Synthesis, spectroscopic, thermal and biological aspects of drug-based copper(II) complexes

Article abstract of DOI:10.1002/aoc.1786

A series of novel complexes of the type Cu(II)(L_n) ₂(H₂O)₂]^?xH₂O [where L_n = L_1-4, these ligands being described as: L ₁, 2-({4-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl] phenylimino}methyl)phenol, x = 1; L₂, 2-({4-[6,7-dihydrothieno[3,2-c] pyridin-5(4H)-ylsulfonyl]phenylimino}methyl)-5-(methoxy)phenol, x = 2; L ₃, 5-chloro-2-({4-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl] phenylimino}methyl)phenol, x = 2; and L₄, 5-bromo-4-chloro-2-({4-[6, 7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl]phenylimino} methyl)phenol, x = 1] was investigated. They were characterized by elemental analysis, IR, ¹H-NMR, ¹³C-NMR and electronic spectra, magnetic measurements and thermal studies. The FAB-mass spectrum of [Cu(II)(L ₁)₂(H₂O)₂]^?H ₂O was determined. A magnetic moment and reflectance spectral study revealed that an octahedral geometry could be assigned to all the prepared complexes. Ligands (L_n) and their metal complexes were screened for their in vitro antibacterial activity against Bacillus subtillis, Pseudomonas aeruginosa, Escherichia coli and Serratia marcescens bacterial strains. Kinetic parameters such as order of reaction (n), the energy of activation (E _a), the pre-exponential factor (A), the activation entropy (ΔS^≠), the activation enthalpy (ΔH^≠) and the free energy of activation (ΔG^≠) are reported.

Full text of DOI:10.1002/aoc.1786

Full Paper
Received: 14 November 2010
Revised: 4 January 2011
Accepted: 19 January 2011
Published online in Wiley Online Library: 28 April 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1786
Synthesis, spectroscopic, thermal
and biological aspects of drug-based
copper(II) complexes
Paresh N. Patel, Darshana J. Patel and Hasmukh S. Patel∗
A series of novel complexes of the type Cu(II)(Ln)2(H2O)2]•xH2O [where Ln = L1–4, these ligands being described as: L1,
2-({4-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl]phenylimino}methyl)phenol, x = 1; L2, 2-({4-[6,7-dihydrothieno[3,2-c]
pyridin-5(4H)-ylsulfonyl]phenylimino}methyl)-5-(methoxy)phenol, x = 2; L3, 5-chloro-2-({4-[6,7-dihydrothieno[3,2-c]pyridin-
5(4H)-ylsulfonyl]phenylimino}methyl)phenol, x = 2; and L4, 5-bromo-4-chloro-2-({4-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
ylsulfonyl]phenylimino} methyl)phenol, x = 1] was investigated. They were characterized by elemental analysis, IR, 1H-NMR,
13C-NMRandelectronicspectra,magneticmeasurementsandthermalstudies.TheFAB-massspectrumof[Cu(II)(L1)2(H2O)2]•H2O
was determined. A magnetic moment and reflectance spectral study revealed that an octahedral geometry could be assigned to
all the prepared complexes. Ligands (Ln) and their metal complexes were screened for their in vitro antibacterial activity against
Bacillus subtillis, Pseudomonas aeruginosa, Escherichia coli and Serratia marcescens bacterial strains. Kinetic parameters such as
order of react=ion (n), the energy of activation (Ea), the pre-exponential factor (A), the activation entropy (ꢀS=), the activation
=
c
enthalpy (ꢀH ) and the free energy of activation (ꢀG ) are reported. Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Keywords: Cu(II) complexes; spectroscopic; Freeman-Carroll method; antibacterial activity
Introduction
rial activity profile. From this point of view, the objective of
the present communication comprises the synthesis of a se-
ries of new compounds. The synthetic approach is shown in
Scheme 1.
Compounds 4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 4-
aminobenzene-1-sulfonylchloride are extensively studied com-
pounds owing to their wide spectrum of bioactivities.
Despite numerous attempts to develop new structural
prototypes in the search for more effective antimicro-
bials, N-benzylidene-4-{6,7-dihydrothieno[3,2-c] pyridin-5(4H)-
ylsulfonyl}aniline and its complexes comprise one of the
most versatile classes of compounds against microbes and
therefore are important components of molecules in drug
discovery.
Many drugs possess modified pharmacological and toxico-
logical properties when administered in the form of metallic
complexes. Probably the most widely studied cation in this re-
spect is Cu(II), since a host of low-molecular-weight copper
complexes have been proven beneficial against diseases such
as tuberculosis, rheumatoid, gastric ulcers and cancers.[7–10]
There is a continuing interest in metal complexes of Schiff
bases because of the presence of nitrogen and oxygen donor
atoms in the backbones of these ligands. This means that
they readily coordinate with a wide range of transition metal
ions, yielding stable and intensely colored metal complexes,
some of which have been shown to exhibit interesting physi-
cal and chemical properties[11–13] and potentially useful biological
activities.[14–16]
Thermalanalysistechniquesareextensivelyusedinstudyingthe
thermal behavior of metal complexes.[17–19] Thermogravimetry is
a process in which a substance is decomposed in the presence
of heat, which causes bonds of the molecules to be broken.[20,21]
The present work describes the synthetic, thermal, spectroscopic
aspects and anti•-bacterial activity of new copper complexes
[Cu(II)(Ln)2(H2O)2] xH2O.
A literature survey revealed that 4,5,6,7-tetrahydrothieno[3,2-
c]pyridine and its various derivatives, such as clopidogrel[1,2]
and ticlopidine,[3,4] are acknowledged to show noncyto-
toxic and complement inhibition properties.
A series of
substituted 4,5,6,7-tetrahydrothieno[3,2-c]pyridines (THTPs) was
synthesized and evaluated for human phenylethanolamine
N-methyltransferase (hPNMT) inhibitory potency and affinity
for the α2-adrenoceptor.[5] Various sulfonamide derivatives
of 4-aminobenzene-1-sulfonylchloride like benzo[d]-isothiazol-
3-one benzenesulfonamides are also well known to have
antimicrobial activity.[6] These medicinal properties render
the two compounds useful structural units in drug re-
search.
These findings prompted us to synthesize benzylidene
derivatives of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine as part
of our ongoing research program aiming at the synthe-
sis of their various complexes for biological evaluation.
Herein, we report the synthesis of a novel series of com-
plexesofN-benzylidene-4-{6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
ylsulfonyl}aniline derivatives and investigation of their antibacte-
∗
Correspondence to: Hasmukh S. Patel, Department of Chemistry, Sardar Patel
University, Vallabh Vidyanagar-388120, Gujarat, India.
E-mail: drhspatel786@yahoo.com
DepartmentofChemistry,SardarPatelUniversity,VallabhVidyanagar-388120,
Gujarat, India
c
Appl. Organometal. Chem. 2011, 25, 454–463
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

Aspects of drug-based copper(II) complexes
Scheme 1. Synthetic pathway for the preparation of derivatives of 4-(6,7-dihydrothieno[3,2-clpyridin-5(4H)-ylsulfonyl)aniline. Where, R = (L1)-C6H5, (L2)
4-OCH3-C6H4, (L3) 4-Cl-C6H4, (L4) 4-Cl-5-Br-C6H4.
Materials and Methods
1487.5–1469.7 (C C str. ring), 1224 (C–N str.), 1356–1148 (SO2,
str.), 748.4 (C–H def, aromatic), 721 (C–S–C str., thiophene), 3352,
3378 (-NHCO), 1665 (>C O of amide). 1H-NMR (400 MHz, DMSO-
d6), δ (ppm): 2.42 (2H, t, proton at C7), 3.07 (2H, t, proton at C6),
3.64 (2H, s, proton at C4), 6.48 (1H, s, -CONH-), 2.45 (3H, s,-COCH3),
6.20–7.46 (6H, m, proton at C2 –H, C3 –H, C10 –H, C11 –H, C13 –H,
C14 –H). 13C-NMR (400 MHz, DMSO-d6), δ (ppm): 123.35 (C2), 123.58
(C3), 45.57 (C4), 43.83 (C6), 24.35 (C7), 130.38 (C3a), 129.78 (C7a),
131.77 (C9), 124.43 (C10, C14), 117.54 (C11, C13), 132.30 (C12), 172.46
(-CO- of aceyle group).
Materials
All the chemicals used were of analytical grade. Salicylaldehyde,
ethyl acetoacetate, chloroform, hexane, ethanol, acrtonirile, 4-
aminobenzene-1-sulfonylchloride, 4,5,6,7-tetrahydrothieno[3,2-
c]pyridine, cyclohexanone, triethyl amine, dimethyl formamide
and Cu(NO3)•3H2O were purchased from E. Merck (India) Limited,
2
Mumbai.Luriabrothandagar-agarwerepurchasedfromSRL,India.
AceticacidandEthyleneDiamineTetraAceticAcidwerepurchased
from Sigma Chemical Co., India. The organic solvents were puri-
fied by the recommended method.[22] The metal contents of the
complexes were determined by the EDTA titration technique[23]
after treating them with a mixture of HClO4, H2SO4 and HNO3
(1 : 1.5 : 2.5). Elemental analysis was carried out using Perkin Elmer,
USA 2400-II CHN analyzer. The magnetic moments were obtained
by Gouy’s method using mercury tetra-thiocyanatocobaltate(II) as
a calibrant (χg = 16.44 × 10−6 c.g.s. units at 20 ◦C). Diamagnetic
corrections were made using Pascal’s constant.[24] A simultane-
ous Thermogravimetry/Derivative Thermogravimetry had been
obtained using a model 5000/2960 SDT, TA Instruments, USA. The
experimen◦t was performed in a nitrogen atmosphere at a heating
rate of 10 C min−1 in the temperature range 50–800 ◦C, using
an Al2O3 crucible. The IR spectra were recorded on an Fourier
Transform Infrared Spectroscopy Nicolet 400D spectrophotome-
ter using KBr pellets. NMR spectra were recorded on a model
Bruker Advance (400 MHz). The FAB mass spectrum was carried
out using a Jeol SX-102/DA-6000 mass spectrometer.
Preparation of 4-{6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
ylsulfonyl}aniline (3)
Compound
3 was prepared by base-catalyzed hydrolysis
of 0.01 mol (3.36 g) N-(4-{6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
ylsulfonyl}phenyl) acetamide (2) using (25 ml) 10% sodium hy-
droxide solution. The reaction mixture was then refluxed for
2 h. The solid separated was filtred, dried, purified by column
chromatography and recrystallized from ethanol to give white
crystalline compound. Yield, 68.7%; m.p. 172–174 ◦C. Anal. calcd
forC13H14O2N2S2 (294):requiresC, 53.06;H, 4.76;N, 9.52;S, 21.77%.
Found:C, 53.04;H, 4.75;N, 9.49;S, 21.74%. IR(νmax, KBr, cm−1):3082
(C–Hstr.,aromatic),1542.5(C C,asymmetric,str.),1478.4–1473.5
(C C str. ring), 1226 (C–N str.), 752.8 (C–H def, aromatic), 724
1
(C–S–C str., thiophene), 3306 (N–H, amine). H-NMR (400 MHz,
acetone-d6), δ (ppm): 2.47 (2H, t, proton at C7), 3.09 (2H, t, proton
at C6), 3.68 (2H, s, proton at C4), 6.28–7.56, (6H, m, protons at
C2 –H, C3 –H, C10 –H, C11 –H, C14 –H), 11.24 (2H, s, -NH2). 13C-NMR
(400 MHz, DMSO-d6), δ (ppm): 123.36 (C2), 123.59 (C3), 45.58 (C4),
43.85 (C6), 24.37 (C7), 130.39 (C3a), 129.79 (C7a), 131.78 (C9), 124.45
(C10, C14), 117.55 (C11, C13), 132.32 (C12).
