Novel drug-based Fe(III) heterochelates: Synthetic, spectroscopic, thermal and in-vitro antibacterial significance

Article abstract of DOI:10.1002/aoc.1581

A series of novel heterochelates of the type [Fe(Aⁿ)(L)(H ₂O)₂]*MH₂O[where H₂A ⁿ = 4,4'-(arylmethylene)bis(3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol- 5-ol); aryl = 4-nitrophenyl, m = 1(H

Full text of DOI:10.1002/aoc.1581

Full Paper
Received: 9 August 2009
Revised: 3 October 2009
Accepted: 5 October 2009
Published online in Wiley Interscience: 30 November 2009
(www.interscience.com) DOI 10.1002/aoc.1581
Novel drug-based Fe(III) heterochelates:
synthetic, spectroscopic, thermal and in-vitro
antibacterial significance
D.H. Jania, H.S. Patela, H. Kehariab and C.K. Modic∗
A series of novel heterochelates of the type [Fe(An)(L)(H2O)2]•mH2O [where H2An = 4,4ꢀ-(arylmethylene)bis(3-methyl-1-
phenyl-4,5-dihydro-1H-pyrazol-5-ol); aryl = 4-nitrophenyl, m = 1 (H2A1); 4-chlorophenyl, m = 2 (H2A2); phenyl, m = 2 (H2A3);
4-hydroxyphenyl, m = 2 (H2A4); 4-methoxyphenyl, m = 2 (H2A5); 4-hydroxy-3-methoxyphenyl, m = 1.5 (H2A6); 2-nitrophenyl,
m = 1.5 (H2A7); 3-nitrophenyl, m = 0.5 (H2A8); p-tolyl, m = 1 (H2A9) and HL = 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-
1,4-dihydroquinoline-3-carboxylicacid]wereinvestigated.Theywerecharacterizedbyelementalanalysis(FT-IR,1H-&13C-NMR,
and electronic) spectra, magnetic measurements and thermal studies. The FAB-mass spectrum of [Fe(A3)(L)(H2O)2]•2H2O was
determined. Magnetic moment and reflectance spectral studies revealed that an octahedral geometry could be assigned to
all the prepared heterochelates. Ligands (H2An) and their heterochelates were screened for their in-vitro antibacterial activity
against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Serratia marcescens bacterial strains. The kinetic parameters
such as order of reaction (n), the energy of activation (Ea), the pre-exponential factor (A), the activation entropy (ꢀS#), the
#
#
c
activation enthalpy (ꢀH ) and the free energy of activation (ꢀG ) are reported. Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Keywords: Fe(III) heterochelates; bis-pyrazolones; spectroscopic; thermal studies; in-vitro antibacterial activity
Introduction
fluorescence properties[25–27] and some of them have antitumor
activities in vitro and high herbicidal activities.
Iron plays a crucial role in the survival of terrestrial organ-
isms and participates in biochemical processes like ribonucleic
reduction, energy production, photosynthesis, nitrogen reduc-
tion, oxygen transport and oxygenation.[1] Fluoroquinolone
drugs are known for their wide range of applications in
medicinal and life sciences.[2] They are typically polyfunc-
tional compounds, designed to interact with specific receptors
or organs. The design of metal–fluoroquinolone drug com-
plexes is of particular interest in pharmacological research
to improve the drugs activity and to decrease their toxic-
ity. Transition metal complexes of these antibiotics with en-
hanced potentiality against bacterial strains have been reported
elsewhere.[3–6] Ciprofloxacin[1-cyclopropyl-6-fluoro-1, 4-dihydro-
4oxo-7-(1-piperazinyl)-3quinolone carboxylic acid] is a synthetic
fluoroquinolone antibiotic with a broad spectrum of activity. It
is active against a wide variety of aerobic Gram-negative and
Gram-positive bacteria. Turel[7] prepared copper(II) ciprofloxacin
complexes and tested them against the growth of various
Gram-positive and Gram-negative microorganism. These com-
plexes showed comparable antimicrobial activity with the free
ligand.
Pyrazolone-5 derivatives form an important class of organic
compounds and represent a major scientific and applied interest
in biological, analytical applications, catalysis, dye and extraction
metallurgy.[8–12] Furthermore, they have the potential to form
different types of coordination compounds due to the several
electron-rich donor centers.[13,14] Meanwhile, the design of
new bis-pyrazolone-based chelating ligands in coordination
chemistry has been extensively investigated.[15–24] The studies
on bis-pyrazolone-based complexes reveal that they have strong
Accordingly, we have synthesized a series of bis-pyrazolone
based ligands, 4,4ꢁ-(arylmethylene)bis(3-methyl-1-phenyl-4,5-
dihydro-1H-pyrazol-5-ol) (H2An). This new type of chelating ligand
has two donor cites centered at 5,5ꢁ-OH groups. Because of the
presence of two active donor sites, they can form various types
of metal complexes. In continuation to our earlier work on bis-
pyrazolonebasedcompounds,[28–30] hereinwedescribesynthetic,
spectroscopic, thermal and in-vitro antibacterial studies of some
novel drug-based Fe(III) heterochelates. The general structure of
the ligands (H2An) is shown in Scheme 1.
Materials and Methods
Materials
All the chemicals used were of analytical grade and used
without further purification. The compound 1-phenyl-3-methyl-
2-pyrazoline-5-ol was purchased from E. Merck Ltd (India).
∗
Correspondenceto:C.K. Modi,DepartmentofChemistry,BhavnagarUniversity,
Bhavnagar-364 002, Gujarat, India. E-mail: modi ck@yahoo.co.in
a
b
c
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar-388
120, Gujarat, India
Department of Bio Sciences, Sardar Patel University, Vallabh Vidyanagar-388
120, Gujarat, India
Department of Chemistry, Bhavnagar University, Bhavnagar-364 002, Gujarat,
India
c
Appl. Organometal. Chem. 2010, 24, 99–111
Copyright ꢀ 2009 John Wiley & Sons, Ltd.

D. H. Jani et al.
R3
17
R2
R1
16
15
18
19
6
H3C
6′
14
13
CH3
3
3′
4
4′
5′
N
N
5
N
N
12
12′
11′
10′
7
OH
OH
7′
8′
11
8
10
9
9′
Ligands
H2A1
H2A2
H2A3
H2A4
H2A5
H2A6
H2A7
H2A8
H2A9
R1
-H
R2
-H
R3
-NO2
-Cl
Figure 2. Freeman–Carroll plot of the heterochelate [Fe(A5)
(L)(H2O)2] 2H2O.
•
-H
-H
-H
-H
-H
-H
-H
-OH
the organic matter with a mixture of concentrated HClO4, H2SO4
and HNO3 (1 : 1.5 : 2.5). Infrared spectra (4000–400 cm−1) were
recorded on Nicolet-400D spectrophotometer using KBr pellets.
1H- and 13C-NMR and DEPT-135 spectra were recorded on a
model Advance 400 Bruker FT-NMR instrument and DMSO-d6
used as a solvent. The FAB mass spectrum of the heterochelate
was recorded at SAIF, CDRI, Lucknow with Jeol SX-102/DA-6000
mass spectrometer. The magnetic moments were obtained by the
Gouy’s method using mercury tetrathiocyanato cobaltate (II) as
a calibrant (g = 16.44 × 10−6 c.g.s. units at 20 ◦C). Diamagnetic
corrections were made using Pascal’s constant. The reflectance
spectra of the free ligands (H2An) and their heterochelates were
recorded in the range 1700–350 nm (as MgO disks) on a Beck-
man DK-2A spectrophotometer. A simultaneous •TG/DTG was
obtained by a model 5000/2960 SDT, TA Instruments, USA. The
experiments were performed in an N2 atmosphere at a heating
rate of 10 ◦C min−1 in the temperature range 50–800 ◦C, using an
Al2O3 crucible. The sample sizes ranged in mass from 5 to 8 mg.
The DSC was recorded using a DSC 2920, TA Instruments, USA. The
DSC curves were obtained at a heating rate of 10 ◦C min−1 in an
N2 atmosphere over the temperature range 50–400 ◦C, using an
aluminum crucible.
-OCH3
-OH
-H
-H
-H
-OCH3
-NO2
-H
-H
-H
-H
-NO2
-H
-H
CH3
Scheme 1. The general structure of ligands (H2An).
4-Substituted benzaldehydes were purchased from Qualigens
Fine Chemicals, India and used without further purification.
Ciprofloxacin hydrochloride was purchased from Bayer AG
(Wuppertal, Germany). The organic solvents were purified by
standard methods.[31] Luria broth was purchased from Hi-media
Laboratories Pvt. Ltd, India.
