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Acta Crystallographica Section E: Structure Reports Online logoLink to Acta Crystallographica Section E: Structure Reports Online
. 2012 Jun 13;68(Pt 7):o2008–o2009. doi: 10.1107/S1600536812023781

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

Daniela F Maluf a, Sailer S dos Santos b, Claudia C Gatto c,*, Brás H de Oliveira d
PMCID: PMC3393280  PMID: 22807837

Abstract

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.

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)-1,1-dichloro­ethane] 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 ▶).graphic file with name e-68-o2008-scheme1.jpg

Experimental  

Crystal data  

  • C16H14Cl2O2

  • M r = 309.17

  • Triclinic, Inline graphic

  • a = 7.5728 (2) Å

  • b = 10.2268 (2) Å

  • c = 11.2858 (2) Å

  • α = 63.357 (1)°

  • β = 84.021 (1)°

  • γ = 71.194 (1)°

  • V = 738.68 (3) Å3

  • Z = 2

  • Mo Kα radiation

  • μ = 0.44 mm−1

  • T = 296 K

  • 0.59 × 0.56 × 0.29 mm

Data collection  

  • Bruker SMART APEXII CCD diffractometer

  • Absorption correction: multi-scan (SADABS; Bruker, 2009 ▶) T min = 0.783, T max = 0.883

  • 24953 measured reflections

  • 4556 independent reflections

  • 3654 reflections with I > 2σ(I)

  • R int = 0.022

Refinement  

  • R[F 2 > 2σ(F 2)] = 0.040

  • wR(F 2) = 0.117

  • S = 1.05

  • 4556 reflections

  • 181 parameters

  • H-atom parameters constrained

  • Δρmax = 0.37 e Å−3

  • Δρmin = −0.29 e Å−3

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.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812023781/bx2412sup1.cif

e-68-o2008-sup1.cif (17.7KB, cif)

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812023781/bx2412Isup2.hkl

e-68-o2008-Isup2.hkl (223.2KB, hkl)

Supplementary material file. DOI: 10.1107/S1600536812023781/bx2412Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A D—H H⋯A D⋯A D—H⋯A
C12—H12⋯O1 0.93 2.38 3.046 (2) 128
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Acknowledgments

The authors thank the Brazilian agencies CNPq and CAPES (grants 141600/2008–0 and 2847/10–8, respectively) for financial support and Dr Jaísa F. Soares for helpful discussions.

supplementary crystallographic information

Comment

The title compound, which crystallizes from methanol as a racemic mixture, has been obtained after C1 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 C1 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 rings – leads 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 C1 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. 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 C2, O2, C4 and C5 in the same plane, with the O1 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 p-chloro-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 Uiso(H) =1.2Ueq(C).

Figures

Fig. 1.

Fig. 1.

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The molecular structure of the title compound, with atom labels and 30% probability displacement ellipsoids for non-H atoms.

Crystal data

C16H14Cl2O2 Z = 2
Mr = 309.17 F(000) = 320
Triclinic, P1 Dx = 1.39 Mg m−3
a = 7.5728 (2) Å Mo Kα radiation, λ = 0.71073 Å
b = 10.2268 (2) Å Cell parameters from 4556 reflections
c = 11.2858 (2) Å θ = 4.2–57.4°
α = 63.357 (1)° µ = 0.44 mm−1
β = 84.021 (1)° T = 296 K
γ = 71.194 (1)° Block, colourless
V = 738.68 (3) Å3 0.59 × 0.56 × 0.29 mm
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Data collection

Bruker SMART APEXII CCD diffractometer 4556 independent reflections
Radiation source: sealed tube 3654 reflections with I > 2σ(I)
Graphite monochromator Rint = 0.022
phi & ω scans θmax = 30.7°, θmin = 2.0°
Absorption correction: multi-scan (SADABS; Bruker, 2009) h = −10→10
Tmin = 0.783, Tmax = 0.883 k = −14→14
24953 measured reflections l = −16→16
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Refinement

Refinement on F2 Primary atom site location: structure-invariant direct methods
Least-squares matrix: full Secondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.040 H-atom parameters constrained
wR(F2) = 0.117 w = 1/[σ2(Fo2) + (0.0556P)2 + 0.1712P] where P = (Fo2 + 2Fc2)/3
S = 1.05 (Δ/σ)max = 0.001
4556 reflections Δρmax = 0.37 e Å−3
181 parameters Δρmin = −0.29 e Å−3
0 restraints
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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 F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > 2σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.
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Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

x y z Uiso*/Ueq
Cl1 0.77214 (6) 0.38255 (5) 0.01175 (4) 0.06217 (13)
Cl2 1.10734 (6) −0.41352 (5) 0.31682 (5) 0.06334 (13)
C6 0.51390 (16) 0.19844 (14) 0.17862 (11) 0.0346 (2)
H6 0.5131 0.2544 0.0818 0.041*
C13 0.65594 (16) 0.04056 (14) 0.21569 (11) 0.0335 (2)
C15 0.86840 (19) −0.19344 (15) 0.37708 (13) 0.0417 (3)
H15 0.9191 −0.2545 0.4634 0.05*
C14 0.73344 (18) −0.05219 (15) 0.34448 (12) 0.0379 (2)
H14 0.6938 −0.0186 0.4098 0.046*
C7 0.57303 (16) 0.28987 (14) 0.23302 (13) 0.0377 (2)
C16 0.92668 (18) −0.24239 (15) 0.27971 (14) 0.0414 (3)
C2 0.31576 (17) 0.19008 (16) 0.21133 (13) 0.0406 (3)
H2 0.2303 0.2932 0.1918 0.049*
C17 0.8485 (2) −0.15571 (17) 0.15211 (14) 0.0479 (3)
H17 0.8857 −0.1914 0.088 0.058*
C18 0.7135 (2) −0.01446 (16) 0.12117 (13) 0.0437 (3)
H18 0.6605 0.0446 0.0353 0.052*
C8 0.69189 (19) 0.37655 (15) 0.16361 (16) 0.0458 (3)
C9 0.7506 (2) 0.4593 (2) 0.2126 (2) 0.0655 (5)
H9 0.8287 0.5168 0.1639 0.079*
C5 0.1532 (2) 0.0332 (2) 0.34243 (16) 0.0560 (4)
H5A 0.033 0.1052 0.3428 0.067*
H5B 0.1653 −0.0658 0.4177 0.067*
C12 0.5178 (2) 0.28940 (17) 0.35447 (16) 0.0483 (3)
H12 0.4384 0.2333 0.4035 0.058*
C11 0.5776 (3) 0.3703 (2) 0.4049 (2) 0.0630 (4)
H11 0.5397 0.3666 0.4872 0.076*
C4 0.1763 (3) 0.0197 (2) 0.21519 (17) 0.0620 (4)
H4A 0.2555 −0.0822 0.2289 0.074*
H4B 0.0563 0.0397 0.1765 0.074*
C10 0.6927 (3) 0.4557 (2) 0.3333 (2) 0.0729 (5)
H10 0.7314 0.511 0.3664 0.088*
O1 0.30232 (14) 0.08905 (13) 0.34445 (9) 0.0480 (2)
O2 0.26110 (15) 0.13305 (14) 0.13264 (10) 0.0536 (3)
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Atomic displacement parameters (Å2)

U11 U22 U33 U12 U13 U23
Cl1 0.0564 (2) 0.0582 (2) 0.0640 (2) −0.02759 (18) 0.01797 (18) −0.01678 (18)
Cl2 0.0595 (2) 0.0481 (2) 0.0721 (3) 0.00034 (16) −0.00404 (19) −0.02775 (19)
C6 0.0336 (5) 0.0369 (6) 0.0318 (5) −0.0132 (4) 0.0005 (4) −0.0123 (4)
C13 0.0329 (5) 0.0370 (6) 0.0337 (5) −0.0155 (4) 0.0016 (4) −0.0151 (4)
C15 0.0460 (7) 0.0399 (6) 0.0344 (6) −0.0138 (5) −0.0027 (5) −0.0109 (5)
C14 0.0439 (6) 0.0405 (6) 0.0315 (5) −0.0151 (5) 0.0027 (4) −0.0165 (5)
C7 0.0319 (5) 0.0330 (5) 0.0463 (6) −0.0083 (4) −0.0025 (5) −0.0161 (5)
C16 0.0401 (6) 0.0364 (6) 0.0484 (7) −0.0119 (5) 0.0004 (5) −0.0188 (5)
C2 0.0348 (6) 0.0478 (7) 0.0385 (6) −0.0163 (5) −0.0002 (4) −0.0157 (5)
C17 0.0540 (8) 0.0516 (8) 0.0451 (7) −0.0119 (6) −0.0003 (6) −0.0297 (6)
C18 0.0487 (7) 0.0488 (7) 0.0348 (6) −0.0119 (6) −0.0042 (5) −0.0205 (5)
C8 0.0371 (6) 0.0369 (6) 0.0601 (8) −0.0121 (5) 0.0005 (5) −0.0177 (6)
C9 0.0532 (9) 0.0539 (9) 0.1019 (14) −0.0269 (7) 0.0039 (9) −0.0379 (9)
C5 0.0488 (8) 0.0723 (10) 0.0500 (8) −0.0347 (7) 0.0054 (6) −0.0195 (7)
C12 0.0481 (7) 0.0489 (7) 0.0559 (8) −0.0162 (6) 0.0048 (6) −0.0295 (7)
C11 0.0651 (10) 0.0654 (10) 0.0756 (11) −0.0147 (8) −0.0005 (8) −0.0483 (9)
C4 0.0702 (10) 0.0756 (11) 0.0547 (9) −0.0449 (9) 0.0033 (7) −0.0260 (8)
C10 0.0665 (11) 0.0683 (11) 0.1120 (16) −0.0252 (9) −0.0017 (10) −0.0592 (12)
O1 0.0450 (5) 0.0713 (7) 0.0346 (4) −0.0322 (5) 0.0057 (4) −0.0203 (4)
O2 0.0545 (6) 0.0796 (7) 0.0372 (5) −0.0400 (6) −0.0004 (4) −0.0209 (5)
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Geometric parameters (Å, º)

Cl1—C8 1.7388 (16) C17—C18 1.387 (2)
Cl2—C16 1.7402 (13) C17—H17 0.93
C6—C7 1.5146 (17) C18—H18 0.93
C6—C13 1.5189 (16) C8—C9 1.390 (2)
C6—C2 1.5278 (17) C9—C10 1.375 (3)
C6—H6 0.98 C9—H9 0.93
C13—C18 1.3885 (18) C5—O1 1.4261 (17)
C13—C14 1.3926 (16) C5—C4 1.491 (2)
C15—C16 1.3794 (19) C5—H5A 0.97
C15—C14 1.3843 (19) C5—H5B 0.97
C15—H15 0.93 C12—C11 1.390 (2)
C14—H14 0.93 C12—H12 0.93
C7—C12 1.389 (2) C11—C10 1.373 (3)
C7—C8 1.3980 (18) C11—H11 0.93
C16—C17 1.380 (2) C4—O2 1.4181 (19)
C2—O1 1.4067 (16) C4—H4A 0.97
C2—O2 1.4131 (17) C4—H4B 0.97
C2—H2 0.98 C10—H10 0.93
C7—C6—C13 111.98 (9) C17—C18—H18 119.3
C7—C6—C2 113.89 (10) C13—C18—H18 119.3
C13—C6—C2 112.22 (10) C9—C8—C7 121.93 (15)
C7—C6—H6 106 C9—C8—Cl1 117.88 (12)
C13—C6—H6 106 C7—C8—Cl1 120.19 (11)
C2—C6—H6 106 C10—C9—C8 119.73 (16)
C18—C13—C14 118.17 (12) C10—C9—H9 120.1
C18—C13—C6 120.66 (11) C8—C9—H9 120.1
C14—C13—C6 121.16 (11) O1—C5—C4 102.77 (12)
C16—C15—C14 119.10 (12) O1—C5—H5A 111.2
C16—C15—H15 120.5 C4—C5—H5A 111.2
C14—C15—H15 120.5 O1—C5—H5B 111.2
C15—C14—C13 121.18 (12) C4—C5—H5B 111.2
C15—C14—H14 119.4 H5A—C5—H5B 109.1
C13—C14—H14 119.4 C7—C12—C11 121.95 (15)
C12—C7—C8 116.50 (12) C7—C12—H12 119
C12—C7—C6 122.60 (11) C11—C12—H12 119
C8—C7—C6 120.88 (12) C10—C11—C12 119.98 (18)
C15—C16—C17 121.23 (12) C10—C11—H11 120
C15—C16—Cl2 119.47 (10) C12—C11—H11 120
C17—C16—Cl2 119.26 (11) O2—C4—C5 104.37 (13)
O1—C2—O2 106.64 (11) O2—C4—H4A 110.9
O1—C2—C6 112.75 (10) C5—C4—H4A 110.9
O2—C2—C6 108.83 (11) O2—C4—H4B 110.9
O1—C2—H2 109.5 C5—C4—H4B 110.9
O2—C2—H2 109.5 H4A—C4—H4B 108.9
C6—C2—H2 109.5 C11—C10—C9 119.91 (16)
C16—C17—C18 118.86 (12) C11—C10—H10 120
C16—C17—H17 120.6 C9—C10—H10 120
C18—C17—H17 120.6 C2—O1—C5 104.87 (10)
C17—C18—C13 121.38 (12) C2—O2—C4 108.24 (11)
C7—C6—C13—C18 −133.67 (12) C14—C13—C18—C17 −1.9 (2)
C2—C6—C13—C18 96.78 (13) C6—C13—C18—C17 177.41 (12)
C7—C6—C13—C14 45.63 (15) C12—C7—C8—C9 −0.6 (2)
C2—C6—C13—C14 −83.91 (14) C6—C7—C8—C9 −178.89 (13)
C16—C15—C14—C13 0.08 (19) C12—C7—C8—Cl1 179.03 (10)
C18—C13—C14—C15 1.94 (18) C6—C7—C8—Cl1 0.74 (17)
C6—C13—C14—C15 −177.38 (11) C7—C8—C9—C10 0.6 (3)
C13—C6—C7—C12 −92.97 (14) Cl1—C8—C9—C10 −179.00 (14)
C2—C6—C7—C12 35.70 (17) C8—C7—C12—C11 −0.2 (2)
C13—C6—C7—C8 85.22 (14) C6—C7—C12—C11 178.07 (13)
C2—C6—C7—C8 −146.12 (12) C7—C12—C11—C10 0.9 (3)
C14—C15—C16—C17 −2.2 (2) O1—C5—C4—O2 −28.32 (18)
C14—C15—C16—Cl2 175.65 (10) C12—C11—C10—C9 −0.9 (3)
C7—C6—C2—O1 −74.72 (14) C8—C9—C10—C11 0.1 (3)
C13—C6—C2—O1 53.83 (15) O2—C2—O1—C5 −31.23 (15)
C7—C6—C2—O2 167.18 (10) C6—C2—O1—C5 −150.62 (12)
C13—C6—C2—O2 −64.28 (13) C4—C5—O1—C2 36.44 (17)
C15—C16—C17—C18 2.2 (2) O1—C2—O2—C4 12.74 (16)
Cl2—C16—C17—C18 −175.63 (11) C6—C2—O2—C4 134.64 (13)
C16—C17—C18—C13 −0.1 (2) C5—C4—O2—C2 9.89 (18)
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Hydrogen-bond geometry (Å, º)

D—H···A D—H H···A D···A D—H···A
C6—H6···Cl1 0.98 2.57 3.0566 (13) 111
C12—H12···O1 0.93 2.38 3.046 (2) 128
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Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: BX2412).

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812023781/bx2412sup1.cif

e-68-o2008-sup1.cif (17.7KB, cif)

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812023781/bx2412Isup2.hkl

e-68-o2008-Isup2.hkl (223.2KB, hkl)

Supplementary material file. DOI: 10.1107/S1600536812023781/bx2412Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Articles from Acta Crystallographica Section E: Structure Reports Online are provided here courtesy of International Union of Crystallography

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