Preparation of N-(4-{6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
ylsulfonyl}phenyl) acetamide (2)
An equimolecular mixture of 4,5,6,7-tetrahydrothieno[3,2-c] pyri-
dine hydrochloride (1) prepared using a reported method[25,26]
(0.01 mol/1.755 g) and 4-acetamidobenzene-1-sulfonyl chloride
(0.01 mol/2.335 g) was dissolved in anhydrous acetonitrile (20 ml)
using tetra-ethyl amine as base under constant stirring, and the
reaction mixture was refluxed for 5 h. After completion of the
reaction, it was poured in ice-cold water to obtain a light yellow
product (2), which was filtered and dried. It was purified by column
chromatography and recrystallized from ethanol to give a light
yellow crystalline compound. Yield 84.5%; m.p. 180–182 ◦C. Anal.
calcd for C15H16O3N2S2 (336): requires C, 53.57; H, 4.76; N, 8.33; S,
19.05%. Found: C, 53.56; H, 4.74; N, 8.32; S, 18.98%. IR (νmax, KBr,
cm−1): 3084 (C–H str., aromatic), 1546.7 (C C asymmetric str.),
Preparation of Ligands L1–4
An equimolecular mixture of 4-{6,7-dihydrothieno[3,2-c] pyridin-
5(4H)-ylsulfonyl}aniline (3) (0.01 mol/2.94 g) was refluxed with
2-hydroxy-benzaldehyde and its derivatives, like 2-hydroxy-4-
methoxybenzaldehyde, 4-chloro-2-hydroxybenzaldehyde and 5-
bromo-4-chloro-2-hydroxybenzaldehyde in ethanol (15 ml), with
a few drops of H2SO4 as catalyst, on a water bath for 1.5–2 hrs.
Excesssolventwasremovedundervacuumandthesolidseparated
was filtered, dried, purified by column chromatography and
recrystallized from ethanol or chloroform. The preparation of
ligands is shown in Scheme 1 and the proposed structure is shown
in Fig. 1.
c
Appl. Organometal. Chem. 2011, 25, 454–463
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

H. S. Patel, P. N. Patel and D. J. Patel
Figure 1. Proposed structure of ligand.
2-[(4-{6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
ylsulfonyl}phenylimino)methyl]phenol L1
1230 (C–N str.), 738 (C–S–C, str., thiophene), 1630 (-N CH-), 3468
(O–H). 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.46 (2H, t, proton
at C7), 3.09(2H, t, proton at C6), 3.66 (2H, s, proton at C4), 4.92
[1H, s, proton at C16 (-N CH-)], 6.33–7.62 (10H, m, protons at
C2 –H, C3 –H, C10 –H, C11 –H, C13 –H, C14 –H, C19 –H, C20 –H, C21 –H,
C22 –H), 9.51 (1H, s, proton-OH). 13C-NMR (400 MHz, DMSO-d6), δ
(ppm): 123.39 (C2), 123.69 (C3), 45.65 (C4), 43.86 (C6), 24.37 (C7),
Yellow crystalline compound. Yield, 62.4%; m.p. 186–188 ◦C, IR
(νmax, KBr, cm−1): 3075 (C–H str., aromatic), 1484–1474.8 (C
C
str. ring), 1226 (C–N str.), 736 (C–S–C, str., thiophene), 1643 (-
CH-), 3410 (O–H). 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.50
N
(2H, t, proton at C7), 3.13(2H, t, proton at C6), 3.70 (2H, s, proton
at C4), 4.96 [1H,s, proton at C16(-N CH-)], 6.37–7.66 (10H, m,
protons at C2 –H, C3 –H, C10 –H, C11 –H, C13 –H, C14 –H, C19 –H,
C20 –H, C21 –H, C22 –H), 9.55 (1H, s, proton-OH). 13C-NMR (400 MHz,
DMSO-d6), δ, (ppm): 123.37 (C2), 123.62 (C3), 45.60 (C4), 43.84 (C6),
24.36 (C7), 130.42 (C3a), 129.78 (C7a), 131.80 (C9), 124.46 (C10, C14),
117.57 (C11, C13), 132.32 (C12), 157.07 (C16), 113.19 (C17), 157.16
(C18), 103.21 (C19), 129.22 (C20), 115.04 (C21), 128.84 (C22).
130.45 (C3a), 129.77 (C7a), 31.83 (C9), 124.48 (C10, C14), 117.59 (C11
,
C13), 132.34 (C12), 157.09 (C16), 113.20 (C17), 157.17 (C18), 103.23
(C19), 129.25 (C20), 115.07 (C21), 128.87 (C22).
General procedure for synthesis of Cu(II) complexes
An ethanolic solution (25 ml) of Cu(NO3)•3H2O (10 mmol) was
2
added to an ethanolic solution (50 ml) of ligand (Ln) (20 mmol); the
pH was adjusted to 4.5–6.0 with dilute sodium hydroxide solution.
The resulting solution was refluxed for 5 h and then heated
over a steam bath to evaporate up to half of the volume. The
reaction mixture was then kept overnight at room temperature.
A colored crystalline product was obtained. The obtained product
was washed with ether and dried in vacuum desiccators. The
suggested structure is shown in Fig. 2 and analytical and physical
data are shown in Table 1.
2-[(4-{6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
ylsulfonyl}phenylimino]methyl)-5-(methoxy)phenol L2
Orange-colored crystalline compound. Yield, 58.64%; m.p.
208–210 ◦C, IR (νmax, KBr, cm−1): 3079 (C–H str., aromatic),
1487–1476 (C C str. ring), 1229 (C–N str.), 738 (C–S–C, str., thio-
phene),1640(-N CH-),3413(O–H).1H-NMR(400 MHz,DMSO-d6),
δ (ppm): 2.31 (3H, s, C23, -OCH3), 2.54 (2H, t, proton at C7), 3.17(2H,
t, proton at C6), 3.74 (2H, s, proton at C4), 4.98 [1H, s, proton at
C16 (-N CH-)], 6.39–7.69 (10H, m, protons at C2 –H, C3 –H, C10 –H,
C11 –H, C13 –H, C14 –H, C19 –H, C20 –H, C21 –H, C22 –H), 9.59 (1H, s,
proton-OH). 13C-NMR (400 MHz, acetone-d6), δ (ppm): 23.36 (C2),
123.63 (C3), 45.60 (C4), 43.85 (C6), 24.35 (C7), 130.41 (C3a), 129.79
(C7a), 131.81 (C9), 124.47 (C10, C14), 117.56 (C11, C13), 132.33 (C12),
157.09 (C16), 113.20 (C17), 157.18 (C18), 103.22 (C19), 129.43 (C20),
118.6 (C21), 128.83 (C22).
Antibacterial Studies
Preparation of stock solution
A stock solution of 10 mg ml−1 was made by dissolving compound
in the minimum amount of Dimethyl Sulfoxide and making it up
with double-distilled water.
5-Chloro-2-[(4-{6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
ylsulfonyl}phenylimino) methyl]phenol L3
Preparation of agar plates
Orange-yellow crystalline compound. Yield, 64.5%; m.p.
168–170 ◦C, IR (νmax, KBr, cm−1): 3077 (C–H str., aromatic),
1484–1476 (C C str. ring), 1226 (C–N str.), 737 (C–S–C, str., thio-
phene),1643(-N CH-),3423(O–H).1H-NMR(400 MHz,DMSO-d6),
δ(ppm): 2.48 (2H, t, proton at C7), 3.10 (2H, t, proton at C6), 3.68
(2H, s, proton at C4), 4.93 [1H,s, proton at C16 (-N CH-)], 6.34–7.63
(10H, m, protons at C2 –H, C3 –H, C10 –H, C11 –H, C13 –H, C14 –H,
C19 –H, C20 –H, C21 –H, C22 –H), 9.52 (1H, s, proton-OH). 13C-NMR
(400 MHz, acetone-d6), δ (ppm): 123.38 (C2), 123.64 (C3), 45.63 (C4),
43.82 (C6), 24.37 (C7), 130.43 (C3a), 129.77 (C7a), 131.82 (C9), 124.47
(C10, C14), 117.58 (C11, C13), 132.33 (C12), 157.09 (C16), 113.17 (C17),
157.18 (C18), 103.22 (C19), 115.05 (C21), 129.26 (C20), 128.83 (C22).
The media was made up by dissolving bacteriological agar (20 g)
and Luria broth (20 g) (SRL, India) in 1:l distilled water. The mixture
was autoclave for 15 min at 120 ◦C and then dispensed into
sterilized Petri dishes, allowed to solidify and then used for
inoculation.
Procedure of inoculation
The target microorganism cultures were prepared separately in
15 ml of liquid Luria broth medium for activation. Inoculation was
done with the help of a micropipette with sterilized tips; 100 µl of
activated strain was placed onto the surface of an agar plate and
spread evenly over the surface by means of a sterile bent glass
rod. Then two wells with a diameter of 10 mm were made using a
sterilized borer in each plate.
5-Bromo-4-chloro-2-[(4-{6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
ylsulfonyl}phenyl- imino)methyl]phenol L4
Dark yellow crystalline compound. Yield, 58.6%; m.p. 208–210 ◦C.
IR (νmax, KBr, cm−1): 3074 (C–H str., aromatic), 1486 (C C str. ring),
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 454–463

Aspects of drug-based copper(II) complexes
where T is the temperature in K, R is the gas constant, Wr = Wc −W
(Wc is the weight loss at the completion of the reaction and W
is the total mass loss up to time t) and Ea and n are the energy
of activation and order of reaction respectively. A typical curve
of [ꢀ log(dW/dt) = ꢀ log Wr] vs [ꢀ(1/T)/ꢀ log Wr] for the Cu(II)
complex is shown in Fig. 3. The slope of the plot gave the value
of Ea = 2.303R and the order of reaction (n) was determined from
the intercept. The linear relationship confirmed that the assumed
order of n = 1 is correct.
Results and Discussion
The analytical and physical data of the ligands L1–4 and their
complexes are listed in Table 1. The following reaction describes
the formation of the complexes:
Figure 2. The suggested structure of metal complexes, where R = H,
4-OCH3, 4-Cl-5-Br.
Cu(NO3)•3H2O + L −−−→ [Cu(L)2(H2O)2]•xH2O + 2HNO3 + nH2O
2
Application of disks
where L = L1–4; x = 1, 2, 2, 1 and n = 2, 1, 1, 2, respectively.
All the complexes were insoluble in all common organic
solvents, suchasacetone, ethanol, chloroform, methanol, benzene
and dimethyl formamide, but were least soluble in dimethyl
sulfoxide.
Sterilized stock solutions (10 mg ml−1) were used for the applica-
tion in the well of earlier inoculated agar plates. When the disks
were applied, they were incubated at 30 ◦C (Gram-positive) and
37 ◦C (Gram-negative) for 24 h. The zone of inhibition was then
measured (in mm) around the disk. The control experiments were
performed with only the equivalent volume of solvents without
added test compounds and the zone of inhibition was measured
(in mm). All experiments were performed using ciprofloxacin as
the standard drug.[27]
IR Spectra
The important infrared spectral bands and their tentative
assignments for the synthesized metal complexes are summarized
in Table 2. All the ligands (L1–4) in the present investigation exhibit
a broad band centered at 1355–1370 cm−1 (SO2, asymmetric
str.), and a second band at 1145–1163 cm−1 (SO2, symmetric
str.) shows the presence of the SO2 group.[29,30] The band at
1638–1648 cm−1 present in all the ligand molecules indicates
-N CH- stretching. Also, all the ligands (L1–4) exhibit a broad
band centered at 3428–3410 cm−1, which is assigned to ν(O–H)
for the free hydroxyl group on benzilidine ring at ortho position,
Thermal Studies
The thermodynamic activation parameters of the decomposition
process of the metal complexes such as energy of activation (Ea)
and order of reaction (n) were evaluated graphically employing
the Freeman–Carroll method[28] using the following relation:
[(−Ea/2.303R)ꢀ(1/T)]ꢀ log Wr = −n + ꢀ log(dW/dt)ꢀ log Wr(1)
Table 1. Physical and analytical data of the ligand and its metal complexes
Analysis found %/(calcd. %)
Empirical formula of
ligand/metal complexes
Molecular
weight
µeff
(B.M.)
Color
Yield (%)
C
H
N
S
Cu
L1 (C20H18N2S2O3)
L2 (C21H20N2S2O4)
Pale Yellow
Dark yellow
62.4
58.6
398.50
428.52
60.28 (60.29) 4.55 (4.57) 7.03 (7.06) 16.09 (16.07)
–
–
–
–
58.86 (58.81)
4.70
(4.72)
3.96
6.54 (6.56) 14.97 (14.95)
L3 (C20H17N2S2O3Cl)
Brown
64.5
58.6
432.94
511.84
55.48 (55.52)
6.47 (6.49) 14.81 (14.79)
–
–
–
–
(3.95)
3.15
L4 (C20H16N2S2O3ClBr)
Light brown
46.93
5.47
12.53
(46.95)
(3.13)
(5.50)
(12.52)
•
[Cu(L1)2(H2O)2] H2O
Dark brown
Dark brown
Dark brown
69.4
76.8
58.3
912.57
990.64
999.48
52.65 (52.61) 4.42 (4.38) 6.14 (6.16) 14.05 (14.04) 6.96 (6.94)
1.79
1.93
1.77
(C40H40CuO9N4S4)
•
[Cu(L2)2(H2O)2] 2H2O
50.92 (50.94) 4.68 (4.65) 5.66 (5.67) 12.95 (12.94) 6.41 (6.45)
(C42H46CuO12N4S4)
•
[Cu(L3)2(H2O)2] 2H2O
48.07 (48.05) 4.03 (4.07) 5.61 (5.63) 12.83 (12.82)
6.36
(C40H40CuO10N4S4Cl2)
(6.34)
•
[Cu(L4)2(H2O)2] H2O
Dark brown
64.7
1139.26
42.17
3.19 (3.16)
4.92
11.26 (11.24) 5.58 (5.57)
1.98
(C40H36CuO9N4S4Br2Cl2)
(42.15)
(4.96)
c
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 454–463
wileyonlinelibrary.com/journal/aoc

H. S. Patel, P. N. Patel and D. J. Patel
ylsulfonyl}phenylimino)methyl]phenol (L1–4) behaves as a biden-
tate ligand, forming a metal complex.
1H-NMR and 13C-NMR Spectra of the Ligands (L1–4
)
Structural analyses of the ligands were carried out using 1H-NMR
and 13C-NMR acquired on a Bruker 400 MHz NMR spectrometer
using DMSO-d6 as the solvent. The data are presented in the
Experimental Section.
In the case of 1H-NMR spectra for all the ligands, a peak
was observed as a triplet centered at 2.50 δ (3J = 5.6 Hz) and
3.13 δ (3J = 5.6 Hz), each integrating for two protons on C7
and C6 respectively. A singlet observed at 3.70 δ is due to
two protons attached at C4. A peak observed as a singlet at
4.96 δ is due to a proton attached to C16 (-N CH-). A total of
10 aromatic protons were observed in the region 6.37–7.66δ.
The most downfield signal observed at 9.55 δ as a singlet is
due to a hydroxyl proton (-OH), confirmed by D2O exchange
experiment.
Figure 3. Freeman–Carroll
[Cu(L3)(H2O)2] 2H2O.
plot
for
the
metal
complex
•
The 13C-NMR spectrum showed 19 nonequivalent carbon
signals. The signals at 24.36δ, 43.84δ and 45.60δ are due to
C7, C6 and C4, respectively. This was confirmed by the DEPT-135
spectrum, in which these signals were inverted. A signal observed
at 157.16δ is due to C16 (-N CH-). The aromatic carbons appeared
between 103.19 and 157.16δ.
which was further confirmed by 1H-NMR and 13C-NMR studies in
the solution state.
Comparing the main IR frequencies of Cu(II) cyclic com-
plexes with that of the free ligand (Table 2), the following
results were found. The broad band around 3420 cm−1 ob-
served in the case of ligands was shifted at 3440 cm−1
,
The Thermal Behavior of the Prepared Metal Complexes
which was attributed to υ(O–H) of coordinated water
molecules.
Thermal data and kinetic parameters of the metal com-
plexes are given in Tables 3 and 4, respectively. Typical
TG/DTG and Differential Scanning Calorimetry curves of the
metal complex [Cu(II)(L3)2(H2O)2]•xH2O (where x = 2) and
[Cu(II)(L1)2(H2O)2]•xH2O (where x = 2) are presented in Figs 4
and 5, respectively.
This was further supported by the bands observed in the
regions 3418–3437, 1278–1295, 865–875 and 705–710 cm−1
,
which are attributed to -OH stretching, bending, rocking and
wagging vibrations, respectively, due to the presence of wa-
ter molecules.[31,32] The presence of a rocking band indicates
the coordination nature of the water molecule.[33] The presence
of coordinated water were further supported by TG analy-
sis. In addition, the shifting of the band around 1640 cm−1
for free -N CH- to the higher frequency of 1665 cm−1 in
metal complexes clearly indicates the coordination of the
ligands with Cu metal in these complexes.[34–36] The weak
bands are attributed to the υ(Cu–O) and υ(Cu–N) stretching
frequencies.[37]
In the far-IR region, two new bands around 520 and
775 cm−1 in the complexes were assigned to ν(Cu–O) coor-
dination of the hydroxyl group and ν(Cu–N) coordination of
the N lone pair of Schiff’s base, respectively. All these data
confirm the fact that 2-[(4-{6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
50-260°C
[Cu(II)(L3)2]
xH2O
[Cu(II)(L3)2(H2O)2].xH2O
where x = 2;
2H O
2
+
+
Removal of lattice water molecules
+ coordinated water molecule
260-760°C
Cu(II)(L3)2]
Metal residue
removal of Ligand (L3)
molecules
where metal residue = CuO.
The thermodynamic activation parameters of the decomposi-
tion process of dehydrated complexes such as activation entropy
Table 2. The characteristic IR bands of ligand (L1–4) and their metal complexes
ν (O
Antisymmetric
S O)
Compounds
ν (O–H)
ν (C N)
ν (S–N)
Symmetric
ꢀν
ν (Cu–O)
ν (Cu–N)
C20H18N2S2O3
3410
3428
3418
3436
–
1643
1638
1645
1648
1664
1658
1672
1668
276
264
270
259
274
263
268
257
1370
1358
1361
1372
1367
1355
1359
1368
1168
1148
1143
1152
1164
1146
1141
1150
202
210
218
220
203
209
218
220
–
–
–
–
C
C
C
21H20N2S2O4
20H17N2S2O3Cl
20H16N2S2O3ClBr
–
–
–
–
[Cu(L1)2(H2O)] (C40H38CuO8N4S4)
[Cu(L2)2(H2O)] (C42H42CuO10N4S4)
[Cu(L3)2(H2O)] (C40H36CuO8N4S4Cl2)
[Cu(L4)2(H2O)] (C40H34CuO8N4S4Br2Cl2)
519
517
522
518
778
767
772
769
–
–
–
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 454–463

Aspects of drug-based copper(II) complexes
Table 3. Thermo-analytical data of the Metal complexes
TG range
(◦C)
DTGmax
(◦C)
DSCmax
(◦C)
Mass loss (%),
observed (calcd)
Compounds
Assignment
•
[Cu(L1)2(H2O)2] H2O
50–240
60–68
61.56
7.17 (7.26)
82.09 (82.03)
89.26∗(89.29)
Loss of one lattice + two coordinated water molecules
Removal of (L1) ligand molecule
240–720
496.76
149.60
Leaving CuO residue
•
[Cu(L2)2(H2O)2] 2H2O
50–130
130–280
280–760
68.74
–
84.48
160.34
–
4.88 (4.76)
4.61 (4.76)
Loss of two lattice water molecules
Loss of two coordination water molecules
Removal of (L2) ligand molecule
Leaving free CuO residue
474.54
82.69 (82.58)
92.18∗(92.10)
•
[Cu(L3)2(H2O)2] 2H2O
50–260
67.96
155.99
–
9.36 (9.51)
80.62 (80.57)
89.98∗(90.08)
Loss of two lattice + two coordinated water molecules
Removal of (L3) ligand molecule
260–760
432.78
Leaving CuO residue
•
[Cu(L4)2(H2O)2] H2O
50–130
130–260
260–260
64.50
–
58.91
2.28 (2.45)
4.85 (4.90)
Loss of one lattice water molecule
Loss of two coordination water molecules
Removal of (L4) ligand molecule
Leaving CuO residue
143.44
429.89
81.94 (81.80)
89.07 (89.15)
Table 4. Kinetic parameters of the Metal complexes
Compounds
TG range (◦C)
Ea (kJ mol−1
)
n
A (s−1
)
ꢀS# (J K−1 mol−1
)
ꢀH# (J K−1 mol−1
)
ꢀG# (J K−1 mol−1
)
•
[Cu(L1)2(H2O)2] H2O
50–260
3.36
0.00
0.12
−102.38
−94.45
−102.02
−101.98
−93.00
0.59
34.75
260–760
69.88
1.00 0.79 × 104
63.49
136.09
•
[Cu(L2)2(H2O)2] 2H2O
50–130
130–280
280–760
3.18
4.90
0.00
0.15
0.97
1.28
141.00
35.83
45.46
1.49
0.12
101.02
1.00 0.26 × 106
94.83
•
[Cu(L3)2(H2O)2] 2H2O
50–260
3.80
0.00
0.15
−102.00
0.96
106.58
35.80
260–760
81.40
1.00 0.21 × 106
−93.60
75.50
•
[Cu(L4)2(H2O)2] H2O
50–130
130–260
260–780
3.52
5.19
0.00
0.13
−102.25
−101.98
−95.67
0.73
1.36
35.13
48.34
1.50
0.11
45.35
1.00 0.26 × 103
39.52
106.58
(ꢀS#), pre-exponential factor (A), activation enthalpy (ꢀH#) and
free energy of activation (ꢀG#) were calculated using the reported
equations.[38,39]
difficult to assign, even with relatively simple ligands because of
the breadth of absorption band even at low temperatures. The
different coordination numbers have a wide range of geometry.
The copper(II) complexes exhibit magnetic moments of 1.79, 1.93,
1.77 and 1.98 BM (Bohr magneton), respectively. These values
are close to the spin-allowed values expected for an S = 1/2
system (1.73 BM) and may be indicative of an octahedral ge-
According to the kinetic data obtained from DTG curves,
all the metal complexes have negative entropy, which indi-
cates that the studied metal complexes have more ordered
systems than the reactants.[40] The kinetic parameters, espe-
cially energy of activation (Ea), are helpful in assigning the
strength of the metal complexes. The calculated Ea values of
the investigated complexes, i.e. the stage of the formation
of volatile gas products, are relatively high, which indicates
that the ligand is strongly bonded to the metal ion.[41] The
calculated Ea values of the investigated metal complexes for
the first dehydration step are in the range 3.36–3.81 kJ mol−1
(Table 4).
ometry around the copper(II) ions. The copper (II) complexes
2
display a broad band at ca. 15 000 cm−1 due to the Eg
→
2T2g
transition.[42]
FAB Mass Spectra
In the mass spectra of [Cu(L1)2(H2O)2]•H2O, the peak at m/z =
893 stands for the molecular ion peak of complex (without
water of crystallization). The proposed fragmentation pattern
of [Cu(L1)2(H2O)2]•H2O is given in Scheme 2. The measured
molecular weights were consistent with expected values, and
the mass spectrum of [Cu(L1)2(H2O)2]•H2O complex is shown in
Fig. 6.
Magnetic Moments and Electronic Spectra
The information regarding the geometry of the metal complexes
was obtained from their electronic spectral data and magnetic
moments. Copper (II) complex d9 systems are known for their
varieties of structures owing to their different coordination num-
bers. A six-coordinated copper (II) complex possesses distorted
octahedral geometry. The spectra of copper complexes are very
Antibacterial Results
The increase in antimicrobial activity may be considered in
light of Overtone’s concept[43] and Tweedy’s chelation theory.[44]
c
Appl. Organometal. Chem. 2011, 25, 454–463
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

H. S. Patel, P. N. Patel and D. J. Patel
•
Figure 4. TGA/DTG curves of [Cu(II)(L3)(H2O)2] 2H2O.
•
Figure 5. DSC curve of [Cu(II)(L1)(H2O)2] xH2O.
According to Overtone’s concept of cell permeability, the lipid
membrane that surrounds the cell favors the passage of only
lipid-soluble materials, which indicates that liposolubility is
an important factor controlling the antimicrobial activity. On
chelation, the polarity of the metal ion will be reduced to a greater
extentowingtotheoverlapoftheligandorbitalandpartialsharing
of the positive charge of the metal ion with donor groups. Further,
it increases the delocalization of π-electrons over the whole
chelate ring and enhances the lipophilicity of the complexes. This
increased lipophilicity enhances the penetration of the metal
chelate into lipid membranes and blocks the metal binding
sites in the enzymes of microorganisms. These metalchelates
also disturb the respiration process of the cell and thus block
the synthesis of proteins, which restricts further growth of the
organisms.
Furthermore, the mode of action of the compounds may
involve the formation of a hydrogen bond through the azome-
thine/carbonyl/amine group with the active center of cell con-
stituents resulting in interference with the normal cell process.[45]
Metal complexes exhibit higher biocidal activity as compared with
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 454–463

Aspects of drug-based copper(II) complexes
Scheme 2. The suggested fragmentation pattern of [Cu(L1)(H2O)2].H2O.
•
Figure 6. Fab mass spectra of metal complex [Cu(II)(L1)(H2O)2] H2O.
the free ligands, metal salts and control dimethyl sulfoxide. From
the comparative analysis shown in Fig. 7, it is observed that all the
microorganisms. In comparison with both the ligands and the
metal salt, the Cu(II) metal complexes were more active against
one or more bacterial strains, thus introducing a novel class of
metal-based bactericidal agents.
The information regarding geometry of the metal complexes
was obtained from their electronic and magnetic moment
values. Magnetic moment values indicate that Cu(II) metal
complexes are high-spin, lacking exchange interactions. The
studies reveal that an octahedral geometry can be assigned to
metal complexes.
metal complexes are more potent biocidals than the ligands L1–4
.
The zone of inhibition was measured (in mm) around the disk and
the results are represented in Table 5. From the graph it is clear
that Cu(II) is highly active among the complexes of the respective
metal.
Conclusion
All the synthesized compounds were screened for their biocidal
activity. The metal complexes exhibited strong activities against
two Gram-negative (Escherichia coli, Serratia marcescens) and
two Gram-positive (Bacillus subtillis, Pseudomonas aeruginosa)
Acknowledgments
One of the authors, D. J. Patel, is thankful to UGC (New
Delhi) for awarding a meritorious scholarship. The authors are
c
Appl. Organometal. Chem. 2011, 25, 454–463
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

H. S. Patel, P. N. Patel and D. J. Patel
Figure 7. Comparative analysis of ligand and its metal complexes.
Table 5. Agar plate technique
Zone of inhibition (mm)
Gram-negative
Gram-positive
Pseudomonas aeruginosa
Compound
Escherichia coli
Serratia marcescens
Bacillus substilis
Control (DMSO)
12
15
35
14
14
13
12
25
30
28
22
11
17
44
17
18
17
16
27
32
28
31
12
19
52
12
15
14
16
22
29
20
23
12
18
44
14
13
11
12
29
34
24
22
•
Cu(NO3)2 3H2O
Ciprofloxacin
L1
L2
L3
L4
Cu(1)
Cu(2)
Cu(3)
Cu(4)
grateful to the Department of Chemistry, for providing the
necessary laboratory facilities. Analytical facilities provided by
the SAIF, Central Drug Research Institute, Lucknow, India and
the Sophisticated Instrumentation Centre for Applied Research
and Testing, Vallabh Vidyanagar, Gujarat, India are gratefully
acknowledged.
[8] D. H. Brown, A. J. Lewis, W. E. Smith, J. W. Teape,J.Med.Chem. 1980,
23, 729.
[9] D. R. Williams, The Metals of Life, Van Nostrand Reinhold: London,
1971.
[10] M. Ruiz, L. Perello, R. Ortiz, A. Castineiras, C. Maichlemossmer,
E. Canton, J. Inorg. Biochem. 1995, 59, 801.
[11] Y. P. Tian, C. Y. Duan, C. Y. Zhao, X. Z. You, T. C. W. Mak, Z. Zhang,
Inorg. Chem. 1997, 36, 1247.
[12] Y. P. Tian,C. Y. Duan,X. Z. You,T. C. W. Mak,Q. Luo,C. Y. Zhao,Trans.
Met. Chem. 1998, 23, 17.
[13] A. Aburaqabah, G. Davies, M. A. Elsayed, A. Eltoukhy, S. N. Shaikh,
J. Zubieta, Inorg. Chim. Acta 1992, 193, 43.
[14] S. Karabocek, S. Guner, N. Karabocek, J. Inorg. Biochem., 1997, 66,
57.
[15] D. X. West, S. B. Padhy, P. B. Sonawane, Struct. Bond. (Berlin), 1991,
76, 1.
[16] M. Das, S. E. Livingstone, Br. J. Cancer 1978, 37, 466.
[17] A. A. Soliman, J. Therm. Anal. Calorim. 2001, 63, 221.
[18] G. G. Mohamed, Z. H. Abdel-Wahab, J. Therm. Anal. Calorim. 2003,
73, 347.
[19] H.A. El-Borai, J. Therm. Anal. Calorim. 2005, 81, 339.
[20] C. L. Albano, R. Sciamanna, T. Aquino, J. J. Martinez, European
Congress on Computational Methods in Applied Sciences and
Engineering, ECOMAS 2000, Barcelona, 11–14 September, 2000.
References
[1] P. Collet, J. S. Hulot, G. Montalescot, The Lancet 2009, 373, 1172.
[2] D. J. Angiolillo, A. F. Ortiz, E. Bernardo, F. Alfonso, C. Macaya,
T. A. Bass, M. A. Costa, J. Am. Coll. Cardiol. 2007, 49, 1505.
[3] S. C. Gujarathi, A. R. Shah, S. C. Jagdale, P. A. Datar, V. P. Choudhari,
B. S. Kuchekar, Int. J. Pharm. Sci. 2010, 3, 1.
[4] Q. Ruan, M. Zhu. Chem. Res. Toxicol. 2010, 23(5), 909.
[5] G. L. Grunewald, M. R. Seim, S. R. Bhat, M. E. Wilson, K. R. Criscione,
Bioorg. Med. Chem. 2008, 16(1), 542.
[6] F. Zani, M. Incerti, R. Ferretti, P. Vicini, Eur. J. Med. Chem. 2009, 44(6),
2741.
[7] J. R. Sorenson, J. Med. Chem. 1976, 19, 135.
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 454–463

Aspects of drug-based copper(II) complexes
[21] F. Carrasco, Thermochim. Acta 1993, 213, 115.
[22] A. I. Vogel, Textbook of Practical Organic Chemistry, 5th edn,
Longman: London, 1989.
[23] G. H. Jeffrey, J. Bassett, J. Mendham, R. C. Denney, Vogel’s Textbook
of Quantitative Chemical Analysis, 5th edn, Longman: Harlow, 1989.
[24] A. Weiss, H. Witte, Magneto Chemie, Verlag Chemie: Weinheim,
1973.
[34] K. S. Abou-Melha, H. Frank, J. Iran. Chem. Soc. 2008, 5(1), 122.
[35] H. N. Aliyu, H. J. Abdullahi, African Sci. 2009, 10(4), 199.
[36] A. A. Sheikh, M. Muhammad, F. Annum, N. Sumera, I, Zeeshan, BIOL
(e-J. Life Sci.) 2010, 1(2), 37.
[37] P. B. Pansuriya, M. N. Patel, Appl. Organomet. Chem. 2007, 21, 739.
[38] M. Sekerci, F.J. Yakuphanoglu, J. Therm. Anal. Calorim. 2004, 75(1),
189.
[25] G. L. Grunewald, M. R. Seim, S. R. Bhat, M. E. Wilson, K. R. Criscione,
Bioorg. Med. Chem. 2008, 16(1), 542.
[39] A. A. Abou-Hussen, N. M. El-Metwally, E. M. Saad, A. A. El-Asmy,
J. Coord. Chem. 2005, 58(18), 1735.
[26] F. Zani, M. Incerti, R. Ferretti, P. Vicini, Eur. J. Med. Chem. 2009, 44(6),
2741.
[40] M.E. El-Zaria, Spectrochim. Acta, Pt A 2008, 69(1), 216.
[41] J. Garcice, M. C. Molla, J. Borras, E. Escriva, Thermochim. Acta 1986,
106, 155.
[42] A. L. Abuhijleh, C. Woods, I. Y. Ahmed, Inorg. Chim. Acta 1991, 190,
1.
[27] G. J. Kharadi, K. D. Patel, Appl. Organomet. Chem. 2009, 23(10), 391.
[28] E. S. Freeman, B. Carroll, J. Phys. Chem. 1958, 62, 394.
[29] S. Ghosh, S. Malik, e-J. Chem. 2010, 7(4), 1391.
[30] N. B. Patel, V. N. Patel, H. R. Patel, F. M. Shaikh, J. C. Patel, Acta
Poloniae Pharma. Drug Res. 2010, 67(3), 267.
[43] H. M. Parekh, P. B. Pansuriya, M. N. Patel, Polish J. Chem. 2005, 79,
1843.
[31] P. K. Panchal, M. N. Patel, Synth. React. Inorg. Met.-Org. Chem. 2004,
34, 1277.
[32] H. M. Parekh, P. K. Panchal, M. N. Patel, J.Therm.Anal.Calorim. 2006,
86, 803.
[44] B. G. Tweedy, Phytopathology 1964, 55, 910.
[45] Z. H. Chohan, K. M. Khan, C. T. Supuran, Appl. Organomet. Chem.
2004, 18, 305.
[33] N. Nakamoto, Infrared Spectra and Raman Spectra of Inorganic and
Coordination Compounds, John Wiley & Sons: New York, 1978.
c
Appl. Organometal. Chem. 2011, 25, 454–463
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc