1-Butyl-1-chloro-3-methyl-3H-2,1λ4-benzoxatellurole: crystal structure and Hirshfeld analysis

Two chemically similar molecules comprise the asymmetric unit and these are connected via Te⋯O secondary bonding. The coordination geometry for each molecule is based on an octahedron with the lone-pair of electrons occupying a position opposite to the n-butyl group.

Two independent molecules comprise the asymmetric unit in the title benzoxatellurole compound, C 12 H 17 ClOTe. The molecules, with the same chirality at the methine C atom, are connected into a loosely associated dimer by TeÁ Á ÁO interactions, leading to a {Á Á ÁTe-O} 2 core. The resultant C 2 ClO 2 donor set approximates a square pyramid with the lone pair of electrons projected to occupy a position trans to the n-butyl substituent. Interestingly, the Te IV atoms exhibit opposite chirality. The major difference between the independent molecules relates to the conformation of the five-membered chelate rings, which is an envelope with the O atom being the flap, in one molecule and is twisted about the O-C(methine) bond in the other. No directional intermolecular interactions are noted in the molecular packing beyond the aforementioned TeÁ Á ÁO secondary bonding. The analysis of the Hirshfeld surface reveals the dominance of HÁ Á ÁH contacts, i.e. contributing about 70% to the overall surface, and clearly differentiates the immediate crystalline environments of the two independent molecules in terms of both HÁ Á ÁH and HÁ Á ÁCl/ClÁ Á ÁH contacts.

Chemical context
Tellurium is not the first element that comes to mind when considering the modern pharmacopoeia (Tiekink, 2012). However, investigations into pharmaceutical applications of compounds of this generally regarded as relatively non-toxic element (Nogueira et al., 2004) date back to the times of Sir Alexander Fleming who tested the efficacy of potassium tellurite, K 2 [TeO 3 ], against microbes, such as penicillin-insensitive bacteria (Fleming, 1932). It is in fact another salt, ammonium trichloro(dioxyethylene-O,O 0 )tellurate, [NH 4 ][(OCH 2 CH 2 O)-TeCl 3 ] (Albeck et al., 1998), also known as AS-101, that has attracted the most attention as a potential tellurium-based pharmaceutical, being in clinical trials for the treatment of psoriasis (Halpert & Sredni, 2014). Other potential applications of AS-101 include its use as an anti-inflammatory agent (Brodsky, et al., 2010), as a topical treatment for human papilloma virus (Friedman et al., 2009) and its ability to inhibit angiogenesis (Sredni, 2012). The anti-cancer potential of tellurium compounds has also attracted attention (Seng & Tiekink, 2012;Silberman et al., 2016). The cation in AS-101 has long been known to be a specific inhibitor of both papain and cathepsin B, i.e. cysteine proteases, by forming a covalent Te-S(cysteine) bond (Albeck et al., 1998). Organotellurium compounds also inhibit cathepsin B (Cunha et al., 2005) and docking studies confirm this hypothesis (Caracelli et al., 2012, ISSN 2056-9890 2016. It was in this context that the title compound, (I), was prepared. Herein, the crystal and molecular structures of (I) are described as well as an analysis of its Hirshfeld surface. Finally, a preliminary inhibition assay on (I) against cathepsin B has been performed.

Structural commentary
The asymmetric unit of (I) comprises two independent molecules, which are connected into a loosely associated dimer via secondary TeÁ Á ÁO interactions, as shown in Fig. 1. The immediate geometry for the Te IV atom in the Te1-containing molecule is defined by chlorido, oxygen and carbon (within the oxatellurole ring) and n-butyl alpha-carbon atoms. While the bridging-O2 atom forms a significantly longer TeÁ Á ÁO2 bond than the Te-O1 bond, Table 1, it must be included in the coordination geometry, which is then best described as being distorted square pyramidal. This arrangement accommodates a stereochemically active lone-pair of electrons in the position trans to the n-butyl group. The coordination geometry for the Te2-containing molecule is essentially the same.
The bond lengths about the Te IV atoms in the independent molecules are similar, Table 1. However, the Te1-Cl1 bond length is longer by approximately 0.02 Å than the chemically equivalent Te-Cl2 bond. The three remaining 'short' bond lengths are equal within experimental error. The disparity in the Te-Cl bond lengths is probably compensated by the TeÁ Á ÁO secondary bond, which is shorter, by approximately 0.03 Å , in the Te1-molecule. The key pairs of bond angles for the molecules are essentially the same with the major difference, i.e. 0.8 , seen in the Cl-Te-O long angle. A distinguishing feature of the independent molecules is noted in the conformation of the five-membered, chelate rings. Thus, in the Te1-molecule, the chelate ring has the form of an envelope with the flap atom being the O1 atom [the O1 atom lies 0.254 (8) Å out of the plane through the remaining atoms; r.m.s. deviation = 0.0107 Å ]. For the Te2-molecule, the chelate ring is twisted about the O2-C13 bond, as seen in the Te2-O2-C13-C15 torsion angle of 12.1 (7) .

