Structure of 7-hy­droxy-3-(2-meth­oxy­phen­yl)-2-tri­fluoro­meth­yl-4H-chromen-4-one

Low, J.N.; Gomes, L.R.; Gaspar, A.; Borges, F.

doi:10.1107/S2056989017009896

research communications

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ISSN: 2056-9890

Volume 73| Part 8| August 2017| Pages 1130-1134

https://doi.org/10.1107/S2056989017009896

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Structure of 7-hydroxy-3-(2-methoxyphenyl)-2-trifluoromethyl-4H-chromen-4-one

John Nicolson Low,^a ^* Ligia R. Gomes,^b,^c Alexandra Gaspar ^d and Fernanda Borges ^d

^aDepartment of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen, AB24 3UE, Scotland, ^bFP-ENAS-Faculdade de Ciências de Saúde, Escola Superior de Saúde da UFP, Universidade Fernando Pessoa, Rua Carlos da Maia, 296, P-4200-150 Porto, Portugal, ^cREQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre, 687, P-4169-007, Porto, Portugal, and ^dCIQ/Departamento de Quιmica e Bioquιmica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
^*Correspondence e-mail: jnlow111@gmail.com

Edited by W. T. A. Harrison, University of Aberdeen, Scotland (Received 23 June 2017; accepted 3 July 2017; online 7 July 2017)

Herein, the synthesis and crystal structure of 7-hydroxy-3-(2-methoxyphenyl)-2-trifluoromethyl-4H-chromen-4-one, C₁₇H₁₁F₃O₄, are reported. This isoflavone is used as a starting material in the preparation an array of potent and competitive FPR antagonists. The pyran ring significantly deviates from planarity and the dihedral angle between the benzopyran mean plane and that of the exocyclic benzene ring is 88.18 (4)°. In the crystal, O—H⋯O hydrogen bonds connect the molecules into C(8) chains propagating in the [010] direction.

Keywords: crystal structure; isoflavone; chromone.

CCDC reference: 1453086

1. Chemical context

Isoflavones are a subclass of a larger chemical family, the flavonoids, being characterized by possessing a 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) backbone instead of the 2-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure of flavanones and flavones (Szeja et al., 2016 ). Dietary isoflavones are secondary metabolites that occur in plants of the Fabaceae family and as such are present in soy beans, soy foods and legumes. The health benefits of isoflavones have been linked to cholesterol-reducing, anti-inflammatory, chemotherapeutic and antioxidant properties (Jie et al., 2016 ). However, the best known property of isoflavones is related to their phytoestrogenic activity (Vitale et al., 2013 ). More recently, isoflavones of synthetic origin have been shown to be potent and competitive antagonists of formyl peptide receptors (FPRs), playing an important role in the regulation of inflammatory processes (Schepetkin et al., 2014 ).

Herein we describe the synthesis and characterization of an isoflavone, 7-hydroxy-3-(2-methoxyphenyl)-2-trifluoromethyl-4H-chromen-4-one, 1, a precursor used in the preparation of relevant FPRs antagonists.

2. Structural commentary

The molecular structure of 1 is shown in Fig. 1 (left). This compound consists of a chromone core with several substituents, viz. a trifluoromethyl group at position 2, a 2-(methoxy)phenyl at position 3 and finally an hydroxy group at position 7 of the chromone ring.

Figure 1
The molecular structure of 1 (left) and (right)the rotation of the exocyclic benzene relative to the benzopyran best plane [dihedral angle = 88.18 (4)°]. Displacement ellipsoids are drawn at the 70% probability level.

The pyran ring is not planar as the weighted average absolute torsion angle is 6.77 (7)°; for planarity this should be below 5.00° (Domenicano et al., 1975 ). In fact, as a Cremer & Pople puckering analysis shows, the pyran ring has a twist-boat pucker with puckering amplitude Q = 0.1085 (13) Å, θ = 90.0 (7)° and φ = 148.6 (7)°. The fused aromatic benzopyran ring system shows a slight distortion from planarity as a result of the puckering of the pyran ring. The dihedral angle between the pyran ring and the exocyclic benzene ring is 89.26 (6)°. The mean plane of the ten atoms of the benzopyran ring system was used to evaluate the degree of twisting of the 2-methoxyphenyl ring in relation to the chromone as depicted in Fig. 1 (right). The dihedral angle between the benzopyran mean plane and the exocyclic benzene ring is 88.18 (4)°; the major rotation is around the C3—C31 bond, which has sp³ character, with a bond length of 1.4983 (17) Å. This conformation is to be expected and probably results from minimization of the steric hindrance between the 2-methoxy substituent of the exocyclic benzene ring with the voluminous –CF₃ group and/or the oxo oxygen atom of the chromone ring.

Regarding the mean plane involving the benzopyran atoms, it is found that atoms O1 and C3 lie more than 0.1 Å out of it [the perpendicular vectors having values of 0.1039 (9) Å and −0.1398 (10) Å, respectively], showing again that the benzopyran ring itself does not show the typical planarity observed for similar chromone and coumarin structures (e.g. Gomes et al., 2016 ; Reis et al., 2013 ) in which the pyran and benzopyran ring systems are essentially planar. As can be seen in Table 1, the atoms of the pyran ring lie below the mean plane of the chromone benzene ring.

Table 1
Deviations (in Å) of the pyran ring atoms and attached atoms from the mean plane of the chromone benzene ring

Atom	O1	C2	C3′	C4	C21	C31	O4
Distance	−0.0092 (18)	−0.243 (2)	−0.380 (2)	−0.155 (2)	−0.372 (3)	−0.805 (3)	−0.1267 (16)

3. Supramolecular features

Details of the hydrogen-bonding interactions are given in Table 2. The O7—H7⋯O4( $[{1\over 2}]$ − x, − $[{1\over 2}]$ + y, z) link forms a C(8) chain, which runs parallel to the b axis. This is formed by the action of the c-glide plane at y = $[{1\over 4}]$ , Fig. 2.

Table 2
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O7—H7⋯O4ⁱ	0.87 (2)	1.79 (2)	2.6416 (13)	166 (2)
C6—H6⋯O3ⁱⁱ	0.95	2.59	3.4309 (16)	148
C36—H36⋯O7ⁱⁱⁱ	0.95	2.49	3.3886 (18)	157
C8—H8⋯Cg3^iv	0.95	2.93	3.5972 (14)	128
C321—H32b⋯Cg3^v	0.98	2.75	3.6348 (17)	150
Symmetry codes: (i) $[-x+{\script{1\over 2}}, y-{\script{1\over 2}}, z]$ ; (ii) -x, -y+1, -z+1; (iii) -x+1, -y+1, -z+1; (iv) $[x, -y-{\script{3\over 2}}, z-{\script{1\over 2}}]$ ; (v) $[x-{\script{3\over 2}}, y, -z-{\script{1\over 2}}]$ .

Figure 2
Compound 1, the simple C8 chain formed by the O7—H7⋯O4ⁱ hydrogen bond. This chain extends along the b axis. Symmetry codes: (i) −x + $[{1\over 2}]$ , y − $[{1\over 2}]$ , z; (ii) −x + $[{1\over 2}]$ , y + $[{1\over 2}]$ , z). Hydrogen atoms not involved in the hydrogen bonding have been omitted.

The molecules are linked into alternating pairs of dimers to form a ladder. The C36—H36⋯O7(1 − x, 1 − y, 1 − z) interaction forms an R₂²(20) centrosymmetric dimer across the centre of symmetry at ( $[{1\over 2}]$ , $[{1\over 2}]$ , $[{1\over 2}]$ ). The C6—H6⋯O3(−x, 1 − y, 1 − z) interaction forms an R₂²(18) centrosymmetric dimer across the centre of symmetry at (0, $[{1\over 2}]$ , $[{1\over 2}]$ ). Together, these interactions form the ladder, which lies in plane (011) and which runs parallel to the a axis, Fig. 3. There are also C—H⋯π interactions present (Table 2).

Figure 3
Compound 1, view of the ladder of alternating linked R₂²(18) and R₂²(20) structures formed by the interaction of centrosymmetrically related pairs of C6—H6⋯O3ⁱⁱ hydrogen bonds across the centre of symmetry at (0, $[{1\over 2}]$ , $[{1\over 2}]$ ) and centrosymmetrically related pairs of C36—H36⋯O7ⁱⁱⁱ hydrogen bonds across the centre of symmetry at ( $[{1\over 2}]$ , $[{1\over 2}]$ , $[{1\over 2}]$ ). This chain extends by unit translation along the a axis. Hydrogen atoms not involved in the hydrogen bonding have been omitted.

4. Hirshfeld surfaces

The Hirshfeld surfaces and two-dimensional fingerprint (FP) plots (McKinnon et al., 2004 ) provide complementary information concerning the intermolecular interactions discussed above. They were generated using Crystal Explorer 3.1 (Wolff et al., 2012 ). The Hirshfeld surface mapped over d_norm is scaled between −0.250 to 1.200. The electrostatic potential (ESP) was calculated with TONTO (Jayatilaka & Grimwood, 2003 ) as implemented in Crystal Explorer 3.

The contributions from various contacts, listed in Table 3, were selected by the partial analysis of the FP plots. Besides the H⋯H contacts the other most significant contacts are the H⋯F/F⋯H due to the fluorine atoms on the surface. The remaining high percentage contacts are H⋯O/O⋯H that include the relevant C—H⋯O and the O—H⋯O intermolecular interactions and also the H⋯C/C⋯H contacts including C—H⋯C contacts. The percentage of C⋯C contacts is 6.1% but they are too long to be considered as π–π stacking. The structure has four oxygen atoms, defining different functional groups, that may act as acceptors for hydrogen bonds: one oxo group, a methoxy group, a hydroxyl group and an alkoxy O atom, all of which participate in short atom–atom contacts with the exception of the chromone alkoxy O atom.

Table 3
Percentages for the most relevant atom–atom contacts in 1

H⋯H'	H⋯O/O⋯H	H⋯F/F⋯H	H⋯C/C⋯H	C⋯C	C⋯O/O⋯C	O⋯F/F⋯C	O⋯O	F⋯O/O⋯F	F⋯F
22.1	18.3	25.1	18.3	6.1	2.3	0.2	3.0	0.8	3.4

The Hirshfeld surfaces mapped over d_norm for 1 (see Fig. 4) show three sets of complementary red spot areas: one of those pairs consist of two intense red areas, circular in shape, that are located near the carbonyl oxygen atom O4 and near the hydroxyl substituent. This close contact accounts for the O4⋯H7—O7 hydrogen bond as indicated in Fig. 4. Another pair is consists of two light-red areas resulting from the overlap of two red spots near H36 and near the hydroxyl group; they suggest interactions between this hydrogen atom and O7 (that forms a C36—H36⋯O7 hydrogen contact) and with the carbon atom C7 of the chromone ring (Fig. 5 contains a detail of this contact and the corresponding FP plot area). Finally, there are two complementary very light-red spots of small diameter that suggest the existence of a close contact involving the oxygen atom O3 of the methoxy substituent with hydrogen atom H8 of the chromone ring (O3⋯H6—C6).

Figure 4
Views of the Hirshfeld surface mapped over d_norm for 1 and the corresponding FP plot. The highlighted red spots with large area on the top left image indicate O⋯H contact points involving the carbonyl oxygen atom of the chromone core and the hydrogen atom of the hydroxyl substituent while the pair of superposed light-red spots indicate C⋯H and O⋯H close contacts. The small red-spot areas on the concave and convex face of the right image are due to C⋯H close contacts. The bottom of the figure presents the FP plot for molecule 1 The light-blue area in the middle of the FP plot at d_e/d_i ∼ 1.9 Å shows a higher frequency of the pixels that are due to C⋯C contacts. The sharp spikes pointing to southwest are due to O⋯H contacts: the inner one on the right is related to O⋯H contacts and the short wings due to C⋯H close contacts (see Fig. 5

for details).

Figure 5
Detail of the FP plot for 1 highlighting the H⋯C contacts (blue) and the corresponding areas in the Hirshfeld surface; The blue area covers the C⋯H/ H⋯C close contacts and displays two small wings as well as a pair of short spikes pointing to southwest ending at (d_e/d_i)/(1.5/1.0) Å and vice versa that reflect the C36—H36⋯C7 contact area.

The FP plot for 1 is included in Fig. 4. The light-blue area in the middle of it at d_e/d_i approximately equal to 1.9 Å shows a higher frequency of the pixels that are due to C⋯C contacts. The sharp spikes pointing to the southwest are due to O⋯H contacts and the short wings due to C⋯H close contacts (see Fig. 5 for details).

In Fig. 6 the mapping of the molecular electrostatic potential (ESP) in the context of crystal packing is shown. As the Hirshfeld surface partitions of the crystal space give non-overlapping volumes associated with each molecule, these surfaces give a kind of `electrostatic complementarity'; red areas indicate negative electrostatic potential while blue areas indicate a positive one. The ESP mapped in the Hirshfeld surface for 1 reveals a red area of strongly negative electrostatic potential surrounding the carbonyl region of the chromone and light red areas surrounding the fluorine atoms of the –CF₃ and as well on the areas covering the oxygen atoms of the hydroxyl and methoxy substituents showing the negative electrostatic potential. The blue region, strongly electropositive, is predominantly located on the hydrogen atom of the hydroxyl substituent and the light electropositive blue patch areas are also surrounding the H atoms of the methoxy substituent and well as H8 and H6 hydrogen atoms of the chromone. The remainder of the Hirshfeld surface is close to neutrality as seen by the grey regions. Thus, the figures highlight the electrostatic complementarity in the O4⋯H7—O7 contact as well as in the O3⋯H6—C6 contact.

Figure 6
The electrostatic potential surfaces for 1 (ranging from −0.0920 to 0.2582 a.u.). The surfaces show the complementary of electropositive area (blue) near the hydrogen atom of the hydroxyl substituent and red electronegative area surrounding the vicinity of the lone pairs of the oxo oxygen atom O4.

5. Database survey

A search made in the Cambridge Structural Database, (Groom et al., 2016 ), revealed the existence of seven polymorphic and pseudopolymorphic crystal structures of 7-hydroxy-3-phenyl-4H-chromen-4-one (Gong et al., 2016 ). In these structures, the pyran rings are essentially planar. The dihedral angles between the benzopyran ten-membered ring mean plane and the exocyclic benzene ring are given below. KUZJEW, 7-hydroxy-3-phenyl-4H-chromen-4-one: 2-methylpropan-2-ol solvate, dihedral angle= 48.28 (7)°. KUZJIA, 7-hydroxy-3-phenyl-4H-chromen-4-one, dihedral angle = 55.23 (8)°. KUZJIA01, 7-hydroxy-3-phenyl-4H-chromen-4-one, dihedral angle = 56.83 (7)°(molecule A), 48.27 (6)° (molecule B). KUZNIE, 7-hydroxy-3-phenyl-4H-chromen-4-one; dimethyl sulfoxide solvate, dihedral angle = 45.91 (7)°. KUZJUM, 7-hydroxy-3-phenyl-4H-chromen-4-one N,N-dimethylformamide solvate, dihedral angle = 41.70 (7)°. KUZKAT, 7-hydroxy-3-phenyl-4H-chromen-4-one propan-1-ol, solvate, dihedral angle = 45.18 (9)°. KUZKEX, 7-hydroxy-3-phenyl-4H-chromen-4-one butan-1-ol solvate, dihedral angle = 45.11 (11)°. In all solvated structures, the 7-OH hydroxyl group is involved in hydrogen bonding with the solvent. In the two KUZJIA(01) structures, –OH⋯O chains are formed as in 1.

6. Synthesis and crystallization

The title compound was obtained by a two-step synthesis (Balasubramanian & Nair, 2000 ; Eiffe et al., 2009 ). Resorcinol and 2-methoxyphenylacetic acid, in equimolar amounts, were suspended in boron trifluoride diethyl etherate (BF₃·Et₂O) and heated at 358 K, for 90 min. Then the mixture was poured into water and stirred until the formation of a solid and extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The product was recrystallized from ethyl acetate solution and used in the subsequent reaction to obtain the isoflavone.

1-(2,4-Dihydroxyphenyl)-2-(2-methoxyphenyl)ethan-1-one (1 mmol), trifluoroacetic anhydride (3 mmol) and trimethylamine (2 ml) were refluxed for 1 h. After cooling, water (15 ml) was added. The solution was acidified (pH 5) with 2 M HCl and stirred at room temperature for 2 h. After extraction with ethyl acetate, the combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The isoflavone was recrystallized from ethyl acetate solution. Overall yield: 55%

¹H NMR (DMSO-d₆): 3.69 (1H, s), 6.95 (1H, d, J = 2.20 Hz), 7.00 (1H, ddd, J = 0.97, 7.45, 7.45 Hz), 7.02 (1H, dd, J = 2.26, 8.82 Hz), 7.09 (1H, dd, J = 0.90, 8.38 Hz), 7.15 (1H, dd, J = 1.70, 7.46 Hz), 7.42 (1H, ddd, J = 1.73, 7.47, 8.31 Hz), 7.92 (1H, d, J = 8.76 Hz), 11.13 (1H, s).

7. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 4. The hydroxyl H atom, H7, was refined isotropically. All other H atoms were treated as riding atoms: C—H = 0.95–0.98 Å with U_iso = 1.5U_eq(C-methyl) and 1.2U_eq(C) for other H atoms.

Table 4
Experimental details

Crystal data
Chemical formula	C₁₇H₁₁F₃O₄
M_r	336.27
Crystal system, space group	Orthorhombic, Pbca
Temperature (K)	100
a, b, c (Å)	7.9147 (5), 16.2171 (11), 22.5254 (16)
V (Å³)	2891.2 (3)
Z	8
Radiation type	Mo Kα
μ (mm⁻¹)	0.14
Crystal size (mm)	0.21 × 0.07 × 0.01

Data collection
Diffractometer	Rigaku AFC12
Absorption correction	Multi-scan (CrystalClear-SM Expert; Rigaku, 2012 )
T_min, T_max	0.775, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	35487, 3314, 2777
R_int	0.058
(sin θ/λ)_max (Å⁻¹)	0.649

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.036, 0.103, 1.02
No. of reflections	3314
No. of parameters	222
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.34, −0.21
Computer programs: CrystalClear-SM Expert (Rigaku, 2012), SHELXT (Sheldrick, 2015a ), OSCAIL (McArdle et al., 2004 ), ShelXle (Hübschle et al., 2011 ), SHELXL2014 (Sheldrick, 2015b ), Mercury (Macrae et al., 2006 ) and PLATON (Spek, 2009 ).

Supporting information

CCDC reference: 1453086

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S2056989017009896/hb7688sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989017009896/hb7688Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989017009896/hb7688Isup3.cml

checkCIF report

Computing details top

Data collection: CrystalClear-SM Expert (Rigaku, 2012); cell refinement: CrystalClear-SM Expert (Rigaku, 2012); data reduction: CrystalClear-SM Expert (Rigaku, 2012); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: OSCAIL (McArdle et al., 2004), ShelXle (Hübschle et al., 2011) and SHELXL2014 (Sheldrick, 2015b); molecular graphics: Mercury (Macrae et al., 2006); software used to prepare material for publication: OSCAIL (McArdle et al., 2004), SHELXL2014 (Sheldrick, 2015b) and PLATON (Spek, 2009).

7-Hydroxy-3-(2-methoxyphenyl)-2-trifluoromethyl-4H-chromen-4-one top

Crystal data top

C₁₇H₁₁F₃O₄	D_x = 1.545 Mg m⁻³
M_r = 336.27	Mo Kα radiation, λ = 0.71075 Å
Orthorhombic, Pbca	Cell parameters from 31907 reflections
a = 7.9147 (5) Å	θ = 2.5–27.5°
b = 16.2171 (11) Å	µ = 0.14 mm⁻¹
c = 22.5254 (16) Å	T = 100 K
V = 2891.2 (3) Å³	Plate, colourless
Z = 8	0.21 × 0.07 × 0.01 mm
F(000) = 1376

Data collection top

Rigaku AFC12 diffractometer	3314 independent reflections
Radiation source: Rotating Anode	2777 reflections with I > 2σ(I)
Detector resolution: 28.5714 pixels mm^-1	R_int = 0.058
profile data from ω–scans	θ_max = 27.5°, θ_min = 2.5°
Absorption correction: multi-scan (CrystalClear-SM Expert; Rigaku, 2012)	h = −10→10
T_min = 0.775, T_max = 1.000	k = −20→20
35487 measured reflections	l = −29→29

Refinement top

Refinement on F²	0 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.036	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.103	w = 1/[σ²(F_o²) + (0.0543P)² + 1.0823P] where P = (F_o² + 2F_c²)/3
S = 1.02	(Δ/σ)_max < 0.001
3314 reflections	Δρ_max = 0.34 e Å⁻³
222 parameters	Δρ_min = −0.21 e Å⁻³

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
F21	0.37922 (12)	0.49225 (7)	0.27664 (4)	0.0476 (3)
F22	0.59157 (13)	0.56872 (5)	0.29861 (4)	0.0459 (3)
F23	0.59737 (12)	0.43950 (5)	0.31761 (4)	0.0416 (2)
O1	0.38627 (12)	0.44652 (5)	0.40256 (4)	0.0248 (2)
O3	0.13208 (12)	0.65679 (5)	0.33431 (4)	0.0276 (2)
O4	0.29964 (14)	0.66084 (5)	0.49162 (4)	0.0323 (2)
O7	0.08054 (13)	0.29227 (6)	0.54664 (4)	0.0293 (2)
H7	0.114 (3)	0.2531 (13)	0.5233 (9)	0.055 (6)*
C2	0.42085 (16)	0.52119 (7)	0.37796 (6)	0.0235 (3)
C3	0.38708 (16)	0.59517 (7)	0.40248 (6)	0.0232 (3)
C4	0.31834 (16)	0.59616 (7)	0.46352 (6)	0.0243 (3)
C5	0.17944 (17)	0.50964 (7)	0.54149 (6)	0.0253 (3)
H5	0.1607	0.5575	0.5649	0.030*
C4A	0.26922 (16)	0.51638 (7)	0.48767 (5)	0.0230 (3)
C6	0.11873 (17)	0.43488 (7)	0.56045 (6)	0.0256 (3)
H6	0.0579	0.4311	0.5967	0.031*
C7	0.14709 (17)	0.36333 (7)	0.52579 (6)	0.0248 (3)
C8	0.24070 (17)	0.36720 (7)	0.47361 (6)	0.0244 (3)
H8	0.2647	0.3190	0.4512	0.029*
C8A	0.29805 (16)	0.44429 (7)	0.45536 (5)	0.0224 (3)
C21	0.49789 (19)	0.50614 (7)	0.31732 (6)	0.0277 (3)
C31	0.40573 (17)	0.67677 (7)	0.37198 (6)	0.0244 (3)
C32	0.26803 (16)	0.70816 (7)	0.33969 (5)	0.0237 (3)
C33	0.27695 (18)	0.78732 (8)	0.31499 (6)	0.0274 (3)
H33	0.1837	0.8090	0.2935	0.033*
C34	0.42290 (19)	0.83407 (8)	0.32209 (6)	0.0303 (3)
H34	0.4285	0.8878	0.3055	0.036*
C35	0.56005 (19)	0.80327 (8)	0.35305 (6)	0.0314 (3)
H35	0.6600	0.8352	0.3571	0.038*
C36	0.55002 (18)	0.72477 (8)	0.37832 (6)	0.0290 (3)
H36	0.6433	0.7039	0.4002	0.035*
C321	−0.01472 (19)	0.69009 (9)	0.30555 (7)	0.0343 (3)
H32A	−0.1047	0.6486	0.3052	0.051*
H32B	0.0137	0.7053	0.2647	0.051*
H32C	−0.0533	0.7391	0.3271	0.051*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
F21	0.0446 (6)	0.0703 (7)	0.0280 (5)	0.0018 (5)	−0.0036 (4)	−0.0067 (4)
F22	0.0623 (6)	0.0276 (4)	0.0478 (5)	−0.0090 (4)	0.0258 (5)	−0.0027 (4)
F23	0.0549 (6)	0.0325 (4)	0.0373 (5)	0.0188 (4)	0.0129 (4)	0.0034 (3)
O1	0.0320 (5)	0.0160 (4)	0.0265 (5)	0.0010 (3)	0.0023 (4)	−0.0003 (3)
O3	0.0260 (5)	0.0259 (4)	0.0308 (5)	0.0002 (4)	−0.0032 (4)	0.0043 (4)
O4	0.0432 (6)	0.0178 (4)	0.0357 (5)	−0.0001 (4)	0.0037 (4)	−0.0044 (4)
O7	0.0375 (6)	0.0178 (4)	0.0327 (5)	−0.0016 (4)	0.0040 (4)	0.0008 (4)
C2	0.0248 (6)	0.0188 (6)	0.0269 (6)	0.0001 (5)	−0.0016 (5)	0.0017 (4)
C3	0.0228 (6)	0.0189 (5)	0.0280 (6)	0.0008 (4)	−0.0030 (5)	0.0005 (5)
C4	0.0251 (6)	0.0184 (5)	0.0294 (6)	0.0017 (5)	−0.0031 (5)	−0.0006 (5)
C5	0.0307 (7)	0.0191 (5)	0.0262 (6)	0.0022 (5)	−0.0019 (5)	−0.0027 (5)
C4A	0.0257 (6)	0.0174 (5)	0.0258 (6)	0.0016 (5)	−0.0030 (5)	−0.0012 (4)
C6	0.0299 (7)	0.0223 (6)	0.0245 (6)	0.0027 (5)	0.0006 (5)	−0.0003 (5)
C7	0.0270 (7)	0.0188 (5)	0.0286 (6)	0.0008 (5)	−0.0037 (5)	0.0018 (5)
C8	0.0296 (7)	0.0161 (5)	0.0275 (6)	0.0012 (5)	−0.0022 (5)	−0.0018 (4)
C8A	0.0246 (6)	0.0197 (6)	0.0231 (6)	0.0016 (5)	−0.0017 (5)	−0.0007 (4)
C21	0.0336 (7)	0.0202 (6)	0.0294 (6)	0.0015 (5)	0.0020 (5)	0.0004 (5)
C31	0.0296 (7)	0.0176 (5)	0.0258 (6)	0.0016 (5)	0.0017 (5)	0.0001 (4)
C32	0.0276 (6)	0.0203 (5)	0.0231 (6)	0.0016 (5)	0.0025 (5)	−0.0006 (4)
C33	0.0339 (7)	0.0223 (6)	0.0259 (6)	0.0055 (5)	0.0028 (5)	0.0019 (5)
C34	0.0426 (8)	0.0196 (6)	0.0287 (7)	0.0007 (5)	0.0081 (6)	0.0019 (5)
C35	0.0361 (7)	0.0220 (6)	0.0361 (7)	−0.0056 (5)	0.0043 (6)	−0.0028 (5)
C36	0.0301 (7)	0.0222 (6)	0.0346 (7)	0.0000 (5)	−0.0015 (5)	−0.0007 (5)
C321	0.0292 (7)	0.0375 (7)	0.0362 (7)	0.0034 (6)	−0.0058 (6)	0.0056 (6)

Geometric parameters (Å, º) top

F21—C21	1.3314 (17)	C6—C7	1.4164 (17)
F22—C21	1.3256 (15)	C6—H6	0.9500
F23—C21	1.3371 (15)	C7—C8	1.3908 (19)
O1—C2	1.3594 (15)	C8—C8A	1.3921 (17)
O1—C8A	1.3796 (15)	C8—H8	0.9500
O3—C32	1.3662 (15)	C31—C36	1.3895 (19)
O3—C321	1.4356 (16)	C31—C32	1.4057 (18)
O4—C4	1.2340 (15)	C32—C33	1.4008 (17)
O7—C7	1.3514 (15)	C33—C34	1.391 (2)
O7—H7	0.87 (2)	C33—H33	0.9500
C2—C3	1.3475 (17)	C34—C35	1.384 (2)
C2—C21	1.5158 (18)	C34—H34	0.9500
C3—C4	1.4788 (18)	C35—C36	1.3967 (18)
C3—C31	1.4983 (17)	C35—H35	0.9500
C4—C4A	1.4564 (16)	C36—H36	0.9500
C5—C6	1.3723 (17)	C321—H32A	0.9800
C5—C4A	1.4094 (18)	C321—H32B	0.9800
C5—H5	0.9500	C321—H32C	0.9800
C4A—C8A	1.3960 (16)

C2—O1—C8A	118.46 (9)	F22—C21—F21	107.78 (11)
C32—O3—C321	116.62 (10)	F22—C21—F23	106.92 (12)
C7—O7—H7	107.1 (13)	F21—C21—F23	106.39 (11)
C3—C2—O1	125.88 (12)	F22—C21—C2	112.84 (10)
C3—C2—C21	126.33 (11)	F21—C21—C2	111.33 (12)
O1—C2—C21	107.75 (10)	F23—C21—C2	111.26 (10)
C2—C3—C4	117.63 (11)	C36—C31—C32	119.18 (11)
C2—C3—C31	125.38 (12)	C36—C31—C3	121.91 (12)
C4—C3—C31	116.93 (10)	C32—C31—C3	118.73 (11)
O4—C4—C4A	122.10 (12)	O3—C32—C33	124.28 (12)
O4—C4—C3	122.03 (11)	O3—C32—C31	115.83 (10)
C4A—C4—C3	115.84 (10)	C33—C32—C31	119.89 (12)
C6—C5—C4A	120.84 (11)	C34—C33—C32	119.71 (13)
C6—C5—H5	119.6	C34—C33—H33	120.1
C4A—C5—H5	119.6	C32—C33—H33	120.1
C8A—C4A—C5	117.78 (11)	C35—C34—C33	120.85 (12)
C8A—C4A—C4	120.36 (11)	C35—C34—H34	119.6
C5—C4A—C4	121.66 (11)	C33—C34—H34	119.6
C5—C6—C7	119.78 (12)	C34—C35—C36	119.34 (13)
C5—C6—H6	120.1	C34—C35—H35	120.3
C7—C6—H6	120.1	C36—C35—H35	120.3
O7—C7—C8	122.67 (11)	C31—C36—C35	121.02 (13)
O7—C7—C6	116.44 (12)	C31—C36—H36	119.5
C8—C7—C6	120.88 (11)	C35—C36—H36	119.5
C7—C8—C8A	117.63 (11)	O3—C321—H32A	109.5
C7—C8—H8	121.2	O3—C321—H32B	109.5
C8A—C8—H8	121.2	H32A—C321—H32B	109.5
O1—C8A—C8	116.31 (10)	O3—C321—H32C	109.5
O1—C8A—C4A	120.69 (10)	H32A—C321—H32C	109.5
C8—C8A—C4A	123.01 (12)	H32B—C321—H32C	109.5

C8A—O1—C2—C3	4.95 (19)	C4—C4A—C8A—O1	5.63 (18)
C8A—O1—C2—C21	−172.99 (10)	C5—C4A—C8A—C8	0.76 (19)
O1—C2—C3—C4	5.0 (2)	C4—C4A—C8A—C8	−174.13 (12)
C21—C2—C3—C4	−177.39 (12)	C3—C2—C21—F22	25.4 (2)
O1—C2—C3—C31	−171.91 (12)	O1—C2—C21—F22	−156.64 (11)
C21—C2—C3—C31	5.7 (2)	C3—C2—C21—F21	−95.91 (15)
C2—C3—C4—O4	172.60 (12)	O1—C2—C21—F21	82.03 (13)
C31—C3—C4—O4	−10.19 (19)	C3—C2—C21—F23	145.61 (13)
C2—C3—C4—C4A	−9.24 (17)	O1—C2—C21—F23	−36.46 (15)
C31—C3—C4—C4A	167.97 (11)	C2—C3—C31—C36	−95.96 (16)
C6—C5—C4A—C8A	−1.73 (19)	C4—C3—C31—C36	87.07 (16)
C6—C5—C4A—C4	173.08 (12)	C2—C3—C31—C32	88.86 (16)
O4—C4—C4A—C8A	−177.67 (12)	C4—C3—C31—C32	−88.10 (14)
C3—C4—C4A—C8A	4.17 (18)	C321—O3—C32—C33	−5.40 (18)
O4—C4—C4A—C5	7.6 (2)	C321—O3—C32—C31	175.24 (11)
C3—C4—C4A—C5	−170.51 (12)	C36—C31—C32—O3	178.68 (11)
C4A—C5—C6—C7	0.3 (2)	C3—C31—C32—O3	−6.01 (17)
C5—C6—C7—O7	−178.66 (12)	C36—C31—C32—C33	−0.71 (18)
C5—C6—C7—C8	2.2 (2)	C3—C31—C32—C33	174.60 (11)
O7—C7—C8—C8A	177.81 (12)	O3—C32—C33—C34	−178.71 (12)
C6—C7—C8—C8A	−3.06 (19)	C31—C32—C33—C34	0.63 (18)
C2—O1—C8A—C8	169.42 (11)	C32—C33—C34—C35	0.3 (2)
C2—O1—C8A—C4A	−10.35 (17)	C33—C34—C35—C36	−1.2 (2)
C7—C8—C8A—O1	−178.16 (11)	C32—C31—C36—C35	−0.2 (2)
C7—C8—C8A—C4A	1.6 (2)	C3—C31—C36—C35	−175.30 (12)
C5—C4A—C8A—O1	−179.48 (11)	C34—C35—C36—C31	1.1 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O7—H7···O4ⁱ	0.87 (2)	1.79 (2)	2.6416 (13)	166 (2)
C6—H6···O3ⁱⁱ	0.95	2.59	3.4309 (16)	148
C36—H36···O7ⁱⁱⁱ	0.95	2.49	3.3886 (18)	157
C8—H8···Cg3^iv	0.95	2.93	3.5972 (14)	128
C321—H32b···Cg3^v	0.98	2.75	3.6348 (17)	150

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

Deviations (in Å) of the pyran ring atoms and attached atoms from the mean plane of the chromone benzene ring top

Atom	O1	C2	C3'	C4	C21	C31	O4
Distance	-0.0092 (18)	-0.243 (2)	-0.380 (2)	-0.155 (2)	-0.372 (3)	-0.805 (3)	-0.1267 (16)

Percentages for the most relevant atom–atom contacts in 1 top

H···H'	H···O/O···H	H···F/F···H	H···C/C···H	C···C	C···O/O···C	O···F/F···C	O···O	F···O/O···F	F···F
22.1	18.3	25.1	18.3	6.1	2.3	0.2	3.0	0.8	3.4

Acknowledgements

The authors thank the staff at the National Crystallographic Service, University of Southampton, for the data collection, help and advice (Coles & Gale, 2012 ).

Funding information

This work was supported by the Portuguese Foundation for Science and Technology (FCT) UID/Multi/04546/2013 and FEDER/COMPETE (UID/QUI/UI0081/2013 and POCI-01-0145-FEDER-006980). AG (SFRH/BPD/93331/2013) grant is supported by FCT, POPH and QREN.

References

Balasubramanian, S. & Nair, M. G. (2000). Synth. Commun. 30, 469–484. Web of Science CrossRef CAS Google Scholar
Coles, S. J. & Gale, P. A. (2012). Chem. Sci. 3, 683–689. Web of Science CSD CrossRef CAS Google Scholar
Domenicano, A., Vaciago, A. & Coulson, C. A. (1975). Acta Cryst. B31, 221–234. CrossRef CAS IUCr Journals Web of Science Google Scholar
Eiffe, E., Heaton, A., Walker, C. & Husband, A. (2009). US Patent WO 2009003229 A1. Google Scholar
Gomes, L. R., Low, J. N., Fonseca, A., Matos, M. J. & Borges, F. (2016). Acta Cryst. E72, 1121–1125. Web of Science CSD CrossRef IUCr Journals Google Scholar
Gong, N., Zhang, G., Jin, G., Du, G. & Lu, Y. (2016). J. Pharm. Sci. 105, 1387–1397. Web of Science CSD CrossRef CAS PubMed Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CSD CrossRef IUCr Journals Google Scholar
Hübschle, C. B., Sheldrick, G. M. & Dittrich, B. (2011). J. Appl. Cryst. 44, 1281–1284. Web of Science CrossRef IUCr Journals Google Scholar
Jayatilaka, D. & Grimwood, D. J. (2003). ICCS, 4, 142–151. Google Scholar
Jie Yu, J., Bi, X. J., Yu, B. & Chen, D. (2016). Nutrients, 8, 361–365. Google Scholar
Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. (2006). J. Appl. Cryst. 39, 453–457. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
McArdle, P., Gilligan, K., Cunningham, D., Dark, R. & Mahon, M. (2004). CrystEngComm, 6, 303–309. Web of Science CSD CrossRef CAS Google Scholar
McKinnon, J. J., Spackman, M. A. & Mitchell, A. S. (2004). Acta Cryst. B60, 627–668. Web of Science CrossRef CAS IUCr Journals Google Scholar
Reis, J., Gaspar, A., Borges, F., Gomes, L. R. & Low, J. N. (2013). Acta Cryst. C69, 1527–1533. Web of Science CSD CrossRef IUCr Journals Google Scholar
Rigaku (2012). CrystalClear-SM Expert. Rigaku Corporation, Tokyo, Japan. Google Scholar
Schepetkin, I. A., Kirpotina, L. N., Khlebnikov, A. I., Cheng, N., Ye, R. D. & Quinn, M. T. (2014). Biochem. Pharmacol. 92, 627–641. Web of Science CrossRef CAS PubMed Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Spek, A. L. (2009). Acta Cryst. D65, 148–155. Web of Science CrossRef CAS IUCr Journals Google Scholar
Szeja, W., Grynkiewicz, G. & Rusin, A. (2016). Curr. Org. Chem. 21, 218–235. Web of Science CrossRef Google Scholar
Vitale, D. C., Piazza, C., Melilli, B., Drago, F. & Salomone, S. (2013). Eur. J. Drug Metab. Pharmacokinet. 38, 15–25. Web of Science CrossRef CAS PubMed Google Scholar
Wolff, S. K., Grimwood, D. J., McKinnon, J. J., Turner, M. J., Jayatilaka, D. & Spackman, M. A. (2012). Crystal Explorer. The University of Western Australia. Google Scholar

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