Synthesis, structure and in vitro cytotoxicity testing of some 1,3,4-oxadiazoline derivatives from 2-hydroxy-5-iodobenzoic acid

Article abstract of DOI:10.1107/S2053229618008719

The syntheses of nine new 5-iodosalicylic acid-based 1,3,4-oxadiazoline derivatives starting from methyl salicylate are described. These compounds are 2-[4-acetyl-5-methyl-5-(3-nitrophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4- iodophenyl acetate (6a), 2-[4-acetyl-5-methyl-5-(4-nitrophenyl)-4,5-dihydro- 1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6b), 2-(4-acetyl-5-methyl-5-phenyl- 4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-iodophenyl acetate, C₁₉H₁₇IN₂O₄ (6c), 2-[4-acetyl-5-(4-fluorophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate, C₁₉H₁₆FIN₂O₄ (6d), 2-[4-acetyl-5-(4-chlorophenyl)-5-methyl- 4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate, C₁₉H₁₆ClIN₂O₄ (6e), 2-[4-acetyl-5-(3-bromophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6f), 2-[4-acetyl-5-(4-bromophenyl)-5-methyl-4,5-dihydro-1,3,4- oxadiazol-2-yl]-4-iodophenyl acetate (6g), 2-[4-acetyl-5-methyl-5-(4-methylphenyl)- 4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6h) and 2-[5-(4- acetamidophenyl)-4-acetyl-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6i). The compounds were characterized by mass,¹H NMR and¹³C NMR spectroscopies. Single-crystal X-ray diffraction studies were also carried out for 6c, 6d and 6e. Compounds 6c and 6d are isomorphous, with the 1,3,4-oxadiazoline ring having an envelope conformation, where the disubstituted C atom is the flap. The packing is determined by C—H…O, C—H…and I…π interactions. For 6e, the 1,3,4-oxadiazoline ring is almost planar. In the packing, Cl…π interactions are observed, while the I atom is not involved in short interactions. Compounds 6d, 6e, 6f and 6h show good inhibiting abilities on the human cancer cell lines KB and Hep-G2, with IC₅₀ values of 0.9-4.5 μM.

Full text of DOI:10.1107/S2053229618008719

research papers
Synthesis, structure and in vitro cytotoxicity
testing of some 1,3,4-oxadiazoline derivatives
from 2-hydroxy-5-iodobenzoic acid
ISSN 2053-2296
Cong Nguyen Tien,a Thin Nguyen Van,b Giang Le Duc,b Manh Vu Quoc,c Trung Vu
Quoc,d Thang Pham Chien,e Hung Nguyen Huy,e Anh Dang Thi Tuyet,f Tuyen
Nguyen Vanf and Luc Van Meerveltg*
Received 31 May 2018
Accepted 13 June 2018
aFaculty of Chemistry, Ho Chi Minh City University of Education, 280 An Duong Vuong Street, District No. 5, Ho Chi
Minh City, Vietnam, bSchool of Natural Sciences Education, Vinh University, 182 Le Duan St., Vinh City, Vietnam,
cFaculty of Foundation Science, College of Printing Industry, Phuc Dien, Bac Tu Liem, Hanoi, Vietnam, dFaculty of
Chemistry, Hanoi National University of Education, 136 Xuan Thuy, Cau Giay, Hanoi, Vietnam, eDepartment of
Edited by A. L. Spek, Utrecht University, The
Netherlands
f
Inorganic Chemistry, VNU University of Science, 19 Le Thanh Tong, Hanoi, Vietnam, Institute of Chemistry, Vietnam
Keywords: 1,3,4-oxadiazoline; crystal structure;
5-iodosalicylic acid; cytotoxicity; biological
activity.
Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay District, Hanoi, Vietnam, and gDepartment of
Chemistry, KU Leuven, Biomolecular Architecture, Celestijnenlaan 200F, Leuven (Heverlee), B-3001, Belgium.
*Correspondence e-mail: luc.vanmeervelt@kuleuven.be
CCDC references: 1849175; 1849174;
The syntheses of nine new 5-iodosalicylic acid-based 1,3,4-oxadiazoline
derivatives starting from methyl salicylate are described. These compounds
are 2-[4-acetyl-5-methyl-5-(3-nitrophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-
iodophenyl acetate (6a), 2-[4-acetyl-5-methyl-5-(4-nitrophenyl)-4,5-dihydro-
1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6b), 2-(4-acetyl-5-methyl-5-phenyl-
4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-iodophenyl acetate, C19H17IN2O4 (6c),
2-[4-acetyl-5-(4-fluorophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodo-
phenyl acetate, C19H16FIN2O4 (6d), 2-[4-acetyl-5-(4-chlorophenyl)-5-methyl-
4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate, C19H16ClIN2O4 (6e),
2-[4-acetyl-5-(3-bromophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodo-
phenyl acetate (6f), 2-[4-acetyl-5-(4-bromophenyl)-5-methyl-4,5-dihydro-1,3,4-
oxadiazol-2-yl]-4-iodophenyl acetate (6g), 2-[4-acetyl-5-methyl-5-(4-methylphen-
yl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6h) and 2-[5-(4-
acetamidophenyl)-4-acetyl-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodo-
phenyl acetate (6i). The compounds were characterized by mass, 1H NMR and
13C NMR spectroscopies. Single-crystal X-ray diffraction studies were also
carried out for 6c, 6d and 6e. Compounds 6c and 6d are isomorphous, with the
1,3,4-oxadiazoline ring having an envelope conformation, where the disub-
stituted C atom is the flap. The packing is determined by C—Hꢀ ꢀ ꢀO, C—Hꢀ ꢀ ꢀꢀ
and Iꢀ ꢀ ꢀꢀ interactions. For 6e, the 1,3,4-oxadiazoline ring is almost planar. In the
packing, Clꢀ ꢀ ꢀꢀ interactions are observed, while the I atom is not involved in
short interactions. Compounds 6d, 6e, 6f and 6h show good inhibiting abilities on
the human cancer cell lines KB and Hep-G2, with IC50 values of 0.9–4.5 mM.
1849173
Supporting information: this article has
supporting information at journals.iucr.org/c
1. Introduction
Derivatives of 1,3,4-oxadiazoline show a broad spectrum of
biological activity, including antibacterial (Joshi et al., 2008;
Suresh Kumar et al., 2010; Mohitea & Bhaskar, 2011; Hamdi et
al., 2011; Naveena et al., 2011; Kotb et al., 2009), antifungal
(Mohitea & Bhaskar, 2011; Naveena et al., 2011; Kotb et al.,
2009), antitubercular (Joshi et al., 2008; Suresh Kumar et al.,
2010), anti-inflammatory (Rajak et al., 2007; Sahoo et al.,
2014), antioxidant (Hamdi et al., 2011; Sahoo et al., 2014;
Manojkumar et al., 2009; Fadda et al., 2011) and antitumour
activities (Kotb et al., 2009; Manojkumar et al., 2009; Fadda et
al., 2011). Furthermore, it is well documented that 1,3,4-oxa-
diazoline derivatives display a pronounced effect on the
# 2018 International Union of Crystallography
Acta Cryst. (2018). C74
https://doi.org/10.1107/S2053229618008719 1 of 8

