Synthesis, characterization, crystal structure and Hirshfeld surface analysis of isobutyl 4-[4-(di­fluoro­meth­oxy)phen­yl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexa­hydro­quinoline-3-carboxyl­ate

Yıldırım, S. Ö.; Akkurt, M.; Çetin, G.; Şimşek, R.; Butcher, R.J.; Bhattarai, A.

doi:10.1107/S2056989023009623

research communications

CRYSTALLOGRAPHIC
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ISSN: 2056-9890

Volume 79| Part 12| December 2023| Pages 1132-1136

https://doi.org/10.1107/S2056989023009623

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Synthesis, characterization, crystal structure and Hirshfeld surface analysis of isobutyl 4-[4-(difluoromethoxy)phenyl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

Sema Öztürk Yıldırım,^a,^b Mehmet Akkurt,^c Gökalp Çetin,^d Rahime Şimşek,^e Ray J. Butcher ^f and Ajaya Bhattarai ^g ^*

^aDepartment of Physics, Faculty of Science, Eskisehir Technical University, Yunus Emre Campus 26470 Eskisehir, Türkiye, ^bDepartment of Physics, Faculty of Science, Erciyes University, 38039 Kayseri, Türkiye, ^cDepartment of Physics, Faculty of Sciences, Erciyes University, 38039 Kayseri, Türkiye, ^dDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, 24100 Erzincan, Türkiye, ^eDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye-Ankara, Türkiye, ^fDepartment of Chemistry, Howard University, Washington DC 20059, USA, and ^gDepartment of Chemistry, M.M.A.M.C (Tribhuvan University), Biratnagar, Nepal
^*Correspondence e-mail: ajaya.bhattarai@mmamc.tu.edu.np

Edited by S. P. Kelley, University of Missouri-Columbia, USA (Received 2 October 2023; accepted 3 November 2023; online 10 November 2023)

In the title compound, C₂₄H₂₉F₂NO₄, which crystallizes in the orthorhombic Pca2₁ space group with Z = 4, the 1,4-dihydropyridine ring adopts a distorted boat conformation, while the cyclohexene ring is in a distorted half-chair conformation. In the crystal, the molecules are linked by N—H⋯O and C—H⋯O interactions, forming supramolecular chains parallel to the a axis. These chains pack with C—H⋯π interactions between them, forming layers parallel to the (010) plane. The cohesion of the crystal structure is ensured by van der Waals interactions between these layers. Hirshfeld surface analysis shows the major contributions to the crystal packing are from H⋯H (56.9%), F⋯H/H⋯F (15.7%), O⋯H/H⋯O (13.7%) and C⋯H/H⋯C (9.5%) contacts.

Keywords: crystal structure; 1,4-dihydropyridine ring; cyclohexene ring; quinoline ring system; van der Waals interactions; Hirshfeld surface analysis.

CCDC reference: 2305562

1. Chemical context

Hexahydroquinoline (HHQ) ring systems occupy a prominent place in medicinal chemistry, attracting the attention of researchers for their versatile structural attributes and pharmacological potential. These ring systems, characterized by a unique combination of pyridine and cyclohexane rings, have shown remarkable bioactivity across a spectrum of therapeutic areas. Their capacity to interact with specific biological targets has led to the development of HHQ-based compounds with diverse medicinal properties, including antimicrobial, anti-inflammatory, and anticancer activities (Ranjbar et al., 2019 ). Recent studies have shown that these compounds are effective in cancer-related inflammatory pathways such as TGF-β (Längle et al., 2019 ). Additionally, they have been demonstrated to have inhibitory effects on receptors involved in cancer development, such as EGFR, or to reverse multi-drug resistance (Abo Al-Hamd et al., 2023 ; Shahraki et al., 2020 ).

The choice to synthesize HHQs is also fueled by the accessibility of various synthetic routes and the opportunity to fine-tune their chemical structure to optimize drug-like properties. Multi-component reactions and cyclization strategies provide versatile platforms for their synthesis, allowing for systematic modifications to explore structure–activity relationships (SAR; Batista et al., 2016 ). As a result, the strategic pursuit of hexahydroquinoline synthesis continues to be a compelling avenue in medicinal chemistry, promising innovative solutions to pressing medical challenges and drug discovery endeavors.

In this study, isobutyl 4-(4-difluoromethoxyphenyl)-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate was synthesized and its molecular structure was confirmed by IR, ¹H NMR, ¹³C NMR, HRMS and X-ray crystallography. The intermolecular interactions observed in the crystal packing were investigated by Hirshfeld surface analysis.

2. Structural commentary

The 1,4-dihydropyridine ring (N1/C1/C6–C9) of the title compound (Fig. 1), which crystallizes in the orthorhombic Pca2₁ space group with Z = 4, adopts a distorted boat conformation [puckering parameters (Cremer & Pople, 1975 ) are Q_T = 0.2779 (16) Å, θ = 73.7 (3)° and φ = 179.1 (3)°], while the cyclohexene ring (C1–C6) has a distorted half-chair conformation [puckering parameters are Q_T = 0.4464 (18) Å, θ = 48.9 (2)° and φ = 126.3 (3)°]. The 4-(4-difluoromethoxyphenyl) ring (C18–C23) makes a dihedral angle of 88.73 (6)° with the mean plane of the quinoline ring system [N1/C1–C9; maximum deviation = 0.415 (2) Å for C3]. The geometrical parameters of the title compound are in agreement with those reported for similar compounds in the Database survey section.

Figure 1
View of the title molecule. Displacement ellipsoids are drawn at the 30% probability level.

3. Supramolecular features and Hirshfeld surface analysis

In the crystal, the molecules are linked by N—H⋯O and C—H⋯O interactions, forming supramolecular chains parallel to the a-axis direction (see Table 1; Figs. 2 and 3). These chains pack with C—H⋯π interactions between them, forming layers parallel to the (010) plane (Fig. 4). The cohesion of the crystal structure is ensured by van der Waals interactions between these layers.

Table 1
Hydrogen-bond geometry (Å, °)

Cg3 is the centroid the benzene ring of the 4-(4-difluoromethoxyphenyl group of the title compound.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1N⋯O1ⁱ	0.87 (2)	1.98 (2)	2.8426 (17)	173 (2)
C19—H19A⋯O2ⁱ	0.95	2.43	3.100 (2)	127
C3—H3A⋯Cg3ⁱⁱ	0.99	2.84	3.7345 (18)	151
Symmetry codes: (i) $[x-{\script{1\over 2}}, -y+1, z]$ ; (ii) $[-x+1, -y+1, z+{\script{1\over 2}}]$ .

Figure 2
A view of the molecular packing of the title compound along the a-axis with the N—H⋯O, C—H⋯O hydrogen bonds and C—H⋯π interactions shown as dashed lines.

Figure 3
View of the molecular packing along the b-axis. Hydrogen bonds are shown as dashed lines.

Figure 4
View of the molecular packing along the c-axis. Hydrogen bonds are shown as dashed lines.

The Hirshfeld surfaces and their corresponding two-dimensional fingerprint plots were calculated using the software package Crystal Explorer 17.5 (Spackman et al., 2021 ). The d_norm surfaces are mapped over a fixed color scale from −0.5961 (red) to 1.9017 (blue) a.u. Red spots on the surface correspond to O⋯H/H⋯O interactions (Tables 1 and 2; Fig. 5a,b).

Table 2
Summary of short interatomic contacts (Å) in the title compound

H15A⋯H10B	2.37	1 − x, 1 − y, − $[{1\over 2}]$ + z
F2⋯H11B	2.83	$[{1\over 2}]$ − x, y, − $[{1\over 2}]$ + z
O1⋯H1N	1.98	$[{1\over 2}]$ + x, 1 − y, z
H10A⋯H22A	2.47	$[{3\over 2}]$ − x, y, $[{1\over 2}]$ + z
H17B⋯H22A	2.58	x, −1 + y, z
H12A⋯H17C	2.54	− $[{1\over 2}]$ + x, −y, z

Figure 5
(a) Front and (b) back views of the three-dimensional Hirshfeld surface for the title compound.

In Fig. 6, fingerprint plots of the most important non-covalent interactions for the title compound are shown. The major contributions to the crystal packing are from H⋯H (56.9%), F⋯H/H⋯F (15.7%), O⋯H/H⋯O (13.7%) and C⋯H/H⋯C (9.5%) contacts. O⋯C/C⋯O (1.1%), F⋯C/C⋯F (1.0%), C⋯C (0.7%), F⋯O/O⋯F (0.6%), O⋯N/N⋯O (0.5%) and N⋯H/H⋯N (0.2%) contacts, which contribute less than 1.1%, are not shown in Fig.7.

Figure 6
The two-dimensional fingerprint plots for the title compound showing (a) all interactions, and delineated into (b) H⋯H, (c) F⋯H/H⋯F, (d) O⋯H/H⋯O and (e) C⋯H/H⋯C interactions. The d_i and d_e values are the closest internal and external distances (in Å) from given points on the Hirshfeld surface.

4. Database survey

A search of the Cambridge Structural Database (CSD, Version 5.42, update of September 2021; Groom et al., 2016 ) for similar structures with the 1,4,5,6,7,8-hexahydroquinoline group showed that the nine most closely related to the title compound are LIMYUF (Pehlivanlar et al., 2023 ), WEZJUK (Yıldırım et al., 2023 ), ECUCUE (Yıldırım et al., 2022 ), LOQCAX (Steiger et al., 2014 ), NEQMON (Öztürk Yildirim, et al., 2013 ), PECPUK (Gündüz et al., 2012 ), IMEJOA (Linden et al., 2011 ), PUGCIE (Mookiah et al., 2009 ), UCOLOO (Linden et al., 2006 ) and DAYJET (Linden et al., 2005 ). In all of these compounds, molecules are linked by N—H⋯O hydrogen bonds. Furthermore, C—H⋯F hydrogen bonds in LIMYUF, C—H⋯O hydrogen bonds in WEZJUK, ECUCUE, NEQMON, IMEJOA and PUGCIE and C—H⋯π interactions in LIMYUF, WEZJUK and ECUCUE were also observed.

5. Synthesis and crystallization

The synthesis of the compound was carried out by refluxing 1 mmol of 4-(4-difluoromethoxy)benzaldehyde, isobutyl acetoacetate, 4,4-methyl-1,3-cyclohexandione and 5 mmol of ammonium acetate in methanol. The reaction process was monitored by thin-layer chromatography [ethyl acetate-n-hexane (1:1)], and after the reaction was complete, the mixture was allowed to stand at room temperature for a while and then poured into an ice–water mixture (Fig. 7). The resulting precipitates were purified again by crystallization with methanol (Yıldırım et al., 2023).

Figure 7
Synthetic scheme.

Isobutyl 4-(4-difluoromethoxyphenyl)-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

Light-yellow solid, m.p: 489–491 K, yield: 85%. IR (cm⁻¹) 3291 (N—H), 1674 (C=O, ester), 1597 (C=O, ketone). ¹H NMR (400 MHz, DMSO-d₆): δ 0.69 [3H, d, J = 9 Hz, –CH(CH₃)_a], 0.77 [3H, d, J = 9 Hz, –CH(CH₃)_b], 0.81 (3H, s, 6-CH₃), 0.97 (3H, s, 6-CH₃), 1.52–1.65 (2H, m, quinoline H₇), 1.72–1.81 (H, m, –CH–), 2.26 (3H, s, 2-CH₃), 2.46–2.50 (2H, m, quinoline H₈), 3.63–3.72 (2H, m, –CH₂)–, 4.94 (H, s, quinoline H₄), 6.96 (2H, dd, J = 9.2, 6.8 Hz, Ar-H_3,5), 7.16 (2H, dd, J = 9.2, 6.8 Hz, Ar-H_4,6), 7.26 (H, s, OCHF₂), 9.02 (H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): 18.6 (2-CH₃), 22.3 [–CH(CH₃)_a], 22.9 [–CH(CH₃)_b], 23.4 (C-8), 24.2 (6-CH₃), 24.8 (6-CH₃), 33.5 (C-7), 34.1 (C-4), 35 (–CH–), 39.5 (C-6), 68.2 (–CH₂–), 103.8 (C-3), 108.4 (C-4a), 114.2, 116.7, 125.4, 128.2, 135.5, 157.4 (phenyl carbons), 147.1(C-2), 150.6 (C-8a), 166.9 (–COO–), 168.3 (OCHF₂) 199.6 (C-5). HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calculated for C₂₃H₂₅F₄NO₃: 420.1942; found: 420.2150.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3. The N-bound H atom was located in a difference-Fourier map and refined freely [N1—H1N = 0.87 (2) Å]. All C-bound H atoms were positioned geometrically [C—H = 0.95–1.00 Å] and refined using a riding model with U_iso(H) = 1.2 or 1.5U_eq(C).

Table 3
Experimental details

Crystal data
Chemical formula	C₂₄H₂₉F₂NO₄
M_r	433.48
Crystal system, space group	Orthorhombic, Pca2₁
Temperature (K)	100
a, b, c (Å)	11.9879 (7), 12.1807 (7), 15.4518 (9)
V (Å³)	2256.3 (2)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.10
Crystal size (mm)	0.27 × 0.24 × 0.16

Data collection
Diffractometer	Bruker Quest D8 with Photon 2 detector
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 )
T_min, T_max	0.718, 0.744
No. of measured, independent and observed [I > 2σ(I)] reflections	103269, 9491, 7264
R_int	0.080
(sin θ/λ)_max (Å⁻¹)	0.826

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.045, 0.107, 1.03
No. of reflections	9491
No. of parameters	289
No. of restraints	1
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.32, −0.29
Absolute structure	Flack x determined using 2721 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	0.0 (2)
Computer programs: APEX2 and SAINT (Bruker, 2018 ), SHELXT (Sheldrick, 2015a ), SHELXL (Sheldrick, 2015b ), ORTEP-3 for Windows (Farrugia, 2012 ) and PLATON (Spek, 2020 ).

Supporting information

CCDC reference: 2305562

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989023009623/ev2001sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989023009623/ev2001Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989023009623/ev2001Isup3.cml

checkCIF report

Computing details top

Isobutyl 4-[4-(difluoromethoxy)phenyl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate top

Crystal data top

C₂₄H₂₉F₂NO₄	D_x = 1.276 Mg m⁻³
M_r = 433.48	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, Pca2₁	Cell parameters from 9859 reflections
a = 11.9879 (7) Å	θ = 2.4–32.7°
b = 12.1807 (7) Å	µ = 0.10 mm⁻¹
c = 15.4518 (9) Å	T = 100 K
V = 2256.3 (2) Å³	Chunk, light yellow
Z = 4	0.27 × 0.24 × 0.16 mm
F(000) = 920

Data collection top

Bruker Quest D8 with Photon 2 detector diffractometer	7264 reflections with I > 2σ(I)
φ and ω scans	R_int = 0.080
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	θ_max = 36.0°, θ_min = 2.4°
T_min = 0.718, T_max = 0.744	h = −18→19
103269 measured reflections	k = −20→19
9491 independent reflections	l = −25→21

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.045	w = 1/[σ²(F_o²) + (0.0508P)² + 0.3823P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.107	(Δ/σ)_max < 0.001
S = 1.03	Δρ_max = 0.32 e Å⁻³
9491 reflections	Δρ_min = −0.29 e Å⁻³
289 parameters	Absolute structure: Flack x determined using 2721 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
1 restraint	Absolute structure parameter: 0.0 (2)

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
F1	0.49509 (14)	0.92511 (11)	0.20621 (10)	0.0455 (4)
F2	0.36176 (12)	0.80630 (13)	0.21602 (10)	0.0467 (4)
O1	0.65307 (10)	0.66738 (10)	0.65205 (8)	0.0198 (2)
O2	0.72200 (10)	0.33422 (10)	0.48402 (9)	0.0239 (3)
O3	0.60039 (10)	0.19451 (9)	0.48360 (8)	0.0184 (2)
O4	0.53670 (11)	0.76006 (11)	0.24983 (8)	0.0236 (3)
N1	0.36644 (10)	0.41080 (11)	0.60065 (9)	0.0143 (2)
H1N	0.299 (2)	0.3886 (19)	0.6122 (14)	0.019 (5)*
C1	0.40589 (12)	0.50413 (12)	0.63969 (10)	0.0128 (3)
C2	0.32686 (12)	0.56285 (13)	0.69932 (10)	0.0149 (3)
H2A	0.279873	0.508580	0.730076	0.018*
H2B	0.277189	0.611193	0.665143	0.018*
C3	0.39163 (14)	0.63141 (13)	0.76504 (11)	0.0171 (3)
H3A	0.429018	0.581636	0.806558	0.021*
H3B	0.338594	0.677625	0.797973	0.021*
C4	0.47947 (13)	0.70546 (13)	0.72264 (11)	0.0165 (3)
C5	0.55598 (12)	0.63711 (12)	0.66451 (10)	0.0142 (3)
C6	0.51077 (12)	0.54097 (12)	0.62178 (10)	0.0134 (3)
C7	0.57801 (12)	0.48870 (12)	0.54998 (10)	0.0129 (2)
H7A	0.658250	0.488219	0.567679	0.015*
C8	0.54078 (12)	0.37018 (12)	0.53589 (10)	0.0135 (3)
C9	0.43551 (13)	0.33826 (12)	0.55678 (10)	0.0142 (3)
C10	0.54927 (15)	0.76147 (18)	0.79303 (13)	0.0285 (4)
H10A	0.584192	0.705497	0.829657	0.043*
H10B	0.500970	0.808215	0.828535	0.043*
H10C	0.607286	0.806523	0.765913	0.043*
C11	0.42455 (16)	0.79274 (14)	0.66419 (14)	0.0246 (4)
H11A	0.482159	0.841376	0.640633	0.037*
H11B	0.371361	0.835939	0.698245	0.037*
H11C	0.385240	0.756348	0.616550	0.037*
C12	0.37972 (13)	0.22972 (13)	0.53973 (11)	0.0186 (3)
H12A	0.400712	0.203315	0.482072	0.028*
H12B	0.298580	0.238862	0.542595	0.028*
H12C	0.403522	0.176294	0.583404	0.028*
C13	0.62870 (13)	0.30006 (12)	0.49936 (10)	0.0150 (3)
C14	0.68925 (15)	0.12977 (14)	0.44523 (12)	0.0208 (3)
H14A	0.751816	0.122384	0.486642	0.025*
H14B	0.717478	0.166562	0.392459	0.025*
C15	0.64362 (16)	0.01733 (14)	0.42246 (14)	0.0260 (4)
H15A	0.576642	0.027434	0.384717	0.031*
C16	0.6088 (3)	−0.04712 (19)	0.5015 (2)	0.0529 (8)
H16A	0.544199	−0.011657	0.528503	0.079*
H16B	0.670705	−0.049424	0.542902	0.079*
H16C	0.588934	−0.122088	0.484414	0.079*
C17	0.7331 (2)	−0.04286 (16)	0.37018 (15)	0.0330 (4)
H17A	0.747606	−0.002683	0.316403	0.050*
H17B	0.706990	−0.117084	0.356413	0.050*
H17C	0.801872	−0.047357	0.404232	0.050*
C18	0.56699 (12)	0.55695 (12)	0.46724 (10)	0.0137 (3)
C19	0.46204 (13)	0.59010 (14)	0.43930 (11)	0.0184 (3)
H19A	0.398046	0.567489	0.470878	0.022*
C20	0.44827 (14)	0.65559 (15)	0.36621 (12)	0.0208 (3)
H20A	0.375930	0.676416	0.347231	0.025*
C21	0.54288 (14)	0.68982 (13)	0.32165 (11)	0.0183 (3)
C22	0.64869 (13)	0.65619 (13)	0.34636 (11)	0.0175 (3)
H22A	0.712375	0.678221	0.314155	0.021*
C23	0.66020 (13)	0.58949 (13)	0.41925 (11)	0.0159 (3)
H23A	0.732370	0.565862	0.436503	0.019*
C24	0.45780 (18)	0.84020 (16)	0.25354 (14)	0.0294 (4)
H24A	0.444326	0.863192	0.314777	0.035*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
F1	0.0608 (9)	0.0302 (6)	0.0454 (8)	0.0086 (6)	0.0104 (7)	0.0181 (6)
F2	0.0317 (7)	0.0612 (9)	0.0474 (8)	0.0089 (6)	−0.0074 (6)	0.0154 (7)
O1	0.0120 (5)	0.0199 (5)	0.0276 (6)	−0.0016 (4)	0.0042 (4)	−0.0068 (5)
O2	0.0134 (5)	0.0212 (5)	0.0371 (7)	−0.0005 (4)	0.0070 (5)	−0.0075 (5)
O3	0.0158 (5)	0.0142 (5)	0.0252 (6)	0.0018 (4)	0.0030 (4)	−0.0036 (4)
O4	0.0262 (6)	0.0255 (6)	0.0191 (6)	0.0043 (5)	0.0044 (5)	0.0068 (5)
N1	0.0093 (5)	0.0162 (6)	0.0173 (6)	−0.0009 (4)	0.0014 (5)	−0.0004 (5)
C1	0.0110 (6)	0.0149 (6)	0.0124 (6)	0.0015 (5)	0.0006 (5)	0.0011 (5)
C2	0.0116 (6)	0.0179 (6)	0.0153 (7)	0.0009 (5)	0.0033 (5)	−0.0012 (5)
C3	0.0151 (7)	0.0203 (7)	0.0158 (7)	−0.0002 (6)	0.0034 (5)	−0.0026 (6)
C4	0.0129 (6)	0.0187 (7)	0.0177 (7)	−0.0003 (5)	0.0031 (5)	−0.0051 (5)
C5	0.0122 (7)	0.0156 (6)	0.0148 (6)	0.0015 (5)	0.0004 (5)	−0.0007 (5)
C6	0.0113 (6)	0.0143 (6)	0.0145 (6)	0.0004 (5)	0.0005 (5)	−0.0005 (5)
C7	0.0095 (6)	0.0147 (6)	0.0145 (6)	0.0001 (5)	0.0017 (5)	−0.0013 (5)
C8	0.0110 (6)	0.0141 (6)	0.0154 (6)	0.0006 (5)	0.0009 (5)	−0.0011 (5)
C9	0.0130 (6)	0.0151 (6)	0.0146 (7)	0.0004 (5)	−0.0001 (5)	0.0012 (5)
C10	0.0201 (8)	0.0368 (10)	0.0285 (9)	−0.0063 (7)	0.0049 (7)	−0.0175 (8)
C11	0.0202 (8)	0.0184 (7)	0.0353 (10)	0.0029 (6)	0.0080 (7)	0.0023 (7)
C12	0.0159 (7)	0.0172 (7)	0.0229 (8)	−0.0034 (5)	0.0021 (6)	−0.0016 (6)
C13	0.0141 (6)	0.0153 (6)	0.0156 (7)	0.0010 (5)	−0.0002 (5)	−0.0020 (5)
C14	0.0185 (7)	0.0177 (7)	0.0261 (8)	0.0051 (6)	0.0032 (6)	−0.0039 (6)
C15	0.0286 (9)	0.0163 (7)	0.0331 (10)	0.0030 (6)	0.0065 (7)	−0.0029 (7)
C16	0.0751 (19)	0.0233 (10)	0.0603 (17)	0.0074 (11)	0.0366 (15)	0.0097 (10)
C17	0.0388 (11)	0.0202 (8)	0.0401 (11)	0.0047 (7)	0.0097 (9)	−0.0055 (8)
C18	0.0115 (6)	0.0139 (6)	0.0157 (7)	−0.0003 (5)	0.0021 (5)	−0.0013 (5)
C19	0.0124 (6)	0.0234 (7)	0.0195 (7)	0.0007 (6)	0.0024 (5)	0.0035 (6)
C20	0.0144 (7)	0.0279 (8)	0.0201 (8)	0.0024 (6)	0.0000 (6)	0.0044 (7)
C21	0.0202 (7)	0.0183 (7)	0.0164 (7)	0.0010 (6)	0.0036 (6)	0.0019 (6)
C22	0.0160 (7)	0.0176 (7)	0.0190 (7)	−0.0020 (5)	0.0049 (6)	−0.0007 (6)
C23	0.0118 (6)	0.0160 (6)	0.0200 (7)	−0.0013 (5)	0.0023 (5)	−0.0015 (5)
C24	0.0336 (10)	0.0265 (9)	0.0280 (10)	0.0059 (7)	0.0031 (8)	0.0076 (7)

Geometric parameters (Å, º) top

F1—C24	1.343 (2)	C10—H10B	0.9800
F2—C24	1.354 (3)	C10—H10C	0.9800
O1—C5	1.2361 (19)	C11—H11A	0.9800
O2—C13	1.2166 (19)	C11—H11B	0.9800
O3—C13	1.3518 (18)	C11—H11C	0.9800
O3—C14	1.4520 (19)	C12—H12A	0.9800
O4—C24	1.360 (2)	C12—H12B	0.9800
O4—C21	1.403 (2)	C12—H12C	0.9800
N1—C1	1.371 (2)	C14—C15	1.516 (2)
N1—C9	1.388 (2)	C14—H14A	0.9900
N1—H1N	0.87 (2)	C14—H14B	0.9900
C1—C6	1.363 (2)	C15—C16	1.511 (3)
C1—C2	1.503 (2)	C15—C17	1.530 (3)
C2—C3	1.527 (2)	C15—H15A	1.0000
C2—H2A	0.9900	C16—H16A	0.9800
C2—H2B	0.9900	C16—H16B	0.9800
C3—C4	1.533 (2)	C16—H16C	0.9800
C3—H3A	0.9900	C17—H17A	0.9800
C3—H3B	0.9900	C17—H17B	0.9800
C4—C5	1.530 (2)	C17—H17C	0.9800
C4—C10	1.532 (2)	C18—C19	1.390 (2)
C4—C11	1.543 (2)	C18—C23	1.398 (2)
C5—C6	1.449 (2)	C19—C20	1.392 (2)
C6—C7	1.512 (2)	C19—H19A	0.9500
C7—C8	1.527 (2)	C20—C21	1.391 (2)
C7—C18	1.531 (2)	C20—H20A	0.9500
C7—H7A	1.0000	C21—C22	1.386 (2)
C8—C9	1.359 (2)	C22—C23	1.396 (2)
C8—C13	1.469 (2)	C22—H22A	0.9500
C9—C12	1.505 (2)	C23—H23A	0.9500
C10—H10A	0.9800	C24—H24A	1.0000

C13—O3—C14	113.95 (12)	C9—C12—H12B	109.5
C24—O4—C21	116.16 (14)	H12A—C12—H12B	109.5
C1—N1—C9	122.48 (13)	C9—C12—H12C	109.5
C1—N1—H1N	119.2 (15)	H12A—C12—H12C	109.5
C9—N1—H1N	117.1 (15)	H12B—C12—H12C	109.5
C6—C1—N1	120.11 (14)	O2—C13—O3	121.40 (14)
C6—C1—C2	123.32 (14)	O2—C13—C8	122.38 (14)
N1—C1—C2	116.55 (13)	O3—C13—C8	116.23 (13)
C1—C2—C3	110.33 (12)	O3—C14—C15	108.70 (14)
C1—C2—H2A	109.6	O3—C14—H14A	109.9
C3—C2—H2A	109.6	C15—C14—H14A	109.9
C1—C2—H2B	109.6	O3—C14—H14B	109.9
C3—C2—H2B	109.6	C15—C14—H14B	109.9
H2A—C2—H2B	108.1	H14A—C14—H14B	108.3
C2—C3—C4	112.76 (13)	C16—C15—C14	112.43 (19)
C2—C3—H3A	109.0	C16—C15—C17	111.82 (17)
C4—C3—H3A	109.0	C14—C15—C17	107.61 (16)
C2—C3—H3B	109.0	C16—C15—H15A	108.3
C4—C3—H3B	109.0	C14—C15—H15A	108.3
H3A—C3—H3B	107.8	C17—C15—H15A	108.3
C5—C4—C10	109.37 (13)	C15—C16—H16A	109.5
C5—C4—C3	110.02 (13)	C15—C16—H16B	109.5
C10—C4—C3	109.49 (14)	H16A—C16—H16B	109.5
C5—C4—C11	106.68 (13)	C15—C16—H16C	109.5
C10—C4—C11	109.99 (15)	H16A—C16—H16C	109.5
C3—C4—C11	111.25 (13)	H16B—C16—H16C	109.5
O1—C5—C6	121.47 (14)	C15—C17—H17A	109.5
O1—C5—C4	119.58 (14)	C15—C17—H17B	109.5
C6—C5—C4	118.88 (13)	H17A—C17—H17B	109.5
C1—C6—C5	121.21 (14)	C15—C17—H17C	109.5
C1—C6—C7	120.13 (14)	H17A—C17—H17C	109.5
C5—C6—C7	118.37 (13)	H17B—C17—H17C	109.5
C6—C7—C8	110.30 (12)	C19—C18—C23	118.43 (15)
C6—C7—C18	109.76 (12)	C19—C18—C7	119.69 (13)
C8—C7—C18	111.67 (12)	C23—C18—C7	121.86 (13)
C6—C7—H7A	108.3	C18—C19—C20	121.71 (15)
C8—C7—H7A	108.3	C18—C19—H19A	119.1
C18—C7—H7A	108.3	C20—C19—H19A	119.1
C9—C8—C13	126.22 (14)	C21—C20—C19	118.47 (15)
C9—C8—C7	120.53 (13)	C21—C20—H20A	120.8
C13—C8—C7	113.25 (12)	C19—C20—H20A	120.8
C8—C9—N1	119.20 (14)	C22—C21—C20	121.41 (15)
C8—C9—C12	128.48 (14)	C22—C21—O4	116.50 (14)
N1—C9—C12	112.32 (13)	C20—C21—O4	122.09 (15)
C4—C10—H10A	109.5	C21—C22—C23	118.99 (15)
C4—C10—H10B	109.5	C21—C22—H22A	120.5
H10A—C10—H10B	109.5	C23—C22—H22A	120.5
C4—C10—H10C	109.5	C22—C23—C18	120.93 (15)
H10A—C10—H10C	109.5	C22—C23—H23A	119.5
H10B—C10—H10C	109.5	C18—C23—H23A	119.5
C4—C11—H11A	109.5	F1—C24—F2	106.55 (17)
C4—C11—H11B	109.5	F1—C24—O4	107.35 (17)
H11A—C11—H11B	109.5	F2—C24—O4	110.76 (17)
C4—C11—H11C	109.5	F1—C24—H24A	110.7
H11A—C11—H11C	109.5	F2—C24—H24A	110.7
H11B—C11—H11C	109.5	O4—C24—H24A	110.7
C9—C12—H12A	109.5

C9—N1—C1—C6	13.6 (2)	C13—C8—C9—C12	−7.0 (3)
C9—N1—C1—C2	−168.22 (14)	C7—C8—C9—C12	173.21 (15)
C6—C1—C2—C3	−25.9 (2)	C1—N1—C9—C8	−13.9 (2)
N1—C1—C2—C3	155.98 (14)	C1—N1—C9—C12	165.30 (14)
C1—C2—C3—C4	50.56 (18)	C14—O3—C13—O2	−1.8 (2)
C2—C3—C4—C5	−53.48 (18)	C14—O3—C13—C8	178.30 (14)
C2—C3—C4—C10	−173.70 (14)	C9—C8—C13—O2	−178.39 (17)
C2—C3—C4—C11	64.52 (17)	C7—C8—C13—O2	1.4 (2)
C10—C4—C5—O1	−31.4 (2)	C9—C8—C13—O3	1.5 (2)
C3—C4—C5—O1	−151.72 (15)	C7—C8—C13—O3	−178.68 (13)
C11—C4—C5—O1	87.49 (18)	C13—O3—C14—C15	−174.28 (15)
C10—C4—C5—C6	151.64 (15)	O3—C14—C15—C16	−64.8 (2)
C3—C4—C5—C6	31.3 (2)	O3—C14—C15—C17	171.65 (16)
C11—C4—C5—C6	−89.44 (17)	C6—C7—C18—C19	−48.25 (19)
N1—C1—C6—C5	−177.73 (14)	C8—C7—C18—C19	74.40 (18)
C2—C1—C6—C5	4.2 (2)	C6—C7—C18—C23	130.33 (15)
N1—C1—C6—C7	8.5 (2)	C8—C7—C18—C23	−107.02 (16)
C2—C1—C6—C7	−169.55 (14)	C23—C18—C19—C20	−1.0 (2)
O1—C5—C6—C1	176.01 (15)	C7—C18—C19—C20	177.62 (15)
C4—C5—C6—C1	−7.1 (2)	C18—C19—C20—C21	−1.3 (3)
O1—C5—C6—C7	−10.1 (2)	C19—C20—C21—C22	2.8 (3)
C4—C5—C6—C7	166.76 (14)	C19—C20—C21—O4	−176.98 (16)
C1—C6—C7—C8	−26.47 (19)	C24—O4—C21—C22	−142.79 (17)
C5—C6—C7—C8	159.58 (13)	C24—O4—C21—C20	37.0 (2)
C1—C6—C7—C18	96.98 (16)	C20—C21—C22—C23	−2.1 (3)
C5—C6—C7—C18	−76.97 (17)	O4—C21—C22—C23	177.71 (14)
C6—C7—C8—C9	26.2 (2)	C21—C22—C23—C18	−0.2 (2)
C18—C7—C8—C9	−96.17 (17)	C19—C18—C23—C22	1.8 (2)
C6—C7—C8—C13	−153.64 (13)	C7—C18—C23—C22	−176.84 (14)
C18—C7—C8—C13	84.02 (15)	C21—O4—C24—F1	151.23 (16)
C13—C8—C9—N1	172.06 (15)	C21—O4—C24—F2	−92.82 (19)
C7—C8—C9—N1	−7.7 (2)

Hydrogen-bond geometry (Å, º) top

Cg3 is the centroid the benzene ring of the 4-(4-difluoromethoxyphenyl group of the title compound.

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···O1ⁱ	0.87 (2)	1.98 (2)	2.8426 (17)	173 (2)
C12—H12A···O3	0.98	2.40	2.817 (2)	105
C19—H19A···O2ⁱ	0.95	2.43	3.100 (2)	127
C3—H3A···Cg3ⁱⁱ	0.99	2.84	3.7345 (18)	151

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

Summary of short interatomic contacts (Å) in the title compound top

H15A···H10B	2.37	1 - x, 1 - y, -1/2 + z
F2···H11B	2.83	1/2 - x, y, - 1/2 + z
O1···H1N	1.98	1/2 + x, 1 - y, z
H10A···H22A	2.47	3/2 - x, y, 1/2 + z
H17B···H22A	2.58	x, -1 + y, z
H12A···H17C	2.54	-1/2 + x, -y, z

Acknowledgements

Authors' contributions are as follows. Conceptualization, RS and SÖY; methodology, RS and GÇ; investigation, RS and SÖY; writing (original draft), GÇ and MA; writing (review and editing of the manuscript), RS and SÖY; crystal data production and validation, RJB and SÖY; visualization, MA; funding acquisition, RJB; resources, AB, RJB and RS.

References

Abo Al-Hamd, M. G., Tawfik, H. O., Abdullah, O., Yamaguchi, K., Sugiura, M., Mehany, A. B. M., El-Hamamsy, M. H. & El-Moselhy, T. F. (2023). J. Enzyme Inhib. Med. Chem. 38, 2241674. https://doi. org/10.1080/14756366.2023.2241674. Google Scholar
Batista, V. F., Pinto, D. C. G. A. & Silva, A. M. S. (2016). ACS Sustainable Chem. Eng. 4, 4064–4078. Web of Science CrossRef CAS Google Scholar
Bruker (2018). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354–1358. CrossRef CAS Web of Science Google Scholar
Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849–854. Web of Science CrossRef CAS IUCr Journals Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
Gündüz, M. G., Butcher, R. J., Öztürk Yildirim, S., El-Khouly, A., Şafak, C. & Şimşek, R. (2012). Acta Cryst. E68, o3404–o3405. CSD CrossRef IUCr Journals Google Scholar
Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3–10. Web of Science CSD CrossRef ICSD CAS IUCr Journals Google Scholar
Längle, D., Werner, T. R., Wesseler, F., Reckzeh, E., Schaumann, N., Drowley, L., Polla, M., Plowright, A. T., Hirt, M. N., Eschenhagen, T. & Schade, D. (2019). ChemMedChem, 14, 810–822. Web of Science PubMed Google Scholar
Linden, A., Gündüz, M. G., Şimşek, R. & Şafak, C. (2006). Acta Cryst. C62, o227–o230. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Linden, A., Şafak, C., Şimşek, R. & Gündüz, M. G. (2011). Acta Cryst. C67, o80–o84. Web of Science CSD CrossRef IUCr Journals Google Scholar
Linden, A., Şimşek, R., Gündüz, M. & Şafak, C. (2005). Acta Cryst. C61, o731–o734. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Mookiah, P., Rajesh, K., Narasimhamurthy, T., Vijayakumar, V. & Srinivasan, N. (2009). Acta Cryst. E65, o2664. Web of Science CSD CrossRef IUCr Journals Google Scholar
Öztürk Yildirim, S., Butcher, R. J., Gündüz, M. G., El-Khouly, A., Şimşek, R. & Şafak, C. (2013). Acta Cryst. E69, o40–o41. CSD CrossRef IUCr Journals Google Scholar
Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249–259. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Pehlivanlar, E., Yıldırım, S. Ö., Şimşek, R., Akkurt, M., Butcher, R. J. & Bhattarai, A. (2023). Acta Cryst. E79, 664–668. Web of Science CSD CrossRef IUCr Journals Google Scholar
Ranjbar, S., Edraki, N., Firuzi, O., Khoshneviszadeh, M. & Miri, R. (2019). Mol. Divers. 23, 471–508. Web of Science CrossRef CAS PubMed Google Scholar
Shahraki, O., Khoshneviszadeh, M., Dehghani, M., Mohabbati, M., Tavakkoli, M., Saso, L., Edraki, N. & Firuzi, O. (2020). Molecules, 25, 1839. https://doi. org/10.3390/molecules25081839. 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
Spackman, P. R., Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Jayatilaka, D. & Spackman, M. A. (2021). J. Appl. Cryst. 54, 1006–1011. Web of Science CrossRef CAS IUCr Journals Google Scholar
Spek, A. L. (2020). Acta Cryst. E76, 1–11. Web of Science CrossRef IUCr Journals Google Scholar
Steiger, S. A., Monacelli, A. J., Li, C., Hunting, J. L. & Natale, N. R. (2014). Acta Cryst. C70, 790–795. Web of Science CSD CrossRef IUCr Journals Google Scholar
Yıldırım, S. Ö., Akkurt, M., Çetin, G., Şimşek, R., Butcher, R. J. & Bhattarai, A. (2022). Acta Cryst. E78, 798–803. Web of Science CSD CrossRef IUCr Journals Google Scholar
Yıldırım, S. Ö., Akkurt, M., Çetin, G., Şimşek, R., Butcher, R. J. & Bhattarai, A. (2023). Acta Cryst. E79, 187–191. Web of Science CSD CrossRef IUCr Journals Google Scholar

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