Synthesis, structural, and antibacterial studies of some mixed ligand complexes of Zn(II), Cd(II), and Hg(II) derived from citral thiosemicarbazone and N-phthaloyl amino acids

Article abstract of DOI:10.1080/10426500600865137

A series of new mixed ligand complexes of Zn(II), Cd(II), and Hg(II) with cis-3,7-dimethyl-2,6-octadienthiosemicarbazone (CDOTSC; LH) and N-phthaloyl amino acids (AH) have been synthesized by the reaction of metal dichloride with ligands CDOTSC and N-phthaloyl derivative of DL-glycine (A₁H), L-alanine (A₂H), or L-valine (A₃H) in a 1:1:1 molar ratio in dry refluxing ethanol. All the isolated complexes have the general composition [M(L)(A)]. The plausible structure of these newly synthesized complexes has been proposed on the basis of elemental analyses, molar conductances, molecular weight measurement, and various spectral (IR, ¹H NMR, and ¹³C NMR) studies, and four coordinated geometries have been assigned to these complexes. All the complexes and ligands have been screened for their antibacterial activity. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500600865137

Phosphorus, Sulfur, and Silicon, 181:2863–2875, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600865137
Synthesis, Structural, and Antibacterial Studies of Some
Mixed Ligand Complexes of Zn(II), Cd(II), and Hg(II)
Derived From Citral Thiosemicarbazone and N-Phthaloyl
Amino Acids
Renu Sharma
Meena Nagar
Department of Chemistry, University of Rajasthan, Jaipur, India
A series of new mixed ligand complexes of Zn(II), Cd(II), and Hg(II) with cis-3,7-
dimethyl-2,6-octadienthiosemicarbazone (CDOTSC; LH) and N-phthaloyl amino
acids (AH) have been synthesized by the reaction of metal dichloride with ligands
CDOTSC and N-phthaloyl derivative of DL-glycine (A1H), L-alanine (A2H), or L-
valine (A3H) in a 1:1:1 molar ratio in dry refluxing ethanol. All the isolated com-
plexes have the general composition [M(L)(A)]. The plausible structure of these newly
synthesized complexes has been proposed on the basis of elemental analyses, molar
conductances, molecular weight measurement, and various spectral (IR, 1H NMR,
and 13C NMR) studies, and four coordinated geometries have been assigned to these
complexes. All the complexes and ligands have been screened for their antibacterial
activity.
Keywords Mixed ligand complexes; thiosemicarbazone; N-phthaloyl amino acids;
antibacterial activity
INTRODUCTION
During the last few decades, there are numerous reports on transi-
tion metal complexes derived from various ligands, such as amino
acids,1,2 Schiff bases of amino acids,3,4 N-protected amino acids,5 semi-
–
–
carbazone, thiosemicarbazone,6 14 and oximes.15 19 N-protected amino
acids and thiosemicarbazones are potential ligands that have aroused
Received March 31, 2006; accepted May 5, 2006.
The authors are greatly indebted to the head of the Chemistry Department, University
of Rajasthan, Jaipur, for providing laboratory and instrumentation facilities. The authors
are also grateful to Professor P. Bhatnagar, Zoology Department, University of Rajasthan,
Jaipur, for his help during the antibacterial studies.
Address correspondence to Meena Nagar, University of Rajasthan, Department of
Chemistry, Jaipur, 302004 India. E-mail: renusharma26@yahoo.co.in
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R. Sharma and M. Nagar
much interest because of their interesting bonding pattern and poten-
tial biological applications of their metal complexes. The triorganotin
(IV) compounds of N-protected amino acids exhibit some insecticidal
effects on Bean Weevils (Sitophilus graneria) and also show fungicidal
activity on Aspergillus niger and Helminthosponum taulosum.20 The
study of semi- and thiosemicarbazone compounds has received great im-
petus in recent years due perhaps to their remarkable activity against
bacteria21 and fungi;22 these compounds also have been shown to pos-
sess antitubercular,23 antimalarial,24 and antitumor25 activities. The
biological activities of thiosemicarbazone ligands have been attributed
to their trace metal complexing abilities, and the metal compounds have
been generally found to possess enhanced therapeutic properties.26 Re-
cently, a publication reported on the synthesis and characterization of
mixed ligand complexes of titanocene dichloride derived from hetero-
cyclic β-diketonates and N-protected amino acids.27 However, there are
no literature reports on the synthesis of mixed ligand complexes de-
rived from thiosemicarbazone of citral and N-phthaloyl amino acids.
As an extension of work described in our previous communications,28,29
in the present communication we report the synthesis, structural, and
antibacterial studies of some mixed ligand complexes of transition met-
als derived from these potential organic ligands.
EXPERIMENTAL
All reactants and solvents were of analytical grade. The tri-ethylamine
was distilled over KOH pellets. Solvents were purified by the literature
method.30 Metal contents of complexes were measured by complexo-
metric titration with EDTA.31 Sulfur was estimated gravimetrically
as BaSO4. The ligands cis-3,7-dimethyl-2,6-octadienthiosemicarbazone
(CDOTSC)28 and N-phthaloyl derivative of amino acids32 used were
synthesized by a reported method. Elemental analyses were per-
formed at the Regional Sofisticated Instrumentation Centre, Central
Drug Research Institute, Lucknow. Molar conductances were mea-
sured in 10−4 M DMF solution on a µp-based conductivity meter
model 1601/E. Melting points were determined in sealed capillaries.
IR absorption spectra were recorded in the 4000–200 cm−1 region
(KBr disc) on a Shimadzu FT-IR 8400/8900 spectrometer, and 1H NMR
spectra were recorded on a Jeol 300 MHz FT-NMR system. Chemical
shift are reported in δ (ppm) versus SiMe4 with CDCl3 and DMSO-d6
solvents proton residuals as the internal standard. Molecular weights
of these complexes were determined by the cryoscopic method using
Backmann’s thermometer and were found to be in agreement with
calculated value (Table I).

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R. Sharma and M. Nagar
Synthesis of CDOTSC (LH)
The ligand CDOTSC was prepared from 3,7-dimethyl-2,6-octadienal
(citral) and thiosemicarbazide (1:1 molar ratio) in absolute EtOH in
the presence of glacial AcOH. The mixture was refluxed for 1 h, cooled,
filtered the mixture and the obtained yellow solid was recrystallized
from EtOH (50%), and dried under reduced pressure.
The Synthesis of N-Phthaloyl Amino Acids (AH)
A intimate mixture of 0.06 mole of finely ground phthalic anhydride and
0.06 mole of respective amino acids (viz., DL-glycine or L-alanine or L-
valine) was heated for 30 min with stirring in an oil bath at 140–160oC.
After cooling, the solid material was dissolved in 40 mL of hot MeOH;
the filtered solution was diluted with H2O (40 mL), and the product was
allowed to crystallize slowly. It yielded colorless needle-shape crystals
of N-phthaloyl amino acid.
The Synthesis of Complexes
A weighted amount of cis-3,7-dimethyl-2,6-octadienthiosemicarbazone
(1.1268 g, 5 mmol) was mixed with the corresponding metal dichlo-
ride (5 mmol) solution in anhydrous EtOH (60 mL) followed by the
addition of a corresponding N-phthaloyl derivative of glycine, alanine,
or valine (5 mmol). After shaking the reaction mixture, triethylamine
(1.0119 g, 10 mmol) was added dropwise with constant stirring. After re-
fluxing this reaction mixture for ∼9 h, the resulting solid was filtered off,
washed with anhydrous Et2O to apparent dryness, and dried under re-
duced pressure. All the complexes were synthesize by the same method.
RESULTS AND DISCUSSION
A systematic study of the reactions of metal dichlorides with ligands
CDOTSC (LH) and a N-phthaloyl derivative of DL-glycine (A1H), L-
alanine (A2H), or L-valine (A3H) (1:1:1) molar ratio in anhydrous EtOH
in the presence of Et3N have been carried out. The reactions can be
represented by Equation (1).
EtOH
MCl2 + LH + AH −−→ [M(L)(A)] + 2Et3N.HCl
(1)
Et3N
where M = Zn+2, Cd+2, and Hg+2; LH = CDOTSC
AH = HOOC − CHR − NC(O)C6H4C(O); [R = H, CH3, CH(CH3)2]

Some Mixed Ligand Complexes of Zn(II), Cd(II), and Hg(II)
2867
The analytical data of the complexes together with their molar con-
ductances are given in Table I. The data are consistent with the pro-
posed formulas for the complexes. All the complexes are insoluble in
water and slightly soluble in common organic solvents but are readily
soluble in DMSO and DMF. The molecular-weights measurement data
of these complexes show their monomeric nature. The molar conduc-
tance data suggests the non-electrolytic nature of complexes. All the
complexes are stable at r.t. and decompose on heating at ∼300◦C.
Infrared Spectra
The IR spectrum of the ligand CDOTSC shows bands in the region
3475–3283 cm−1 due to stretching frequencies for NH2, while the ab-
sorption for NH is present at 3154 cm−1. An absorption band for CN
appears at 1622 cm−1. No band due to the SH group is observed be-
tween 2600 and 2500 cm−1 in agreement with the thione form of the
ligand and with the presence of a band at 836 cm−1 for CS.
In the IR spectra of N-phthaloyl amino acids, the carboxylic OH (ex-
cept for N-phthaloyl glycine) is observed at ∼3400 cm−1 as a broad band
while a ν(OH) deformation appeared as a sharp band at ∼900 cm−1
.
The band observed at ∼1750 cm−1 may be assigned to a νCO(asym)
(imido) vibration, and the band observed at ∼1700 cm−1 is due to the
mixing of νCO(sym) (imido) and νCOO(asym) vibrations. The νCOO(sym)
band observed at ∼1400 cm−1 is a weak band. The value of ꢁν =
νCOO(asym) − νCOO(sym) has been found to be in the range 300–320 cm−1
for these ligands.
A study and comparison of infrared spectra of thiosemicarbazone
(CDOTSC), N-phthaloyl amino acids, and their mixed ligand complexes
(Table II) imply that both ligands behave as a monobasic bidentate lig-
and. The ν (C N) shift of the CDOTSC from 1622 cm−1 to a lower fre-
quency in the spectra of the metal complexes indicated a coordination
of the azomethine nitrogen atom.33 The appearance of a new band in
the 408–467 cm−1 region are assigned to ν(M-N) and support the coor-
dination of a nitrogen of the azomethine group.34 The band having con-
siderable ν(C S) character, a shift from 836 cm−1 in the uncomplexed
CDOTSC to 725–768 cm−1 from spectra of the complexes, indicates co-
ordination of a thione/thiolato sulfur atom.35 The ν(M-S) bands have
been assigned in the 352–385 cm−1 range and support the coordination
of the thione/thiolato sulfur atom36 on a loss of the N(3) hydrogen from
the thiosemicarbazone moiety in the complex; an additional carbon–
nitrogen double bond N(3) = C(2) is formed. This new ν(C N) vibration
band is observed in 1565–1580 cm−1 region.34

2868

Some Mixed Ligand Complexes of Zn(II), Cd(II), and Hg(II)
2869
The broad band appearing around ∼1700 cm−1 due to [νCO(sym)
+
νCOO(asym)] in the spectra of the N-phthaloyl amino acids is splits
into two after complexation.37 The sharp band at ∼1700 cm−1 and a
medium intensity band at 1564–1600 cm−1 may be due to νCO(sym) and
νCOO(asym) vibrations, respectively. The lower shift of the order of 137–
175 cm−1 in the νCOO(asym) frequency [ꢁν = νCOO(asym) − νCOO(sym)
]
upon complexation indicates a chelating nature of the carboxylate group
of N-phthaloyl amino acids. The band appearing in the region 393–
423 cm−1 may be due to M-O vibrations.
1H NMR Spectra
1H NMR spectra of the [M(L)(A)] type complexes have been recorded in
CDCl3 and DMSO-d6 (Table III). 1H NMR spectra display the expected
signals of a different type of proton present in complexes, but a com-
parison of the spectra of ligand with those of the complexes can lead to
the following results:
1. The free ligand CDOTSC exhibits a signal at δ 9.45 ppm due to the
N(3) proton. The absence of this signal in spectra of the complexes
suggests that the proton has been lost via thioenolization and coor-
dination of the sulfur atom.
2. The aldehyde proton (CH N) shifts downfield from δ 7.8 ppm in
the ligand CDOTSC to δ 7.82–8.01 ppm in the spectra of complexes,
which is consistent with the formation of a coordination band be-
tween the azomethine nitrogen and metal ion.
3. The fre+e N-phthaloyl glycine (A1H) exhibits a signal at δ 4.5 ppm
due to H. N-phthaloyl L-alanine (A H) and N-phthaloyl L-valine
N
1
(A3H) exhibit a singlet at δ 9.26 and 8.97 ppm, respectively, due to
a carboxylate proton (COOH). The absence of these signals in the
spectra of complexes suggests The deprotonation of a COOH group
of N-phthaloyl amino acids and the coordination of a COO group to
metal.
13C NMR Spectra
13C NMR spectra of ligands CDOTSC; N-phthaloyl glycine (A1H);
and their Zn(II), Cd(II), and Hg(II) complexes were recorded in
CDCl3 and DMSO-d6 (Table IV). The 13C resonance signals are as-
signed according to the chemical shift theory. 13C NMR spectra display
the expected signals of a different type of a carbon present in complexes,

2870

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R. Sharma and M. Nagar
FIGURE 1 The proposed structure formula for the complexes.
but a comparision of the spectra of ligands with those of the complexes
can lead to the following conclusions:
1. A considerable upfield shift takes places in the position of C S
(177.2 ppm, CDOTSC), and C N (151.2 ppm, CDOTSC), indicating
coordination through the azomethine nitrogen and the thiol group
and consistent with earlier reports.12,38
2. The 13C NMR spectra of some of these complexes show a downfield
shift of ∼4 ppm in the position of carboxylic carbon signal as com-
pared to its position in the parent N-phthaloyl glycine, revealing a
bidentate nature of a COO group of a the ligand, which is consistent
with the assignment reported previously.20,39
On the basis of the previously discussed spectral data, the
four-coordinated geometry has been suggested for these complexes
(Figure 1).
Antibacterial Activity Test
Antibacterial activity of these compounds on selected bacteria Staphy-
lococcus aureus, Bacillus subtilis Gram (+) and Escherichia coli Gram
(−) were carried out using the filter paper scrap diffusion method using
agar nutrient as the medium. Small (8-mm, diam.) circular scraps of fil-
ter paper were prepared for the purpose of making bacteriostatic slices.
Ca. 2 mg of the compound (the ligands CDOTSC, N-phthaloyl amino
acids, and their metal complexes) was dissolved in 10 cm3 DMSO (1%) to
make a concentration of 0.2 mg/cm3. The solution (0.1 cm3) was poured
into a small bottle containing 12 paper slices; it was ensured that all the
solution was bottled up. The bottle was covered with a gauze and ster-
ilized by moist heat in an autoclave at 100oC using 15 Ib/in2 pressure

Some Mixed Ligand Complexes of Zn(II), Cd(II), and Hg(II)
2873
TABLE V Antibacterial Activity Data of CDOTSC
(LH) and N-Phthaloyl Amino Acids (AH) and Their
Metal Complexes
Average value of bacteriostatic diameter (mm)a
Compound
S. aureus
B. subtilis
E. coli
LH
A1H
A2H
A3H
[Zn(L)(A1)]
[Cd(L)(A1)]
[Zn(L)(A2)]
[Cd(L)(A2)]
[Zn(L)(A3)]
[Cd(L)(A3)]
13
14
12
15
16
18
19
18
17
18
16
13
14
13
15
17
16
17
18
19
14
12
15
13
16
15
16
17
15
17
aAverage values from four experiments.
for 15 min. Bacterial strains were inoculated onto the medium plate
with absorbent cotton, and three previously prepared bacteriostatic
slices containing the compound were put on the medium plate. One
sample was inoculated in parallel on four medium plates. All plates
were incubated at 35◦C for 24 h and then examined. The average value
of bacteriostatic diameter was calculated in mm from four experiments
for each compound and are given in Table V.
It is observed from these tests that metal chelates have a higher ac-
tivity than the free ligands. Such increased activity of the metal chelates
can be explained on the basis of Overtone’s concept and Tweedy’s chela-
tion theory.40 According to Overtone’s concept of cell permeability, the
lipid membrane that surrounds the cell favors the passage of only lipid-
soluble material due to liposolubility, which is an important factor that
controls antibacterial activity. On chelation, the polarity of the metal
ion is reduced to a greater extent due to the overlap of the ligand orbital
and partial sharing of the positive charge of the metal ion with a donor
group. Further, it increases the delocalization of π-electrons over the
whole chelates ring and enhances the penetration of the complexes into
lipid membranes and blocks metal binding sites on the enzymes of the
microorganism.
CONCLUSION
The type of mixed ligand complexes isolated during the present study
demonstrate that the interaction of Zn+2, Cd+2, and Hg+2 salts with Cit-
ral thiosemicarbazone and N-phthaloyl amino acids leads to complexes

2874
R. Sharma and M. Nagar
with 1:1:1 stoichiometry and are found to be monomeric in nature. The
bidentate nature of N-phthaloyl amino acids and thiosemicarbazone
has been suggested on the basis of spectral evidences. The Zn(II) and
Cd(II) complexes showed enhanced antibacterial activity than the par-
ent ligands.
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