Synthesis, crystal structure and Hirshfeld surface analysis of N-(2,6-di­methyl­phen­yl)-2-morpholinoacetamide, a Lidocaine analog

Maimoune, I.; El Moutaouakil Ala Allah, A.; Kariuki, B.M.; Alsubari, A.; Mague, J.T.; Zarrouk, A.; Ramli, Y.

doi:10.1107/S2056989026006043

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 82| Part 7| July 2026| Pages 829-833

https://doi.org/10.1107/S2056989026006043

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Synthesis, crystal structure and Hirshfeld surface analysis of N-(2,6-dimethylphenyl)-2-morpholinoacetamide, a Lidocaine analog

Imane Maimoune,^a,^b Abderrazzak El Moutaouakil Ala Allah,^a Benson M. Kariuki,^c Abdulsalam Alsubari,^d ^* Joel T. Mague,^e Abdelkader Zarrouk ^b and Youssef Ramli ^a ^*

^aLaboratory of Medicinal Chemistry, Drug Sciences Research Center, Faculty of Medicine and Pharmacy Mohammed V University in Rabat, Morocco, ^bLaboratory of Materials Nanotechnology and Environment, Faculty of Sciences, Mohammed V University in Rabat, PO Box 1014, Rabat, Morocco, ^cSchool of Chemistry, Cardiff University, Main Building Park Place, Cardiff, CF10 3AT, United Kingdom, ^dLaboratory of Medicinal Chemistry, Faculty of Clinical Pharmacy, 21 September University, Yemen, and ^eDepartment of Chemistry, Tulane University New Orleans, LA, 70118, USA
^*Correspondence e-mail: [email protected], [email protected]

Edited by J. Ellena, Universidade de Sâo Paulo, Brazil (Received 11 May 2026; accepted 8 June 2026; online 16 June 2026)

In the title molecule, C₁₄H₂₀N₂O₂, the dihedral angle between the mean plane of the phenyl ring and that defined by the ipso-C—NH—(C= O)—CH₂— unit is 66.59 (11)°. The morpholine unit adopts a chair conformation. In the crystal, N—H⋯O hydrogen bonds and C—H⋯π(ring) interactions form chains extending along the b-axis direction. A Hirshfeld surface analysis showed H⋯H contacts to constitute nearly 70% of the intermolecular contacts in the crystal.

Keywords: crystal structure; acetamide; hydrogen bond; morpholine; Lidocaine; Hirshfeld surface.

CCDC reference: 2560706

1. Chemical context

In medicinal chemistry, heterocyclic compounds, particularly those with a nitrogen atom, are crucial, forming the core of over 90% of new drugs and vital biomolecules such as vitamins and DNA (Al Mulla, 2017 ). Numerous studies on the acetamide family have shown that it can be found in a variety of well-known medications from different classes with a range of therapeutic effects. They have a wide range of biological activities due to their structural resemblance to numerous bioactive natural and synthetic molecules (Missioui et al., 2022a ). A heterocyclic substance with local anesthetic properties is lidocaine. It is composed of a hydrophilic amine and a lipophilic aromatic ring. Its primary target in excitable cells is the voltage-gated sodium channel, which causes the elevated sodium permeability seen in skeletal muscles, peripheral nerves, neuroendocrine, and cardiac cells during the rising phase of the action potential.

As part of our research in this field (Maimoune et al., 2025 ), we synthesized the lidocaine analogue N-(2,6-dimethylphenyl)-2-morpholinoacetamide, 3, via an alkylation reaction of morpholine by 2-chloro-N-(2,6-dimethylphenyl)acetamide under refluxing toluene, the crystal structure of which is presented in this paper. The intermolecular interactions were examined using a Hirshfeld surface analysis.

2. Structural commentary

In the title molecule 3, Fig. 1, the dihedral angle between the mean plane of the C1–C6 ring and the plane defined by atoms C1/N1/C9/C10 is 66.59 (11)° while the dihedral angle between the latter plane and that defined by atoms C11–C14 is 63.59 (11)°. The morpholine unit adopts a chair conformation. Bond lengths and interbond angles are as expected. An intramolecular N—H⋯N contact is observed (Table 1).

Table 1
Hydrogen-bond geometry (Å, °)

Cg2 is the centroid of the C1–C6 ring.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯N2	0.88 (2)	2.278 (18)	2.738 (2)	112.5 (16)
N1—H1⋯O1ⁱ	0.88 (2)	2.34 (2)	3.0798 (18)	141.3 (16)
C10—H10B⋯Cg2ⁱⁱ	0.97	2.94	3.782 (2)	146
Symmetry codes: (i) $[-x+{\script{3\over 2}}, y+{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (ii) $[-x+{\script{3\over 2}}, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ .

Figure 1
Perspective view of the title molecule with the abeling scheme and 30% probability ellipsoids.

3. Supramolecular features

In the crystal, N1—H1⋯O1ⁱ hydrogen bonds and C10—H10B⋯Cg2ⁱⁱ interactions (Table 1) form chains extending along the b-axis direction (Fig. 2). The chains largely pack with normal van der Waals contacts.

Figure 2
Packing viewed along the c-axis direction with N—H⋯O hydrogen bonds and C—H⋯π(ring) interactions depicted, respectively, by blue and green dashed lines.

