Synthesis, characterization, and biological activity of transition metal complexes of oxadiazole

Article abstract of DOI:10.1080/15533174.2011.555862

A new oxadiazole and its metal complexes have been synthesized and characterized. The ligand potassium 2-(2- phenylisonicotinoyl) hydrazinecarbodithioate [K⁺(H²L)^-] (1) on reaction with transition metals in EtOH-H₂

Full text of DOI:10.1080/15533174.2011.555862

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Synthesis, Characterization, and Biological Activity
of Transition Metal Complexes of Oxadiazole
D Harikishore Kumar Reddy a , Y Harinath a , Y Suneetha a , K Seshaiah a & A V.R. Reddy b
a Inorganic and Analytical Chemistry Division, Department of Chemistry , Sri
Venkateswara University , Tirupati, India
b Analytical Chemistry Division , Bhaba Atomic Research Centre , Trombay, Mumbai,
India
Published online: 12 Apr 2011.
To cite this article: D Harikishore Kumar Reddy , Y Harinath , Y Suneetha , K Seshaiah & A V.R. Reddy (2011) Synthesis,
Characterization, and Biological Activity of Transition Metal Complexes of Oxadiazole, Synthesis and Reactivity in
Inorganic, Metal-Organic, and Nano-Metal Chemistry, 41:3, 287-294
To link to this article: http://dx.doi.org/10.1080/15533174.2011.555862
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 41:287–294, 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2011.555862
Synthesis, Characterization, and Biological Activity of
Transition Metal Complexes of Oxadiazole
D. Harikishore Kumar Reddy,1 Y. Harinath,1 Y. Suneetha,1 K. Seshaiah,1
and A. V. R. Reddy2
1Inorganic and Analytical Chemistry Division, Department of Chemistry, Sri Venkateswara University,
Tirupati, India
2Analytical Chemistry Division, Bhaba Atomic Research Centre, Trombay, Mumbai, India
anti-inflammatory, antimitotic, antiarrhythmic, and insecticidal
activities,[5−8] and are among the most widely employed in
several areas such as corrosion inhibition, molecular sensory
systems, and organic light-emitting diodes (OLEDs).[9−12] The
heterocyclic thiones represent an important type of compound
in the field of coordination chemistry because of their poten-
tial multifunctional donor sites, viz either exocyclic sulfur or
endocyclic nitrogen.[13−14]
The classical synthetic routes to substituted 1,3,4-
oxadiazoles thione/thiolate involve ring-forming reactions.
Their syntheses attracted considerable attention and a num-
ber of methods have been used for their synthesis. The
widely used strategy involves the cyclization of acyldithio-
carbate esters, N-aroylditiocarbazates, and their salts to
1,3,4-oxadiazoles in the presence of a base.[13,14] Sev-
eral other reported methods for synthesis of oxadia-
zoles include oxidative cylization of acylhydrazones,[15]
acylthiourea,[16−18] and acylthiosemicrbazide.[19−22] Cycliza-
tion of N2-[bis(benzylsulfanyl)methylene] benzohydrazide
(N2-Hbmbh) to 2-benzylsulfanyl-5-(2-methoxyphenyl)-1,3,4-
oxadiazole during complexation with metals under normal con-
dition without the use of any other reagent viz. base or acid was
reported by Sigh and coworkers.[23]
A
new oxadiazole and its metal complexes have been
synthesized and characterized. The ligand potassium 2-(2-
phenylisonicotinoyl)hydrazinecarbodithioate [K+(H2L)−] (1) on
reaction with transition metals in EtOH-H2O medium under-
goes cyclization and converted to 5-(2-phenyl-4-pyridyl)-1,3,4-
oxadiazole-2-thione (ppot), which yielded a series of mononuclear
transition metal complexes. Four transition metal complexes of lig-
and are prepared and characterized based on elemental analysis,
IR,1H NMR, UV-vis spectra, and thermogravimetry-differential
thermal analysis (TG-DTA). From the obtained data, the struc-
ture of complexes has the general formula [M(ppot)2Cl2(H2O)2],
where M = Cu(II), Co(II), Ni(II), Zn(II). The thermal behaviors of
these complexes showed that the complexes lost coordinated water
molecules in the first step followed by decomposition of the lig-
and molecule in the subsequent steps. The ligand and its transition
metal complexes were screened against fungi and bacteria in vitro.
