Crystal structure of (2E)-3-[4-(dimethylamino)phenyl]-1-(thiophen-2-yl)prop-2-en-1-one

In the title chalcone-thiophene derivative, the dihedral angle between the aromatic and the thiophene rings is 11.4 (2)°. In the crystal, molecules are linked by C—H⋯O and C—H⋯S weak interactions along [100], forming rings of R22(8) graph-set motif, by C—H⋯O weak interactions along [010], forming C(6) chains, and by weak H(methyl–group)⋯Cg(thiophene ring) interactions into dimers; the crystal packing resembles a herringbone arrangement when viewed along [100]. A molecular docking calculation of the title compound with the neuraminidase enzyme was carried out.

The equimolar reaction between 4-(dimethylamino)benzaldehyde and 2-acetylthiophene in basic ethanolic solution yields the title compound, C 15 H 15 NOS, whose molecular structure matches the asymmetric unit. The molecule is not planar, the dihedral angle between the aromatic and the thiophene rings being 11.4 (2) . In the crystal, molecules are linked by C-HÁ Á ÁO and weak C-HÁ Á ÁS interactions along [100], forming R 2 2 (8) rings, and by weak C-HÁ Á ÁO interactions along [010], forming chains with a C(6) graph-set motif. In addition, molecules are connected into centrosymmetric dimers by weak C-HÁ Á Á interactions, as indicated by the Hirshfeld surface analysis. The most important contributions for the crystal structure are the HÁ Á ÁH (46.50%) and HÁ Á ÁC (23.40%) interactions. The crystal packing resembles a herringbone arrangement when viewed along [100]. A molecular docking calculation of the title compound with the neuraminidase enzyme was carried out. The enzyme shows (ASN263)N-HÁ Á ÁO, (PRO245)C-HÁ Á ÁCg(thiophene ring) and (AGR287)C-HÁ Á ÁN intermolecular interactions with the title compound. The crystal structure was refined as a two-component twin with a fractional contribution to the minor domain of 0.0181 (8).

Chemical context
Chalcone derivatives are compounds with an aromatic conjugated enone as the main fragment and are synthesized by hydroxide-catalysed aldol condensation between an aromatic aldehyde and a ketone. Some of the first preparative methods of the aldol condensation were reported in the second half of the 19th Century (Claisen & Claparè de, 1881;Schmidt, 1881) and the experimental procedure remains the same to the present time. Chalcone compounds can be obtained from a great number of starting materials, resulting in a class of compounds with a wide range of properties and applications, specially in the medicinal chemistry. Several 4-dialkylaminochalcones have shown antiproliferative activity on cancer cell lines and one method to monitor the chalcone-protein interaction, e.g. tubulin proteins, is the chalcone's fluorescence (Zhou et al., 2016). Another example of the pharmacological background for the title compound and its derivatives is the anti-influenza viral activity through the neuraminidase enzymatic inhibition in vitro (Kinger et al., 2012). Thus, the crystal structure determination of chalcone-based molecules is an intensive research area, in particular for its contributions in medicinal chemistry. As part of our studies in this field, we describe herein the crystal structure, the Hirshfeld surface analysis and the molecular docking evaluation of the title compound.

Structural commentary
In the crystal structure of the title compound, a chalconethiophene derivative, the asymmetric unit contains one crystallographically independent molecule (Fig. 1). The molecule is not planar: the r.m.s deviations from the mean plane of the non-H atoms range from À0.158 (3) Å for C3 to 0.1318 (15) Å for S1 and the dihedral angle between the benzene and thiophene rings amounts to 11.4 (2) . In addition, the plane through the amino group atoms (C7/C8/N1) is rotated by 9.7 (6) with respect to the plane of the aromatic ring. Finally, the molecule shows the E configuration about the C9-C10 bond.

Supramolecular features
In the crystal, the molecules are connected by very weak C13-H13Á Á ÁO1 i and C14-H14Á Á ÁS1 i hydrogen-bonding interactions (see Table 1 for symmetry codes), forming rings with an R 2 2 (8) graph-set motif. The R 2 2 (8) rings are the subunits of the periodic arrangement along [100] and one very weak H7Á Á ÁH2 i contact is also observed [HÁ Á ÁH = 2.26 Å ]. The molecular units are also linked by very weak C15-H15Á Á ÁO1 ii links into chains along [010] with a C(6) graph-set motif ( Fig. 2; Table 1). Additionally, the molecules are connected into centrosymmetric dimers by very weak C-HÁ Á Á interactions involving the thiophene ring ( Fig. 3; Table 1). The intermolecular contacts are slightly longer than the sum of the van der Waals radii for the respective atoms (Bondi, 1964;Rowland & Taylor, 1996) and suggest weak interactions only.