4. Database survey

A search of the Cambridge Structural Database (CSD, updated to April 2026; Groom, et al., 2016 ) with the fragment pictured in Fig. 3 (R = N) gave 99 hits, many of which were either metal complexes or salts in which R = R′R′′NH⁺ (R′ and R′′ = alkyl groups). Excluding these, 36 hits remained that were considered similar to the title molecule and of these, 25 were co-crystals (Table 2 with R defined in Fig. 3). One of the more salient quantities common to all, and the most likely to vary, is the dihedral angle between the mean plane of the 2,6-dimethylphenyl ring and the plane defined by the ipso-C—NH—(C=O)—CH₂— unit. This is likely to be large to avoid close contacts between the methyl and carbonyl groups. Indeed, the smallest value is 57.2 (2)° in CINBEK but can be as large as 86.4 (3)° in WEDXAH, although the majority are in the range 60–75° as is the case for 3. Considering those that are not co-crystals, this angle has a range of 57.2 (2)° (in CINBEK) to 82.0° (in LIDCAN10) and since the R group is fairly remote from the ipso-C—N bond, the variation is likely due to packing considerations. A comparable range for the dihedral angle is also seen in the co-crystals and there does not appear to be any definite correlation with the size of the second component.

Table 2
Database Survey

REFCODE	R	Component 2	Dihedral angle (°)	Reference
BIDVET	NEt₂	2-i-propyl-5-methylcyclohexanol	85.4 (13)	Ma et al. (2023 )
BIDVET01	NEt₂	2-i-propyl-5-methylcyclohexanol	85.6 (14)	Ma et al. (2023)
BIDVET02	NEt₂	2-i-propyl-5-methylcyclohexanol	84.4 (6)	Ma et al. (2023)
DALJIN	NEt₂	nonanedioic acid	58.90 (15), 65.00 (15)	Zotova et al. (2021 )
LIDCAN10	NEt₂	–	82.0, 77.8	Hanson & Banner (1974 )
LIDCAN11	NEt₂	–	76.0 (6), 75.6 (6)	Bambagiotti-Alberti et al. (2007 )
LIDCAN12	NEt₂	–	79.79 (15), 72.74 (10), 68.41 (16), 78.93 (16)	Gryl (2015 )
SEQRAJ	NEt₂	2-i-propyl-5-methylcyclohexanol	76.05 (18)	Corvis et al. (2010 )
TURNOW	NEt₂	1,3,5-trihydroxybenzene	71.24 (8)	Magaña-Vergara et al. (2018 )
WEDWUA	NEt₂	1,4-dibromo-2,3,5,6-tetrafluorobenzene	78.42 (17)	Choquesillo-Lazarte et al. (2017 )
WEDXAH	NEt₂	1,4-diiodo-2,3,5,6-tetrafluorobenzene	86.4 (3)	Choquesillo-Lazarte et al. (2017)
GENRAT	pyrrolidin-2-one-1-yl	–	66.49 (15)	Wang et al. (2006b )
KAJSIB	pyrrolidin-2-one-1-yl	2-hydroxy-2-phenylacetic acid	60.87 (16)	Buol et al. (2020a )
KAJSIB01	pyrrolidin-2-one-1-yl	2-hydroxy-2-phenylacetic acid	60.84 (14)	Buol et al. (2020a)
OYUWOX	pyrrolidin-2-one-1-yl	2-phenylsuccinic acid	61.23 (18)	Buol et al. (2020a)
OYUWUD01	pyrrolidin-2-one-1-yl	5-nitroisophthalic acid	71.59 (13)	Buol et al. (2020a)
OYUXAK	pyrrolidin-2-one-1-yl	4-hydroxybenzoic acid	64.89 (12)	Buol et al. (2020b )
OYUXIS	pyrrolidin-2-one-1-yl	5-cyanoisophthalic acid	68.75 (19)	Buol et al. (2020b)
OYUXOY	pyrrolidin-2-one-1-yl	2-benzoylbenzoic acid	60.03 (17)	Buol et al. (2020b)
OYUXUE	pyrrolidin-2-one-1-yl	2-hydroxy-3-phenylpropanoic acid	60.4 (2)	Buol et al. (2020b)
OYUYAL	pyrrolidin-2-one-1-yl	2-phenylbutyric acid	61.6 (8)	Buol et al. (2020b)
OYUYEP	pyrrolidin-2-one-1-yl	5-hydroxyisophthalic acid	74.91 (9), 78.08 (9)	Buol et al. (2020a)
OYUYIT	pyrrolidin-2-one-1-yl	2-hydroxypropane-1,2,3-tricarboxylic acid	69 (9)	Buol et al. (2020a)
OYUYIT01	pyrrolidin-2-one-1-yl	2-hydroxypropane-1,2,3-tricarboxylic acid	69.7 (9), 69.0 (9), 67.7 (7), 70.5 (8)	Buol et al. (2020b)
OYUZAM	pyrrolidin-2-one-1-yl	oxalic acid	69.6 (6), 67.0 (7), 68.9 (8), 77.0 (8)	Buol et al. (2020a)
OYUZOA	pyrrolidin-2-one-1-yl	3,4,5-trihydroxybenzoic acid	70.4 (7), 72.1 (9)	Buol et al. (2020b)
ACEZAK	4-R′-piperazin-1-yl^a	–	64.23 (19)	Wang et al. (2004 )
CINBEK	4-R′-piperazin-1-yl^b	–	57.2 (2)	Silva et al. (2023 )
JAYSAE	4-R′-piperazin-1-yl^c	–	67.73 (16)	Wang et al. (2005b )
LIPFAZ	4-R′'-piperazin-1-yl^d	–	73.3 (4)	Germain et al. (1977 )
MAPKIY	4-R′-piperazin-1-yl^e	–	63.86 (17)	Wang et al. (2005a )
SENCAQ	4-R′-piperazin-1-yl^f	–	65.5 (6)	Wang et al. (2006a )
SEJLOM	3-hydroxy-3-methoxymethyl-2-oxoindolin-1-yl	–	72.76 (8)	Nchioua et al. (2022 )
VAVGIM	4-(2,6-dimethylphenyl)-3,5-dioxopiperazin-1-yl	–	73.98 (15)	Heim et al. (2021 )
YOTROO	N(CH₂COOH)₂	–	60.88 (18)	Ribár et al. (1995 )
YOTRUU	N(CH₂COOH)[CH₂C(O)OMe]	–	74.5 (4)	Ribár et al. (1995)
Notes: (a) R′ = 3-(4-nitrophenyl)-1,2,4-oxadiazol-5-ylmethyl; (b) R′ = 2-hydroxy-3-(2-methoxyphenoxy)propyl; (c) R′ = 3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-ylmethyl; (d) R′ = 4,4-bis(4-fluorophenyl)butyl; (e) R′ = 3-(2-chlorophenyl)-1,2,4-oxadiazol-5-ylmethyl; (f) R′ = 3-(4-bromophenyl)-1,2,4-oxadiazol-5-ylmethyl.

Figure 3
The search fragment used for the Database survey.

5. Hirshfeld surface analysis

The Hirshfeld surface of 3 was calculated with CrystalExplorer17 (Spackman et al., 2021 ) and mapped over d_norm from −0.1546 to 1.1576 in arbitrary units. It is shown, together with two neighboring molecules and the hydrogen bonds between them, in Fig. 4. Details of the appearance and interpretations of the plots generated by CrystalExplorer have been published (Tan et al., 2019 ). The ensemble in Fig. 4 is a portion of the hydrogen-bonded chain depicted in Fig. 2. Fig. 5 presents the fingerprint plots showing all intermolecular contacts (5a) and those showing each of the three most significant ones. The H⋯H contacts (5b) comprise 69.2% of the total, consistent with the periphery of the molecule being largely hydrogen atoms. The next most important are the O⋯H/H⋯O contacts at 16.7% of the total (5c), which appear as a pair of sharp spikes at d_e + d_i ≃ 2.3 Å with broad shoulders at d_e + d_i ≃ 2.6 Å: the former represent the N1—H1⋯O1ⁱ hydrogen bonds (Table 1) while the latter are attributed to C—H⋯O contacts, which range from 2.66 to 2.73 Å and are considered to be slightly compressed van der Waals contacts rather than significant C—H⋯O hydrogen bonds. The last are the C⋯H/H⋯C contacts (5d) appearing as a pair of broad peaks at d_e + d_i ≃ 2.8 Å and attributed, in part, to the C—H⋯π(ring) interactions listed in Table 1 and contributing 14.0% to the total. The results of this analysis show a strong, 1-D supramolecular component to the crystal but relatively weak interactions in the other two directions.

Figure 4
The d_norm Hirshfeld surface of the title molecule with two neighboring molecules in the hydrogen-bonded chain. The N—H⋯O hydrogen bonds are shown as dashed lines.

Figure 5
The two-dimensional fingerprint plots for the title molecule showing (a) all contacts, (b) H⋯H contacts, (c) O⋯H/H⋯O contacts and (d) C⋯H/H⋯C contacts.

6. Synthesis and crystallization

The reaction sequence for preparing 3 is shown in Fig. 6. 2-Chloro-N-(2,6-dimethylphenyl)acetamide, 1, was synthesized according to the procedure described in the literature (Missioui et al., 2022b ). Next, 1.2 mmol of morpholine, 2, were mixed with 1 mmol of 2-chloro-N-(4-nitrophenyl)acetamide and refluxed in toluene for 4 h. Upon completion of the reaction, toluene was removed by liquid–liquid extraction, and the aqueous phase was subsequently acidified with hydrochloric acid to adjust its pH to about 4, prompting the precipitation of 3. The precipitate was filtered off, dried, and recrystallized from ethanol solution, yielding white crystals.

Figure 6
Reaction scheme for the formation of the title compound 3.

