Crystal structure and Hirshfeld surface analysis of an etoxazole metabolite designated R4

Sowbhagya, C.; Mohan Kumar, T.M.; Bhavya, P.; Yathirajan, H.S.; Parkin, S.

doi:10.1107/S2056989025008084

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 81| Part 10| October 2025| Pages 964-967

https://doi.org/10.1107/S2056989025008084

Open

access

Crystal structure and Hirshfeld surface analysis of an etoxazole metabolite designated R4

Chaluvarangaiah Sowbhagya,^a Thaluru M. Mohan Kumar,^a Papegowda Bhavya,^b Hemmige S. Yathirajan ^c ^* and Sean Parkin ^d

^aDepartment of Physical Sciences, Amrita School of Engineering, Amrita Vishwa Vidyapeetham, Bengaluru-560 035, India, ^bDepartment of Applied Sciences, New Horizon College of Engineering, Bengaluru-560 103, India, ^cDepartment of Studies in Chemistry, University of Mysore, Manasagangotri, Mysuru-570 006, India, and ^dDepartment of Chemistry, University of Kentucky, Lexington, KY, 40506-0055, USA
^*Correspondence e-mail: [email protected]

Edited by X. Hao, Institute of Chemistry, Chinese Academy of Sciences (Received 3 September 2025; accepted 10 September 2025; online 19 September 2025)

A metabolite of the insecticide/acaricide etoxazole, designated R4 {systematic name N-[1-(4-tert-butyl-2-ethoxyphenyl)-2-hydroxyethyl]-2,6-difluorobenzamide, C₂₁H₂₅F₂NO₃}, is presented. The molecular structure has a central N-(2-hydroxyethyl)formamide group flanked by 4-tert-butyl-2-ethoxyphenyl and 2,6-difluorophenyl-substituted rings. The overall conformation is defined by its torsional degrees of freedom [N—C—C—C = 56.09 (18) and 99.41 (18)°], which place the 4-tert-butyl-2-ethoxyphenyl and 2,6-difluorophenyl rings at a dihedral angle of 70.66 (5)°. In the crystal, molecules are linked by a strong O—H—O hydrogen bond into chains that extend parallel to the a-axis. There are also weaker C—H—F and π-stacking [centroid–centroid distance = 4.266 (2) Å] interactions. A Hirshfeld surface analysis reveals that the intermolecular contacts are dominated by interactions involving hydrogen, the most abundant being H⋯H (54.1%), H⋯O/O⋯H (13.0%), H⋯F/F⋯H (12.8%), and H⋯C/C⋯H (12.8%).

Keywords: etoxazole metabolite R4; insecticide; acaricide; Hirshfeld-surface analysis; crystal structure.

CCDC reference: 2487064

1. Chemical context

The etoxazole metabolite designated R4 [systematic name: N-[1-(4-tert-butyl-2-ethoxyphenyl)-2-hydroxyethyl]-2,6-difluorobenzamide], C₂₁H₂₅F₂NO₃, which is found in metabolism studies of plants and rats, as well as in soil, is derived from etoxazole, an organofluorine chitin synthesis inhibitor. Etoxazole is a member of the oxazoline class of insecticides, having been developed as a new-generation insecticide and acaricide (Li et al., 2014 ). It has been used globally since 1998 (Park et al., 2020 ). A comprehensive review of the biological activity of oxazole derivatives was published by Kakkar & Narasimhan (2019 ), while Joshi et al. (2023 ) provided a detailed review of their chemistry. Recent research has also assessed the risks of oxidative stress and multiple toxicities induced by etoxazole (Macar et al., 2022 ). The synthesis and activity of novel acaricidal/insecticidal 2,4-diphenyl-1,3-oxazolines were reported by Suzuki et al. (2002 ).

Several analogues of etoxazole and its precursors have been synthesized by Liu et al. (2013 ). We have recently reported the crystal structures of etoxazole (Sowbhagya et al., 2025 ) and the etoxazole metabolite R13 (Mohan Kumar et al., 2024 ). In view of the agricultural importance of etoxazole and its metabolites, this paper reports the crystal structure and Hirshfeld-surface analysis of the etoxazole metabolite R4.

2. Structural commentary

The crystal structure of R4 is monoclinic, having the symmetry of space group Cc, with a single molecule in the asymmetric unit (Z′ = 1). The molecular structure (Fig. 1) consists of a central (2-hydroxyethyl)formamide moiety flanked by 4-tert-butyl-2-ethoxyphenyl and 2,6-difluorophenyl substituted rings. Individual bond lengths and angles all fall within the normal ranges (Allen et al., 1987 ).

