1-{(E)-[4-(4-Hydroxyphenyl)butan-2-ylidene]amino}-3-phenylthiourea: crystal structure, Hirshfeld surface analysis and computational study

The title thiourea derivative adopts a U-shaped conformation, which incorporates an intramolecular amine-N—H⋯N(imine) hydrogen bond. In the molecular packing, supramolecular chains are formed through hydroxyl-O—H⋯S(thione) and amine-N—H⋯O hydrogen bonding.


Chemical context
Raspberry ketone, also known as 4-(4-hydroxyphenyl)-2butanone (C 10 H 12 O 2 ), is a natural phenolic compound found in raspberries, kiwi fruit, brewed coffee, yew and orchid flowers (Lee, 2016). This ketone is the primary compound responsible for the fruity aroma and has long been used commercially as a fragrance and flavouring agent for cosmetics, perfume, food and beverages. The pharmaceutical attributes exhibited by this ketone include anti-androgenic activity in human breast cancer cells, de-pigmentation, antiinflammatory activity and cardioprotective action in rats (Dziduch et al., 2020;Yuan et al., 2020). In this work, raspberry ketone was condensed with 4-phenyl-3-thiosemicarbazide to form the title thiourea derivative, C 17 H 19 N 3 OS, hereafter designated as (I). Such compounds are of much interest due to their attractive and widespread pharmacological activities including anti-bacterial, anti-fungal, anti-tubercular, anticonvulsant, anti-tumour, anti-oxidant, anti-malarial and antihelmintic properties (Dincel & Guzeldemirci, 2020). In a continuation of on-going studies on related derivatives and complexes (Tan, Ho et al. 2020;Tan, Kwong et al. 2020a,b), herein the synthesis, structure determination, Hirshfeld ISSN 2056-9890 surface analysis and computational chemistry of (I) are reported.

Structural commentary
The molecular structure of (I), Fig. 1, comprises an almost planar central chromophore with the r.m.s. deviation for the C1, N1-N3 and S1 atoms being 0.0039 Å ; the maximum deviation from the least-squares plane is 0.0054 (12) Å for the C1 atom. The pendant C2 and C8 atoms lie 0.065 (3) and 0.072 (2) Å out of and to the same side of the central plane. While the N1-bound phenyl ring is approximately co-planar with the central residue, forming a dihedral angle of 7.94 (8) , the terminal 4-hydroxybenzene ring is not, forming a dihedral angle of 67.00 (4) ; the dihedral angle between the rings is 73.64 (5) . This conformation arises as there is a twist about the ethane bond, i.e. the C8-C10-C11-C12 torsion angle is À78.12 (18) . Globally, both aromatic residues lie to the same side of the molecule so that it has a U-shaped conformation.
The C1-S1 bond length is 1.6910 (15) Å , the C1-N1 bond [1.340 (2) Å ] is marginally shorter than the C1-N2 [1.356 (2) Å ] bond, the formally C8-N3 double bond is 1.284 (2) Å and N2-N3 is 1.3857 (18) Å . These values, coupled with the observed planarity in this region of the molecule, is suggestive of some delocalization of -electron density over this residue. The configuration about the C8 N3 imine bond is E. The N-bound H atoms lie to opposite sides of the molecule, a conformation that allows for the formation of an intramolecular amine-N-HÁ Á ÁN(imine) hydrogen bond, Table 1.

Supramolecular features
In the crystal, hydrogen bonding leads to the formation of a linear, supramolecular chain parallel to [473]. These chains arise because the hydroxyl-O-H atom forms a hydrogen bond to the thione-S1 atom and the hydroxyl-O1 atom simultaneously accepts a N-HÁ Á ÁO hydrogen bond from the amine-N2-H atom, Fig. 2(a). They are connected into a supramolecular layer parallel to the c axis via methylene-C-HÁ Á ÁS(thione) and methylene-C-HÁ Á ÁO(hydroxyl) interactions as well as methyl-C-HÁ Á Á(phenyl) and phenyl-C-HÁ Á Á(hydroxybenzene) contacts, Table 1 and Fig. 2(b). The layers thus formed are two molecules thick and stack along the c-axis direction without directional interactions between them, Fig. 2(c). Finally, as indicated in Fig. 2(b) and (c), the supramolecular connectivity brings two sulfur atoms into close proximity, with an S1Á Á ÁS1 i separation of 3.3534 (6) Å , cf. the sum of the van der Waals radii of 3.60 Å (Spek, 2020); symmetry operation (i): 2 À x, Ày, 1 À z.

