Crystal structures of ethyl 6-(4-methyl­phen­yl)-4-oxo-4H-chromene-2-carboxyl­ate and ethyl 6-(4-fluoro­phen­yl)-4-oxo-4H-chromene-2-carboxyl­ate

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

doi:10.1107/S2056989015022781

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ISSN: 2056-9890

Volume 72| Part 1| January 2016| Pages 8-13

doi:10.1107/S2056989015022781

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Crystal structures of ethyl 6-(4-methylphenyl)-4-oxo-4H-chromene-2-carboxylate and ethyl 6-(4-fluorophenyl)-4-oxo-4H-chromene-2-carboxylate

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

^aFP-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, ^bREQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre, 687, P-4169-007, Porto, Portugal, ^cDepartment of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen, AB24 3UE, Scotland, and ^dCIQ/Departamento de Química e Bioquímica, 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 17 November 2015; accepted 28 November 2015; online 1 January 2016)

The crystal structures of two chromone derivatives, viz. ethyl 6-(4-methylphenyl)-4-oxo-4H-chromene-2-carboxylate, C₁₉H₁₆O₄, (1), and ethyl 6-(4-fluorophenyl)-4-oxo-4H-chromene-2-carboxylate C₁₈H₁₃FO₄, (2), have been determined: (1) crystallizes with two molecules in the asymmetric unit. A comparison of the dihedral angles beween the mean planes of the central chromone core with those of the substituents, an ethyl ester moiety at the 2-position and a para-substituted phenyl ring at the 6-position shows that each molecule differs significantly from the others, even the two independent molecules (a and b) of (1). In all three molecules, the carbonyl groups of the chromone and the carboxylate are trans-related. The supramolecular structure of (1) involves only weak C—H⋯π interactions between H atoms of the substituent phenyl group and the phenyl group, which link molecules into a chain of alternating molecules a and b, and weak π–π stacking interactions between the chromone units. The packing in (2) involves C—H⋯O interactions, which form a network of two intersecting ladders involving the carbonyl atom of the carboxylate group as the acceptor for H atoms at the 7-position of the chromone ring and from an ortho-H atom of the exocyclic benzene ring. The carbonyl atom of the chromone acts as an acceptor from a meta-H atom of the exocyclic benzene ring. π–π interactions stack the molecules by unit translation along the a axis.

Keywords: crystal structure; drug design; chromone; conformation supramolecular structure.

CCDC references: 1439394; 1439393

1. Chemical context

Benzopyran derivatives represent a large class of natural and synthetic heterocycles that are often linked to a broad array of biological activities, (Gaspar et al., 2014 , 2015 ). Within this vast class of compounds, the chromone core has emerged as a privileged structure for drug discovery and development programs (Welsch et al., 2010 ). Chemically, the chromone scaffold is a rigid benzoannelated γ-pyrone ring, which can be modulated by diversity-oriented synthesis, (Gaspar et al., 2015; Welsch et al., 2010; Ko et al., 2006 ; Nicolaou et al., 2000 ), exhibiting a diversity of pharmacological properties such as anti-inflammatory, antimicrobial and anticancer among others (Gaspar et al., 2015). The application of chromones as a valid scaffold for the development of therapeutic solutions for aging-related diseases is still an emerging field, even though the data acquired indicate their importance in the development of new drug candidates for targets ascribed with respect to Alzheimer's and Parkinson's diseases, namely as adenosine receptors ligands (Cagide et al., 2015a ) and/or as monoamino oxidase B inhibitors, (Cagide et al., 2015b ).

Within this framework, our project has been focused on the discovery of new chemical entities based on a chromone scaffold. Herein we describe the crystal structures of two new chromone derivatives, viz. ethyl-6-(4-methylphenyl)-4-oxo-4H-chromene-2-carboxylate (1) and ethyl-6-(4-fluorophenyl)-4-oxo-4H-chromene-2-carboxylate (2).

2. Molecular Geometry

Ellipsoid plots of the molecules are given in Figs. 1 and 2. Compound (1) crystallizes with two molecules (a and b) in the asymmetric unit.

Figure 1
A view of the asymmetric unit of (1), with displacement ellipsoids drawn at the 70% probability level.

Figure 2
A view of the asymmetric unit of (2), with displacement ellipsoids drawn at the 70% probability level.

The molecules consist of a central chromone core with an ethylester substituent at the 2-position and a p-substituted phenyl group at the 6-position of the chromone ring system. Those constitutive fragments are essentially planar, therefore the major contribution to the definition of the molecular conformations are the rotations around the C—C bonds that connect the substituents to the chromone ring. As such, the analysis of the molecular geometry will be based on the values for the dihedral angles between the mean planes of the chromone and the phenyl ring (θ_Chr–Phe) and the chromone and the ethyl carboxylate moiety (θ_{Chr–carboxlylate}), Table 1. As can be seen, the dihedral angles for molecules a and b of (1) are significantly different from each other. An overlay fit using the quaternion transformation method (Mackay, 1984 ) shows that molecule i inverts on molecule ii where the weighted/unit weight r.m.s. fits are 0.090/0.089 Å for 23 atoms. The largest individual displacement is 0.169 Å (O14/O24 pair). The r.m.s. bond fit is 0.0021 Å and the r.m.s. angle fit is 0.376°. These values show that, in spite of the large differences in the dihedral angles, the molecules are quite similar overall.

Table 1
Selected dihedral angles (°)

θ_Chr–C3ring is the dihedral angle between the mean planes of the chromene and the phenyl ring. θ_{Chr–C6ester} is the dihedral angle between the mean planes of the chromone ring and the plane defined by the ester atoms attached to C2 but not including it. θ_Chr–OCO is the dihedral angle between the mean planes of the chromone ring and the OCO atoms of the ester.

Compound	θ_Chr–Phe	θ_{Chr–carboxylate}	θ_Chr–OCO
(1) molecule a	32.8754)	23.23 (7)	21.16 (16)
(1) molecule b	24.14 (5)	14.191 (7)	12.16 (17)
(2)	36.05 (5)	9.52 (6)	12.97 (13)

Considering the relative position of the ethyl carboxylate residue with respect to the chromone ring as may be seen in Fig. 3, the molecules may have any conformation between two possible extremes: conformation A where the carbonyl groups are trans-related and conformation B where they are cis-related. A theoretical calculation made with Gaussian03 (Frisch et al., 2004 ) at the B3LYP /631++(d,p) level shows that the energy associated with each of the boundary conformations is similar in adiabatic conditions [see supporting information; the B3LYP model combines the hybrid exchange functional of Becke (1997 ) with the gradient-correlation functional of Lee et al. (1988 ) and the split-valence polarized 6-311+G(d, p) basis set (Hehre et al., 1986 )]. Thus the adopted conformation in the solid state, with a geometry closer to A where the degree of twist lies between 9 and 21° (as measured by dihedral angles) may be due to packing factors. Preliminary results for the structures of similar compounds such as 6-(phenyl)-4-oxo-4H-chromene-2-carboxylate, 6-(4-methoxyphenyl)-4-oxo-4H-chromene-2-carboxylate and 6-(4-3,4-dimethoxyphenyl)-4-oxo-4H-chromene-2-carboxylate indicate that the major components have the same trans conformation as described above. These structures are imprecisely determined (the crystal quality was poor and the structures appeared to be intractably disordered).

Figure 3
The relative position of the ethyl carboxylate residue with respect to the chromone ring. Molecules may have any conformation between two possible extremes: conformation A where the carbonyl groups are trans-related and conformation B where they are cis-related.

The rotation around the C(phenyl)—C(chromone) bond is higher than the rotation around the C(chromone)—C(carboxyethyl) bond for all of the three molecules. This rotation may also contribute to the molecular packing since, in the absence of electronically crowded substituents in the o- or m- positions, the phenyl substituent does not impose steric hindrance with respect to the chromone ring.