Instruments
Carbon, hydrogen and nitrogen were analyzed with a Perkin
Elmer, USA 2400-II CHN analyzer. The metal contents of the hete-
rochelates were analyzed by EDTA titration[32] after decomposing
•
Figure 1. FAB mass spectra of the heterochelate [Fe(A3)(L)(H2O)2] 2H2O.
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 99–111

Novel drug based-Fe(III) heterochelates
•
Figure 3. TGA/DTG curves of the heterochelate [Fe(A5)(L)(H2O)2] 2H2O.
Synthesis of Ligands (H2A1 –H2A9)
4-nitrobenzaldehyde (5 mmol, 0.76 g) in 2 : 1 molar ratio with a
catalytic amount of SDS in aqueous solution (5 ml) were mixed
together at room temperature with constant stirring for 30 min
andthenrefluxedfor3 honawaterbath.Theresultingmixturewas
then allowed to stand overnight at room temperature. The pinkish
products formed were collected by filtration, washed with diethyl
ether and dried in vacuo to constant mass and then finally purified
by crystallized in chloroform–hexane (70 : 30) mixture to obtain
pink crystalline products. Yield, 86%; m.p. 228–230 ◦C. Found (%):
C, 67.60, H, 4.74, N, 14.44. C27H23N5O4 (481.50) requires (%): C,
67.35, H, 4.81, N, 14.54. IR: 3392 (O–H), 1600 (C O); 1H-NMR: 2.30
The dinegative bidentate ligands were synthesized by conden-
sation of 3-methyl-1-phenyl-2-pyrazoline-5-one (10 mmol), with
various substituted benzaldehydes (5 mmol), in the presence of
catalytic amounts of sodium dodecyl sulfate (SDS).
4,4ꢁ-[(4-Nitrophenyl)methylene]bis(3-methyl-1-phenyl-4,5-dihydro-
1H-pyrazol-5-ol) (H2A1)
An ethanolic solution (50 ml) of 3-methyl-1-phenyl-2-pyrazoline-
5-one (10 mmol, 2.16 g) and an ethanolic solution (25 ml) of
Table 1. Physical and analytical data of the heterochelates
Analysis (%) Found (calcd)
Melting
Formula
Sample no.
1
Compounds
weight (g mol−1
)
Color (yield%)
point (◦C)
C
H
N
M
µeff (B.M.)
•
[Fe(A1)(L)(H2O)2] H2O
44H48FFeN8O10
923.73
Reddish brown (79)
214
57.20
(57.21)
56.72
5.25
(5.24)
5.40
12.12
(12.13)
10.52
6.03
(6.05)
6.00
5.98
C
•
2
3
4
5
6
7
8
9
[Fe(A2)(L)(H2O)2] 2H2O
931.18
896.73
912.73
926.76
933.76
932.73
914.73
892.76
Reddish brown (83)
Reddish brown (85)
Orange (88)
188
204
176
195
289
273
294
297
6.05
5.95
5.99
6.01
6.07
6.15
5.98
5.97
C
44H50ClFFeN7O9
(56.75)
58.90
(5.41)
5.71
(10.53)
10.95
(6.00)
6.21
•
[Fe(A3)(L)(H2O)2] 2H2O
C
44H51FFeN7O9
(58.93)
57.88
(5.73)
5.63
(10.93)
10.73
(6.23)
6.10
•
[Fe(A4)(L)(H2O)2] 2H2O
C
44H51FFeN7O10
(57.90)
58.30
(5.63)
5.72
(10.74)
10.55
(6.12)
6.01
•
[Fe(A5)(L)(H2O)2] 2H2O,
Dark green (86)
Dull orange (90)
Reddish brown (85)
Reddish brown (81)
Orange (92)
C
45H53FFeN7O10
(58.32)
57.85
(5.76)
5.60
(10.58)
10.48
(6.03)
5.96
•
[Fe(A6)(L)(H2O)2] 1.5H2O
C
45H52FFeN7O10.5
(57.88)
56.65
(5.61)
5.27
(10.50)
12.00
(5.98)
5.98
•
[Fe(A7)(L)(H2O)2] 1.5H2O
C
44H49FFeN8O10.5
(56.66)
57.76
(5.29)
5.15
(12.01)
12.22
(5.99)
6.10
•
[Fe(A8)(L)(H2O)2] 0.5H2O
C
44H47FFeN8O9.5
(57.77)
60.53
(5.18)
5.75
(12.25)
10.97
(6.11)
6.25
•
[Fe(A9)(L)(H2O)2] H2O
C45H51FFeN7O8
(60.54)
(5.76)
(10.98)
(6.26)
c
Appl. Organometal. Chem. 2010, 24, 99–111
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
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D. H. Jani et al.
Table 2. The characteristic IR bands of ligand (HL)a and their heterochelates
ν(COO
−
)
b
c
Compounds
HL
ν(O–H)
ν(O–H)
ν(C
1635
Antisymmetric
Symmetric
ꢀν
ν(C–O)
ν(M–O)
ν(M–O)
O)
–
1707
1618
1600
1600
1598
1600
1597
1597
1599
1599
1600
1384
1384
1384
1384
1380
1380
1384
1380
1384
1384
234
216
216
214
220
217
213
219
215
216
–
–
–
•
[Fe(A1)(L)(H2O)2] H2O
3418
3422
3430
3438
3435
3330
3420
3428
3430
–
–
–
–
–
–
–
–
–
1624
1620
1624
1625
1626
1624
1620
1620
1622
1316
1305
1309
1303
1312
1308
1303
1306
1310
449
472
448
449
448
449
449
448
444
420
418
419
420
417
417
418
415
428
•
[Fe(A2)(L)(H2O)2] 2H2O
•
[Fe(A3)(L)(H2O)2] 2H2O
•
[Fe(A4)(L)(H2O)2] 2H2O
•
[Fe(A5)(L)(H2O)2] 2H2O
•
[Fe(A6)(L)(H2O)2] 1.5H2O
•
[Fe(A7)(L)(H2O)2] 1.5H2O
•
[Fe(A8)(L)(H2O)2] 0.5H2O
•
[Fe(A9)(L)(H2O)2] H2O
a HL = 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid. b ν(O–H) of the carboxylic group; c ν(M–O) of the ketone
group of HL.
•
Figure 4. DSC curve of the heterochelate [Fe(A5)(L)(H2O)2] 2H2O.
(6H, s, protons at C6, C6ꢁ ), 5.10 (1H, s, protons at C13), 7.20–8.10
(14H, m, protons at C8 –H, C9 –H, C10 –H, C11 –H, C12 –H, C15 –H,
4,4ꢁ-[(4-Chlorophenyl)methylene]bis(3-methyl-1-phenyl-4,5-
dihydro-1H-pyrazol-5-ol) (H2A2)
H2A2 was synthesized by same method used for H2A1 using
4-chlorobenzaldehyde instead of 4-nitrobenzaldehyde. Yield,
88%; m.p. 207–209 ◦C. Found (%): C, 68.92, H, 4.93, N, 11.83.
C27H23N4O2Cl (470.93) requires (%): C, 68.86, H, 4.81, N, 11.89. IR:
3400 (O–H), 1600 (C O); 1H-NMR: 2.36 (6H, s, protons at C6, C6ꢁ ),
4.90 (1H, s, protons at C13), 7.20–7.70 (14H, m, protons at C8 –H,
C9 –H, C10 –H, C11 –H, C12 –H, C15 –H, C16 –H, C18 –H, C19 –H, C8ꢁ –H,
C9ꢁ –H, C10ꢁ –H, C11ꢁ –H, C12ꢁ –H), 12.50 (1H, s, protons -OH), 13.80
C
16 –H, C18 –H, C19 –H, C8ꢁ –H, C9ꢁ –H, C10ꢁ –H, C11ꢁ –H, C12ꢁ –H),
12.60 (1H, s, protons -OH), 13.80 (1H, s, protons H OH); 13C-NMR:
· · ·
11.40 (C6, C6ꢁ ), 33.60 (C13), 121.50 (C4, C4ꢁ ), 123.60 (C8, C12, C8ꢁ ,
C12ꢁ ), 126.70 (C10, C10ꢁ ), 128.10 (C16, C18), 129.02 (C9, C11, C15, C19
C9ꢁ , C11ꢁ ), 136.34 (C7, C7ꢁ ), 146.12 (C14), 146.55 (C17), 148.30 (C3,
C3ꢁ ), 157.76 (C5, C5ꢁ ); DEPT-135: 11.30 (C6, C6ꢁ ), 33.60 (C13), 121.50
,
(C4, C4ꢁ ), 123.60 (C8, C12, C8ꢁ , C12ꢁ ), 126.70 (C10, C10ꢁ ), 128.10 (C16
18), 129.04 (C9, C11, C15, C19, C9ꢁ , C11ꢁ ).
,
C
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 99–111

Novel drug based-Fe(III) heterochelates
+.
H3C
CH3
N
N
N
N
O
O
-2H2O (-36)
Fe
O
O
F
O
N
N
NH
m/z = 818 (820.23) (b)
m/z = 856 (856.26) (a)
+.
+.
H3C
N
CH3
N
N
O
N
Fe
O
O
O
N
F
m/z = 263 (262.11) (c)
O
(base peak)
N
NH
m/z = 557 (558.12) (d)
-CH3 (-15.02)
-C4H9N2 (-85.08)
•
Scheme 2 The suggested fragmentation pattern of [Fe(A3)(L)(H2O)2] 2H2O.
(1H, s, protonsH OH);13C-NMR:12.02(C6, C6ꢁ ), 33.10(C13), 121.00
(C6, C6ꢁ ), 33.60 (C13), 121.00 (C4, C4ꢁ ), 126.00 (C17), 126.30 (C10, C10ꢁ ),
127.60 (C16, C18), 128.60 (C15, C19), 129.30 (C8, C12, C8ꢁ , C12ꢁ ), 129.70
· · ·
(C4, C4ꢁ ), 126.00 (C10, C10ꢁ ), 128.50 (C8, C12, C8ꢁ , C12ꢁ ), 129.30 (C9,
C11, C16, C18, C9ꢁ , C11ꢁ ), 129.60 (C15, C19), 131.10 (C14, C17), 137.70
(C7, C7ꢁ ), 141.60 (C3, C3ꢁ ), 146.70 (C5, C5ꢁ ); DEPT-135: 12.00 (C6, C6ꢁ ),
33.10 (C13), 121.00 (C4, C4ꢁ ), 126.00 (C10, C10ꢁ ), 128.50 (C8, C12, C8ꢁ ,
C12ꢁ ), 129.30 (C9, C11, C16, C18, C9ꢁ , C11ꢁ ), 129.60 (C15, C19).
(C9, C11,, C9 , C11 ).
ꢁ
ꢁ
4,4ꢁ-[(4-Hydroxyphenyl)methylene]bis(3-methyl-1-phenyl-1H-
pyrazol-5-ol) (H2A4)
4,4ꢁ-(Phenylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
H2A4 was synthesized by same method used for H2A1 by using
4-hydroxybenzaldehyde instead of 4-nitrobenzaldehyde. Yield,
82%; m.p. 152–153 ◦C. Found (%): C, 71.79, H, 5.35, N, 12.21.
C27H24N4O3 (452.50) requires (%): C, 71.67, H, 5.34, N, 12.38. IR:
3402 (O–H), 1600 (C O); 1H-NMR: 2.30 (6H, s, protons at C6, C6ꢁ ),
4.80 (1H, s, protons at C13), 6.68–7.70 (14H, m, protons at C8 –H,
C9 –H, C10 –H, C11 –H, C12 –H, C15 –H, C16 –H, C18 –H, C19 –H, C8ꢁ –H,
(H2A3)
H2A3 was synthesized by same method used for H2A1 by using
benzaldehyde instead of 4-nitrobenzaldehyde. Yield, 80%; m.p.
171–173 ◦C. Found (%): C, 74.68, H, 5.37, N, 12.87. C27H24N4O2
(436.50) requires (%): C, 74.29, H, 5.53, N, 12.83. IR: 3410 (O–H),
1602 (C O); 1H-NMR: 2.20 (6H, s, protons at C6, C6ꢁ ), 4.90 (1H, s,
protons at C13), 7.10–7.90 (14H, m, protons at C8 –H, C9 –H, C10 –H,
C11 –H,C12 –H,C15 –H,C16 –H,C18 –H,C19 –H,C8ꢁ –H,C9ꢁ –H,C10ꢁ –H,
C9ꢁ –H, C10ꢁ –H, C11ꢁ –H, C12ꢁ –H), 12.30 (1H, s, protons -OH), 13.90
13
· · ·
ꢁ
(1H, s, protonsH OH); C-NMR:12.10(C6, C6 ), 32.90(C13), 115.30
(C16, C18), 120.90 (C4, C4ꢁ ), 125.90 (C8, C12, C8ꢁ , C12ꢁ ), 128.60 (C10
,
C11ꢁ –H, C12ꢁ –H), 12.40 (1H, s, protons -OH), 13.90 (1H, s, protons
13
C10
C7ꢁ ), 146.70 (C3, C3ꢁ ), 156.00 (C5, C17, C5ꢁ ); DEPT-135: 12.10 (C6, C6ꢁ ),
ꢁ ), 125.90 (C , C12, C ꢁ ,
ꢁ ), 129.30 (C9, C11, C15, C19, C ꢁ , C ꢁ ), 132.70 (C14), 137.90 (C7,
· · ·
H
OH); C-NMR: 12.10 (C6, C6 ), 33.60 (C13), 121.00 (C4, C4 ),
ꢁ ꢁ
9
11
125.02 (C8, C12, C8ꢁ , C12ꢁ ), 126.00 (C17), 126.30 (C10, C10ꢁ ), 127.60
(C16, C18), 128.60 (C15, C19), 129.30 (C9, C11, C9ꢁ , C11ꢁ ), 137.80 (C7,
C7ꢁ ), 142.70 (C14), 146.80 (C3, C3ꢁ ), 149.80 (C5, C5ꢁ ); DEPT-135: 12.10
32.90 (C13), 115.30 (C16, C18), 120.90 (C4, C4
C12ꢁ ), 128.60 (C10, C10ꢁ ), 129.30 (C9, C11, C15, C19, C9ꢁ , C11ꢁ ).
8
8
c
Appl. Organometal. Chem. 2010, 24, 99–111
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
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D. H. Jani et al.
+.
N
N
O
Fe
O
O
N
F
O
m/z = 460 (461.05) (e)
-C3H5 (-41.04)
-C6H5 (-77.04)
-F (-19)
-C3H5 (-41.04)
+.
+.
N
N
N
N
O
O
Fe
Fe
O
O
N
O
O
N
F
O
O
m/z = 341 (342.97) (f)
m/z = 400 (401.01) (g)
Scheme 2 (Continued).
4,4ꢁ-((4-methoxyphenyl)methylene)bis(3-methyl-1-phenyl-1H-
4,4ꢁ-[(4-Hydroxy-3-methoxyphenyl)methylene]bis(3-methyl-1-
pyrazol-5-ol) (H2A5)
phenyl-1H-pyrazol-5-ol) (H2A6)
H2A6 was synthesized by same method used for H2A1
by using 4-hydroxy-3-methoxybenzaldehyde instead of 4-
nitrobenzaldehyde. Yield, 85%; m.p. 199–201 ◦C. Found (%): C,
69.78, H, 5.39, N, 11.69. C28H26N4O4 (482.52) requires (%): C,
69.70, H, 5.42, N, 11.61. IR: 3405 (O–H), 1610 (C O); 1H-NMR:
2.30 (6H, s, protons at C6, C6ꢁ ), 3.60 (3H, s, protons -OCH3), 4.80
(1H, s, proton at C13), 6.90–7.82 (14H, m, protons at C8 –H, C9 –H,
C10 –H, C11 –H, C12 –H, C15 –H, C16 –H, C18 –H, C19 –H, C8ꢁ –H, C9ꢁ –H,
C10ꢁ –H, C11ꢁ –H, C12ꢁ –H), 8.70 (1H, s, protons at C17 –OH), 12.30
H2A5 was synthesized by same method used for H2A1 by using
4-methoxybenzaldehyde instead of 4-nitrobenzaldehyde. Yield,
78%; m.p. 213–215 ◦C. Found (%): C, 72.12, H, 5.55, N, 11.88.
C
28H26N4O3 (466.52) requires (%): C, 72.08, H, 5.61, N, 12.00. IR:
3390 (O–H), 1602 (C O); 1H-NMR: 2.33 (6H, s, protons at C6, C6ꢁ ),
3.70 (3H, s, protons -OCH3), 4.90 (1H, s, protons C13), 7.20–8.10
(14H, m, protons at C8 –H, C9 –H, C10 –H, C11 –H, C12 –H, C15 –H,
C
16 –H, C18 –H, C19 –H, C8ꢁ –H, C9ꢁ –H, C10ꢁ –H, C11ꢁ –H, C12ꢁ –H),
12.40 (1H, s, protons -OH), 13.90 (1H, s, protons H OH); 13C-NMR:
(1H, s, protons -OH), 13.90 (1H, s, protons H OH); 13C-NMR: 12.10
· · ·
· · ·
12.00 (C6, C6ꢁ ), 32.90 (C13), 55.40 (carbon of -OCH3 group), 114.00
(C6, C6ꢁ ), 33.30 (C13), 56.10 (carbon of -OCH3 group), 112.50 (C15),
(C16, C18), 120.90 (C4, C4ꢁ ), 123.80 (C8, C12, C8ꢁ , C12ꢁ ), 125.90 (C10
,
115.60 (C18), 120.10 (C4, C4 ), 121.00 (C8, C12, C19, C8 , C12 ), 126.00
ꢁ
ꢁ
ꢁ
C10ꢁ ), 128.60 (C9, C11, C9ꢁ , C11ꢁ ), 129.30 (C14, C15, C19,), 134.50 (C7,
C7ꢁ ), 137.90 (C3, C3ꢁ ), 146.70 (C5, C5ꢁ ), 158.00 (C17); DEPT-135: 12.00
(C10, C10
ꢁ ), 129.30 (C9, C11, C14, C19, C9ꢁ , C11ꢁ ), 133.70 (C7, C7ꢁ ), 145.70
(C3, C3ꢁ ), 148.30 (C17), 155.60 (C16), 157.76 (C5, C5ꢁ ); DEPT-135: 12.00
(C6, C6ꢁ ), 33.30 (C13), 56.10 (carbon of -OCH3 group), 112.40 (C15),
115.60 (C18), 120.10 (C4, C4ꢁ ), 121.00 (C8, C12, C19, C8ꢁ , C12ꢁ ), 126.00
(C10, C10ꢁ ), 129.04 (C9, C11, C9ꢁ , C11ꢁ ).
(C6, C6ꢁ ), 32.80 (C13), 55.40 (carbon of -OCH3 group), 113.90 (C16
18), 120.90 (C4, C4ꢁ ), 123.90 (C8, C12, C8ꢁ , C12ꢁ ), 125.90 (C10, C10ꢁ ),
,
C
128.60 (C9, C11, C9ꢁ , C11ꢁ ), 129.30 (C14, C15, C19).
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 99–111

Novel drug based-Fe(III) heterochelates
Table 3. Minimum inhibitory concentrations (ppm) of the compounds against bacteria
Compounds
Bacillus subtilis
Staphylococcus aureus
Escherichia coli
Serratia marcescens
Fe(NO3)3•9H2O
Ciprofloxacin (HL)
H2A1
750
0.4
600
0.6
600
0.5
600
0.6
50
100
200
200
100
125
125
100
125
167
1.6
100
100
200
100
125
100
100
125
125
20
100
100
200
100
125
100
100
125
125
1.25
5.0
H2A2
200
200
100
125
100
100
167
125
5
H2A3
H2A4
H2A5
H2A6
H2A7
H2A8
H2A9
•
[Fe(A1)(L)(H2O)2] H2O
•
[Fe(A2)(L)(H2O)2] 2H2O
5.0
20
20
•
[Fe(A3)(L)(H2O)2] 2H2O
0.6
0.25
10
20
20
•
[Fe(A4)(L)(H2O)2] 2H2O
1.0
10
–
•
[Fe(A5)(L)(H2O)2] 2H2O
2.5
0.25
0.25
20
50
50
•
[Fe(A6)(L)(H2O)2] 1.5H2O
2.5
20
20
•
[Fe(A7)(L)(H2O)2] 1.5H2O
2.5
1.0
2.5
5.0
10
•
[Fe(A8)(L)(H2O)2] 0.5H2O
1.6
5.0
0.25
1.0
•
[Fe(A9)(L)(H2O)2] H2O
1.0
1.25
4,4ꢁ-[(3-Nitrophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-
4,4ꢁ-(p-Tolylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
5-ol) (H2A7)
(H2A9)
H2A9 was synthesized by same method used for H2A1 by using 4-
methylbenzaldehyde instead of 4-nitrobenzaldehyde. Yield, 86%;
m.p. 203–204 ◦C. Found (%): C, 72.77, H, 5.63, N, 12.18. C28H26N4O2
(462.54) requires (%): C, 72.70, H, 5.66, N, 12.11. IR: 3410 (O–H),
1599 (C O); 1H-NMR: 2.30 (6H, s, protons at C6, C6ꢁ ), 2.20 (3H,
s, protons -CH3), 4.90 (1H, s, protons -CH), 7.00–7.70 (14H, m,
protons at C8 –H, C9 –H, C10 –H, C11 –H, C12 –H, C15 –H, C16 –H,
C18 –H, C19 –H, C8ꢁ –H, C9ꢁ –H, C10ꢁ –H, C11ꢁ –H, C12ꢁ –H), 12.40 (1H,
H2A7 was synthesized by same method used for H2A1 by using
3-nitrobenzaldehyde instead of 4-nitrobenzaldehyde. Yield, 87%;
m.p. 230–232 ◦C. Found (%): C, 67.54, H, 4.83, N, 14.57. C27H23N5O4
(481.50) requires (%): C, 67.35, H, 4.81, N, 14.54. IR: 3398 (O–H),
1612 (C O); 1H-NMR: 2.20 (6H, s, protons at C6, C6ꢁ ), 5.40 (1H, s,
proton at C13), 7.20–7.70 (14H, m, protons at C8 –H, C9 –H, C10 –H,
C11 –H,C12 –H,C15 –H,C16 –H,C18 –H,C19 –H,C8ꢁ –H,C9ꢁ –H,C10ꢁ –H,
C11ꢁ –H, C12ꢁ –H), 12.60 (1H, s, protons -OH), 13.30 (1H, s, protons
s, protons -OH), 13.90 (1H, s, protons H OH). 13C-NMR: 12.00
13
· · ·
· · ·
H
OH). C-NMR: 11.90 (C6, C6 ), 29.80 (C13), 121.00 (C4, C4 ),
ꢁ ꢁ
(C6, C6ꢁ ), 21.0 (carbon of -CH3 group), 33.20 (C13), 120.90 (C4, C4ꢁ ),
124.50 (C8, C12, C8ꢁ , C12ꢁ ), 126.10 (C10, C10ꢁ ), 128.20 (C17), 128.60
(C16), 129.02 (C9, C11, C9ꢁ , C11ꢁ ), 130.50 (C19), 132.30 (C14), 134.70
(C18), 137.64 (C7, C7ꢁ ), 146.40 (C3, C3ꢁ ), 149.70 (C15), 152.76 (C5, C5ꢁ ).
DEPT-135: 12.10 (C6, C6ꢁ ), 29.90 (C13), 116.70 (C18), 121.00 (C4, C4ꢁ ),
124.50 (C8, C12, C8ꢁ , C12ꢁ ), 128.20 (C10, C10ꢁ ), 129.40 (C9, C11, C9ꢁ ,
C11ꢁ ), 130.50 (C19), 132.30 (C15).
125.90 (C8, C12, C8ꢁ , C12ꢁ ), 127.50 (C10, C10ꢁ ), 129.10 (C15, C16, C18
,
C19), 129.30(C9, C11, C9ꢁ , C11ꢁ ), 135.20(C14, C17, C19), 137.80(C7, C7ꢁ ),
(C3, C3ꢁ ), 146.70 (C5, C5ꢁ ). DEPT-135: 12.10 (C6, C6ꢁ ), 21.0 (carbon of
-CH3 group), 33.20 (C13), 120.90 (C4, C4ꢁ ), 125.90 (C8, C12, C8ꢁ , C12ꢁ ),
127.50 (C10, C10ꢁ ), 129.10 (C15, C16, C18, C19), 129.30 (C9, C11, C9ꢁ ,
C11).
4,4ꢁ-[(2-Nitrophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol) (H2A8)
General Procedure for the Synthesis of Heterochelates
A methanolic solution (25 ml) of Fe(NO3)3•9H2O (10 mmol) was
added to hot methanolic solution (50 ml) of ligand (H2An)
(10 mmol), followed by addition of ciprofloxacin (HL) (10 mmol)
in distilled water; the pH was adjusted to 6–7 with dilute NaOH
solution in distilled water. The resulting solution was refluxed for
4 h at 70 ◦C and then heated over a steam bath to evaporate up
to half of the volume. The reaction mixture was kept overnight
at room temperature. A colored crystalline product was obtained.
The obtained product was washed with water, methanol and
finally with ether and dried over vacuum desiccators.
H2A8 was synthesized by same method used for H2A1 by using
2-nitrobenzaldehyde instead of 4-nitrobenzaldehyde. Yield, 84%;
m.p. 148–150 ◦C. Found (%): C, 67.40, H, 4.82, N, 14.60. C27H23N5O4
(481.50) requires (%): C, 67.35, H, 4.81, N, 14.54. IR: 3402 (O–H),
1601 (C O); 1H-NMR: 2.34 (6H, s, protons at C6, C6ꢁ ), 5.10 (1H, s,
proton at C13), 7.20–8.10 (14H, m, protons at C8 –H, C9 –H, C10 –H,
C11 –H,C12 –H,C15 –H,C16 –H,C18 –H,C19 –H,C8ꢁ –H,C9ꢁ –H,C10ꢁ –H,
C11ꢁ –H, C12ꢁ –H), 12.60 (1H, s, protons -OH), 13.80 (1H, s, protons
13
· · ·
H
OH). C-NMR: 12.00 (C6, C6 ), 33.40 (C13), 121.60 (C4, C4 ),
ꢁ ꢁ
121.10 (C8, C12, C8ꢁ , C12ꢁ ), 126.20 (C10, C10ꢁ ), 122.20(C17), 129.40 (C9,
C11, C15, C19, C9ꢁ , C11ꢁ ), 130.1 (C18), 134.8 (C19), 136.10 (C14), 137.60
(C7, C7ꢁ ), 145.10 (C3, C3ꢁ ), 146.55 (C17), 148.20 (C5, C5ꢁ ); DEPT-135:
12.00 (C6, C6ꢁ ), 33.30 (C13), 116.80 (C16), 121.60 (C4, C4ꢁ ), 121.10 (C8,
Minimum Inhibitory Concentration Value
The minimal inhibitory concentration (MIC) was ascertained using
serial tube dilution technique[33] by variation of compound con-
centration. The antibacterial activity of the control, standard drug
C12, C8ꢁ , C12ꢁ ), 122.20 (C17), 126.20 (C10, C10ꢁ ), 129.40 (C9, C11, C15
C9ꢁ , C11ꢁ ), 130.10 (C18), 134.80 (C19).
,
c
Appl. Organometal. Chem. 2010, 24, 99–111
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/aoc

D. H. Jani et al.
IR Spectra
Table 4. Electronic spectral data of free ligands (H2An) and their
heterochelates
The important infrared spectral bands and their tentative
assignments for the synthesized heterochelates were recorded
as KBr disks and the data are presented in Table 2. All the ligands
(H2An) in the present investigation exhibit a broad band centered
at 3390–3410 cm−1. We assigned this peak to ν(O–H) for the
ILCT (π → π∗)
d–d transitions
in cm−1
Compounds
transition in cm−1
H2A1
H2A2
H2A3
H2A4
H2A5
H2A6
H2A7
H2A8
H2A9
32 500
32 600
32 600
32 500
32 650
32 600
32 500
32 550
32 550
32 400
–
–
· · ·
intramolecular hydrogen-bonded (H O–H) form between two
–
1
5-OH groups, which was further confirmed by H- and 13C-NMR
–
studies in solution state (discussed below). It also suggested that
theligands(H2An)existinenolforminboththestates. Thereaction
of the enolic ligands with Fe3+ ion is revealed by the presence of
a new band in the spectra of heterochelates at 1303–1316 cm−1
due to the ν(C–O) (enolic).[34]
In the investigated heterochelates, the bands observed in
the region 3418–3437, 1278–1295, 865–875 and 705–710 cm−1
are attributed to -OH stretching, bending, rocking and wagging
vibrations, respectively, due to the presence of water molecules.
The presence of rocking band indicates the coordination nature
of the water molecule.[35]
–
–
–
–
–
•
[Fe(A1)(L)(H2O)2] H2O
20 200
18 500
20 000
18 500
20 000
18 450
20 000
–
•
[Fe(A2)(L)(H2O)2] 2H2O
32 450
32 200
32 500
32 400
32 500
32 350
32 200
32 400
•
[Fe(A3)(L)(H2O)2] 2H2O
Comparing the main IR frequencies of Fe(III) heterochelates
with that of ciprofloxacin (HL) ligand (Table 2), the following
results were found. Two very strong absorption peaks in the
spectrum of the ligand were observed at 1707 and 1635 cm−1 due
•
[Fe(A4)(L)(H2O)2] 2H2O
•
[Fe(A5)(L)(H2O)2] 2H2O
20 350
–
to ν(O–H) of the carboxylic group and v(C
group, respectively.
O)
•
[Fe(A6)(L)(H2O)2] 1.5H2O
20 000
18 200
20 200
–
Absence of the former band in the spectra of the heterochelates
suggests that this moiety participated in the bonding to the
•
[Fe(A7)(L)(H2O)2] 1.5H2O
metal ion.[36] The later band corresponding to v(C
shifted to
O)
the lower frequency region (∼1624 cm−1) in the spectra of the
heterochelates could be due to coordination through either the
ketone group or the carboxylic group bonded to the metal ion.
We confirm that the coordination was through the ketonic group
of the HL ligand as the antisymmetric and symmetric modes of
•
[Fe(A8)(L)(H2O)2] 0.5H2O
20 050
–
•
[Fe(A9)(L)(H2O)2] H2O
20 200
–
the carboxylate group were observed at 1618 and 1384 cm−1
respectively. The νas(COO and νs(COO vibrational frequencies,
,
−
−
)
)
(ciprofloxacin), ligands (H2An), metal salts and its heterochelates
were screened for their anti-bacterial activity using different
bacterial strains such as Staphylococcus aureus, Bacillus subtilis,
Escherichia coli and Serratia marcescens. All the compounds were
found to be more potent against bacterial strains with different
MIC values.
together with the ν(COO values for the carboxylate group of the
−
)
ciprofloxacin (HL) ligand and their heterochelates are listed in
Table 2. The heterochelates produced a ꢀν value of >200 cm−1
,
suggesting unidentate carboxylate coordination to the central
metal ions.[37–39] Accordingly ciprofloxacin (HL), in the isolated
heterochelates appears to act as a uninegative bidentate ligand
throughtheoxygenatom ofthecarbonylgroupandenolicoxygen
of the carboxylate group.
In the far-IR region, two new bands at 444–472 and
410–430 cm−1 in the heterochelates were assigned to ν(M–O)
pyrazolone and ν(M–O) ketone of HL modes, respectively. All of
these data confirm the fact that bis-pyrazolones (H2An) behave as
dinegative bidentate ligands forming a conjugated chelate ring
with existing heterochelates in the enolized form.
Results and Discussion
The structural investigation of all the prepared ligands (H2An)
was done using elemental analyses, IR, 1H- and 13C-NMR and
DEPT-135 spectroscopy. The heterochelates were prepared by
reacting ferric nitrate with ciprofloxacin (HL) and variable ligands
(H2A1 –H2A9) in a 1 : 1 : 1 ratio. The analytical and physical data of
the heterochelates are given in Table 1. The following chemical
reaction describes the formation of the heterochelates:
1H- and 13C-NMR Spectra of the Ligands (H2An)
Structural analysis of the ligands was carried out with the help of
1H- and 13C-NMR using DMSO-d6 at room temperature. The data
are presented in the Experimental section. In the case of 1H-NMR
spectra for the ligand, two broad singlets equivalent to one proton
each were observed around δ 12.30–12.60 and 13.30–13.90 ppm
•
Fe(NO3)3 9H2O + H2An + HL −−−→ [Fe(An)(L)(H2O)2]•
mH2O + (7 − m)H2O + 3HNO3
where n = 1 and 9, m = 1; n = 2–5, m = 2; n = 6 and 7, m = 1.5;
n = 8, m = 0.5.
· · ·
corresponding to O–H and H O–H groups, respectively. These
signalsdisappearedwhenaD2Oexchangeexperimentwascarried
out. The later peak was observed in the strongly deshielded region
because of hydrogen bonding (H· · ·O–H) with the other oxygen
atom of the 5-OH group of the remaining pyrazolone moiety. It
shows the enolic nature of ligand and the broadness of these
All the heterochelates are insoluble in water, ethanol, methanol,
chloroform,acetonitrile,CCl4 andhexane,whilesolubleinDMFand
DMSO, so it is difficult to grow single crystals for X-ray diffraction
analysis.
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 99–111

Novel drug based-Fe(III) heterochelates
Table 5. Thermo analytical data of the heterochelates
TG range (◦C)
DTGmax (◦C)
DSCmax (◦C)
Assignment
Mass loss (%)
obs. (calcd.)
Heterochelates
•
[Fe(A1)(L)(H2O)2] H2O
50–110
–
–
1.90 (1.95)
3.85 (3.92)
Loss of one lattice water molecules
110–190
160
134.12 (+)
Loss of two coordinated water
molecules
190–475
475–800
390
–
272.12 (−)
35.80 (35.93)
49.68 (49.55)
Loss of HL ligand
Loss of remaining A1 ligand leaving
Fe2O3 residue
–
91.23 (91.35)
7.70 (7.77)
•
[Fe(A2)(L)(H2O)2] 2H2O
50–210
172
–
Loss of two lattice + two
coordinated water molecules
210–335
335–800
275
–
191.93, 291.52
35.37 (35.66)
48.33 (48.03)
Loss of HL ligand
Loss of remaining A2 ligand leaving
Fe2O3 residue
(−)
–
91.40 (91.46)
•
[Fe(A3)(L)(H2O)2] 2H2O
50–115
–
104.37 (+)
3.96 (4.03)
3.92 (4.03)
Loss of two lattice water molecules
115–190
160
–
Loss of two coordinated water
molecules
190–430
430–800
295
730
184.63, 269.11 (−)
37.18 (37.02)
46.19 (46.00)
Loss of HL ligand
Loss of remaining A3 ligand Leaving
Fe2O3 residue
–
91.25 (91.08)
•
[Fe(A4)(L)(H2O)2] 2H2O
50–105
–
–
3.99 (3.96)
3.90 (3.96)
Loss of two lattice water molecules
105–190
165
130.12 (+)
Loss of two coordinated water
molecules
190–425
425–800
290
520
182.43, 266.10 (−)
56.96
26.23
Loss of HL ligand + some part of A4
ligand
–
Loss of remaining part of A4 ligand
Leaving Fe2O3 residue
•
[Fe(A5)(L)(H2O)2] 2H2O
50–195
170
84.89 (+)
7.75 (7.80)
Loss of two lattice + two
coordinated water molecules
195–455
455–600
255
480
208.77 (−)
35.58 (35.81)
47.89 (47.76)
Loss of HL ligand
Loss of remaining A5 ligand leaving
Fe2O3 residue
–
91.22 (91.37)
6.67 (6.77)
•
[Fe(A6)(L)(H2O)2] 1.5H2O
50–190
–
103.08 (+)
Loss of 1.5 lattice + two
coordinated water molecules
190–350
350–500
273
–
195.31 (−)
353.70 (−)
35.42 (35.54)
49.29 (49.12)
Loss of HL ligand
Loss of remaining A6 ligand leaving
Fe2O3 residue
91.38 (91.43)
•
[Fe(A7)(L)(H2O)2] 1.5H2O
50–95
–
94.31 (+)
2.87 (2.90)
3.79 (3.87)
Loss of 1.5 lattice water molecules
95–195
180
–
Loss of two coordinated water
molecules
195–455
455–700
333
530
203.47 (−)
58.65
26.15
Loss of HL ligand + some part of A7
ligand
–
Loss of remaining part of A7 ligand
Leaving Fe2O3 residue
•
[Fe(A8)(L)(H2O)2] 0.5H2O
50–220
200
134.69 (+)
4.88 (4.94)
Loss of 0.5 lattice + two
coordinated water molecules
220–465
465–700
410
–
193.73 (−)
36.15 (36.29)
50.22 (50.04)
Loss of HL ligand
Loss of remaining A8 ligand leaving
Fe2O3 residue
–
91.25 (91.27)
•
[Fe(A9)(L)(H2O)2] H2O
50–120
–
–
–
1.98 (2.02)
3.94 (4.04)
Loss of one lattice water molecules
120–185
137.35 (+)
Loss of two coordinated water
molecules
185–495
495–800
285
–
188.22, 271.00 (−)
37.05 (37.18)
49.33 (49.14)
Loss of HL ligand
Loss of remaining A9 ligand leaving
Fe2O3 residue
–
92.30 (92.38)
(+): Endothermic; (−): exothermic.
c
Appl. Organometal. Chem. 2010, 24, 99–111
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/aoc

D. H. Jani et al.
Table 6. Kinetic parameters of the heterochelates
Heterochelates
TG range (◦C)
Ea (kJ mol−1
)
n
A (s−1
)
S∗ (J K−1 mol−1
)
H∗ (kJ mol−1
)
G∗ (kJ mol−1
)
•
[Fe(A1)(L)(H2O)2] H2O
50–110
110–190
190–475
475–800
3.26
7.77
0.98
0.98
1.00
0.99
0.129
0.358
12.23
28.05
−102.34
−100.46
−96.75
−95.35
−102.57
−101.88
−98.61
−102.17
−101.50
−98.06
−94.43
−102.45
−101.81
−99.42
−95.63
−102.90
−99.68
−99.87
−102.94
−98.65
−95.00
−102.99
−100.96
−99.62
−93.45
−103.13
−101.08
−98.06
.60
4.00
33.66
49.51
90.46
95.35
22.23
31.83
26.32
28.44
•
[Fe(A2)(L)(H2O)2] 2H2O
50–210
210–335
335–800
3.09
5.24
0.99
1.00
1.00
0.112
0.123
1.930
0.408
1.478
33.53
47.63
66.98
16.14
11.468
•
[Fe(A3)(L)(H2O)2] 2H2O
50–115
115–190
190–430
430–800
3.45
5.82
0.99
1.00
1.00
0.98
0.144
0.160
4.002
6.023
0.772
2.057
13.84
33.51
33.77
48.04
68.07
70.05
11.52
18.43
•
[Fe(A4)(L)(H2O)2] 2H2O
50–105
105–190
190–425
425–800
3.19
5.23
0.98
0.99
1.00
1.01
0.120
0.132
0.767
9.721
0.508
1.549
8.205
18.48
33.60
46.65
64.18
65.51
12.88
28.48
•
[Fe(A5)(L)(H2O)2] 2H2O
50–195
195–455
455–600
3.34
9.65
1.00
1.00
0.99
0.078
0.733
0.398
0.162
5.884
8.241
39.57
51.04
77.45
14.00
•
[Fe(A6)(L)(H2O)2] 1.5H2O
50–190
190–350
350–500
3.39
13.68
49.26
1.01
1.00
1.00
0.074
2.133
17.52
0.128
09.67
44.00
40.58
57.32
104.14
•
[Fe(A7)(L)(H2O)2] 1.5H2O
50–95
95–195
195–455
455–700
3.36
7.51
1.01
0.98
1.00
0.99
0.072
0.215
0.083
3.334
9.802
11.13
40.55
54.12
72.32
82.82
15.98
22.23
0.483
13.554
•
[Fe(A8)(L)(H2O)2] 0.5H2O
50–220
220–465
465–700
3.30
8.42
1.00
0.98
1.00
0.065
0.169
3.543
−0.04
3.57
41.51
62.51
76.68
20.76
15.58
•
[Fe(A9)(L)(H2O)2] H2O
50–120
120–185
185–495
495–800
3.32
10.63
22.25
31.10
1.00
0.99
1.00
1.01
0.077
0.674
34.43
54.55
−102.92
−99.67
−95.55
−96.46
0.140
6.499
26.13
33.42
39.56
56.13
73.22
83.81
two singlets due to fast exchange interaction of proton via keto-
enol tautomerism. It may be noted that the integration of these
signals perfectly matches with one proton each. We did not do
any temperature-dependent experiments. Comparing with the
solid-state study, we prefer to assign these signals to O–H and
· · ·
represents the molecular ion peak of the heterochelate (without
water of crystallization). Scheme 2 demonstrates the possible
degradation pathway for the investigated heterochelate. The
primary fragmentation of the heterochelate takes place due to
the loss of two coordinated H2O molecules from the species (a) to
give species (b) with peak at m/z 818. The species (b) further
degrades to give species (d) with loss of species (c). The sharp peak
(base peak) observed at m/z 263 represents the stable species
(c) with 99.5% abundance. Species (d) further degrades with the
loss of -CH3 and -C4H9N2 moieties forming species (e) with a peak
at m/z 460. Species (e) has two possibilities for degradation, either
degradingwiththelossof-C6H5 and-C3H5 moietiestogivespecies
(f) (m/z 341) or degrading with the loss of -C3H5 and -F moieties to
give species (g) with a peak at m/z 400. The measured molecular
weights for all the suggested degradation steps were consistent
with expected values.
H
O–H; however, the provided solid-state structural evidence
has not been considered.
1
In the case of H-NMR spectra of the ligand, peaks observed
at ∼6.68–8.10 ppm were assigned to the aromatic protons. The
two singlet peaks at ∼5.10 and ∼2.30 ppm were assigned to
aliphatic proton (C13 –H) and six protons of two -CH3 groups of bis-
pyrazolones, respectively. In l3C-NMR spectra peaks observed at
124–138 ppm were assigned to aromatic carbons. Peak observed
at ∼157 was assigned to C–O of C5, C5ꢁ carbons. Aliphatic carbon
(C13) was observed at ∼33 ppm.
FAB Mass Spectra
Antibacterial Screening
The recorded FAB mass spectrum (Fig. 1) and the molecular ion
peak for the heterochelate [Fe(A3)(L)(H2O)2]•2H2O were used to
confirm the molecular formulae. The proposed fragmentation
pattern is shown in Scheme 2. The first peak at m/z 856
The antibacterial activity of the control, standard drug
(ciprofloxacin), metal salts, ligands (H2An) and their heterochelates
were screened against different bacterial strains as stated above.
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 99–111

Novel drug based-Fe(III) heterochelates
Staphylococcus aureus is the preliminary screening test organism
of choice for several reasons. It is a systemic pathogen and seems
to develop antibiotic resistance more readily than any other bac-
teria, and laboratory animals can be readily infected with it. The
inhibition of growth of these Gram-positive organisms produced
by various concentrations of the test compounds were compared
under identical conditions with the inhibition of growth of the
same organism by ciprofloxacin, which is a standard antibiotic
and resists the growth of organism. Similarly, the inhibitions of
the Gram-negative organism growth produced by the test com-
pounds were compared with those for the same concentrations
of ciprofloxacin, which is a broad-spectrum antibiotic.
A standard volume (5 ml) of Luria broth medium (2%) to support
thegrowthofthetestorganismwasaddedtoseverallabeledsterile
stopper identical assay tubes. A solution of each test compound
was prepared in DMSO and a series of dilutions was prepared.
Concentrations tested were 0.25–20 ppm of the ligands and their
heterochelates under investigation, a broad-spectrum antibiotic,
the respective metal salt (20–800 ppm) dissolved in DMSO and
a blank (DMSO). A control tube containing no test compound
was also included. A 0.1 ml aliquot of the test organism from the
overnight grown test cultures was added. All these operations
were carefully performed under aseptic conditions. Assay tubes
were incubated at 30 ◦C for 24 h. The resultant turbidities were
measured using a Systronics spectrophotometer model no. 106.
The minimum inhibitory concentration (MIC) of a test compound
is the lowest concentration showing no visible turbidity. However,
the final concentration of bacterial growth inhibition produced
by a certain concentration of the test compound was calculated
using the following relationship:
Heterochelates
1
R2
R3
mH2O
R1
-H
-H
-NO2
1H2O
-H
-H
-H
-H
-H
-H
-H
-H
-Cl
-H
2
3
4
5
2H2O
2H2O
2H2O
2H2O
-OH
-OCH3
6
7
-H
-H
-OCH3
-NO2
1.5H2O
1.5H2O
-OH
-H
Tc − Tt
%inhibition =
× 100
-H
-H
8
9
-NO2
-H
-H
0.5H2O
1H2O
Tc
-CH3
where Tc is the turbidity of the control and Tt is the turbidity of the
specific treatment or the test compound.
Figure 5. The proposed structure of heterochelates.
TheheterochelatesexhibitedstrongactivitiesagainsttwoGram-
negative (Escherichia coli, Serratia marcescens) and two Gram-
positive (Staphylococcus aureus, Bacillus subtilis) microorganisms.
The antimicrobial activity data of the compounds are summarized
in Table 3. Comparative analysis showed higher antibacterial
activityoftheheterochelatesthanfreeligandsandmetalsalt.Some
of the heterochelates exhibited moderate activities as compared
with the standard drug ciprofloxacin. It was also observed that
someoftheheterochelatesweremorepotentbactericidesthanthe
ligands. This enhancement in antibacterial activity is rationalized
on the basis of Overtone’s concept, Tweedy’s chelation theory
and the partial sharing of the positive charge of metal ions with
donor groups.[40–44] This may support the argument that some
type of bimolecular binding to the metal ions or intercalation
or electrostatic interaction causes the inhibition of biological
synthesis and prevents the organisms from reproducing. The
results of our studies (Table 3) indicate that compounds 3, 5 and
6 have good activity against Staphylococcus aureus, while 8 has
good activity against Escherichia coli, displaying high affinities
towards most of the receptors. The strong antimicrobial activities
of these compounds against tested organisms suggest further
investigation on these compounds.
values. The electronic spectral data of the free ligands (H2An)
and their heterochelates are presented in Table 4. The diffused
reflectance spectra of free ligands showed an intense band at
32 600 cm−1.Thehighintensityofthisbandmaybeduetoπ → π∗
intraligand charge transfer transition (ILCT). The reflectance
spectra of heterochelates [Fe(An)(L)(H2O)2]•mH2O exhibited two
additionalbandsatabout∼20 000and∼18 000 cm−1, whichwere
assigned to d–d transitions. In the case of compounds 4, 5, 7, 8
and 9, the second band was not observed (Table 4), which is due to
the greater absorption in the ultraviolet portion of the spectrum.
From the electronic spectra, an octahedral geometry around the
central metal ion is suggested.[45–47] This is further supported by
the magnetic measurement data of Fe(III) heterochelates which
falls in the range 5.90–6.01 B.M.
Thermal Studies
Each decomposition process follows the trend
heat
Solid-1
Solid-2 + Gas
Electronic Spectra and Magnetic Moments
This process comprises several stages. The method re-
ported by Freeman and Carroll[48] has been adopted. Plots of
[ꢀlog(dw/dt)/ꢀlogwr] vs [ꢀ(1/T)/ꢀlogwr] were linear for all of
The information regarding geometry of the heterochelates was
obtainedfromtheirelectronicspectraldataandmagneticmoment
c
Appl. Organometal. Chem. 2010, 24, 99–111
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/aoc

D. H. Jani et al.
the decomposition steps. The energy of activation Ea was calcu-
lated from the slopes of these plots for a particular stage and the
order of reactions (n) were determined from the intercept, show-
ing first-order reaction over the entire range of decomposition for
all the heterochelates. A typical plot for the thermal degradation
of [Fe(A5)(L)(H2O)2]•2H2O is shown in Fig. 2.
follow the general trend found by Irving and Williams[51] for the
stabilities of complexes in solution. The heterochelates 2, 5, 6 and
8 deviate from this general behavior. Since the Irving-Williams
series reflects electrostatic effects, this observation indicates that
the water–metal interaction in these heterochelates is almost of
ion-dipole type. A similar relationship was observed in the case
of the double ammonium sulfate hexahydrate salts of the first
raw transition metals.[52] From the above discussion an octahedral
structure of the heterochelates can tentatively be assumed, as
shown in Fig. 5.
The Thermal Behavior of the Prepared Heterochelates
Thermal data and kinetic parameters of the heterochelates
are given in Tables 5 and 6, respectively. The typical TG/DTG
and DSC curves of the heterochelate [Fe(A5)(L)(H2O)2]•2H2O
are represented in Figs 3 and 4, respectively. The thermal
fragmentation scheme for the heterochelates is shown below:
Conclusions
The results obtained in this study allow the following conclusions:
1. The design and synthesis of new bis-pyrazolone ligands (H2An)
havesuccessfullybeendemonstrated.FT-IR,1H-NMR,13C-NMR
and DEPT-135 spectral studies reveal that ligands exist in the
tautomeric enol form both in solid and solution states with
intramolecular hydrogen bonding. We have synthesized a
series of some novel drug based Fe(III) heterochelates with
bis-pyrazolone derivatives and quinolone-based drug (HL)
and characterized their properties.
50–120°C
[Fe(An)(L)(H2O)2]. mH2O
removal of crystalline water molecules
[Fe(An)(L)(H2O)2] + mH2O
(Where n = 1&9, m = 1; n = 3&4, m = 2; n = 7, m = 1.5)
120–195°C
[Fe(An)(L)(H2O)2]
removal of coordinated water molecules
[Fe(An)(L)] + 2H2O
2. All the synthesized compounds were screened for their bioas-
say. The heterochelates exhibited strong activities against
two Gram-negative (Escherichia coli, Serratia marcescens) and
two Gram-positive (Staphylococcus aureus, Bacillus subtilis) mi-
croorganisms. In comparison with both the ligands and metal
salt, the Fe(III) heterochelates were more active against one
or more bacterial strains, thus introducing a novel class of
metal-based bactericidal agents.
195–495°C
removal of HL ligand
[Fe(An)]
[Fe(An)(L)]
495–800°C
removal of H2An ligand
[Fe(An)]
Fe2O3
whereas for compounds 2, 5, 6 and 8 the thermal fragmentation
scheme is shown below:
3. Theinformationregardinggeometryoftheheterochelateswas
obtained from their electronic and magnetic moment values.
Magnetic moment values indicate that Fe(III) heterochelates
are high-spin, lacking exchange interactions. The studies
reveal that an octahedral geometry can be assigned to
heterochelates.
50–220°C
[Fe(An)(L)(H2O)2]. mH2O
removal of crystalline + coordinated
water molecules
[Fe(An)(L)] + 2H2O + mH2O
(Where n = 2&5, m = 2; n = 6, m = 1.5; n = 8, m = 0.5)
220–465°C
[Fe(An)]
[Fe(An)(L)]
removal of HL ligand
Acknowledgments
465–800°C
[Fe(An)]
Fe2O3
We express our gratitude to Department of Chemistry, Bhavna-
gar University, Bhavnagar and Sardar Patel University, Vallabh
Vidyanagar, India for providing laboratory facilities. We expressed
ourgratitudetoMissB. Kavita, researchstudent, DepartmentofBio
Sciences, Sardar Patel University for her valuable support. Analyti-
cal facilities provided by the SAIF, Central Drug Research Institute,
Lucknow, India and the Sophisticated Instrumentation Centre
for Applied Research and Testing (SICART), Vallabh Vidyanagar,
Gujarat, India is gratefully acknowledged.
removal of H2An ligand
The anhydrous heterochelates show great thermal stability up
to 190 ◦C, and in the third subsequent stage for heterochelates,
the decomposition and combustion of ligand (HL) occurs. In the
fourth subsequent stage for heterochelates, the decomposition
and combustion of ligand (H2An) occurs. The removal of ligand
(H2An) undergoes decomposition, forming Fe2O3 as the final
residue.
The thermodynamic activation parameters of the decompo-
sition process of dehydrated heterochelates such as activation
entropy (S∗), pre-exponential factor (A), activation enthalpy (H∗)
and free energy of activation (G∗) were calculated using re-
ported equations.[49] According to the kinetic data obtained from
DTG curves, all the heterochelates have negative entropy, which
indicates that the studied heterochelates have more ordered
systems.[50] The energy of activation (Ea) is helpful in assigning
the strength of the bonding of ligand moieties with the metal
ion. The relatively high Ea value (Table 6) indicates that both the
ligands are strongly bonded to the metal ion.[37] The thermal
stabilities of the heterochelates 1, 3, 4, 7 and 9 in the solid state
References
[1] E. C. Theil, Iron Biomineralization (Ed.: R. B. Frankel). Plenum Press:
London, 1990.
[2] P. B. Pansuriya, M. N. Patel, Appl. Organomet. Chem. 2007, 21, 926.
[3] M. Benigno, V. Marya, R. Inmaculada, J. Inorg. Biochem. 2001, 84,
163.
[4] A. M. Jamil, Acta Chim. Slov. 2002, 49, 457.
[5] K. S. Dilip, P. Subhash, Trans. Met. Chem. 2003, 28, 579.
[6] R. A. Juan, T. Caredmy, Trans. Met. Chem. 2001, 26, 228.
[7] I. Turel, Coord. Chem. Rev. 2002, 232, 27.
[8] N. Raman,
A. Kulandaisamy,
A. Shunmugasundaram,
K. Jeyasubramanian, Trans. Met. Chem. 2001, 26, 131.
c
www.interscience.wiley.com/journal/aoc
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 99–111

Novel drug based-Fe(III) heterochelates
[9] B. A. Uzoukwu, P. U. Adiukwu, S. S. Al-Juaid, P. B. Hitchcock,
J. D. Smith, Inorg. Chim. Acta 1996, 250, 173.
[32] A. I. Vogel, TextbookofQuantitativeInorganicAnalysis, 4th edn. ELBS
and Longman: London, 1978.
[10] Z. Y. Yang, R. D. Yang, F. S. Li, K. B. Yu, Polyhedron 2000, 19, 2599.
[11] W. F. Yang, S. G. Yuan, Y. B. Xu, Y. H. Xiao, K. M. Fang, J. Radioanal.
Nucl. Chem. 2003, 256, 149.
[12] P. Chiba, W. Holzer, M. Landau, G. Bechmann, K. Lorenz, B. Plagens,
M. Hitzler, E. Richter, G. Ecker, J. Med. Chem. 1998, 41, 4001.
[13] A. K. El-Sawaf, D. X. West, Trans. Met. Chem. 1998, 23, 417.
[14] N. Kalarani, S. Sangeetha, P. Kamalakannan, D. Venkappayya, Russ.
J. Coord. Chem. 2003, 29, 845.
[33] M. J. Pelczar, R. D. Reid, E. C. S. Chan, Microbiology, 4th edn. Tata
McGraw-Hill: New Delhi, 1979.
[34] L. Liu, D. Jia, Y. Ji, Synth. React. Inorg. Met.-Org. Chem. 2002, 32, 739.
[35] N. Nakamoto, Infrared Spectra and Raman Spectra of Inorganic and
Coordination compounds, John Wiley & Sons: New York, 1978.
[36] L. Bellamy, The Infrared Spectra of Complex Molecules, 3rd edn.
Chapman and Hall: London, 1975.
[37] C. K. Modi, M. N. Patel, J. Therm. Anal. Cal. 2008, 94(1), 247.
[38] B. S. Creaven, D. A. Egan, K. Kavanagh, M. McCann, A. Noble,
B. Thati, M. Walsh, Inorg. Chim. Acta 2006, 359, 3976.
[39] M. S. Masoud, M. F. Amira, A. M. Ramadana, G. M. El-Ashry,
Spectrochim. Acta Part A 2008, 69, 230.
[15] T. Yoshikuni, J. Mol. Catal. A: Chem. 1999, 148, 285.
[16] F. Marchetti, C. Pettinari, R. Pettinari, A. Cingolani, D. Leonesi,
A. Lorenzotti, Polyhedron 1999, 18, 3041.
[17] F. Marchetti, C. Pettinari, R. Pettinari, Coord. Chem. Rev. 2005, 249,
2909.
[40] Z. H. Chohan, Appl. Organomet. Chem. 2002, 16, 17.
[41] N. Dharmaraj, P. Viswanathamurthi, K. Natarajan, Trans. Met. Chem.
2001, 26, 105.
´
[18] J. S. Casas, M. S. García-Tasende, A. Sa´nchez, J. Sordo, A. Touceda,
Coord. Chem. Rev. 2007, 251, 1561.
[19] C. Pettinari, F. Marchetti, A. Drozdov, V. Vertlib, S. I. Troyanov, Inorg.
[42] Z. H. Chohan, K. M. Khan, C. T. Supuran, Appl. Organomet. Chem.
Chem. Commun. 2001, 4, 290.
2004, 18, 305.
[20] C. Pettinari, F. Marchetti, R. Pettinari, A. Cingolani, A. Drozdov,
S. I. Troyanov, J. Chem. Soc. Dalton Trans. 2002, 188.
[21] S. N. Semenov, A. Yu. Rogachev, S. V. Eliseeva, C. Pettinari,
F. Marchetti, A. A. Drozdov, S. I. Troyanov, Chem. Commun. 2008,
1992.
[43] P. K. Panchal, P. B. Pansuriya, M. N. Patel. J. Enz. Inhib. Med. Chem.
2006, 21(2), 203.
[44] F. Caruso, M. Rossi, J. Tanski, R. Sartori, R. Sariego, S. Moya, S. Diez,
E. Navarrete, A. Cingolani, F. Marchetti, C. Pettinari, J. Med. Chem.
2000, 43, 3665.
[22] D. W. Johnson, J. Xu, R. W. Saalfrank, K. N. Raymond, Angew. Chem.
Int. Ed. 1999, 38, 2882.
[23] J. Xu, K. N. Raymond, Angew. Chem. Int. Ed. 2000, 39, 2745.
[24] C. Pettinari, F. Marchetti, R. Pettinari, D. Martini, A. Drozdov,
S. I. Troyanov, J. Chem. Soc. Dalton Trans. 2001, 1790.
[25] L. Yang, R. Yang, Polyhedron 1995, 14, 507.
[45] D. Danuta, B. J. Lucjan, D. Marek, Polyhedron 2005, 24, 407.
[46] F. A. Cotton, G. Wilkinson, The elements of first transition series, in
Avanced Inorganic Chemistry, 3rd edn, Wiley: Chichester, 1992.
[47] A. B. P. Lever, Electronic spectra of dn ions, in Inorganic Electronic
Spectroscopy, 2nd edn. Elsevier: Amsterdam, 1984.
[48] E. S. Freeman, B. Carroll, J. Phys. Chem. 1958, 62, 394.
[49] C. K. Modi, S. H. Patel, M. N. Patel, J. Therm. Anal. Cal. 2007, 87, 441.
[50] M. E. El-Zaria, Spectrochim. Acta Part A 2008, 69, 216.
[51] H. Irving, R. J. P. Williams, J. Chem. Soc. 1953, 3192.
[26] X. Li, R. Yang, Polyhedron 1992, 11, 1545.
[27] L. Yang, R. Yang, Acta Chim. Sinica 1989, 47, 911.
[28] C. K. Modi, Spectrochim. Acta Part A 2009, 71, 1741.
[29] C. K. Modi, I. A. Patel, B. T. Thaker,J.Coord.Chem. 2008, 61(19), 3110.
[30] C. K. Modi, B. T. Thaker, J. Therm. Anal. Cal. 2008, 94(2), 567.
[31] A. I. Vogel, Textbook of Practical Organic Chemistry, 5th edn.
Longman: London, 1989.
¨
[52] V. T. Yilmaz, H. Ic¸budak, H. Olmez, Thermochim. Acta 1994, 244, 85.
c
Appl. Organometal. Chem. 2010, 24, 99–111
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
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