Synthesis of novel ferrocene containing vic-dioxime ligands and their Ni(II), Cu(II) and Co(II) complexes: Spectral, electrochemical and biological activity studies

Article abstract of DOI:10.1016/j.jorganchem.2011.08.040

Two new vic-dioxime ligands bearing an important redox-active substituent, anti-β-ferrocenylethylaminoglyoxime (1a) and anti-β- ferrocenylethylaminophenylglyoxime (1b), have been synthesized, and their Ni(II), Cu(II) and Co(II) (2a-4a, 2b-4b) complexes we

Full text of DOI:10.1016/j.jorganchem.2011.08.040

Journal of Organometallic Chemistry 696 (2011) 3756e3763
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Synthesis of novel ferrocene containing vic-dioxime ligands and their Ni(II), Cu(II)
and Co(II) complexes: Spectral, electrochemical and biological activity studies
,
b
Pervin Devecia , Ugur Arslan
*
ꢀ
a Selcuk University, Faculty of Science, Department of Chemistry, Konya, Turkey
b Selcuk University, Selcuklu Medical Faculty, Department of Clinical Microbiology, Konya, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new vic-dioxime ligands bearing an important redox-active substituent, anti-b-ferrocenylethyla-
minoglyoxime (1a) and anti-b-ferrocenylethylaminophenylglyoxime (1b), have been synthesized, and
Received 18 June 2011
Received in revised form
23 August 2011
their Ni(II), Cu(II) and Co(II) (2a-4a, 2b-4b) complexes were obtained. The composition and structure of
the products were determined by elemental analysis, Fourier transform infrared (FT-IR), ultraviolet
evisible (UVevis), mass spectrometry (MS), one-dimensional (1D) 1H, 13C NMR, and two-dimensional
(2D) heteronuclear multiple bond correlation (HMBC) techniques. The redox behaviors of the ligands
and their complexes were investigated by cyclic voltammetry (CV), which revealed that all the ferrocenyl
redox centers are electrochemically independent and undergo a quasi-reversible oxidation at similar
potentials. Also, antibacterial activity was studied against Staphylococcus aureus ATCC 29213, Strepto-
coccus mutans RSHM 676, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922 and Pseudomonas
aeruginosa ATCC 27853. The antimicrobial test results indicated that all the compounds have mild levels
of antibacterial activity against both gram negative and gram-positive bacterial species.
Ó 2011 Elsevier B.V. All rights reserved.
Accepted 25 August 2011
Keywords:
vic-Dioxime
Ferrocene
Electrochemical study
Biological activity
Metal complex
1. Introduction
lead to new vic-dioxime derivatives with important pharmaco-
logical properties (Scheme 1). As an extension of this idea, in the
Tschugaev’s isolation of vic-dioximes in 1905 initiated intense
research activity into the coordination chemistry of these versatile
ligands [1e3]. The potential applications of these compounds and
their complexes have been shown to be useful in many search areas
such as medicine [4], bioorganic systems [5], catalysis [51], and
electrooptical sensors [6]. The cobaloximes have acquired an
independent research field among the oxime complexes because of
their usage as model compounds for the study of the vitamin B12
coenzyme [7,8]. Like oximes, ferrocene-based ligands have been
employed in various fields, such as semiconductors, [9] biosensors,
[10] asymmetric catalysis, [11] and nonlinear optics. [12]. The
activities of certain drugs are reported to be enhanced by the
addition of ferrocene moiety to their structures; e.g., ferrocene
aspirin [13], the antimalarial drug ferrocene quinine [14], and
anticancer drug ferrocifen [15]. The anticancer potential of
ferrocene-containing compounds is also well reported [16e18].
