3,3-Bis(2-hydroxyethyl)-1-(4-methylbenzoyl)thiourea: crystal structure, Hirshfeld surface analysis and computational study

The title tri-substituted thiourea derivative is twisted with a dihedral angle of 72.12 (9)° between the planes through the CN2S atoms and the 4-tolyl ring; an intramolecular N–H⋯O hydrogen bond leads to an S(7) loop. In the crystal. hydroxyl-O—H⋯O(hydroxyl) and hydroxyl-O—H⋯S(thione) hydrogen bonds give rise to a supramolecular layer in the ab plane.

In the title tri-substituted thiourea derivative, C 13 H 18 N 2 O 3 S, the thione-S and carbonyl-O atoms lie, to a first approximation, to the same side of the molecule [the S-C-N-C torsion angle is À49.3 (2) ]. The CN 2 S plane is almost planar (r.m.s. deviation = 0.018 Å ) with the hydroxyethyl groups lying to either side of this plane. One hydroxyethyl group is orientated towards the thioamide functionality enabling the formation of an intramolecular N-HÁ Á ÁO hydrogen bond leading to an S(7) loop. The dihedral angle [72.12 (9) ] between the planes through the CN 2 S atoms and the 4-tolyl ring indicates the molecule is twisted. The experimental molecular structure is close to the gas-phase, geometryoptimized structure calculated by DFT methods. In the molecular packing, hydroxyl-O-HÁ Á ÁO(hydroxyl) and hydroxyl-O-HÁ Á ÁS(thione) hydrogen bonds lead to the formation of a supramolecular layer in the ab plane; no directional interactions are found between layers. The influence of the specified supramolecular interactions is apparent in the calculated Hirshfeld surfaces and these are shown to be attractive in non-covalent interaction plots; the interaction energies point to the important stabilization provided by directional O-HÁ Á ÁO hydrogen bonds.

Chemical context
The amine-H atoms in thiourea, H 2 NC( S)NH 2 , can be systematically replaced to generate up to tetra-functionalized molecules, i.e. R 1 (R 2 )NC( S)N(R 3 )R 4 for R 1-4 = alkyl/aryl. The present study concerns a tri-substituted example, i.e. an N,N 0 -di(alkyl/aryl)-N 0 -benzoylthiourea derivative, notable for having a carbonyl group connected to the thiourea framework. Thiourea molecules are of interest in themselves and as ligands for metal ions (Saeed et al., 2014). The free molecules, including benzoyl derivatives, are well-known to exhibit various biological properties, for example, anti-bacterial, antifungal and anti-viral activities as well as cytotoxicity (Hallur et al., 2006;Cunha et al., 2007;Saeed et al., 2010;Gunasekaran et al., 2017;Zhang et al., 2018;. The combination of hard (oxygen) and soft (sulfur) donor atoms along with nitrogen suggests that benzoylthioureas can function as versatile ligands to metals. Indeed, a variety of coordination modes have been observed such as monodentate-S for the neutral ligand (Saeed et al., 2014;. When deprotonated, a common mode of coordination is O-,S-chelation with considerable delocalization ofelectron density over the ensuing six-membered chelate ring (Saeed et al., 2014). While the motivations for preparing metal complexes of benzoylthioureas are varied, e.g. for anion recognition and as catalysts (Saeed et al., 2014;Zhang & Schreiner, 2009;Nishikawa, 2018), there is continuing interest in exploring their biological potential as coordination of these ligands to metals generally enhances their biological efficacy, such as anti-cancer (Peng et al., 2016;Barolli et al., 2017;Jeyalakshmi et al., 2019), anti-microbial (Gemili et al., 2017;Binzet et al., 2018;Saeed et al., 2018) and anti-mycobacterium tuberculosis (Plutín et al., 2016) activities. The present study was motivated by these applications and by previous structural studies (Gunasekaran et al., 2017; and the known catalytic applications of their cobalt complexes (Gunasekaran, Jerome et al., 2012). Herein, the synthesis, spectroscopic characterization and X-ray crystallographic investigation of the title compound, 4-MePhC( O)N(H)C( S)N(CH 2 -CH 2 OH) 2 , (I), are described, along with an analysis of the calculated Hirshfeld surfaces, non-covalent interaction plots as well as a computational chemistry study.