Data obtained showed that the ligand itself showed moderate bi-
ological activity, whereas the metal complexes exhibited a higher
inhibition towards both bacteria and fungi.
Keywords 1,3,4-oxadiazole, biological activity, complexes, metal
complexes
INTRODUCTION
1,3,4-oxadiazoles are an important class of heterocyclic
The wide spectrum of biological properties and other ap-
compounds whose chemistry and uses have been highlighted plications of oxadiazoles and their metal complexes prompted
in numerous reports.[1−4] Their syntheses and transformations the study of the metal complexes of 5-(2-phenyl-4-pyridyl)-
have been of interest for a long time as they demonstrated a 1,3,4-oxadiazole-2-thione obtained by the cyclization of
broad spectrum of biological properties in both pharmaceuti- potassium 2-(2-phenylisonicotinoyl)hydrazinecarbodithioate.
cal and agrochemical fields. They have proven antimicrobial, We report herein the synthesis, spectroscopic characterization,
thermogravimetric, and antimicrobial activity of the oxadiazole
ligand and its Cu(II), Co(II), Ni(II) and Zn(II) complexes.
Received 29 June 2010; accepted 14 September 2010.
The authors gratefully acknowledge the financial support by Board
of Research in Nuclear Sciences, Mumbai under Project BRNS No:
EXPERIMENTAL
2007/37/48/BRNS/2919. One of the authors, D. H. K. Reddy thanks
BRNS for his Junior Research Fellowship (JRF).
Address correspondence to K. Seshaiah, Inorganic and Analytical
Chemistry Division, Department of Chemistry, Sri Venkateswara Uni-
versity, Tirupati – 517 502, India. E-mail: seshaiahsvu@yahoo.co.in
Materials and Physical Measurement
Analytical grade (AR) chemicals with highest purity avail-
able were used. The analysis of CHNS/O contents of ligand
and metal complexes were done on Euro elemental analyzer.
287

288
D. H. K. REDDY ET AL.
IR spectra were recorded on (Thermo-Nicolet FT-IR, Nicolet 9.20 %. Found: C, 49.01; H, 2.48; N, 13.08; S, 10.04, Ni, 9.18%.
IR-200, USA) spectrometer using KBr pellets. TG/DTA curves FTIR (KBr, cm−1): v(OH) 3371m; v(C N) 1607s; vas(C-O-C)
for the complexes were recorded on Nietzsche thermobalance 1233; vs(C-O-C) 1154; v(N-N) 1097m; v(C-S) 842 s. UV-Vis
(model-STA 40 g) with PtVs Pt 10% Rh thermocouple in dy- spectrum [λmax DMF, cm−1]: 24813, 32786, 34843, 37594.
namic air conditions between the room temperature (∼20◦C)
and 1020◦C (gradient 10K/min).
[Zn(ppot)2Cl2(H2O)2] (5)
Color: Light Yellow. m.p.: 235◦C. Anal. calc. for
C26H16N6O4S2ZnCl2: C, 48. 42; H, 2.50; N, 13.03; S, 9.94;
Zn, 10.14 %. Found: C, 48.50; H, 2.48; N, 13.01; S, 9.84, Zn,
10.03%. FTIR (KBr, cm−1): v(OH) 3218m; v(C N) 1607s;
vas(C-O-C) 1233; vs(C-O-C) 1158; v(N-N) 1098m; v(C-S) 841
s. UV-Vis spectrum [λmax DMF, cm−1]: 25773, 31645, 37453.
