Synthesis of 5-heptadecyl- and 5-heptadec-8-enyl substituted 4-amino-1,2,4-triazole-3-thiol and 1,3,4-oxadiazole-2-thione from (Z)-octadec-9-enoic acid: preparation of Palladium(II) complexes and evaluation of their antimicrobial activity

Article abstract of DOI:10.1007/s00706-019-02540-1

Abstract: Two 4-amino-1,2,4-triazoles and two 1,3,4-oxadiazoles are obtained in a common synthetic route including hydrogenation-hydrazidation of (Z)-methyl octadec-9-enoate to octadecanoic hydrazide under atmospheric air. Preservation of olefinic bond in heptadec-8-enyl group is achieved by carrying out hydrazidation reaction under the presence of an argon atmosphere. The disappearance of the olefinic bond is detected by physical data, IR, ¹H, and¹³C NMR spectroscopy. New palladium complexes derived from 4-amino-5-heptadecyl-1,2,4-triazole-3-thiol and 5-heptadecyl-1,3,4-oxadiazole-2(3H)-thione are obtained and characterized by elemental analysis (solid state), IR, ¹H, ¹³C NMR spectroscopy, XRD, and XPS. These resulting metallic entities are also identified in solution based in mass spectrometry (MS-ESI) experiments. Most compounds and their palladium(II) complexes are tested in vitro against Gram-positive, Gram-negative bacteria, and fungi, some of them showed variable activity. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-019-02540-1

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-019-02540-1
ORIGINAL PAPER
Synthesis of 5‑heptadecyl‑ and 5‑heptadec‑8‑enyl substituted
4‑amino‑1,2,4‑triazole‑3‑thiol and 1,3,4‑oxadiazole‑2‑thione
from (Z)‑octadec‑9‑enoic acid: preparation of Palladium(II) complexes
and evaluation of their antimicrobial activity
Manel Chehrouri1 · Adil A. Othman1 · Cristina Moreno‑Cabrerizo2 · Mohammad Gholinejad3 · José M. Sansano2
Received: 11 September 2019 / Accepted: 17 December 2019
© Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract
Two 4-amino-1,2,4-triazoles and two 1,3,4-oxadiazoles are obtained in a common synthetic route including hydrogenation-
hydrazidation of (Z)-methyl octadec-9-enoate to octadecanoic hydrazide under atmospheric air. Preservation of olefnic bond
in heptadec-8-enyl group is achieved by carrying out hydrazidation reaction under the presence of an argon atmosphere. The
disappearance of the olefnic bond is detected by physical data, IR, 1H, and13C NMR spectroscopy. New palladium complexes
derived from 4-amino-5-heptadecyl-1,2,4-triazole-3-thiol and 5-heptadecyl-1,3,4-oxadiazole-2(3H)-thione are obtained and
characterized by elemental analysis (solid state), IR, 1H, 13C NMR spectroscopy, XRD, and XPS. These resulting metallic enti-
ties are also identifed in solution based in mass spectrometry (MS-ESI) experiments. Most compounds and their palladium(II)
complexes are tested in vitro against Gram-positive, Gram-negative bacteria, and fungi, some of them showed variable activity.
Graphic abstract
N
_
N
_
_
N
N
S
S
S
N
N
(
)
16
(
(
)
)
16
Pd
Pd
H2N
H2N
2 Pd2Cl2
2
2
ANTIBACTERIAL AGENTS
N
N
_
N
N
S
O
O
(
)
16
16
2 Pd2Cl2
Keywords (Z)-Octadec-9-enoic acid · 1,3,4-Oxadiazole · Amino-1,2,4-triazole · Organometallic complexes · Antimicrobial
activity
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-019-02540-1) contains
supplementary material, which is available to authorized users.
