Synthesis, crystal structure and Hirshfeld analysis of a crystalline compound comprising a 1/1 mixture of 1-[(1R,4S)- and 1-[(1S,4R)-1,7,7-trimethyl-2-oxobicyclo[2.2.1]heptan-3-ylidene]hydrazinecarbothioamide

A racemic mixture of (R)- and (S)-camphor thiosemicarbazone, which crystallizes in the centrosymmetric space group C2/c, is reported.


Chemical context
The origin of thiosemicarbazone (TSC) chemistry can be traced back to the beginning of the 20th century, when thiosemicarbazide was used for the chemical characterization of the R 1 R 2 C O group and it was pointed out that the R 1 R 2 C N-N(H)C( S)NH 2 compound was the main product of the condensation reaction (Freund & Schander, 1902). In the second half of the 1940 0 s, new insight into the TSC chemistry emerged, namely the applications in medicinal chemistry as chemotherapeutic agents against tuberculosis (Domagk et al., 1946;Hoggarth et al., 1949). Initially, the biological research concerning TSC derivatives was focused on the molecules as free ligands, but very quickly the scope expanded to coordination compounds. One of the first reports about metal compounds of thiosemicarbazones in medicinal chemistry regards a Cu II complex with Mycobacterium tuberculosis growth inhibition activity that was published few years later (Kuhn & Zilliken, 1954). Another milestone in this chemistry, after the reported tuberculostatic property, was the discovery of the antineoplastic activity of TSC derivatives in the 1960 0 s (Sartorelli & Booth, 1967). Concerning the molecular structure of the title compound class, the N-N-C-S entity is a key feature, which has hard (N) and soft (S) donor atoms in chain (Pearson & Songstad, 1967), and so TSCs can act as N,S, O,N,S or N,N,S donors depending on the derivative.
As a result of its molecular geometry, the sulfur-containing group enables the formation of several different coordination modes, including complexes with five-membered metallarings, that are well-known chelate arrangements in coordination chemistry (Lobana et al., 2009). The biochemical and pharmacological applications of the TSCs is a topic that remains up-to-date and two different approaches can be considered. One is how the chemotherapeutic activity deals with the TSC compounds in form of uncoordinated ligands, so they can act as metal ion-sequestering agents for Cu II , Zn II and Fe II/III and reducing the bioavailability of these essential metals, which impacts the growth of tumor cells (Kowol et al., 2016;Miklos et al., 2015). The biological activity of thiosemicarbazones as metal-free molecules is also possible because of the hydrogenbonding andintermolecular interactions with selected biomolecules, as reported for one isatin derivative on replication inhibition of the Chikungunya virus in silico and in vitro (Mishra et al., 2016). The second approach deals with the biological activity of coordination compounds, with TSCs acting as ligands. For example, Pd II complexes with cinnamaldehyde-thiosemicarbazone turned out to be very active on Human Topoisomerase II (TOP2A) inhibition in vitro, a key biological target for cancer research (Rocha et al., 2019), and the Au III coordination compound with vaniline-thiosemicarbazone, which has shown antimalarial and antitubercular activity in in vitro assays (Khanye et al., 2011). Thus, the synthesis and structural determination of new thiosemicarbazone derivatives is a topic of current interest in the field of medicinal chemistry.

Structural commentary
A racemic mixture of camphorquinone was used for the synthesis of the title compound and as a result the thiosemicarbazone derivative was obtained in a 1/1 mixture of the two isomers. The asymmetric unit comprises two molecules of the camphor thiosemicarbazone derivative, one of them being the (1R)-and the other the (1S)-isomer. For the first molecule, the 1R and the 4S chiral centers are labelled C2 and C5, and the thiosemicarbazone unit is nearly planar with a N1-N2-C11-N3 torsion angle of À4.7 (2) (Fig. 1). In the second molecule, the 1S and 4R chiral centers are at C13 and C15, and the thiosemicarbazone fragment shows also a slight distortion from the planarity, the torsion angle for the N4-N5-C22-N6 chain being 2.4 (2) ( The molecular structure of (1R)-camphor thiosemicarbazone in the asymmetric unit, showing the atom labelling and displacement ellipsoids drawn at the 40% probability level. The (1S)-isomer was omitted for clarity.

Figure 2
The molecular structure of the second isomer of the title compound in the asymmetric unit, (1S)-camphor thiosemicarbazone, showing the atom labelling and displacement ellipsoids drawn at the 40% probability level. The (1R)-isomer was omitted for clarity. Table 1 Selected torsion angles ( ).

Isomer
Chiral center Atom chain Torsion angle asymmetric unit are shown separately for clarity and the torsion angles about the chiral C atoms are listed in Table 1.