Due to the broad pharmacological interest in oxime and ferrocene
derivatives, and their great potential for important applications, the
attachment of ferrocene moiety on vic-dioxime compounds can
present contribution, we have enlarged the focus of our work to
design and successfully synthesize two new vic-dioxime ligands
bearing ferrocene moiety and their Ni(II), Cu(II) and Co(II)
complexes as a new class of synthetic antimicrobial agents, along
with their in vitro antimicrobial activity. In this manuscript, the
structure of the vic-dioxime ligands, anti-
b-ferrocenylethylamino-
glyoxime (1a) and anti- -ferrocenylethylaminophenylglyoxime
b
(1b), is characterized in detail for the first time to confirm the
proposed structure by means of elemental analysis, FT-IR, UVevis,
MS, 1D 1H NMR and 13C NMR and HMBC techniques. The compo-
sition of metal complexes was identified with elemental analysis,
FT-IR, UVevis and MS. The study also reported the 1H and 13C NMR
spectra of the Ni(II) complexes (2a, 2b). With the recent growing
interest in the reduction and oxidation process of the compounds,
the electrochemical properties of the ligands and their metal
complexes were investigated by CV. A screening of the compounds’
antibacterial activities with five bacteria was also performed. To the
best of our knowledge, this is the first manuscript that includes the
synthesis, spectral characterization, antibacterial activity and
electrochemical properties of anti-
ime (1a), anti- -ferrocenylethylaminophenylglyoxime (1b) and
their Ni(II), Cu(II) and Co(II) complexes.
b-ferrocenylethylaminoglyox-
b
* Corresponding author. Tel.: þ90 332 2233892; fax: þ90 332 2412499.
E-mail address: pervindeveci@gmail.com (P. Deveci).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2011.08.040

P. Deveci, U. Arslan / Journal of Organometallic Chemistry 696 (2011) 3756e3763
3757
Scheme 2. The numbering of 1a and 1b for 1H NMR,13C NMR and HMBC.
vic-dioxime group (C7, C8). Two frequencies of the dioxime group in
13C NMR indicate that the vic-dioxime has an anti- structure [28].
More information about the structure of the ligand is provided by
the 2D HMBC spectrum (Fig. 1) and the specific assignments of
protons and carbons are shown in Table 1. The HMBC spectrum
shows that OeH protons (Ha, Hb) exhibit long range coupling with
hydroxyimino carbons (C7, C8). Other correlations also agree with
the proposed structure (Table 1).
Scheme 1. Synthesis of vic-dioxime ligands (1a, 1b) and their complexes (2a-4a, 2b-
4b), (i): tetrahydrofuran, methanol, triethyamine and room temperature (ii): methanol,
H2O, NiCl.26H2O, CuCl2$2H2O or CoCl2$6H2O.
2. Results and discussion
2.1. Characterization of the vic-dioxime ligands (1a, 1b)
The new vic-dioxime ligands (1a, 1b) were subjected to
elemental analyses, FT-IR, UVevis, MS and NMR (1H NMR, 13C NMR
and HMBC) spectral studies. Our analyses of 1a and 1b agree with
the suggested structures. The experimental section shows the
results of the elemental analyses (C, H and N) with a molecular
formula and the melting points. The results agree with those
calculated for the suggested formula; the melting point is sharp,
indicating the purity of the vic-dioxime ligands. Scheme 1 illus-
trates the structure of the vic-dioximes under study.
In the mass spectrum of 1a and 1b (Fig. A1 and Fig. A2), the
peaks observed at m/z 315.6225, 316.6301, 317.6185 and m/z
391.7297, 392.7350 and 393.7401 can be assigned to the molecular
(M)þ ion peaks (fragments are based on 56Fe, 57Fe and 58Fe) for 1a
and 1b. The peak at m/z 376.7208 may be assigned to the loss of the
hydroxyl group from the ligand in 1b. The FT-IR spectra of these
ligands exhibit the expected bands; the most characteristic exam-
ples are the nC¼N stretching observed at 1650 cmꢀ1 for 1a and at
1654 cmꢀ1 for 1b. The bands for the NeO group present in the
ligands are distinct and occur at 884 cmꢀ1 and 857 cmꢀ1 [19]. The
UVevis spectra for the ligands are recorded in DMSO at
200e600 nm. Compounds 1a and 1b showed a strong absorption
band at about 260 nm, apparently corresponding to a
transition of aromatic ring or azomethine (eC¼Ne) groups [20],
and a shoulder at about 320 nm corresponding to an n/ * tran-
p/p*
p
sition of the eC¼Ne group [21], and a weak band at about 470 nm
that corresponds to a d/d transition for the iron of ferrocene [22].
The 1H NMR spectra for the ligands showed peaks in the ferrocene
region that were characteristic of a monosubstituted ferrocene
moiety [23,24]. The deuterium exchangeable protons of the eOH
groups appear as two singlets for each ligand (Scheme 2). These
two deuterium exchangeable singlets correspond to two
nonequivalent eOH protons, which also indicate the anti-configu-
ration of the eOH groups relative to one another [25]. The 13C NMR
spectra of the ligands show signals typical of a monosubstituted
ferrocene moiety in the range of
d 67.65e86.31 ppm, which agrees
with previous results [26,27]. In the 13C NMR spectra of 1a, the
signals at 144.77 ppm and 148.84 ppm, and for 1b, the signals at
148.79 ppm and 151.15 ppm are assigned to the carbon atoms of the
Fig. 1. HMBC correlations for a) 1a (DMSO-d6) b) 1b (DMSO-d6).