* Adil A. Othman
Síntesis Orgánica (ISO), Facultad de Ciencias, Universidad
de Alicante, 03080 Alicante, Spain
adelaliothman@gmail.com
3
* José M. Sansano
Department of Chemistry, Institute for Advanced Studies
in Basic Sciences, P. O. Box 45195-1159, Gavazang,
Zanjan 45137-66731, Iran
jmsansano@ua.es
1
Laboratoire de Synthèse Organique Bioactive, Département
de Chimie Physique, Faculté de Chimie, Université des
Sciences et de la Technologie d’Oran, Mohamed Boudiaf-
USTO-MB, BP. 1505, El-M’naouer, 31003 Oran, Algeria
2
Departamento de Química Orgánica, Centro de Innovación
en Química Avanzada (ORFEO-CINQA), Instituto de
Vol.:(0123456789)
1 3

M. Chehrouri et al.
Mobile oxidation or/and hydrogenation of unsaturated
bond have been also reported [17, 18] as a case that involves
a serious danger to human health, caused by the food indus-
try and synthetic works [19, 20]. This observation of mobile
reactional changes from unsaturated to saturated fatty acid
prompted us to investigate a similar work under atmosphere
of air and argon to preserve the double bond.
Introduction
Saturated and unsaturated fats and their saturated and
unsaturated fatty acids have been the concern of many
chemists and biologists since a long time because of their
advantages and disadvantages to the health of human
beings via his dietary [1–6]. The importance of fatty acids
in membrane function has been reinforced by observations
that their defciencies in brain and retinal tissues can result
in compromised visual acuity [7], learning ability and even
in neurologic problems [4, 8]. Concerning the importance
of protein function, each fatty acid has the disadvantage
of involving non-physiological conditions of making it
difcult to assess their functional signifcance. However,
many review articles recommended a diet low in saturated
fat and argue it will lower risks of cardiovascular diseases,
diabetes, or death [9, 10].
In this article, we studied the behavior of the employment
of saturated and unsaturated fatty acids during the process to
prepare two 4-amino-1,2,4-triazoles and two 1,3,4-oxadia-
zoles through a common synthetic route. Also, the prepara-
tion of palladium complexes from saturated amino-1,2,4-
triazole and 1,3,4-oxadiazole were considered. Biological
activity was tested upon saturated heterocyclic products,
their intermediates, and their palladium(II) complexes.
Results and discussion
Fatty acids have also industrial uses as fuels, surfactants
[11, 12], and catalysts [12]. Fatty acid derivatives such
as branched chain-fatty acids and cyclic fatty acids have
antibacterial efects [13]. Heterocyclic derivatives form
suitable precursors for nucleoside, nucleotides formations
[14] and showed high tendency to form complexes with
various metals. Some of these complexes have been used
as efcient antibiotics [15] and as catalysts in many reac-
tions such as Tsuji–Trost and Mizoroki–Heck [16].
Synthesis of heterocyclic compounds 5, 6, 9, and 10
Ester 2 of (Z)-octadec-9-enoic acid (1, oleic acid) have
been prepared and identifed by classical methods [16].
When ester 2 was treated with hydrazine hydrate (85%),
under atmospheric oxygen, a non-catalytic hydrogena-
tion–hydrazination process took place (see Scheme 1) and
octadecanoic hydrazide 3 was exclusively obtained. The 1H
NMR spectrum did not show the olefnic protons indicating
Scheme 1
1 3

Synthesis of 5-heptadecyl- and 5-heptadec-8-enyl substituted…
that the double bond was reduced by the hydrazine hydrate
under atmospheric oxygen. This behavior was documented
in the literature [21, 22] (Scheme 2). Hydrazide 3 was trans-
formed into 4-amino-5-heptadecyl-1,2,4-triazole-3-thiol (5)
and 5-heptadecyl-(3H)-1,3,4-oxadiazole-2-thione (6) [16] as
illustrated in Scheme 1. Structures of intermediates and het-
erocyclic products 5 and 6 were determined by IR, 1H NMR,
13C NMR, and MS. The selection of these heterocycles as
suitable ligands of palladium(II) salts was carried out with
the idea of improving the biological activity of the pure iso-
lated heterocycles.
1H NMR spectrum (basic line in Fig. 1) illustrating clearly
the presence of olefnic bond at 5.35 ppm with an integra-
tion of two protons and about twenty parafnic protons at
1.28 ppm. In addition, its 13C NMR spectra in Fig. 2 showed
a signal at 129.84 ppm for (C=C) (basic line in Fig. 2).
After the exposure to air, the olefnic and allylic protons
diminished as illustrated at chemical shift positions at 5.35,
2.01 ppm, while the integration of parafnic protons at
1.29 ppm were increased by two protons (see upper line in
Fig. 1). Also, 13C NMR spectra in Fig. 2 showed the disap-
pearance of the signal at 129.84 ppm for (C=C).
However, when ester 2 was treated with hydrazine hydrate
(99%) under the atmosphere of argon (using freezing-pump
conditions before the mixture of the reagents) (Z)-octadec-
9-ene hydrazide 7 was isolated. IR spectrum showed absorp-
tion at 1535 cm−1 indicating the presence of the olefnic
When the hydrazide 7 was kept for almost 1 year under
the atmosphere of argon, its 1H NMR of 7 remained unal-
tered, but immediately diminished within few hours when
compound 7 was exposed to air. Therefore, due to sensitivity
of the olefnic bond in (Z)-octadec-9-ene hydrazide 7 and
other products to air, no further application reactions neither
complex formation nor biological activity test were carried
out with these unsaturated derivatives.
1
bond, which was confirmed by H NMR (multiplet at
5.35 ppm) and 13C NMR (signal at 129.84 ppm) (see Figs. 1,
2, basic lines). The salt 8, (Z)-4-amino-5-heptadec-8-enyl-
1,2,4-triazole-3-thiol (9), and (Z)-5-heptadec-8-enyl-1,3,4-
oxadiazole-2(3H)-thione (10) were obtained by the known
method [16] under argon atmosphere. Structural proof for
Preparation of palladium(II) complexes 11a, 11b,
12a, 12b
1
8–10 were provided by IR, H NMR, 13C NMR, and MS
data.
Compounds 4-amino-5-heptadecyl-1,2,4-triazole-3-thiol (5)
and 5-heptadecyl-1,3,4-oxadiazole-2(3H)-thione (6) were
treated individually with palladium salts, Pd(OAc)2 and
K2PdCl4 at room temperature. In all cases, orange color solu-
tions were obtained. The possible structures of complexes
11a, 11b, 12a, 12b were very difcult to determine despite
many spectroscopic data and microanalysis performed. For
example, FT-IR results showed that the disappearance of
N–H in 11a, 11b, and 12a and the delocalization of C=N
absorption in IR is a clear evidence for the formation metal-
lic palladium(II) complexes. Similarly, the diferences in 1H
NMR and 13C NMR between ligands 5 and 6 and their Pd-
complexes 11a, 11b, 12a, and 12b supported that structural
arrangement occurred.
A plausible mechanism for the non-catalytic hydrogena-
tion of the carbon–carbon double bond can be observed in
Scheme 2. The easy oxidation and disproportionation of the
hydrazine could contribute to the hydrogen transfer from the
diimide to the olefn with the subsequent extrusion of nitro-
gen. This process is very fast and the presence of oxygen was
crucial to enhance it.
Stability of the olefnic bond
in (Z)‑octadec‑9‑enehydrazide (oleic hydrazide) 7
Such as it was mentioned earlier, (Z)-octadec-9-enehy-
drazide 7, prepared under the atmosphere of argon, showed
1 3

M. Chehrouri et al.
Scheme 3
N
_
N
Pd(OAc)2, CHCl3
rt, 1 d
S
N
( )16
Pd
NH
H2N
N
2
N
_
N
S
11a
K2PdCl4, CHCl3
rt, 1 d
S
N
( )16
N
( )16
NH2
H2N
Pd Cl
2
2
2
5
11b
N
_
N
Pd(OAc)2, CHCl3
rt, 1 d
S
O
( )16
NH
Pd
N
2
S
12a
K2PdCl4, CHCl3
rt, 1 d
O
( )16
N
_
N
S
6
O
( )16
2 Pd2Cl2
12b
Fig. 1 1H NMR spectra of oleic hydrazide 7 synthesized under the atmosphere of argon (basic line) and after exposure to air (upper line)
1 3

Synthesis of 5-heptadecyl- and 5-heptadec-8-enyl substituted…
Fig. 2 13C NMR spectra of oleic hydrazide 7 under the atmosphere of argon (in black line) and after exposure to air (in red line)
XPS and XRD analysis were another instrumental tech-
niques used for the characterization of these complexes
(see SI). Mass spectra analysis also confrmed the presence
of the dinuclear/dimeric structures using ESI, which was
not determining (Scheme 3).
mononuclear species with two heterocyclic ligands [29],
homobinuclear complexes [30], etc.