Yield = 45%, color: white, m.p. = 399–401 K. FT–IR (ATR, cm⁻¹) : 3228 (N—H amide), 2956 (C—H aliphatic), 1661(C=O). ¹H NMR (500 MHz, DMSO-d₆) δ(ppm): 2.10 (s, 6 H, CH₃), 2.5 (t, 4 H, N—CH₂—C), 3.09 (s, 2 H, CH₂ amide), 3.62 (t, 4 H, O—CH₂—C), 7.02–7.04 (m, 3 H, H_ar), and 9.20 (s, 1 H, NH amide). ¹³C NMR (125 MHz, DMSO-d₆) δ(ppm): 18.76 (CH₃), 53.97 (N—CH₂—C), 62.15 (N—CH₂—C—O), 66.62 (O—CH₂—C), 126.94, 128.20, 135.59, 135.74 (C_ar), and 168.34 (C=O). HRMS (ESI): calculated for C₁₄H₂₀N₂O₂ [M + H]⁺ 249.1525; found 249.15874.

7. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3. The N—H H atom was refined freely. C-bound H atoms were positioned with idealized geometry (C—H = 0.93–0.97 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	C₁₄H₂₀N₂O₂
M_r	248.32
Crystal system, space group	Monoclinic, P2₁/n
Temperature (K)	293
a, b, c (Å)	12.2417 (9), 10.4498 (4), 12.2866 (9)
β (°)	118.704 (9)
V (Å³)	1378.59 (18)
Z	4
Radiation type	Cu Kα
μ (mm⁻¹)	0.65
Crystal size (mm)	0.49 × 0.23 × 0.14

Data collection
Diffractometer	SuperNova, Dual, Cu at home/near, Atlas
Absorption correction	Gaussian (CrysAlis PRO; Rigaku OD, 2024 )
T_min, T_max	0.326, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	9760, 2709, 1991
R_int	0.028
(sin θ/λ)_max (Å⁻¹)	0.620

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.046, 0.142, 1.04
No. of reflections	2709
No. of parameters	169
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)	0.15, −0.18
Computer programs: CrysAlis PRO (Rigaku OD, 2024), SHELXT (Sheldrick, 2015a ), SHELXL (Sheldrick, 2015b ) and , DIAMOND (Brandenburg & Putz, 2012 ).

Supporting information

CCDC reference: 2560706

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989026006043/ex2100sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989026006043/ex2100Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989026006043/ex2100Isup3.cml

checkCIF report

Computing details top

N-(2,6-Dimethylphenyl)-2-(morpholin-4-yl)acetamide top

Crystal data top

C₁₄H₂₀N₂O₂	F(000) = 536
M_r = 248.32	D_x = 1.196 Mg m⁻³
Monoclinic, P2₁/n	Cu Kα radiation, λ = 1.54184 Å
a = 12.2417 (9) Å	Cell parameters from 3200 reflections
b = 10.4498 (4) Å	θ = 4.2–72.3°
c = 12.2866 (9) Å	µ = 0.65 mm⁻¹
β = 118.704 (9)°	T = 293 K
V = 1378.59 (18) Å³	Block, colourless
Z = 4	0.49 × 0.23 × 0.14 mm

Data collection top

SuperNova, Dual, Cu at home/near, Atlas diffractometer	1991 reflections with I > 2σ(I)
Detector resolution: 10.5082 pixels mm^-1	R_int = 0.028
ω scans	θ_max = 73.0°, θ_min = 4.2°
Absorption correction: gaussian (CrysAlisPro; Rigaku OD, 2024)	h = −13→15
T_min = 0.326, T_max = 1.000	k = −12→12
9760 measured reflections	l = −15→14
2709 independent reflections

Refinement top

Refinement on F²	1 restraint
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.046	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.142	w = 1/[σ²(F_o²) + (0.0713P)² + 0.2035P] where P = (F_o² + 2F_c²)/3
S = 1.03	(Δ/σ)_max < 0.001
2709 reflections	Δρ_max = 0.15 e Å⁻³
169 parameters	Δρ_min = −0.18 e Å⁻³

Special details top

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

Refinement. Single-crystal X-ray diffraction data were collected on an Agilent SuperNova Dual Atlas diffractometer, equipped with a mirror monochromator and using Mo radiation. The data were processed using CrysAlisPro (Rigaku OD, 2024) and the crystal structures were solved using SHELXT(Sheldrick, 2015a) and refined using SHELXL(Sheldrick, 2015b). Non-hydrogen atoms were refined with anisotropic displacement parameters.

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

	x	y	z	U_iso*/U_eq
C1	0.59743 (15)	0.60953 (13)	0.71939 (15)	0.0484 (4)
C2	0.51238 (15)	0.65227 (14)	0.59945 (16)	0.0515 (4)
C3	0.38984 (18)	0.67279 (17)	0.5722 (2)	0.0661 (5)
H3	0.332387	0.701082	0.493473	0.079*
C4	0.3519 (2)	0.6523 (2)	0.6586 (2)	0.0799 (6)
H4	0.269123	0.665369	0.638096	0.096*
C5	0.4366 (2)	0.6123 (2)	0.7762 (2)	0.0776 (6)
H5	0.409988	0.599209	0.834640	0.093*
C6	0.56176 (18)	0.59086 (16)	0.80978 (18)	0.0601 (4)
C7	0.55179 (17)	0.67607 (17)	0.50351 (16)	0.0627 (5)
H7A	0.615717	0.740284	0.532914	0.094*
H7B	0.481579	0.704990	0.428263	0.094*
H7C	0.583419	0.598230	0.487688	0.094*
C8	0.6532 (2)	0.5506 (2)	0.94016 (19)	0.0789 (6)
H8A	0.623068	0.576806	0.995803	0.118*
H8B	0.732437	0.590077	0.964372	0.118*
H8C	0.662476	0.459214	0.943309	0.118*
C9	0.77763 (16)	0.47292 (15)	0.76710 (16)	0.0552 (4)
C10	0.90876 (18)	0.47159 (18)	0.7846 (2)	0.0701 (5)
H10A	0.967251	0.474147	0.872751	0.084*
H10B	0.921820	0.391831	0.752147	0.084*
C11	1.06707 (17)	0.6107 (2)	0.77925 (19)	0.0723 (6)
H11A	1.113068	0.540388	0.768972	0.087*
H11B	1.100787	0.626798	0.867333	0.087*
C12	1.0799 (2)	0.7277 (3)	0.7164 (3)	0.0927 (7)
H12A	1.033815	0.797529	0.727217	0.111*
H12B	1.166922	0.752477	0.754614	0.111*
C13	0.9087 (2)	0.6687 (3)	0.5317 (2)	0.0856 (7)
H13A	0.879929	0.650423	0.444758	0.103*
H13B	0.859282	0.738908	0.536367	0.103*
C14	0.88885 (18)	0.55288 (19)	0.59218 (18)	0.0681 (5)
H14A	0.800777	0.532485	0.552940	0.082*
H14B	0.932346	0.480240	0.581836	0.082*
N1	0.72330 (13)	0.58889 (13)	0.74639 (13)	0.0509 (3)
N2	0.93530 (13)	0.57730 (13)	0.72435 (13)	0.0560 (4)
O1	0.72824 (12)	0.37440 (11)	0.77594 (13)	0.0708 (4)
O2	1.03491 (16)	0.70609 (19)	0.58815 (17)	0.0980 (5)
H1	0.7656 (17)	0.651 (2)	0.7350 (17)	0.063 (5)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0522 (9)	0.0332 (7)	0.0626 (10)	−0.0040 (6)	0.0298 (8)	−0.0032 (6)
C2	0.0541 (9)	0.0345 (7)	0.0616 (10)	−0.0016 (6)	0.0244 (8)	−0.0046 (6)
C3	0.0557 (11)	0.0564 (10)	0.0773 (12)	0.0046 (8)	0.0247 (9)	−0.0071 (9)
C4	0.0616 (12)	0.0824 (14)	0.0993 (16)	0.0035 (10)	0.0415 (12)	−0.0113 (12)
C5	0.0845 (14)	0.0762 (13)	0.0971 (15)	−0.0076 (11)	0.0636 (13)	−0.0083 (11)
C6	0.0716 (11)	0.0480 (8)	0.0692 (11)	−0.0065 (8)	0.0405 (9)	−0.0021 (7)
C7	0.0663 (11)	0.0556 (9)	0.0587 (10)	−0.0013 (8)	0.0240 (9)	0.0031 (8)
C8	0.1016 (16)	0.0738 (13)	0.0672 (12)	−0.0096 (11)	0.0454 (12)	0.0046 (10)
C9	0.0610 (10)	0.0412 (8)	0.0593 (9)	0.0059 (7)	0.0256 (8)	0.0059 (7)
C10	0.0655 (11)	0.0585 (10)	0.0839 (13)	0.0172 (9)	0.0340 (10)	0.0170 (9)
C11	0.0520 (10)	0.0900 (14)	0.0732 (12)	0.0018 (10)	0.0286 (9)	−0.0206 (10)
C12	0.0801 (15)	0.1038 (18)	0.1115 (19)	−0.0305 (13)	0.0599 (14)	−0.0280 (15)
C13	0.0780 (15)	0.1089 (18)	0.0800 (14)	0.0046 (12)	0.0459 (12)	0.0102 (12)
C14	0.0577 (11)	0.0731 (12)	0.0684 (11)	0.0027 (9)	0.0261 (9)	−0.0114 (9)
N1	0.0518 (8)	0.0385 (6)	0.0625 (8)	0.0000 (6)	0.0274 (7)	0.0047 (6)
N2	0.0500 (8)	0.0539 (8)	0.0638 (9)	0.0054 (6)	0.0270 (7)	−0.0005 (6)
O1	0.0787 (9)	0.0401 (6)	0.0902 (9)	0.0026 (6)	0.0376 (7)	0.0090 (6)
O2	0.0848 (11)	0.1313 (15)	0.1008 (12)	−0.0166 (10)	0.0629 (10)	−0.0041 (10)

Geometric parameters (Å, º) top

C1—C6	1.388 (2)	C9—C10	1.514 (3)
C1—C2	1.408 (2)	C10—N2	1.451 (2)
C1—N1	1.428 (2)	C10—H10A	0.9700
C2—C3	1.388 (2)	C10—H10B	0.9700
C2—C7	1.493 (2)	C11—N2	1.461 (2)
C3—C4	1.363 (3)	C11—C12	1.495 (3)
C3—H3	0.9300	C11—H11A	0.9700
C4—C5	1.378 (3)	C11—H11B	0.9700
C4—H4	0.9300	C12—O2	1.415 (3)
C5—C6	1.400 (3)	C12—H12A	0.9700
C5—H5	0.9300	C12—H12B	0.9700
C6—C8	1.508 (3)	C13—O2	1.412 (3)
C7—H7A	0.9600	C13—C14	1.499 (3)
C7—H7B	0.9600	C13—H13A	0.9700
C7—H7C	0.9600	C13—H13B	0.9700
C8—H8A	0.9600	C14—N2	1.462 (2)
C8—H8B	0.9600	C14—H14A	0.9700
C8—H8C	0.9600	C14—H14B	0.9700
C9—O1	1.225 (2)	N1—H1	0.88 (2)
C9—N1	1.347 (2)