Structural commentary
The title compound, (I), is illustrated in Fig. 1, and selected interatomic parameters are given in Table 1. The structure features a tri-substituted thiourea molecule with one N atom bearing a benzoyl residue and the other, carrying two hydroxyethyl groups. The thione-S and carbonyl-O atoms lie to the same side of the molecule but are only approximately syn as the S1-C1-N2-C6 torsion angle is À49.3 (2) ; the O3-C6-N2-C1 torsion angle is À6.8 (3) . The hydroxyethyl groups lie to either side of the CN 2 S plane (r.m.s. deviation = 0.018 Å ). The O1-hydroxyethyl group is folded toward the thioamide part of the molecule, an orientation that allows for the formation of an intramolecular N2-HÁ Á ÁO1 hydrogen bond that closes an S(7) loop, Table 2. Overall, the molecule is twisted as seen in the dihedral angle of 72.12 (9) between the CN 2 S atoms and the terminal aryl ring. The C1-N1 bond length is considerably shorter than the C1-N2 bond, which suggests some delocalization of -electron density over the S1-C1-N1 atoms that does not extend over the C1-N1-C6 atoms, consistent with the large twist about the C1-N2 bond (see above). The bond angles subtended at the C1 and C6 atoms follow the expected trends in that those involving the formally doubly bonded atoms are wider, by approximately 10 , compared with the other angles, Table 1.

Gas-phase theoretical structure
Compound (I) was subjected to gas-phase geometry optimization by long-range corrected wB97XD density functional with Grimme's D2 dispersion model (Chai & Head-Gordon, 2008) coupled with Pople's 6-311+G(d,p) basis set (Petersson et al., 1988) as implemented in Gaussian16 (Frisch et al., 2016) in order to compare the optimized molecule with the experimental structure. The results of the optimization show that the local minimum structure in the gas-phase was located as confirmed through a frequency analysis with zero imaginary frequency. The superimposition of the experimental and theoretical structures (Macrae et al., 2006), Fig. 2 57.5 (2) 69.0

Figure 1
The molecular structure of (I) showing the atom-labelling scheme and displacement ellipsoids at the 50% probability level.

Table 2
Hydrogen-bond geometry (Å , ). Symmetry codes: (i) Àx; y À 1 2 ; Àz þ 1 0.014 Å . Salient geometric data for the gas-phase structure are included in Table 1 and correlate very well with the experimental results. The major differences between the experimental and geometry-optimized structures relates to differences in the (i) O3-C6-N2-C1 torsion angles, which deviates further, by approximately 10 , from the anti-disposition in the optimized structure, and (ii) N1-C2-C3-O1 and N1-C4-C5-O2 torsion angles, which are disparate, by about 12 , in the experimental structure but are symmetric, i.e. AE69 , in the optimized structure.

Supramolecular features
In the crystal of (I), the O1-hydroxyl group acts as a hydrogenbond donor to the O2-hydroxy group, which in turn functions as a donor to the S1-atom, Table 2. The O-HÁ Á ÁO hydrogen bonding is propagated by 2 1 symmetry to generate helical chains along the b-axis direction. The O-HÁ Á ÁS hydrogen bonding serves to connect translationally related chains along the a-axis direction and these contacts are reinforced by phenyl-C-HÁ Á ÁO(carbonyl) interactions. In this way, a supramolecular layer in the ab plane is formed, Fig. 3(a). Layers stack along the c-axis direction without directional interactions between them, Fig. 3(b).

Hirshfeld surface analysis
The calculations of the Hirshfeld surfaces and the twodimensional fingerprint plots (overall and delineated) for (I) were performed using Crystal Explorer 17 (Turner et al., 2017) and published protocols (Tan et al., 2019). The Hirshfeld surface mapped over electrostatic potential in Fig. 4, shows different potentials surrounding the key functional groups. Thus, the donors and acceptors of conventional O-HÁ Á ÁO and O-HÁ Á ÁS hydrogen bonds and C-HÁ Á ÁO contacts appear as blue and red regions, respectively, corresponding to positive and negative potential. The Hirshfeld surface mapped over d norm in Fig. 5 also gives the usual indications of these intermolecular interactions through the appearance of bright-red spots near participating atoms. In addition, short interatomic contacts between the hydroxyl-H atom, and carbonyl-C6 and hydroxyl-O2 atoms, and between the ethyl-C5 and hydroxyl-H1O atoms, Table 3   A view of the Hirshfeld surface mapped over the calculated electrostatic potential for (I). The red and blue regions represent negative and positive electrostatic potentials, respectively. The potentials were calculated using the STO-3G basis set at Hartree-Fock level of theory over a range of AE0.18 atomic units.

Figure 2
Overlay diagram for experimental (green image) and geometryoptimized (red) molecules for (I). The molecules have been overlapped so the S C-N-C O fragments are coincident. characterized as faint-red spots or merged within the brightred spots corresponding to the conventional hydrogen bonds in Fig. 5.
The intermolecular contacts in the crystal of (I) were further analysed using an enrichment ratio (ER) descriptor, which is derived from the analysis of the Hirshfeld surface (Jelsch et al., 2014). The ER relates the propensity of pair of chemical species to form a specific interaction in a crystal. The enrichment ratio, ER(X, Y), for a pair of elements (X, Y) is defined as the ratio between proportion of actual contacts in the crystal to the theoretical proportion of random contacts. This ratio is greater than unity for a pair of elements having a high likelihood to form contacts in a crystal, while it is less than one for a pair which tends to avoid contacts with each other. A listing of ER values for (I) is given in Table 4. The enrichment ratios greater than unity for the atom pairs (O, H) and (S, H), Table 4, are consistent with the high propensity for the formation of the O-HÁ Á ÁO and O-HÁ Á ÁS hydrogen bonds in the crystal. It is also evident that the value greater than unity for (C, H) arises from the CÁ Á ÁH/HÁ Á ÁC contacts.
The interatomic distances are calculated in Crystal Explorer 17 (Turner et al., 2017) whereby the X-H bond lengths are adjusted to their neutron values.

Contact
Distance Symmetry operation Two views of the Hirshfeld surface mapped over d norm for (I) in the range À0.132 to +1.682 arbitrary units.   from HÁ Á ÁH contacts are reflected in the middle of the scattered point and cover the greatest area in the plot, and make the most significant contribution (52.5%) to the total Hirshfeld surface, Fig. 6(b) and has an ER value of 0.92, i.e. close to unity. The contribution from OÁ Á ÁH/HÁ Á ÁO contacts is viewed as long spikes at d e + d i $1.8 Å , with points scattered around different regions in the delineated fingerprint plot, Fig. 6(c). In the fingerprint delineated into CÁ Á ÁH/HÁ Á ÁC contacts in Fig. 6 Fig. 6(e).

Computational chemistry
The intermolecular O-HÁ Á ÁO, O-HÁ Á ÁS and C-HÁ Á ÁO interactions occurring between the respective pairs of molecules were subjected to energy calculations by DFT-wB97XD/aug-cc-pVTZ (Woon & Dunning, 1993) for the evaluation of the strength of these interactions. With reference to the BSSE corrected interaction energies (E BSSE int ) listed in Table 6, the O-HÁ Á ÁO hydrogen bond has the greatest interaction energy, followed by C-HÁ Á ÁO and O-HÁ Á ÁS. Unexpectedly, the C-HÁ Á ÁO interaction has an energy approximately 3-4 kcal mol À1 more stable than the O-HÁ Á ÁS interaction despite phenyl-C-H being a weak hydrogen-bond donor and thione-S a weak acceptor, and that such interactions are known to be dispersive in nature (Bhattacharyya et al., 2013). The donor-acceptor interactions were also evaluated by a natural bond orbital (NBO) population analysis (Reed et al., 1988), which revealed that the net NBO charge for H8Á Á ÁO3 is 0.8 compared to 0.6 for H2OÁ Á ÁS1, thereby confirming the relative strength of these interactions.
To complement the results of the calculations on the interaction energies, the dimeric structures were subjected to further analysis by NCIPLOT (Johnson et al., 2010). The analysis provides a convenient visualization index on the strength of any existing non-covalent interactions through a red-blue-green colour scheme on the isosurface, i.e. red is indicative of a strong repulsive interaction, blue is indicative of strong attractive interaction while green is indicative of a weak interaction (Contreras-García et al., 2011). The results, illustrated in Fig. 7, reveal that the O-HÁ Á ÁO interaction is clearly strong and attractive, while both O-HÁ Á ÁS and C-HÁ Á ÁO are considered weak interactions.
As the molecular packing is governed directionally by hydrogen bonding between molecules, the energy frameworks were simulated (Turner et al., 2017)    The energy framework diagrams for (I) showing (a) E electrostatic (red cylinders), (b) E dispersion (green cylinders) and (c) E total (blue cylinders), viewed along the a axis. The frameworks were adjusted to the same scale factor of 50 with a cut-off value of 2.39 kcal mol À1 within 2 Â 2 Â 2 unit cells. The corresponding cylinder radii are proportional to the relative magnitude of the energies. analysis of the energy frameworks shown in Fig. 8 reveals the crystal of (I) is mainly stabilized by electrostatic and dispersive forces. The total electrostatic energy (E electrostatic ) of all pairwise interactions sums to À36.11 kcal mol À1 , while the total dispersion energy term (E dispersion ) computes to À43.83 kcal mol À1 .