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enzyme tyrosinase (El Sadek et al., 2013) or chitin biosynthesis
(Ke et al., 2009).
2-Hydroxy-5-iodo-N0-[1-(3-nitrophenyl)ethylidene]benzo-
hydrazide (5a): yield 88%, m.p. 508–509 K; IR (ꢁ, cmꢁ1): 3217
1
On the other hand, salicylic acid and structurally related
compounds were found to possess antimicrobial (Khiati et al.,
2007; Sarshira et al., 2016), analgesic and antitumour activities
(Pattan et al., 2009; Vejselova & Kutlu, 2015; Huang et al.,
2018). Research on the antibacterial properties of salicylic acid
derivatives with respect to viscose fabrics shows that the
antibacterial activity of salicylic acid and its derivatives are in
the following order: 5-bromosalicylic acid > salicylic acid > 5-
chlorosalicylic acid > 4-chlorosalicylic acid (Kantouch et al.,
2013). However, iodinated derivatives of salicylic acid have
not been studied much. Recently, a series of salicylic acid-
based 1,3,4-oxadiazole derivatives were synthesized and some
of them showed good antitumour activities, with IC50 values
ranging from 31.19 to 57.21 mM (Murty et al., 2014). As a
continuation of our research work exploring potent bioactive
5-iodosalicylic acid-based oxadiazole derivatives (Cong et al.,
2012), nine new 2-(4-acetyl-5-aryl-5-methyl-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-4-iodophenyl acetate compounds were
synthesized (see Scheme 1) and their antitumour activities
evaluated against KB and Hep-G2.
(OH, N—H), 1636, 1559 (C O, C N); H NMR (ꢂ in ppm
and J in Hz): ꢂ 12.07 (1H, br, OH), 11.42 (1H, s, NH), 8.65 (1H,
s, Ar-H), 8.29 (2H, m, Ar-H), 8.22 (1H, d, 4J = 2.0, Ar-H), 7.77
4
(1H, dd, 3J1 = 3J1 = 8.0, ArH), 7.73 (1H, dd, 3J = 8.5, J = 2.0,
ArH), 6.89 (1H, d, 3J = 8.5, ArH), 2.42 (3H, s, CH3); 13C NMR:
ꢂ 161.2 (C O), 156.4, 150.8, 148.5, 142.0, 140.0, 139.1, 134.2,
133.3, 130.6, 124.4, 121.2, 121.1, 120.1, 82.3, 14.4; MS:
m/z 447.9718 (M + Na)+, calculated for C16H15NO7SNa:
447.9770; MS: m/z 425.9924 (M + H)+, calculation for C15H13-
IN3O4: M = 425.9951 a.u.
2. Experimental
All chemicals were obtained from commercial sources and
used without further purification. The melting points were
determined in open capillaries and are uncorrected. The IR
spectra were recorded on an FT–IR Shimadzu 8400-S. NMR
spectra were measured on a Bruker Avance 500 MHz in
dimethyl sulfoxide (DMSO-d6) using tetramethylsilane (TMS)
as an internal reference. All NMR spectra are available in the
supporting information. Mass spectra were recorded on a
Bruker micrOTOF-Q 10187 mass spectrometer.
2-Hydroxy-5-iodo-N0-[1-(4-nitrophenyl)ethylidene]benzo-
hydrazide (5b): yield 82%, m.p. 532–533 K; IR (ꢁ, cmꢁ1): 3094
1
(OH, N—H), 1643, 1535 (C O, C N); H NMR (ꢂ in ppm
and J in Hz): ꢂ 12.07 (1H, br, OH), 11.43 (1H, s, NH), 8.31 (2H,
d, 3J = 8.5, Ar-H), 8.22 (1H, d, 4J = 2.0, Ar-H), 8.12 (2H, d, 3J =
8.5, Ar-H), 7.74 (1H, dd, 3J = 8.5, 4J = 2.0, ArH), 6.89 (1H, d,
3J = 8.5, ArH), 2.40 (3H, s, CH3); 13C NMR: ꢂ 161.2 (C O),
156.7, 150.8, 148.1, 144.4, 142.1, 139.1, 128.1, 124.1, 121.1, 120.1,
82.3, 14.3; MS: m/z 447.9718 (M + Na)+, calculation for C15H12-
IN3NaO4: M = 447.9770 a.u.
2.1. Synthesis and crystallization
Methyl salicylate (2), methyl 2-hydroxy-5-iodobenzoate (3)
and 2-hydroxy-5-iodobenzohydrazide (4) were synthesized
according to previously reported methods (Cong et al., 2012).
Methyl salicylate (2): liquid; b.p. 494–495 K, yield 73%.
Methyl 2-hydroxy-5-iodobenzoate (methyl 5-iodosalicylate)
(3): white needles, m.p. 347–348 K, yield 85%; IR (ꢁ, cmꢁ1):
3156, 3080, 2949, 1676, 1604, 527.
2-Hydroxy-5-iodo-N0-(1-phenylethylidene)benzohydrazide
(5c): yield 84%, m.p. 452–453 K; IR (ꢁ, cmꢁ1): 3295, 3040
1
(OH, N—H), 2917 (Csp3—H), 1643, 1566 (C O, C N); H
NMR (ꢂ in ppm and J in Hz): ꢂ 12.06 (1H, br, OH), 11.29 (1H,
s, NH), 8.23 (1H, d, 4J = 2.0, Ar-H), 7.87 (2H, m, Ar-H), 7.73
(1H, dd, 3J = 8.5, 4J = 2.0, ArH), 7.46 (3H, m, Ar-H), 6.89 (1H,
d, 3J = 8.5, ArH), 2.35 (3H, s, CH3); 13C NMR: ꢂ 160.6 (C O),
156.3, 152.9, 141.4, 138.5, 137.8, 129.5, 128.4, 126.5, 120.6,
119.6, 81.8, 13.9; MS: m/z 380.9992 (M + H)+, calculation for
C15H14IN2O2: M = 381.0100 a.u.
2-Hydroxy-5-iodobenzohydrazide (4): white needles, m.p.
451 K, yield 79%; IR (ꢁ, cmꢁ1): 3405, 3322, 1626, 1574, 529; 1H
NMR (ꢂ in ppm and J in Hz): ꢂ 12.41 (1H, br, OH), 10.12 (1H,
br, NH), 8.12 (1H, d, 4J = 2.0, ArH), 7.65 (1H, dd, 3J = 9.0, 4J =
2.0, ArH), 6.75 (1H, d, 3J = 9.0, ArH), 4.80 (2H, br, NH2); 13
C
NMR: 166.1 (CO), 158.9, 141.3, 135.5, 119.9, 117.4, 80.5.
2.1.1. General procedure for the synthesis of N0-(1-aryl-
ethylidene)-2-hydroxy-5-iodobenzohydrazide compounds
(5a–5i). Equimolar quantities of hydrazide 4 and a substi-
tuted acetophenone (X = 3-NO2, 4-NO2, 4-H, 4-F, 4-Cl, 3-Br,
4-Br, 4-CH3 and 4-NH2) were refluxed in ethanol for 2 h. The
reaction mixture was cooled to room temperature and the pre-
cipitate was filtered off and crystallized from dioxane or a mix-
ture of DMFand water to give the corresponding products 5a–5i.
N0-[1-(4-Fluorophenyl)ethylidene]-2-hydroxy-5-iodobenzo-
hydrazide (5d): yield 77%, m.p. 507–508 K; IR (ꢁ, cmꢁ1): 3295,
3102 (OH, N—H), 2930 (Csp3—H), 1643, 1605 (C O, C N);
1H NMR (ꢂ in ppm and J in Hz): ꢂ 12.04 (1H, br, OH), 11.27
(1H, s, NH), 8.22 (1H, d, 4J = 2.0, Ar-H), 7.92 (2H, dd, 3J = 8.5,
3
4
4JH-F = 5.5, Ar-H), 7.72 (1H, dd, J = 8.5, J = 2.0, ArH), 7.29
(2H, dd, 3J = 8.5, 3JH-F = 8.5, Ar-H), 6.88 (1H, d, 3J = 8.5, ArH),
ꢂ
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In vitro cytotoxicity of some 1,3,4-oxadiazoline derivatives
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1
2.34 (3H, s, CH3); 13C NMR: ꢂ 162.9 (d, JC-F = 982.0), 160.6
2.1.2. General procedure for the synthesis of 2-(4-acetyl-5-
aryl-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-iodophenyl
acetate compounds (6a–6i). A mixture of N-substituted
hydrazides (5a–5i) (5 mmol) and acetic anhydride (10 ml) was
taken into a 100 ml round-bottomed flask. The mixture was
refluxed for 4 h. After cooling to room temperature, the
reaction mixture was poured into ice cold water. The preci-
pitate obtained was filtered off and crystallized from a mixture
of ethanol and water to give the corresponding products. For
compounds 6c, 6d and 6e, the crystals were suitable for X-ray
diffraction.
(C O), 156.2, 151.9, 141.4, 138.5, 134.3 (d, 4JC-F = 11.0), 128.7
(d, 3JC-F = 33.5), 120.6, 119.6, 115.3 (d, 2JC-F = 86.0), 81.7, 13.9;
MS: m/z 399.0007 (M + H)+, calculation for C15H13FIN2O2: M=
399.0006 a.u.
N0-[1-(4-Chlorophenyl)ethylidene]-2-hydroxy-5-iodobenzo-
hydrazide (5e): yield 85%, m.p. 542–543 K; IR (ꢁ, cmꢁ1): 3287,
3088 (OH, N—H), 2932 (Csp3—H), 1643, 1550 (C O, C N);
1H NMR (ꢂ in ppm and J in Hz): ꢂ 12.05 (1H, br, OH), 11.30
3
(1H, s, NH), 8.22 (1H, s, Ar-H), 7.89 (2H, d, J = 8.0, Ar-H),
7.73 (1H, dd, 3J = 8.5, 4J = 1.5, ArH), 7.53 (2H, d, 3J = 8.0, Ar-
H), 6.89 (1H, d, 3J = 8.5, ArH), 2.33 (3H, s, CH3); 13C NMR: ꢂ
160.6 (C O), 156.2, 151.5, 141.4, 138.5, 136.6, 134.2, 128.4,
128.2, 120.6, 119.6, 81.8, 13.7; MS: m/z 414.9674 (M + H)+,
calculation for C15H13ClIN2O2: M = 414.9710 a.u.
2-[4-Acetyl-5-methyl-5-(3-nitrophenyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl]-4-iodophenyl acetate (6a): IR (ꢁ, cmꢁ1): 3079
(Csp2—H), 2986 (Csp3—H), 1751, 1659 (C O), 1589 (C N,
C
C); 1H NMR (ꢂ in ppm and J in Hz): ꢂ 8.30 (2H, m, Ar-H),
8.10 (1H, d, 4J = 2.0, Ar-H), 8.00 (2H, m, Ar-H), 7.77 (1H, t, 3J =
8.0, Ar-H), 7.16 (1H, d, 3J = 8.5, Ar-H), 2.26 (9H, m, 3 ꢃ CH3);
13C NMR: ꢂ 169.2, 166.9, 149.4, 148.7, 148.4, 142.1, 141.0, 137.3,
132.9, 130.9, 127.0, 124.8, 121.1, 120.0, 99.4, 91.7, 22.7, 22.6,
21.2; MS: m/z 531.9991 (M + Na)+; calculation for C19H16I-
N3NaO6: M = 532.0008 a.u.
N0-[1-(3-Bromophenyl)ethylidene]-2-hydroxy-5-iodobenzo-
hydrazide (5f): yield 82%, m.p. 546–547 K; IR (ꢁ, cmꢁ1): 3412,
1
3071 (OH, N—H), 1644, 1556 (C O, C N); H NMR (ꢂ in
ppm and J in Hz): ꢂ 12.01 (1H, br, OH), 11.30 (1H, s, NH), 8.21
(1H, d, 4J = 1.5, Ar-H), 8.03 (1H, s, Ar-H), 7.83 (1H, d, 3J = 8.0,
Ar-H), 7.71 (1H, dd, 3J = 8.0, 4J = 1.5, ArH), 7.63 (1H, d, 3J =
8.0, Ar-H), 7.42 (1H, dd, 3J1 = 3J2 = 8.0, ArH), 6.87 (1H, d, 3J =
8.5, ArH), 2.32 (3H, s, CH3); 13C NMR: ꢂ 161.2 (C O), 156.7,
151.6, 141.9, 140.6, 139.0, 132.6, 131.1, 129.3, 126.1, 122.4, 121.1,
120.1, 82.2, 14.3; MS: m/z 414.9674 (M + H)+, calculation for
C15H12BrIN2O2: M = 457.9127 a.u.
N0-[1-(4-Bromophenyl)ethylidene]-2-hydroxy-5-iodobenzo-
hydrazide (5g): yield 86%, m.p. 555–556 K; IR (ꢁ, cmꢁ1): 3285,
3034 (OH, N—H), 2938 (Csp3—H), 1647, 1593 (C O, C N);
1H NMR (ꢂ in ppm and J in Hz): ꢂ 12.03 (1H, br, OH), 11.30
(1H, s, NH), 8.22 (1H, d, 4J = 2.0, Ar-H), 7.82 (2H, d, 3J = 8.5,
Ar-H), 7.72 (1H, dd, 3J = 8.5, 4J = 2.0, ArH), 7.66 (2H, d, 3J =
2-[4-Acetyl-5-methyl-5-(4-nitrophenyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl]-4-iodophenyl acetate (6b): IR (ꢁ, cmꢁ1): 3055
(Csp2—H), 2940 (Csp3—H), 1759, 1667 (C O), 1605 (C N,
C
C); 1H NMR (ꢂ in ppm and J in Hz): ꢂ 8.29 (2H, d, 3J = 9.0,
Ar-H), 8.08 (1H, d, 4J = 2.0, Ar-H), 8.00 (1H, dd, 3J = 8.5, 4J =
3
3
2.0, Ar-H), 7.83 (2H, d, J = 8.5, Ar-H), 7.15 (1H, d, J = 8.5,
Ar-H), 2.26 (6H, m, 2 ꢃ CH3), 2.23 (3H, s, CH3); 13C NMR: ꢂ
169.2, 166.8, 149.4, 148.7, 148.4, 145.4, 142.1, 137.3, 128.0, 127.0,
124.2, 120.0, 99.3, 91.7, 22.7, 22.6, 21.2; MS: m/z 531.9991 (M +
Na)+; calculation for C19H16IN3NaO6: M = 531.9981 a.u.
2-(4-Acetyl-5-methyl-5-phenyl-4,5-dihydro-1,3,4-oxadiazol-
2-yl)-4-iodophenyl acetate (6c): IR (ꢁ, cmꢁ1): 2950 (Csp3—H),
8.5, Ar-H), 6.89 (1H, d, 3J = 8.5, ArH), 2.33 (3H, s, CH3); 13
NMR: ꢂ 161.1 (C O), 156.7, 152.1, 141.9, 139.0, 137.5, 131.9,
129.0, 123.5, 121.1, 120.1, 82.3, 14.2; MS: m/z 458.8999 (M +
H)+, calculation for C15H13BrIN2O2: M = 458.9205 a.u.
C
1
1767, 1667 (C O); H NMR (ꢂ in ppm and J in Hz): ꢂ 8.05
(1H, d, 4J = 2.0, Ar-H), 7.98 (1H, dd, 3J = 8.5, 4J = 2.0, Ar-H),
3
7.51 (2H, d, J = 7.0, Ar-H), 7.44 (3H, m, Ar-H), 7.13 (1H, d,
3J = 8.5, Ar-H), 2.25 (3H, s, CH3), 2.24 (3H, s, CH3), 2.20 (3H,
s, CH3); 13C NMR: ꢂ 169.2, 166.5, 149.3, 148.7, 141.9, 139.1,
137.2, 129.8, 129.0, 126.9, 126.1, 120.3, 100.4, 91.7, 22.8, 22.7,
21.1; MS: m/z 487.0126 (M + Na)+; calculation for C19H17I-
N2NaO4: 487.0131 a.u.
2-[4-Acetyl-5-(4-fluorophenyl)-5-methyl-4,5-dihydro-1,3,4-
oxadiazol-2-yl]-4-iodophenyl acetate (6d): IR (ꢁ, cmꢁ1): 3094
(Csp2—H), 2940 (Csp3—H), 1759, 1659 (C O), 1605 (C N,
2-Hydroxy-5-iodo-N0-[1-(4-methylphenyl)ethylidene]benzo-
hydrazide (5h): yield 76%, m.p. 501–502 K; IR (ꢁ, cmꢁ1): 3279,
3035 (OH, N—H), 2940 (Csp3—H), 1645, 1600 (C O, C N);
1H NMR (ꢂ in ppm and J in Hz): ꢂ 12.04 (1H, br, OH), 11.24
(1H, s, NH), 8.23 (1H, d, 4J = 2.0, Ar-H), 7.76 (2H, d, 3J = 8.5,
Ar-H), 7.72 (1H, dd, 3J = 8.5, 4J = 2.5, ArH), 7.26 (2H, d, 3J =
3
8.5, Ar-H), 6.88 (1H, d, J = 8.5, ArH), 2.32 (3H, s, Ar-CH3),
2.31 (3H, s, CH3); 13C NMR: ꢂ 160.6 (C O), 156.3, 152.9,
141.3, 139.2, 138.5, 135.0, 129.0, 126.4, 120.6, 119.6, 81.7, 20.9,
13.8; MS: m/z 395.0247 (M + H)+, calculation for C16H16IN2O2:
M = 395.0256 a.u.
C
C); 1H NMR (ꢂ in ppm and J in Hz): ꢂ 8.07 (1H, s, Ar-H),
7.98 (1H, dd, 3J = 8.5, 4J = 2.0, Ar-H), 7.57 (2H, m, Ar-H), 7.26
(2H, dd, 3J = 8.0, Ar-H), 7.16 (1H, 3JH-H = 3JH-F = 9.0, Ar-H),
3
N0-[1-(4-Aminophenyl)ethylidene]-2-hydroxy-5-iodobenzo-
hydrazide (5i): yield 78%, m.p. 515–516 K; IR (ꢁ, cmꢁ1): 3440,
3298, 3201 (OH, N—H), 2932 (Csp3—H), 1634, 1577 (C O,
7.13 (1H, d, J = 8.5, Ar-H), 2.25 (3H, s, CH3), 2.24 (3H, s,
CH3), 2.19 (3H, s, CH3); 13C NMR: ꢂ 169.1, 166.5, 163.9, 161.9,
(149.3, 148.7), 141.9, 137.3, (135.477, 135.453), (128.739,
128.670), 126.9, 120.3, (115.922, 115.749), 99.9, 91.6, 22.8, 22.7,
21.1; MS: m/z 505.0044 (M + Na)+; calculation for C19H16FI-
N2NaO4: M = 505.0036 a.u.
2-[4-Acetyl-5-(4-chlorophenyl)-5-methyl-4,5-dihydro-1,3,4-
oxadiazol-2-yl]-4-iodophenyl acetate (6e): IR (ꢁ, cmꢁ1): 3094
(Csp2—H), 1767, 1667 (C O), 1597 (C N, C C); 1H NMR
(ꢂ in ppm and J in Hz): ꢂ 8.06 (1H, d, 4J = 2.0, Ar-H), 7.98 (1H,
C
N); 1H NMR (ꢂ in ppm and J in Hz): ꢂ 11.11 (1H, s, NH),
8.23 (1H, s, Ar-H), 7.70 (1H, d, 3J = 8.5, ArH), 7.59 (2H, d, 3J =
8.5, Ar-H), 6.86 (1H, d, 3J = 8.5, ArH), 6.59 (2H, d, 3J = 8.5, Ar-
H), 5.55 (2H, br, NH2), 2.22 (3H, s, CH3); 13C NMR: ꢂ 161.1
(C O), 157.0, 154.8, 150.9, 141.6, 138.7, 128.3, 125.2, 121.0,
120.1, 113.7, 82.0, 14.1; MS: m/z 396.0069 (M + H)+, calculation
for C15H15IN3O2: M = 396.0209 a.u.
ꢂ
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Table 1
Experimental details.
6c
6d
6e
Crystal data
Chemical formula
Mr
C19H17IN2O4
464.24
C19H16FIN2O4
482.24
C19H16ClIN2O4
498.69
Crystal system, space group
Temperature (K)
Monoclinic, P21/c
100
8.837 (1), 20.056 (1), 11.015 (1)
110.18 (1)
1832.4 (3)
4
Mo Kꢄ
1.77
Monoclinic, P21/c
100
9.1241 (4), 20.0980 (9), 10.7456 (5)
110.224 (2)
1849.00 (15)
4
Mo Kꢄ
1.77
0.60 ꢃ 0.37 ꢃ 0.29
Monoclinic, P21/c
100
11.703 (2), 22.037 (4), 7.4073 (12)
92.888 (8)
1907.9 (5)
4
Mo Kꢄ
1.85
˚
a, b, c (A)
ꢃ (ꢄ)
3
˚
V (A )
Z
Radiation type
ꢅ (mmꢁ1
Crystal size (mm)
)
0.42 ꢃ 0.20 ꢃ 0.16
0.22 ꢃ 0.12 ꢃ 0.12
Data collection
Diffractometer
Absorption correction
Bruker APEXII CCD
Multi-scan (SADABS; Bruker,
2014)
Bruker APEXII CCD
Multi-scan (SADABS; Bruker,
2014)
Bruker APEXII CCD
Multi-scan (SADABS; Bruker,
2014)
Tmin, Tmax
0.627, 0.747
54289, 5600, 4994
0.610, 0.746
52242, 4033, 3703
0.640, 0.746
62840, 4387, 3863
No. of measured, independent and
observed [I > 2ꢆ(I)] reflections
Rint
0.029
0.714
0.048
0.639
0.042
0.650
ꢁ1
˚
(sin ꢇ/ꢈ)max (A
)
Refinement
R[F2 > 2ꢆ(F2)], wR(F2), S
No. of reflections
No. of parameters
0.022, 0.050, 1.05
5600
238
H-atom parameters constrained
0.020, 0.047, 1.06
4033
247
H-atom parameters constrained
0.021, 0.051, 1.04
4387
247
H-atom parameters constrained
H-atom treatment
˚
ꢁ3
Áꢉmax, Áꢉmin (e A
)
0.97, ꢁ0.59
0.56, ꢁ0.32
0.40, ꢁ0.66
Computer programs: APEX2 (Bruker, 2014), SAINT (Bruker, 2013), SHELXS97 (Sheldrick, 2008), SHELXT (Sheldrick, 2015a), SHELXL2014 (Sheldrick, 2015b) and OLEX2
(Dolomanov et al., 2009).
dd, 3J = 8.5, 4J = 2.0, Ar-H), 7.50 (2H, d, 3J = 8.5, Ar-H), 7.51
(2H, d, 3J = 8.5, Ar-H), 7.14 (1H, d, 3J = 8.5, Ar-H), 2.25 (3H, s,
CH3), 2.24 (3H, s, CH3), 2.18 (3H, s, CH3); 13C NMR: ꢂ 168.7,
166.1, 148.8, 148.2, 141.5, 137.5, 136.8, 134.1, 128.6, 127.8,
126.5, 119.7, 99.3, 91.2, 22.2, 22.1, 20.7; MS: m/z 520.9743 (M +
Na)+; calculation for C19H16ClIN2NaO4: 520.9741 a.u.
2-[4-Acetyl-5-(3-bromophenyl)-5-methyl-4,5-dihydro-1,3,4-
oxadiazol-2-yl]-4-iodophenyl acetate (6f): IR (ꢁ, cmꢁ1): 3071
(Csp2—H), 2932 (Csp3—H), 1767, 1651 (C O); 1H NMR (ꢂ in
ppm and J in Hz): ꢂ 8.07 (1H, d, 4J = 2.0, Ar-H), 7.98 (1H, dd,
2-[4-Acetyl-5-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl]-4-iodophenyl acetate (6h): IR (ꢁ, cmꢁ1): 3009
(Csp2—H), 2924 (Csp3—H), 1767, 1667 (C O), 1620 (C N,
C
C); 1H NMR (ꢂ in ppm and J in Hz): ꢂ 8.04 (1H, d, 4J = 2.0,
Ar-H), 7.97 (1H, dd, 3J = 8.5, 4J = 2.0, Ar-H), 7.39 (2H, d, 3J =
3
3
8.0, Ar-H), 7.24 (2H, d, J = 8.0, Ar-H), 7.13 (1H, d, J = 8.5,
Ar-H), 2.32 (3H, s, CH3), 2.24 (3H, s, CH3), 2.23 (3H, s, CH3),
2.18 (3H, s, CH3); 13C NMR: ꢂ 169.1, 166.3, 149.3, 148.7, 141.8,
139.3, 137.2, 136.2, 129.5, 126.9, 126.1, 120.4, 100.4, 91.6, 22.8,
22.7, 21.2, 21.1; MS: m/z 501.0261 (M + Na)+; calculation for
C20H19IN2NaO4: M = 501.0267 a.u.
4
3
3J = 8.5, J = 2.0, Ar-H), 7.70 (1H, s, Ar-H), 7.64 (1H, t, J1 =
3J2 = 7.0, Ar-H), 7.52 (1H, d, 3J = 7.5, Ar-H), 7.41 (1H, m, Ar-
H), 2.25 (6H, m, 2 ꢃ CH3), 2.18 (3H, s, CH3); 13C NMR: ꢂ
169.1, 166.7, 149.4, 148.7, 142.0, 141.5, 137.3, 132.8, 131.3, 129.0,
126.9, 125.4, 122.3, 120.2, 99.6, 91.7, 22.7, 22.6, 21.1; MS: m/z
564.9230 (M + Na)+; calculation for C19H16BrIN2NaO4: M =
564.9236 a.u.
2-[5-(4-Acetamidophenyl)-4-acetyl-5-methyl-4,5-dihydro-
1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6i): IR (ꢁ, cmꢁ1):
3320 (NH), 3070 (Csp2—H), 2934 (Csp3—H), 1763, 1655
(C O), 1601 (C N, C C); 1H NMR (ꢂ in ppm and J in Hz):
ꢂ 10.08 (1H, s, NH), 8.03 (1H, d, 4J = 2.0, Ar-H), 7.97 (1H, dd,
3J = 8.5, 4J = 2.0, Ar-H), 7.62 (2H, d, 3J = 7.0, Ar-H), 7.41 (2H,
3
3
2-[4-Acetyl-5-(4-bromophenyl)-5-methyl-4,5-dihydro-1,3,4-
oxadiazol-2-yl]-4-iodophenyl acetate (6g): IR (ꢁ, cmꢁ1): 3094
(Csp2—H), 1767, 1667 (C O), 1620, 1589 (C N, C C); 1H
d, J = 7.0, Ar-H), 7.13 (1H, d, J = 8.5, Ar-H), 2.24 (3H, s,
CH3), 2.23 (3H, s, CH3), 2.18 (3H, s, CH3), 2.16 (3H, s, CH3),
2.05 (3H, s, CH3); 13C NMR: ꢂ 172.7, 169.2, 166.6, 149.3, 148.7,
141.9, 140.8, 137.3, 133.6, 129.7, 126.9, 120.4, 119.2, 100.3, 91.6,
27.2, 24.5, 22.8, 22.7, 21.1; MS: m/z 544.0173 (M + Na)+;
calculation for C21H20IN3NaO5: M = 544.0345 a.u.
4
NMR (ꢂ in ppm and J in Hz): ꢂ 8.05 (1H, d, J = 2.0, Ar-H),
7.98 (1H, dd, 3J = 8.5, 4J = 2.0, Ar-H), 7.65 (2H, d, 3J = 8.5, Ar-
3
3
H), 7.47 (2H, d, J = 8.0, Ar-H), 7.14 (1H, d, J = 8.5, Ar-H),
2.25 (3H, s, CH3), 2.23 (3H, s, CH3), 2.17 (3H, s, CH3); 13C
NMR: ꢂ 169.1, 166.6, 149.3, 148.7, 142.0, 138.4, 137.3, 132.0,
128.6, 127.0, 123.3, 120.2, 99.8, 91.7, 22.7, 22.6, 21.1; MS: m/z
564.9244 (M + Na)+; calculation for C19H16BrIN2NaO4: M =
564.9236 a.u.
2.2. Structure solution and refinement
Crystal data, data collection and structure refinement
details for 6c, 6d and 6e are summarized in Table 1. H atoms
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were placed in calculated positions and refined using a riding
˚
model, with C—H distances of 0.95 (aromatic) and 0.98 A
(CH3), and Uiso(H) = 1.2Ueq(C) or 1.5Ueq(C) for methyl
groups.
2.3. In vitro cell tests
The synthesized compounds 6a–6i were evaluated for their
cytotoxicity against two human cancer cell lines, including KB
(epidermoid carcinoma cancer) and HepG2 (hepatoma
carcinoma cancer). The cell lines were obtained from the
American Type Culture Collection (USA) ATCC. The cells
were grown in RPMI 1640 medium supplemented with 10%
fetal bovine serum, 100 U mlꢁ1 penicillin, and 100 mg mlꢁ1
streptomycin at 310 K in a humidified atmosphere (95% air
and 5% CO2). The exponentially growing cells were used
throughout the experiments. The inhibitory effects of the
compounds on the growth of the human cancer cell lines were
determined by measuring metabolic activity using a 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
assay. Briefly, human cancer cell lines (1 ꢃ 105 cells/ml) were
treated for 3 d with a series of concentrations of the
compoundsꢁ(1in DMSO), i.e. 0.125, 0.5, 2.0, 8.0, 32.0, and
128.0 mg ml . After incubation, 0.1 mg MTT solution (50 ml
of a 2 mg mlꢁ1 solution) was added to each well and the cells
were then incubated at 310 K for 4 h. The plates were
centrifuged at 1000 rpm for 10 min at room temperature and
the media were then carefully aspirated. DMSO (150 ml) was
added to each well to dissolve the formazan crystals. The
plates were read immediately at 540 nm on a microplate
reader (TECAN GENIOUS). All the experiments were
performed three times and the mean absorbance values were
calculated. The results are expressed as the percentage of
inhibition that produced a reduction in the absorbance by the
treatment of the compounds compared to the untreated
controls. A dose-response curve was generated and the inhi-
bitory concentration of 50% (IC50) was determined for each
compound as well as for each cell line.
Figure 1
The molecular structure of 6c, showing the atom-labelling scheme.
Displacement ellipsoids are drawn at the 50% probability level.
6.75 ppm (1H, doublet, 3J = 9.0 Hz) indicate that the benzene
ring contains three substituents at positions of 1, 2 and 5.
The reaction of aromatic ketones with hydrazide 4 to obtain
the desired N-substituted hydrazides 5a–5i occurs easily and
may be observed clearly by the appearance of a precipitate
during and after the progress of the reaction. In comparison
with 4, the corresponding N0-(1-arylethylidene)-2-hydroxy-5-
iodobenzohydrazides 5a–5i show similar spectra, except for
the absence of bands due to the NH2 group. Each compound
shows absorptions at 1636–1645 and 1535–1605 cmꢁ1 corre-
sponding to C O and C N or C C bonds present in the
molecule. Besides that, the absorption around 2917–
2940 cmꢁ1 corresponds to the CH3 group present in the N-
substituted hydrazides.
3. Results and discussion
3.1. Synthesis of 1,3,4-oxadiazoline derivatives 6a–6i
Nine new 2-(4-acetyl-5-aryl-5-methyl-4,5-dihydro-1,3,4-oxa-
diazol-2-yl)-4-iodophenyl acetate derivatives, 6a–6i, were
synthesized starting from salicylic acid 1 (Scheme 1). In the
initial steps, salicylic acid 1 is converted into 2-hydroxy-5-
iodobenzohydrazide 4. The IR spectrum of 4 shows an
absorption at 1626 cmꢁ1 corresponding to a C O stretching
vibration of the amide group. Two bands at 3405 and
3322 cmꢁ1 are due to the presence of OH and NH2 groups,
1
respectively. The H NMR spectrum of 4, displays a broad
singlet at 4.80 ppm (2H) corresponding to the NH2 protons.
Two broad peaks appear at ꢂ 12.41 and 10.12 ppm, repre-
senting the OH and NHCO protons. The appearance of three
signals in the aromatic area at 8.12 (1H, doublet, 4J = 2.0 Hz),
Figure 2
Packing diagram for 6c, showing C—Hꢀ ꢀ ꢀO (red), C—Iꢀ ꢀ ꢀꢀ (grey) and
C—Hꢀ ꢀ ꢀꢀ (grey) interactions. Cg2 is the centroid of the C1–C6 ring and
1
2
Cg3 is the centroid of the C9–C14 ring. [Symmetry codes: (i) ꢁx + 1, y ꢁ ,
3
4
1
2
3
2
1
2
7.6 (1H, doublet of doublet, J = 9.0 Hz, J = 2.0 Hz) and
ꢁz + ; (ii) ꢁx + 2, ꢁy + 1, ꢁz + 1; (iii) x, ꢁy + , z + .]
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Table 2
Hydrogen-bond geometry (A, ) for 6c.
ꢄ
˚
Cg3 is the centroid of the C9–C14 ring.
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
C5—H5ꢀ ꢀ ꢀO4i
0.95
0.98
0.98
2.51
2.55
2.70
3.2828 (19)
3.529 (2)
3.5766 (17)
139
177
150
C16—H16Bꢀ ꢀ ꢀO4ii
C17—H17Cꢀ ꢀ ꢀCg3iii
1
2
1
2
3
2
1
2
3
2
1
2
Symmetry codes: (i) ꢁx þ 1; y ꢁ ; ꢁz þ ; (ii) x; ꢁy þ ; z ꢁ ; (iii) x; ꢁy þ ; z þ .
3.2. Crystal structures of 1,3,4-oxadiazoline derivatives 6c,
6d and 6e
Crystallization experiments for compounds 6a–6i using a
mixture of ethanol and water resulted in crystals suitable for
X-ray diffraction for compounds 6c, 6d and 6e. The crystals
belong to the monoclinic space group P21/c.
Figure 3
The molecular structure of 6d, showing the atom-labelling scheme.
Displacement ellipsoids are drawn at the 50% probability level.
The central 1,3,4-oxadiazoline ring in 6c displays an
envelope conformation (Fig. 1) with the C8 atom as the flap
ꢄ
˚
[puckering parameters: Q = 0.1310 (14) A and ’ = 322.2 (6) ].
The best plane through the 1,3,4-oxadiazoline ring makes
angles of 7.84 (8) and 78.48 (8)ꢄ with the 4-iodophenyl ring
(atoms C1–C6) and the phenyl ring (atoms C9–C14), respec-
tively. Both aromatic rings are inclined to each other by
82.11 (8)ꢄ.
Hydrazones 5a–5i on cyclization with acetic anhydride
afforded 1,3,4-oxadiazoline derivatives 6a–6i. In the IR
spectra of 1,3,4-oxadiazoline compounds 6a–6h (except for 6i),
no N—H bond stretching is present around 3200 cmꢁ1, while
strong bands in the ranges 1751—1767 and 1651–1667 cmꢁ1
indicated the presence of acetyl groups. Comparing the 13C
NMR spectra of 5a–5i with those of 6a–6i showed the
appearance of a signal around 100.00 ppm; this was assigned to
the C-5 atom of the oxadiazoline ring, i.e. atom C8. Besides
that, the signals of the methyl group in the 1H NMR spectra of
In the crystal, molecules of 6c are linked by C—Hꢀ ꢀ ꢀO and
C—Hꢀ ꢀ ꢀꢀ interactions, forming chains propagating along the
b-axis direction (Fig. 2 and Table 2). Molecules in parallel
chains form inversion dimers by Iꢀ ꢀ ꢀꢀ interactions [Fig. 2;
iv
˚
Iꢀ ꢀ ꢀCg2 = 3.7888 (8) A; Cg2 is the centroid of the C1–C6 ring;
1
5a–5i were shifted upfield in the H NMR spectra of 6a–6i.
Those spectral characteristics are compatible with the trans-
formation of hydrazones to oxadiazoline compounds.
symmetry code: (iv) ꢁx + 2, ꢁy + 1, ꢁz + 1].
The crystal structures of 6c and 6d (Fig. 3) are isomorphous;
˚
the r.m.s. overlay fit is 0.0438 A for the non-H atoms. The
Figure 4
3
2
1
2
Partial packing diagram for 6d, showing dimer formation by C—Hꢀ ꢀ ꢀO (red) interactions. [Symmetry code: (i) x, ꢁy + , z + .]
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Table 3
Hydrogen-bond geometry (A, ) for 6d.
ꢄ
˚
Cg3 is the centroid of the C9–C14 ring.
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
C5—H5ꢀ ꢀ ꢀO4i
0.95
0.95
0.98
0.98
2.53
2.51
2.54
2.50
3.331 (2)
3.335 (2)
3.513 (2)
3.407 (2)
142
145
174
154
C14—H14ꢀ ꢀ ꢀO2ii
C16—H16Aꢀ ꢀ ꢀO4iii
C17—H17Cꢀ ꢀ ꢀCg3ii
1
2
1
2
3
2
1
2
3
2
1
2
Symmetry codes: (i) ꢁx þ 1; y ꢁ ; ꢁz þ ; (ii) x; ꢁy þ ; z þ ; (iii) x; ꢁy þ ; z ꢁ .
Table 4
Hydrogen-bond geometry (A, ) for 6e.
ꢄ
˚
Cg2 is the centroid of the C1–C6 ring.
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
C6—H6ꢀ ꢀ ꢀO2i
0.95
0.95
0.98
2.47
2.55
2.75
3.258 (2)
3.435 (2)
3.649 (2)
140
155
153
C11—H11ꢀ ꢀ ꢀO1ii
C19—H19Bꢀ ꢀ ꢀCg2iii
Figure 5
The molecular structure of 6e, showing the atom-labelling scheme.
Displacement ellipsoids are drawn at the 50% probability level.
Symmetry codes: (i) x; y; z þ 1; (ii) ꢁx þ 1; ꢁy þ 1; ꢁz þ 1; (iii) x; y; z ꢁ 1.
with the C16—H16Aꢀ ꢀ ꢀO4iii interaction, results in the form-
ation of a dimer, generating an R22(11) loop (Fig. 4).
Compound 6e is not isomorphous with analogues 6c and 6d.
The 1,3,4-oxadiazoline ring is almost planar (r.m.s. deviation =
puckering parameters of the 1,3,4-oxadiazoline ring of 6d are
ꢄ
˚
Q = 0.1159 (17) A and ’ = 325.4 (8) .
The crystal packing is built up by C—Hꢀ ꢀ ꢀO, C—Hꢀ ꢀ ꢀꢀ and
C—Iꢀ ꢀ ꢀꢀ interactions, as for 6c [Table 3; Iꢀ ꢀ ꢀCg2i
=
˚
0.024 A) and is inclined to the planes of the aromatic rings by
˚
11.95 (8) (ring C1–C6) and 78.28 (8)ꢄ (ring C9–C14) (Fig. 5).
The orientation of the acetate group in 6e is different
compared to compounds 6c and 6d, as illustrated by the
torsion angle C3—C4—O1—C15 [ꢁ83.55 (18)ꢄ in 6e,
81.17 (17)ꢄ in 6c and 81.5 (2)ꢄ in 6d]. As a result, in structures
6c and 6d, the acetate group and the C8-aryl substituent are
syn with respect to one another, while in 6e they are anti. In all
three cases, the carbonyl O atom (O4) of acetate is close to
being eclipsed with respect to atom C4 of the aromatic ring,
which may indicate a favourable interaction between a non-
bonded pair of electrons on O4 and the ꢀ* orbital of the
aromatic C1–C6 ring.
3.7807 (8) A; Cg2 is the centroid of the C1–C6 ring; symmetry
code: (i) ꢁx + 2, ꢁy + 1, ꢁz + 1]. In addition, a C14—
H14ꢀ ꢀ ꢀO2ii interaction (Table 3) is observed, which together
In the crystal, inversion dimers are formed by C11—
H11ꢀ ꢀ ꢀO1ii interactions (Table 4 and Fig. 6). These dimers
interact further by C6—H6ꢀ ꢀ ꢀO2i and C19—H19Bꢀ ꢀ ꢀꢀiii
interactions with the iodo-substituted phenyl ring (Table 4 and
Fig. 6), resulting in chains of molecules running in the c
direction. Parallel chains interact further by Clꢀ ꢀ ꢀꢀ contacts,
again with the iodo-substituted phenyl ring (Table 4 and
Fig. 6). In contrast to the crystal packings of the two previous
analogues, the packing of 6e does not show Iꢀ ꢀ ꢀꢀ interactions.
The closest neighbour for atom I1 is H17B (I1ꢀ ꢀ ꢀH17Bi =
˚
3.13 A). The shortest Iꢀ ꢀ ꢀCl distance in the crystal packing is
I1ꢀ ꢀ ꢀCl1iv = 3.850 (2) A [symmetry code: (iv) x + 1, ꢁy + ,
1
2
˚
z + 12].
The crystal packings of compounds 6c, 6d and 6e contain no
voids.
Figure 6
Partial packing diagram for 6e, showing C—Hꢀ ꢀ ꢀO (red), C—Hꢀ ꢀ ꢀꢀ
(grey) and C—Clꢀ ꢀ ꢀꢀ (grey) interactions. Cg2 is the centroid of the C1–
C6 ring. [Symmetry codes: (i) ꢁx + 1, ꢁy + 1, ꢁz + 1; (ii) x, y, z + 1; (iii) x,
y, z ꢁ 1; (iv) x ꢁ 1, y, z.]
3.3. In vitro cytotoxicity of compounds 6a–6i
Complexes 6a–6i were assayed for in vitro cytotoxicity
against human cancer cells KB-CCL-17 (Human epidemic
ꢂ
Acta Cryst. (2018). C74
Nguyen Tien et al.
In vitro cytotoxicity of some 1,3,4-oxadiazoline derivatives 7 of 8

research papers
Table 5
carcinoma) and Hep-G2-HB-8065 (Hepatocellular carci-
noma). The IC50 values are listed in Table 5, together with
literature data for ellipcitine (Hoang et al., 2015).
Cytotoxic effects of the examined compounds 6a–6i (IC50a in ꢅM).
Compound
KB
Hep-G2
The results indicate that most of the examined compounds
possess at least moderate cytotoxic activity, and some
compounds even display a promising activity profile. It is
important to note that these separate pharmacophores display
considerably less potent cytotoxic activities (IC50 values
ranging from 42 to more than 400 mM) compared to the most
promising compounds 6d, 6e, 6f and 6h (IC50 values between
0.9 and 4.5 mM), showing a reasonable activity against two
human cancer cell lines. In particular, compound 6f exhibits a
strong anticancer effect against KB cells, with an IC50 value
(0.9 mM) lower than ellipticine (1.2 mM).
6a
6b
6c
6d
6e
6f
6g
3.733ꢅ0.472
9.214ꢅ0.884
5.280ꢅ0.819
1.867ꢅ0.568
4.012ꢅ0.622
0.921ꢅ0.360
6.262ꢅ0.645
3.166ꢅ0.398
12.476ꢅ0.979
1.260ꢅ0,528
12.574ꢅ0.766
14.735ꢅ0.727
12.284ꢅ0.625
4.564ꢅ0.539
3.811ꢅ0.822
3.315ꢅ0.552
13.260ꢅ0.866
3.983ꢅ0.482
11.900ꢅ1.036
2.358ꢅ0.407
6h
6i
Ellipcitine
Note: (a) IC50 is the concentration of the compound required to inhibit cell growth by
50%.
Joshi, S. D., Vagdevi, H. M., Vaidya, V. P. & Gadaginamath, G. S.
(2008). Eur. J. Med. Chem. 43, 1989–1996.
4. Conclusions
Kantouch, A., El-Sayed, A. A., Salama, M., El-Kheir, A. A. &
Mowafi, S. (2013). Int. J. Biol. Macromol. 62, 603–607.
Ke, S., Liu, F., Wang, N., Yang, Q. & Qian, X. (2009). Bioorg. Med.
Chem. Lett. 19, 332–335.
Khiati, Z., Othman, A. A. & Guessas, B. (2007). S. Afr. J. Chem. 60,
20–24.
Kotb, E. R., El-Hashash, M. A., Salama, M. A., Kalf, H. S. & Abdel
Wahed, N. A. M. (2009). Acta Chim. Slov. 56, 908–919.
Manojkumar, P., Ravi, T. K. & Subbuchettiar, G. (2009). Acta Pharm.
59, 159–170.
Mohitea, P. B. & Bhaskar, V. H. (2011). Orbital: Electron. J. Chem. 3,
117–124.
In this study, we have synthesized nine new 2-(4-acetyl-5-aryl-
5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-iodophenyl ace-
tate compounds in five steps starting from salicylic acid with
moderate yield. The compounds were characterized spectro-
scopically and by single-crystal X-ray diffraction for 6c, 6d and
6e. The in vitro cytotoxicity of 6a–6i against two human cancer
cell lines (KB and Hep-G2) was determined and illustrated,
implying their potential for further studies in the field of
anticancer research.
Murty, M. S. R., Penthala, R., Nath, L. R. & Anto, R. J. (2014). Lett.
Drug. Des. Discov. 11, 1133–1142.
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8 of 8 Nguyen Tien et al.
In vitro cytotoxicity of some 1,3,4-oxadiazoline derivatives
Acta Cryst. (2018). C74

supporting information
supporting information
Acta Cryst. (2018). C74 [https://doi.org/10.1107/S2053229618008719]
Synthesis, structure and in vitro cytotoxicity testing of some 1,3,4-oxadiazoline
derivatives from 2-hydroxy-5-iodobenzoic acid
Cong Nguyen Tien, Thin Nguyen Van, Giang Le Duc, Manh Vu Quoc, Trung Vu Quoc, Thang
Pham Chien, Hung Nguyen Huy, Anh Dang Thi Tuyet, Tuyen Nguyen Van and Luc Van Meervelt
Computing details
For all structures, data collection: APEX2 (Bruker, 2014); cell refinement: SAINT (Bruker, 2013); data reduction: SAINT
(Bruker, 2013). Program(s) used to solve structure: SHELXS97 (Sheldrick, 2008) for (6c), (6e); SHELXT (Sheldrick,
2015a) for (6d). For all structures, program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular
graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et
al., 2009).
2-(4-Acetyl-5-methyl-5-phenyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-iodophenyl acetate (6c)
Crystal data
C19H17IN2O4
Mr = 464.24
F(000) = 920
Dx = 1.683 Mg m−3
Mo Kα radiation, λ = 0.71073 Å
Cell parameters from 9773 reflections
θ = 3.2–33.1°
Monoclinic, P21/c
a = 8.837 (1) Å
b = 20.056 (1) Å
c = 11.015 (1) Å
β = 110.18 (1)°
V = 1832.4 (3) Å3
Z = 4
µ = 1.77 mm−1
T = 100 K
Block, colourless
0.42 × 0.20 × 0.16 mm
Data collection
Bruker APEXII CCD
diffractometer
φ and ω scans
5600 independent reflections
4994 reflections with I > 2σ(I)
Rint = 0.029
Absorption correction: multi-scan
(SADABS; Bruker, 2014)
θmax = 30.5°, θmin = 2.8°
h = −12→12
k = −28→28
l = −15→15
T
min = 0.627, Tmax = 0.747
54289 measured reflections
Refinement
Refinement on F2
Least-squares matrix: full
R[F2 > 2σ(F2)] = 0.022
wR(F2) = 0.050
S = 1.05
5600 reflections
238 parameters
0 restraints
Primary atom site location: structure-invariant
direct methods
Hydrogen site location: inferred from
neighbouring sites
H-atom parameters constrained
w = 1/[σ2(Fo2) + (0.0212P)2 + 1.2207P]
where P = (Fo2 + 2Fc2)/3
(Δ/σ)max = 0.003
Acta Cryst. (2018). C74
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supporting information
Δρmax = 0.97 e Å−3
Δρmin = −0.59 e Å−3
Special details
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)
x
y
z
Uiso*/Ueq
I1
O1
N1
C1
O2
N2
C2
H2
1.02273 (2)
0.42189 (12)
0.44105 (14)
0.81918 (17)
0.57214 (14)
0.43632 (14)
0.75217 (17)
0.795397
0.44378 (2)
0.51004 (5)
0.63918 (6)
0.46520 (7)
0.56173 (6)
0.70564 (6)
0.52839 (7)
0.560319
0.71043 (2)
0.22300 (10)
0.32433 (11)
0.54844 (14)
0.12194 (11)
0.36222 (11)
0.53642 (13)
0.603141
0.02391 (4)
0.0198 (2)
0.0172 (2)
0.0185 (3)
0.0265 (2)
0.0170 (2)
0.0177 (3)
0.021*
O3
C3
O4
C4
C5
H5
0.63889 (13)
0.62097 (16)
0.31986 (13)
0.55900 (17)
0.62622 (19)
0.582960
0.65492 (5)
0.54536 (7)
0.80687 (5)
0.49706 (7)
0.43404 (7)
0.401921
0.51584 (9)
0.42630 (13)
0.32597 (11)
0.33034 (13)
0.34230 (15)
0.275960
0.0191 (2)
0.0162 (2)
0.0240 (2)
0.0175 (3)
0.0221 (3)
0.027*
C6
H6
0.75733 (19)
0.804238
0.41777 (7)
0.374628
0.45167 (15)
0.460211
0.0226 (3)
0.027*
C7
C8
C9
0.55901 (16)
0.58015 (17)
0.70562 (16)
0.82350 (18)
0.828901
0.93294 (19)
1.012829
0.92662 (19)
1.001008
0.8109 (2)
0.806516
0.70118 (18)
0.623057
0.44235 (18)
0.2830 (2)
0.245772
0.61343 (7)
0.72191 (7)
0.76014 (7)
0.72550 (8)
0.678281
0.75959 (9)
0.735524
0.82828 (9)
0.851359
0.86321 (9)
0.910437
0.82959 (8)
0.853966
0.54575 (7)
0.55892 (8)
0.518532
0.41634 (13)
0.47773 (13)
0.43953 (13)
0.40745 (15)
0.414448
0.36537 (16)
0.343917
0.35443 (16)
0.324678
0.38721 (17)
0.380223
0.43030 (15)
0.453485
0.12345 (14)
0.02103 (15)
−0.030777
−0.034930
0.061592
0.0161 (2)
0.0165 (2)
0.0170 (2)
0.0225 (3)
0.027*
0.0289 (3)
0.035*
0.0294 (3)
0.035*
0.0299 (3)
0.036*
0.0235 (3)
0.028*
0.0197 (3)
0.0274 (3)
0.041*
C10
H10
C11
H11
C12
H12
C13
H13
C14
H14
C15
C16
H16A
H16B
H16C
C17
H17A
H17B
H17C
0.294126
0.204476
0.5379 (2)
0.456948
0.494300
0.595176
0.571687
0.75217 (8)
0.724354
0.797093
0.041*
0.041*
0.0236 (3)
0.035*
0.035*
0.58752 (14)
0.605601
0.563247
0.634896
0.754692
0.664922
0.035*
Acta Cryst. (2018). C74
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supporting information
C18
C19
H19A
H19B
H19C
0.31788 (16)
0.18862 (18)
0.101667
0.145536
0.234431
0.74827 (7)
0.71930 (8)
0.751907
0.678758
0.708341
0.29343 (13)
0.17778 (15)
0.143604
0.203469
0.110914
0.0176 (3)
0.0227 (3)
0.034*
0.034*
0.034*
Atomic displacement parameters (Å2)
U11
U22
U33
U12
U13
U23
I1
O1
N1
C1
O2
N2
C2
O3
C3
O4
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
0.02366 (5)
0.0188 (5)
0.0175 (5)
0.0184 (6)
0.0257 (6)
0.0163 (5)
0.0192 (6)
0.0241 (5)
0.0167 (6)
0.0233 (5)
0.0173 (6)
0.0257 (7)
0.0263 (7)
0.0177 (6)
0.0182 (6)
0.0162 (6)
0.0198 (7)
0.0195 (7)
0.0201 (7)
0.0276 (8)
0.0214 (7)
0.0245 (7)
0.0264 (8)
0.0307 (8)
0.0149 (6)
0.0162 (6)
0.02116 (5)
0.0201 (5)
0.0151 (5)
0.0178 (6)
0.0309 (6)
0.0159 (5)
0.0171 (6)
0.0154 (5)
0.0158 (6)
0.0190 (5)
0.0180 (6)
0.0166 (7)
0.0145 (6)
0.0165 (6)
0.0165 (6)
0.0197 (6)
0.0243 (7)
0.0388 (9)
0.0400 (9)
0.0243 (8)
0.0208 (7)
0.0168 (6)
0.0299 (8)
0.0251 (7)
0.0204 (6)
0.0265 (7)
0.02296 (5)
0.00370 (3)
−0.0032 (4)
0.0000 (4)
0.0005 (5)
−0.0008 (4)
0.0010 (4)
−0.0010 (5)
0.0027 (4)
−0.0008 (5)
0.0038 (4)
−0.0026 (5)
−0.0025 (5)
0.0014 (5)
−0.0008 (5)
0.0028 (5)
0.0008 (5)
0.0021 (5)
0.0001 (6)
−0.0065 (6)
−0.0043 (6)
0.0015 (5)
0.0003 (5)
0.0022 (6)
0.0042 (6)
0.0017 (5)
0.0008 (5)
0.00299 (4)
0.0038 (4)
0.0065 (4)
0.0064 (5)
0.0096 (4)
0.0041 (4)
0.0070 (5)
0.0029 (4)
0.0078 (5)
0.0083 (4)
0.0060 (5)
0.0070 (6)
0.0082 (6)
0.0068 (5)
0.0046 (5)
0.0028 (5)
0.0077 (5)
0.0111 (6)
0.0071 (6)
0.0090 (7)
0.0080 (6)
0.0058 (5)
0.0014 (6)
0.0122 (6)
0.0085 (5)
0.0040 (5)
0.00274 (3)
0.0003 (4)
−0.0022 (4)
0.0028 (5)
0.0042 (4)
−0.0023 (4)
0.0001 (5)
−0.0007 (4)
0.0003 (5)
0.0007 (4)
0.0009 (5)
−0.0029 (5)
0.0002 (5)
−0.0013 (5)
−0.0010 (5)
−0.0022 (5)
−0.0033 (6)
−0.0033 (7)
0.0020 (7)
0.0014 (7)
−0.0018 (6)
−0.0021 (5)
−0.0003 (6)
−0.0020 (5)
0.0026 (5)
0.0013 (6)
0.0183 (5)
0.0192 (5)
0.0192 (6)
0.0238 (5)
0.0175 (5)
0.0173 (6)
0.0148 (4)
0.0175 (6)
0.0290 (5)
0.0172 (6)
0.0230 (7)
0.0264 (7)
0.0151 (6)
0.0141 (6)
0.0133 (6)
0.0235 (7)
0.0304 (8)
0.0272 (8)
0.0361 (9)
0.0279 (7)
0.0169 (6)
0.0206 (7)
0.0179 (6)
0.0195 (6)
0.0231 (7)
Geometric parameters (Å, º)
I1—C1
2.0951 (14)
C9—C10
1.395 (2)
O1—C4
O1—C15
N1—N2
N1—C7
C1—C2
C1—C6
O2—C15
N2—C8
N2—C18
1.3948 (17)
1.3727 (17)
1.4017 (16)
1.2851 (18)
1.386 (2)
C9—C14
1.396 (2)
0.9500
1.388 (2)
0.9500
1.382 (3)
0.9500
1.386 (2)
0.9500
C10—H10
C10—C11
C11—H11
C11—C12
C12—H12
C12—C13
C13—H13
C13—C14
1.392 (2)
1.1966 (19)
1.4917 (18)
1.3614 (18)
1.392 (2)
Acta Cryst. (2018). C74
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supporting information
C2—H2
C2—C3
O3—C7
O3—C8
C3—C4
C3—C7
O4—C18
C4—C5
C5—H5
C5—C6
C6—H6
C8—C9
C8—C17
0.9500
C14—H14
C15—C16
0.9500
1.493 (2)
0.9800
0.9800
0.9800
0.9800
0.9800
0.9800
1.504 (2)
0.9800
0.9800
0.9800
1.4004 (19)
1.3631 (16)
1.4493 (16)
1.3986 (19)
1.4610 (19)
1.2270 (18)
1.383 (2)
0.9500
1.392 (2)
0.9500
1.522 (2)
1.5107 (19)
C16—H16A
C16—H16B
C16—H16C
C17—H17A
C17—H17B
C17—H17C
C18—C19
C19—H19A
C19—H19B
C19—H19C
C15—O1—C4
C7—N1—N2
C2—C1—I1
C2—C1—C6
C6—C1—I1
N1—N2—C8
C18—N2—N1
C18—N2—C8
C1—C2—H2
C1—C2—C3
C3—C2—H2
C7—O3—C8
C2—C3—C7
C4—C3—C2
C4—C3—C7
O1—C4—C3
C5—C4—O1
C5—C4—C3
C4—C5—H5
C4—C5—C6
C6—C5—H5
C1—C6—H6
C5—C6—C1
C5—C6—H6
N1—C7—O3
N1—C7—C3
O3—C7—C3
N2—C8—C9
N2—C8—C17
O3—C8—N2
O3—C8—C9
O3—C8—C17
C17—C8—C9
C10—C9—C8
117.34 (11)
104.29 (11)
118.81 (10)
120.65 (13)
120.47 (11)
110.97 (11)
121.85 (12)
127.06 (12)
119.9
C11—C10—H10
C10—C11—H11
C12—C11—C10
C12—C11—H11
C11—C12—H12
C11—C12—C13
C13—C12—H12
C12—C13—H13
C12—C13—C14
C14—C13—H13
C9—C14—H14
C13—C14—C9
C13—C14—H14
O1—C15—C16
O2—C15—O1
O2—C15—C16
C15—C16—H16A
C15—C16—H16B
C15—C16—H16C
H16A—C16—H16B
H16A—C16—H16C
H16B—C16—H16C
C8—C17—H17A
C8—C17—H17B
C8—C17—H17C
H17A—C17—H17B
H17A—C17—H17C
H17B—C17—H17C
N2—C18—C19
119.8
119.7
120.55 (15)
119.7
120.3
119.49 (15)
120.3
119.8
120.47 (16)
119.8
119.9
120.17 (15)
119.9
110.24 (13)
122.81 (13)
126.93 (14)
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
116.25 (13)
120.54 (13)
123.21 (13)
109.5
109.5
109.5
120.26 (13)
119.9
107.38 (10)
117.97 (12)
118.53 (13)
123.48 (13)
120.69 (12)
118.05 (12)
121.16 (13)
120.0
119.91 (14)
120.0
120.3
119.49 (14)
120.3
116.29 (12)
128.01 (13)
115.68 (12)
111.22 (11)
113.42 (12)
99.15 (10)
108.96 (11)
107.66 (11)
115.08 (12)
119.86 (13)
O4—C18—N2
O4—C18—C19
C18—C19—H19A
C18—C19—H19B
C18—C19—H19C
Acta Cryst. (2018). C74
sup-4

supporting information
C10—C9—C14
C14—C9—C8
C9—C10—H10
C11—C10—C9
118.89 (14)
121.19 (13)
119.8
H19A—C19—H19B
H19A—C19—H19C
H19B—C19—H19C
109.5
109.5
109.5
120.41 (15)
I1—C1—C2—C3
I1—C1—C6—C5
O1—C4—C5—C6
N1—N2—C8—O3
N1—N2—C8—C9
N1—N2—C8—C17
N1—N2—C18—O4
N1—N2—C18—C19
C1—C2—C3—C4
C1—C2—C3—C7
N2—N1—C7—O3
N2—N1—C7—C3
N2—C8—C9—C10
N2—C8—C9—C14
C2—C1—C6—C5
C2—C3—C4—O1
C2—C3—C4—C5
C2—C3—C7—N1
C2—C3—C7—O3
O3—C8—C9—C10
O3—C8—C9—C14
C3—C4—C5—C6
C4—O1—C15—O2
C4—O1—C15—C16
C4—C3—C7—N1
C4—C3—C7—O3
C4—C5—C6—C1
176.86 (10)
−177.27 (11)
−176.23 (13)
−13.43 (13)
101.12 (13)
−127.29 (12)
−177.27 (12)
2.50 (19)
C6—C1—C2—C3
C7—N1—N2—C8
C7—N1—N2—C18
C7—O3—C8—N2
C7—O3—C8—C9
C7—O3—C8—C17
C7—C3—C4—O1
C7—C3—C4—C5
C8—N2—C18—O4
C8—N2—C18—C19
C8—O3—C7—N1
C8—O3—C7—C3
C8—C9—C10—C11
C8—C9—C14—C13
C9—C10—C11—C12
C10—C9—C14—C13
C10—C11—C12—C13
C11—C12—C13—C14
C12—C13—C14—C9
C14—C9—C10—C11
C15—O1—C4—C3
C15—O1—C4—C5
C17—C8—C9—C10
C17—C8—C9—C14
C18—N2—C8—O3
C18—N2—C8—C9
C18—N2—C8—C17
0.0 (2)
9.02 (14)
−174.80 (12)
12.66 (13)
−103.64 (12)
130.93 (12)
−6.1 (2)
177.43 (13)
−1.7 (2)
0.6 (2)
−177.68 (13)
−0.09 (16)
−178.50 (13)
−88.99 (15)
88.16 (15)
−0.4 (2)
175.70 (12)
−0.8 (2)
179.85 (14)
1.42 (18)
19.29 (17)
−163.56 (12)
0.3 (2)
5.2 (2)
−176.26 (12)
1.6 (2)
178.03 (12)
−8.94 (16)
169.68 (11)
176.32 (14)
−175.89 (14)
−0.1 (2)
1.3 (2)
0.7 (3)
−0.3 (3)
−0.7 (3)
−0.9 (2)
81.18 (16)
−102.23 (15)
140.28 (14)
−42.57 (18)
170.64 (12)
−74.81 (16)
56.77 (18)
−176.80 (12)
0.3 (2)
Hydrogen-bond geometry (Å, º)
Cg3 is the centroid of the C9–C14 ring.
D—H···A
D—H
H···A
D···A
D—H···A
C5—H5···O4i
C16—H16B···O4ii
C17—H17C···Cg3iii
0.95
0.98
0.98
2.51
2.55
2.70
3.2828 (19)
3.529 (2)
3.5766 (17)
139
177
150
Symmetry codes: (i) −x+1, y−1/2, −z+1/2; (ii) x, −y+3/2, z−1/2; (iii) x, −y+3/2, z+1/2.
2-[4-Acetyl-5-(4-fluorophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6d)
Crystal data
C19H16FIN2O4
Mr = 482.24
Monoclinic, P21/c
a = 9.1241 (4) Å
b = 20.0980 (9) Å
c = 10.7456 (5) Å
Acta Cryst. (2018). C74
sup-5

supporting information
β = 110.224 (2)°
V = 1849.00 (15) Å3
Z = 4
F(000) = 952
Dx = 1.732 Mg m−3
Mo Kα radiation, λ = 0.71073 Å
Cell parameters from 9994 reflections
θ = 2.9–30.5°
µ = 1.77 mm−1
T = 100 K
Block, colourless
0.60 × 0.37 × 0.29 mm
Data collection
Bruker APEXII CCD
diffractometer
φ and ω scans
4033 independent reflections
3703 reflections with I > 2σ(I)
Rint = 0.048
Absorption correction: multi-scan
(SADABS; Bruker, 2014)
θmax = 27.0°, θmin = 2.7°
h = −11→11
k = −25→25
l = −13→13
T
min = 0.610, Tmax = 0.746
52242 measured reflections
Refinement
Refinement on F2
Least-squares matrix: full
R[F2 > 2σ(F2)] = 0.020
wR(F2) = 0.047
S = 1.06
4033 reflections
Hydrogen site location: inferred from
neighbouring sites
H-atom parameters constrained
w = 1/[σ2(Fo2) + (0.0179P)2 + 1.3214P]
where P = (Fo2 + 2Fc2)/3
(Δ/σ)max = 0.002
Δρmax = 0.56 e Å−3
Δρmin = −0.32 e Å−3
247 parameters
0 restraints
Primary atom site location: iterative
Special details
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)
x
y
z
Uiso*/Ueq
I1
F1
1.02927 (2)
0.99431 (14)
0.43234 (14)
0.45186 (17)
0.8281 (2)
0.56974 (16)
0.44708 (17)
0.7610 (2)
0.803774
0.64636 (15)
0.6303 (2)
0.33470 (15)
0.5691 (2)
0.6368 (2)
0.594019
0.43863 (2)
0.86573 (7)
0.50760 (6)
0.63451 (7)
0.46130 (9)
0.56291 (6)
0.70043 (7)
0.52365 (8)
0.554529
0.64956 (6)
0.54116 (8)
0.80138 (6)
0.49418 (8)
0.43237 (8)
0.401213
0.70991 (2)
0.31186 (15)
0.22482 (12)
0.33434 (14)
0.54780 (17)
0.11907 (14)
0.37438 (14)
0.54173 (17)
0.611907
0.52903 (12)
0.43227 (17)
0.34228 (13)
0.33133 (17)
0.33789 (19)
0.268247
0.02562 (5)
0.0482 (4)
0.0221 (3)
0.0196 (3)
0.0208 (3)
0.0287 (3)
0.0193 (3)
0.0193 (3)
0.023*
0.0221 (3)
0.0185 (3)
0.0275 (3)
0.0197 (3)
0.0244 (4)
0.029*
O1
N1
C1
O2
N2
C2
H2
O3
C3
O4
C4
C5
H5
C6
0.7674 (2)
0.41554 (9)
0.44590 (19)
0.0247 (4)
Acta Cryst. (2018). C74
sup-6

supporting information
H6
C7
C8
C9
C10
H10
C11
H11
C12
C13
0.814835
0.5681 (2)
0.5860 (2)
0.7052 (2)
0.8228 (2)
0.835259
0.9221 (2)
1.002324
0.9018 (2)
0.7907 (2)
0.781470
0.6923 (2)
0.615284
0.4463 (2)
0.2891 (2)
0.294383
0.213370
0.256482
0.5423 (2)
0.463240
0.500112
0.635236
0.3312 (2)
0.2035 (2)
0.119864
0.161775
0.245578
0.373124
0.450193
0.030*
0.60868 (8)
0.71636 (8)
0.75722 (8)
0.72585 (9)
0.678999
0.76212 (10)
0.740675
0.82967 (10)
0.86302 (9)
0.910050
0.82630 (9)
0.848465
0.54563 (9)
0.55914 (10)
0.599001
0.42603 (16)
0.49331 (17)
0.45591 (16)
0.42326 (19)
0.433228
0.3763 (2)
0.353709
0.3632 (2)
0.3985 (2)
0.390699
0.44565 (18)
0.471304
0.12336 (18)
0.02252 (19)
−0.028300
0.067348
−0.037665
0.60655 (18)
0.621914
0.0185 (3)
0.0197 (3)
0.0190 (3)
0.0254 (4)
0.030*
0.0327 (4)
0.039*
0.0301 (4)
0.0293 (4)
0.035*
0.0242 (4)
0.029*
0.0221 (4)
0.0298 (4)
0.045*
H13
C14
H14
C15
C16
H16A
H16B
H16C
C17
H17A
H17B
H17C
C18
0.566258
0.521035
0.74413 (10)
0.715531
0.789140
0.045*
0.045*
0.0274 (4)
0.041*
0.041*
0.584128
0.686984
0.30679 (17)
0.1893 (2)
0.156118
0.745718
0.041*
0.74345 (9)
0.71544 (10)
0.748393
0.675041
0.704600
0.0207 (3)
0.0281 (4)
0.042*
0.042*
0.042*
C19
H19A
H19B
H19C
0.215776
0.119275
Atomic displacement parameters (Å2)
U11
U22
U33
U12
U13
U23
I1
F1
0.02788 (7)
0.0294 (6)
0.0241 (6)
0.0225 (7)
0.0221 (8)
0.0305 (7)
0.0216 (7)
0.0240 (9)
0.0313 (7)
0.0224 (8)
0.0282 (7)
0.0215 (8)
0.0319 (10)
0.0313 (10)
0.0226 (8)
0.0248 (9)
0.0197 (8)
0.02021 (7)
0.0459 (8)
0.0200 (6)
0.0160 (7)
0.0187 (8)
0.0300 (7)
0.0172 (7)
0.0172 (8)
0.0163 (6)
0.0170 (8)
0.0218 (7)
0.0190 (8)
0.0163 (8)
0.0138 (8)
0.0180 (8)
0.0175 (8)
0.0201 (8)
0.02625 (7)
0.00422 (5)
−0.0073 (6)
−0.0051 (5)
0.0003 (5)
0.0002 (7)
−0.0029 (6)
0.0024 (5)
−0.0015 (6)
0.0061 (5)
−0.0004 (6)
0.0070 (5)
−0.0036 (6)
−0.0052 (7)
0.0010 (7)
−0.0013 (6)
0.0065 (7)
0.0027 (6)
0.00614 (5)
0.0236 (7)
0.0061 (5)
0.0094 (6)
0.0091 (7)
0.0125 (6)
0.0062 (6)
0.0109 (7)
0.0043 (5)
0.0118 (7)
0.0092 (6)
0.0087 (7)
0.0106 (8)
0.0131 (8)
0.0098 (7)
0.0050 (7)
0.0009 (6)
0.00214 (5)
0.0089 (7)
0.0002 (5)
−0.0008 (6)
0.0035 (7)
0.0043 (6)
−0.0010 (6)
−0.0002 (6)
−0.0008 (5)
0.0020 (6)
0.0012 (5)
0.0016 (7)
−0.0036 (7)
0.0006 (7)
−0.0008 (6)
0.0004 (6)
−0.0036 (6)
0.0738 (10)
0.0208 (6)
0.0217 (7)
0.0227 (9)
0.0275 (7)
0.0184 (7)
0.0194 (8)
0.0156 (6)
0.0197 (8)
0.0317 (7)
0.0199 (8)
0.0257 (9)
0.0308 (10)
0.0172 (8)
0.0152 (8)
0.0135 (8)
O1
N1
C1
O2
N2
C2
O3
C3
O4
C4
C5
C6
C7
C8
C9
Acta Cryst. (2018). C74
sup-7

