -H9 atoms indicate the presence of intermolecular C-HÁ Á ÁN interactions. In addition to the above, the crystal also features comparatively weak intermolecular C-HÁ Á ÁS interactions and short interatomic CÁ Á ÁS/ SÁ Á ÁC contacts, Table 2, viewed as faint-red spots in Fig. 3. The Hirshfeld surfaces mapped over electrostatic potential shown in Fig Two views of the Hirshfeld surface mapped over d norm for (I) in the range À0.110 to +1.348 au, highlighting N-HÁ Á ÁN and N-HÁ Á ÁS hydrogen bonds through yellow dashed lines and short interatomic CÁ Á ÁS/SÁ Á ÁC contacts through black dashed lines. Table 2 Summary of short interatomic contacts (Å ) in (I).

Figure 4
Two views of the Hirshfeld surface mapped over the electrostatic potential for (I) in the range À0.103 to +0.104 au. The red and blue regions represent negative and positive electrostatic potentials, respectively.  (Table 2) and C-HÁ Á Á interaction (Table 1), viewed as a pair of very short peaks at d e + d i $2.8 Å and the parabolic distribution of points around d e + d i $2.9 Å , respectively. The points related to the most prominent interlayer contact, i.e. S1Á Á ÁH7 (Table 2), are merged within the plot delineated into SÁ Á ÁH/HÁ Á ÁS contacts (Fig. 5d) due to the presence of N-HÁ Á ÁS hydrogen bonds. The contribution of 0.6% from CÁ Á ÁS/ SÁ Á ÁC contacts to the Hirshfeld surfaces of (I) indicate the presence of the short C4Á Á ÁS1 contact listed in Table 2. The other interatomic contacts summarized in Table 3 having large interatomic separations have a negligible effect on the packing.

Database survey
Reflecting the interest in this class of compounds, there are no fewer than 16 structures related to (I) included in the Cambridge Structural Database (Version 5.38; Groom et al., 2016), i.e. that are neutral and feature N1-bound alkyl or aryl group and a C3-bound pyridyl ring; the C4-bound methyl group is common to all structures. The most closely related structure to (I), i.e. with an unsubstituted 2-pyridyl ring at the C3-position, has been described three times, being originally reported in 1999 (Bermejo et al., 1999). Most structures feature N1-bound aryl rings, and all feature an anti-disposition of the N-H groups.

Synthesis and crystallization
All chemicals were of analytical grade and were used without any further purification. 2-Acetyl-4-methyl pyridine (0.68 g, 0.005 mol) in absolute ethanol (40 ml) was dissolved and added to 4-methyl-3-thiosemicarbazide (0.52 g, 0.005 mol) dissolved in absolute ethanol (40 ml). The mixture was then heated in a water bath for 10 mins with constant and vigorous stirring until the volume reduced to 30 ml. The product that formed was filtered off, washed with cold ethanol and dried in a desiccator over anhydrous silica gel. Brown platy crystals suitable for single crystal X-ray diffraction analysis were obtained by recrystallization with absolute ethanol as solvent.

3-Methyl-1-{(E)-[1-(4-methylpyridin-2-yl)ethylidene]amino}thiourea
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.