Synthesis and redetermination of the crystal structure of salicylaldehyde N(4)-morpholinothiosemicarbazone

In the crystalline state, salicylaldehyde N(4)-morpholinothiosemicarbazone forms sheets parallel to (002) and consisting of two parallel chains running in the a-axis direction and formed by N—H⋯O and C—H⋯O hydrogen bonds.

The structure of the title compound (systematic name: N-{[(2-hydroxyphenyl)methylidene]amino}morpholine-4-carbothioamide), C 12 H 15 N 3 O 2 S, was previously determined (Koo et al., 1977) using multiple-film equi-inclination Weissenberg data, but has been redetermined with higher precision to explore its conformation and the hydrogen-bonding patterns and supramolecular interactions. The molecular structure shows intramolecular O-HÁ Á ÁN and C-HÁ Á ÁS interactions. The configuration of the C N bond is E. The molecule is slightly twisted about the central N-N bond. The best planes through the phenyl ring and the morpholino ring make an angle of 43.44 (17) . In the crystal, the molecules are connected into chains by N-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds, which combine to generate sheets lying parallel to (002). The most prominent contribution to the surface contacts are HÁ Á ÁH contacts (51.6%), as concluded from a Hirshfeld surface analysis.

Chemical context
For many years, scientific studies on cancer have attracted a lot of attention, especially in the field of antitumor drugs. Cisplatin is well known as an effective therapy to prohibit the proliferation of tumor cells (Berners-Price, 2011). However, this drug has some unforeseen side effects with detrimental effects on the patient's health (Lé vi et al., 2000;Go & Adjei, 1999;Harbour et al., 1996). In a search for antitumour drugs with fewer harmful side effects, thiosemicarbazides were examined since this organic class of thiourea derivatives was known to possess a diversity of biological activities such as antitumoral, antibacterial, and antifungal activities owing to presence of the N-N-C S system (Dilović et al., 2008;Liberta & West, 1992). Many mechanisms have been advanced to probe the role of this conjugated system. In general, thiosemicarbazones can bind to nucleotides of tumour cells by the nitrogen and sulfur atoms, which prevents the distorted DNA from translation and encryption for their growth (Dilović et al., 2008).
Thiosemicarbazones are synthesized by the condensation between an aldehyde or ketone and an N(4)-substituted thiosemicarbazide. Many reports have demonstrated that N(4)-aromatic or heterocyclic substituted thiosemicarbazides are biologically more active than thiosemicarbazones without ISSN 2056-9890 substituted groups (Dilović et al., 2008;Chen et al., 2004;Shi et al., 2009). In addition, salicylaldehyde is a key compound in the synthesis of a variety of potential therapeutic products (Bindu et al., 1998).
The crystal and molecular structure of salicylaldehyde N(4)morpholinothiosemicarbazone was published previously (Koo et al., 1977) based on multiple-film equi-inclination Weissenberg data using Cu K radiation and refined to an R value of 0.11. In this study, we present the synthesis of salicylaldehyde N(4)-morpholinothiosemicarbazone (3) together with its structural characteristics and crystal structure redetermination using present-day technology.

Figure 1
A view of the molecular structure of (3), with atom labels and displacement ellipsoids drawn at the 50% probability level. H atoms are shown as small circles of arbitrary radii and the intramolecular O-HÁ Á ÁN and C-HÁ Á ÁS interactions, respectively, by blue and grey dashed lines.

Supramolecular features
The crystal packing of (3) is dominated by N9-H9Á Á ÁO4 hydrogen bonds (Table 1), resulting in the formation of chains of molecules with graph-set motif C 1 1 (7) propagating along the a-axis direction (Fig. 2). Furthermore, a second parallel chain of molecules with graph-set motif C 1 1 (5) running along the aaxis direction is formed by C15-H15Á Á ÁO18 interactions (Fig. 3). These two chain motifs combine to generate a sheet lying parallel to (002). No voids orstackings are observed in the crystal packing of (3).

Figure 5
Full two-dimensional fingerprint plots for (3)  Partial crystal packing of (3), showing the C-HÁ Á ÁO interactions (red dashed lines) resulting in chain formation in the a-direction [see Table 1; symmetry code: (ii) x + 1 2 , Ày + 3 2 , z].  Fig. 6b,c illustrate the histograms of the distribution of torsion angles 1 and 2 . The histogram of 1 shows a major preference for the Àsp/+sp (or cis) conformation and a minor preference for the Àap/+ap (or trans) conformation. For torsion angle 2 , only one region is preferred: a narrow spread in the region Àap/+ap (or trans).

Synthesis and crystallization
The reaction scheme for the synthesis of (3) is given in Fig. 7.
Synthesis of 2-((morpholine-4-carbonothioyl)thio)acetic acid (1): A mixture consisting of carbon disulfide (0.2 mol) and concentrated ammonia (25 mL) was stirred to form a homogeneous solution at 278 K. Then, morpholine (0.2 mol) was added dropwise to this solution. The yellow solid that separated from the solution was filtered off and immediately dissolved in deionized water (300 mL) at room temperature to generate a yellow solution. Sodium chloroacetate (0.2 mol) was added to this solution and the reaction mixture maintained for 6 h at room temperature. The yellowish solution was acidified with concentrated hydrochloric acid and the resulting white precipitate was filtered off and recrystallized from ethanol.
Synthesis of N(4)-morpholinothiosemicarbazide (2): A mixture composed of (1) (50 mmol), deionized water (10 mL) and hydrazine hydrate (25 mL) was refluxed for 30 minutes at 353 K. The white solid which precipitated from the transparent solution was filtered off and recrystallized from ethanol to give (2).

Synthesis of salicylaldehyde N(4)-morpholinothiosemicarbazone (3):
After dissolving (2) in hot ethanol, the solution was added to an equivalent amount of salicylaldehyde. The final solution was refluxed at 353 K for 2 h in the presence of acetic acid as a catalyst. The resulting solution was gradually reduced in volume at room temperature overnight. The needle-shaped crystals that formed were filtered off and recrystallized from ethanol to give (3)

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Both H atoms H9 and H18 were located from difference electron density maps and refined freely. The other H atoms were placed in idealized positions and included as riding contributions with U iso ( Reaction scheme for the synthesis of (3).  (aromatic, CH N) and 0.97 Å (CH 2 ). In the final cycles of refinement, 4 outliers were omitted.  CrysAlis PRO (Rigaku OD, 2018); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

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.