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

In the title tri-substituted thiourea molecule, a substantial twist is evident as seen in the dihedral angle of 65.92 (12)° between the planes through the CN2S residue and the 4-nitroaryl ring; an intramolecular N—H⋯O hydrogen bond leading to an S(7) loop is noted. In the molecular packing, O—H⋯O and O—H⋯S hydrogen bonds lead to supramolecular layers propagating in the ab plane.

In the title compound, C 12 H 15 N 3 O 5 S, a trisubstituted thiourea derivative, the central CN 2 S chromophore is almost planar (r.m.s. deviation = 0.018 Å ) and the pendant hydroxyethyl groups lie to either side of this plane. While to a first approximation the thione-S and carbonyl-O atoms lie to the same side of the molecule, the S-C-N-C torsion angle of À47.8 (2) indicates a considerable twist. As one of the hydroxyethyl groups is orientated towards the thioamide residue, an intramolecular N-HÁ Á ÁO hydrogen bond is formed which leads to an S(7) loop. A further twist in the molecule is indicated by the dihedral angle of 65.87 (7) between the planes through the CN 2 S chromophore and the 4-nitrobenzene ring. There is a close match between the experimental and gas-phase, geometry-optimized (DFT) molecular structures. In the crystal, O-HÁ Á ÁO and O-HÁ Á ÁS hydrogen bonds give rise to supramolecular layers propagating in the ab plane. The connections between layers to consolidate the three-dimensional architecture are of the type C-HÁ Á ÁO, C-HÁ Á ÁS and nitro-OÁ Á Á. The nature of the supramolecular association has been further analysed by a study of the calculated Hirshfeld surfaces, non-covalent interaction plots and computational chemistry, all of which point to the significant influence and energy of stabilization provided by the conventional hydrogen bonds.

Chemical context
In addition to accepting C-HÁ Á ÁO interactions, nitro groups are known to form nitro-N-OÁ Á Á(aryl) interactions (Huang et al., 2008) as well as participate as donors and acceptors in -hole interactions (Bauzá et al., 2014). Hence, when the title nitro-containing compound, (I), became available, a crystallographic analysis was undertaken. Compound (I) is an example of a tri-substituted thiourea molecule, H 2 NC( S)NH 2 , whereby three of the four hydrogen atoms have been substituted to yield 4-NO 2 C 6 H 4 C( O)N(H)C-( S)N(CH 2 CH 2 OH) 2 . Such N,N 0 -di(alkyl/aryl)-N 0 -benzoylthiourea derivatives have a carbonyl group connected to the thiourea framework and offer opportunities for rich coordination chemistry as these molecules feature both hard (oxygen) and soft (sulfur) donor atoms along with nitrogen donors and indeed, a variety of coordination modes have been observed. The neutral molecule has been observed to coordinate in a monodentate-S mode Saeed et al., 2014). In its deprotonated form, O-,Schelation is often observed (Saeed et al., 2014). There are a variety of motivations for investigating metal complexes of benzoylthiourea derivatives such as for catalytic applications and for anion recognition (Zhang & Schreiner, 2009;Guna-sekaran, Jerome et al., 2012;Nishikawa, 2018). Over and above these considerations, there are continuing investigations into their biological potential, such as anti-microbial (Gemili et al., 2017;Binzet et al., 2018;Saeed et al., 2018), anti-cancer (Peng et al., 2016;Barolli et al., 2017;Jeyalakshmi et al., 2019) and anti-mycobacterium tuberculosis (Plutín et al., 2016) agents. In a continuation of our on-going work on these molecules and their metal complexes Gunasekaran et al., 2017;Tan, Azizan et al., 2019), we now describe the synthesis, spectroscopic characterization and X-ray crystallographic investigation of (I). Further, an analysis of the calculated Hirshfeld surfaces, non-covalent interaction plots as well as a computational chemistry study for (I) are described.

Structural commentary
Selected geometrical data for (I), Fig. 1, are given in Table 1.
The key feature of the structure is that it is a tri-substituted thiourea molecule with one of the nitrogen atoms having a benzoyl residue and the other bearing two hydroxyethyl groups. An approximate syn relationship is established between the thione-S and carbonyl-O atoms. Even though they lie to the same side of the molecule, the S1-C1-N2-C6 torsion angle of À47.8 (2) is consistent with a significant twist in the molecule about the C1-N2 bond; the O3-C6-N2-C1 torsion angle is À3.6 (2) .
The hydroxyethyl groups lie to either side of the CN 2 S plane (r.m.s. deviation = 0.017 Å ). Crucially, the O1hydroxyethyl group is folded towards the thioamide residue, which allows for the formation of an intramolecular N2-HÁ Á ÁO1 hydrogen bond and an S(7) loop, Table 2. That the molecule is highly twisted is evidenced by the dihedral angle of 65.87 (7) between the CN 2 S atoms and the terminal C7-C12 aryl ring. From Table 1, it is apparent that the C1-N1 bond length is considerably shorter than C1-N2, indicating delocalization of -electron density over the S1-C1-N1 atoms. However, the large twist for the C1-N2 bond mentioned above does not allow significant delocalization to extend to atoms C1, N1 and C6. The expected trends relating to the nature of the bonds about the quaternary-C1 atom are seen in the bond angles about that atom. Thus, the angles subtended by the formally doubly bonded S1 atom are appreciably wider. Finally, the nitro group is effectively coplanar with the aryl ring to which it is attached, as seen in the O4-N3-C10-C9 torsion angle of 5.2 (2) .

Figure 2
Overlay diagram for the experimental (green image) and geometryoptimized (red) molecules of (I). The molecules have been overlapped so the S C-N-C O fragments are coincident.
set (Petersson et al., 1988), as implemented in Gaussian16 (Frisch et al., 2016), the gas-phase geometry-optimized structure of (I) was calculated. As confirmed through a frequency analysis with zero imaginary frequency, the local minimum structure in the gas-phase was located in this study. The experimental and theoretical structures are superimposed (Macrae et al., 2006) in Fig. 2. The analysis shows that there are only minor differences between the molecules with the r.m.s. deviation between the conformations being only 0.015 Å . The derived interatomic data for the geometry-optimized structure are included in Table 1 from which it can be seen there is a close correlation between the experimental and calculated geometries. It is evident that the only major differences between the experimental and geometry-optimized structures relate to some of the torsion angles. Thus, the most significant conformational difference is evidenced by a nearly 13 difference in the O3-C6-N2-C1 torsion angles, i.e. À3.6 (2) (X-ray) versus À16.5 (calculation), indicating a greater deviation from the anti-disposition in the optimized structure. Also, the N1-C2-C3-O1 and N1-C4-C5-O2 torsion angles are close to symmetric in the optimized structure cf. the experimental structure. Similar trends were noted in analogous calculations performed on the 4-methyl analogue (Tan, Azizan et al., 2019).

Supramolecular features
In the crystal of (I), O1-H1OÁ Á ÁO2 hydrogen bonds (Table 2) lead to a helical chain propagating along the b-axis direction, with adjacent molecules related by the 2 1 screw axis. The O2-H2OÁ Á ÁS1 hydrogen bonding serves to cross-link translationally related chains along the a axis to form a supramolecular layer in the ab plane, Fig. 3(a). The layers are connected into a three-dimensional architecture by methylene-C-HÁ Á Á O(carbonyl), methylene-C-HÁ Á ÁS(thione) and comparatively rare nitro-OÁ Á Á(aryl) contacts, Fig. 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. Table 2 Hydrogen-bond geometry (Å , ).

Hirshfeld surface analysis
Cg1 is the centroid of the (C7-C12) ring. (1) 3.1724 (12) 175 (2) (1) 3.6927 (16) 83 (1) for (I) were calculated. In the Hirshfeld surface mapped over electrostatic potential in Fig. 4, the donors and acceptors of the conventional O-HÁ Á ÁO and O-HÁ Á ÁS hydrogen bonds and C-HÁ Á ÁO contacts appear as blue (positive potential) and red (negative potential) regions, respectively. The brightred spots near the participating atoms in the Hirshfeld surface mapped over d norm in Fig. 5 also give indications of these intermolecular interactions. Additional diminutive red spots near the methylene-H2B and H5A, thione-S1 and carbonyl-O3 atoms are indicative of weaker C-HÁ Á ÁS and C-HÁ Á ÁO interactions, Table 2. Further, the presence of faint-red spots near the ethyl-C3 and nitro-O5 atoms on the surface indicate C-HÁ Á ÁO contacts in the packing involving the nitro substituent. The other faint-red spots appearing in Fig. 5 indicate the presence of short interatomic contacts as summarized in Table 3. The influence of the nitro group is also seen in the nitro-O4Á Á Á(C7-C12) interaction, illustrated through yellow dotted lines in Fig. 6. The enrichment ratio (ER) descriptor, which is derived from the analysis of the Hirshfeld surface (Jelsch et al., 2014), was also employed to analyse the intermolecular contacts in the crystal of (I). The ER(X, Y) reflects the relative likelihood of the formation of X-to-Y interactions in a crystal, i.e. the ratio between the proportion of actual contacts in a crystal to the theoretical proportion of random contacts. Data for (I) are given in Table 4. The enrichment ratios greater than unity for the atom pairs (O, H) and, in particular, (S, H), are consistent with the relatively high likelihood for the formation of the O-HÁ Á ÁO and O-HÁ Á ÁS hydrogen bonds in the crystal of (I). It is also evident that the value greater than unity for (C, O) arises from the nitro-OÁ Á Á(aryl) contacts.

Table 3
A summary of short interatomic contacts (Å ) in (I) a .

Figure 5
Two views of the Hirshfeld surface mapped over d norm for (I) in the range À0.127 to +1.259 arbitrary units. the various contacts given in Table 5. The greatest contribution to the overall surface is from HÁ Á ÁH contacts and this is closely followed by OÁ Á ÁH/HÁ Á ÁO contacts, as viewed by the pair of long spikes at d e + d i $1.8 Å in Fig. 7(c). The prominent features in Fig. 7 Fig. 7(e). The 5.8% contribution from CÁ Á ÁO/OÁ Á ÁC contacts and the aforementioned ER value of 1.66 clearly indicate the significance of the nitro-N-OÁ Á Á interaction upon the packing; this interaction is reflected in the pair of short spikes d e + d i $3.0 Å , Fig. 7(f).

Computational chemistry
The energy calculations were performed using DFT-wB97XD/ aug-cc-pVTZ (Woon & Dunning, 1993) to evaluate the strength of the intermolecular O-HÁ Á ÁO, O-HÁ Á ÁS and C-HÁ Á ÁO interactions between the respective pairs of molecules. The BSSE corrected interaction energies (E BSSE int ) are listed in Table 6. From these data, it is clear the O-HÁ Á ÁO hydrogen bond has the greatest interaction energy, followed by C-HÁ Á ÁO and O-HÁ Á ÁS. These results reflect those reported recently for the 4-methyl analogue (Tan, Azizan et al., 2019).
The non-covalent interaction plots generated by calculations performed with NCIPLOT (Johnson et al., 2010) provide complementary results for the interaction energies. Thus, the pairs of molecules associated with each of the energies tabulated in Table 6 were subjected to calculation as this provides a useful visualization index corresponding to the strength of any non-covalent interactions through a red-blue-green colour scheme on the isosurface. Thus, a blue coloration is indicative of a strong attractive interaction, green indicates a weak interaction while red is indicative of a strong repulsive interaction (Contreras-García et al., 2011). As seen from Fig. 8      O-HÁ Á ÁO interaction is clearly strong and attractive, while each of O-HÁ Á ÁS and C-HÁ Á ÁO are less so. From the aforementioned, the molecular packing is clearly governed by directional hydrogen bonding between molecules. The simulated energy frameworks (Turner et al., 2017) were calculated to compare the topology of the intermolecular interactions in the crystal of (I). An analysis of the resultant energy frameworks is shown in Fig. 9 and 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 À45.89 kcal/mol, while the total dispersion energy term (E dispersion ) computes to À51.51 kcal/mol.

Database survey
There are three literature precedents to (I), i.e. molecules of the general formula 4-YC 6 H 4 C( O)N(H)C( S)N(CH 2 CH 2 -OH) 2 , namely Y = H, which has been reported twice (Koch et al., 1995;Cornejo et al., 2005), Y = F (Hennig et al., 2009) and Y = Me (Tan, Azizan et al., 2019). As seen in the overlay diagram of Fig. 10, whereby the central CN 2 S residues are overlapped, there is a very close coincidence in the molecular structures. The differences in conformation are most conveniently expressed in terms of the dihedral angles formed between the central CN 2 S chromophore and pendant aryl ring, i.e. 65.92 (12)

Synthesis and crystallization
Synthesis of (I): an excess of thionyl chloride (Merck) was mixed with 4-nitrobenzoic 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-nitrobenzoyl chloride, which is a yellow, viscous liquid. Ammonium thiocyanate (Fisher, 1 mmol) was added to an acetone (30 ml) solution of 4-nitrobenzoyl 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 was from its hot acetone solution yielding pale-yellow blocks of (I) after slow evaporation. Yield 69%. The pyrolytic process (Perkin Elmer STA 6000 Simultaneous Thermogravimetric Analyzer) for (I) showed the liberation of NO 2 , equivalent a 15% weight loss, in the first stage in the range 194 and 222 C. This was followed by the liberation of a benzene molecule, corresponding to 29% weight loss, between 222 and 282 C, whereas the subsequent stages involve the pyrolysis of CO (282 to 360 C) and OH (360 to 496 C) corresponding to 15 and 11% weight loss, respectively. Gradual weight loss continued beyond 800 C. 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 within 2 Â 2 Â 2 unit cells. The corresponding cylinder radii are proportional to the relative magnitude of the energies.

Figure 10
An overlay diagram of the four known structures of general formula 4-YC 6 H 4 C( O)N(H)C( S)N(CH 2 CH 2 OH) 2 : Y = NO 2 (I) red image, Y = H (green), Y = F (blue) and Y = Me (pink). The molecules are overlapped so the central CN 2 S residues are coincident.

(I)
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.