Figure 1
An ellipsoid plot (50% probability) of etoxazole metabolite R4. Hydrogen atoms are drawn as small circles of arbitrary radius.

The amide group (C1,O1,C16,N1,H1N,C3) is almost planar [r.m.s.d. = 0.0343 Å, largest = 0.049 (6) Å at N1]. The molecular conformation is determined by torsion about the bonds connecting the rings to this central linker: N1—C3—C4—C9 [56.09 (18) Å] and N1—C1—C16—C17 [99.41 (18) Å]. These torsions lead to dihedral angles between the mean amide plane (excluding H1N) and the 4-t-butyl-2-ethoxyphenyl and 2,6-difluorophenyl rings of 49.84 (5)° and 82.74 (5)°, and a dihedral angle between the two benzene rings of 70.66 (5)°. Additional degrees of conformational flexibility serve to orient the ethoxy group [C4—C9—O2—C10 = −164.82 (12)°], hydroxyethyl [N1—C3—C2—O3 = −63.45 (15)°] and tert-butyl [C6—C7—C12—C13 = 60.97 (16)°] groups.

3. Supramolecular features

There is only one conventional hydrogen bond in the crystal structure of R4, i.e., O3—H3A⋯O1ⁱ with d_D⋯A = 2.8068 (17) Å, which links molecules into chains that propagate parallel to the a-axis, as shown in Fig. 2. However, there are also weak hydrogen-bond like contacts between adjacent difluorophenyl rings: C18—H18⋯F2ⁱⁱ [d_D⋯A = 3.505 (2) Å], and C20—H20⋯F1ⁱⁱⁱ [d_D⋯A = 3.473 (2) Å] (all symmetry codes are as per Table 1), forming ribbons roughly parallel to ( $[\overline{3}]$ ,1,6) extending approximately along the [ $[\overline{1}]$ ,0, $[\overline{0.5}]$ ], also shown in Fig. 2. These interactions are quantified in Table 1. The difluorophenyl rings of glide-related (x, 1 − y, z + $[{1\over 2}]$ ) molecules also stack into slightly zigzagged alternating columns parallel to the c-axis, as shown in Fig. 3, with centroid–centroid stacking distances of 4.266 (2) Å. The dihedral angles between adjacent rings in these stacks is 8.68 (8)°.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O3—H3A⋯O1ⁱ	0.85	1.96	2.8068 (17)	173
C18—H18⋯F2ⁱⁱ	0.95	2.57	3.505 (2)	168
C20—H20⋯F1ⁱⁱⁱ	0.95	2.56	3.473 (2)	162
Symmetry codes: (i) ; (ii) $[x-1, -y+1, z-{\script{1\over 2}}]$ ; (iii) $[x+1, -y+1, z+{\script{1\over 2}}]$ .

Figure 2
A partial packing plot of the R4 crystal structure viewed down the c-axis. Conventional O—H⋯O hydrogen bonds are drawn as solid dashed lines, while weaker C—H⋯F contacts are drawn as open dashed lines.

Figure 3
A partial packing plot of R4 viewed approximately down the a-axis. Stacking of the difluorophenyl rings is highlighted by dotted lines joining adjacent ring centroids.

A Hirshfeld surface (HS) analysis performed using CrystalExplorer (Spackman et al., 2021 ) indicates that the majority (92.7%) of intermolecular contacts involve hydrogen. Two-dimensional fingerprint plots for H⋯H (54.1%), H⋯O/O⋯H (13.0%), H⋯F/F⋯H (12.8%), and H⋯C/C⋯H (12.8%) are shown in Fig. 4. All other types of intermolecular contacts contribute 2.3% or less to the HS.

Figure 4
Two-dimensional fingerprint plots showing the most abundant types of atom–atom contacts present in the crystal packing: (a) H⋯H = 54.1%, (b) H⋯O/O⋯H = 13.0%, (c) H⋯F/F⋯H = 12.8%, and (d) C⋯H/H⋯C = 12.8%.