Figure 1
The molecular structures of the two independent molecules comprising the asymmetric unit of (I), showing the atom-labelling scheme and displacement ellipsoids at the 50% probability level. The molecules associate via secondary TeÁ Á ÁO bonding shown as dashed bonds.

Figure 2
An overlay diagram of the Te1-and Te2-containing molecules, shown as red and blue images, respectively. The molecules have been overlapped so that the phenyl rings are coincident.
The central {Á Á ÁTe-O} 2 core of the dimeric aggregate, Fig. 1, is almost planar (r.m.s. deviation = 0.0106 Å ) and has the form of a parallelogram with distinctive edge lengths of approximately 2.0 and 3.0 Å , reflecting the disparity of the TeÁ Á ÁO interactions. To a first approximation, the fused phenyl ring in each molecule, (C3-C8) and (C13-C20), is co-planar with the core, forming dihedral angles of 14.2 (2) and 13.6 (3) , respectively; the dihedral angle between the phenyl rings is 8.3 (3) . As the n-butyl groups lie to either side of the dimeric aggregate, there is a suggestion that the independent molecules are related across a pseudo centre of inversion. However, the configuration of the chiral-C2 and C13 atoms in the Te1-and Te-molecules, respectively, is R. This is highlighted in the overlay diagram shown in Fig. 2. Also highlighted is that the tellurium atoms have opposite chirality. When projected down the Te-C(n-butyl) bond, the chirality about the Te1 atom is S and that about Te2, R.

Supramolecular features
Beyond the secondary TeÁ Á ÁO secondary contacts, leading to dimeric aggregates, Fig. 1, no directional interactions, according to the criteria in PLATON (Spek, 2009), are apparent in the crystal of (I). A view of the unit-cell contents is shown in Fig. 3.

Hirshfeld surface analysis
An analysis of the Hirshfeld surface for (I) was conducted using protocols established earlier (Jotani et al., 2016). The overall two-dimensional fingerprint plot for the asymmetric unit is shown in Fig. 4a and those for the individual Te1-and Te2-containing molecules are shown in Fig. 4 b and c. The shape-index surface properties are also illustrated in Fig. 4. These confirm the absence of significant directional interactions in the crystal.
Referring to Fig. 5 and Table 2, the Hirshfeld surface is dominated by HÁ Á ÁH interactions, contributing around 70% to the overall surface of the asymmetric unit and about 65% for each independent molecule. While not within the sum of the respective van de Waals radii, the C-HÁ Á ÁCl contacts make the next greatest contribution to the overall surface, i.e. ca 15%. Others interactions each contribute less than 5% to the   Hirshfeld surface. It should be noted that the C-HÁ Á ÁO contacts, TeÁ Á ÁO secondary interactions and most of the C-HÁ Á ÁTe contacts are formed between the two independent molecules, thus they are overlapped and do not contribute to surface area of the asymmetric unit. The main differences between the surface areas of the independent molecules are in the interactions of the type HÁ Á ÁH and C-HÁ Á ÁCl. Referring to Fig. 6, the red circles on the fingerprint plots delineated into HÁ Á ÁH, Fig. 6a and HÁ Á ÁCl/ClÁ Á ÁH contacts, Fig. 6b, highlight the distinctive features of the interactions for the two molecules. For example, short HÁ Á ÁH interactions for the Te2-molecule, Fig. 6a, occur at shorter distances that those of the Te1-molecules. With regard to the HÁ Á ÁCl/ClÁ Á ÁH contacts, there is a wider spread at lower d e + d i for the Te1-cf. the Te2-molecule.

Database survey
A search of the Cambridge Crystallographic Database (Groom et al., 2016) reveals there are only 28 analogous structures featuring the TeOC 3 donor set as in (I) without the bond type being specified. The number of 'hits' reduces to five with the inclusion of the aromatic ring in the side chain. Of the latter, the most closely related compound is 1-bromo-1-butyl-3H-2,1-benzoxatellurol (Maksimenko et al., 1994), which is in fact very similar to (I), being derived from this by substituting the tellurium-bound chlorido atom with bromido and the removal of the methyl group. Here, the five-membered chelate ring is strictly planar.

Inhibition of cathepsin B
Compound (I) was screened for its ability to inhibit cathepsin B employing standard literature procedures (Cunha et al., 2005). The determined value of the inhibition constant was 372 AE 40 M À1 s À1 , indicating some inhibitory potential, but not as potent as for other organotellurium(IV) compounds studied earlier (Cunha et al., 2005).

Synthesis and crystallization
The compound was prepared following a literature procedure (Engman, 1984). The precursor chalcogenide, [2-(R)-MeCH(OH)]C 6 H 4 Te(nBu) (1.52 g, 5 mmol), prepared as in the literature (Piovan et al., 2011), was dissolved in dry dichloromethane (20 ml) and cooled to 253 K. To the stirred, cooled solution, sulfuryl chloride (0.4 ml, 5 mmol) dissolved in dichloromethane (5 ml) was added dropwise. The stirring was maintained for 20 minutes at 273 K and the solvent was then removed under reduced pressure. The oily product thus obtained was purified by crystallization from a mixture of dry benzene and pentane, yielding colourless crystals in 89% yield, m.

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq