Crystal Structure of 2-(Pyridin-4-yl)-5-(Undecylthio)-1,3,4-Oxadiazole

Article abstract of DOI:10.1134/S0022476618050323

The title compound 2-(pyridin-4-yl)-5-(undecylthio)-1,3,4-oxadiazole (C₁₈H₂₇ON₃S) is synthesized, and its structure is confirmed by ¹H NMR, MS, elemental analyses and X-ray diffraction. It crystallizes in the monoclinic system, space group P2(1)/c with a = 24.453(17) ?, b = 10.604(7) ?, c = 7.095(5) ?, β = 91.60(2)°, V = 1839(2) ?³, Z = 4, and R = 0.086 for 2295 observed reflections with I > 2σ(I). The preliminary biological test shows that the title compound has good activity against Pythium ultimum with inhibitory to be 77.78%.

Full text of DOI:10.1134/S0022476618050323

Journal of Structural Chemistry. Vol. 59, No. 5, pp. 1236-1240, 2018.
Original Russian Text © 2018 Z.-H. Shen, Q. Wang, Z.-H. Sun, H.-K. Wu, C.-X. Tan, J.-Q. Weng, X.-H. Liu.
CRYSTAL STRUCTURE OF 2-(PYRIDIN-4-YL)-5-
(UNDECYLTHIO)-1,3,4-OXADIAZOLE
Z.-H. Shen, Q. Wang, Z.-H. Sun, H.-K. Wu,
C.-X. Tan, J.-Q. Weng, and X.-H. Liu*
3
The title compound 2-(pyridin-4-yl)-5-(undecylthio)-1,3,4-oxadiazole (C18H27ON S) is synthesized, and its
1
structure is confirmed by H NMR, MS, elemental analyses and X-ray diffraction. It crystallizes in the
monoclinic system, space group P2(1)/c with a = 24.453(17) Å, b = 10.604(7) Å, c = 7.095(5) Å,
3
β = 91.60(2)°, V = 1839(2) Å , Z = 4, and R = 0.086 for 2295 observed reflections with I > 2σ(I). The
preliminary biological test shows that the title compound has good activity against Pythium ultimum with
inhibitory to be 77.78%.
DOI: 10.1134/S0022476618050323
Keywords: heterocycle, synthesis, crystal structure.
INTRODUCTION
In recent years, heterocycles have received significant attention due to their biological importance [1-3], especially
the 1,3,4-oxadiazole ring. The 1,3,4-oxadiazole derivatives often exhibit diverse biological activities, including antifungal [4],
antioxidant [5], anticancer [6], herbicidal [7], hemolytic [8], and insecticidal [9, 10]. Also, pyridines display the outstanding
activities, such as antifungal [11], nematocidal [12-14], antimicrobial [15], herbicidal [16], anti-inflammatory [17], and so on.
In view of the facts mentioned above and also as a part of our work [18-22] on the synthesis of bioactive lead
compounds for the drug discovery, the title compounds were designed by introducing pyridine pharmacophore into the 1,3,4-
1
oxadiazole scaffold. A new 1,3,4-oxadiazole derivative was synthesized and characterized by H NMR, MS, and elemental
analyses. The single crystal structure of the title compound was determined by X-ray diffraction. The antifungal activity of
the title compound was tested.
RESULTS AND DISCUSSION
Synthesis. The synthetic route for the preparation of the title 1,3,4-oxadiazole compound is depicted in Scheme 1.
Many references reported the synthesis methods for 1,3,4-oxadiazole. In the literature [23], oxadiazole derivatives were often
synthesized by cyclized diacylhydrazines. In this paper, we use acylhydrazine and CS as materials, then cyclized under the
2
base condition. Finally, 5-(pyridin-4-yl)-1,3,4-oxadiazole-2-thiol and 1-chlorododecane reacted smoothly in the presence of
NaOH in DMF under microwave irradiation and resulted in the formation of the final product in an excellent yield. The
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, Zhejiang, P. R. China;
*xhliu@zjut.edu.cn. The text was submitted by the authors in English. Zhurnal Strukturnoi Khimii, Vol. 59, No. 5, pp. 1275-
1279, June-July, 2018. Original article submitted January 18, 2017.
1236
0022-4766/18/5905-1236 © 2018 by Pleiades Publishing, Ltd.