Synthesis of Ligand [K+(H2L)−] (1)
K+(H2L)− was synthesized by the drop wise addi-
tion of CS2(6.09 mL 0.1012 mol) to a solution of 2-
phenylisonicotinohydrazide (6 g 0.0225 mol) and KOH (2.53 g
0.0451 mol) in 50 mL MeOH. The solution was stirred con-
tinuously for 3h at room temperature. The precipitated product
was filtered off and washed with diethyl ether. Color: Yellow.
Yield: 0.76 g 86 %. m.p.: 134◦C. Anal. calc. for C13H10KN3OS2:
C, 47. 68; H, 3.08; N, 12.83; S, 19.58%. Found: C, 47.02; H,
2.98; N, 11.98; S 19.34%. FTIR (KBr, cm−1): v(NH) 3174m;
v(C O) 1647; [β(NH) +v (CN)] (thioamide I) 1454; [v (CN)
Biological Activity
The antibacterial activity of the ligand and its metal com-
plexes (1–5) was tested in vitro against test bacteria S. au-
reus (Gram-positive) and E. coli (Gram-negative) at different
concentrations by disc diffusion technique.[24,25] Twenty-five
milliliters of sterilized nutrient agar media (NA) was poured in
each petriplate. After solidification, 0.1 mL of test bacteria was
spread over the medium using a spreader. The test compounds in
measured quantities were dissolved in DMF to get concentration
of 200, 100, and 50 µg mL−1. The disc Whatmann No. 1 filter
paper having the diameter 5.00 mm each containing (1.5 mg
cm−1) of compounds were placed at four equidistant places at
a distance of 2 cm from the center in the inoculated petriplates.
Filter paper disc treated with DMF served as control and pen-
cillin was used as a standard drug. All determinations were
made in duplicate for each of the compounds. Average of two
independent readings for each compound was recorded. These
petriplates were kept in refrigerator for 24 h for pre-diffusion.
Finally petriplates were incubated at 30◦C for 24 h.
+
β(NH)] (thioamide II) 1374;v(N-N) 1060 m; v(C=S) 997s;
pyridine ring 654.1H NMR (DMSO-d6) s,singlet; m, multiplet):
δ 10.95 (s, 1H secondary amide), δ 2.5 (s, 1H amine), δ 7.31 –
8.20 (m, Ar H’s). UV-Vis spectrum [λmax DMF, cm−1]: 37453,
31847, 24875 cm−1
.
Synthesis of Metal Complexes
All the metal complexes (2–5) were prepared by a general
procedure. Hot solution (60◦C) of the appropriate metal chlo-
rides (1.05 mmol) in an ethanol water mixture (1:1, 25 mL) was
added to the hot solution (60◦C) of the carbodithioate (0.4 g,
1 mmol) in the same solvent (25 mL).The resulting mixture
was stirred under reflux for 1 h, the precipitate was filtered off,
washed twice with a 1:1 ethanol: water mixture.
The in vitro antifungal activity of the ligand and their corre-
sponding complexes was tested by the food poison technique us-
ing potato-dextrose-agar (PDA) medium at 200, 100, and 50 µg
mL−1. R. bataticola and A. alternate were used as test organ-
ism. Stock solutions of compounds were prepared by dissolving
the compounds (0.064 mg) in DMF. Chlorothalonil was used as
commercial fungicide and DMF served as control. Appropriate
quantities of the compounds in DMF was added to potato dex-
trose agar medium in order to get a concentrations 200, 100, and
50 µg mL−1 of compounds in the medium. The medium was
poured into a set of two petriplates under aspartic conditions
in a laminar flow hood. When the medium in the plates was
solidifided, a mycelial disc of 0.5 cm in diameter was cut from
the periphery after 7 days old culture, and it was aseptically
inoculated upside down and incubated at 25 1◦C until fungal
growth in the control petriplates was almost complete. All the
measurements were carried out in triplicates.