3. Supramolecular structures

In the absence of strong hydrogen-bond donors, the supramolecular structures depend on weak C—H⋯O hydrogen bonds and C—H⋯π and very weak π–π interactions.

In (1) there are no weak C—H⋯O interactions and aromatic interactions appear to play the major role in the establishment of the packing. There are two T-shaped C—H⋯π interactions, one between C162 and the centroid of the phenyl ring with pivot atom C261, Cg(C261) within the selected asymmetric unit, and the other between C262 and the centroid of the phenyl ring with pivot atom C161, Cg(C161)(x, $[{3\over 2}]$ − y, − $[{1\over 2}]$ + z), Table 2. This forms a chain of alternating glide-related asymmetric units which runs parallel to the c axis. Within the asymmetric unit, the shortest packing contact is between the rings containing C15 and C25 and has a value of 4.2901 (9) Å, with an average perpendicular distance between the planes of 3.5350 Å and an angle between the planes of 6.46 (7)°, suggesting a possible very weak π–π interaction. Centrosymmetrically related pairs of molecule i form π–π stacked pairs, as do centrosymmetric pairs of molecule ii, Table 3. These base-paired units form a column of molecule along the a axis, Fig. 4.

Table 2
Hydrogen-bond geometry (Å, °) for (1)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C162—H162⋯Cg(C261)	0.95	2.85	3.4914 (15)	126
C262—H262⋯Cg(C161)ⁱ	0.95	2.84	3.5408 (4)	131
Symmetry code: (i) $[x, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ .

Table 3
Selected π–π contacts and short intermolecular contacts (Å, °)

In compound (1), Cg1, Cg2, Cg5 and Cg6 are the centroids of the rings containing atoms O11, C15, O21 and C25, respectively. In compound (2), Cg1, Cg2 and Cg6 are the centroids of the rings containing atoms O1, C5 and C61. Values marked with an asterisk are average perpendicular distances and angles between the planes.

Compound	contacts	distance	perp. distance	slippage/angle*
(1)	Cg1⋯Cg2ⁱ	3.7338 (8)	3.503*	0.45*
	Cg2⋯Cg2ⁱ	3.7226 (8)	3.5040 (6)	1.257
	Cg5⋯Cg6ⁱⁱ	3.6743 (9)	3.824*	0.98*
	Cg6⋯Cg6ⁱⁱ	3.9299 (9)	3.5762 (6)	1.630
(2)	Cg1⋯Cg1ⁱⁱⁱ	3.8521 (7)	3.3989 (4)	1.813
	Cg2⋯Cg2ⁱⁱⁱ	3.8521 (7)	3.3957 (4)	1.819
	Cg3⋯Cg3ⁱⁱⁱ'	3.8521 (7)	3.5811 (5)	1.419
Symmetry codes: (i) −x, 1 − y, 1 − z; (ii) 1 − x, 1 − y, 1 − z; (iii) 1 + x, y, z.

Figure 4
A view showing the stacking of the molecules along the a axis. Symmetry codes: (*) −x, −y + 1, −z + 1; (#) −x + 1, −y + 1, −z + 1. H atoms are omitted.

In contrast, compound (2) has a more intricate supramolecular structure, based on C—H⋯O and π–π interactions (Tables 3 and 4). Both carboxylic oxygen atoms (O21 and O4) act as acceptors of C—H⋯O hydrogen bonds. Atom O21 is involved in two centrosymmetrically linked ring structures. In one of these, the C7—H7⋯O21(−x, −y + 1, −z + 1) hydrogen bond forms an R₂²(16) ring, Fig. 5, and in the other the C66—H66⋯O21(−x + 1, −y + 1, −z + 1) hydrogen bond forms an R₂²(22) ring (Fig. 6). These interactions combine to link the molecules into zigzag chains of rings which run parallel to the a axis, Fig. 7. These are linked to form a three-dimensional network by the C65—H65⋯O4(−x + 2, y + $[{1\over 2}]$ , −z + 3/2) weak hydrogen bond formed by the action of the twofold screw axis at (1, y, 3/4), Fig. 8. The molecules are π–π stacked above each other with unit translation along the a axis, Table 3 and Fig. 9.

Table 4
Hydrogen-bond geometry (Å, °) for (2)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C7—H7⋯O21ⁱ	0.95	2.47	3.1977 (13)	133
C65—H65⋯O4ⁱⁱ	0.95	2.50	3.4447 (13)	175
C66—H66⋯O21ⁱⁱⁱ	0.95	2.53	3.4425 (13)	162
Symmetry codes: (i) -x, -y+1, -z+1; (ii) $[-x+2, y+{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (iii) -x+1, -y+1, -z+1.

Figure 5
Compound (2), view of the C7—H7⋯O21 centrosymetric R₂²(16) ring structure centred on (0, ½, ½). Atoms labelelled with a postscript,(i), are in molecules at (−x, −y + 1, −z + 1). Hydrogen atoms not involved in the hydrogen bonding are omitted.

Figure 6
Compound (2), view of the C66—H66⋯O21 centrosymetric R₂²(22) ring structure centred on (½, ½, ½). Symmetry code: (i) = −x + 1, −y + 1, −z + 1. H atoms not involved in the hydrogen bonding are omitted.

Figure 7
Compound (2), the combined ring structure formed by the combination of the ring structures in Figs. 4

and 5

. This chain of rings extends along the a axis. H atoms not involved in the hydrogen bonding are omitted.

Figure 8
Compound (2), the simple C9 chain formed by the C65—H65⋯O4 weak hydrogen bond. This chain of rings extends along the a axis and is generated by the twofold screw axis at (1, y, $[{3\over 4}]$ ). Symmetry codes: (i) −x + 2, y + $[{1\over 2}]$ , −z + $[{3\over 2}]$ ; (ii) −x + 2, y − $[{1\over 2}]$ , −z + $[{3\over 2}]$ . H atoms not involved in the hydrogen bonding are omitted.

Figure 9
A view showing the stacking of the molecules along the a axis. Symmetry codes: (*) x − 1, y, z; (#) x + 1, y, z + 1. H atoms are omitted.

The intermolecular interactions probably account for the significant difference (about 36 K) in the melting points for these compounds [411–418 K for (1) and 446–455 K for (2)]. They also may have an influence in the conformations of the molecules since in (2) the atoms in the carboxyethyl group are involved either as donors or acceptors; these interactions may constrain the conformation of the orientation of the carboxyethyl moiety.

4. Synthesis and crystallization

Compounds (1) and (2) were obtained, in moderate yields, by a two-step synthetic procedure. In the first step, the required phenylacetophenone derivatives were obtained from 5′-bromo-2′-hydroxyacetophenone by a Suzuki C–C cross-coupling reaction assisted by microwave (MW) heating (Soares et al., 2015 ). In the second step, the phenylacetophenone derivatives were converted in the corresponding chromones via an intramolecular Claisen condensation reaction accomplished with diethyl oxalate in the presence of ethanolic sodium ethoxide and cyclization under acidic conditions of the intermediate formed in situ.

Ethyl 6-(4-methylphenyl)-4-oxo-4H-chromene-2-carboxylate (1). Overall yield 50.7%; m.p. 411–418 K. Crystallization: ethyl acetate to form colourless prisms.

Ethyl 6-(4-fluorophenyl)-4-oxo-4H-chromene-2-carboxylate (2). Overall yield 55.9%; m.p. 446–455 K. Crystallization: ethyl acetate, to form colourless needles.

5. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 5. H atoms were treated as riding atoms with C—H(aromatic) = 0.95 Å, with U_iso = 1.2U_eq(C) and C—H(methyl) = 0.98 Å with U_iso = 1.5U_eq(C).

Table 5
Experimental details

	(1)	(2)
Crystal data
Chemical formula	C₁₉H₁₆O₄	C₁₈H₁₃FO₄
M_r	308.32	312.28
Crystal system, space group	Monoclinic, P2₁/c	Monoclinic, P2₁/c
Temperature (K)	100	100
a, b, c (Å)	14.7129 (11), 18.9613 (13), 11.3031 (6)	3.8521 (2), 20.6970 (15), 17.5478 (11)
β (°)	111.632 (7)	91.546 (1)
V (Å³)	2931.2 (4)	1398.52 (15)
Z	8	4
Radiation type	Mo Kα	Mo Kα
μ (mm⁻¹)	0.10	0.11
Crystal size (mm)	0.20 × 0.09 × 0.05	0.42 × 0.02 × 0.01

Data collection
Diffractometer	Rigaku Saturn724+	Rigaku Saturn724+
Absorption correction	Multi-scan (CrystalClear-SM Expert; Rigaku, 20112)	Multi-scan CrystalClear-SM Expert (Rigaku, 20112)
T_min, T_max	0.981, 0.995	0.954, 0.999
No. of measured, independent and observed [I > 2σ(I)] reflections	22133, 6680, 5311	16479, 3177, 2725
R_int	0.033	0.035
(sin θ/λ)_max (Å⁻¹)	0.649	0.650

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.038, 0.104, 1.11	0.031, 0.087, 0.98
No. of reflections	6680	3176
No. of parameters	419	209
H-atom treatment	H-atom parameters constrained	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.33, −0.23	0.31, −0.20
Computer programs: CrystalClear-SM Expert (Rigaku, 2012 ), SHELXT (Sheldrick, 2015a ), SHELXL2014 (Sheldrick, 2015b ), OSCAIL (McArdle et al., 2004 ), ShelXle (Hübschle et al., 2011 ), Mercury (Macrae et al., 2006 ) and PLATON (Spek, 2009 ).

Supporting information

CCDC references: 1439394; 1439393

Crystal structure: contains datablocks general, 1, 2. DOI: 10.1107/S2056989015022781/hb7543sup1.cif

Structure factors: contains datablock 1. DOI: 10.1107/S2056989015022781/hb75431sup2.hkl

Structure factors: contains datablock 2. DOI: 10.1107/S2056989015022781/hb75432sup3.hkl

Supporting information file. DOI: 10.1107/S2056989015022781/hb75431sup4.cml

Supporting information file. DOI: 10.1107/S2056989015022781/hb75432sup5.cml

Supporting information file. DOI: 10.1107/S2056989015022781/hb7543sup6.pdf

checkCIF report

Computing details top

For both compounds, 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) and PLATON (Spek, 2009) for (1); Mercury (Macrae et al., 2006) for (2). For both compounds, software used to prepare material for publication: OSCAIL (McArdle et al., 2004), SHELXL2014 (Sheldrick, 2015b) and PLATON (Spek, 2009).

(1) Ethyl 6-(4-methylphenyl)-4-oxo-4H-chromene-2-carboxylate top

Crystal data top

C₁₉H₁₆O₄	F(000) = 1296
M_r = 308.32	D_x = 1.397 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71075 Å
a = 14.7129 (11) Å	Cell parameters from 18061 reflections
b = 18.9613 (13) Å	θ = 3.0–27.5°
c = 11.3031 (6) Å	µ = 0.10 mm⁻¹
β = 111.632 (7)°	T = 100 K
V = 2931.2 (4) Å³	Prism, colourless
Z = 8	0.20 × 0.09 × 0.05 mm

Data collection top

Rigaku Saturn724+ (2x2 bin mode) diffractometer	6680 independent reflections
Radiation source: Rotating Anode	5311 reflections with I > 2σ(I)
Confocal monochromator	R_int = 0.033
Detector resolution: 28.5714 pixels mm^-1	θ_max = 27.5°, θ_min = 3.0°
profile data from ω–scans	h = −17→19
Absorption correction: multi-scan (CrystalClear-SM Expert; Rigaku, 20112)	k = −17→24
T_min = 0.981, T_max = 0.995	l = −14→14
22133 measured reflections

Refinement top

Refinement on F²	0 restraints
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.038	H-atom parameters constrained
wR(F²) = 0.104	w = 1/[σ²(F_o²) + (0.0504P)² + 0.4579P] where P = (F_o² + 2F_c²)/3
S = 1.11	(Δ/σ)_max = 0.001
6680 reflections	Δρ_max = 0.33 e Å⁻³
419 parameters	Δρ_min = −0.23 e Å⁻³

Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O11	0.13984 (7)	0.39931 (4)	0.51267 (8)	0.0167 (2)
O14	0.14523 (8)	0.46234 (5)	0.86202 (8)	0.0239 (2)
O121	0.18698 (7)	0.26721 (4)	0.47772 (8)	0.0186 (2)
O122	0.13729 (7)	0.23141 (4)	0.63468 (8)	0.0162 (2)
C12	0.14765 (9)	0.35255 (6)	0.60658 (11)	0.0153 (3)
C13	0.14901 (9)	0.37041 (6)	0.72208 (11)	0.0161 (3)
H13	0.1540	0.3344	0.7827	0.019*
C14	0.14293 (10)	0.44401 (6)	0.75658 (11)	0.0166 (3)
C14A	0.13289 (9)	0.49463 (6)	0.65301 (11)	0.0150 (2)
C15	0.12422 (9)	0.56769 (6)	0.66738 (11)	0.0156 (3)
H15	0.1247	0.5855	0.7462	0.019*
C16	0.11494 (9)	0.61435 (6)	0.56912 (11)	0.0147 (2)
C17	0.11434 (10)	0.58625 (6)	0.45309 (11)	0.0171 (3)
H17	0.1084	0.6175	0.3849	0.021*
C18	0.12206 (10)	0.51512 (7)	0.43612 (11)	0.0176 (3)
H18	0.1209	0.4972	0.3571	0.021*
C18A	0.13157 (9)	0.46978 (6)	0.53635 (11)	0.0150 (3)
C121	0.15961 (9)	0.27911 (6)	0.56400 (11)	0.0152 (3)
C122	0.16128 (10)	0.15886 (6)	0.61422 (11)	0.0173 (3)
H12A	0.2328	0.1535	0.6384	0.021*
H12B	0.1288	0.1457	0.5235	0.021*
C123	0.12554 (11)	0.11295 (6)	0.69613 (12)	0.0222 (3)
H12C	0.1445	0.0639	0.6900	0.033*
H12D	0.0542	0.1162	0.6671	0.033*
H12E	0.1546	0.1287	0.7848	0.033*
C161	0.10558 (9)	0.69191 (6)	0.58084 (11)	0.0141 (2)
C162	0.14423 (9)	0.73832 (6)	0.51543 (11)	0.0160 (3)
H162	0.1776	0.7200	0.4645	0.019*
C163	0.13461 (9)	0.81085 (6)	0.52375 (11)	0.0168 (3)
H163	0.1612	0.8412	0.4779	0.020*
C164	0.08671 (9)	0.83989 (6)	0.59792 (11)	0.0162 (3)
C165	0.04831 (9)	0.79352 (6)	0.66303 (11)	0.0164 (3)
H165	0.0150	0.8120	0.7140	0.020*
C166	0.05741 (9)	0.72085 (6)	0.65533 (11)	0.0157 (3)
H166	0.0306	0.6906	0.7011	0.019*
C167	0.07977 (10)	0.91884 (6)	0.60848 (12)	0.0208 (3)
H16A	0.0176	0.9310	0.6167	0.031*
H16B	0.0831	0.9412	0.5320	0.031*
H16C	0.1341	0.9356	0.6836	0.031*
O21	0.36690 (7)	0.39338 (4)	0.38688 (8)	0.0173 (2)
O24	0.39990 (8)	0.46146 (5)	0.74405 (8)	0.0256 (2)
O221	0.34285 (7)	0.25860 (4)	0.32365 (8)	0.0197 (2)
O222	0.39836 (7)	0.22764 (4)	0.53103 (8)	0.0170 (2)
C22	0.37715 (9)	0.34766 (6)	0.48321 (11)	0.0151 (3)
C23	0.38783 (9)	0.36726 (6)	0.60153 (11)	0.0166 (3)
H23	0.3942	0.3321	0.6639	0.020*
C24	0.38986 (10)	0.44161 (6)	0.63652 (11)	0.0170 (3)
C24A	0.37849 (9)	0.49097 (6)	0.53085 (11)	0.0152 (3)
C25	0.37738 (9)	0.56447 (6)	0.54600 (11)	0.0155 (3)
H25	0.3850	0.5832	0.6270	0.019*
C26	0.36546 (9)	0.61053 (6)	0.44566 (11)	0.0154 (3)
C27	0.35322 (10)	0.58073 (6)	0.32652 (12)	0.0182 (3)
H27	0.3446	0.6111	0.2564	0.022*
C28	0.35334 (10)	0.50898 (7)	0.30850 (12)	0.0190 (3)
H28	0.3444	0.4901	0.2271	0.023*
C28A	0.36677 (9)	0.46452 (6)	0.41131 (11)	0.0159 (3)
C221	0.37034 (9)	0.27309 (6)	0.43493 (11)	0.0156 (3)
C222	0.38561 (10)	0.15314 (6)	0.49520 (11)	0.0187 (3)
H22A	0.4129	0.1431	0.4289	0.022*
H22B	0.3154	0.1405	0.4615	0.022*
C223	0.43928 (11)	0.11188 (7)	0.61367 (12)	0.0211 (3)
H22C	0.4313	0.0613	0.5947	0.032*
H22D	0.4127	0.1233	0.6791	0.032*
H22E	0.5089	0.1240	0.6446	0.032*
C261	0.36521 (9)	0.68856 (6)	0.46004 (11)	0.0146 (3)
C262	0.31923 (9)	0.73240 (6)	0.35536 (11)	0.0163 (3)
H262	0.2869	0.7120	0.2738	0.020*
C263	0.31995 (9)	0.80523 (6)	0.36846 (11)	0.0167 (3)
H263	0.2885	0.8336	0.2955	0.020*
C264	0.36574 (9)	0.83778 (6)	0.48628 (11)	0.0165 (3)
C265	0.41121 (10)	0.79387 (6)	0.59067 (11)	0.0175 (3)
H265	0.4428	0.8144	0.6723	0.021*
C266	0.41138 (9)	0.72107 (7)	0.57822 (11)	0.0166 (3)
H266	0.4434	0.6928	0.6512	0.020*
C267	0.36524 (11)	0.91687 (6)	0.49995 (12)	0.0211 (3)
H26A	0.3662	0.9391	0.4221	0.032*
H26B	0.4231	0.9316	0.5725	0.032*
H26C	0.3061	0.9313	0.5141	0.032*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O11	0.0239 (5)	0.0110 (4)	0.0160 (4)	0.0018 (4)	0.0083 (4)	0.0015 (3)
O14	0.0381 (6)	0.0187 (5)	0.0180 (4)	−0.0004 (4)	0.0138 (4)	−0.0006 (4)
O121	0.0209 (5)	0.0164 (4)	0.0209 (4)	0.0001 (4)	0.0103 (4)	−0.0004 (3)
O122	0.0215 (5)	0.0103 (4)	0.0174 (4)	0.0006 (3)	0.0079 (4)	0.0009 (3)
C12	0.0135 (6)	0.0129 (6)	0.0182 (6)	−0.0002 (5)	0.0044 (5)	0.0023 (4)
C13	0.0154 (7)	0.0149 (6)	0.0175 (6)	−0.0010 (5)	0.0053 (5)	0.0023 (5)
C14	0.0173 (7)	0.0157 (6)	0.0168 (6)	−0.0006 (5)	0.0063 (5)	−0.0002 (5)
C14A	0.0131 (6)	0.0145 (6)	0.0167 (6)	0.0002 (5)	0.0047 (5)	0.0006 (5)
C15	0.0155 (6)	0.0157 (6)	0.0155 (6)	−0.0011 (5)	0.0058 (5)	−0.0015 (5)
C16	0.0123 (6)	0.0138 (6)	0.0170 (6)	−0.0001 (5)	0.0042 (5)	−0.0010 (4)
C17	0.0210 (7)	0.0138 (6)	0.0163 (6)	0.0017 (5)	0.0065 (5)	0.0023 (4)
C18	0.0228 (7)	0.0158 (6)	0.0149 (6)	0.0022 (5)	0.0076 (5)	−0.0006 (5)
C18A	0.0145 (7)	0.0111 (6)	0.0190 (6)	0.0008 (5)	0.0059 (5)	−0.0011 (4)
C121	0.0123 (6)	0.0139 (6)	0.0175 (6)	0.0001 (5)	0.0033 (5)	0.0005 (5)
C122	0.0224 (7)	0.0106 (6)	0.0186 (6)	0.0017 (5)	0.0071 (5)	−0.0009 (4)
C123	0.0317 (8)	0.0125 (6)	0.0231 (6)	0.0001 (6)	0.0109 (6)	0.0015 (5)
C161	0.0136 (6)	0.0125 (6)	0.0140 (5)	0.0001 (5)	0.0024 (5)	−0.0006 (4)
C162	0.0161 (7)	0.0165 (6)	0.0159 (6)	0.0015 (5)	0.0065 (5)	−0.0012 (5)
C163	0.0180 (7)	0.0146 (6)	0.0172 (6)	−0.0015 (5)	0.0059 (5)	0.0008 (5)
C164	0.0152 (7)	0.0136 (6)	0.0155 (6)	0.0007 (5)	0.0005 (5)	−0.0020 (4)
C165	0.0155 (7)	0.0177 (6)	0.0151 (6)	0.0014 (5)	0.0047 (5)	−0.0032 (5)
C166	0.0155 (7)	0.0164 (6)	0.0140 (5)	−0.0009 (5)	0.0042 (5)	−0.0003 (4)
C167	0.0241 (8)	0.0141 (6)	0.0237 (6)	0.0007 (5)	0.0084 (6)	−0.0017 (5)
O21	0.0246 (5)	0.0114 (4)	0.0164 (4)	0.0006 (4)	0.0082 (4)	0.0010 (3)
O24	0.0415 (7)	0.0190 (5)	0.0152 (4)	−0.0008 (4)	0.0091 (4)	−0.0007 (3)
O221	0.0232 (5)	0.0172 (5)	0.0163 (4)	0.0007 (4)	0.0046 (4)	−0.0006 (3)
O222	0.0224 (5)	0.0109 (4)	0.0163 (4)	0.0013 (4)	0.0053 (4)	0.0008 (3)
C22	0.0137 (6)	0.0134 (6)	0.0167 (6)	0.0003 (5)	0.0040 (5)	0.0025 (4)
C23	0.0160 (7)	0.0151 (6)	0.0166 (6)	0.0000 (5)	0.0037 (5)	0.0028 (5)
C24	0.0169 (7)	0.0168 (6)	0.0154 (6)	−0.0008 (5)	0.0036 (5)	0.0012 (5)
C24A	0.0130 (6)	0.0152 (6)	0.0156 (6)	0.0000 (5)	0.0031 (5)	0.0011 (4)
C25	0.0155 (7)	0.0155 (6)	0.0147 (5)	−0.0011 (5)	0.0047 (5)	−0.0018 (4)
C26	0.0126 (6)	0.0162 (6)	0.0174 (6)	−0.0004 (5)	0.0055 (5)	−0.0008 (5)
C27	0.0226 (7)	0.0149 (6)	0.0188 (6)	0.0012 (5)	0.0096 (5)	0.0028 (5)
C28	0.0257 (7)	0.0165 (6)	0.0161 (6)	0.0003 (5)	0.0092 (5)	−0.0010 (5)
C28A	0.0154 (7)	0.0130 (6)	0.0196 (6)	0.0008 (5)	0.0068 (5)	−0.0006 (5)
C221	0.0130 (6)	0.0151 (6)	0.0186 (6)	0.0004 (5)	0.0055 (5)	0.0014 (5)
C222	0.0235 (7)	0.0114 (6)	0.0202 (6)	−0.0015 (5)	0.0070 (5)	−0.0021 (5)
C223	0.0280 (8)	0.0142 (6)	0.0222 (6)	0.0005 (5)	0.0107 (6)	0.0024 (5)
C261	0.0139 (6)	0.0138 (6)	0.0179 (6)	0.0006 (5)	0.0082 (5)	−0.0001 (4)
C262	0.0149 (7)	0.0181 (6)	0.0157 (6)	−0.0011 (5)	0.0056 (5)	−0.0021 (5)
C263	0.0158 (7)	0.0170 (6)	0.0168 (6)	0.0019 (5)	0.0056 (5)	0.0029 (5)
C264	0.0151 (7)	0.0158 (6)	0.0207 (6)	−0.0004 (5)	0.0090 (5)	−0.0013 (5)
C265	0.0174 (7)	0.0175 (6)	0.0171 (6)	−0.0009 (5)	0.0057 (5)	−0.0039 (5)
C266	0.0157 (7)	0.0179 (6)	0.0159 (6)	0.0014 (5)	0.0054 (5)	0.0020 (5)
C267	0.0253 (8)	0.0148 (6)	0.0228 (6)	0.0002 (5)	0.0085 (6)	−0.0023 (5)

Geometric parameters (Å, º) top

O11—C12	1.3551 (14)	O21—C22	1.3561 (14)
O11—C18A	1.3769 (14)	O21—C28A	1.3770 (14)
O14—C14	1.2299 (14)	O24—C24	1.2282 (14)
O121—C121	1.2057 (14)	O221—C221	1.2025 (14)
O122—C121	1.3258 (14)	O222—C221	1.3274 (14)
O122—C122	1.4597 (14)	O222—C222	1.4625 (14)
C12—C13	1.3418 (16)	C22—C23	1.3403 (16)
C12—C121	1.5046 (17)	C22—C221	1.5056 (17)
C13—C14	1.4606 (17)	C23—C24	1.4615 (17)
C13—H13	0.9500	C23—H23	0.9500
C14—C14A	1.4785 (16)	C24—C24A	1.4777 (16)
C14A—C18A	1.3936 (16)	C24A—C28A	1.3911 (16)
C14A—C15	1.4061 (16)	C24A—C25	1.4049 (17)
C15—C16	1.3869 (16)	C25—C26	1.3904 (17)
C15—H15	0.9500	C25—H25	0.9500
C16—C17	1.4126 (16)	C26—C27	1.4095 (16)
C16—C161	1.4875 (16)	C26—C261	1.4885 (16)
C17—C18	1.3729 (17)	C27—C28	1.3757 (17)
C17—H17	0.9500	C27—H27	0.9500
C18—C18A	1.3877 (16)	C28—C28A	1.3895 (17)
C18—H18	0.9500	C28—H28	0.9500
C122—C123	1.5001 (17)	C222—C223	1.4998 (17)
C122—H12A	0.9900	C222—H22A	0.9900
C122—H12B	0.9900	C222—H22B	0.9900
C123—H12C	0.9800	C223—H22C	0.9800
C123—H12D	0.9800	C223—H22D	0.9800
C123—H12E	0.9800	C223—H22E	0.9800
C161—C166	1.3973 (17)	C261—C266	1.3989 (16)
C161—C162	1.3979 (17)	C261—C262	1.3995 (16)
C162—C163	1.3893 (17)	C262—C263	1.3885 (17)
C162—H162	0.9500	C262—H262	0.9500
C163—C164	1.3924 (17)	C263—C264	1.3952 (17)
C163—H163	0.9500	C263—H263	0.9500
C164—C165	1.3930 (17)	C264—C265	1.3968 (17)
C164—C167	1.5083 (16)	C264—C267	1.5079 (17)
C165—C166	1.3901 (17)	C265—C266	1.3875 (17)
C165—H165	0.9500	C265—H265	0.9500
C166—H166	0.9500	C266—H266	0.9500
C167—H16A	0.9800	C267—H26A	0.9800
C167—H16B	0.9800	C267—H26B	0.9800
C167—H16C	0.9800	C267—H26C	0.9800

C12—O11—C18A	118.08 (9)	C22—O21—C28A	118.25 (9)
C121—O122—C122	114.80 (9)	C221—O222—C222	115.53 (9)
C13—C12—O11	124.30 (11)	C23—C22—O21	124.14 (11)
C13—C12—C121	125.68 (11)	C23—C22—C221	126.14 (11)
O11—C12—C121	109.95 (10)	O21—C22—C221	109.67 (9)
C12—C13—C14	121.37 (11)	C22—C23—C24	121.38 (11)
C12—C13—H13	119.3	C22—C23—H23	119.3
C14—C13—H13	119.3	C24—C23—H23	119.3
O14—C14—C13	123.11 (11)	O24—C24—C23	123.13 (11)
O14—C14—C14A	122.88 (11)	O24—C24—C24A	122.83 (11)
C13—C14—C14A	114.01 (10)	C23—C24—C24A	114.04 (10)
C18A—C14A—C15	118.18 (11)	C28A—C24A—C25	118.24 (11)
C18A—C14A—C14	119.48 (11)	C28A—C24A—C24	119.56 (11)
C15—C14A—C14	122.34 (10)	C25—C24A—C24	122.19 (11)
C16—C15—C14A	121.49 (11)	C26—C25—C24A	121.82 (11)
C16—C15—H15	119.3	C26—C25—H25	119.1
C14A—C15—H15	119.3	C24A—C25—H25	119.1
C15—C16—C17	117.90 (11)	C25—C26—C27	117.43 (11)
C15—C16—C161	122.99 (10)	C25—C26—C261	122.68 (11)
C17—C16—C161	119.11 (10)	C27—C26—C261	119.89 (10)
C18—C17—C16	121.85 (11)	C28—C27—C26	122.09 (11)
C18—C17—H17	119.1	C28—C27—H27	119.0
C16—C17—H17	119.1	C26—C27—H27	119.0
C17—C18—C18A	118.90 (11)	C27—C28—C28A	118.93 (11)
C17—C18—H18	120.6	C27—C28—H28	120.5
C18A—C18—H18	120.6	C28A—C28—H28	120.5
O11—C18A—C18	115.60 (10)	O21—C28A—C28	115.91 (10)
O11—C18A—C14A	122.73 (10)	O21—C28A—C24A	122.62 (10)
C18—C18A—C14A	121.67 (11)	C28—C28A—C24A	121.47 (11)
O121—C121—O122	126.18 (11)	O221—C221—O222	126.22 (11)
O121—C121—C12	123.04 (11)	O221—C221—C22	123.05 (11)
O122—C121—C12	110.77 (10)	O222—C221—C22	110.73 (10)
O122—C122—C123	106.78 (10)	O222—C222—C223	106.56 (10)
O122—C122—H12A	110.4	O222—C222—H22A	110.4
C123—C122—H12A	110.4	C223—C222—H22A	110.4
O122—C122—H12B	110.4	O222—C222—H22B	110.4
C123—C122—H12B	110.4	C223—C222—H22B	110.4
H12A—C122—H12B	108.6	H22A—C222—H22B	108.6
C122—C123—H12C	109.5	C222—C223—H22C	109.5
C122—C123—H12D	109.5	C222—C223—H22D	109.5
H12C—C123—H12D	109.5	H22C—C223—H22D	109.5
C122—C123—H12E	109.5	C222—C223—H22E	109.5
H12C—C123—H12E	109.5	H22C—C223—H22E	109.5
H12D—C123—H12E	109.5	H22D—C223—H22E	109.5
C166—C161—C162	117.85 (11)	C266—C261—C262	117.31 (11)
C166—C161—C16	121.74 (11)	C266—C261—C26	121.49 (11)
C162—C161—C16	120.40 (11)	C262—C261—C26	121.20 (11)
C163—C162—C161	121.06 (11)	C263—C262—C261	121.22 (11)
C163—C162—H162	119.5	C263—C262—H262	119.4
C161—C162—H162	119.5	C261—C262—H262	119.4
C162—C163—C164	121.27 (11)	C262—C263—C264	121.58 (11)
C162—C163—H163	119.4	C262—C263—H263	119.2
C164—C163—H163	119.4	C264—C263—H263	119.2
C163—C164—C165	117.54 (11)	C263—C264—C265	117.07 (11)
C163—C164—C167	120.28 (11)	C263—C264—C267	121.25 (11)
C165—C164—C167	122.16 (11)	C265—C264—C267	121.68 (11)
C166—C165—C164	121.70 (11)	C266—C265—C264	121.70 (11)
C166—C165—H165	119.2	C266—C265—H265	119.1
C164—C165—H165	119.2	C264—C265—H265	119.1
C165—C166—C161	120.59 (11)	C265—C266—C261	121.12 (11)
C165—C166—H166	119.7	C265—C266—H266	119.4
C161—C166—H166	119.7	C261—C266—H266	119.4
C164—C167—H16A	109.5	C264—C267—H26A	109.5
C164—C167—H16B	109.5	C264—C267—H26B	109.5
H16A—C167—H16B	109.5	H26A—C267—H26B	109.5
C164—C167—H16C	109.5	C264—C267—H26C	109.5
H16A—C167—H16C	109.5	H26A—C267—H26C	109.5
H16B—C167—H16C	109.5	H26B—C267—H26C	109.5

