Crystal structure and Hirshfeld surface analysis of lapachol acetate 80 years after its first synthesis

A modified synthesis procedure allowed lapachol acetate (acetic acid 3-(3-methyl-but-2-en­yl)-1,4-dioxo-1,4-di­hydro- naphthalen-2-yl ester) to be obtained in high yield and its crystal structure is reported for the first time 80 years after its first synthesis. The lapachol acetate mol­ecular conformation is very similar to that of reported lapachol mol­ecules and other derivatives. The monoclinic P2₁/n crystal structure packs through weak inter­molecular π–π and C—H⋯O inter­actions as described by Hirshfeld surface analysis.

Abstract

Lapachol acetate [systematic name: 3-(3-methyl­but-2-en­yl)-1,4-dioxonaph­thalen-2-yl acetate], C₁₇H₁₆O₄, was prepared using a modified high-yield procedure and its crystal structure is reported for the first time 80 years after its first synthesis. The full spectroscopic characterization of the mol­ecule is reported. The mol­ecular conformation shows little difference with other lapachol derivatives and lapachol itself. The packing is directed by inter­molecular π–π and C—H⋯O inter­actions, as described by Hirshfeld surface analysis. The former inter­actions make the largest contributions to the total packing energy in a ratio of 2:1 with respect to the latter.

Chemical context  

Naphto­quinones are natural products characterized by a naphthalene ring system exhibiting a para-quinone motif in positions 1,4. They are natural pigments and normally substituted by hydroxyl or methyl groups or present as glycosides (Bruneton, 2001 ▸). Among the natural products, they possess remarkable biological activity such as anti­bacterial, anti­fungal, anti­parasitic, anti­viral and anti­cancer (Babula et al., 2007 ▸; da Silva & Ferreira, 2016 ▸; Miranda et al., 2019 ▸; Araújo et al., 2019 ▸; Barbosa Coitinho et al., 2019 ▸; Strauch et al., 2019 ▸). Lapachol (2-hy­droxy-3-(3-methyl-but-2-en­yl)[1,4]naphtho­quinone), isolated from Handroanthus Heptaphyllus (Vell.) Mattos, a native species from Paraguay, was studied as a hemisynthetic precursor of lapachol acetate {[3-(3-methyl-but-2-en­yl)-1,4-dioxonaphthalen-2-yl]acetate} for the first time by Cooke et al. (1939 ▸). Jacobsen & Torsell (1973 ▸) prepared lapachol acetate using 2-acet­oxy-1,4-naphtho­quinone as a precursor with 79% yield. We developed an optimization of the first synthesis of lapachol acetate developed by Cooke et al. (1939 ▸), introducing several modifications with the purpose of standardizing it and increasing the yield to 97.5%. Details of the synthesis and the spectroscopic characterization are included in the supporting information. Noting that the crystal structure of lapachol acetate had not been reported, we also undertook the crystallization and structure determination.

Structural commentary  

The lapachol acetate mol­ecule (Fig. 1 ▸) is the ester of lapachol at the alcohol moiety (O2 in Larsen et al., 1992 ▸). The mol­ecule is composed of three planar groups, the naptho­quinone nucleus comprising atoms C1 to C11, O1, O2 and O4, and two smaller butenyl and acetate residues at the sides. The butenyl and acetate mean planes are inclined to the naphthoquinone mean plane by 65.80 (10) and 78.52 (11)°, respectively. The lapachol acetate mol­ecule shows typical bond distances and angles, and overlaps very closely with the common part of the lapachol mol­ecule in the structure LAPA II reported by Larsen et al. (1992 ▸) (Fig. 2 ▸), with an average deviation of C/O atomic positions of 0.158 Å and a maximum deviation of 0.309 Å for atom O4. This is rather unexpected, since the butenyl moiety shows rotational flexibility around the C3—C11 and C11—C12 bonds. However, in both reported lapachol polymorphs (Larsen et al., 1992 ▸) and two derivatives (Eyong et al., 2015 ▸; da Silva et al., 2012 ▸) reported in the CSD (Groom et al., 2016 ▸) with the same rotational freedom, the dihedral angle between the planar C=C(CH₃)₂ group and the naphtho­quinone nucleus is close to 70°, as observed in lapachol acetate.