4. Database survey

A search of the Cambridge Structural Database [CSD, v6.00, April 2025; Groom et al., 2016 ) on the core framework of R4 but with the fluorine, hydroxymethyl, ethoxy, and tert-butyl groups specified as ‘any' returned 2593 hits. If the two fluorines were set to ‘any halogen', then ten (nine unique) matches were found. A similar search fragment, but with the two fluorines in place gave six structures, five of which were unique. CSD entry CEDQIN (Valkonen et al., 2010 ) is N-benzyl-2,3,4,5,6-pentafluorobenzamide. Structure NUCYOZ (Kaukorat et al., 1996 ), or N-benzyl-N-(2,6-difluorobenzoyl)aminomethyldimethylphosphine oxide includes the difluorophenyl group of R4, but has benzyl and methyl-dimethylphosphine oxide attached at its N atom. Structure KOWTOJ (Puigcerver et al., 2024 ) is a large urea-based rotaxane, while PUMHAH and PUMHEL (Arunachalam & Ghosh, 2009 ) are hexapodal amides. These latter three structures have little in common with R4.

In addition to the above, crystal structures of etoxazole (DULGUQ: Sowbhagya et al., 2025) and its metabolite R13 (UGUQUM: Mohan Kumar et al., 2024) were recently reported. Lei et al. (2009 ) published the crystal structure of 2-(3-methyl-2-nitrophenyl)-4,5-dihydro-1,3-oxazole (MOKMAB), an intermediate in the synthesis of anthranilamide insecticides. A crystal structure of ethyl 3-(4-chlorophenyl)-5-[(E)-2-(dimethylamino)ethenyl]-1,2-oxazole-4-carboxylate (JADRIS), was described by Efimov et al. (2015 ), while the structure of 2,2-diphenyl-5-dichloromethylene-3-oxazoline-4-ethylcarboxylate (KUXKIX), a diphenyl oxazoline compound, was reported by Puranik et al. (1992 ). Phenylpyrazole-based insecticide structures have been reported by Priyanka et al. (2022 ) and Vinaya et al., (2023 ) (FERPOL and GIBJEK, respectively).

5. Synthesis and crystallization

The sample of R4 was obtained as a gift from Honeychem Pharma Research Pvt. Ltd. It was purified by column chromatography and recrystallized from hexane by slow evaporation to yield colourless crystals.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. All hydrogen atoms were found in difference-Fourier maps. Those bonded to carbon were included in the refinement using riding models, with constrained distances set to 0.95 Å (Csp²—H), 0.98 Å (RCH₃), 0.99 Å (R₂CH₂) and 1.00 Å (R₃CH). The hydroxyl hydrogen was also treated as riding, but its bond distance was refined. The amide hydrogen atom coordinates were refined freely. U_iso(H) parameters were set to values of either 1.2U_eq or 1.5U_eq (RCH₃, OH, NH) of the parent atom.

Table 2
Experimental details

Crystal data
Chemical formula	C₂₁H₂₅F₂NO₃
M_r	377.42
Crystal system, space group	Monoclinic, Cc
Temperature (K)	100
a, b, c (Å)	5.7145 (1), 39.3575 (8), 8.4490 (2)
β (°)	95.500 (1)
V (Å³)	1891.50 (7)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.10
Crystal size (mm)	0.16 × 0.08 × 0.04

Data collection
Diffractometer	Bruker D8 Venture dual source
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 )
T_min, T_max	0.916, 0.959
No. of measured, independent and observed [I > 2σ(I)] reflections	32266, 4721, 4583
R_int	0.032
(sin θ/λ)_max (Å⁻¹)	0.668

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.025, 0.063, 1.05
No. of reflections	4721
No. of parameters	253
No. of restraints	2
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.18, −0.15
Absolute structure	Flack x determined using 2201 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	−0.04 (15)
Computer programs: APEX5 (Bruker, 2023 ), SHELXT (Sheldrick, 2015a ), SHELXL2019/3 (Sheldrick, 2015b ), XP in SHELXTL (Sheldrick, 2008 ), SHELXTL (Sheldrick, 2008) and publCIF (Westrip, 2010 ).

Supporting information

CCDC reference: 2487064

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S2056989025008084/nx2029sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989025008084/nx2029Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989025008084/nx2029Isup3.cml

checkCIF report

Computing details top

N-[1-(4-tert-Butyl-2-ethoxyphenyl)-2-hydroxyethyl]-2,6-difluorobenzamide top

Crystal data top

C₂₁H₂₅F₂NO₃	F(000) = 800
M_r = 377.42	D_x = 1.325 Mg m⁻³
Monoclinic, Cc	Mo Kα radiation, λ = 0.71073 Å
a = 5.7145 (1) Å	Cell parameters from 9223 reflections
b = 39.3575 (8) Å	θ = 2.6–28.3°
c = 8.4490 (2) Å	µ = 0.10 mm⁻¹
β = 95.500 (1)°	T = 100 K
V = 1891.50 (7) Å³	Cut block, colourless
Z = 4	0.16 × 0.08 × 0.04 mm

