rac-2-[(2-Chlorophenyl)(4-chlorophenyl)methyl]-1,3-dioxolane

The title compound, C16H14Cl2O2, is a chiral mitotane derivative that contains a dioxolane ring and crystallizes from methanol as a racemic mixture. It was obtained in high yield from mitotane and ethyleneglycol in alkaline medium, followed by neutralization with sulfuric acid and extraction with ethyl acetate. The molecular structure is stabilized by an intramolecular C— H⋯ O hydrogen bond. The dihedral angle between the aromatic rings is 80.1 (2)°. The dioxolane ring adopts a puckered envelope conformation with an O atom as the flap.

The title compound, C 16 H 14 Cl 2 O 2 , is a chiral mitotane derivative that contains a dioxolane ring and crystallizes from methanol as a racemic mixture. It was obtained in high yield from mitotane and ethyleneglycol in alkaline medium, followed by neutralization with sulfuric acid and extraction with ethyl acetate. The molecular structure is stabilized by an intramolecular C-HÁ Á Á O hydrogen bond. The dihedral angle between the aromatic rings is 80.1 (2) . The dioxolane ring adopts a puckered envelope conformation with an O atom as the flap.

Related literature
For related dioxolane geometry, see: Bolte et al. (1997). For organochlorines, see: Smith & Bennett (1977); Cantillana & Eriksson (2009) ;Jabbar et al. (2006). For dechlorination of organochlorine compounds, see: Grummitt et al. (1946). For their adrenolytic activity, see: Fassnacht et al. (2010); Berruti et al. (2005). For organochlorine as insecticide metabolites in bioremediation studies, see: Purnomo et al. (2011); Fuentes et al. (2010); Matsumoto et al. (2009). For the use of mitotane [systematic name: 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1dichloroethane] in adrenocortical carcinoma treatment, see: Maluf et al. (2011);Rosati et al. (2008); Terzolo et al. (2007). For structure-activity studies of mitotane derivatives, see: Bleiberg & Larson (1973); Schteingart et al. (1993).  Table 1 Hydrogen-bond geometry (Å , ). Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL; molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: SHELXTL. The title compound, which crystallizes from methanol as a racemic mixture, has been obtained after C 1 oxidation and dechlorination of 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethane, also known as mitotane or o,p′-DDD. The reaction generated an additional structural feature in the molecule, the dioxolane ring. While organochlorine compounds are widely described in the literature as insecticide metabolites in bioremediation studies (Purnomo et al., 2011;Fuentes et al., 2010;Matsumoto et al., 2009), mitotane itself is a drug used exclusively for adrenocortical carcinoma treatment (Maluf et al., 2011;Rosati et al., 2008, Terzolo et al., 2007. However, mitotane therapy produces important side effects due to its toxicity. Therefore, derivatives have been prepared in order to overcome those limitations. Several studies of structure-activity relationship report that the substitution of the hydrogen at the C 1 position of mitotane results in the loss of activity and the use of the o,p′-DDD isomer -which refers to a specific substitution pattern in the aromatic ringsleads to a better pharmacological effect than that provided by the m,p′ and p,p′ isomers (Bleiberg and Larson, 1973;Schteingart et al., 1993). Search for new compounds that keep the single hydrogen bound to C 1 and also the o,p′substitution in the aromatic rings is necessary for an improved treatment of this malignant cancer. The molecule described herein is a good example of a mitotane derivative that presents these structural features relevant for adrenolytic activity.

Experimental
The molecular structure of the title compound is depicted in Figure 1. Bond lenghts and angles are as expected. The dioxolane ring adopts a puckered envelope conformation with C 2 , O 2 , C 4 and C 5 in the same plane, with the O 1 atom placed about 0.4661 (1) Å above it. The coplanar atoms of the dioxolane ring form a dihedral angle of 74.63 (3)° with pchloro-phenyl ring and an angle of 9.83 (3)° with the o-chloro-phenyl ring. The angle between the aromatic groups is 80.1 (2)°. The molecular structure is stabilized by an intramolecular C-H··· O hydrogen bond interaction (C···O 3.046 (2)Å; C-H···O 128° ). Weak C-H···Cl is also observed.

Experimental
Mitotane (o,p′-DDD) was added to a mixture of ethylene glycol, KOH and water. The reaction was carried out overnight under reflux at 137°C. After this period, the reaction mixture was cooled down to room temperature and diluted with water. Concentrated sulfuric acid (98%) was then added to take the solution pH down to 3.0. The salt formed was removed by filtration on a Büchner funnel. The filtrate was extracted with ethyl acetate, the organic layer was concentrated by rotary evaporation and the oily yellow residue was redissolved in warm methanol (30°C). Thin, colorless plate-like crystals suitable for X-ray diffraction analysis were obtained from this methanol solution. Total reaction yield: 84%.

Refinement
All H-atoms were positioned geometrically and refined using a riding model, with C-H = 0.93-0.98 Å and U iso (H) =1.2U eq (C).

Figure 1
The molecular structure of the title compound, with atom labels and 30% probability displacement ellipsoids for non-H atoms. where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.001 Δρ max = 0.37 e Å −3 Δρ min = −0.29 e Å −3 Special details Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.