Database survey
The crystal structure of the parent compound, PhC( O)N(H)C( S)N(CH 2 CH 2 OH) 2 , (II), has been reported twice (Koch et al., 1995;Cornejo et al., 2005; refcodes ZAJWAI and ZAJWAI01, respectively). The conformation of this molecule and that of (I

Synthesis and crystallization
All chemicals and solvents were used as purchased without purification. The reactions were carried out under ambient conditions. The melting point was measured using a Hanon MP-450 melting point apparatus. The CHN elemental analysis was performed on a LECO TruSpec Micro analyser under helium atmosphere with glycine being used as the standard. The IR spectrum was measured on a Bruker Vertex 70v FT-IR spectrophotometer from 4000 to 400 cm À1 . The 1 H and 13 C{ 1 H} spectra were recorded in DMSO-d 6 solutions on a Bruker Ascend 400 MHz NMR spectrometer with chemical shifts relative to tetramethylsilane (TMS). The optical absorption spectra were measured on 10 and 100 mM ethanol:acetonitrile (1:1) solutions in the range 190-1100 nm on a double-beam Shimadzu UV 3600 Plus UV-vis spectrophotometer. The thermogravimetric analysis (TGA) was performed on a Perkin Elmer STA 6000 Simultaneous Thermogravimetric Analyzer in the range of 35-900 C under a nitrogen atmosphere at a flow rate of 10 C min À1 . The experimental powder X-ray diffraction pattern was measured on a Rigaku MiniFlex diffractometer with Cu K 1 radiation ( = 1.54056 Å ) in the 2 range of 5-70 and a step size of 0.02 .
The experimental PXRD patterns were compared to the simulated PXRD patterns calculated from the CIF using the Rigaku PDXL structure analysis software package. The patterns matched indicating that the reported crystal structure is representative of the bulk material.
Synthesis of (I): An excess of thionyl chloride (Merck) was mixed with 4-methylbenzoic acid (Merck, 1 mmol) and the resulting solution was refluxed until a pale-yellow solution was obtained. The excess thionyl chloride was removed on a water bath, leaving only 4-methylbenzoyl chloride, which is a yellow, viscous liquid. Ammonium thiocyanate (Fisher, 1 mmol) was added into an acetone (30 ml) solution of 4-methylbenzoyl chloride (1 mmol). The solution turned yellow after stirring for 2 h. The white precipitate (ammonium chloride) was isolated upon filtration and to the yellow filtrate, bis(hydroxyethyl)amine (Acros, 1 mmol) was carefully added followed by stirring for 1 h. Upon the addition of dichloromethane (50 ml), a yellow precipitate was obtained, which was collected by filtration. Recrystallization from its hot acetone solution yielded colourless blocks after slow evaporation. The pyrolytic processes for (I) was resolved into four main stages. The first stage involves the liberation of H 2 O between 135 and 165 C, which corresponds to approximate 6% of the weight for (I). The second stage between 160 and 240 C is attributed to the loss of a 4-methylbenzaldehyde fragment, corresponding to 45% weight loss. Subsequently, the remaining fragments undergo further pyrolysis to result in the liberation of ethanol (31% weight) and ammonia (17-18%) in the range 230 to 300 C and 300 C onward, respectively. Compound (I) decomposed at temperatures beyond 700 C.

3,3-Bis(2-hydroxyethyl)-1-(4-methylbenzoyl)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.