Data collection top

Bruker D8 Venture dual source diffractometer	4721 independent reflections
Radiation source: microsource	4583 reflections with I > 2σ(I)
Detector resolution: 7.41 pixels mm^-1	R_int = 0.032
φ and ω scans	θ_max = 28.4°, θ_min = 2.1°
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	h = −7→7
T_min = 0.916, T_max = 0.959	k = −52→52
32266 measured reflections	l = −11→11

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.025	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.063	w = 1/[σ²(F_o²) + (0.0319P)² + 0.425P] where P = (F_o² + 2F_c²)/3
S = 1.05	(Δ/σ)_max = 0.001
4721 reflections	Δρ_max = 0.18 e Å⁻³
253 parameters	Δρ_min = −0.15 e Å⁻³
2 restraints	Absolute structure: Flack x determined using 2201 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.04 (15)

Special details top

Experimental. The crystal was mounted using polyisobutene oil on the tip of a fine glass fibre, which was fastened in a copper mounting pin with electrical solder. It was placed directly into the cold gas stream of a liquid-nitrogen based cryostat (Hope, 1994; Parkin & Hope, 1998).

Diffraction data were collected with the crystal at 100K.

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.

Refinement. Refinement progress was checked using Platon (Spek, 2020) and by an R-tensor (Parkin, 2000). The final model was further checked with the IUCr utility checkCIF.