Figure 1.

ORTEP view of a lapachol acetate mol­ecule with the labelling scheme, and displacement ellipsoids drawn at the 50% probability level. One of the two positions of the disordered C17 methyl group has been omitted for clarity.

Figure 2.

Overlay of a lapachol acetate (blue) and a lapachol (red) mol­ecule (LAPA II mol­ecule as described by Larsen et al., 1992 ▸). Only the common C/O atoms were fitted.

Supra­molecular features  

Crystals of lapachol acetate are held together by weak dipolar and dispersion forces because there is no strong H-donor residue in the mol­ecule. Mol­ecules connect with other units through weak C(sp³)—H⋯O=C hydrogen bonds H11B⋯O4ⁱ and H15A⋯O1ⁱⁱ (Table 1 ▸, Fig. S4a in the supporting information) defining double sheets of mol­ecules parallel to (01). The butenyl residue of a screw-rotation-related mol­ecule adds an inter­molecular π–π inter­action with the naphto­quinone residue to the sheets with atoms C12ⁱⁱⁱ and C13ⁱⁱⁱ located at 3.243 and 3.544 Å, respectively, from the naphto­quinone plane (Fig. S4b). Finally, the double sheets stack along the [01] direction where naphtho­quinone nuclei of inversion-related mol­ecules display π–π inter­actions. Ring 1 (C1–C4/C10/C9; centroid Cg1) of the mol­ecule is close to ring 2 (C5—C10; centroid Cg2), the Cg2⋯Cg1^iv distance being 3.8532 (12) Å); Cg2⋯Cg2^iv is the shortest distance [3.8035 (13) Å], with an average perpendicular distance between naphto­quinone planes of 3.3787 (9) Å, as shown in Fig. S4c [symmetry codes: (i) −x + , y − , −z + ; (ii) x + , −y + , z +  ; (iii)  − x,  + y,  − z; (iv) 1 − x, 1 − y, 1 − z). Considering the Hirshfeld (HF) surface (Turner et al., 2017 ▸) mapped over d _norm (analysis of the contact distances d _i and d _e from the HF surface to the nearest atom inside and outside, respectively), these inter­actions in one mol­ecule are shown in Fig. 3 ▸ a and the sheets of mol­ecules defined by them in Fig. 3 ▸ b. The 2D fingerprints of lapachol acetate (shown in Fig. S5 of the supporting information) show no particular features other than the aforementioned H⋯O/O⋯H contacts, which comprise 28.2% of the total HF surface, revealing their importance in the formation of the crystal.

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C11—H11B⋯O4i	0.97	2.55	3.274 (3)	131
C15—H15A⋯O1ii	0.96	2.59	3.485 (3)	156

Symmetry codes: (i) ; (ii) .

Figure 3.

(a) View of the Hirshfeld surface for lapachol acetate mapped over d _norm showing the C—H⋯O hydrogen-bond inter­actions. (b) The mol­ecular structure of lapachol acetate showing the formation of stacked (01) sheets.