Figure 1
The molecular structure of the title compound, showing displacement ellipsoids drawn at the 40% probability level.

Molecular docking evaluation
In addition, a lock-and-key supramolecular analysis between the neuraminidase enzyme, whose inhibition is believed to be a key point to block the influenza viral infection (Kinger et al., 2012), and the title compound was performed. The semiempirical equilibrium energy of the title compound was obtained using the PM6 Hamiltonian and the experimental bond lengths were conserved. The calculated parameters were: heat of formation = 139.28 kJ mol À1 , gradient normal = 0.62031, HOMO = À8.96 eV, LUMO = À0.866 eV and energy gap = 7.421 eV (Stewart, 2013). The rigid molecular docking was carried out with the GOLD software (Jones et al., 1997) using the ChemPLP score function (Chen, 2015). The chalcone thiophene derivative and the active site of the neuraminidase match (Fig. 7) and the structure-activity relationship can be assumed by the following observed intermolecular interactions (HÁ Á ÁA distance values given in Å ): C-HÁ Á ÁCg(thiophene ring) (d = 2.829) and (AGR287)C-HÁ Á ÁN1 (d = 2.620) (Fig. 8). More details about the in silico evaluation, with additional references, can be found in the Supporting Information. For the intermolecular interactions, it is important to report that the HÁ Á ÁCg(thiophene ring) contact is observed in the structure interpretation, by the centrosymmetric dimeric arrangement of the molecules (Figs. 3 and 9), in the Hirshfeld surface analysis (Fig. 5) and in the molecular docking evaluation (Fig. 8).

Database survey
Chalcone-thiophene derivatives have some molecular structural features in common, namely the nearly planar geometry, as a result of the sp 2 -hybridized C atoms of the main fragment, and the weak intermolecular interactions, e.g. HÁ Á ÁH, HÁ Á ÁC orcontacts. One example for comparison with the title compound is the crystal structure of the compound 3-(4methylphenyl)-1-(3-thienyl)-2-propen-1-one (Li & Su, 1993)

Figure 4
A graphical representation of the Hirshfeld surface (d norm ) for the title compound. The surface is drawn with transparency and all atoms are labelled. The surface regions with strongest intermolecular interactions for atoms H2, H15 and O1 are shown in magenta.

Figure 5
A graphical representation of the Hirshfeld surface (d norm ) for the title compound. The surface is drawn with transparency and all atoms are labelled. The surface regions with strongest intermolecular interactions for atoms H7, H8, H13 and O1, and for the thiophene ring, are shown in magenta.
packing shows a herringbone motif: for the title compound this molecular arrangement is clear when looking along the [100] direction (Fig. 9a) and for the above-mentioned 3-thienyl derivative, along [001] (Fig. 9b).

Synthesis and crystallization
All starting materials are commercially available and were used without further purification. The synthesis of the title compound was adapted from a previously reported procedure (Claisen & Claparè de, 1881;Schmidt, 1881;Zhou et al., 2016). In a hydroxide-catalysed reaction, a mixture of 4-(dimethylamino)benzaldehyde (10 mmol) and 2-acetylthiophene (10 mmol) in ethanol (80 mL) was stirred under room temperature for 4 h. After cooling in an ice bath and filtering, an orange solid was obtained. Orange crystals were grown from the solution after 24 h.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. H atoms were located in a difference-Fourier map but were positioned with idealized geometry and were refined with isotropic displacement parameters using a riding model (HFIX command) with U iso (H) = 1.2U eq (C) or 1.5U eq (C) for methyl H atoms. A rotating model was used for the methyl groups. The crystal was refined as a two-component twin {twin law: two-axis (001) [105], BASF = 0.0181 (8)}.

Figure 7
Graphical representation of the lock-and-key model for the title compound, with the molecular main fragment in green, and the neuraminidase structure, with selected amino acids residues, in stick model. The structure of the enzyme is simplified for clarity.

Figure 8
Intermolecular interactions between the title compound and the neuraminidase enzyme. The interactions are shown as dashed lines and the structure of the enzyme is simplified for clarity.

(2E)-3-[4-(Dimethylamino)phenyl]-1-(thiophen-2-yl)prop-2-en-1-one
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. Refinement. Refined as a 2-component twin.