C18A—O11—C12—C13	−0.81 (19)	C28A—O21—C22—C23	−0.43 (19)
C18A—O11—C12—C121	−177.93 (10)	C28A—O21—C22—C221	177.20 (10)
O11—C12—C13—C14	−0.6 (2)	O21—C22—C23—C24	−0.4 (2)
C121—C12—C13—C14	176.04 (12)	C221—C22—C23—C24	−177.63 (12)
C12—C13—C14—O14	−179.03 (13)	C22—C23—C24—O24	−179.71 (13)
C12—C13—C14—C14A	1.46 (18)	C22—C23—C24—C24A	0.44 (18)
O14—C14—C14A—C18A	179.54 (12)	O24—C24—C24A—C28A	−179.56 (13)
C13—C14—C14A—C18A	−0.96 (17)	C23—C24—C24A—C28A	0.29 (18)
O14—C14—C14A—C15	−0.7 (2)	O24—C24—C24A—C25	−0.7 (2)
C13—C14—C14A—C15	178.85 (12)	C23—C24—C24A—C25	179.18 (12)
C18A—C14A—C15—C16	−0.24 (19)	C28A—C24A—C25—C26	−0.31 (19)
C14—C14A—C15—C16	179.95 (12)	C24—C24A—C25—C26	−179.21 (12)
C14A—C15—C16—C17	0.05 (19)	C24A—C25—C26—C27	0.75 (19)
C14A—C15—C16—C161	179.98 (12)	C24A—C25—C26—C261	−179.29 (12)
C15—C16—C17—C18	0.36 (19)	C25—C26—C27—C28	−0.3 (2)
C161—C16—C17—C18	−179.57 (12)	C261—C26—C27—C28	179.72 (12)
C16—C17—C18—C18A	−0.6 (2)	C26—C27—C28—C28A	−0.5 (2)
C12—O11—C18A—C18	−178.91 (11)	C22—O21—C28A—C28	−178.28 (11)
C12—O11—C18A—C14A	1.31 (18)	C22—O21—C28A—C24A	1.20 (18)
C17—C18—C18A—O11	−179.42 (11)	C27—C28—C28A—O21	−179.49 (12)
C17—C18—C18A—C14A	0.4 (2)	C27—C28—C28A—C24A	1.0 (2)
C15—C14A—C18A—O11	179.80 (11)	C25—C24A—C28A—O21	179.94 (11)
C14—C14A—C18A—O11	−0.39 (19)	C24—C24A—C28A—O21	−1.13 (19)
C15—C14A—C18A—C18	0.03 (19)	C25—C24A—C28A—C28	−0.60 (19)
C14—C14A—C18A—C18	179.84 (12)	C24—C24A—C28A—C28	178.33 (12)
C122—O122—C121—O121	8.49 (18)	C222—O222—C221—O221	−5.78 (19)
C122—O122—C121—C12	−170.74 (10)	C222—O222—C221—C22	174.17 (10)
C13—C12—C121—O121	−156.97 (13)	C23—C22—C221—O221	165.68 (13)
O11—C12—C121—O121	20.10 (17)	O21—C22—C221—O221	−11.89 (17)
C13—C12—C121—O122	22.30 (18)	C23—C22—C221—O222	−14.27 (18)
O11—C12—C121—O122	−160.63 (10)	O21—C22—C221—O222	168.16 (10)
C121—O122—C122—C123	−176.76 (10)	C221—O222—C222—C223	168.94 (11)
C15—C16—C161—C166	−33.27 (18)	C25—C26—C261—C266	24.15 (19)
C17—C16—C161—C166	146.65 (12)	C27—C26—C261—C266	−155.89 (12)
C15—C16—C161—C162	147.55 (12)	C25—C26—C261—C262	−156.33 (12)
C17—C16—C161—C162	−32.53 (18)	C27—C26—C261—C262	23.63 (18)
C166—C161—C162—C163	−0.31 (18)	C266—C261—C262—C263	0.30 (18)
C16—C161—C162—C163	178.90 (11)	C26—C261—C262—C263	−179.24 (11)
C161—C162—C163—C164	0.36 (19)	C261—C262—C263—C264	−0.47 (19)
C162—C163—C164—C165	−0.32 (18)	C262—C263—C264—C265	0.19 (18)
C162—C163—C164—C167	178.21 (12)	C262—C263—C264—C267	−179.32 (12)
C163—C164—C165—C166	0.26 (18)	C263—C264—C265—C266	0.26 (19)
C167—C164—C165—C166	−178.24 (11)	C267—C264—C265—C266	179.76 (12)
C164—C165—C166—C161	−0.23 (19)	C264—C265—C266—C261	−0.4 (2)
C162—C161—C166—C165	0.25 (18)	C262—C261—C266—C265	0.14 (19)
C16—C161—C166—C165	−178.95 (11)	C26—C261—C266—C265	179.68 (12)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C162—H162···Cg(C261)	0.95	2.85	3.4914 (15)	126
C262—H262···Cg(C161)ⁱ	0.95	2.84	3.5408 (4)	131

Symmetry code: (i) x, −y+1/2, z−1/2.