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

	x	y	z	U_iso*/U_eq
F1	0.10244 (19)	0.54111 (3)	0.65974 (15)	0.0408 (3)
F2	0.82092 (19)	0.54312 (2)	0.97487 (15)	0.0397 (3)
O1	0.3290 (2)	0.59371 (3)	0.93314 (15)	0.0302 (3)
O2	0.71769 (19)	0.62031 (3)	0.43543 (12)	0.0212 (2)
O3	0.9202 (2)	0.63295 (3)	0.94174 (13)	0.0250 (2)
H3A	1.037 (4)	0.6195 (6)	0.9370 (4)	0.038*
N1	0.5634 (2)	0.59924 (3)	0.73239 (15)	0.0194 (2)
H1N	0.647 (4)	0.5885 (5)	0.667 (3)	0.029*
C1	0.4443 (3)	0.58136 (4)	0.83255 (18)	0.0197 (3)
C2	0.8474 (3)	0.64540 (4)	0.78773 (18)	0.0215 (3)
H2A	0.947047	0.635476	0.709989	0.026*
H2B	0.866100	0.670400	0.785862	0.026*
C3	0.5898 (2)	0.63611 (3)	0.74138 (17)	0.0179 (3)
H3	0.498334	0.644115	0.829372	0.021*
C4	0.4911 (2)	0.65424 (3)	0.59172 (16)	0.0173 (3)
C5	0.3322 (2)	0.68064 (4)	0.60233 (16)	0.0184 (3)
H5	0.279190	0.685846	0.702732	0.022*
C6	0.2485 (2)	0.69966 (4)	0.47053 (17)	0.0183 (3)
H6	0.140387	0.717618	0.482167	0.022*
C7	0.3215 (2)	0.69264 (4)	0.32149 (16)	0.0163 (3)
C8	0.4776 (3)	0.66565 (3)	0.30836 (17)	0.0172 (2)
H8	0.526510	0.660023	0.207261	0.021*
C9	0.5625 (2)	0.64686 (3)	0.44178 (16)	0.0172 (3)
C10	0.8387 (3)	0.61756 (4)	0.29405 (18)	0.0227 (3)
H10A	0.901343	0.640002	0.266150	0.027*
H10B	0.729145	0.609578	0.203843	0.027*
C11	1.0372 (3)	0.59254 (4)	0.3269 (2)	0.0258 (3)
H11A	1.120836	0.589981	0.231619	0.039*
H11B	0.973612	0.570494	0.355537	0.039*
H11C	1.146264	0.600885	0.414935	0.039*
C12	0.2316 (2)	0.71494 (3)	0.17940 (16)	0.0165 (2)
C13	0.3109 (3)	0.75181 (4)	0.21162 (17)	0.0214 (3)
H13A	0.258401	0.765956	0.119536	0.032*
H13B	0.482702	0.752639	0.230125	0.032*
H13C	0.241988	0.760353	0.305750	0.032*
C14	0.3229 (3)	0.70329 (4)	0.02407 (17)	0.0202 (3)
H14A	0.259798	0.718142	−0.062863	0.030*
H14B	0.272400	0.679858	0.001201	0.030*
H14C	0.495007	0.704400	0.034257	0.030*
C15	−0.0377 (2)	0.71376 (4)	0.15693 (18)	0.0216 (3)
H15A	−0.095577	0.730599	0.077110	0.032*
H15B	−0.100581	0.718903	0.258160	0.032*
H15C	−0.089114	0.691042	0.121158	0.032*
C16	0.4627 (3)	0.54335 (4)	0.81631 (19)	0.0204 (3)
C17	0.2889 (3)	0.52419 (4)	0.7333 (2)	0.0267 (3)
C18	0.2970 (3)	0.48934 (4)	0.7214 (2)	0.0327 (4)
H18	0.174972	0.477132	0.661880	0.039*
C19	0.4885 (3)	0.47258 (4)	0.7989 (2)	0.0330 (4)
H19	0.498128	0.448527	0.792403	0.040*
C20	0.6650 (3)	0.49042 (4)	0.8852 (2)	0.0330 (4)
H20	0.794767	0.478893	0.939638	0.040*
C21	0.6492 (3)	0.52529 (4)	0.8907 (2)	0.0261 (3)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
F1	0.0317 (6)	0.0354 (6)	0.0509 (7)	−0.0035 (4)	−0.0197 (5)	0.0103 (5)
F2	0.0310 (5)	0.0247 (5)	0.0585 (7)	0.0000 (4)	−0.0204 (5)	−0.0013 (4)
O1	0.0325 (6)	0.0265 (5)	0.0342 (6)	0.0047 (5)	0.0164 (5)	0.0063 (5)
O2	0.0269 (5)	0.0203 (5)	0.0172 (5)	0.0079 (4)	0.0072 (4)	0.0038 (4)
O3	0.0270 (6)	0.0303 (6)	0.0169 (5)	0.0050 (5)	−0.0021 (4)	0.0001 (4)
N1	0.0233 (6)	0.0179 (6)	0.0173 (5)	−0.0010 (5)	0.0043 (5)	0.0011 (4)
C1	0.0181 (6)	0.0204 (6)	0.0202 (6)	0.0012 (5)	0.0002 (5)	0.0045 (6)
C2	0.0237 (7)	0.0217 (7)	0.0186 (6)	−0.0023 (6)	−0.0009 (5)	0.0025 (5)
C3	0.0225 (7)	0.0165 (6)	0.0147 (6)	−0.0002 (5)	0.0022 (5)	0.0006 (5)
C4	0.0182 (6)	0.0182 (6)	0.0155 (6)	−0.0023 (5)	0.0018 (5)	0.0010 (5)
C5	0.0200 (6)	0.0210 (6)	0.0146 (6)	−0.0013 (5)	0.0036 (5)	−0.0015 (5)
C6	0.0176 (6)	0.0188 (6)	0.0187 (6)	0.0018 (5)	0.0027 (5)	−0.0005 (5)
C7	0.0144 (6)	0.0176 (6)	0.0167 (6)	−0.0017 (5)	0.0005 (5)	0.0003 (5)
C8	0.0187 (6)	0.0198 (6)	0.0133 (6)	0.0003 (5)	0.0031 (5)	0.0000 (5)
C9	0.0175 (6)	0.0161 (6)	0.0182 (6)	0.0009 (5)	0.0028 (5)	0.0001 (5)
C10	0.0276 (8)	0.0221 (7)	0.0199 (7)	0.0068 (6)	0.0096 (6)	0.0025 (6)
C11	0.0274 (8)	0.0235 (7)	0.0275 (8)	0.0064 (6)	0.0076 (6)	0.0022 (6)
C12	0.0161 (6)	0.0183 (6)	0.0149 (6)	−0.0003 (5)	0.0011 (5)	0.0010 (5)
C13	0.0259 (7)	0.0194 (6)	0.0187 (7)	−0.0013 (5)	0.0002 (5)	0.0014 (5)
C14	0.0213 (7)	0.0246 (7)	0.0146 (6)	0.0028 (5)	0.0003 (5)	0.0013 (5)
C15	0.0176 (7)	0.0249 (7)	0.0220 (7)	0.0019 (5)	−0.0003 (5)	0.0042 (6)
C16	0.0208 (6)	0.0190 (6)	0.0215 (6)	−0.0014 (5)	0.0023 (5)	0.0043 (5)
C17	0.0231 (7)	0.0285 (7)	0.0274 (7)	−0.0034 (6)	−0.0036 (6)	0.0069 (6)
C18	0.0328 (9)	0.0282 (8)	0.0359 (9)	−0.0110 (7)	−0.0028 (7)	0.0015 (7)
C19	0.0378 (9)	0.0187 (7)	0.0426 (10)	−0.0031 (7)	0.0036 (7)	0.0015 (7)
C20	0.0294 (8)	0.0227 (7)	0.0456 (10)	0.0038 (6)	−0.0035 (7)	0.0036 (7)
C21	0.0220 (7)	0.0218 (7)	0.0333 (8)	−0.0016 (6)	−0.0042 (6)	0.0016 (6)

Geometric parameters (Å, º) top

F1—C17	1.3557 (19)	C10—H10A	0.9900
F2—C21	1.3517 (18)	C10—H10B	0.9900
O1—C1	1.2251 (19)	C11—H11A	0.9800
O2—C9	1.3749 (17)	C11—H11B	0.9800
O2—C10	1.4405 (17)	C11—H11C	0.9800
O3—C2	1.4152 (18)	C12—C14	1.528 (2)
O3—H3A	0.85 (3)	C12—C15	1.5334 (19)
N1—C1	1.3356 (19)	C12—C13	1.5367 (19)
N1—C3	1.4601 (18)	C13—H13A	0.9800
N1—H1N	0.88 (2)	C13—H13B	0.9800
C1—C16	1.5068 (19)	C13—H13C	0.9800
C2—C3	1.531 (2)	C14—H14A	0.9800
C2—H2A	0.9900	C14—H14B	0.9800
C2—H2B	0.9900	C14—H14C	0.9800
C3—C4	1.5132 (19)	C15—H15A	0.9800
C3—H3	1.0000	C15—H15B	0.9800
C4—C5	1.389 (2)	C15—H15C	0.9800
C4—C9	1.3982 (18)	C16—C21	1.381 (2)
C5—C6	1.388 (2)	C16—C17	1.384 (2)
C5—H5	0.9500	C17—C18	1.376 (2)
C6—C7	1.3918 (19)	C18—C19	1.387 (3)
C6—H6	0.9500	C18—H18	0.9500
C7—C8	1.3984 (19)	C19—C20	1.379 (3)
C7—C12	1.5352 (18)	C19—H19	0.9500
C8—C9	1.3958 (19)	C20—C21	1.376 (2)
C8—H8	0.9500	C20—H20	0.9500
C10—C11	1.508 (2)

C9—O2—C10	116.88 (11)	H11A—C11—H11B	109.5
C2—O3—H3A	109.5	C10—C11—H11C	109.5
C1—N1—C3	123.16 (13)	H11A—C11—H11C	109.5
C1—N1—H1N	119.4 (13)	H11B—C11—H11C	109.5
C3—N1—H1N	116.9 (14)	C14—C12—C15	107.80 (12)
O1—C1—N1	124.83 (13)	C14—C12—C7	112.58 (11)
O1—C1—C16	120.26 (13)	C15—C12—C7	109.65 (11)
N1—C1—C16	114.90 (13)	C14—C12—C13	108.45 (12)
O3—C2—C3	110.08 (12)	C15—C12—C13	109.00 (12)
O3—C2—H2A	109.6	C7—C12—C13	109.30 (11)
C3—C2—H2A	109.6	C12—C13—H13A	109.5
O3—C2—H2B	109.6	C12—C13—H13B	109.5
C3—C2—H2B	109.6	H13A—C13—H13B	109.5
H2A—C2—H2B	108.2	C12—C13—H13C	109.5
N1—C3—C4	113.38 (11)	H13A—C13—H13C	109.5
N1—C3—C2	110.07 (12)	H13B—C13—H13C	109.5
C4—C3—C2	111.93 (11)	C12—C14—H14A	109.5
N1—C3—H3	107.0	C12—C14—H14B	109.5
C4—C3—H3	107.0	H14A—C14—H14B	109.5
C2—C3—H3	107.0	C12—C14—H14C	109.5
C5—C4—C9	117.61 (12)	H14A—C14—H14C	109.5
C5—C4—C3	119.53 (12)	H14B—C14—H14C	109.5
C9—C4—C3	122.77 (12)	C12—C15—H15A	109.5
C6—C5—C4	121.93 (13)	C12—C15—H15B	109.5
C6—C5—H5	119.0	H15A—C15—H15B	109.5
C4—C5—H5	119.0	C12—C15—H15C	109.5
C5—C6—C7	120.58 (13)	H15A—C15—H15C	109.5
C5—C6—H6	119.7	H15B—C15—H15C	109.5
C7—C6—H6	119.7	C21—C16—C17	115.80 (13)
C6—C7—C8	118.13 (12)	C21—C16—C1	121.81 (14)
C6—C7—C12	119.16 (12)	C17—C16—C1	122.31 (14)
C8—C7—C12	122.71 (12)	F1—C17—C18	119.11 (15)
C9—C8—C7	120.90 (12)	F1—C17—C16	117.33 (14)
C9—C8—H8	119.6	C18—C17—C16	123.56 (15)
C7—C8—H8	119.6	C17—C18—C19	118.04 (16)
O2—C9—C8	123.15 (12)	C17—C18—H18	121.0
O2—C9—C4	116.02 (12)	C19—C18—H18	121.0
C8—C9—C4	120.83 (12)	C20—C19—C18	120.74 (15)
O2—C10—C11	107.99 (12)	C20—C19—H19	119.6
O2—C10—H10A	110.1	C18—C19—H19	119.6
C11—C10—H10A	110.1	C21—C20—C19	118.62 (16)
O2—C10—H10B	110.1	C21—C20—H20	120.7
C11—C10—H10B	110.1	C19—C20—H20	120.7
H10A—C10—H10B	108.4	F2—C21—C20	119.27 (14)
C10—C11—H11A	109.5	F2—C21—C16	117.50 (13)
C10—C11—H11B	109.5	C20—C21—C16	123.23 (15)

