Crystal structure of anabolic steroid metabolite 4-chloro­androst-4-ene-3,17-dione

Nithimanon, S.; Sermmai, P.; Thongpanchang, C.; Saepua, S.; Thongpanchang, T.

doi:10.1107/S2056989022010891

research communications

CRYSTALLOGRAPHIC
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ISSN: 2056-9890

Volume 78| Part 12| December 2022| Pages 1228-1232

https://doi.org/10.1107/S2056989022010891

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Crystal structure of anabolic steroid metabolite 4-chloroandrost-4-ene-3,17-dione

Saitarn Nithimanon,^a Patpanat Sermmai,^a Chawanee Thongpanchang,^b Siriporn Saepua ^b and Tienthong Thongpanchang ^a

^aDepartment of Chemistry and Center of Excellence for Innovation in Chemistry, (PERCH-CIC), Faculty of Science, Mahidol University, Rama 6 Road, Bangkok, 10400, Thailand, and ^bNational Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Thailand Science Park, Phathumthani 12120, Thailand

Edited by A. V. Yatsenko, Moscow State University, Russia (Received 4 August 2022; accepted 14 November 2022; online 17 November 2022)

The title compound, NorClAD, C₁₈H₂₃ClO₂, a metabolite of an anabolic steroid norchlorotestosterone acetate (NClTA), was successfully synthesized. Its molecular structure was characterized by ¹H NMR and ¹³C NMR spectroscopy and single-crystal X-ray diffraction. The positions of the chlorine substituent, carbonyl groups and the double bond, as well as the absolute configuration of the molecule, were established. A Hirshfeld surface analysis was performed.

Keywords: anabolic steroid; doping agent; crystal structure; metabolite; testosterone; absolute configuration; Hirshfeld analysis.

CCDC reference: 2130048

1. Chemical context

Anabolic steroids have been reported to be used as growth-accelerating agents (Schanzer, 1996 ). Norchlorotestosterone acetate (NClTA), one of the synthetic anabolic steroids, is applied by athletes as a testosterone mimetic for an improvement of their performance. The use of testosterone derivatives has therefore been banned by the World Anti-Doping Agency (WADA) (Wood & Stanton, 2012 ). The metabolism of anabolic steroids is divided into two phases. In phase I, the functional group of anabolic steroids is converted into a more polar functional group. In phase II, the metabolite of anabolic steroids is transformed to glucuronic acid or a sulfate derivative that may easily be eliminated from the human body. Knowledge of its metabolic pathway is therefore necessary to prove the illegal administration of NClTA.

The metabolism of NClTA has been investigated successfully in invertebrates (Neomysis integer) and vertebrates (bovine) through oral and subcutaneous administration (Leyssens et al., 1994 ; Hendriks et al., 1994 ; Bizec et al., 1998 ). Mass spectrometry results indicate that one of the most abundant metabolites, found in both invertebrates and vertebrates (after subcutaneous injection), is 4-chloroandrost-4-ene-3,17-dione (NorClAD), the oxidized form of NClTA (see Fig. 1). NorClAD was synthesized through hydrolysis of NClTA followed by an oxidation (Hoof et al., 2004 ). However, elucidation of its crystal and molecular structures and its absolute stereochemistry were required. In this work, NorClAD was successfully synthesized in two steps according to the given scheme (Ringold et al., 1956 ), and its X-ray structure and absolute stereochemistry were determined.

Figure 1
The structures of NClTA and NorClAD.

2. Structural commentary

The molecular structure of the title compound is represented in Fig. 2. The compound consists of three six-membered rings A(C1–C4/C16/C17), B(C4/C5/C13–C16), C(C5–C8/C12/C13) and one five-membered ring D (C8–C12). Cyclohexenone ring A adopts a half-chair conformation while cyclohexane rings B and C adopt chair conformations. Cyclopentanone ring D adopts an envelope conformation with C12 as the flap. It is evident from the bond dimensions that the chlorine atom lies at C17, C1 and C9 are involved in carbonyl groups, and that the C16—C17 bond has double-bond character. The title compound adopts an all-trans ring junction and the absolute stereochemistry of atoms C4(R), C5(S) C8(S) C12(S) and C13(R) were properly determined using Cu Kα radiation and confirmed by the Flack parameter of 0.029 (4) (Parsons et al., 2013 ).

Figure 2
The molecular structure of the title compound, NorClAD. Displacement ellipsoids are drawn at the 50% probability level.

3. Supramolecular features and Hirshfeld surface analysis

A view of the unit-cell content of the title compound is presented in Fig. 3. There are several C—H⋯O and C—H⋯Cl contacts that can be considered as weak hydrogen bonds (see Table 1). In order to better understand the importance of these contacts, a Hirshfeld surface (Hirshfeld, 1977 ) was performed and the two-dimensional fingerprint plots were generated with Crystal Explorer 21.0 (Spackman et al., 2021 ). The Hirshfeld surface mapped over d_norm (see Fig. 4) is scaled between −0.1622 to 1.3540 a.u. The bright-red spots indicate the positions of the respective H-atom donors and H-atom acceptors (Venkatesan et al., 2016 ). Fig. 5 shows how these red spots correspond to short intermolecular contacts. The overall two-dimensional fingerprint plot and those delineated into H⋯H, H⋯Cl/Cl⋯H, H⋯O/O⋯H, H⋯C/C⋯H, Cl⋯C/C⋯Cl, and Cl⋯O/O⋯Cl contacts (McKinnon et al., 2007 ) are presented in Fig. 6a–g, respectively, together with their relative contributions to the Hirshfeld surface. The most abundant interaction is H⋯H, contributing 56.2% to the overall crystal packing, which is reflected in Fig. 6b as widely scattered points of high density owing to the large hydrogen content of the molecule. The blue region fingerprint plot of H⋯O/O⋯H interaction represents a symmetric distribution of points (22.8% contribution, Fig. 6d). While, the contribution of H⋯Cl/Cl⋯H contacts (Fig. 6c) is 13.7%. Percentages of other types of contacts are given in Table 2. The large number of H⋯H interactions indicate that van der Waals interactions play a major role in the crystal packing (Hathwar et al., 2015 ).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C2—H2A⋯O2ⁱ	0.99	2.60	3.563 (2)	165
C10—H10A⋯O2ⁱⁱ	0.99	2.57	3.398 (3)	141
C18—H18B⋯O2ⁱⁱ	0.98	2.56	3.507 (3)	163
C10—H10B⋯O1ⁱⁱⁱ	0.99	2.48	3.443 (3)	164
C4—H4⋯Cl1^iv	1.00	2.88	3.8202 (18)	158
Symmetry codes: (i) $[-x+{\script{1\over 2}}, -y+1, z+{\script{1\over 2}}]$ ; (ii) $[x+{\script{1\over 2}}, -y+{\script{3\over 2}}, -z+1]$ ; (iii) $[x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+1]$ ; (iv) $[-x+1, y+{\script{1\over 2}}, -z+{\script{3\over 2}}]$ .

Table 2
Percentage contributions of the most relevant atom–atom contacts to the Hirshfeld surface in the title structure

Atom-atom interaction	Percentage
H⋯H	56.2
H⋯O/O⋯H	22.8
H⋯Cl/Cl⋯H	13.7
H⋯C/C⋯H	5.6
Cl⋯O/O⋯Cl	1.6
Cl⋯C/C⋯Cl	0.2

Figure 3
The packing of the title compound viewed down the a axis.

Figure 4
The three-dimensional Hirshfeld surface of the title compound plotted over d_norm.

Figure 5
View of the three-dimensional Hirshfeld surface of the title compound together with the hydrogen-bonding (dashed lines) between adjacent molecules.

Figure 6
The two-dimensional fingerprint plots for the title compound, showing all interactions (a), and those delineated into H⋯H (b), H⋯Cl/Cl⋯H (c), H⋯O/O⋯H (d), H⋯C/C⋯H (e), Cl⋯C/C⋯Cl (f) and Cl⋯O/O⋯Cl (g) interactions.

4. Database survey

A search of Cambridge Structure Database (CSD, version 5.42, update of May 2021; Groom et al., 2016 ) found four structures that are closely related to the title compound and which play significant roles in the biological mechanisms. For the disordered structure of cortisol (11b,17a,21-trihydroxy-4-pregnene-3,20-dione), see CORTSL (Castellano, 1980 ). For dexamethasone at 119 K, see DEXMET11 (Raynor et al., 2007 ). For 17β-hydroxy-17a-methylandrostano[3,2-c]pyrazole, stanozolol, see AVENUL (Karpinska et al., 2011 ). For the crystal structure, Hirshfeld surface analysis, interaction energies, and DFT studies of cholesteryl heptanoate, see ZZZBIP01 (Akduran et al., 2021 ).

5. Synthesis and crystallization

The target compound was synthesized in two steps as shown in the scheme.

To a solution of norandrostenedione (5.00 g, 18.36 mmol) in methanol (100 mL) at 273 K were slowly added 30% H₂O₂ (4.5 mL, 57.55 mmol) and 6N NaOH (1.5 mL, 9.0 mmol). The mixture was then stirred at 273 K for 1 h. After that, the reaction solution was warmed up to room temperature and stirring continued for 2 h. After completion, water was added to the reaction mixture and the solvent was evaporated. The aqueous residue was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous Na₂SO₄ and then concentrated to dryness in vacuo to provide epoxide 1, which was used in the next step without further purification.

A solution of epoxide 1 (4.13 g) in acetone (100 mL) was treated with conc. HCl (1.5 mL) and the mixture was stirred at room temperature for 30 min. After that, water was added to the reaction mixture and it was extracted three times with dichloromethane. The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated to dryness. The solid product was recrystallized from MeOH:CH₂Cl₂ (3:1) at room temperature to provide 3.19 g of 4-chloroandrost-4-ene-3,17-dione (NorClAD) (56% yield).

Compound characterization: ¹H NMR (400 MHz, chloroform-d) δ 3.42 (ddd, J = 15.0, 4.1, 2.4 Hz, 1H), 2.66 (dt, J = 16.2, 4.4 Hz, 1H), 2.55–2.36 (m, 2H), 2.36–2.25 (m, 2H), 2.19–2.08 (m, 2H), 2.07–1.92 (m, 3H), 1.88 (dt, J = 9.3, 2.7 Hz, 1H), 1.65–1.49 (m, 3H), 1.39–1.30 (m, 3H), 1.20 (tdd, J = 13.3, 11.7, 4.0 Hz, 1H), 1.05 0.97 (m, 1H), 0.95 (s, 3H). ¹³C NMR (101 MHz, chloroform-d) δ 220.3, 191.1, 159.6, 127.9, 50.1, 49.4, 47.7, 44.8, 39.7, 36.6, 35.8, 31.9, 31.3, 29.3, 25.7, 25.5, 21.7, 13.9.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3. All H atoms were positioned geometrically, with C—H = 0.98, 0.99 and 1.00 Å for methyl, methylene and methine protons, respectively, and refined as riding with U_iso(H) = 1.2 or 1.5U_eq(C). In addition, the absolute configuration of this compound was confirmed by the Flack parameter of 0.029 (4) (Parsons et al., 2013).

Table 3
Experimental details

Crystal data
Chemical formula	C₁₈H₂₃ClO₂
M_r	306.81
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	100
a, b, c (Å)	7.4379 (4), 12.7142 (6), 16.4790 (8)
V (Å³)	1558.37 (13)
Z	4
Radiation type	Cu Kα
μ (mm⁻¹)	2.18
Crystal size (mm)	0.05 × 0.01 × 0.01

Data collection
Diffractometer	Bruker D8 VENTURE
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 )
T_min, T_max	0.678, 0.753
No. of measured, independent and observed [I > 2σ(I)] reflections	18469, 2907, 2787
R_int	0.031

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.024, 0.065, 1.04
No. of reflections	2907
No. of parameters	191
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.17, −0.18
Absolute structure	Flack x determined using 1150 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013)
Absolute structure parameter	0.029 (4)
Computer programs: APEX3 and SAINT (Bruker, 2016 ), SHELXT (Sheldrick, 2015 ), SHELXL (Sheldrick, 2008 ) and OLEX2 (Dolomanov et al., 2009 ).

Supporting information

CCDC reference: 2130048

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S2056989022010891/yk2175sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989022010891/yk2175Isup2.hkl

checkCIF report

Computing details top

Data collection: APEX3 (Bruker, 2016); cell refinement: SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); program(s) used to solve structure: SHELXT (Sheldrick, 2015); program(s) used to refine structure: SHELXL (Sheldrick, 2008); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

4-Chloroandrost-4-ene-3,17-dione top

Crystal data top

C₁₈H₂₃ClO₂	D_x = 1.308 Mg m⁻³
M_r = 306.81	Cu Kα radiation, λ = 1.54178 Å
Orthorhombic, P2₁2₁2₁	Cell parameters from 9974 reflections
a = 7.4379 (4) Å	θ = 4.4–70.2°
b = 12.7142 (6) Å	µ = 2.18 mm⁻¹
c = 16.4790 (8) Å	T = 100 K
V = 1558.37 (13) Å³	Block, clear light colourless
Z = 4	0.05 × 0.01 × 0.01 mm
F(000) = 656

Data collection top

BRUKER D8 VENTURE diffractometer	2907 independent reflections
Radiation source: X-ray tube, Micro focus tube	2787 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.031
Detector resolution: 10.4167 pixels mm^-1	θ_max = 70.1°, θ_min = 4.4°
ω and φ scans	h = −9→9
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	k = −15→15
T_min = 0.678, T_max = 0.753	l = −20→19
18469 measured reflections

Refinement top

Refinement on F²	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F² > 2σ(F²)] = 0.024	w = 1/[σ²(F_o²) + (0.0383P)² + 0.2052P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.065	(Δ/σ)_max = 0.001
S = 1.04	Δρ_max = 0.17 e Å⁻³
2907 reflections	Δρ_min = −0.18 e Å⁻³
191 parameters	Absolute structure: Flack x determined using 1150 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
0 restraints	Absolute structure parameter: 0.029 (4)
Primary atom site location: dual

Special details top

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 (Å²) top

	x	y	z	U_iso*/U_eq
Cl1	0.53413 (6)	−0.00451 (3)	0.67248 (3)	0.02851 (13)
O1	0.1878 (2)	−0.02569 (11)	0.74872 (9)	0.0345 (3)
O2	0.3004 (2)	0.70098 (13)	0.43229 (10)	0.0401 (4)
C1	0.2157 (3)	0.06557 (15)	0.73085 (11)	0.0242 (4)
C5	0.2976 (2)	0.36358 (14)	0.60909 (11)	0.0191 (3)
H5	0.259997	0.323792	0.559582	0.023*
C6	0.1640 (2)	0.45474 (14)	0.62010 (12)	0.0228 (4)
H6A	0.188454	0.489661	0.672646	0.027*
H6B	0.040622	0.425670	0.622443	0.027*
C17	0.3824 (2)	0.09845 (14)	0.68886 (11)	0.0214 (4)
C3	0.0974 (2)	0.24336 (14)	0.69275 (11)	0.0234 (4)
H3A	0.017607	0.300838	0.711313	0.028*
H3B	0.051866	0.217948	0.639818	0.028*
C7	0.1726 (2)	0.53763 (15)	0.55206 (12)	0.0243 (4)
H7A	0.128879	0.506525	0.500636	0.029*
H7B	0.093792	0.597774	0.565909	0.029*
C4	0.2882 (2)	0.28617 (13)	0.68182 (11)	0.0193 (3)
H4	0.319484	0.326567	0.731938	0.023*
C16	0.4260 (2)	0.19893 (13)	0.67251 (11)	0.0206 (3)
C13	0.4912 (2)	0.40302 (14)	0.59430 (11)	0.0197 (4)
H13	0.534533	0.439779	0.644250	0.024*
C9	0.4042 (3)	0.64247 (15)	0.46663 (12)	0.0278 (4)
C15	0.6121 (3)	0.23322 (15)	0.64898 (13)	0.0277 (4)
H15A	0.684117	0.170390	0.634705	0.033*
H15B	0.670068	0.267385	0.696210	0.033*
C2	0.0914 (3)	0.15384 (15)	0.75394 (12)	0.0263 (4)
H2A	0.125680	0.180934	0.808097	0.032*
H2B	−0.033061	0.126618	0.757601	0.032*
C8	0.3650 (2)	0.57594 (14)	0.54125 (11)	0.0215 (4)
C18	0.4268 (3)	0.64214 (15)	0.61467 (12)	0.0255 (4)
H18A	0.340763	0.699209	0.624110	0.038*
H18B	0.545813	0.671945	0.603545	0.038*
H18C	0.433172	0.597296	0.662951	0.038*
C14	0.6134 (2)	0.30946 (15)	0.57747 (12)	0.0262 (4)
H14A	0.737587	0.334569	0.567856	0.031*
H14B	0.572060	0.272622	0.527940	0.031*
C12	0.4880 (2)	0.48125 (14)	0.52440 (11)	0.0221 (4)
H12	0.435207	0.443399	0.476847	0.027*
C10	0.5982 (3)	0.62344 (17)	0.44187 (13)	0.0336 (5)
H10A	0.671889	0.687004	0.451795	0.040*
H10B	0.605681	0.605168	0.383565	0.040*
C11	0.6645 (3)	0.53098 (16)	0.49478 (13)	0.0302 (4)
H11A	0.735925	0.480383	0.462438	0.036*
H11B	0.738045	0.556310	0.540879	0.036*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.0383 (2)	0.0235 (2)	0.0237 (2)	0.00946 (18)	0.00264 (17)	0.00324 (19)
O1	0.0444 (8)	0.0246 (7)	0.0345 (8)	−0.0055 (6)	0.0073 (7)	0.0060 (6)
O2	0.0503 (9)	0.0395 (8)	0.0305 (8)	0.0078 (8)	0.0007 (7)	0.0141 (7)
C1	0.0307 (9)	0.0246 (9)	0.0173 (9)	−0.0043 (8)	−0.0020 (7)	−0.0001 (7)
C5	0.0164 (8)	0.0212 (8)	0.0198 (8)	−0.0009 (7)	0.0004 (7)	−0.0029 (7)
C6	0.0190 (8)	0.0252 (9)	0.0241 (10)	0.0023 (7)	0.0021 (7)	0.0019 (7)
C17	0.0263 (9)	0.0229 (8)	0.0151 (8)	0.0034 (7)	−0.0013 (7)	−0.0013 (7)
C3	0.0189 (8)	0.0237 (9)	0.0275 (10)	−0.0015 (7)	0.0027 (7)	−0.0004 (7)
C7	0.0212 (8)	0.0279 (9)	0.0237 (9)	0.0042 (7)	−0.0011 (7)	0.0033 (7)
C4	0.0176 (7)	0.0199 (8)	0.0203 (8)	−0.0011 (6)	0.0008 (7)	−0.0025 (7)
C16	0.0206 (8)	0.0229 (8)	0.0183 (8)	0.0011 (6)	−0.0004 (7)	−0.0018 (7)
C13	0.0171 (8)	0.0208 (8)	0.0212 (9)	−0.0008 (7)	0.0026 (6)	−0.0022 (7)
C9	0.0387 (10)	0.0246 (9)	0.0202 (9)	−0.0019 (8)	0.0012 (8)	−0.0007 (8)
C15	0.0186 (8)	0.0259 (9)	0.0386 (11)	0.0029 (7)	0.0001 (8)	0.0025 (8)
C2	0.0260 (9)	0.0277 (9)	0.0253 (9)	−0.0046 (7)	0.0060 (7)	0.0006 (8)
C8	0.0241 (9)	0.0224 (8)	0.0179 (8)	0.0016 (7)	0.0004 (7)	0.0008 (7)
C18	0.0320 (10)	0.0232 (9)	0.0211 (9)	0.0018 (7)	−0.0011 (7)	0.0001 (7)
C14	0.0192 (8)	0.0261 (9)	0.0332 (10)	0.0025 (7)	0.0069 (8)	−0.0001 (8)
C12	0.0214 (8)	0.0242 (9)	0.0207 (9)	−0.0007 (7)	0.0031 (6)	−0.0026 (7)
C10	0.0411 (11)	0.0313 (11)	0.0285 (10)	−0.0027 (9)	0.0117 (9)	0.0048 (8)
C11	0.0281 (9)	0.0302 (10)	0.0323 (11)	−0.0007 (8)	0.0109 (8)	0.0021 (8)

Geometric parameters (Å, º) top

Cl1—C17	1.7493 (17)	C13—C14	1.523 (2)
O1—C1	1.215 (2)	C13—C12	1.522 (3)
O2—C9	1.212 (3)	C9—C8	1.521 (3)
C1—C17	1.480 (3)	C9—C10	1.519 (3)
C1—C2	1.503 (3)	C15—H15A	0.9900
C5—H5	1.0000	C15—H15B	0.9900
C5—C6	1.538 (2)	C15—C14	1.526 (3)
C5—C4	1.552 (2)	C2—H2A	0.9900
C5—C13	1.544 (2)	C2—H2B	0.9900
C6—H6A	0.9900	C8—C18	1.544 (3)
C6—H6B	0.9900	C8—C12	1.538 (2)
C6—C7	1.540 (3)	C18—H18A	0.9800
C17—C16	1.345 (2)	C18—H18B	0.9800
C3—H3A	0.9900	C18—H18C	0.9800
C3—H3B	0.9900	C14—H14A	0.9900
C3—C4	1.530 (2)	C14—H14B	0.9900
C3—C2	1.521 (3)	C12—H12	1.0000
C7—H7A	0.9900	C12—C11	1.537 (2)
C7—H7B	0.9900	C10—H10A	0.9900
C7—C8	1.522 (3)	C10—H10B	0.9900
C4—H4	1.0000	C10—C11	1.544 (3)
C4—C16	1.518 (2)	C11—H11A	0.9900
C16—C15	1.502 (3)	C11—H11B	0.9900
C13—H13	1.0000

O1—C1—C17	121.74 (18)	C16—C15—H15A	109.0
O1—C1—C2	123.14 (18)	C16—C15—H15B	109.0
C17—C1—C2	115.01 (15)	C16—C15—C14	112.91 (15)
C6—C5—H5	107.2	H15A—C15—H15B	107.8
C6—C5—C4	110.95 (14)	C14—C15—H15A	109.0
C6—C5—C13	112.12 (14)	C14—C15—H15B	109.0
C4—C5—H5	107.2	C1—C2—C3	111.88 (15)
C13—C5—H5	107.2	C1—C2—H2A	109.2
C13—C5—C4	111.73 (14)	C1—C2—H2B	109.2
C5—C6—H6A	108.8	C3—C2—H2A	109.2
C5—C6—H6B	108.8	C3—C2—H2B	109.2
C5—C6—C7	113.78 (15)	H2A—C2—H2B	107.9
H6A—C6—H6B	107.7	C7—C8—C18	111.28 (15)
C7—C6—H6A	108.8	C7—C8—C12	109.28 (15)
C7—C6—H6B	108.8	C9—C8—C7	116.95 (16)
C1—C17—Cl1	113.65 (13)	C9—C8—C18	105.85 (15)
C16—C17—Cl1	121.62 (14)	C9—C8—C12	100.08 (14)
C16—C17—C1	124.31 (16)	C12—C8—C18	113.01 (15)
H3A—C3—H3B	107.9	C8—C18—H18A	109.5
C4—C3—H3A	109.3	C8—C18—H18B	109.5
C4—C3—H3B	109.3	C8—C18—H18C	109.5
C2—C3—H3A	109.3	H18A—C18—H18B	109.5
C2—C3—H3B	109.3	H18A—C18—H18C	109.5
C2—C3—C4	111.81 (15)	H18B—C18—H18C	109.5
C6—C7—H7A	109.6	C13—C14—C15	110.60 (15)
C6—C7—H7B	109.6	C13—C14—H14A	109.5
H7A—C7—H7B	108.2	C13—C14—H14B	109.5
C8—C7—C6	110.07 (15)	C15—C14—H14A	109.5
C8—C7—H7A	109.6	C15—C14—H14B	109.5
C8—C7—H7B	109.6	H14A—C14—H14B	108.1
C5—C4—H4	107.5	C13—C12—C8	112.60 (14)
C3—C4—C5	111.00 (14)	C13—C12—H12	106.5
C3—C4—H4	107.5	C13—C12—C11	119.74 (15)
C16—C4—C5	110.76 (14)	C8—C12—H12	106.5
C16—C4—C3	112.21 (14)	C11—C12—C8	104.11 (14)
C16—C4—H4	107.5	C11—C12—H12	106.5
C17—C16—C4	120.72 (15)	C9—C10—H10A	110.6
C17—C16—C15	123.32 (16)	C9—C10—H10B	110.6
C15—C16—C4	115.87 (14)	C9—C10—C11	105.83 (16)
C5—C13—H13	108.8	H10A—C10—H10B	108.7
C14—C13—C5	109.38 (14)	C11—C10—H10A	110.6
C14—C13—H13	108.8	C11—C10—H10B	110.6
C12—C13—C5	108.50 (14)	C12—C11—C10	102.70 (16)
C12—C13—H13	108.8	C12—C11—H11A	111.2
C12—C13—C14	112.45 (15)	C12—C11—H11B	111.2
O2—C9—C8	126.60 (18)	C10—C11—H11A	111.2
O2—C9—C10	125.27 (19)	C10—C11—H11B	111.2
C10—C9—C8	108.13 (16)	H11A—C11—H11B	109.1