Palladium(II) complexes for ligands 9 and 10 had not
been performed due to the fact that mobility of the olefnic
bond in them may be afected by Pd ions and atmospheric
oxygen during synthetic and structural determination times.
We have studied X-ray powder difraction (XRD) of
two resulting complexes (11b and 12a) using K2PdCl4 and
Pd(OAc)2 palladium sources (see SI). Resulting spectra
showed intense Bragg’s refections related to the palladium
which are very similar to PdCl2 or (NH)4PdCl2 pattern [23,
24] confrming the presence of palladium(II) species in
complexes structure.
Antimicrobial activity
(Z)-Octadec-9-enoic acid (oleic acid) (1), the ester 2,
octadecanehydrazide (3), 4-amino-5-heptadecyl-1,2,4-
triazole-3-thiol (5), and 5-heptadecyl-1,3,4-oxadiazole-
2(3H)-thione (6) and palladium(II) complexes 11a, 11b,
12a, 12b, were tested in vitro against eight strains, Gram-
positive bacteria Staphylococcus aureus (ATCC 25923),
Staphylococcus aureus laboratory isolate, Enterococcus
faecalis (ATCC 29212), Gram-negative bacteria, Escher-
ichia coli (ATCC 25922), Pseudomonas aeruginosa
(ATCC 27853), and fungus Aspergillus niger, Candida
albicans, Trichosporon. Vancomycin, colistin were used
as positive references and DMSO as negative reference.
Results are summarized in Tables 1, 2, and 3. Table 1
showed that 4-amino triazole 5 had signifcant efect upon
Gram-positive, Gram-negative bacteria, and one fungus
The reported X-ray difraction analysis of similar tria-
zol-palladium(II) complexes did not provide an uniform
trend for these complexes and are not helpful to deter-
mine the exact nature of complexes 11 and 12. Thus, a
dinuclear structure with strong S–Pd coordination [25],
a dinuclear paddle-wheel structure incorporating phos-
phines as ligands [26], mono- and binuclear complexes
with S–Pd–N coordination [27], etc. In similar way, oxa-
diazole-2-thiones formed complexes with palladium(II)
salts and stabilizing phosphines to give mononuclear
complexes with two units of the heterocyclic moiety [28],
1 3

M. Chehrouri et al.
Table 1 Antimicrobial activity
of synthesized compounds
(10 mg cm−3), zone inhibition
in mm
Comp.
G(+) bacteria
G(−) bacteria
Fungi
vi
i
ii
iii
iv
v
vii
viii
1
–
7
8
9
–
–
–
19
–
–
9
–
–
–
7
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
10
–
–
–
–
–
–
–
–
–
–
–
–
–
10
–
–
–
–
–
–
2
3
–
29
–
–
15
–
–
22
–
–
34
–
5
11a
11b
–
12
–
–
14
–
–
–
–
–
6
12a
–
7
–
7
11
–
12b
7
–
9
–
Control DMSO
Vancomycin
Colistin
–
23
–
18
–
30
–
–
14
–
11
(-): Inactive, no inhibition zone
i: Staphylococcus aureus (ATCC 25923), ii: Staphylococcus aureus laboratory isolate, iii: Enterococcus
faecalis (ATCC 29212), iv: Escherichia coli (ATCC 25922), v: Pseudomonas aeruginosa (ATCC 27853),
vi: Aspergillusniger, vii: Candida albicans, viii: Trichosporon
Table 2 The minimal inhibitory concentrations (MIC/mg cm−3) data
aminotriazole 11a and 11b and Pd complex of oxadiazole
12a were almost inefective against Gram-positive, Gram-
negative bacteria nor fungus due to the powerful attach-
ment of ligand-Pd [22]. Only compounds active in this
primary screening were further tested in a second set of
dilution 5 μg cm−3 and downward against all microorgan-
isms as shown in Table 3.
Comp.