(2) Ethyl 6-(4-fluorophenyl)-4-oxo-4H-chromene-2-carboxylate top

Crystal data top

C₁₈H₁₃FO₄	F(000) = 648
M_r = 312.28	D_x = 1.483 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71075 Å
a = 3.8521 (2) Å	Cell parameters from 15331 reflections
b = 20.6970 (15) Å	θ = 2.3–27.5°
c = 17.5478 (11) Å	µ = 0.11 mm⁻¹
β = 91.546 (1)°	T = 100 K
V = 1398.52 (15) Å³	Needle, colourless
Z = 4	0.42 × 0.02 × 0.01 mm

Data collection top

Rigaku Saturn724+ (2x2 bin mode) diffractometer	3177 independent reflections
Radiation source: Sealed Tube	2725 reflections with I > 2σ(I)
Graphite Monochromator monochromator	R_int = 0.035
Detector resolution: 28.5714 pixels mm^-1	θ_max = 27.5°, θ_min = 2.3°
profile data from ω–scans	h = −4→4
Absorption correction: multi-scan CrystalClear-SM Expert (Rigaku, 20112)	k = −26→26
T_min = 0.954, T_max = 0.999	l = −22→22
16479 measured reflections

Refinement top

Refinement on F²	0 restraints
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.031	H-atom parameters constrained
wR(F²) = 0.087	w = 1/[σ²(F_o²) + (0.0482P)² + 0.4787P] where P = (F_o² + 2F_c²)/3
S = 0.98	(Δ/σ)_max = 0.001
3176 reflections	Δρ_max = 0.31 e Å⁻³
209 parameters	Δρ_min = −0.20 e Å⁻³

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
C2	0.3562 (3)	0.34130 (5)	0.52749 (6)	0.0141 (2)
C3	0.5254 (3)	0.30718 (5)	0.58218 (6)	0.0155 (2)
H3	0.5714	0.2626	0.5741	0.019*
C4	0.6397 (3)	0.33746 (5)	0.65381 (6)	0.0149 (2)
C5	0.6674 (3)	0.44460 (5)	0.72144 (6)	0.0138 (2)
H5	0.7882	0.4245	0.7630	0.017*
C4A	0.5615 (3)	0.40718 (5)	0.65824 (6)	0.0135 (2)
C6	0.5990 (3)	0.51041 (5)	0.72442 (6)	0.0137 (2)
C7	0.4184 (3)	0.53915 (5)	0.66195 (6)	0.0145 (2)
H7	0.3699	0.5841	0.6633	0.017*
C8	0.3108 (3)	0.50362 (5)	0.59912 (6)	0.0147 (2)
H8	0.1891	0.5237	0.5577	0.018*
C8A	0.3843 (3)	0.43766 (5)	0.59763 (6)	0.0134 (2)
C21	0.2302 (3)	0.31555 (5)	0.45161 (6)	0.0143 (2)
C22	0.2530 (3)	0.22857 (5)	0.36482 (6)	0.0175 (2)
H22A	0.3781	0.2496	0.3230	0.021*
H22B	0.0005	0.2343	0.3553	0.021*
C23	0.3417 (3)	0.15775 (5)	0.36840 (6)	0.0193 (2)
H23A	0.2795	0.1373	0.3195	0.029*
H23B	0.2120	0.1372	0.4091	0.029*
H23C	0.5914	0.1526	0.3789	0.029*
C61	0.7187 (3)	0.55070 (5)	0.79004 (6)	0.0142 (2)
C62	0.7275 (3)	0.52672 (5)	0.86460 (6)	0.0169 (2)
H62	0.6491	0.4840	0.8740	0.020*
C63	0.8493 (3)	0.56456 (5)	0.92520 (6)	0.0193 (2)
H63	0.8535	0.5483	0.9759	0.023*
C64	0.9640 (3)	0.62638 (5)	0.90974 (6)	0.0182 (2)
C65	0.9542 (3)	0.65260 (5)	0.83766 (6)	0.0179 (2)
H65	1.0299	0.6956	0.8290	0.021*
C66	0.8302 (3)	0.61423 (5)	0.77786 (6)	0.0161 (2)
H66	0.8207	0.6315	0.7277	0.019*
F64	1.0940 (2)	0.66280 (3)	0.96871 (4)	0.02586 (17)
O1	0.27388 (19)	0.40483 (3)	0.53315 (4)	0.01485 (17)
O4	0.7946 (2)	0.30785 (4)	0.70522 (4)	0.02071 (19)
O21	0.0372 (2)	0.34557 (4)	0.40948 (4)	0.02041 (18)
O22	0.3576 (2)	0.25727 (4)	0.43820 (4)	0.01680 (17)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C2	0.0153 (5)	0.0131 (5)	0.0141 (5)	−0.0001 (4)	0.0014 (4)	−0.0013 (4)
C3	0.0180 (5)	0.0132 (5)	0.0151 (5)	0.0016 (4)	−0.0001 (4)	−0.0010 (4)
C4	0.0163 (5)	0.0143 (5)	0.0141 (5)	0.0011 (4)	0.0001 (4)	0.0009 (4)
C5	0.0141 (5)	0.0151 (5)	0.0121 (5)	−0.0001 (4)	−0.0001 (4)	0.0018 (4)
C4A	0.0134 (5)	0.0139 (5)	0.0132 (5)	0.0004 (4)	0.0012 (4)	0.0005 (4)
C6	0.0130 (5)	0.0155 (5)	0.0126 (5)	−0.0014 (4)	0.0011 (4)	−0.0006 (4)
C7	0.0151 (5)	0.0126 (4)	0.0157 (5)	0.0002 (4)	0.0012 (4)	0.0006 (4)
C8	0.0154 (5)	0.0150 (5)	0.0138 (5)	0.0013 (4)	−0.0005 (4)	0.0020 (4)
C8A	0.0140 (5)	0.0149 (5)	0.0113 (4)	−0.0014 (4)	0.0005 (4)	−0.0011 (4)
C21	0.0154 (5)	0.0144 (5)	0.0133 (5)	−0.0012 (4)	0.0014 (4)	0.0006 (4)
C22	0.0198 (5)	0.0194 (5)	0.0130 (5)	0.0002 (4)	−0.0033 (4)	−0.0046 (4)
C23	0.0193 (6)	0.0183 (5)	0.0203 (5)	0.0004 (4)	−0.0002 (4)	−0.0050 (4)
C61	0.0135 (5)	0.0152 (5)	0.0139 (5)	0.0013 (4)	0.0001 (4)	−0.0015 (4)
C62	0.0201 (5)	0.0143 (5)	0.0161 (5)	−0.0008 (4)	0.0006 (4)	0.0004 (4)
C63	0.0250 (6)	0.0199 (5)	0.0130 (5)	0.0004 (4)	−0.0004 (4)	0.0007 (4)
C64	0.0197 (5)	0.0198 (5)	0.0149 (5)	−0.0013 (4)	−0.0010 (4)	−0.0065 (4)
C65	0.0199 (5)	0.0149 (5)	0.0190 (5)	−0.0019 (4)	0.0020 (4)	−0.0017 (4)
C66	0.0180 (5)	0.0159 (5)	0.0144 (5)	0.0004 (4)	0.0009 (4)	0.0005 (4)
F64	0.0363 (4)	0.0244 (3)	0.0167 (3)	−0.0080 (3)	−0.0025 (3)	−0.0070 (3)
O1	0.0197 (4)	0.0123 (3)	0.0123 (3)	0.0017 (3)	−0.0030 (3)	−0.0008 (3)
O4	0.0290 (5)	0.0163 (4)	0.0165 (4)	0.0055 (3)	−0.0062 (3)	0.0002 (3)
O21	0.0265 (4)	0.0183 (4)	0.0161 (4)	0.0045 (3)	−0.0046 (3)	0.0003 (3)
O22	0.0204 (4)	0.0154 (4)	0.0143 (4)	0.0026 (3)	−0.0039 (3)	−0.0039 (3)

Geometric parameters (Å, º) top

C2—C3	1.3457 (14)	C21—O22	1.3257 (12)
C2—O1	1.3568 (12)	C22—O22	1.4647 (12)
C2—C21	1.5025 (14)	C22—C23	1.5059 (15)
C3—C4	1.4617 (14)	C22—H22A	0.9900
C3—H3	0.9500	C22—H22B	0.9900
C4—O4	1.2315 (13)	C23—H23A	0.9800
C4—C4A	1.4766 (14)	C23—H23B	0.9800
C5—C6	1.3886 (14)	C23—H23C	0.9800
C5—C4A	1.4042 (14)	C61—C62	1.3989 (14)
C5—H5	0.9500	C61—C66	1.4015 (14)
C4A—C8A	1.3984 (14)	C62—C63	1.3920 (15)
C6—C7	1.4135 (14)	C62—H62	0.9500
C6—C61	1.4851 (14)	C63—C64	1.3829 (16)
C7—C8	1.3797 (14)	C63—H63	0.9500
C7—H7	0.9500	C64—F64	1.3646 (12)
C8—C8A	1.3948 (14)	C64—C65	1.3759 (15)
C8—H8	0.9500	C65—C66	1.3903 (14)
C8A—O1	1.3774 (12)	C65—H65	0.9500
C21—O21	1.2065 (13)	C66—H66	0.9500

C3—C2—O1	124.47 (9)	O22—C22—H22A	110.2
C3—C2—C21	125.77 (9)	C23—C22—H22A	110.2
O1—C2—C21	109.76 (8)	O22—C22—H22B	110.2
C2—C3—C4	121.14 (9)	C23—C22—H22B	110.2
C2—C3—H3	119.4	H22A—C22—H22B	108.5
C4—C3—H3	119.4	C22—C23—H23A	109.5
O4—C4—C3	123.05 (9)	C22—C23—H23B	109.5
O4—C4—C4A	122.91 (9)	H23A—C23—H23B	109.5
C3—C4—C4A	114.03 (9)	C22—C23—H23C	109.5
C6—C5—C4A	121.29 (9)	H23A—C23—H23C	109.5
C6—C5—H5	119.4	H23B—C23—H23C	109.5
C4A—C5—H5	119.4	C62—C61—C66	118.41 (9)
C8A—C4A—C5	118.51 (9)	C62—C61—C6	121.68 (9)
C8A—C4A—C4	119.79 (9)	C66—C61—C6	119.91 (9)
C5—C4A—C4	121.69 (9)	C63—C62—C61	120.93 (10)
C5—C6—C7	118.26 (9)	C63—C62—H62	119.5
C5—C6—C61	121.65 (9)	C61—C62—H62	119.5
C7—C6—C61	120.07 (9)	C64—C63—C62	118.27 (10)
C8—C7—C6	121.77 (9)	C64—C63—H63	120.9
C8—C7—H7	119.1	C62—C63—H63	120.9
C6—C7—H7	119.1	F64—C64—C65	118.67 (10)
C7—C8—C8A	118.68 (9)	F64—C64—C63	118.35 (10)
C7—C8—H8	120.7	C65—C64—C63	122.98 (10)
C8A—C8—H8	120.7	C64—C65—C66	117.97 (10)
O1—C8A—C8	116.10 (9)	C64—C65—H65	121.0
O1—C8A—C4A	122.40 (9)	C66—C65—H65	121.0
C8—C8A—C4A	121.50 (9)	C65—C66—C61	121.41 (10)
O21—C21—O22	125.79 (10)	C65—C66—H66	119.3
O21—C21—C2	122.64 (9)	C61—C66—H66	119.3
O22—C21—C2	111.57 (9)	C2—O1—C8A	118.08 (8)
O22—C22—C23	107.55 (8)	C21—O22—C22	115.51 (8)

O1—C2—C3—C4	−0.66 (17)	C3—C2—C21—O22	−11.10 (15)
C21—C2—C3—C4	179.33 (10)	O1—C2—C21—O22	168.89 (8)
C2—C3—C4—O4	179.88 (11)	C5—C6—C61—C62	−35.73 (15)
C2—C3—C4—C4A	−1.71 (15)	C7—C6—C61—C62	145.98 (11)
C6—C5—C4A—C8A	0.07 (15)	C5—C6—C61—C66	143.58 (11)
C6—C5—C4A—C4	178.64 (10)	C7—C6—C61—C66	−34.71 (15)
O4—C4—C4A—C8A	−179.98 (10)	C66—C61—C62—C63	−1.07 (16)
C3—C4—C4A—C8A	1.60 (14)	C6—C61—C62—C63	178.25 (10)
O4—C4—C4A—C5	1.48 (16)	C61—C62—C63—C64	−0.46 (17)
C3—C4—C4A—C5	−176.94 (9)	C62—C63—C64—F64	−177.91 (10)
C4A—C5—C6—C7	0.08 (15)	C62—C63—C64—C65	1.81 (18)
C4A—C5—C6—C61	−178.24 (9)	F64—C64—C65—C66	178.21 (10)
C5—C6—C7—C8	−0.02 (16)	C63—C64—C65—C66	−1.50 (17)
C61—C6—C7—C8	178.33 (10)	C64—C65—C66—C61	−0.15 (16)
C6—C7—C8—C8A	−0.20 (16)	C62—C61—C66—C65	1.39 (16)
C7—C8—C8A—O1	−179.34 (9)	C6—C61—C66—C65	−177.94 (10)
C7—C8—C8A—C4A	0.36 (16)	C3—C2—O1—C8A	3.16 (15)
C5—C4A—C8A—O1	179.38 (9)	C21—C2—O1—C8A	−176.84 (8)
C4—C4A—C8A—O1	0.79 (15)	C8—C8A—O1—C2	176.53 (9)
C5—C4A—C8A—C8	−0.30 (15)	C4A—C8A—O1—C2	−3.17 (14)
C4—C4A—C8A—C8	−178.89 (10)	O21—C21—O22—C22	0.82 (15)
C3—C2—C21—O21	168.95 (11)	C2—C21—O22—C22	−179.12 (8)
O1—C2—C21—O21	−11.05 (14)	C23—C22—O22—C21	−165.47 (9)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C7—H7···O21ⁱ	0.95	2.47	3.1977 (13)	133
C65—H65···O4ⁱⁱ	0.95	2.50	3.4447 (13)	175
C66—H66···O21ⁱⁱⁱ	0.95	2.53	3.4425 (13)	162

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

Selected dihedral angles (°) top

Compound	θ_Chr–Phe	θ_{Chr–carboxylate}	θ_Chr–OCO
(1) a	32.8754)	23.23 (7)	21.16 (16)
(1) b	24.14 (5)	14.191 (7)	12.16 (17)
(2)	36.05 (5)	9.52 (6)	12.97 (13)

Selected π–π contacts and short intermolecular contacts (Å, °) top

Compound	contacts	distance	perpendicular distance	slippage/angle*
(1)	Cg1···Cg2ⁱ	3.7338 (8)	3.503*	0.45*
	Cg2···Cg2ⁱ	3.7226 (8)	3.5040 (6)	1.257
	Cg5···Cg6ⁱⁱ	3.6743 (9)	3.824*	0.98*
	Cg6···Cg6ⁱⁱ	3.9299 (9)	3.5762 (6)	1.630
(2)	Cg1···Cg1ⁱⁱⁱ	3.8521 (7)	3.3989 (4)	1.813
	Cg2···Cg2ⁱⁱⁱ	3.8521 (7)	3.3957 (4)	1.819
	Cg3···Cg3ⁱⁱⁱ'	3.8521 (7)	3.5811 (5)	1.419

Symmetry codes: (i) -x, 1 - y, 1 - z; (ii) 1 - x, 1 - y, 1 - z; (iii) 1 + x, y, z.

Acknowledgements

The authors thank the staff at the National Crystallographic Service, University of Southampton, for the data collection, help and advice (Coles & Gale, 2012 ), and the Foundation for Science and Technology (FCT) of Portugal (QUI/UI0081/2015) for financial support. CF (SFRH/BD/98519/2013) and AG (SFRH/BPD/93331/2013) are supported by FCT, POPH and QREN.

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