Analysis of the Hirshfeld surfaces
The Hirshfeld surface analysis comprising the calculation of the d norm surface (McKinnon et al., 2004), electrostatic potential (Spackman et al., 2008), using the wave function at the HF/STO-3G level of theory, and two-dimensional fingerprint plots (Spackman & McKinnon, 2002) were generated to further elucidate the interactions in the crystal of (I), in particular within the inter-layer region. This study was carried out using Crystal Explorer 17 (Turner et al., 2017) following literature procedures (Tan et al., 2019).

Figure 1
The molecular structure of (I) showing the atom-labelling scheme and displacement ellipsoids at the 70% probability level.
atoms, correspond to the amine-N2-H2NÁ Á ÁO1(hydroxyl), hydroxyl-O1-H1OÁ Á ÁS1(thione) hydrogen bonds and the thione-S1Á Á ÁS1(thione) short contact; these and other short contacts calculated using Crystal Explorer 17 are collated in Table 2. These hydrogen bonds are also reflected in the Hirshfeld surface mapped over the electrostatic potential shown in Fig. 3(b), where the positive electrostatic potential (blue) and negative electrostatic potential (red) regions are observed around the amine-H2N and thione-S1 atoms, respectively. The faint red spots appearing near the thione-S1, hydroxyl-O1 and methylene-H11A and H11B atoms ( Fig. 4) correspond to methylene-C-HÁ Á ÁS(thione) and methylene-C-HÁ Á ÁO1(hydroxyl) interactions, with separations $0.2 Å shorter than the sum of their respective van der Waals radii,      C6-H6Á Á Á(C12-C17; Cg2) interactions are shown as faint red spots on the d norm surface in Fig. 5(a) and as two distinctive orange 'potholes' on the shape-index-mapped over Hirshfeld surface in Fig. 5 Table 1, was not manifested on the d norm -mapped Hirshfeld surface. However, this interaction clearly shows up as an orange 'pothole' on the shape-index-mapped Hirshfeld surface in Fig. 6. The overall two-dimensional fingerprint plot computed for (I) is shown in Fig. 7(a) and those delineated into HÁ Á ÁH, HÁ Á ÁC/CÁ Á ÁH, HÁ Á ÁS/SÁ Á ÁH and HÁ Á ÁO/OÁ Á ÁH contacts are illustrated in Fig. 7(b)-(e), respectively. The percentage contributions to the Hirshfeld surface of (I) from the different interatomic contacts are summarized in Table 3. The HÁ Á ÁH contacts are the most prominent of all contacts and contribute 49.6% to the entire surface. The HÁ Á ÁH contact manifested as a duckbill peak tipped at d e = d i $2.1 Å , Fig. 7(b), corresponds to the intra-layer H1OÁ Á ÁH2N contact listed in Table 2. The HÁ Á ÁC/CÁ Á ÁH contacts contribute 22.6% to the Hirshfeld surface, Fig. 7(c), reflecting the significant C-HÁ Á Á interactions evinced in the packing analysis, Table 1. Consistent with the O-HÁ Á ÁS and N-HÁ Á ÁO hydrogen bonds occurring in the crystal, HÁ Á ÁS/SÁ Á ÁH and HÁ Á ÁO/OÁ Á ÁH contacts contribute 10.5 and 6.4%, respectively, to the overall Hirshfeld surface. These two contacts appear as two sharp spikes in the fingerprint plots at d e = d i ' 2.2 Å in Fig. 7 Table 3 The percentage contributions from interatomic contacts to the Hirshfeld surface for (I).

Figure 4
Two views of the Hirshfeld surface mapped for (I) over (a) d norm in the range À0.490 to +1.188 arbitrary units.
respectively. The contributions from the other six interatomic contacts summarized in Table 3 have a reduced influence on the calculated Hirshfeld surface of (I), as each contributes less than 3.0%.

Computational chemistry
The energy frameworks were calculated for (I) by summing the four energy components -the electrostatic (E ele ), polarization (E pol ), dispersion (E dis ) and exchange-repulsion (E rep ) energy components (Turner et al., 2017). The individual energy components as well as the total energy for the identified intermolecular interactions are summarized in Table 4. As the intra-layer region is mainly consolidated by C-HÁ Á Á and C-HÁ Á ÁS/O interactions, the E dis component makes the major contribution to the interaction energies. The most significant stabilization energies are found in the intra-layer region, as outlined in Supramolecular Features. The S1Á Á ÁS1 short contact is dominated by the E ele (À8.9 kJ mol À1 ) and E rep (12.2 kJ mol À1 ) terms and having a total energy of 11.7 kJ mol À1 is non-attractive. The stabilization energies in the inter-layer region are dominated by the E dis component. The greatest stabilization energy in the inter-layer region arises from methyl-C9-H9BÁ Á ÁO1(hydroxyl) [2.87 Å ; Àx + 1, Ày + 2, Àz] and methylene-H10Á Á ÁH16(hydroxybenzene) interactions [2.59 Å ; Àx + 1, Ày + 2, Àz], which sum to À30.7 kJ mol À1 . Generally, the long-range HÁ Á ÁH contacts are the major interactions stabilizing the molecules within the inter-layer region.

Database survey
In the crystallographic literature, there are two precedents for molecules related to (I) in which the imine bond is connected to an aromatic residue via an ethane link. Each of these is a Nmethyl species, i.e. MeN(H)C( S)N(H)N C(Me)CH 2 -CH 2 Ar, one with Ar = phenyl (Tan, Kwong et al., 2020a) and the other with Ar = 4-methoxybenzene (Tan et al., 2012). In the former, the molecule has a distinctive U-shaped conformation with a twist about the CH 2 -CH 2 bond [the C i -C m -C m -C p (i = imine, m = methylene, p = phenyl) torsion angle = À62.76 (16) ], a conformation stabilized, at least in part, by an intramolecular amine-N-HÁ Á Á(phenyl) interaction. By contrast, in the species with Ar = 4-methoxybenzene, the molecule is close to planar as indicated by the C i -C m -C m -C p torsion angles of 177.51 (12) and À175.80 (12) , respectively, for the two independent molecules comprising the asymmetric unit. Thus, to a first approximation, the conformation observed in (I) matches that seen in the species with Ar = phenyl, even though no intramolecular N-HÁ Á Á(hy-(hydroxybenzene) interaction was noted in (I).

Refinement
Crystal data, data collection and structure refinement details are summarized in Perspective views of the energy frameworks calculated for (I) showing (a) electrostatic potential force, (b) dispersion force and (c) total energy, each plotted down the a axis. The radii of the cylinders are proportional to the relative magnitudes of the corresponding energies and were adjusted to the same scale factor of 55 with a cut-off value of 5 kJ mol À1 . placed in calculated positions (C-H = 0.95-0.99 Å ) and were included in the refinement in the riding-model approximation, with U iso (H) set to 1.2-1.5U eq (C). The O-bound and N-bound H atoms were located in a difference-Fourier map but were refined with O-H = 0.84AE0.01 and N-H = 0.88AE0.01 Å distance restraints, respectively, and with U iso (H) set to 1.5U eq (O) and 1.2U eq (N).

1-{(E)-[4-(4-Hydroxyphenyl)butan-2-ylidene]amino}-3-phenylthiourea
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.