Fenofibric acid

Unlike the related fenofibrate molecule [Henry, Zhang, Gao & Bruckner (2003). Acta Cryst. E59, o699-o700], fenofibric acid {systematic name: 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid}, C₁₇H₁₅ClO₄, contains a carboxylic acid moiety instead of an ester moiety. This polar moiety plays an important role in the formation of a rare acid-to-ketone hydrogen-bond-type packing interaction. The lack of an isopropyl group in fenofibric acid aligns the carboxyl group on the same side as the ketone carbonyl group; this conformation may play an important role in discrimination between the acid and the fenofibrate mol­ecule in molecular recognition.

S1. Comment

Fibrates, such as bezafibrate, clofibric acid and fenofibrate, which are ligands for the nuclear receptor peroxisome proliferator-activated receptor α (PPARα),?? are used as therapeutic agents in the treatment of hyperlipidemia, heart disease and diabetic complications (Throp, 1962; Miller & Spence, 1998; Forcheron et al., 2002). Fenofibrate (TRICOR) is a lipid-regulating agent available as tablets for oral administration (Adkins & Faulds, 1997; Guay 1999; Keating & Ormrod, 2002). Fenofibrate treatment also reduces the angiographic progression of coronary-artery disease in type 2 diabetes (Taniguchi et al., 2001). Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to its active metabolite, fenofibric acid, (I). Unchanged fenofibrate has been reported to be undetectable in plasma samples following an oral dose (Streel et al., 2000). The mechanism of action of fenofibrate and its metabolites is not fully understood. Fenofibric acid is also an activator of PPARα, which ultimately results in the reduction of triglycerides, total cholesterol and low-density lipoprotein cholesterol (LDL-C), as well as an increase in high-density lipoprotein cholesterol (HDL-C) (Adkins & Faulds, 1997; Guay 1999; Keating & Ormrod, 2002). Our lead optimization effort indicates that fenofibric acid may have improved potency over bezafibrate. Since fenofibric acid is not commercially available, we have prepared it in our laboratory by alkaline hydrolysis following modified conditions for biochemical studies. In this article, we describe the synthesis, crystallization and structural characterization of fenofibric acid. This is the first crystal structure report of fenofibric acid.

A projection view of fenofibric acid is presented in Fig. 1. The C—O bond distances in the carboxyl group indicate that the carboxyl moiety is in the acid form [C15—O3 = 1.2014 (19) Å, C15—O4 = 1.3248 (19) Å] rather than the carboxylate form. This observation is further confirmed by the location and refinement of the acidic H atom. The molecules form strong hydrogen bonded dimers due to the presence of the carboxylic –OH group [H4···O1A = 1.72 (3) Å and O4—H4—O1A = 170 (3)°; symmetry code: −x, −y, 1 − z]. The two molecules in the dimer (Fig. 2) are related by an inversion center. The dimer is formed by the hydrogen bonding between the carbonyl O atom of the ketone moiety in one fenofibric acid molecule and the carboxylic acid –OH group of the second molecule rather than by the more usual hydrogen-bonding interaction between two carboxylic acid groups. The crystal packing viewed down the a axis shows that the dimers form layers that stack in the b direction and form a zigzag pattern in the bc plane (Fig. 3). By contrast, fenofibrate, which is the isopropyl ester of the fenofibric acid, does not have the hydroxy H atom required for the formation of the hydrogen-bonding interaction and so packs in a completely different way (Henry et al., 2003).

Fenofibric acid uses a rare hydrogen-bonding pattern to form intermolecular dimers, rather than the acid-to-acid hydrogen-bonding dimerization that is most common in carboxylic acids. Keto-carboxylic acid type compounds such as fenofibric acid contain only one acidic donor H atom and two possible acceptors, namely the O atoms in the ketone carbonyl and carboxyl moieties of an organic acid. Studies have established that ketone-carboxylic acids result in five hydrogen-bonding modes or patterns (Newman et al., 2002), viz. acid-to-acid dimer (Barcon et al., 2002), acid-to-ketone catemer (Barcon et al., 2002), intramolecular or internal (Coté et al., 1996), acid-to-acid catemer (Lalancette et al., 1996), and acid-to-ketone dimer (Newman et al., 2002). Analysis of the structural entries in the Cambridge Structural Database (CSD; Allen, 2002) reveals that acid-to-acid dimerization and acid-to-ketone catemer hydrogen-bonding patterns are most common (Leiserowitz 1976; Lalancette et al., 1998), while intramolecular, acid-to-acid catemer and acid-to-ketone dimer hydrogen-bonding patterns are rare (Coté et al., 1996). We have identified six compounds in the CSD that form acid-to-ketone hydrogen-bonding patterns out of 92 compounds in the literature. They are BOZTUF (Peeters et al., 1983), FAZGAO (Nuhrich et al., 1986), JIKDEM (Abell et al., 1991), TEVGIK (Kosela et al., 1995), EFANEE (Newman et al., 2002) and MOZZOQ (Armstrong et al., 2002). Thus fenofibric acid is the seventh compound to join a very small number of examples in the CSD that form acid-to-ketone hydrogen-bonding dimers.

The intramolecular hydrogen-bonding pattern involving a carbonyl O atom and a carboxyl –OH group has been found in only a few organic acids. Formation of the intramolecular hydrogen-bonding pattern requires mostly a seven-membered hydrogen-bonded ring arrangement (Griffe et al., 1972; Sheldrick & Trowitzsch, 1983; Halfpenny, 1990; Abell et al., 1990). The distances between carbonyl atom O1 and the carboxyl O atoms are more than 6.8 Å in fenofibric acid. This distance is too long to allow the formation of intramolecular hydrogen-bonding interactions and may explain why fenofibric acid does not form an intramolecular hydrogen-bonding interaction.

Alignment of the sp² ketone moiety (the C4/C7/O1/C8 plane) of fenofibric acid and the corresponding plane in the fenofibrate molecule reveals that the carboxyl moiety is positioned almost on the same side as the carbonyl group of the ketone in fenofibric acid (Fig. 4). This configuration may facilitate the formation of intermolecular C—O···H—O hydrogen bonding over the carboxyl –OH dimer. However the carboxyl moiety of the fenofibrate molecule is located away from the carbonyl group of the ketone, at the back of the molecule. This configuration may be due to steric effects and packing interactions, which are caused by the presence of the isopropyl group. This phenomenon may play a significant role in distinguishing fenofibric acid as an activator of PPARα over fenofibrate. In general, if polar groups such as the carbonyl and carboxyl groups in fenofibrate and fenofibric acid are involved in the formation of specific interactions with their target molecules, the orientation of these moieties will alter the binding affinities. Alternatively, these polar groups? may change the binding orientation with a given target molecule.

S2. Experimental

Fenofibric acid was prepared by alkaline hydrolysis of fenofibrate under mild conditions, according to the procedures described below. Fenofibrate (300 mg) was suspended in methanol (10 ml), and 2 N NaOH solution (1 ml) was added to the reaction mixture. Stirring was continued for several hours at room temperature. Thin layer chromatography (TLC) was used to monitor the progress of the reaction. The reaction mixture contained approximately 10% hydrolyzed material and 90% starting material as the intact ester form. The hydrolysis did not proceed further, even after 15–16 h of stirring, and a major amount of starting material was recovered after work-up. In a second experiment, fenofibrate (300 mg) was suspended in methanol (10 ml), 2 N NaOH (2.5 ml) was added, and the resulting suspension was stirred at 343 K for 4 h. The reaction mixture turned to a clear solution during this period (quantitative conversion as per TLC). The solvent was removed under reduced pressure and water (5 ml) was added to the residue. This solution was acidified to an approximate pH of 2 by adding 2 N hydrochloric acid. At a pH of ca 2, a thick precipitate formed. The precipitate was extracted in ethyl acetate (25 ml) and the organic layer was washed three times with brine, dried over sodium sulfate and concentrated to a solid residue. The residue was crystallized from ethyl acetate/hexane to obtain fenofibric acid as a white powder (>97% pure, high-pressure liquid chromatography) in excellent yield (>85%). To obtain single crystals, of fenofibric acid (5.0 mg) was dissolved in high-purity absolute ethanol (225 ml) and heated at 313 K in a water bath. To this solution was added deionized water (25 ml) and the tube was shaken under vortex for 2 min. The clear solution was allowed to cool slowly at room temperature and left overnight. After several hours, colorless plate-like crystals started to form in the tube, and these were preserved by sealing the tube and stored for structural characterization and future studies.

S3. Refinement

All H atoms were located from difference Fourier maps and were refined freely using isotropic thermal parameters [O—H = 0.91 (3) Å and C—H = 0.936 (18)–0.986 (14) Å].

Computing details

Data collection: SMART (Bruker, 2003); cell refinement: SMART; data reduction: SAINT (Bruker, 2003); program(s) used to solve structure: SHELXTL (Sheldrick, 2003); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Figures

	Fig. 1. The crystal structure of (I). Non-H atoms are shown with 50% probability displacement ellipsoids.
	Fig. 2. A dimer of fenofibric acid, showing the rare acid-to-ketone hydrogen-bonding pattern. The symmetry operator (-x, −y, 1 − z) was used to generate atoms labeled with the suffix A.
	Fig. 3. A packing diagram of fenofibric acid, in the orthorhombic space group Pbca, as viewed along the a axis.
	Fig. 4. A view down the C4/C7/O1/C8 plane along the C=O double-bond direction of the ketone moiety. Fenofibric acid and fenofibrate are superimposed with black and grey, respectively. Fenofibric acid atom labels O1, O3 and O4 are shown, whereas the corresponding carboxyl atoms of fenofibrate are denoted O.

2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid

Crystal data

C17H15ClO4	Dx = 1.389 Mg m^−3 Dm = no Mg m^−3 Dm measured by not measured
Mr = 318.74	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, Pbca	Cell parameters from 8481 reflections
a = 18.2168 (4) Å	θ = 2.2–28.3°
b = 7.5623 (2) Å	µ = 0.27 mm^−1
c = 22.1355 (5) Å	T = 160 K
V = 3049.41 (13) Å^3	Plate, colorless
Z = 8	0.47 × 0.43 × 0.14 mm
F(000) = 1328

Data collection

Bruker SMART CCD area-detector diffractometer	3497 independent reflections
Radiation source: normal-focus sealed tube	3081 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.036
ϕ and ω scans	θmax = 27.5°, θmin = 1.8°
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	h = −23→23
Tmin = 0.885, Tmax = 0.964	k = −9→9
47753 measured reflections	l = −28→28

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.042	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.099	All H-atom parameters refined
S = 1.11	w = 1/[σ^2(Fo^2) + (0.0404P)^2 + 1.7773P] where P = (Fo^2 + 2Fc^2)/3
3497 reflections	(Δ/σ)max < 0.001
259 parameters	Δρmax = 0.32 e Å^−3
6 restraints	Δρmin = −0.29 e Å^−3

Special details

Experimental. IR data of the fenofibric acid confirms the absence of the peak around 2900 cm⁻¹ due to the absence of methyl group which is present in the starting material, fenofibrate. Furthermore the peak due to the carbonyl group of the ester in the fenofibrate is shifted in the fenofibric acid indicating the cleavage of the ester to the acid.

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'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 > σ(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.

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

	x	y	z	Uiso*/Ueq
Cl1	0.19052 (3)	1.21263 (6)	0.31797 (2)	0.03663 (13)
O1	0.01318 (6)	0.45447 (15)	0.36502 (5)	0.0290 (3)
O2	0.18624 (5)	0.14587 (14)	0.59212 (5)	0.0236 (2)
O3	0.11915 (6)	−0.17371 (15)	0.56968 (5)	0.0302 (3)
O4	0.05568 (8)	−0.15560 (18)	0.65596 (6)	0.0405 (3)
C1	0.15096 (8)	1.0130 (2)	0.34020 (7)	0.0241 (3)
C2	0.14883 (8)	0.9737 (2)	0.40125 (7)	0.0229 (3)
C3	0.12180 (8)	0.8102 (2)	0.41936 (7)	0.0224 (3)
C4	0.09578 (8)	0.68971 (19)	0.37661 (7)	0.0209 (3)
C5	0.09564 (8)	0.7364 (2)	0.31550 (7)	0.0235 (3)
C6	0.12409 (9)	0.8975 (2)	0.29689 (7)	0.0262 (3)
C7	0.06434 (8)	0.5159 (2)	0.39505 (7)	0.0218 (3)
C8	0.09430 (8)	0.42252 (19)	0.44834 (7)	0.0213 (3)
C9	0.16816 (8)	0.4401 (2)	0.46517 (7)	0.0232 (3)
C10	0.19631 (8)	0.3454 (2)	0.51327 (7)	0.0233 (3)
C11	0.15098 (8)	0.23342 (19)	0.54643 (7)	0.0208 (3)
C12	0.07687 (8)	0.2146 (2)	0.53051 (7)	0.0224 (3)
C13	0.04962 (8)	0.3076 (2)	0.48140 (7)	0.0216 (3)
C14	0.14741 (8)	0.06026 (19)	0.64084 (6)	0.0210 (3)
C15	0.10591 (8)	−0.1016 (2)	0.61680 (7)	0.0229 (3)
C16	0.20949 (9)	−0.0108 (2)	0.68054 (7)	0.0264 (3)
C17	0.09945 (9)	0.1909 (2)	0.67502 (8)	0.0274 (3)
H2	0.1645 (10)	1.056 (2)	0.4300 (8)	0.023 (4)*
H3	0.1196 (9)	0.781 (2)	0.4607 (8)	0.021 (4)*
H4	0.0334 (15)	−0.258 (4)	0.6444 (12)	0.066 (8)*
H5	0.0774 (10)	0.654 (2)	0.2868 (8)	0.025 (4)*
H6	0.1245 (10)	0.931 (2)	0.2553 (9)	0.030 (5)*
H9	0.1984 (10)	0.515 (2)	0.4425 (8)	0.022 (4)*
H10	0.2467 (10)	0.355 (2)	0.5254 (7)	0.023 (4)*
H12	0.0451 (10)	0.136 (2)	0.5523 (8)	0.027 (4)*
H13	−0.0011 (10)	0.293 (2)	0.4699 (8)	0.025 (4)*
H16A	0.2397 (10)	0.088 (2)	0.6953 (8)	0.037 (5)*
H16B	0.1895 (10)	−0.080 (2)	0.7146 (7)	0.031 (5)*
H16C	0.2408 (9)	−0.089 (2)	0.6562 (7)	0.028 (5)*
H17A	0.0578 (10)	0.235 (3)	0.6510 (9)	0.045 (6)*
H17B	0.1297 (11)	0.291 (2)	0.6870 (9)	0.046 (6)*
H17C	0.0799 (11)	0.134 (3)	0.7114 (8)	0.041 (5)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0466 (3)	0.0294 (2)	0.0339 (2)	−0.01281 (18)	0.00476 (18)	0.00496 (17)
O1	0.0273 (6)	0.0291 (6)	0.0307 (6)	−0.0067 (5)	−0.0081 (5)	0.0044 (5)
O2	0.0173 (5)	0.0278 (5)	0.0257 (5)	−0.0010 (4)	−0.0023 (4)	0.0073 (4)
O3	0.0310 (6)	0.0315 (6)	0.0280 (6)	−0.0036 (5)	−0.0002 (5)	−0.0064 (5)
O4	0.0468 (8)	0.0416 (7)	0.0332 (7)	−0.0240 (6)	0.0110 (6)	−0.0067 (6)
C1	0.0217 (7)	0.0218 (7)	0.0290 (8)	−0.0006 (6)	0.0039 (6)	0.0032 (6)
C2	0.0210 (7)	0.0233 (7)	0.0246 (7)	0.0002 (6)	−0.0007 (6)	−0.0029 (6)
C3	0.0219 (7)	0.0259 (7)	0.0195 (7)	0.0011 (6)	0.0005 (6)	0.0017 (6)
C4	0.0175 (7)	0.0227 (7)	0.0223 (7)	0.0005 (5)	0.0007 (5)	0.0018 (6)
C5	0.0229 (7)	0.0255 (7)	0.0220 (7)	−0.0012 (6)	−0.0013 (6)	−0.0013 (6)
C6	0.0280 (8)	0.0302 (8)	0.0203 (7)	0.0000 (6)	0.0014 (6)	0.0036 (6)
C7	0.0197 (7)	0.0227 (7)	0.0229 (7)	0.0006 (6)	0.0014 (5)	−0.0005 (6)
C8	0.0207 (7)	0.0207 (7)	0.0224 (7)	0.0011 (6)	−0.0001 (5)	0.0001 (6)
C9	0.0194 (7)	0.0237 (7)	0.0264 (7)	−0.0029 (6)	0.0018 (6)	0.0033 (6)
C10	0.0171 (7)	0.0255 (7)	0.0274 (8)	−0.0018 (6)	−0.0014 (6)	0.0006 (6)
C11	0.0201 (7)	0.0214 (7)	0.0210 (7)	0.0016 (6)	−0.0012 (5)	0.0005 (6)
C12	0.0186 (7)	0.0241 (7)	0.0243 (7)	−0.0027 (6)	0.0013 (6)	0.0028 (6)
C13	0.0169 (7)	0.0229 (7)	0.0249 (7)	−0.0006 (5)	−0.0002 (6)	−0.0004 (6)
C14	0.0204 (7)	0.0229 (7)	0.0198 (7)	−0.0019 (6)	−0.0011 (5)	0.0022 (6)
C15	0.0221 (7)	0.0239 (7)	0.0226 (7)	−0.0016 (6)	−0.0036 (6)	0.0022 (6)
C16	0.0250 (8)	0.0279 (8)	0.0263 (8)	0.0009 (6)	−0.0046 (6)	0.0026 (7)
C17	0.0271 (8)	0.0274 (8)	0.0278 (8)	0.0020 (7)	−0.0010 (6)	−0.0024 (6)

Geometric parameters (Å, º)

Cl1—C1	1.7439 (15)	C8—C13	1.398 (2)
O1—C7	1.2353 (18)	C8—C9	1.402 (2)
O2—C11	1.3689 (17)	C9—C10	1.382 (2)
O2—C14	1.4430 (17)	C9—H9	0.936 (18)
O3—C15	1.2014 (19)	C10—C11	1.392 (2)
O4—C15	1.3248 (19)	C10—H10	0.960 (19)
O4—H4	0.91 (3)	C11—C12	1.403 (2)
C1—C2	1.384 (2)	C12—C13	1.387 (2)
C1—C6	1.386 (2)	C12—H12	0.961 (19)
C2—C3	1.390 (2)	C13—H13	0.964 (19)
C2—H2	0.936 (18)	C14—C17	1.520 (2)
C3—C4	1.396 (2)	C14—C16	1.530 (2)
C3—H3	0.942 (18)	C14—C15	1.534 (2)
C4—C5	1.398 (2)	C16—H16A	0.984 (15)
C4—C7	1.491 (2)	C16—H16B	0.986 (14)
C5—C6	1.387 (2)	C16—H16C	0.981 (14)
C5—H5	0.947 (18)	C17—H17A	0.984 (15)
C6—H6	0.955 (19)	C17—H17B	0.975 (16)
C7—C8	1.479 (2)	C17—H17C	0.980 (15)
C11—O2—C14	122.62 (11)	C11—C10—H10	117.7 (10)
C15—O4—H4	112.7 (16)	O2—C11—C10	113.92 (13)
C2—C1—C6	122.02 (14)	O2—C11—C12	126.03 (13)
C2—C1—Cl1	118.22 (12)	C10—C11—C12	120.02 (14)
C6—C1—Cl1	119.75 (12)	C13—C12—C11	119.34 (14)
C1—C2—C3	118.84 (14)	C13—C12—H12	119.6 (11)
C1—C2—H2	120.9 (11)	C11—C12—H12	121.0 (11)
C3—C2—H2	120.3 (11)	C12—C13—C8	121.15 (14)
C2—C3—C4	120.34 (14)	C12—C13—H13	119.5 (11)
C2—C3—H3	120.4 (11)	C8—C13—H13	119.4 (11)
C4—C3—H3	119.3 (11)	O2—C14—C17	111.23 (12)
C3—C4—C5	119.44 (14)	O2—C14—C16	102.98 (11)
C3—C4—C7	121.34 (13)	C17—C14—C16	111.55 (13)
C5—C4—C7	119.13 (13)	O2—C14—C15	109.90 (12)
C6—C5—C4	120.58 (14)	C17—C14—C15	114.06 (12)
C6—C5—H5	120.5 (11)	C16—C14—C15	106.45 (12)
C4—C5—H5	118.9 (11)	O3—C15—O4	124.54 (15)
C1—C6—C5	118.69 (14)	O3—C15—C14	124.35 (14)
C1—C6—H6	119.7 (11)	O4—C15—C14	111.05 (13)
C5—C6—H6	121.6 (11)	C14—C16—H16A	109.8 (12)
O1—C7—C8	121.89 (14)	C14—C16—H16B	110.6 (11)
O1—C7—C4	118.28 (13)	H16A—C16—H16B	110.8 (16)
C8—C7—C4	119.82 (13)	C14—C16—H16C	108.9 (11)
C13—C8—C9	118.60 (14)	H16A—C16—H16C	108.2 (16)
C13—C8—C7	119.96 (13)	H16B—C16—H16C	108.5 (15)
C9—C8—C7	121.38 (13)	C14—C17—H17A	113.2 (13)
C10—C9—C8	120.77 (14)	C14—C17—H17B	108.5 (13)
C10—C9—H9	120.6 (11)	H17A—C17—H17B	108.6 (18)
C8—C9—H9	118.6 (11)	C14—C17—H17C	109.4 (12)
C9—C10—C11	120.09 (14)	H17A—C17—H17C	108.1 (17)
C9—C10—H10	122.2 (10)	H17B—C17—H17C	108.9 (18)
C6—C1—C2—C3	2.8 (2)	C8—C9—C10—C11	−1.2 (2)
Cl1—C1—C2—C3	−175.90 (11)	C14—O2—C11—C10	163.74 (13)
C1—C2—C3—C4	−1.4 (2)	C14—O2—C11—C12	−18.3 (2)
C2—C3—C4—C5	−1.4 (2)	C9—C10—C11—O2	179.01 (14)
C2—C3—C4—C7	−178.04 (13)	C9—C10—C11—C12	0.9 (2)
C3—C4—C5—C6	2.9 (2)	O2—C11—C12—C13	−177.47 (14)
C7—C4—C5—C6	179.65 (14)	C10—C11—C12—C13	0.4 (2)
C2—C1—C6—C5	−1.3 (2)	C11—C12—C13—C8	−1.4 (2)
Cl1—C1—C6—C5	177.38 (12)	C9—C8—C13—C12	1.1 (2)
C4—C5—C6—C1	−1.6 (2)	C7—C8—C13—C12	178.16 (14)
C3—C4—C7—O1	145.45 (15)	C11—O2—C14—C17	−58.39 (17)
C5—C4—C7—O1	−31.2 (2)	C11—O2—C14—C16	−177.99 (13)
C3—C4—C7—C8	−34.2 (2)	C11—O2—C14—C15	68.90 (17)
C5—C4—C7—C8	149.18 (14)	O2—C14—C15—O3	18.6 (2)
O1—C7—C8—C13	−27.0 (2)	C17—C14—C15—O3	144.29 (15)
C4—C7—C8—C13	152.55 (14)	C16—C14—C15—O3	−92.25 (17)
O1—C7—C8—C9	149.92 (15)	O2—C14—C15—O4	−163.98 (13)
C4—C7—C8—C9	−30.5 (2)	C17—C14—C15—O4	−38.29 (18)
C13—C8—C9—C10	0.2 (2)	C16—C14—C15—O4	85.17 (15)
C7—C8—C9—C10	−176.80 (14)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O4—H4···O1^i	0.91 (3)	1.72 (3)	2.6264 (17)	170 (3)

Symmetry code: (i) −x, −y, −z+1.