C3—N1—C1—O1	6.4 (2)	C9—O2—C10—C11	166.89 (13)
C3—N1—C1—C16	−172.76 (13)	C6—C7—C12—C14	−178.45 (12)
C1—N1—C3—C4	−120.42 (15)	C8—C7—C12—C14	2.52 (18)
C1—N1—C3—C2	113.35 (15)	C6—C7—C12—C15	−58.45 (16)
O3—C2—C3—N1	−63.45 (15)	C8—C7—C12—C15	122.51 (14)
O3—C2—C3—C4	169.50 (11)	C6—C7—C12—C13	60.97 (16)
N1—C3—C4—C5	127.51 (14)	C8—C7—C12—C13	−118.06 (14)
C2—C3—C4—C5	−107.25 (15)	O1—C1—C16—C21	−95.15 (19)
N1—C3—C4—C9	−56.09 (18)	N1—C1—C16—C21	84.0 (2)
C2—C3—C4—C9	69.15 (17)	O1—C1—C16—C17	81.4 (2)
C9—C4—C5—C6	−1.1 (2)	N1—C1—C16—C17	−99.41 (18)
C3—C4—C5—C6	175.52 (13)	C21—C16—C17—F1	179.55 (15)
C4—C5—C6—C7	0.3 (2)	C1—C16—C17—F1	2.8 (2)
C5—C6—C7—C8	1.1 (2)	C21—C16—C17—C18	−0.8 (3)
C5—C6—C7—C12	−178.00 (12)	C1—C16—C17—C18	−177.54 (16)
C6—C7—C8—C9	−1.7 (2)	F1—C17—C18—C19	−179.42 (16)
C12—C7—C8—C9	177.37 (13)	C16—C17—C18—C19	0.9 (3)
C10—O2—C9—C8	15.5 (2)	C17—C18—C19—C20	0.0 (3)
C10—O2—C9—C4	−164.82 (12)	C18—C19—C20—C21	−1.1 (3)
C7—C8—C9—O2	−179.42 (13)	C19—C20—C21—F2	179.99 (17)
C7—C8—C9—C4	0.9 (2)	C19—C20—C21—C16	1.2 (3)
C5—C4—C9—O2	−179.23 (13)	C17—C16—C21—F2	−179.10 (14)
C3—C4—C9—O2	4.31 (19)	C1—C16—C21—F2	−2.3 (2)
C5—C4—C9—C8	0.5 (2)	C17—C16—C21—C20	−0.3 (3)
C3—C4—C9—C8	−176.00 (13)	C1—C16—C21—C20	176.46 (16)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3A···O1ⁱ	0.85	1.96	2.8068 (17)	173
C18—H18···F2ⁱⁱ	0.95	2.57	3.505 (2)	168
C20—H20···F1ⁱⁱⁱ	0.95	2.56	3.473 (2)	162

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

Acknowledgements

The authors thank Honeychem Pharma Research Pvt. Ltd., Peenya Industrial Area, Bengaluru-560 058, India for the gift sample of etoxazole metabolite R4.

References

Allen, F. H., Kennard, O., Watson, D. G., Brammer, L., Orpen, A. G. & Taylor, R. (1987). J. Chem. Soc. Perkin Trans. 2 pp. S1–S19. Google Scholar
Arunachalam, M. & Ghosh, P. (2009). Org. Lett. 12, 328–331. CSD CrossRef Google Scholar
Bruker (2023). APEX5. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Efimov, I., Slepukhin, P. & Bakulev, V. (2015). Acta Cryst. E71, o1028. Web of Science CSD CrossRef 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
Joshi, S., Mehra, M., Singh, R. & Kakkar, S. (2023). Egypt. J. Basic Appl. Sci. 10, 218–239. Google Scholar
Kakkar, S. & Narasimhan, B. (2019). BMC Chem. 13, 16. Google Scholar
Kaukorat, T., Neda, I., Jones, P. G. & Schmutzler, R. (1996). Phosphorus Sulfur Silicon 112, 247–259. CSD CrossRef CAS 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
Lei, D., Yang, H., Li, B. & Kang, Z. (2009). Acta Cryst. E65, o54. Web of Science CSD CrossRef IUCr Journals Google Scholar
Liu, Y., Wei, X., Li, Y., Yang, N. & Wang, Q. (2013). New J. Chem. 37, 1803–1810. CrossRef CAS Google Scholar
Macar, O., Kalefetoğlu Macar, T., Çavuşoğlu, K. & Yalçın, E. (2022). Sci. Rep. 12, 20453. Web of Science CrossRef PubMed Google Scholar
Mohan Kumar, T. M., Bhaskar, B. L., Priyanka, P., Divakara, T. R., Yathirajan, H. S. & Parkin, S. (2024). Acta Cryst. E80, 1270–1273. Web of Science CSD CrossRef IUCr Journals Google Scholar
Park, W., Lim, W., Park, S., Whang, K.-Y. & Song, G. (2020). Environ. Pollut. 257, 113480. Web of Science CrossRef PubMed 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
Priyanka, P., Jayanna, B. K., Sunil Kumar, Y. C., Shreenivas, M. T., Srinivasa, G. R., Divakara, T. R., Yathirajan, H. S. & Parkin, S. (2022). Acta Cryst. E78, 1084–1088. Web of Science CSD CrossRef IUCr Journals Google Scholar
Puigcerver, J., Zamora-Gallego, J. M., Marin-Luna, M., Martinez-Cuezva, A. & Berna, J. (2024). J. Am. Chem. Soc. 146, 22887–22892. CSD CrossRef CAS PubMed Google Scholar
Puranik, V. G. & Tavale, S. S. (1992). J. Crystallogr. Spectrosc. Res. 22, 733–736. CSD CrossRef CAS Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals 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
Sowbhagya, C., Mohan Kumar, T. M., Yathirajan, H. S. & Parkin, S. (2025). Acta Cryst. E81, 239–242. CSD 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
Suzuki, J., Ishida, T., Kikuchi, Y., Ito, Y., Morikawa, C., Tsukidate, Y., Tanji, I., Ota, Y. & Toda, K. (2002). J. Pestic. Sci. 27, 1–8. CrossRef Google Scholar
Valkonen, A., Lahtinen, T. & Rissanen, K. (2010). Acta Cryst. E66, o3007. CSD CrossRef IUCr Journals Google Scholar
Vinaya, Basavaraju, Y. B., Srinivasa, G. R., Shreenivas, M. T., Yathirajan, H. S. & Parkin, S. (2023). Acta Cryst. E79, 54–59. Web of Science CSD CrossRef IUCr Journals Google Scholar
Wei, L., Hua, R., Li, M., Huang, Y., Li, S., He, Y. & Shen, Z. (2014). J. Insect Sci. 14, 104. Web of Science CrossRef PubMed Google Scholar
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925. Web of Science CrossRef CAS IUCr Journals Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 81| Part 10| October 2025| Pages 964-967

https://doi.org/10.1107/S2056989025008084

Open

access

Format		BIBTeX
		EndNote
		RefMan
		Refer
		Medline
		CIF
		SGML
		Plain Text
		Text

Format		BIBTeX
		EndNote
		RefMan
		Refer
		Medline
		CIF
		SGML
		Plain Text
		Text

Search IUCr Journals		doi		Advanced search
Author		volume	page

research communications\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Crystal structure and Hirshfeld surface analysis of an etoxazole metabolite designated R4

1. Chemical context

2. Structural commentary

3. Supra­molecular features

4. Database survey

5. Synthesis and crystallization

6. Refinement

Supporting information

Acknowledgements

References

research communications

3. Supramolecular features