Supramolecular features and Hirshfeld surface analysis
In the asymmetric unit, the molecules in general positions are connected by the N6-H33Á Á ÁO1 interaction. As suggested by the apolar organic periphery of the camphor fragment, the relevant and the strongest intermolecular interactions are observed mainly in the thiosemicarbazone and the ketone groups. In the crystal, the molecular units are linked by N2- Table 2) into a twodimensional hydrogen-bonded network parallel to the (101) plane (Fig. 5). In addition, the S2-C22-N5-H32 and S1-C11-N2-H15 atom chains are subunits of the periodic arrangement, with graph-set motif R 2 2 (8). Another ring-like structure is observed for the S2Á Á ÁH5-C5-C6-N1-N2-H15 atom sequence, in which the sulfur atom acts as a hydrogen-bond acceptor and bridges two D-HÁ Á ÁS interactions, building an R 1 2 (7) motif. Since the molecules crystallize in the centrosymmetric space group C2/c, chirality does not rise from the molecular to the crystal structure level.
The Hirshfeld surface analysis (Hirshfeld, 1977) of the crystal structure suggests that the most important intermolecular interactions for crystal cohesion are the following Section of the crystal structure of the title compound showing the HÁ Á ÁS and HÁ Á ÁO intermolecular interactions for the (1S)-camphor thiosemicarbazone molecule. The graph-set motif for the hydrogen-bonding interactions (dashed lines) in the crystal packing is R 2 2 (8). The N6-H33Á Á ÁO1 interaction connects the two molecules of the asymmetric unit.

Figure 5
Partial crystal packing of the title compound, viewed down the [010] direction. The HÁ Á ÁS and HÁ Á ÁO interactions are shown as dashed lines and connect the molecules into a tape-like structure along the (101) plane. The asymmetric unit is drawn in space-filling mode and the figure is simplified for clarity. and HÁ Á ÁO/OÁ Á ÁH = 8.4. For clarity, the molecules in the asymmetric unit are represented using a 'ball-and-stick' model with transparency, in two opposite views and separate figures. The strongest intermolecular interactions are located over the thiosemicarbazone and the ketone entities, as show by the graphical representation of the Hirshfeld surface for the molecular units in magenta, e.g. the N-H, C-H, O and S atoms (Figs. 6 and 7). The contributions to the crystal packing are also shown as two-dimensional Hirshfeld surface fingerprint plots with cyan dots (Wolff et al., 2012). The d e (y axis) and d i (x axis) values are the closest external and internal distances (values in Å ) from given points on the Hirshfeld surface contacts (Fig. 8).

Database survey
To the best of pur knowledge and from using database tools such as SciFinder (Chemical Abstracts Service, 2019), there are very few examples of thiosemicarbazone derivatives from camphorquinone. The molecule selected for comparison with the title compound is (R)-camphor 4-phenylthiosemicarbazone (Oliveira et al., 2016). In both of the crystal structures, the camphor entity, with the apolar periphery and steric effect, leads to a high contribution of the HÁ Á ÁH intermolecular interactions for the crystal packing, being 55.00% for the title compound and 55.90% for (   assumed to be due to the geometric impediment of the phenyl ring. The impact of steric effects on the intermolecular interactions sites can be seen in the graphical representation of the Hirshfeld surface in Fig. 9. In addition, the two-dimensional Hirshfeld surface fingerprint plots confirm the relationship between the molecular structure and the contribution of the intermolecular interactions for crystal cohesion (Fig. 10).

Synthesis and crystallization
The starting materials were commercially available and were used without further purification. The racemic mixture of Rand S-camphor was oxidized with SeO 2 to the respective 1,2-diketone (Młochowski & Wó jtowicz-Młochowska, 2015). The synthesis of the 1R-and 1S-camphor thiosemicarbazone derivative was adapted from a procedure reported previously (Freund & Schander, 1902;Oliveira et al. 2016). The glacial acetic acid-catalysed reaction of the 1,2-diketone (3 mmol) and thiosemicarbazide (3 mmol) in ethanol (50 ml) was refluxed funder stirring or 6 h. Single crystals suitable for X-ray diffraction were obtained from an ethanol solution by solvent evaporation. The racemic mixture of the reagent remains unchanged during the synthesis and after crystallization.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. 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, N) and C-H bond distances of 0.98 Å for tertiary carbon atoms and 0.97 Å for secondary C atoms. The N-H bond distances are 0.86 Å . Finally, U iso (H) = 1.5U eq (C) for the methyl groups, with C-H bond distances of 0.96 Å . A rotating model was used for the latter H atoms.      1/1 mixture of 1-[(1R,4S)-and 1-[(1S,4R)-1,7,7- program(s) used to solve structure: SHELXT2014/5 (Sheldrick, 2015a); program(s) used to refine structure:

Funding information
SHELXL2018/3 (Sheldrick, 2015b); molecular graphics: DIAMOND (Brandenburg, 2006); software used to prepare material for publication: publCIF (Westrip, 2010) and enCIFer (Allen et al., 2004). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.001 Δρ max = 0.58 e Å −3 Δρ min = −0.33 e Å −3 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.