C6—C1—C2	121.55 (16)	C9—C10—H10A	108.8
C6—C1—N1	120.77 (15)	N2—C10—H10B	108.8
C2—C1—N1	117.65 (15)	C9—C10—H10B	108.8
C3—C2—C1	118.14 (17)	H10A—C10—H10B	107.7
C3—C2—C7	120.37 (16)	N2—C11—C12	108.90 (17)
C1—C2—C7	121.48 (15)	N2—C11—H11A	109.9
C4—C3—C2	121.4 (2)	C12—C11—H11A	109.9
C4—C3—H3	119.3	N2—C11—H11B	109.9
C2—C3—H3	119.3	C12—C11—H11B	109.9
C3—C4—C5	119.9 (2)	H11A—C11—H11B	108.3
C3—C4—H4	120.1	O2—C12—C11	111.30 (19)
C5—C4—H4	120.1	O2—C12—H12A	109.4
C4—C5—C6	121.5 (2)	C11—C12—H12A	109.4
C4—C5—H5	119.2	O2—C12—H12B	109.4
C6—C5—H5	119.2	C11—C12—H12B	109.4
C1—C6—C5	117.51 (18)	H12A—C12—H12B	108.0
C1—C6—C8	122.04 (17)	O2—C13—C14	112.33 (19)
C5—C6—C8	120.45 (18)	O2—C13—H13A	109.1
C2—C7—H7A	109.5	C14—C13—H13A	109.1
C2—C7—H7B	109.5	O2—C13—H13B	109.1
H7A—C7—H7B	109.5	C14—C13—H13B	109.1
C2—C7—H7C	109.5	H13A—C13—H13B	107.9
H7A—C7—H7C	109.5	N2—C14—C13	109.88 (17)
H7B—C7—H7C	109.5	N2—C14—H14A	109.7
C6—C8—H8A	109.5	C13—C14—H14A	109.7
C6—C8—H8B	109.5	N2—C14—H14B	109.7
H8A—C8—H8B	109.5	C13—C14—H14B	109.7
C6—C8—H8C	109.5	H14A—C14—H14B	108.2
H8A—C8—H8C	109.5	C9—N1—C1	124.03 (14)
H8B—C8—H8C	109.5	C9—N1—H1	114.7 (12)
O1—C9—N1	123.59 (16)	C1—N1—H1	120.2 (12)
O1—C9—C10	120.97 (15)	C10—N2—C11	114.49 (15)
N1—C9—C10	115.40 (14)	C10—N2—C14	111.77 (15)
N2—C10—C9	113.74 (14)	C11—N2—C14	107.98 (14)
N2—C10—H10A	108.8	C13—O2—C12	109.88 (16)

N1—C9—C10—N2	−26.1 (2)

Hydrogen-bond geometry (Å, º) top

Cg2 is the centroid of the C1–C6 ring.

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···N2	0.88 (2)	2.278 (18)	2.738 (2)	112.5 (16)
N1—H1···O1ⁱ	0.88 (2)	2.34 (2)	3.0798 (18)	141.3 (16)
C10—H10B···Cg2ⁱⁱ	0.97	2.94	3.782 (2)	146