supporting information
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
0.0225 (9)
0.0209 (9)
0.0173 (9)
0.0273 (10)
0.0233 (9)
0.0305 (10)
0.0310 (10)
0.0402 (11)
0.0190 (8)
0.0189 (9)
0.0230 (9)
0.0361 (11)
0.0344 (10)
0.0207 (9)
0.0223 (9)
0.0163 (8)
0.0299 (10)
0.0280 (10)
0.0228 (9)
0.0312 (10)
0.0281 (10)
0.0420 (12)
0.0357 (11)
0.0348 (11)
0.0243 (9)
0.0203 (8)
0.0239 (9)
0.0172 (9)
0.0229 (9)
0.0318 (10)
0.0061 (7)
0.0058 (8)
−0.0063 (8)
−0.0020 (7)
0.0030 (7)
−0.0011 (7)
−0.0013 (8)
0.0084 (8)
0.0032 (7)
0.0006 (7)
0.0056 (7)
0.0118 (9)
0.0056 (8)
0.0044 (8)
0.0048 (7)
0.0098 (7)
0.0037 (8)
0.0139 (8)
0.0107 (7)
0.0055 (8)
−0.0018 (7)
−0.0014 (9)
0.0015 (9)
−0.0012 (8)
−0.0044 (7)
−0.0024 (7)
0.0001 (8)
−0.0006 (7)
0.0045 (7)
0.0035 (8)
Geometric parameters (Å, º)
I1—C1
2.0979 (18)
C8—C17
1.512 (2)
F1—C12
O1—C4
O1—C15
N1—N2
N1—C7
C1—C2
C1—C6
O2—C15
N2—C8
N2—C18
C2—H2
C2—C3
O3—C7
O3—C8
C3—C4
C3—C7
O4—C18
C4—C5
C5—H5
C5—C6
C6—H6
C8—C9
1.365 (2)
1.397 (2)
1.373 (2)
1.3983 (19)
1.281 (2)
1.386 (2)
1.390 (3)
1.195 (2)
1.491 (2)
1.364 (2)
0.9500
1.400 (2)
1.365 (2)
1.4515 (19)
1.400 (2)
1.464 (2)
1.222 (2)
1.379 (2)
0.9500
C9—C10
C9—C14
1.390 (2)
1.395 (2)
0.9500
1.387 (3)
0.9500
1.371 (3)
1.373 (3)
0.9500
1.386 (3)
0.9500
1.493 (3)
0.9800
0.9800
0.9800
0.9800
C10—H10
C10—C11
C11—H11
C11—C12
C12—C13
C13—H13
C13—C14
C14—H14
C15—C16
C16—H16A
C16—H16B
C16—H16C
C17—H17A
C17—H17B
C17—H17C
C18—C19
C19—H19A
C19—H19B
C19—H19C
0.9800
0.9800
1.500 (3)
0.9800
0.9800
1.387 (3)
0.9500
1.523 (2)
0.9800
C15—O1—C4
C7—N1—N2
C2—C1—I1
C2—C1—C6
C6—C1—I1
N1—N2—C8
C18—N2—N1
C18—N2—C8
C1—C2—H2
C1—C2—C3
C3—C2—H2
117.16 (13)
104.65 (14)
118.74 (13)
120.79 (17)
120.42 (13)
111.07 (13)
122.51 (14)
126.37 (14)
120.0
C11—C10—H10
C10—C11—H11
C12—C11—C10
C12—C11—H11
F1—C12—C11
F1—C12—C13
C11—C12—C13
C12—C13—H13
C12—C13—C14
C14—C13—H13
C9—C14—H14
119.6
120.8
118.38 (18)
120.8
119.10 (18)
118.09 (18)
122.81 (19)
120.9
118.30 (18)
120.9
119.6
120.05 (16)
120.0
Acta Cryst. (2018). C74
sup-8

supporting information
C7—O3—C8
C2—C3—C4
C2—C3—C7
C4—C3—C7
O1—C4—C3
C5—C4—O1
C5—C4—C3
C4—C5—H5
C4—C5—C6
C6—C5—H5
C1—C6—H6
C5—C6—C1
C5—C6—H6
N1—C7—O3
N1—C7—C3
O3—C7—C3
N2—C8—C9
N2—C8—C17
O3—C8—N2
O3—C8—C9
O3—C8—C17
C17—C8—C9
C10—C9—C8
C10—C9—C14
C14—C9—C8
C9—C10—H10
C11—C10—C9
107.33 (12)
118.51 (16)
118.41 (15)
123.02 (16)
120.58 (15)
118.26 (15)
121.07 (16)
119.9
120.18 (17)
119.9
120.3
119.39 (16)
120.3
116.20 (15)
128.00 (16)
115.78 (15)
111.26 (13)
112.74 (15)
99.24 (12)
109.17 (13)
108.06 (14)
115.09 (15)
120.38 (15)
118.86 (17)
120.64 (15)
119.6
C13—C14—C9
C13—C14—H14
O1—C15—C16
O2—C15—O1
O2—C15—C16
120.78 (17)
119.6
110.38 (15)
122.66 (17)
126.93 (17)
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
116.33 (16)
120.39 (17)
123.28 (16)
109.5
109.5
109.5
109.5
109.5
109.5
C15—C16—H16A
C15—C16—H16B
C15—C16—H16C
H16A—C16—H16B
H16A—C16—H16C
H16B—C16—H16C
C8—C17—H17A
C8—C17—H17B
C8—C17—H17C
H17A—C17—H17B
H17A—C17—H17C
H17B—C17—H17C
N2—C18—C19
O4—C18—N2
O4—C18—C19
C18—C19—H19A
C18—C19—H19B
C18—C19—H19C
H19A—C19—H19B
H19A—C19—H19C
H19B—C19—H19C
120.80 (17)
I1—C1—C2—C3
I1—C1—C6—C5
F1—C12—C13—C14
O1—C4—C5—C6
N1—N2—C8—O3
N1—N2—C8—C9
N1—N2—C8—C17
N1—N2—C18—O4
N1—N2—C18—C19
C1—C2—C3—C4
C1—C2—C3—C7
N2—N1—C7—O3
N2—N1—C7—C3
N2—C8—C9—C10
N2—C8—C9—C14
C2—C1—C6—C5
C2—C3—C4—O1
C2—C3—C4—C5
C2—C3—C7—N1
C2—C3—C7—O3
177.52 (12)
−178.17 (13)
177.44 (17)
−176.19 (16)
−11.66 (16)
103.18 (15)
−125.79 (15)
−177.18 (15)
2.7 (2)
0.8 (2)
−176.69 (15)
0.70 (19)
−177.36 (16)
−90.33 (18)
85.57 (19)
−0.9 (3)
175.43 (14)
−1.0 (2)
C6—C1—C2—C3
C7—N1—N2—C8
C7—N1—N2—C18
C7—O3—C8—N2
C7—O3—C8—C9
C7—O3—C8—C17
C7—C3—C4—O1
C7—C3—C4—C5
C8—N2—C18—O4
C8—N2—C18—C19
C8—O3—C7—N1
C8—O3—C7—C3
C8—C9—C10—C11
C8—C9—C14—C13
C9—C10—C11—C12
C10—C9—C14—C13
C10—C11—C12—F1
C10—C11—C12—C13
C11—C12—C13—C14
C12—C13—C14—C9
0.2 (3)
7.40 (18)
−175.13 (15)
11.41 (16)
−105.04 (15)
129.12 (15)
−7.2 (2)
176.30 (16)
−0.1 (3)
179.75 (15)
−8.6 (2)
169.74 (14)
173.47 (17)
−173.28 (16)
0.2 (3)
2.7 (3)
−177.25 (18)
2.1 (3)
−1.9 (3)
−0.6 (3)
178.95 (17)
0.9 (2)
Acta Cryst. (2018). C74
sup-9

supporting information
O3—C8—C9—C10
O3—C8—C9—C14
C3—C4—C5—C6
C4—O1—C15—O2
C4—O1—C15—C16
C4—C3—C7—N1
C4—C3—C7—O3
C4—C5—C6—C1
18.2 (2)
−165.92 (15)
0.3 (3)
5.6 (2)
−176.14 (14)
1.6 (3)
C14—C9—C10—C11
−2.5 (3)
81.4 (2)
C15—O1—C4—C3
C15—O1—C4—C5
C17—C8—C9—C10
C17—C8—C9—C14
C18—N2—C8—O3
C18—N2—C8—C9
C18—N2—C8—C17
−102.02 (18)
139.87 (17)
−44.2 (2)
170.99 (15)
−74.2 (2)
56.9 (2)
−176.45 (15)
0.6 (3)
Hydrogen-bond geometry (Å, º)
Cg3 is the centroid of the C9–C14 ring.
D—H···A
D—H
H···A
D···A
D—H···A
C5—H5···O4i
0.95
0.95
0.98
0.98
2.53
2.51
2.54
2.50
3.331 (2)
3.335 (2)
3.513 (2)
3.407 (2)
142
145
174
154
C14—H14···O2ii
C16—H16A···O4iii
C17—H17C···Cg3ii
Symmetry codes: (i) −x+1, y−1/2, −z+1/2; (ii) x, −y+3/2, z+1/2; (iii) x, −y+3/2, z−1/2.
2-[4-Acetyl-5-(4-chlorophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6e)
Crystal data
C19H16ClIN2O4
Mr = 498.69
F(000) = 984
Dx = 1.736 Mg m−3
Mo Kα radiation, λ = 0.71073 Å
Cell parameters from 9499 reflections
θ = 2.9–31.1°
Monoclinic, P21/c
a = 11.703 (2) Å
b = 22.037 (4) Å
c = 7.4073 (12) Å
β = 92.888 (8)°
V = 1907.9 (5) Å3
Z = 4
µ = 1.85 mm−1
T = 100 K
Block, colourless
0.22 × 0.12 × 0.12 mm
Data collection
Bruker APEXII CCD
diffractometer
φ and ω scans
4387 independent reflections
3863 reflections with I > 2σ(I)
Rint = 0.042
Absorption correction: multi-scan
SADABS2014/2 (Bruker, 2014)
θmax = 27.5°, θmin = 2.9°
h = −15→15
k = −28→28
l = −9→9
T
min = 0.640, Tmax = 0.746
62840 measured reflections
Refinement
Refinement on F2
Least-squares matrix: full
R[F2 > 2σ(F2)] = 0.021
wR(F2) = 0.051
S = 1.04
4387 reflections
247 parameters
0 restraints
Primary atom site location: structure-invariant
direct methods
Hydrogen site location: inferred from
neighbouring sites
H-atom parameters constrained
w = 1/[σ2(Fo2) + (0.0233P)2 + 1.3951P]
where P = (Fo2 + 2Fc2)/3
(Δ/σ)max = 0.002
Δρmax = 0.40 e Å−3
Δρmin = −0.66 e Å−3
Acta Cryst. (2018). C74
sup-10

supporting information
Special details
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)
x
y
z
Uiso*/Ueq
I1
Cl1
O1
N1
C1
O2
N2
C2
H2
0.89006 (2)
0.06374 (4)
0.77394 (10)
0.64395 (12)
0.84397 (15)
0.91227 (11)
0.56147 (13)
0.77370 (14)
0.742501
0.30547 (2)
0.34278 (2)
0.50823 (5)
0.42152 (6)
0.37358 (8)
0.47025 (6)
0.38760 (6)
0.35965 (7)
0.320035
0.88485 (2)
0.41999 (8)
0.31612 (16)
0.12176 (18)
0.6975 (2)
0.14881 (17)
0.02279 (19)
0.5465 (2)
0.532421
0.03207 (5)
0.03241 (12)
0.0169 (2)
0.0155 (3)
0.0175 (3)
0.0219 (3)
0.0165 (3)
0.0156 (3)
0.019*
O3
C3
O4
C4
C5
H5
0.61627 (10)
0.74881 (14)
0.44240 (12)
0.79720 (14)
0.86500 (15)
0.895568
0.33434 (5)
0.40416 (7)
0.37370 (6)
0.46180 (7)
0.47563 (8)
0.515324
0.27089 (16)
0.4147 (2)
−0.22008 (18)
0.4405 (2)
0.5935 (2)
0.609208
0.0156 (2)
0.0135 (3)
0.0279 (3)
0.0147 (3)
0.0176 (3)
0.021*
C6
H6
0.88836 (15)
0.934058
0.43149 (8)
0.440805
0.7241 (2)
0.830114
0.0183 (3)
0.022*
C7
C8
C9
0.67047 (14)
0.53275 (14)
0.41367 (14)
0.39456 (15)
0.456042
0.28763 (16)
0.275442
0.19911 (15)
0.21483 (16)
0.152988
0.32285 (16)
0.334764
0.84064 (15)
0.81145 (19)
0.801965
0.38903 (7)
0.33051 (7)
0.33227 (7)
0.36749 (8)
0.389965
0.37029 (8)
0.394248
0.33766 (8)
0.30168 (8)
0.279055
0.29914 (8)
0.274592
0.50789 (8)
0.56051 (9)
0.596984
0.2610 (2)
0.1187 (2)
0.1917 (2)
0.3436 (2)
0.399203
0.4149 (2)
0.518796
0.3323 (2)
0.1829 (3)
0.129009
0.1126 (2)
0.009782
0.1683 (2)
0.0475 (3)
0.120947
−0.022698
−0.034917
0.0106 (2)
0.085534
−0.027385
−0.096334
−0.1420 (2)
0.0137 (3)
0.0145 (3)
0.0142 (3)
0.0193 (4)
0.023*
0.0209 (4)
0.025*
0.0191 (4)
0.0226 (4)
0.027*
0.0198 (4)
0.024*
0.0172 (3)
0.0292 (4)
0.044*
C10
H10
C11
H11
C12
C13
H13
C14
H14
C15
C16
H16A
H16B
H16C
C17
H17A
H17B
H17C
C18
0.740015
0.873208
0.55813 (15)
0.548298
0.637073
0.552037
0.567020
0.27428 (8)
0.238187
0.276005
0.044*
0.044*
0.0197 (4)
0.029*
0.029*
0.505453
0.51525 (15)
0.272232
0.40515 (8)
0.029*
0.0190 (4)
Acta Cryst. (2018). C74
sup-11

supporting information
C19
0.55873 (17)
0.516126
0.640246
0.548147
0.46367 (9)
0.473014
0.459579
0.496532
−0.2175 (2)
−0.331441
−0.239569
−0.130830
0.0239 (4)
0.036*
0.036*
H19A
H19B
H19C
0.036*
Atomic displacement parameters (Å2)
U11
U22
U33
U12
U13
U23
I1
Cl1
O1
N1
C1
O2
N2
C2
O3
C3
O4
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
0.02554 (8)
0.0206 (2)
0.0224 (6)
0.0162 (7)
0.0145 (8)
0.0227 (7)
0.0183 (7)
0.0144 (8)
0.0157 (6)
0.0114 (8)
0.0291 (8)
0.0152 (8)
0.0190 (9)
0.0149 (8)
0.0130 (8)
0.0150 (8)
0.0165 (8)
0.0196 (9)
0.0243 (9)
0.0158 (8)
0.0176 (9)
0.0197 (9)
0.0180 (8)
0.0346 (11)
0.0191 (9)
0.0196 (9)
0.0308 (10)
0.03502 (8)
0.0319 (3)
0.0132 (5)
0.0158 (7)
0.0224 (9)
0.0242 (7)
0.0169 (7)
0.0151 (8)
0.0147 (6)
0.0156 (8)
0.0343 (8)
0.0155 (8)
0.0168 (8)
0.0259 (9)
0.0131 (7)
0.0156 (8)
0.0127 (7)
0.0206 (8)
0.0205 (9)
0.0188 (8)
0.0226 (9)
0.0207 (9)
0.0179 (8)
0.0273 (10)
0.0193 (8)
0.0228 (9)
0.0254 (9)
0.03427 (8)
−0.00758 (5)
0.00113 (19)
0.0002 (5)
−0.01207 (5)
0.0134 (2)
0.0019 (5)
−0.0003 (5)
0.0005 (6)
0.0047 (5)
−0.0019 (6)
0.0011 (6)
−0.0048 (5)
0.0018 (6)
−0.0088 (6)
0.0034 (6)
0.0030 (7)
0.0001 (6)
0.0026 (6)
−0.0023 (6)
−0.0018 (6)
−0.0018 (7)
0.0023 (7)
0.0047 (7)
−0.0012 (7)
−0.0008 (7)
−0.0002 (7)
0.0021 (8)
0.0023 (7)
0.0011 (7)
0.0022 (7)
0.02000 (6)
−0.0002 (2)
0.0013 (4)
−0.0009 (5)
0.0049 (7)
0.0013 (5)
0.0012 (5)
0.0005 (6)
0.0014 (4)
−0.0005 (6)
0.0005 (6)
0.0007 (6)
−0.0032 (6)
−0.0018 (7)
−0.0010 (6)
−0.0004 (6)
0.0009 (6)
−0.0049 (7)
−0.0044 (7)
0.0055 (7)
−0.0031 (7)
−0.0062 (7)
0.0010 (6)
0.0121 (8)
−0.0054 (7)
−0.0002 (7)
0.0053 (7)
0.0460 (3)
0.0153 (6)
0.0143 (7)
0.0156 (8)
0.0192 (6)
0.0140 (7)
0.0174 (8)
0.0158 (6)
0.0135 (7)
0.0191 (7)
0.0137 (8)
0.0173 (8)
0.0141 (8)
0.0152 (8)
0.0125 (8)
0.0131 (8)
0.0174 (8)
0.0179 (9)
0.0231 (9)
0.0273 (10)
0.0189 (8)
0.0155 (8)
0.0258 (10)
0.0208 (9)
0.0146 (8)
0.0156 (9)
−0.0012 (5)
−0.0002 (7)
−0.0005 (5)
−0.0030 (6)
−0.0022 (6)
−0.0030 (5)
−0.0004 (6)
−0.0041 (6)
0.0010 (6)
−0.0037 (7)
−0.0037 (7)
−0.0004 (6)
−0.0013 (6)
0.0012 (6)
−0.0013 (7)
0.0040 (7)
0.0027 (7)
−0.0036 (7)
−0.0012 (7)
−0.0062 (7)
−0.0006 (8)
0.0004 (7)
0.0048 (7)
0.0029 (8)
Geometric parameters (Å, º)
I1—C1
2.0963 (17)
C8—C17
C9—C10
C9—C14
C10—H10
C10—C11
C11—H11
C11—C12
C12—C13
C13—H13
C13—C14
1.513 (2)
Cl1—C12
O1—C4
O1—C15
N1—N2
N1—C7
C1—C2
C1—C6
O2—C15
N2—C8
1.7459 (18)
1.395 (2)
1.377 (2)
1.399 (2)
1.281 (2)
1.389 (2)
1.388 (2)
1.193 (2)
1.491 (2)
1.395 (2)
1.394 (2)
0.9500
1.384 (3)
0.9500
1.379 (3)
1.381 (3)
0.9500
1.392 (3)
Acta Cryst. (2018). C74
sup-12

supporting information
N2—C18
C2—H2
C2—C3
O3—C7
O3—C8
C3—C4
C3—C7
O4—C18
C4—C5
C5—H5
C5—C6
C6—H6
C8—C9
1.366 (2)
0.9500
C14—H14
C15—C16
0.9500
1.493 (2)
0.9800
0.9800
0.9800
0.9800
0.9800
0.9800
1.505 (3)
0.9800
0.9800
0.9800
1.404 (2)
1.366 (2)
1.4568 (19)
1.400 (2)
1.464 (2)
1.221 (2)
1.384 (2)
0.9500
C16—H16A
C16—H16B
C16—H16C
C17—H17A
C17—H17B
C17—H17C
C18—C19
C19—H19A
C19—H19B
C19—H19C
1.389 (2)
0.9500
1.520 (2)
C15—O1—C4
C7—N1—N2
C2—C1—I1
C6—C1—I1
C6—C1—C2
N1—N2—C8
C18—N2—N1
C18—N2—C8
C1—C2—H2
C1—C2—C3
C3—C2—H2
C7—O3—C8
C2—C3—C7
C4—C3—C2
C4—C3—C7
O1—C4—C3
C5—C4—O1
C5—C4—C3
C4—C5—H5
C4—C5—C6
C6—C5—H5
C1—C6—C5
C1—C6—H6
C5—C6—H6
N1—C7—O3
N1—C7—C3
O3—C7—C3
N2—C8—C9
N2—C8—C17
O3—C8—N2
O3—C8—C9
O3—C8—C17
C17—C8—C9
C10—C9—C8
114.96 (13)
104.84 (14)
119.80 (13)
118.83 (13)
121.32 (16)
111.55 (13)
123.28 (14)
125.17 (14)
120.0
C11—C10—H10
C10—C11—H11
C12—C11—C10
C12—C11—H11
C11—C12—Cl1
C11—C12—C13
C13—C12—Cl1
C12—C13—H13
C12—C13—C14
C14—C13—H13
C9—C14—H14
C13—C14—C9
C13—C14—H14
O1—C15—C16
O2—C15—O1
O2—C15—C16
C15—C16—H16A
C15—C16—H16B
C15—C16—H16C
H16A—C16—H16B
H16A—C16—H16C
H16B—C16—H16C
C8—C17—H17A
C8—C17—H17B
C8—C17—H17C
H17A—C17—H17B
H17A—C17—H17C
H17B—C17—H17C
N2—C18—C19
119.4
120.6
118.76 (16)
120.6
118.47 (14)
121.84 (16)
119.69 (14)
120.6
118.87 (17)
120.6
119.7
120.60 (16)
119.7
110.52 (15)
122.00 (15)
127.46 (17)
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
119.95 (15)
120.0
107.76 (12)
118.79 (15)
118.07 (15)
123.10 (15)
120.76 (15)
117.65 (15)
121.53 (15)
120.0
120.03 (16)
120.0
119.06 (16)
120.5
120.5
116.24 (15)
128.02 (15)
115.71 (14)
112.35 (14)
112.57 (14)
99.28 (12)
108.34 (13)
108.37 (13)
114.64 (14)
119.22 (15)
109.5
109.5
109.5
116.68 (16)
119.87 (16)
123.46 (16)
109.5
109.5
109.5
O4—C18—N2
O4—C18—C19
C18—C19—H19A
C18—C19—H19B
C18—C19—H19C
Acta Cryst. (2018). C74
sup-13

supporting information
C14—C9—C8
C14—C9—C10
C9—C10—H10
C11—C10—C9
122.03 (15)
118.74 (16)
119.4
H19A—C19—H19B
H19A—C19—H19C
H19B—C19—H19C
109.5
109.5
109.5
121.16 (16)
I1—C1—C2—C3
I1—C1—C6—C5
Cl1—C12—C13—C14
O1—C4—C5—C6
N1—N2—C8—O3
N1—N2—C8—C9
N1—N2—C8—C17
N1—N2—C18—O4
N1—N2—C18—C19
C1—C2—C3—C4
C1—C2—C3—C7
N2—N1—C7—O3
N2—N1—C7—C3
N2—C8—C9—C10
N2—C8—C9—C14
C2—C1—C6—C5
C2—C3—C4—O1
C2—C3—C4—C5
C2—C3—C7—N1
C2—C3—C7—O3
O3—C8—C9—C10
O3—C8—C9—C14
C3—C4—C5—C6
C4—O1—C15—O2
C4—O1—C15—C16
C4—C3—C7—N1
C4—C3—C7—O3
C4—C5—C6—C1
−175.79 (12)
175.24 (13)
178.69 (14)
178.30 (15)
−5.26 (16)
109.07 (15)
−119.69 (15)
−179.05 (16)
0.9 (2)
0.4 (2)
−177.32 (15)
0.98 (19)
−176.59 (16)
−74.07 (19)
106.70 (18)
−2.3 (3)
−178.77 (14)
−1.9 (2)
−174.43 (16)
8.0 (2)
34.6 (2)
−144.63 (15)
1.3 (3)
0.4 (2)
−178.08 (15)
8.0 (3)
−169.58 (15)
0.8 (3)
C6—C1—C2—C3
C7—N1—N2—C8
C7—N1—N2—C18
C7—O3—C8—N2
C7—O3—C8—C9
C7—O3—C8—C17
C7—C3—C4—O1
C7—C3—C4—C5
C8—N2—C18—O4
C8—N2—C18—C19
C8—O3—C7—N1
C8—O3—C7—C3
C8—C9—C10—C11
C8—C9—C14—C13
C9—C10—C11—C12
C10—C9—C14—C13
C10—C11—C12—Cl1
C10—C11—C12—C13
C11—C12—C13—C14
C12—C13—C14—C9
C14—C9—C10—C11
C15—O1—C4—C3
C15—O1—C4—C5
C17—C8—C9—C10
C17—C8—C9—C14
C18—N2—C8—O3
C18—N2—C8—C9
C18—N2—C8—C17
1.7 (3)
2.98 (18)
−176.27 (16)
5.51 (15)
−111.89 (14)
123.16 (14)
−1.2 (2)
175.70 (15)
1.8 (3)
−178.20 (15)
−4.56 (19)
173.32 (13)
−179.82 (16)
179.91 (16)
−0.3 (3)
0.7 (3)
−178.58 (14)
1.1 (3)
−1.0 (3)
0.1 (3)
−0.6 (3)
−83.54 (19)
99.47 (17)
155.75 (16)
−23.5 (2)
173.97 (15)
−71.7 (2)
59.5 (2)
Hydrogen-bond geometry (Å, º)
Cg2 is the centroid of the C1–C6 ring.
D—H···A
D—H
H···A
D···A
D—H···A
C6—H6···O2i
C11—H11···O1ii
C19—H19B···Cg2iii
0.95
0.95
0.98
2.47
2.55
2.75
3.258 (2)
3.435 (2)
3.649 (2)
140
155
153
Symmetry codes: (i) x, y, z+1; (ii) −x+1, −y+1, −z+1; (iii) x, y, z−1.
Acta Cryst. (2018). C74
sup-14