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P. Deveci, U. Arslan / Journal of Organometallic Chemistry 696 (2011) 3756e3763
Table 1
13C NMR data and 1He13C HMBC correlations of 1a and 1b.
Carbon
number
Chemical shift
1a C(ppm)
Chemical shift
1b C(ppm)
1He13C HMBC 1a (2J)-(4J)
1He13C HMBC 1b (2J)-(4J)
d
d
1
86.31
86.10
4.03(H2), 2.38(H5),
3.45e3.48(H6)
3.98(H2), 2.28(H5), 3.03e3.09(H6)
2e4
67.73, 68.62, 69.08
67.65, 68.38, 68.95
4.03(H2), 4.00(H3),
4.08(H4), 2.38(H5)
3.45e3.48(H6)
2.38(H5)
11.30(Ha), 5.51(Hc)
3.98(H2), 3.94(H3), 4.02(H4), 2.28(H5)
5
6
7
31.89
44.64
144.77
31.68
44.34
148.79
3.03e3.09(H6), 3.98(H2)
2.28 (H5), 5.79 (Hc), 3.98(H2)
11.68(Ha), 5.79(Hc),7.59e7.61(H10),
7.35e7.42(H11,12
)
8
148.84
151.15
10.15(Hb), 7.26(H7),3.45e3.48(H6)
9.69(Hb), 3.03e3.09(H6)
9e12
e
128.62, 129.71, 129.83, 132.29
e
7.59e7.61(H10), 7.35e7.42(H11,12)
2.2. Characterization of the vic-dioxime complexes
374 nm and 476 nm may originate from the LMCT and ded electron
transfer [32], respectively. Since no other ded bands are observed
at up to 1200 nm, the simplicity of the spectra and the corre-
sponding band intensities suggest a square planar, rather than
tetrahedral, configuration of the complex in the solution [33]. The
weak ded transition of complexes 3a, 4a, 3b and 4b were not
observed. Also, the ded bands should be present at low intensities
in this range, but they are masked by the stronger CT absorption
band [34].
The formation of complexes 2a and 2b are conveniently moni-
tored by 1H NMR and 13C NMR spectroscopy. The 1H NMR of 2a
shows a singlet at 13.95 ppm, with the chemical shift comparable to
that observed for an analogous Ni(II) complex (2b), which shows
a signal at 14.40 ppm. These signals could be identified easily by
means of a deuterium exchange or they could be assigned to the
formation of a hydrogen bridge [35]. In the 13C NMR spectra of 2a
and 2b, the quaternary carbon signals of the hydroxyiminocarbon
(C¼NeO) appeared at 146.50 and 149.20 ppm for 2a and 149.72 and
151.35 ppm for 2b. The molecular weights of the complexes were
established using the molecular ion peaks observed in the corre-
sponding mass spectra. In the mass spectra [Fig. A3 and Fig. A4
(supplementay material)], the peaks observed at m/z 687.237,
839.466 and 840.507 can be assigned to the molecular ion
(MH)þpeak for 2a, 2b and 3b, respectively. The loss of a Cp ring and/
or a water molecule (Fig. A3 and Fig. A4 in the supplementary
material) is a general feature of the Cu (II) complex (3a); the Co (II)
complexes (4a and 4b) have a characteristic peak at m/z 626.414,
628.454 and 840.673 (Fig. A5).
In a trial, the isolated solid complexes of Ni(II), Cu(II) and Co(II)
ions with the vic-dioxime ligand were subjected to elemental
analyses (C, H and N), FT-IR, UVevis and MS to identify their
tentative formula and thus elucidate their molecular structures. In
addition to these techniques, the 1H and 13C NMR spectra of the 2a
and 2b compounds are reported. The results of elemental analyses
are agree with those required by the proposed formula. The
complexes are insoluble in water and most organic solvents and
soluble in DMF and DMSO solvents. The FT-IR spectra of the
complexes are compared with the free ligand in order to determine
the coordination sites that may be involved in chelation. In
comparison, the nC¼N stretching vibration of the azomethine is
found in the free ligand at about 1650 cmꢀ1 for the ligands. This
band is shifted to lower wavenumbers in the complexes, which
indicates the participation of the azomethine nitrogen in coordi-
nation (MeN) and is supported by a decrease in the NeO band by
50e60 cmꢀ1 [29]. The FT-IR spectra of complexes display a weak
deformation band at 1726e1732 cmꢀ1, which is indicative of the
intramolecular hydrogen-bonded bending vibrations (OeH.O)
associated with the square-planar and octahedral vic-dioxime
complexes [30]. The FT-IR spectra of the Co(II) complexes show
broad bands at about 3400 cmꢀ1, attributed to the eOH stretching
vibration of water molecules participating in the coordination
sphere [31]. The electronic spectra of all the complexes were
recorded in DMSO solution (Fig. 2). The band appearing at about
264 nm is attributed to
p/p* transitions [22]. The band around
310 nm can be assigned to the n/
[23]. In the spectra of the 2a and 2b compounds, two bands at about
p
* transitions of the eC¼N group
2.3. Electrochemical studies
The electrochemical properties of the novel vic-dioxime ligands
(1a, 1b) and their metal complexes (2a-4a, 2b-4b) were investi-
gated by CV. The results were compared to ferrocene in DMSO as
a solvent in the presence of 0.1 M TBATFB as the supporting elec-
trolyte using a glassy carbon (GC) working electrode, a Pt gauze
counter electrode and an Ag/AgCl reference electrode at ambient
temperature and a 1 ꢁ 10ꢀ3 mol concentration of all compounds
(Table 2). For all CV measurements of the compounds, at different
scan rates in the range of 50e800 mV sꢀ1, the Epc values appear to
depend only slightly on the scan rate. Furthermore, in all cases,
a linear relationship between the cathodic peak current (ipc) and
the square root of the scan rate was observed. This implies that
these electrochemical processes are mainly diffusion-controlled.
These couples were regarded as quasi-reversible on the basis of
the separation between the anodic and cathodic potentials (DEp),
as well as the plots of the peak current versus the square root of the
scan rate showing a deviation from a straight line at higher scan
rates. There was no splitting observed for the ferrocene couple,
even at a scan rate of 10 mV sꢀ1, showing that the two ferrocenyl
Fig. 2. UVeVis spectra of 1.10ꢀ4 M 1a and its metal complexes in DMSO solution.

P. Deveci, U. Arslan / Journal of Organometallic Chemistry 696 (2011) 3756e3763
3759
Table 2
Voltammetric data for the compounds in DMSOeTBATFB.
Compound
Redox couple
Epa (V)
Epc (V)
D
Ep (V)
aE1/2 or Ep (V)b
Ferrocene
1a
Fc/Fcþ
0.559
0.437
0.471
0.356
0.088
0.081
0.515
0.397
ꢀ2.10
0.364
ꢀ2.03
0.407
e
Fc/Fcþ
Ox/Oxꢀ
Fc/Fcþ
1b
2a
0.402
0.476
0.325
0.337
0.077
0.139
Ox/Oxꢀ
Fc/Fcþ
Ox/Oxꢀ
Ni(II)/Ni(I)
Fc/Fcþ
ꢀ1.40
0.463
e
2b
3a
3b
4a
4b
0.511
0.495
0.483
0.559
0.460
0.415
0.433
0.412
0.449
0.347
0.096
0.062
0.071
0.110
0.113
Ox/Oxꢀ
Ni(II)/Ni(I)
Fc/Fcþ
ꢀ1.39
0.464
ꢀ2.06
0.15
0.448
ꢀ1.84
0.11
0.504
ꢀ2.03
ꢀ1.23
0.404
e
Ox/Oxꢀ
Cu(II)/Cu(I)
Fc/Fcþ
Ox/Oxꢀ
Cu(II)/Cu(I)
Fc/Fcþ
Fig. 4. Cyclic voltammograms of 2a-4a in DMSO containing 0.1 M TBATFB with the
Ox/Oxꢀ
Co(II)/Co(I)
Fc/Fcþ
potential range of 1 to ꢀ2.5 V with a scan rate of 100 mVsꢀ1
.
Ox/Oxꢀ
Co(II)/Co(I)
compound 1b. In all complexes, the first ferrocenyl-centered
oxidations are shifted anodically by 0.010e0.107 and
ꢀ1.51
V
0.040e0.099 V when compared to the parent ligands. The positive
shifts indicate that the ferrocene center is harder to oxidise upon
complexation, as a result of the effect of the positively charged
metal centers [38]. The cyclic voltammogram of 1a in the potential
range of 1 to ꢀ2.5 V with a scan rate of 100 mVsꢀ1 showed the
ferrocene couple at 0.39 V along with an irreversible peak
at ꢀ2.10 V that could be ascribed to oxime-centered reductions
(Fig. 2b) [39]. The other ligand, 1b, behaved similarly, but the two
processes were well-defined. When comparing the reduction
potentials of the oxime-center of these ligands (ꢀ2.10 V for 1a
and ꢀ2.03 V for 1b), it is clear that a phenyl ring facilitates the
Epa (anodic peak potential), Epc (cathodic peak potential).
a
Half-wave (E1/2) or peak (Ep) potentials in DMSO/TBATFB versus Fc/Fcþ couple
correspond approximately with the above data - 0.50 V. Data was acquired by cyclic
voltammetry.
b
E1/2 ¼ (EpaþEpc)/2 for reversible or quasi-reversible processes. Ep indicates the
cathodic peak potential for irreversible reduction processes and the anodic peak
potential for irreversible oxidation processes.
moieties behave independently and are oxidized at the same
potential in all compounds.
Compounds 1a and 1b show an oxidation peak at 0.437 V (1a)
and 0.402 V (1b), and a corresponding reduction peak in the anodic
region (up to þ1 V) (Fig. 2a, Table 2). In all compounds, ferrocenyl-
centered oxidations are shifted catodically by 0.011e0.151 V,
compared to the parent compound ferrocene (E0/ ¼ 0.515 V, in
DMSO). This could be explained by the electron-donating nature of
the ethyl functionality, which makes the ferrocenyl part easier to
oxidize [36,37]. These results also indicate that the cyclic voltam-
metric behavior of compounds 1a and 1b are more or less the same,
addition of electrons to the
p system. Fig. 3 shows the cyclic vol-
tammogram of 2a-4a complexes. The other complexes, 2b-4b,
behaved similarly (Table 2). Apart from the ferrocene couple at
about 0.450 V, the voltammogram displays a reduction at ꢀ1.40 V,
which is characteristic of nickel(II)/nickel(I) reduction [40]. As seen,
4a displayed an irreversible peak at Epc ¼ - 1.23 V. The reduction
wave is assigned to the Co(II)/Co(I) process [41,42]. Compound 3a
shows a reduction peak at 0.15 V and a corresponding oxidation
peak in the anodic region corresponds to the Cu(II)/Cu(I) couple.
[43]. For 3a and 4a, oxime-centered reductions were observed at
approximately ꢀ2.05 V. The absence of a reduction peak of the
where DEp values are 0.081 and 0.077 V for 1a and 1b, respectively,
while a positive shift of 0.033 mV in the E0/ was observed between
compounds 1a and 1b.The replacement of the hydrogen atom in 1a
by the -phenyl group in 1b facilitates the redox process of
Fig. 3. a)Cyclic voltammograms recorded for the oxidation of 1.0 mM Fc (black curve), 1a (light blue curve), 2a (dark blue curve), 3a (green curve), 4a (red curve) at a GC electrode in
DMSO containing 0.1 M TBATFB with the potential range of 0 to þ1 V with a scan rate of 50 mVꢀ1 b) Cyclic voltammograms of 1a and 1b in DMSO containing 0.1 M TBATFB with the
potential range of 1 to ꢀ2.5 V with a scan rate of 100 mVsꢀ1. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of
this article.)

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P. Deveci, U. Arslan / Journal of Organometallic Chemistry 696 (2011) 3756e3763
Table 3
The spectral data suggested a square-planar geometry for the Ni(II)
and Cu(II) complexes and an octahedral geometry for the Co(II)
complexes. The redox behaviour was explored by cyclic voltam-
metry based on the metal-centered reduction processes for all
complexes. Electrochemical studies show that in all compounds,
ferrocenyl-centered oxidations are shifted catodically by
0.011e0.151 V in comparison to the parent compound ferrocene
(E0/ ¼ 0.515 V, in DMSO). The antimicrobial test results indicated
that the complexes have mild antibacterial activity against both
gram negative and gram-positive bacterial species.
Antibacterial activities of 1a-4a and 1b-4b as MICs values (mg/ml).
Compounds
S.aureus
ATCC
29213
S.mutans
RSHM
676
E.faecalis
ATCC
29212
E.coli
ATCC
25922
P.auriginosa
ATCC
27853
Ampicilline
Gentamycin
0,125
0,25
64
32
32
32
32
32
64
1
4
1
4
2
1
128
64
128
128
128
128
64
128
0,25
128
64
128
128
128
128
64
1a
2a
3a
4a
1b
2b
3b
4b
64
32
32
32
32
32
64
64
64
32
32
32
32
32
64
64
4. Experimental
64
128
128
4.1. Chemicals
b
-Ferrocenylethylamine [46e48], anti-chloroglyoxime [49] and
imino group for 2a indicates that, because of the lack of transferable
hydroxylic protons, the reduction potentials of the dianionic
ligands shifted beyond the lower limit of the potential interval
considered in the experimental measurements [44] (Fig. 4).
anti-chlorophenylglyoxime [50] were prepared according to the
procedures reported in the literature. All other chemicals were
purchased from Merck or SigmaeAldrich, and used as supplied.
Silica gel (70e230 mesh) was used for chromatographic separa-
tions. All organic solvents were dried and purified by means of the
usual methods. All the processes were performed in aqueous media
and the preparation of the aqueous solutions was carried out using
2.4. Biological activity
A screening of antibacterial activities with five bacteria [S.aureus
ATCC 29213, S.mutans RSHM 676, E.faecalis ATCC 29212, E.coli ATCC
25922 and P.auriginosa ATCC 27853] was performed and the
minimum inhibitory concentrations (MICs in mg/mL) were deter-
mined (Table 3). MICs were found for 1a-4a and 1b-4b, ranging
ultra-pure water with a resistance of w18.3 M
U cm (Human Power
1þ Scholar purification system).
4.2. Apparatus
from 32 mg/ml to 128 mg/ml. A comparative study of the MICs values
The elemental analyses (C, H and N) were performed using
a LECO-932 CHNSO model analyzer. NMR experiments were per-
formed with a Varian Unity INOVA 500 spectrometer using a 5 mm
ID-PFG probe at 298.15 K. Samples were dissolved in DMSO.
for the ligand, 1a and its complexes (2a-4a) indicates that the free
ligand is less active against gram-positive bacterias (S.aureus ATCC
29213, S.mutans RSHM 676 and E.faecalis ATCC 29212) than the
metal complexes. 1a exhibited antibacterial activity in a 64
concentration, while the antibacterial activity of the complexes was
observed in 32 g/ml MICs value. Cu, Co and Ni metals increased
mg/ml
Chemical shifts were reported in ppm relative to TMS for 1H and 13
C
NMR spectra. 1H NMR, 13C NMR and HMBC NMR spectra were ob-
tained at a base frequency of 125.71 MHz for 13C and 499.95 MHz
for 1H nuclei. The two-dimensional gradient HMBC technique was
measured using standard pulse programs provided by Varian. The
spectra were acquired with 512 increments in the F1 dimension
and 2048 data points in the F2 dimension. The FT-IR spectra of solid
samples were recorded on a PerkineElmer Spectrum 100 FT-IR
spectrometer (Universal/ATR Sampling Accessary). UVeVis
spectra were obtained using Shimadzu UVe1700 visible recording
spectrophotometers. Melting points were determined with an
electrothermal apparatus and were not corrected. MS spectra were
recorded on a Bruker Micro TOF LC-MS spectrometer. All electro-
chemical experiments were performed using a CH Instruments
electrochemical analyzer (Model 600C Series) equipped with a BAS
C3 cell stand. The working electrode was a bare glassy carbon disk
(BAS Model MF-2012) with a geometric area of 0.027 cm2. The
reference electrode was Ag/AgCl/KCl(sat.) and the counter electrode
was a Pt wire.
m
the effect of 1a against gram-positive bacterias. However, 1b shows
high bactericidal activity against gram-positive bacterias (MICs:
32 mg/ml) compared to 3b and 4b (MICs: 64 mg/ml). When exam-
ining the effectiveness of the compounds against the gram-
negative bacteria (Escherichia coli and Pseudomonas aeruginosa),
all compounds were as effective as Ampicilin. In particular, 2a and
3b have lower MIC values (32
mg/ml) than Ampicilin. In our
previous study regarding the vic-dioxime ligand and its complexes
containing aza crown ether moiety [43], we obtained higher and
similar MIC values (64 and 128 lg/mL) when using the complexes
against the same bacteria. But in the case of the vic-dioxime ligand
and complex that contain the piperazine group, the antimicrobial
screening data revealed that the newly synthesized compounds
exhibited mild activity compared to that of the control drugs. From
our observations, we thought that introducing the ferrocenyl unit
into a vic-dioxime ligand might provide interesting biological
properties, like those of the piperazine group [45] and the metal
complexes generally capable of enhancing the activity of biological
compounds. Therefore, we can say the ferrocene moiety is as
effective as the piperazine group. Also, we will synthesize novel
ferrocene moiety compounds, and try our best to discover their
structureeactivity relationships.
4.3. Synthesis
4.3.1. Synthesis of the ligands 1a and 1b
A solution of
b-Ferrocenylethylamine (0.34 g, 1.50 mmol) in
10 mL THF was added to a stirred mixture of anti-chloroglyoxime
(0.18 g, 1.50 mmol) or anti-chlorophenylglyoxime (0.29 g,
1.50 mmol) and triethylamine (0.21 mL, 1.50 mmol) in methanol
(10 mL). The mixture was stirred at room temperature for 2 h and
monitored by TLC using ethyl acetate/n-hexane (3:1). The solvent
was evaporated and the residue was purified by column chroma-
tography on silica gel with ethyl acetate/n-hexane (3:1) to give the
vic-dioxime derivative 1a or 1b.
3. Conclusion
We have described the preparation, characterization and bio-
logical activities of two novel vic-dioxime ligands and the Ni(II),
Cu(II) and Co(II) metal complexes that were substituted peripher-
ally with the ferrocene moiety. The spectroscopic analysis
confirmed the composition and structure of the new compounds.

P. Deveci, U. Arslan / Journal of Organometallic Chemistry 696 (2011) 3756e3763
3761
1a: Yield: 0.28 g (59%) and m.p.: 137 ꢂC. Anal. Calc. for
C14H17N3O2Fe : C, 53.32; H, 5.44; N, 13.33. Found: C, 53.29; H, 5.40;
N, 13.36%. MS (fragments are based on 56Fe, 57Fe and 58Fe): m/z
315.6225 (M)þ, 316.6301 and 317.6185; (Calc. 315.0666, 316.0675
and 317.0654).
(Becton Dickinson, Sparks, MD) with an inoculum of approximately
5.105 colony-forming units (CFU)/mL, according to Clinical and
Laboratory Standards Instıtute (CLSI) guidelines (2009). The in vitro
antibacterial activity of the complexes was evaluated against
standard strains Staphylococcus aureus ATCC (American Type
Culture Collection) 29213, Streptococcus mutans RSHM 676,
Enterococcus faecalis ATCC 29212, E. coli ATCC 25922 and Pseudo-
monas aeruginosa ATCC 27853. The antibacterial activity was per-
formed in MHB (Becton Dickinson, Sparks, MD). The synthesized
complexes were weighed (10.24 mg) and dissolved in DMSO
(10 mL) to prepare the stock solutions. The serial dilution from 256
1b: Yield: 0.39 g (66%) and m.p.: 134 ꢂC. Anal. Calc. for
C20H21N3O2Fe : C, 61.37; H, 5.41; N, 10.74. Found: C, 61.36; H, 5.55;
N, 10.76%. MS (fragments are based on 56Fe, 57Fe and 58Fe): m/z
391.7297 (M)þ, 392.7350 and 393.7401; (Calc. 391.0979, 392.0988
and 393.0967).
4.3.2. Synthesis of the vic-dioxime complexes: 2a-b, 3a-b, 4a-b
A solution of NiCl2. 6H2O (0.059 g, 0.25 mmol), CuCl2. 2H2O
(0.043 g, 0.25 mmol) and CoCl.26H2O (0.059 g, 0.25 mmol) in water
(5 mL) was added to a solution of 1a (0.157 g, 0.50 mmol) or 1b
(0.196 g, 0.50 mmol) in 5 mL methanol at room temperature. A
distinct change in color and a decrease in the pH of the solution
(3.5e4.0) was observed. While stirring at the same temperature,
NaOH (1%) was added to increase the pH to 7. The reaction mixture
was stirred for 30 min at room temperature. The precipitate was
filtered off, washed several times with water, and then dried in
vacuum.
to 0.25 mg/mL was made in a 96-well plate. 100 mL of a bacterial
suspension obtained from a 24-h culture and containing w5.105
colony-forming units (CFU)/mL was added to each well. The plate
was incubated at 35 ꢂC for 24 h. The data were reported as MICs, the
lowest concentration of antibiotic and complexes inhibiting visible
growth after 24 h of incubation at 35 ꢂC. To control the quality of
the method ampicilline (IE Ulugay, Turkey) and Gentamicine (IE
Ulugay, Turkey) were tested as antimicrobial agents. These exper-
iments were carried out in duplicate.
Appendixes
2a: Yield: 0.15 g (87%) and m.p.:>300 ꢂC. Anal. Calc. For
C28H32N6O4Fe2Ni: C, 48.98; H, 4.70; N 12.25. Found: C, 48.92; H,
4.74; N 12.28%. MS (fragments are based on 56Fe and 58Ni): m/z
687.237 (MH)þ; (Calc. 687.0607).
Fig. A1. a) MS spectrum of the 1a; b) Observed isotope distri-
bution patterns of the 1a.
2b: Yield: 0.16 g (76%) and m.p.:>300 ꢂC. Anal. Calc. For
C40H40N6O4Fe2Ni: C, 57.27; H, 4.81; N 10.02. Found: C, 57.22; H,
4.84; N 10.06%. MS (fragments are based on 56Fe and 58Ni): m/z
839.4660 (MH)þ; (Calc. 839.1233).
3a: Yield: 0.12 g (70%) and m.p.: 195 ꢂC. Anal. Calc. for
C28H32N6O4Fe2Cu: C, 48.62; H, 4.67; N, 12.16. Found: C, 48.65; H,
4.62; N, 12.21%. MS (fragments are based on 56Fe and 63Cu): m/z
626.414 (M-(C5H5))þ;(Calc. 626.0080).
3b: Yield: 0.16 g (76%) and m.p.: 195 ꢂC. Anal. Calc. for
C40H40N6O4Fe2Cu: C, 57.20; H, 4.80; N, 10.01. Found: C, 57.25; H,
4.85; N, 10.03%. MS (fragments are based on 54Fe and 63Cu): m/z
840.507 (MH)þ;(Calc. 840.1277).
4a: Yield: 0.12 g (66%) and m.p.: >300 ꢂC. Anal. Calc. for.
C28H36N6O6Fe2Co: C, 46.47; H, 5.02; N, 11.62, Found: C, 46.51; H,
5.04; N, 11.60%. MS (fragment is based 56Fe and 59Co): m/z 628.4540
(Me(C5H5)eH2O)þ;(Calc. 628.0221).
4b: Yield: 0.14 g (64%) and m.p.: >300 ꢂC. Anal. Calc. for.
C40H44N6O8Fe2Co: C, 54.85; H, 5.07; N, 9.60. Found: C, 54.81; H,
5.20; N, 9.60%. MS (fragment is based 56Fe and 59Co): m/z 840.6730
(MH-H2O)þ;(Calc. 840.1211).
Fig. A2. a) MS spectrum of the 1b; b) Observed isotope distri-
bution patterns of the 1b.
4.4. Electrochemical studies
GC electrodes were prepared by polishing them with fine, wet
emery papers with a grain size of 4000 (Buehler, Lake Bluff, IL, USA)
followed by a 0.1 mm and 0.05 mm alumina slurry on a polishing pad
(Buehler, Lake Bluff, IL, USA), in order to achieve mirror-like
appearance. The electrodes were sonicated for 5 min in water and
in a 50:50 (v/v) isopropyl alcohol and acetonitrile (IPA þ MeCN)
solution, purified over activated carbon. Before electrochemical
experiments, the electrodes were dried with an argon gas stream
and the solutions were purged with a pure argon gas (99.999%) for
at least 10 min, and an argon atmosphere was maintained over the
solution during experiments.
4.5. Determination of antibacterial activities
The minimal inhibitory concentrations (MICs) were determined
by broth microdilution methods in MuellereHinton broth (MHB)

3762
P. Deveci, U. Arslan / Journal of Organometallic Chemistry 696 (2011) 3756e3763
Fig. A3. a) MS spectrum of the 2a; b) MS spectrum of the 2b.

P. Deveci, U. Arslan / Journal of Organometallic Chemistry 696 (2011) 3756e3763
3763
Fig. A4. a) MS spectrum of the 3a; b) MS spectrum of the 3b.
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