[Cu(ppot)2Cl2(H2O)2] (2)
Color: Brown. m.p.: 232◦C. Anal. calc. for
C26H16N6O4S2CuCl2: C, 48. 56; H, 2.51; N, 13.07; S,
9.97, Cu, 9.88 %. Found: C, 45.60; H, 2.42; N, 12.98; S, 9.34,
Cu, 9.78%. FTIR (KBr, cm−1): v(OH) 3371 m; v(C N) 1604s;
vas(C-O-C) 1233; vs(C-O-C) 1154; v(N-N) 1094m; v(C-S) 840
s. UV-Vis spectrum [λmax DMF, cm−1]: 24682, 37453, 31545.
[Co(ppot)2Cl2(H2O)2] (3)
Color: Black. m.p.: 201◦C. Anal. calc. for
C26H16N6O4S2CoCl2: C, 48. 91; H, 2.53; N, 13.16; S,
10.05; Co, 9.23%. Found: C, 48.89; H, 2.51; N, 13.10; S, 10.02,
Co, 9.12 %. FTIR (KBr, cm−1): v(OH) 3215m; v(C N) 1606s;
vas(C-O-C) 1236; vs(C-O-C) 1156; v(N-N) 1096m; v(C-S) 843
s. UV-Vis spectrum [λmax DMF, cm−1]: 24691, 33112, 34722,
40160.
[Ni(ppot)Cl2(H2O)2] (4)
RESULTS AND DISCUSSION
Color: Green Yellow.. m.p.: 243◦C. Anal. calc. for
Potassium2-(2-phenylisonicotinoyl)hydrazinecarbodithioate
C26H16N6O4S2NiCl2i: C, 48. 93; H, 2.53; N, 13.17; S, 10.05; Ni, (1) was synthesized from 2-phenylisonicotinohydrazide and its

TRANSITION METAL COMPLEXES OF OXADIAZOLE
289
S
N
N
H
N
H
N
+
CS2 + KOH
N
H
S-K+
NH2
O
O
MCl2 X.(H2O)
H2O-EtOH
N
N
Cl
Cl
N
O
M
S
S
O
N
H2O
OH2
N
N
M = Cu(II), Co(II), Ni(II), or Zn(II)
FIG. 1. Synthesis of the ligand [K+(H2L)−] (1) and its metal complexes (2–5).
metal complexes were prepared, as shown in the Figure 1. The thioamide I, thioamide II and v(C=S) were absent. Appearance
transition metal complexes were obtained by substitution reac- of new bands at 1604–1609 cm−1 (endocyclic C N), 1408–
tion of metal halide with bidentate ligand, in 1:2 molar ratios. 1412 cm−1 for vas(C-O-C), and 1279–1280 cm−1 for vs(C-O-C)
Microanalytical data (CHNS), FT-IR, Uv-vis spectroscopy, 1H suggest cyclization of acyclic dithiocarbazate (1). The IR data
NMR, and TG/DTA were used to characterize the complexes are consistent with the presence of a 1,3,4-oxadiazole moiety.[26]
and are consistent with the proposed formula (Table 1). The The spectra of all complexes exhibited intense broad bands
room temperature molar conductivity measurement (10−3) in at 3400–3200 cm−1 due to v(OH) of the coordinated water
DMSO indicated that the complexes are non-electrolytes. All molecule(s).[27] The presence of coordinate water molecules
the complexes (2–5) are non-hygroscopic and are stable in air, also confirmed by elemental and thermogravimetric analyses.
but are insoluble in common organic solvents.
UV-Vis Absorption Spectra
The electronic absorption spectra (not shown) of the lig-
and (1) and its metal complexes (2–5) were recorded in DMF
IR Spectra
The characteristic IR absorption bands of the functional
groups of the complexes showed significant changes when com-
pared with that of the parent free ligand. Shift of IR absorption of
some of characteristic vibrational frequencies of the functional
(a)
groups of the ligand upon complexation provides evidence for
the mode of binding of the ligand and to the metal ion. The
IR spectra of the complexes are very similar to each other, ex-
cept some slight shifts and intensity change of a few vibration
bands caused by different metal ions, which indicate that the
complexes have similar structures. Representative IR spectra of
the ligand (1) and complex (4) are shown in Figure 2.