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

Database Survey top

REFCODE	R	Component 2	Dihedral angle (°)	Reference
BIDVET	NEt₂	2-i-propyl-5-methylcyclohexanol	85.4 (13)	Ma et al. (2023)
BIDVET01	NEt₂	2-i-propyl-5-methylcyclohexanol	85.6 (14)	Ma et al. (2023)
BIDVET02	NEt₂	2-i-propyl-5-methylcyclohexanol	84.4 (6)	Ma et al. (2023)
DALJIN	NEt₂	nonanedioic acid	58.90 (15), 65.00 (15)	Zotova et al. (2021)
LIDCAN10	NEt₂	–	82.0, 77.8	Hanson & Banner (1974)
LIDCAN11	NEt₂	–	76.0 (6), 75.6 (6)	Bambagiotti-Alberti et al. (2007)
LIDCAN12	NEt₂	–	79.79 (15), 72.74 (10), 68.41 (16), 78.93 (16)	Gryl (2015)
SEQRAJ	NEt₂	2-i-propyl-5-methylcyclohexanol	76.05 (18)	Corvis et al. (2010)
TURNOW	NEt₂	1,3,5-trihydroxybenzene	71.24 (8)	Magaña-Vergara et al. (2018)
WEDWUA	NEt₂	1,4-dibromo-2,3,5,6-tetrafluorobenzene	78.42 (17)	Choquesillo-Lazarte et al. (2017)
WEDXAH	NEt₂	1,4-diiodo-2,3,5,6-tetrafluorobenzene	86.4 (3)	Choquesillo-Lazarte et al. (2017)
GENRAT	pyrrolidin-2-one-1-yl	–	66.49 (15)	Wang et al. (2006b)
KAJSIB	pyrrolidin-2-one-1-yl	2-hydroxy-2-phenylacetic acid	60.87 (16)	Buol et al. (2020a)
KAJSIB01	pyrrolidin-2-one-1-yl	2-hydroxy-2-phenylacetic acid	60.84 (14)	Buol et al. (2020a)
OYUWOX	pyrrolidin-2-one-1-yl	2-phenylsuccinic acid	61.23 (18)	Buol et al. (2020a)
OYUWUD01	pyrrolidin-2-one-1-yl	5-nitroisophthalic acid	71.59 (13)	Buol et al. (2020a)
OYUXAK	pyrrolidin-2-one-1-yl	4-hydroxybenzoic acid	64.89 (12)	Buol et al. (2020b)
OYUXIS	pyrrolidin-2-one-1-yl	5-cyanoisophthalic acid	68.75 (19)	Buol et al. (2020b)
OYUXOY	pyrrolidin-2-one-1-yl	2-benzoylbenzoic acid	60.03 (17)	Buol et al. (2020b)
OYUXUE	pyrrolidin-2-one-1-yl	2-hydroxy-3-phenylpropanoic acid	60.4 (2)	Buol et al. (2020b)
OYUYAL	pyrrolidin-2-one-1-yl	2-phenylbutyric acid	61.6 (8)	Buol et al. (2020b)
OYUYEP	pyrrolidin-2-one-1-yl	5-hydroxyisophthalic acid	74.91 (9), 78.08 (9)	Buol et al. (2020a)
OYUYIT	pyrrolidin-2-one-1-yl	2-hydroxypropane-1,2,3-tricarboxylic acid	69 (9)	Buol et al. (2020a)
OYUYIT01	pyrrolidin-2-one-1-yl	2-hydroxypropane-1,2,3-tricarboxylic acid	69.7 (9), 69.0 (9), 67.7 (7), 70.5 (8)	Buol et al. (2020b)
OYUZAM	pyrrolidin-2-one-1-yl	oxalic acid	69.6 (6), 67.0 (7), 68.9 (8), 77.0 (8)	Buol et al. (2020a)
OYUZOA	pyrrolidin-2-one-1-yl	3,4,5-trihydroxybenzoic acid	70.4 (7), 72.1 (9)	Buol et al. (2020^b)
ACEZAK	4-R'-piperazin-1-yl^a	–	64.23 (19)	Wang et al. (2004)
CINBEK	4-R'-piperazin-1-yl^b	–	57.2 (2)	Silva et al. (2023)
JAYSAE	4-R'-piperazin-1-yl^c	–	67.73 (16)	Wang et al. (2005b)
LIPFAZ	4-R'-piperazin-1-yl^d	–	73.3 (4)	Germain et al. (1977)
MAPKIY	4-R'-piperazin-1-yl^e	–	63.86 (17)	Wang et al. (2005a)
SENCAQ	4-R'-piperazin-1-yl^f	–	65.5 (6)	Wang et al. (2006a)
SEJLOM	3-hydroxy-3-methoxymethyl-2-oxoindolin-1-yl	–	72.76 (8)	Nchioua et al. (2022)
VAVGIM	4-(2,6-dimethylphenyl)-3,5-dioxopiperazin-1-yl	–	73.98 (15)	Heim et al. (2021)
YOTROO	N(CH₂COOH)₂	–	60.88 (18)	Ribár et al. (1995)
YOTRUU	N(CH₂COOH)[CH₂C(O)OMe]	–	74.5 (4)	Ribár et al. (1995)

Notes: (a) R' = 3-(4-nitrophenyl)-1,2,4-oxadiazol-5-ylmethyl; (b) R' = 2-hydroxy-3-(2-methoxyphenoxy)propyl; (c) R' = 3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-ylmethyl; (d) R' = 4,4-bis(4-fluorophenyl)butyl; (e) R' = 3-(2-chlorophenyl)-1,2,4-oxadiazol-5-ylmethyl; (f) R' = 3-(4-bromophenyl)-1,2,4-oxadiazol-5-ylmethyl.

Acknowledgements

YR is thankful to the National Center for Scientific and Technical Research of Morocco (CNRST) for its continuous support. The contributions of the authors are as follows: conceptualization, YR; methodology, AA; investigation, IM and AEMAA; writing (original draft), JTM and AEMAA; writing (review and editing of the manuscript), YR and BMK; formal analysis, YR and JTM; supervision, YR and AZ; crystal structure determination, BMK.

References

Al Mulla, A. (2017). Der Pharma Chemica. 9, 141–147. CAS Google Scholar
Bambagiotti-Alberti, M., Bruni, B., Di Vaira, M., Giannellini, V. & Guerri, A. (2007). Acta Cryst. E63, o768–o770. Web of Science CrossRef IUCr Journals Google Scholar
Brandenburg, K. & Putz, H. (2012). DIAMOND. Crystal Impact GbR, Bonn, Germany. Google Scholar
Buol, X., Caro Garrido, C., Robeyns, K., Tumanov, N., Collard, L., Wouters, J. & Leyssens, T. (2020a). Cryst. Growth Des. 20, 7979–7988. CrossRef CAS Google Scholar
Buol, X., Robeyns, K., Garrido, C. C., Tumanov, N., Collard, L., Wouters, J. & Leyssens, T. (2020b). Pharmaceutics 12, 653-669. CrossRef CAS PubMed Google Scholar
Choquesillo-Lazarte, D., Nemec, V. & Cinčić, D. (2017). CrystEngComm 19, 5293–5299. CAS Google Scholar
Corvis, Y., Négrier, P., Lazerges, M., Massip, S., Léger, J.-M. & Espeau, P. (2010). J. Phys. Chem. B 114, 5420–5426. CrossRef CAS PubMed Google Scholar
Germain, G., Declercq, J. P., Van Meerssche, M. & Koch, M. H. J. (1977). Acta Cryst. B33, 1971–1972. 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
Gryl, M. (2015). Acta Cryst. B71, 392–405. Web of Science CSD CrossRef IUCr Journals Google Scholar
Hanson, A. W. & Banner, D. W. (1974). Acta Cryst. B30, 2486–2488. CrossRef IUCr Journals Web of Science Google Scholar
Heim, P., Twamley, B., O'Brien, J. & McDonald, A. R. (2021). Chemistry Select 6, 9663-9668. CAS Google Scholar
Ma, P., Toussaint, B., Roberti, E. A., Scornet, N., Silva, A. S., Henriquez, L. C., Cadasse, M., Negrier, P., Massip, S., Dufat, H., Hammad, K., Baraldi, C., Gamberini, M. C., Richard, C., Veesler, S., Espeau, P., Lee, T. & Corvis, Y. (2023). Pharmaceutics 15, 1102-1126. CrossRef CAS PubMed Google Scholar
Magaña-Vergara, N., De la Cruz-Cruz, P., Peraza-Campos, A., Martínez-Martínez, F. & González-González, J. (2018). Crystals 8, 130–138. Google Scholar
Maimoune, I., Kariuki, B. M., El Moutaouakil Ala Allah, A., Nchioua, I., Alsubari, A., Mague, J. T., Zarrouk, A. & Ramli, Y. (2025). Acta Cryst. E81, 69–73. CrossRef IUCr Journals Google Scholar
Missioui, M., Guerrab, W., Nchioua, I., El Moutaouakil Ala Allah, A., Kalonji Mubengayi, C., Alsubari, A., Mague, J. T. & Ramli, Y. (2022b). Acta Cryst. E78, 687–690. CrossRef IUCr Journals Google Scholar
Missioui, M., Mortada, S., Guerrab, W., Demirtaş, G., Mague, J. T., Ansar, M., El Abbes Faouzi, M., Essassi, E. M., Mehdar, Y. T. H., Aljohani, F. S., Said, M. & Ramli, Y. (2022a). Arab. J. Chem. 15, 103851–103870. CrossRef CAS Google Scholar
Nchioua, I., Alsubari, A., Mague, J. T. & Ramli, Y. (2022). Acta Cryst. E78, 922–925. Web of Science CSD CrossRef IUCr Journals Google Scholar
Ribár, B., Mészáros, C., Vladimirov, S., Zivanov-Stakić, D., Jovanović, M., Zmbova, B. & Engel, P. (1995). Struct. Chem. 6, 121–125. Google Scholar
Rigaku OD (2024). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England. 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
Silva, J. F. C., Pereira Silva, P. S., Ramos Silva, M., Fantechi, E., Chelazzi, L., Ciattini, S., Eusébio, M. & Rosado, M. T. S. (2023). Cryst. Growth Des. 23, 6679–6691. CrossRef CAS PubMed 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
Tan, S. L., Jotani, M. M. & Tiekink, E. R. T. (2019). Acta Cryst. E75, 308–318. Web of Science CrossRef IUCr Journals Google Scholar
Wang, H.-B., Chen, J.-H., Pu, Y.-Q. & Wang, J.-T. (2004). Acta Cryst. E60, o2041–o2042. Web of Science CrossRef IUCr Journals Google Scholar
Wang, H.-B., Liu, Z.-Q. & Yan, X.-C. (2006a). Acta Cryst. E62, o3465–o3466. CrossRef IUCr Journals Google Scholar
Wang, H.-B., Pu, Y.-Q., Chen, J.-H. & Wang, J.-T. (2005a). Acta Cryst. E61, o1994–o1996. CrossRef IUCr Journals Google Scholar
Wang, H.-B., Pu, Y.-Q., Chen, J.-H. & Wang, J.-T. (2005b). Acta Cryst. E61, o3750–o3751. CrossRef IUCr Journals Google Scholar
Wang, P.-L., Wang, H.-B., Ding, W.-L., Liu, Z.-Q. & Xing, Z.-T. (2006b). Acta Cryst. E62, o3838–o3839. CrossRef IUCr Journals Google Scholar
Zotova, J., Wojnarowska, Z., Twamley, B. & Tajber, L. (2021). J. Mol. Liq. 344, 117737–117747. CrossRef CAS Google Scholar

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