In order to describe these inter­actions in a whole-of-mol­ecule approach, accurate model energies of the inter­actions between mol­ecules of lapachol acetate in the crystal were analysed. The inter­actions were calculated using the B3LYP/6–31 G(d,p) energy model implemented in CrystalExplorer (Turner et al., 2017 ▸), which uses quantum mechanical charge distributions for unperturbed mol­ecules (Mackenzie et al., 2017 ▸). In the calculations, the total energy is modelled as the sum of the electrostatic (E _ele), polarization (E _pol), dispersion (E _dis) and exchange-repulsion (E _rep) terms (Mackenzie et al., 2017 ▸). The strongest pairwise inter­action with a total energy of −54.7 kJ mol⁻¹ corresponds to the inter­action between neighbouring aromatic systems, while the mol­ecules connected through a combination of π–π inter­actions between the butenyl and naphto­quinone residues and C11—H11B⋯O4ⁱ hydrogen bonds have a total energy of −33.6 kJ mol⁻¹. The weakest inter­action, C15–H15A⋯O1ⁱⁱ, shows a total energy of −18.3 kJ mol⁻¹ (Fig. 4 ▸ a). The energy framework diagrams for lapachol acetate (Fig. 4 ▸ b) show that electrostatic forces act to keep pairs of inversion-related chains of mol­ecules joined while dispersion forces act in three dimensions to build the crystal structure. The total energy diagram shows a high resemblance to the dispersion framework, showing that these forces are the most important in the crystal. The inter­action energies for selected mol­ecular pairs in the first coordination sphere around the asymmetric unit are summarized in Table S1 and Fig. S6 of the supporting information.

Figure 4.

(a) Mol­ecular close contacts and (b) energy-framework diagrams for electrostatic (red) and dispersion (green) contributions to the total inter­action energy (blue) in lapachol acetate crystals.

Database survey  

Lapachol and its derivatives are rather scarce in the Cambridge Crystal Structure Database (Version 5.40, update 2 of May 2019; Groom et al., 2016 ▸) with only 31 entries matching the basic C—O framework of lapachol. Two lapachol polymorphs LAPA I and LAPA II (Larsen et al., 1992 ▸) have been reported at 105 K, as mentioned above. Two additional lapachol derivatives obtained by replacing one H atom have been reported during the current decade: 4-(3-hy­droxy-1,4-dioxo-1,4-di­hydro­naphthalen-2-yl)-2-methyl­but-2-enal (Eyong et al., 2015 ▸) is an aldehyde of lapachol at C15 and 3-(3-methyl­but-2-en-1-yl)-1,4-dioxo-1,4-di­hydro­naphthalen-2-yl 4-methyl­benzene­sulfonate (Silva et al., 2012 ▸) is a sulfonate at O2. Lapachol acetate is the third derivative of this kind reported. Some lapachol derivatives where cyclization of the 3-methy-2-butenyl moiety or coordination with metals (as lapacholate) have additionally been reported, but are not related to lapachol acetate.

Synthesis and crystallization  

Lapachol was obtained from an extract of Handroanthus Heptaphyllus (Vell.) Mattos, the pink trumpet tree (or lapacho negro) as described in the supporting information. 201 mg (0.823 mmol) of lapachol were dissolved in 5 ml of dry acetic anhydride and a catalytic amount of dry zinc chloride (ZnCl₂) was added. The suspension was refluxed for 30 min under an inert atmosphere (N₂). The solution was allowed to cool and 5 ml of glacial acetic acid and later 50 ml of distilled water were added. The final mixture was refluxed for 10 min and allowed to precipitate overnight. The crude solid was filtered, dried and purified by column chromatography (hexa­ne: AcOEt, 9: 1 v/v) to obtain pure lapachol acetate as yellow crystals (see the detailed description of the obtention of lapachol and the synthesis of lapachol acetate in the supporting information and the detailed spectroscopic study in Figs. S1–S3). Adequate crystals for diffraction were obtained by dissolving a few mg of the solid in a minimum amount of AcOEt in a rubber-stop vial with a syringe needle through the center to promote slow evaporation of the solvent at room temperature.

Refinement  

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. H atoms were placed in calculated positions (C—H = 0.93–0.97 Å) and included as riding contributions, with isotropic displacement parameters set at 1.2–1.5 times the U _eq value of the parent atom. The C17 methyl group shows rotational disorder that was modelled with two positions that were refined with a fixed C—H bond distance but with rotational freedom (AFIX 147) converging at occupancies of 0.79 (3) and 0.21 (3).

Table 2. Experimental details.

Crystal data
Chemical formula	C17H16O4
M r	284.30
Crystal system, space group	Monoclinic, P21/n
Temperature (K)	296
a, b, c (Å)	12.0914 (8), 9.4741 (6), 12.7761 (9)
β (°)	92.943 (4)
V (Å3)	1461.64 (17)
Z	4
Radiation type	Cu Kα
μ (mm−1)	0.75
Crystal size (mm)	0.26 × 0.22 × 0.18
Data collection
Diffractometer	Bruker D8 Venture/Photon 100 CMOS
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 ▸)
T min, T max	0.654, 0.754
No. of measured, independent and observed [I > 2σ(I)] reflections	7496, 2996, 1972
R int	0.038
(sin θ/λ)max (Å−1)	0.637
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.048, 0.136, 1.03
No. of reflections	2996
No. of parameters	193
H-atom treatment	H-atom parameters constrained
Δρmax, Δρmin (e Å−3)	0.17, −0.16

Computer programs: APEX2 and SAINT (Bruker, 2014 ▸), SHELXT (Sheldrick, 2015a ▸), SHELXL2018 (Sheldrick, 2015b ▸), Mercury (Macrae et al., 2008 ▸) and publCIF (Westrip, 2010 ▸).

Supplementary Material

CCDC reference: 1947085

Additional supporting information: crystallographic information; 3D view; checkCIF report

supplementary crystallographic information

Crystal data

C17H16O4	Dx = 1.292 Mg m−3
Mr = 284.30	Melting point: 352(1) K
Monoclinic, P21/n	Cu Kα radiation, λ = 1.54178 Å
a = 12.0914 (8) Å	Cell parameters from 7958 reflections
b = 9.4741 (6) Å	θ = 4.9–75.7°
c = 12.7761 (9) Å	µ = 0.75 mm−1
β = 92.943 (4)°	T = 296 K
V = 1461.64 (17) Å3	Block, yellow
Z = 4	0.26 × 0.22 × 0.18 mm
F(000) = 600

Data collection

Bruker D8 Venture/Photon 100 CMOS diffractometer	2996 independent reflections
Radiation source: Cu Incoatec microsource	1972 reflections with I > 2σ(I)
Detector resolution: 10.4167 pixels mm-1	Rint = 0.038
\j and ω scans	θmax = 79.2°, θmin = 4.9°
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	h = −13→15
Tmin = 0.654, Tmax = 0.754	k = −11→9
7496 measured reflections	l = −16→15

Refinement

Refinement on F2	Primary atom site location: dual
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.048	Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.136	H-atom parameters constrained
S = 1.03	w = 1/[σ2(Fo2) + (0.053P)2 + 0.3463P] where P = (Fo2 + 2Fc2)/3
2996 reflections	(Δ/σ)max < 0.001
193 parameters	Δρmax = 0.17 e Å−3
0 restraints	Δρmin = −0.16 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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
O1	0.22182 (14)	0.34297 (18)	0.34233 (12)	0.0686 (5)
C1	0.25877 (15)	0.3726 (2)	0.42998 (15)	0.0468 (5)
O2	0.17186 (11)	0.16221 (16)	0.49500 (11)	0.0540 (4)
C2	0.24117 (15)	0.2761 (2)	0.51890 (15)	0.0441 (5)
O3	0.30987 (14)	0.05735 (18)	0.41410 (15)	0.0756 (5)
C3	0.28099 (15)	0.2973 (2)	0.61720 (15)	0.0443 (5)
O4	0.39859 (12)	0.43627 (17)	0.72673 (11)	0.0586 (4)
C4	0.35332 (15)	0.4218 (2)	0.64003 (14)	0.0440 (5)
C5	0.42753 (17)	0.6488 (2)	0.57604 (17)	0.0529 (5)
H5	0.460252	0.663841	0.642578	0.063*
C6	0.43917 (18)	0.7485 (3)	0.49821 (19)	0.0615 (6)
H6	0.479948	0.830043	0.512619	0.074*
C7	0.39054 (19)	0.7275 (3)	0.39920 (19)	0.0612 (6)
H7	0.397581	0.795506	0.347504	0.073*
C8	0.33163 (17)	0.6057 (3)	0.37709 (17)	0.0547 (5)
H8	0.299507	0.591249	0.310242	0.066*
C9	0.32006 (15)	0.5041 (2)	0.45465 (15)	0.0444 (5)
C10	0.36737 (15)	0.5268 (2)	0.55524 (15)	0.0426 (4)
C11	0.26046 (18)	0.1969 (2)	0.70541 (16)	0.0533 (5)
H11A	0.260239	0.249275	0.770631	0.064*
H11B	0.188017	0.154157	0.693426	0.064*
C12	0.34630 (17)	0.0828 (2)	0.71541 (16)	0.0505 (5)
H12	0.350981	0.023269	0.657923	0.061*
C13	0.41622 (17)	0.0566 (2)	0.79619 (16)	0.0510 (5)
C14	0.4219 (2)	0.1431 (3)	0.89505 (18)	0.0719 (7)
H14A	0.412225	0.082669	0.954178	0.108*
H14B	0.364369	0.213071	0.891358	0.108*
H14C	0.492685	0.188880	0.902682	0.108*
C15	0.4952 (2)	−0.0652 (3)	0.7946 (2)	0.0684 (7)
H15A	0.569682	−0.031304	0.805937	0.103*
H15B	0.487694	−0.111606	0.727755	0.103*
H15C	0.478890	−0.130827	0.848916	0.103*
C16	0.2148 (2)	0.0591 (2)	0.43364 (17)	0.0557 (5)
C17	0.1276 (2)	−0.0443 (3)	0.3994 (2)	0.0785 (8)	0.79 (3)
H17A	0.072901	0.001798	0.354279	0.118*	0.79 (3)
H17B	0.093164	−0.081079	0.459726	0.118*	0.79 (3)
H17C	0.160520	−0.120203	0.362194	0.118*	0.79 (3)
C17'	0.1276 (2)	−0.0443 (3)	0.3994 (2)	0.0785 (8)	0.21 (3)
H17D	0.058095	−0.016088	0.425921	0.118*	0.21 (3)
H17E	0.147328	−0.136138	0.426025	0.118*	0.21 (3)
H17F	0.121161	−0.047259	0.324252	0.118*	0.21 (3)

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
O1	0.0903 (12)	0.0652 (12)	0.0484 (8)	−0.0047 (9)	−0.0162 (8)	0.0054 (8)
C1	0.0471 (10)	0.0480 (12)	0.0449 (11)	0.0085 (9)	−0.0009 (8)	0.0029 (9)
O2	0.0536 (8)	0.0488 (9)	0.0596 (8)	−0.0054 (7)	0.0025 (7)	−0.0014 (7)
C2	0.0430 (9)	0.0407 (11)	0.0486 (10)	0.0036 (9)	0.0025 (8)	0.0002 (9)
O3	0.0664 (10)	0.0607 (12)	0.1004 (13)	0.0026 (9)	0.0100 (9)	−0.0191 (10)
C3	0.0449 (10)	0.0430 (12)	0.0456 (10)	0.0058 (9)	0.0060 (8)	0.0037 (9)
O4	0.0653 (9)	0.0646 (11)	0.0452 (8)	0.0030 (8)	−0.0055 (7)	−0.0027 (7)
C4	0.0431 (10)	0.0448 (12)	0.0443 (10)	0.0105 (9)	0.0051 (8)	−0.0028 (9)
C5	0.0557 (12)	0.0456 (13)	0.0581 (12)	0.0034 (10)	0.0095 (10)	−0.0063 (11)
C6	0.0621 (13)	0.0424 (14)	0.0813 (16)	−0.0016 (11)	0.0171 (12)	−0.0029 (12)
C7	0.0673 (14)	0.0464 (14)	0.0715 (15)	0.0066 (11)	0.0198 (12)	0.0138 (12)
C8	0.0571 (12)	0.0534 (14)	0.0539 (12)	0.0109 (11)	0.0061 (9)	0.0098 (11)
C9	0.0457 (10)	0.0428 (12)	0.0452 (10)	0.0088 (9)	0.0065 (8)	0.0049 (9)
C10	0.0431 (9)	0.0373 (11)	0.0479 (10)	0.0086 (8)	0.0078 (8)	−0.0009 (9)
C11	0.0566 (12)	0.0559 (14)	0.0479 (11)	−0.0022 (10)	0.0067 (9)	0.0092 (10)
C12	0.0625 (12)	0.0431 (13)	0.0458 (10)	−0.0042 (10)	0.0010 (9)	0.0028 (9)
C13	0.0543 (11)	0.0490 (13)	0.0494 (11)	−0.0102 (10)	−0.0005 (9)	0.0040 (10)
C14	0.0739 (15)	0.086 (2)	0.0545 (13)	−0.0051 (14)	−0.0078 (11)	−0.0076 (13)
C15	0.0697 (14)	0.0583 (16)	0.0756 (15)	0.0019 (13)	−0.0109 (12)	0.0043 (13)
C16	0.0658 (13)	0.0453 (13)	0.0556 (12)	−0.0005 (11)	−0.0019 (10)	0.0025 (10)
C17	0.0874 (18)	0.0623 (18)	0.0851 (18)	−0.0195 (14)	−0.0028 (14)	−0.0071 (15)
C17'	0.0874 (18)	0.0623 (18)	0.0851 (18)	−0.0195 (14)	−0.0028 (14)	−0.0071 (15)

Geometric parameters (Å, º)

O1—C1	1.217 (2)	C11—C12	1.500 (3)
C1—C9	1.476 (3)	C11—H11A	0.9700
C1—C2	1.482 (3)	C11—H11B	0.9700
O2—C16	1.371 (3)	C12—C13	1.324 (3)
O2—C2	1.391 (2)	C12—H12	0.9300
C2—C3	1.337 (3)	C13—C15	1.499 (3)
O3—C16	1.189 (3)	C13—C14	1.504 (3)
C3—C4	1.489 (3)	C14—H14A	0.9600
C3—C11	1.505 (3)	C14—H14B	0.9600
O4—C4	1.218 (2)	C14—H14C	0.9600
C4—C10	1.487 (3)	C15—H15A	0.9600
C5—C6	1.384 (3)	C15—H15B	0.9600
C5—C10	1.384 (3)	C15—H15C	0.9600
C5—H5	0.9300	C16—C17'	1.488 (3)
C6—C7	1.382 (3)	C16—C17	1.488 (3)
C6—H6	0.9300	C17—H17A	0.9600
C7—C8	1.377 (3)	C17—H17B	0.9600
C7—H7	0.9300	C17—H17C	0.9600
C8—C9	1.394 (3)	C17'—H17D	0.9600
C8—H8	0.9300	C17'—H17E	0.9600
C9—C10	1.396 (3)	C17'—H17F	0.9600
O1—C1—C9	123.21 (19)	H11A—C11—H11B	107.9
O1—C1—C2	120.2 (2)	C13—C12—C11	127.8 (2)
C9—C1—C2	116.57 (16)	C13—C12—H12	116.1
C16—O2—C2	115.91 (16)	C11—C12—H12	116.1
C3—C2—O2	120.42 (18)	C12—C13—C15	121.0 (2)
C3—C2—C1	124.68 (19)	C12—C13—C14	123.5 (2)
O2—C2—C1	114.76 (16)	C15—C13—C14	115.45 (19)
C2—C3—C4	118.84 (18)	C13—C14—H14A	109.5
C2—C3—C11	122.93 (19)	C13—C14—H14B	109.5
C4—C3—C11	118.16 (17)	H14A—C14—H14B	109.5
O4—C4—C10	121.63 (19)	C13—C14—H14C	109.5
O4—C4—C3	119.97 (19)	H14A—C14—H14C	109.5
C10—C4—C3	118.40 (16)	H14B—C14—H14C	109.5
C6—C5—C10	120.2 (2)	C13—C15—H15A	109.5
C6—C5—H5	119.9	C13—C15—H15B	109.5
C10—C5—H5	119.9	H15A—C15—H15B	109.5
C7—C6—C5	120.4 (2)	C13—C15—H15C	109.5
C7—C6—H6	119.8	H15A—C15—H15C	109.5
C5—C6—H6	119.8	H15B—C15—H15C	109.5
C8—C7—C6	120.0 (2)	O3—C16—O2	121.9 (2)
C8—C7—H7	120.0	O3—C16—C17'	127.4 (2)
C6—C7—H7	120.0	O2—C16—C17'	110.7 (2)
C7—C8—C9	120.2 (2)	O3—C16—C17	127.4 (2)
C7—C8—H8	119.9	O2—C16—C17	110.7 (2)
C9—C8—H8	119.9	C16—C17—H17A	109.5
C8—C9—C10	119.8 (2)	C16—C17—H17B	109.5
C8—C9—C1	119.93 (18)	H17A—C17—H17B	109.5
C10—C9—C1	120.30 (18)	C16—C17—H17C	109.5
C5—C10—C9	119.48 (19)	H17A—C17—H17C	109.5
C5—C10—C4	119.83 (18)	H17B—C17—H17C	109.5
C9—C10—C4	120.69 (19)	C16—C17'—H17D	109.5
C12—C11—C3	112.29 (17)	C16—C17'—H17E	109.5
C12—C11—H11A	109.1	H17D—C17'—H17E	109.5
C3—C11—H11A	109.1	C16—C17'—H17F	109.5
C12—C11—H11B	109.1	H17D—C17'—H17F	109.5
C3—C11—H11B	109.1	H17E—C17'—H17F	109.5
C16—O2—C2—C3	−112.3 (2)	O1—C1—C9—C10	−175.23 (19)
C16—O2—C2—C1	71.8 (2)	C2—C1—C9—C10	6.1 (3)
O1—C1—C2—C3	178.0 (2)	C6—C5—C10—C9	1.0 (3)
C9—C1—C2—C3	−3.2 (3)	C6—C5—C10—C4	−178.70 (18)
O1—C1—C2—O2	−6.2 (3)	C8—C9—C10—C5	−1.5 (3)
C9—C1—C2—O2	172.54 (16)	C1—C9—C10—C5	177.96 (17)
O2—C2—C3—C4	−178.93 (16)	C8—C9—C10—C4	178.22 (17)
C1—C2—C3—C4	−3.4 (3)	C1—C9—C10—C4	−2.3 (3)
O2—C2—C3—C11	4.0 (3)	O4—C4—C10—C5	−4.1 (3)
C1—C2—C3—C11	179.59 (18)	C3—C4—C10—C5	175.37 (17)
C2—C3—C4—O4	−173.37 (18)	O4—C4—C10—C9	176.20 (18)
C11—C3—C4—O4	3.8 (3)	C3—C4—C10—C9	−4.4 (3)
C2—C3—C4—C10	7.2 (3)	C2—C3—C11—C12	88.5 (2)
C11—C3—C4—C10	−175.65 (17)	C4—C3—C11—C12	−88.5 (2)
C10—C5—C6—C7	0.3 (3)	C3—C11—C12—C13	118.3 (2)
C5—C6—C7—C8	−1.1 (3)	C11—C12—C13—C15	178.2 (2)
C6—C7—C8—C9	0.6 (3)	C11—C12—C13—C14	−1.0 (4)
C7—C8—C9—C10	0.7 (3)	C2—O2—C16—O3	9.9 (3)
C7—C8—C9—C1	−178.78 (19)	C2—O2—C16—C17'	−170.81 (18)
O1—C1—C9—C8	4.2 (3)	C2—O2—C16—C17	−170.81 (18)
C2—C1—C9—C8	−174.46 (17)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C11—H11B···O4i	0.97	2.55	3.274 (3)	131
C15—H15A···O1ii	0.96	2.59	3.485 (3)	156

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