(b)
The IR spectrum of [K+(H2L)−] exhibited a medium band
at 3174 cm−1 due to v(N-H) and the band at 1647 cm−1 was
assigned to v(C O) vibrations. The characteristic bands due to
v(C O), thioamide I, thioamide II, v(C=S),v(N-N), observed
at 1647, 1454, 1374, 1060 and 997 cm−1, respectively. The band
at 654 cm−1 is due to the pyridine ring.
4000
3500
3000
2500
Wavenumber (cm
2000
1500
1000
500
–1
)
A comparative study of the IR spectra of 2, 3, 4, and 5 with
that of [K+(H2L)−] (1) indicated that bands due to v(C O),
FIG. 2. FTIR spectra of (a) [K+(H2L)−] and (b) [Ni(ppot)2Cl2(H2O)2].

290

TRANSITION METAL COMPLEXES OF OXADIAZOLE
291
solution. The electronic spectra of 1 shows bands at 37453 cm−1
and 31847 cm−1 due to π → π* transition and a band at 24875
cm−1 due to n → π* transition. These bands may be attributed
to the intraligand charge transfer of the NCS− group.[28] The
band at 24875 cm−1 is assignable to the n →2π* transition of
the pyridine ring. A comparison of the spectra of the free lig-
ands and their complexes showed the π → π* presence of the
bands of the ligand in all complexes. On complexation, these
bands suffer considerable shifts due to coordination to respec-
tive metal ions. The absorption bands of the complexes 2–5 in
the same solvent are exhibited bands at 24500–28500 cm−1 and
at 32300–32500 cm−1,which are assigned to the d → d tran-
sitions. The absorption in the ultraviolet region are assignable
to transitions within the ligand orbitals, and that in the visible
region is probably due to charge transfer transition involving
ligand and metal orbitals, transition from S→M.[29] The strong
band at about 24690–28500 cm−1 is assignable to a combination
of metal-ligand charge transfer (M → LCT) and d-d bands.[30]
The nature of electronic spectra of 2–5 were similar to those
observed for other octahedral transition metal complexes.[31]
exhibited mulitiplet signals at δ =7.31 – 8.20 are due to the
protons of the aromatic ring of the ligand.
TG-DTA
Thermogravimetric (TG) and differential thermal (DTA)
analyses were used to describe thermal behavior of the prepared
complexes 2–5. The typical TG-DTA analysis of the complexes
was performed from 20 to 1020◦C at a heating rate of 10 K
min−1 under dynamic air condition. The TG and DTA study
of complex (2) presents two steps of decomposition, shown in
Figure 4. The first decomposition step occured at 70–180◦C.
In the first step, the complex loses the water molecules coor-
dinated to the metal atom. This process is confirmed by two
small endo-effects at 70 and 170◦C. Second decomposition step
occured between 210–700◦C, due to the pyrolysis of the whole
oxadiazole molecule. The degradation of this complexes was
confirmed by two exo-effects, one at 360◦C and another broad
exothermic peak at 520◦C. The TG curve for 3 showed two steps
of decomposition. The first decomposition step occurred with
a narrow temperature range between 90–140◦C, which may be
attributed to the loss of two coordinated water molecules. One
endothermic peak centered at about 120◦C is observed in the
DTA curve. The second decomposition step occured at the tem-
perature range 300 to 770◦C. This may be due to the loss of
oxadiazole moiety. A broad exothermic peak centered at about
620◦C is noticed. The remaining residue is the metal oxide. The
1HNMR Spectra
1
The HNMR spectra of the ligand (Figure 3) showed two
singlets at δ =10.95, 2.5 due to the presence of secondary amide
and primary amine protons, respectively, as they disappeared
on duteration. These two signals are absent in the spectra of
the complexes supports the ring cyclization. The free ligand
FIG. 3. H1NMR spectrum of compound 1.

292
D. H. K. REDDY ET AL.
TABLE 2
In vitro antibacterial activity of ligand 1 and its complexes 2–5
Diameter (mm) of
compounds at
concentrations
(µg mL−1
)
Compounds
Bacteria tested
200
100
50
1
S.aureus
E. coli
S.aureus
E. coli
S.aureus
E. coli
S.aureus
E. coli
10
7
6
4
9
7
7
5
8
7
5
—
—
5
3
4
2
5
2
4
2
17
14
14
11
15
13
12
9
3
4
FIG. 4. TG and DTA thermograms of the complex 2.
5
S.aureus
E. coli
4
2
Pencillin (standard)
S.aureus
E. coli
18
20
10
12
7
8
Biological Activity
The invitro antimicrobial properties of the heterocyclic lig-
and 1 and its metal complexes 2–5 were evaluated against gram-
positive and gram-negative bacteria and fungi, and the results at
different loading volume are presented in Table 2 and Table 3.
All of the tested compounds showed a remarkable biological ac-
tivity at higher concentration (200 µg) against microorganisms.
The ligand 1 exhibit a moderate activity against both bacteria
TABLE 3
In vitro antifungal activity of ligand 1 and its complexes 2–5
FIG. 5. TG and DTA thermograms of the complex 4.
Fungal inhibition (%)
at concentrations
( µg mL−1
)
TG curve for complex 4 showing three decomposition steps is
shown in Figure 5. The first decomposition step occurred at the
temperature range 60 to 165◦C, which corresponds to loss of two
coordinated water molecules. A small endo-effect is observed at
110◦C. Second decomposition step occurred at 330–570◦C, and
the third decomposition step occured at the temperature range
800–960◦C. Three exothermic peaks are observed in the DTA
curve, one broad exothermic peak centered at about 490◦C, an-
other at 820◦C, and the third one at 930◦C. The complex 5 was
thermally stable up to 100◦C after that there was decomposition
up to 180◦C. This loss in weight of the molecule corresponds
to two water molecules. This process is accompanied by endo-
effect observed on the DTA curve with maximum at 120◦C. The
second decomposition occurred at 320–360◦C, and the third de-
composition occurred at 540–680◦C. Four small endothermic
peaks are observed at the temperature 360, 530, 550, and 620◦C
in the DTA.
Compounds
Fungus
200
100
50
1
R. bataticola
A. alternata
R. bataticola
A. alternata
R. bataticola
A. alternata
R. bataticola
A. alternata
R. bataticola
A. alternata
R. bataticola
54.22
34.12
84.21
90.12
76.34
80.12
67.32
72.33
70.22
67.23
85.5
32.0
16.0
14.2
23.22
71.11
74.01
69.23
72.22
56.32
58.11
65.01
68.11
73.9
2
3
4
5
42.10
43.22
38.09
40.03
34.02
36.33
36.11
37.22
45.0
Chlorothalonil
(standard)
A. alternata
94.8
76.0
44.0

TRANSITION METAL COMPLEXES OF OXADIAZOLE
293
and fungi. A significant inhibition activity, higher than that of the
corresponding ligand, is displayed by metal complexes. Copper
complex showed good inhibition against all bacteria at 200 µg
mL−1 concentration when compared to those of cobalt, nickel,
and zinc complexes, which showed moderate activity. The high
antimicrobial activity of the metal complexes than the free lig-
and can be understood in terms of chelation theory, which states
that upon complexation, the polarity of the metal complexes
facilitate them to cross the cell membrane easily.[32] Chelation
reduces the polarity of the metal ion in the complexes consider-
ably, mainly due to the partial sharing of its positive charge with
the donor group. The possible electron delocalization over the
chelate ring system in turn increases the hydrophobic character
of the metal chelate thus favoring its permeation through lipoid
layer of microorganism.
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CONCLUSION
828.
The present article describes the synthesis, characterization,
and antimicrobial activity of transition metal complexes of 5-
(2-phenylpyridin-4-yl)-1,3,4-oxadiazole-2(3H)-thione. The an-
timicrobial activity of the complexes has been found to be en-
hanced as compared to the ligand; Maximum activity is achieved
in case of copper complex. Such a study will be helpful in de-
signing novel antimicrobial metal-based drugs.
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