separated solid was washed with water, filtered, dried, and crystallized from EtOH to furnish the analytically pure white
yellow product (yield 75%).
1
The structure of the pure product 2-(pyridin-4-yl)-5-(undecylthio)-1,3,4-oxadiazole was confirmed by H NMR and
1
MS spectroscopic techniques. From the H NMR data, the appearance of signals at 8.80 ppm and 7. 84 ppm are assigned to
pyridine ring protons. The –SCH protons connected to the phenyl ring are found at 3.42 ppm. The compound showed
2
+
a molecular ion peak at m/z 334 (M+H) in agreement with the molecular formula. The result of the elemental analysis is in
accordance with the calculated results.
Scheme 1. Synthetic route of the title compound.
Crystal structure. The crystal belongs to the monoclinic system with the space group P2(1)/c. The molecular
structure of the title compound is shown in Fig. 1, and the packing diagram is shown in Fig. 2. The selected bond lengths and
torsion angles are listed in Table 1. The optimized parameters obtained using the B3LYP/6-31G method for the title
compound are given in Table 1 and compared with the experimental data of the title compound.
Generally, the average bond lengths and bond angles of the pyridine ring [24-26] and the oxadiazole ring [27-31] are
normal. The C(6)=N(2) bond (1.294(5) Å) is longer than the general C=N double bond of 1.27 Å. The C(7)–S(1)–C(8) bond
angle is 99.30(19)°. The torsion angle of the thioether group C(7)–S(1)–C(8)–C(9) is 176.3(3)°. From Fig. 1 it is seen that the
1,3,4-oxadiazole ring is nearly planar with the pyridine ring with a quite small dihedral angle θ of 8.2°. The intermolecular
face-to-edge C–H–π stacking pattern of the title compound (Fig. 2) exists between CH of the pyridine ring and the oxidiazole
ring of the adjacent molecule. The distance between H and the centroid of the pyridine ring is 3.353 Å. Another interesting
Fig. 1. View of title compound 3 with displacement ellipsoids drawn at the 30%
probability level.
Fig. 2. View of the molecular packing of 3.
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TABLE 1. Selected Bond Lengths (Å) and Bond Angles (deg.)
Bond
Dist.
Cal. Dist.
Angle
(°)
Cal. Angle
S(1)–C(7)
S(1)–C(8)
O(1)–C(7)
O(1)–C(6)
N(1)–C(2)
N(1)–C(3)
N(2)–C(6)
N(2)–N(3)
N(3)–C(7)
C(1)–C(2)
C(1)–C(5)
C(3)–C(4)
C(5)–C(6)
C(8)–C(9)
1.726(4)
1.821(4)
1.362(4)
1.368(5)
1.342(6)
1.344(5)
1.294(5)
1.414(5)
1.303(5)
1.385(6)
1.400(6)
1.378(6)
1.461(5)
1.510(5)
1.72573
1.82098
1.36222
1.36851
1.34395
1.34164
1.29407
1.41388
1.30272
1.38546
1.39940
1.37834
1.46144
1.51011
C(7)–S(1)–C(8)
C(7)–O(1)–C(6)
C(2)–N(1)–C(3)
C(6)–N(2)–N(3)
C(7)–N(3)–N(2)
C(2)–C(1)–C(5)
N(1)–C(2)–C(1)
N(2)–C(6)–O(1)
N(2)–C(6)–C(5)
O(1)–C(6)–C(5)
N(3)–C(7)–S(1)
O(1)–C(7)–S(1)
C(9)–C(8)–S(1)
C(8)–C(9)–C(10)
99.30(19)
101.8(3)
116.6(4)
106.6(3)
105.0(3)
118.7(4)
123.5(4)
112.9(3)
127.9(4)
119.2(3)
129.1(3)
117.2(3)
107.1(3)
113.7(4)
99.30210
101.81446
117.48379
106.54427
106.54427
118.70187
123.57202
112.91902
127.84704
119.22573
129.07541
117.20117
107.12702
113.69935
feature is the intramolecular face-to-face π–π stacking existing between the pyridine ring and the 1,3,4-oxadiazole ring. Their
centroid separation is 3.802 Å, and the dihedral angle between two π planes is 0.00°. These interactions are estimated to play
a role in stabilizing the crystal structure.
Frontier orbital energy analysis. The energy gap between HOMO and LUMO was calculated by B3LYP.
According to the frontier molecular orbital theory, HOMO and LUMO are the most important factors that affect the
bioactivity. HOMO has a priority to provide electrons, while LUMO can accept electrons first. Thus, the study on the frontier
orbital energy can provide useful information about the biological mechanism [32]. The geometry of the title compound was
optimized using the DFT method (Fig. 3). LUMO of the title compound is mainly located on the pyridine ring, the 1,3,4-
oxadizole ring, and the SCH group, while HOMO of the title compound is located on the pyridine ring, the 1,2,4-triazole
2
ring, and the S atom. The fact is that there are electron transitions from the alkyl group to the pyridine ring and the 1,3,4-
oxadizole ring, while the energy gap between HOMO and LUMO is 0.40526 Hartree.
Evaluation of bioactivity. The in vivo fungicidal results of title compounds against Pythium ultimum, Phytophthora
infestans, Corynespora cassiicola, Botrytis cinerea, and Rhizoctonia solani were determined. Zhongshengmycin,
dimethomorph, procymidone, chlorothalonil, and validamycin were used as controls. The primary bioassay showed that the
title compound exhibited a weak inhibiting activity towards Phytophthora infestans, Corynespora cassiicola, Botrytis
cinerea, and Rhizoctonia solani. Its inhibition rates to Phytophthora infestans, Corynespora cassiicola, Botrytis cinerea, and
Rhizoctonia solani reach –0.24, 3.55, 0% at 500 μg/ml, respectively. It is lower than that of the controls (dimethomorph
Fig. 3. Frontier molecular orbitals of 3.
1238

97.76%; procymidone 45.89%; validamycin 62.5%). However, the title compound can accelerate the growth of Botrytis
cinerea; the result is –50.49%. On the other hand, the control chlorothalonil also cannot inhibit the fungi (–7.56%).
Surprisingly, the title compound exhibited excellent activity against Pythium ultimum (77.78%); on the contrary, the control
had no effect against Pythium ultimum.
EXPERIMENTAL
1
Instruments. Melting points were determined using an X-4 apparatus and were uncorrected. The H NMR spectra
were measured on a Bruker AV-400 instrument (Fallanden, Switzerland) using TMS as the internal standard and CDCl as
3
the solvent. Elemental analyses were performed on a Vario EL elemental analyzer (Hanau, Germany). Crystallographic data
of the compound were collected on a Rigaku Saturn diffractometer (Tokyo, Japan). All the reagents were of analytical grade
or freshly prepared before use.
General procedure. Intermediates 1 and 2 were synthesized according to [33]. A CEM designed 10 ml pressure-
rated vial was charged with DMF (5 ml), 4 (0.25 g, 1 mmol), 1-chloroundecane (1.1 mmol), and NaOH (0.05 g, 1.2 mmol).
The mixture was irradiated in a CEM Discover Focused Synthesizer (150 w, 90 °C, 200 psi, 15 min). The mixture was cooled
to room temperature by passing compressed air through the microwave cavity for 2 min. It was poured into cold ice (40 ml)
and the formed precipitate was filtered. The crude solid was recrystallized from EtOH to give 2-(pyridin-4-yl)-5-
1
undecylthio)-1,3,4-oxadiazole, white crystal, yield 75%, m.p. 56-57 °C. H NMR (CDCl , 400 MHz), δ: 0.89 (t, 3H, CH ),
(
3
3
1.27-1.48 (m, 16H, CH ), 1.86 (m, 2H, CH ), 3.41 (t, 2H, CH ), 7.84 (d, J = 5.1 Hz, 2H, Py), 8.80 (d, J = 5.2 Hz, 2H, Py). MS
2 2 2
+
ESI), m/z: 334 (M+1) . Elemental analysis (%), calculated: C 64.83, H 8.16, N 12.60. Found (%): C 64.95, H 8.01, N 12.45.
(
Structure determination. The cube-shaped single crystal of the title compound was obtained by recrystallization
from EtOH. The crystal with dimensions of 0.20×0.18×0.08 mm was mounted on a Rigaku Saturn diffractometer with
graphite-monochromated MoK radiation (λ = 0.71073 Å) using a Phi scan mode at 113(2) K in the range 2.09 ≤ θ ≤ 25.02°.
α
A total of 16274 reflections were collected, out of which 3252 were independent (Rint = 0.0778) and 2295 were observed with
I > 2σ(I). The calculations were performed with the SHELXS-97 program [34] and empirical absorption corrections were
applied to all intensity data. The non-hydrogen atoms were refined anisotropically. The hydrogen atoms were determined by
theoretical calculations and refined isotropically. Crystal data for the title compound: monoclinic system, P2(1)/c space group
3 3
with a = 24.453(17) Å, b = 10.604(7) Å, c = 7.095(5) Å, β = 91.60(2)°, V = 1839(2) Å , Z = 4, D = 1.204 g/cm ,
c
–1
α
μ(MoK ) = 0.184 mm , GOOF = 1.059. The final full-matrix least-squares refinement gave R = 0.0859 and wR = 0.2788
2
2
w = 1/[σ (F ) + (0.2P) + 1.6227P], where P = (F + 2F )/3), S = 1.04, (Δ/σ)max = 0.001, (Δρ)max = 0.22 and (Δρ)min =
2
2
2
(
0 0 c
1
–0.64 e/Å . CCDC-1527940 can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from the
=
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk.
Therotical calculations. According to the above crystal structure, a crystal unit was selected as the initial structure,
while DFT-B3LYP, HF methods in the Gaussian 03 package [35] were used to optimize the structure of the title compound.
The vibrational analysis showed that the optimized structures were in accordance with the minimum points on the potential
energy surfaces, which meant the absence of virtual frequencies, proving that the obtained optimized structures were stable.
All the convergent precisions were the system default values, and all the calculations were carried out on a DELL computer.
Antifungal activity. Antifungal activities of compound 3 against Stemphylium lycopersici (Enjoji) Yamamoto,
Fusarium oxysporum. sp. cucumebrium and Botrytis cinerea were evaluated according to [36, 37].
CONCLUSIONS
In summary, a new crystal structure 2-(pyridin-4-yl)-5-(undecylthio)-1,3,4-oxadiazole has been synthesized by the
1
multi-step reaction and characterized by H NMR, MS, and elemental analyses and the single crystal X-ray structural
1239

determination. The results show that the crystal structure exhibits the intermolecular π–π stacking. The frontier orbital energy
analysis, Mulliken atomic charges and the electrostatic potential were also studied. The antifungal bioassay showed that it
possessed a moderate activity.
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