G(+) bacteria
G(−) bacteria
i
ii
iii
iv
v
1
–
–
–
C/2
–
–
C/4
–
–
–
–
C/2
–
–
C/4
–
–
–
–
–
–
–
C/4
–
–
–
–
–
–
–
–
C/4
–
–
–
–
–
2
3
5
11a
11b
6
12a
12b
–
–
–
–
–
Conclusions
During our attempt to synthesize diazole derivatives from
unsaturated fatty acid, (Z)-octadec-9-enoic acid (1, oleic
acid) was noticed that during hydrazination step, under nor-
mal conditions of the atmosphere of air, the olefnic bond
had been subjected to internal hydrogenation. When the
same hydrazination reaction was repeated under atmospheric
pressure of argon, the olefnic bond kept intact. It was found
also that the double bond was kept as it for a long time-
up to 1 year-under storage under the atmosphere of argon
and gradually diminished after the exposition to air at any
stage of reaction after hydrazination. Therefore, the synthe-
sis of 4-amino-5-heptadecyl-1,2,4-triazole-3-thiol (5) and
5-heptadecyl-1,3,4-oxadiazole-2(3H)-thione (6) were car-
ried out under atmosphere of air and for (Z)-4-amino-5-hep-
tadec-8-enyl-1,2,4-triazole-3-thiol (9) and (Z)-5-heptadec-
8-enyl-1,3,4-oxadiazole-2(3H)-thione (10) were achieved
under atmosphere of argon. Ligands 5 and 6 showed a ten-
dency to form stable Pd complexes 11a, 11b, 12a, and 12b
possessing a weak biological activity.
–
–
C/2=5 mg, C/4=2.5 mg, C/8=1.25 mg, C/16=0.625 mg
Table 3 Bacteriostatic and bactericidal tests
Comp.
i
ii
iii iv
v
11
Bacteriostatic Bacteriostatic
–
Bacteriostatic Bacte-
rio-
static
12
Bacteriostatic Bacteriostatic
–
–
–
Candida albicans. There are cases when ligand 5 against
Gram-positive Staphylococcus aureus (ATCC 25923)
and Gram-negative Escherichia coli (ATCC 25922),
exceeded the references, whilst oxadiazole 6 was efec-
tive against Gram-positive bacteria only. Pd complexes of
1 3

Synthesis of 5-heptadecyl- and 5-heptadec-8-enyl substituted…
1.67 (m, 4H, 2xNH2), 2.70 (m, 4H, 2xCH2CN) ppm;
13C NMR: δ = 14.1 (2xCH3), 31.0 (m, 32xCH2), 158.0
(2xNC=O), 165.3 (2xCS) ppm; MS-ESI: m/z = 712.5
(L2Pd2Cl2·MeCN-(CH2)16-CH3 +1).
Experimental
All chemicals were purchased from Acros, Alpha, or Sigma-
Aldrich and used without further purifcation. Methyl (Z)-
heptadec-9-enoate (methyl oleate, 2) [32], stearohydrazide
(3) [31a], 4-amino-5-heptadecyl-4H-1,2,4-triazole-3-thiol
(5) [33], 5-heptadecyl-1,3,4-oxadiazole-2(3H)-thione (6)
[31a], oleohydrazide (7) [34], (Z)-4-amino-5-(heptadec-
8-en-1-yl)-4H-1,2,4-triazole-3-thiol (9) [31b], and (Z)-5-
(heptadec-8-en-1-yl)-1,3,4-oxadiazole-2(3H)-thione (10)
[31b] are known compounds. Melting points were deter-
mined with a Reichert Thermowar hot plate apparatus.
Only the structurally most important peaks of the IR spectra
(recorded with a FT-IR 4100LE (JASCO) (PIKE MIRacle
12a (C38H70N4O2PdS2) Brown sticky powder; m.p.:
1
> 300 °C (methanol/water); IR: ̄ꢀ = 1597, 1185 cm−1; H
NMR: δ=0.87 (t, 6H, 2xCH3), 1.25 (s, 56H, 28CH2), 1.68
(m, 4H, 2xCH2CH2CN), 2.65 (m, 4H, 2xCH2CN) ppm;
13C NMR: δ = 14.1 (2xCH3), 30.0 (m, 32xCH2), 168.2
(2xNC=O), 178.7 (2xC=S) ppm; MS-ESI: m/z = 993
[L2Pd2(H2O)(MeCN)2 +1].
12b (C38H70Cl2N4O2Pd2S2) Brown sticky solid; m.p.:
>300 °C; IR: ̄ꢀ =3219, 1678, 1185 cm−1; 1H NMR: δ=0.88
(t, 6H, 2xCH3), 1.29 (m, 56H, 28xCH2), 1.67 (m, 4H,
2xCH2CH2), 2.66 (m, 4H, 2xCH2) ppm; 13C NMR: δ=14.1
(2xCH3), 28.5 (32xCH2), 168.2 (2xNC=O), 179.5 (2xC=S)
ppm; MS-ESI: m/z=960 (L2Pd2Cl2).
ATR) are listed. 1H NMR (300, 400, or 500 MHz) and 13
C
NMR (75, 101, or 126 MHz) spectra were recorded using
Bruker AV300, Bruker AV400, and Bruker ADVANCE
DRX500, with CDCl3 as solvent and TMS as internal stand-
ard and chemical shifts are given in ppm. Low-resolution
electron impact (GC-EI) mass spectra were obtained at
70 eV using an Agilent 6890 N Network GC system and
Agilent 5973Network Mass Selective Detector. Microanaly-
ses were performed in a Thermo Finnigan Flash 1112 series.
TLC was performed on Schleicher and Schuell F1400/LS
254 silica gel plates and the spots were visualized under UV
light (λ=254 nm). Merck silica gel 60 (0.040–0.063 mm)
was used for fash chromatography.
Antibacterial and antifungal activity
The respective diferent strain was spread separately on
the Mueller–Hinton for antibacterial activity (CLSI 2004;
CLSI 2012). Then the test organism suspension was added
and incubated at 37 °C for 24 h for bacteria studies. The
drugs colistin and vancomycin were taken as standard drug
to compare the results and dimethylsulfoxide (DMSO) was
taken as blank [35]. Bacteriostatic or bactericide test was
determined as follows: a small sample was taken from each
well where there was no visible growth, using an inoculation
loop, which was then spread on GN plates and incubated
overnight at 37 °C [36]. The minimum inhibitory concentra-
tion (MIC) was the lowest concentration of test compound
that inhibit the visible growth of the organism and was deter-
mined in triplicates [37].
Microorganisms in this study were supplied and identifed
by the laboratory of microbiology by the university hospi-
tal of Oran. The Mueller–Hinton medium was supplied by
(Difco).
Synthesis of the palladium(II) complexes 11 and 12
The complexes were prepared individually by adding
0.011 mol of ligands 5 or 6 in 10 cm3 of chloroform to a
solution of palladium salt (Pd(OAc)2 or K2PdCl4, 0.01 mol)
in 10 cm3 of the same solvent and stirring the solutions at
room temperature for 24 h; orange color solutions were
obtained. Complexes were collected after, the solvents were
evaporated, washed with methanol, and dried under vacuum.
Acknowledgements Financial support was provided by the Spanish
Ministerio de Ciencia e Innovación (MICINN) (projects CTQ2010-
20387, and Consolider-Ingenio 2010, CSD2007-00006), the Span-
ish Ministerio de Economía y Competitividad (MINECO) (projects
CTQ2013-43446-P, and CTQ2014-51912-REDC), FEDER, the
Generalitat Valenciana (PROMETEO 2009/039 and PROMETE-
OII/2014/017) and the University of Alicante. One of us (M.C.) thanks
USTO-MB for scientifc leave.
11a (C38H74N8PdS2) Brown powder; m.p.: >300 °C (meth-
anol/water); IR: ̄ꢀ = 1609, 1313 cm−1; H NMR: δ = 0.87
1
(t, 6H, 2xCH3), 1.48 (m, 60H, 30xCH2), 2.04 (m, 4H,
2xNH2), 2.68 (m, 4H, 2xCH2CN) ppm; 13C NMR: δ=13.8
(2xCH3), 22.8 (m, 32xCH2), 156.1 (2xNC=O), 168.1 (2xCS)
ppm; MS-ESI: m/z=965 [L2Pd2H2O(MeCN)2 +1].
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