Cl1—C17—C16—C4	175.86 (13)	C7—C8—C12—C11	166.87 (15)
Cl1—C17—C16—C15	−7.7 (3)	C4—C5—C6—C7	177.20 (14)
O1—C1—C17—Cl1	−2.6 (2)	C4—C5—C13—C14	59.07 (19)
O1—C1—C17—C16	−175.31 (19)	C4—C5—C13—C12	−177.92 (14)
O1—C1—C2—C3	−150.53 (19)	C4—C3—C2—C1	−56.7 (2)
O2—C9—C8—C7	30.3 (3)	C4—C16—C15—C14	−48.3 (2)
O2—C9—C8—C18	−94.3 (2)	C16—C15—C14—C13	53.9 (2)
O2—C9—C8—C12	148.1 (2)	C13—C5—C6—C7	51.5 (2)
O2—C9—C10—C11	−171.2 (2)	C13—C5—C4—C3	−176.96 (14)
C1—C17—C16—C4	−12.0 (3)	C13—C5—C4—C16	−51.60 (19)
C1—C17—C16—C15	164.43 (18)	C13—C12—C11—C10	−165.63 (16)
C5—C6—C7—C8	−52.9 (2)	C9—C8—C12—C13	174.71 (15)
C5—C4—C16—C17	−136.86 (17)	C9—C8—C12—C11	43.51 (18)
C5—C4—C16—C15	46.5 (2)	C9—C10—C11—C12	18.2 (2)
C5—C13—C14—C15	−59.3 (2)	C2—C1—C17—Cl1	173.68 (13)
C5—C13—C12—C8	58.98 (19)	C2—C1—C17—C16	1.0 (3)
C5—C13—C12—C11	−178.21 (16)	C2—C3—C4—C5	170.25 (14)
C6—C5—C4—C3	57.13 (18)	C2—C3—C4—C16	45.7 (2)
C6—C5—C4—C16	−177.52 (14)	C8—C9—C10—C11	8.9 (2)
C6—C5—C13—C14	−175.66 (15)	C8—C12—C11—C10	−38.77 (19)
C6—C5—C13—C12	−52.7 (2)	C18—C8—C12—C13	62.56 (19)
C6—C7—C8—C9	168.92 (15)	C18—C8—C12—C11	−68.63 (19)
C6—C7—C8—C18	−69.28 (19)	C14—C13—C12—C8	−179.90 (15)
C6—C7—C8—C12	56.2 (2)	C14—C13—C12—C11	−57.1 (2)
C17—C1—C2—C3	33.2 (2)	C12—C13—C14—C15	−179.92 (15)
C17—C16—C15—C14	135.14 (19)	C10—C9—C8—C7	−149.86 (17)
C3—C4—C16—C17	−12.2 (2)	C10—C9—C8—C18	85.56 (18)
C3—C4—C16—C15	171.12 (16)	C10—C9—C8—C12	−32.04 (19)
C7—C8—C12—C13	−61.93 (19)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C2—H2A···O2ⁱ	0.99	2.60	3.563 (2)	165
C10—H10A···O2ⁱⁱ	0.99	2.57	3.398 (3)	141
C18—H18B···O2ⁱⁱ	0.98	2.56	3.507 (3)	163
C10—H10B···O1ⁱⁱⁱ	0.99	2.48	3.443 (3)	164
C4—H4···Cl1^iv	1.00	2.88	3.8202 (18)	158

Symmetry codes: (i) −x+1/2, −y+1, z+1/2; (ii) x+1/2, −y+3/2, −z+1; (iii) x+1/2, −y+1/2, −z+1; (iv) −x+1, y+1/2, −z+3/2.

Percentage contributions of the most relevant atom–atom contacts to the Hirshfeld surface in the title structure top

Atom-atom interaction	Percentage
H···H	56.2
H···O/O···H	22.8
H···Cl/Cl···H	13.7
H···C/C···H	5.6
Cl···O/O···Cl	1.6
Cl···C/C···Cl	0.2

Funding information

Financial support from Mahidol University, the Thailand Research Fund through the Royal Golden Jubilee PhD Program (grant No. PHD/0115/2557 for PS and TT) and the Center of Excellence for Innovation in Chemistry (PERCH-CIC) are gratefully acknowledged.

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