Synthesis, characterization and antibacterial studies of ferrocenyl and cymantrenyl hydrazone compounds

Article abstract of DOI:10.1016/j.jorganchem.2013.02.020

Cymantrenyl Schiff base compounds [(CO)₃Mn{(η⁵- C₅H₄)C(CH₃)N-N(H)C(O)R}] (4-7) (R = C ₆H₄-OH, C₅H₄N-p, C₆H ₅, C₅H₄

Full text of DOI:10.1016/j.jorganchem.2013.02.020

Journal of Organometallic Chemistry 732 (2013) 122e129
Contents lists available at SciVerse ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthesis, characterization and antibacterial studies of ferrocenyl
and cymantrenyl hydrazone compounds
Vijaylakshmi Tirkeya, Sasmita Mishra a, Hirak R. Dash b, Surajit Das b, Bibhukalyan Prasad Nayak c,
,
Shaikh M. Mobin d, Saurav Chatterjee a
*
a Department of Chemistry, National Institute of Technology Rourkela, Orissa 769008, India
b Department of Life Science, National Institute of Technology Rourkela, Orissa 769008, India
c Department of Biotechnology and Medical Engineering, National Institute of Technology Rourkela, Orissa 769008, India
d Schools of Basic Science, Indian Institute of Technology Indore, MP 452017, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Cymantrenyl Schiff base compounds [(CO)3Mn{(
h
5-C5H4)C(CH3)]NeN(H)C(O)R}] (4e7) (R ¼ C6H4eOH,
Received 22 October 2012
Received in revised form
13 February 2013
C5H4N-p, C6H5, C5H4N-o) have been synthesized by room temperature reaction and their structural
characterization was performed by single crystal X-ray diffraction studies. Room temperature reaction of
mono- and di-acetyl ferrocene with salicyloyl and isonicotinyl hydrazides led to the formation of the
some organometallic Schiff base compounds containing monosubstituted, disubstituted and unsym-
Accepted 14 February 2013
metrically substituted ferrocenyl fragments, [(h h
5-C5H5)Fe{( 5-C5H4)C(CH3)]NeN(H)C(O)eR}] (8, 9), [Fe
Keywords:
Ferrocenyl
Half sandwich
Cymantrenyl
{(
h
5-C5H4)C(CH3)]NN(H)C(O)R}2] (10, 12) (R ¼ C6H4eOH, C5H4N), [{(
h
h
5-C5H4)COCH3}Fe{( 5-C5H4)
C(CH3)]NN(H)C(O)(C5H4N)}] (11) and [Fe{(h h
5-C5H4)C(CH3)]NeN(H)C(O)(C5H4N)}{( 5-C5H4)C(CH3)]
NN(H)C(O)C6H4eOH}] (13) respectively. Antibacterial studies and electrochemical analysis were car-
ried out for some of the compounds. Molecular structure determination was performed for compounds 4,
5, 8 and 9 by single crystal X-ray diffraction technique.
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
number of ferrocene containing compounds display interesting
cytotoxic and DNA cleaving activities [21e27]. A large part of the
The chemistry of hydrazone type Schiff-base compounds has
received intense attention because of their unique coordination and
structural properties and for their various biological applications
related to antitumour, antibacterial, antifungal and other inhibitory
activities [1e6]. Among them, studies of Schiff-base compounds
with organometallic tags are increasingly drawing much interest
due to their distinctive properties and features concerning both
organometallic and coordination chemistry [7e15]. Molecular
compounds containing organometallic tags have been found to be
potential therapeutics against major diseases and can play a vital
role as tracers in immunological analysis based on several analytical
methods like FTIR, electrochemical, atomic absorption techniques
etc [16e19,33e35]. Consequently, the research field of bio-
organometallic chemistry is increasingly drawing much interest
due to the development of a new class of organometallic com-
pounds and their ability to play a leading role in the field of biology
[20]. The use of ferrocenyl derivatives as bioactive molecule has
been established recently and several reports show that a large
research is also concentrated on the synthesis of conjugates of
peptides and peptide nucleic acids with organometallic fragments.
Very recent studies on Schiff base compounds containing organo-
metallic fragments reveal that ferrocenyl Schiff base compounds
have exciting biological properties and are potential compounds for
antitumour, antibacterial, antimalarial and antifungal activities
[26e29]. Recently, some Cp based half sandwich organometallic
fragments have been studied for their various biological properties
ranging from antimalarial, antimicrobial, anticancer, enzyme in-
hibitors and phototoxicity [30e36]. Synthesis of cyrhetrenyl,
[CpRe(CO)3], based Schiff base compounds have been carried out
recently and shows comparable antichagasic properties with their
ferrocenyl analogue [14]. Biologically active compounds of techni-
cium, [(CpR)99mTc(CO)3] and rhenium have been synthesized in
aqueous phase for their probable therapeutic and diagnostic ap-
plications [33,34]. Functionalization of peptides by cymantrene
based organometallic fragment has been reported for their use in
biological imaging applications and IR labelling studies [35]. Meg-
gers et al. described the protein inhibitor property of an organo-
ruthenium analogue of staurosporine, which contains a [CpRu(CO)]
fragment attached to indolocarbazole heterocycle [31].
* Corresponding author. Tel.: þ91 661 2462656; fax: þ91 661 2472926.
E-mail addresses: saurav@nitrkl.ac.in, sauravch@yahoo.com (S. Chatterjee).
0022-328X/$ e see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2013.02.020

V. Tirkey et al. / Journal of Organometallic Chemistry 732 (2013) 122e129
123
In view of their enormous opportunity, we became interested to
synthesize some Schiff base compounds containing [(
5-C5H4R)M]
under stirring condition and the reaction was continued for 3e4 h.
After the reaction, the solution was filtered and the pale yellow
precipitate was washed with cold ethanol and vacuum dried. The
product was purified by preparative TLC in 5% ethanol:n-hexane
solvent mixture. (Yield ¼ 35 mg (92%) (4); 32 mg (88%) (5), 29 mg
(81%) (6); 31 mg (86%) (7)).
h
organometallic tags and investigate their biological and electro-
chemical properties. Our aim was to prepare hydrazone type Schiff
base compounds by the condensation of hydrazide derivative with
appropriate organometallic species especially ferrocenyl and
cymantrenyl derivatives. Some synthetic and biological studies on
mono- and di-ferrocenyl hydrazone compounds have been carried
out recently [7e13,27], but 1,10-unsymmetrically substituted fer-
rocenyl hydrozone compounds are not known. We selected cym-
antrenyl moieties as because these compounds contain metal
carbonyls, which show specific IR signals with intense absorption in
the range 1900e2200 cmꢀ1 and can be used as IR probes in various
biological samples. Moreover, to our knowledge cymantrenyl Schiff
base compounds have been rarely studied and one of the reports
show the synthesis of cymantrenyl-biotine compounds for their
use as tracer molecule [36], whereas cymantrenyl-hydrazone
compounds have been largely unexplored and are yet to be inves-
tigated for their possible antibacterial activities. In this report, we
describe the synthesis and characterization of four new cyman-
trenyl hydrazone Schiff base compounds (4e7) along with mono-
and di-substituted (8e10, 12) ferrocenyl hydrazones compounds.
We have also attempted to synthesize hydrazone derivative con-
taining unsymmetrically 1,10 disubstituted ferrocenyl fragment (11,
13). Compounds 4, 5, 8 and 9 have been characterized structurally
by single crystal X-ray diffraction techniques. Antibacterial activity
and electrochemical properties have been studied for some of the
ferrocenyl and cymantrenyl compounds.
4: Anal. Calcd. (found): C, 53.68 (53.45); H, 3.42 (3.37); N, 7.36
(7.45). IR (
(vs), 1630.4 (s), 1601.5 (m). 1H NMR (
(s, 2H,
5-C5H4), 5.38 (s, 2H, 5-C5H4), 6.90e6.94 (t,1H, C6H4), 7.04e
n
, cmꢀ1, CH2Cl2): 3278.7 (br), 3057.4 (br), 2010 (s), 1923.7
d, CDCl3): 2.15 (s, 3H, CH3), 4.84
h
h
7.06 (d,1H, C6H4), 7.45e7.49 (t,1H, C6H4), 9.01 (br,1H, NH),11.66 (br,
1H, OH). MS (ESI): m/z 381 (M)þ.
5: Anal. Calcd. (found): C, 52.60 (52.78); H, 3.28 (3.21); N, 11.50
(11.62). IR (
1669 (s), 1603 (w). 1H NMR (
5-C5H4), 5.11e5.40 (m, 2H,
2H, C6H4N), 8.95 (br, 1H, NH).
n
, cmꢀ1, CH2Cl2): 3210 (br), 2019 (vs), 1929.8 (vs, br),
d
, CDCl3): 2.09 (s, 3H, CH3), 4.79 (s, 2H,
h
h
5-C5H4), 7.67 (s, 2H, C6H4N), 8.78 (s,
6: IR (n
, cmꢀ1, CH2Cl2): 3213 (br), 2018 (vs), 1926 (vs, br), 1658
(br), 1604 (w). 1H NMR ( , CDCl3): 2.09 (s, 3H, CH3), 4.79 (s, 2H, h5
d -
C5H4), 5.17e5.34 (m, 2H, h
5-C5H4), 7.49e7.84 (m, 5H, C6H5), 8.83 (br,
1H, NH). MS (ESI): m/z 365 (M þ 1)þ.
7: IR (n
, cmꢀ1, CH2Cl2): 3195 (br), 2017 (vs), 1925.5 (vs, br), 1654
(br), 1590 (w). 1H NMR (
C5H4), 5.15e5.36 (m, 2H,
d
, CDCl3): 2.1 (s, 3H, CH3), 4.78 (s, 2H, h5
5-C5H4), 7.47 (s, 1H, C6H4N), 8.17 (s, 1H,
-
h
C6H4N), 8.89 (br, 2H, C6H4N), 9.16 (br, 1H, NH). MS (ESI): m/z 366
(M þ 1)þ.
2.3. Synthesis of [(
{R ¼ C6H4eOH (8), C6H4N-p (9)}
h h
5-C5H5)Fe{( 5-C5H4)C(CH3)]NeN(H)C(O)eR}]
2. Experimental sections
In a two necked round bottomed flask respective hydrazide
(0.1 mmol) was taken and 10 ml of ethanol solvent was added. To
the reaction mixture, 23 mg (0.1 mmol) of monoacetyl ferrocene
and two drops of acetic acid was added at room temperature under
stirring condition. The reaction was continued for 6e12 h under
nitrogen atmosphere and monitored using TLC. After the reaction,
the solution was filtered and the orange precipitate was washed
with cold ethanol and vacuum dried. The product was further pu-
rified by preparative TLC in 5% ethanol:n-hexane solvent mixture.
(Yields: 8: 31 mg (85%); 9: 30 mg (87%)).
2.1. General procedures
All reactions and manipulations were carried out under an inert
atmosphere of dry, pre-purified argon using standard schlenk line
techniques. Solvents were purified, dried and distilled under argon
atmosphere prior to use. Infrared spectra were recorded on a Perkin
Elmer Spectrum RX-I spectrometer as KBr pellet or CH2Cl2 solution
and NMR spectra on a 400 MHz Bruker spectrometer in CDCl3 or
DMSO-d6 solvent. Elemental analyzes were performed on a Vario El
Cube analyzer. Mass spectra were obtained on a SQ-300 MS in-
strument operating in ESI mode. Cyclic voltammetric and differ-
ential pulse voltammetric measurements were carried out using a
CH Instruments model 600D electrochemistry system. A platinum
working electrode, a platinum wire auxiliary electrode and a silver/
silver chloride reference electrode were used in a three-electrode
configuration. The supporting electrolyte was 0.1 M [NEt4]ClO4 and
the solute concentration was w10ꢀ3 M. The scan rate used was
50 mV sꢀ1. All electrochemical experiments were carried out under
a nitrogen atmosphere and are uncorrected for junction potentials.
TLC plates (20 ꢁ 20 cm, Silica gel 60 F254) were purchased from
8: Anal. Calcd. (found): C, 62.98 (63.39); H, 4.97 (4.92); N, 7.73
(7.85). IR (
1607 (s), 1542 (s). 1H NMR (
5H, h
5-C5H5), 4.42 (t, 2H, 5-C5H4), 4.69 (t, 2H,
n
cmꢀ1, KBr): 3446 (br), 2667.7 (m), 2577.7 (m), 1628 (s),
d
, DMSO-d6): 2.23 (s, 3H, CH3) 4.23 (s,
h
h
5-C5H4), 6.94e7.01
(m, 2H, C6H4), 7.39e7.42 (t, 1H, C6H4), 7.95e7.97 (d, 1H, C6H4), 11.16
(s, 1H, NH), 11.84 (br, 1H, OH). MS (ESI): m/z 363 (M þ 1)þ.
9: Anal. Calcd. (found): C, 62.24 (62.68); H, 4.89 (4.81); N, 12.10
(12.26). IR (nCO, cmꢀ1, CH2Cl2): 3412 (br), 3146 (m), 1600 (vs), 1578
(vs). 1H NMR (
4.50 (s, 2H,
d, DMSO-d6): 2.30 (s, 3H, CH3), 4.29 (s, 5H, h
5-C5H5),
h
5-C5H4), 4.78 (s, 2H, 5-C5H4), 7.85 (br, 2H, C5H4N), 8.82
h
(br, 2H, C5H4N), 10.95 (s, 1H, NH). MS (ESI): m/z 348 (M þ 1)þ.
Merck.
[(CO)3Mn(
[(
h
h
5-C5H5)Fe(
h
5-C5H4COCH3)],
[Fe(h
5-C5H4COCH3)2],
eC6H4eOH,
5-C5H4COCH3)], [H2NN(H)C(O)R], (R
¼
2.4. Synthesisof[Fe{(h
5-C5H4)C(CH3)]NeN(H)C(O)C6H4eOH}2](10)
C6H4N-p, C6H5, C6H4N-o) were prepared following reported pro-
cedures [37,38,39].
Ethanol solution of salicyloyl hydrazide (31 mg, 0.2 mmol) was
taken in a two necked flask and 27 mg (0.1 mmol) of 1,10-dicetyl
ferrocene and one drop of HCl was added at room temperature
under stirring condition. The reaction was continued for 3 h and
monitored using TLC. After the reaction, the solution was filtered
and the orange precipitate was washed with cold ethanol and dried
under vacuum. The product was purified by preparative TLC in 20%
ethanol:n-hexane solvent mixture. Yield: 50 mg (92%).
2.2. Synthesis of [(CO)3Mn{(
{R ¼ C6H4eOH (4), C6H4N-p (5), C6H5 (6), C6H4N-o (7)}
h
5-C5H4)C(CH3)]NeN(H)C(O)eR}]
In typical synthetic procedure, respective hydrazide
a
(0.1 mmol) was taken in a two neck round bottomed flask and
ethanol (10 ml) solvent was added. The solution was stirred under
nitrogen atmosphere to obtain a clear solution. To the reaction
mixture 0.1 mmol of monoacetyl cymantrene (25 mg, 0.1 mmol)
and two drops of acetic acid was added at room temperature and
10: Anal. Calcd. (found): C, 62.45 (62.17); H, 4.83 (4.62); N, 10.41
(10.58). IR (
n
, cmꢀ1, KBr): 3284 (m), 3078.3 (br), 1633.5 (vs), 1605.8
(s), 1558.7 (vs). 1H NMR (
d, DMSO-d6): 2.17 (s, 6H, CH3) 4.46 (s, 4H,

124
V. Tirkey et al. / Journal of Organometallic Chemistry 732 (2013) 122e129
h
5-C5H4), 4.77 (s, 4H,
h
5-C5H4), 6.77e6.89 (m, 4H, C6H4), 7.25e7.29
solvent mixture to separate an orange coloured compound [Fe{(h5
C5H4)C(CH3)]NeN(H)C(O)(C5H4N)}2] (12) (yield ¼ 32 mg (62%))
or [{(
5-C5H4)C(CH3)]NeN(H)C(O)eC6H4eOH}Fe{( 5-C5H4)C(CH3)
]NeN(H)C(O)(C5H4N)}] (13) (yield 40 mg (78%)). Some
amounts of unreacted compound and decomposition have also been
observed after the reaction.
-
(t, 2H, C6H4), 7.90e7.92 (d, 2H, C6H4), 11.14 (s, 2H, NH), 11.59 (br, 2H,
OH). MS (ESI): m/z 539 (M þ 1)þ, 521 (M ꢀ OH)þ.
h
h
¼
2.5. Reactionof1,10-[Fe{( 5-C5H4)COCH3}2] with isonicotinyl hydrazide
h
In a two necked flask, 10 ml ethanol was added to 1,10-diac-
etylferrocene (135 mg, 0.5 mmol) and isonicotinyl hydrazide
(62 mg, 0.5 mmol). The solution was stirred under nitrogen at-
mosphere for 15 min and two drops of acetic acid was added. The
reaction was continued for 12 h at room temperature under inert
atmosphere and continuously monitored using TLC. After the
completion of the reaction, the solution was filtered, vacuum dried
and preparative TLC was carried out with n-hexane:ethanol
(75:25v/v) solvent mixture to separate trace amount of reactants
12: Anal. Calcd. (found): C, 61.41 (61.75); H, 4.70 (4.59); N, 16.53
(16.64). IR (
DMSO-d6): 2.29 (s, 6H, CH3), 4.61 (s, 4H,
n d,
, cmꢀ1, KBr): 3420 (vs),1642 (vs),1617,1595. 1H NMR (
h
5-C5H4), 4.81 (s, 4H, h5
-
C5H4), 7.84 (m, 4H, C5H4N), 8.81 (m, 4H, C5H4N). MS (ESI): m/z 509
(M þ 1)þ.
13: Anal. Calcd. (found): C, 61.95 (62.27); H, 4.78 (4.70); N, 13.38
(13.46). IR (
(s), 1599.5 (s), 1564.7 (s), 1549.6 (vs). 1H NMR (
3H, CH3), 2.28 (s, 3H, CH3), 4.43 (s, 2H,
5-C5H4), 4.57 (s, 2H, h5
C5H4), 4.74 (s, 2H,
5-C5H4), 4.79 (s, 2H, 5-C5H4), 6.52e7.82 (m, 8H,
C5H4N, C6H4). MS (ESI): m/z 523 (M)þ.
n
, cmꢀ1, CH2Cl2): 3418 (m), 3274.5 (m), 1658.7 (s), 1642.4
d, DMSO-d6): 2.15 (s,
h
-
and an orange compound [{(h h
5-C5H4)COCH3}Fe{( 5-C5H4)C(CH3)]
h
h
NeN(H)C(O)(C5H4N)}] (11) (125 mg (64%)) in the order of elution.
11: Anal. Calcd. (found): C, 61.69 (61.93); H, 4.92 (4.84); N, 10.79
(10.64). IR (
1636 (s), 1601.5 (s), 1549.7 (vs). 1H NMR (
CH3), 2.32 (s, 3H, CH3), 4.49 (s, 2H,
5-C5H4), 4.62 (s, 2H,
4.77 (s, 2H,
5-C5H4), 4.81 (s, 2H, 5-C5H4), 7.87 (br, 2H, C5H4N), 8.92
n
, cmꢀ1, CH2Cl2): 3450.8 (br), 3221.3 (br), 1659.2 (vs),
2.7. Crystal structure determination for 4, 5, 8 and 9
d
, DMSO-d6): 2.21 (s, 3H,
h
h
5-C5H4),
Single crystal X-ray structural studies of 4, 5, 8 and 9 were
performed on a CCD Oxford Diffraction XCALIBUR-S diffractometer
equipped with an Oxford Instruments low-temperature attach-
h
h
(br, 2H, C5H4N), 10.94 (s, 1H, NH). MS (ESI): m/z 390 (M þ 1)þ.
2.6. Reaction of 11 with hydrazide
ment. Data were collected at 150(2) K using graphite-mono-
ꢀ
chromated Mo K
a
radiation (la ¼ 0.71073 A). The strategy for the
data collection was evaluated by using the CrysAlisPro CCD soft-
ware. The data were collected by the standard phi-omega scan
techniques, and were scaled and reduced using CrysAlisPro RED
software. The structures were solved by direct methods using
SHELXS-97 and refined by full matrix least-squares with SHELXL-
97, refining on F2 [40]. The positions of all the atoms were ob-
tained by direct methods. All non-hydrogen atoms were refined
anisotropically. The remaining hydrogen atoms were placed in
geometrically constrained positions and refined with isotropic
temperature factors, generally 1.2 Ueq of their parent atoms. The
crystallographic details are summarized in Table 1.
Ethanol solution (10 ml) of compound 11 (39 mg, 0.1 mmol) was
taken in a two necked round bottomed flask and an equivalent
amount of the respective hydrazide (0.1 mmol) (isonicotinyl hydra-
zide or salicyloyl hydrazide) and acetic acid (two drops) was added
under stirring and inert atmospheric condition. The solution was
stirred at room temperature and under nitrogen atmosphere for 2 h.
The reaction was continuously monitored using TLC. After the
completion of the reaction, the solution was filtered and the volume
was reduced to minimum amount. Preparative TLC was carried out
with the reaction mixture using n-hexane:ethanol (80:20v/v)
Table 1
Crystal data and structure refinement parameters for compounds 4, 5, 8 and 9.
4
5
8
9
Empirical formula
Formula weight
Crystal system
Space group
C17H13MnN2O5
380.23
Monoclinic
P 21/c
12.2632(6)
10.5915(6)
12.7224(7)
C16H12MnN3O4
365.23
Orthorhombic
P b c a
7.9517(3)
18.8279(6)
21.5734(7)
C19H18 FeN2O2
362.20
Orthorhombic
P b c a
10.8288(5)
12.7875(7)
23.4845(12)
C36H34Fe2N6O3
710.39
Tetragonal
Iꢀ4
ꢀ
a, A
21.4833(4)
ꢀ
b, A
21.4833(4)
6.9735(2)
ꢀ
c, A
a
b
g
deg
deg
deg
90
99.307(5)
90
90
90
90
90
90
90
3252.0(3)
90
90
90
3
ꢀ
V, A
1630.70(15)
3229.84(19)
3218.49(13)
Z
4
8
8
4
Dcalcd, Mg mꢀ3
Abs coeff, mmꢀ1
F(000)
1.549
0.840
776
1.502
0.842
1488
1.480
0.941
1504
1.466
0.948
1472
Cryst size, mm
0.33 ꢁ 0.28 ꢁ 0.23
0.32 ꢁ 0.26 ꢁ 0.23
0.33 ꢁ 0.26 ꢁ 0.21
0.23 ꢁ 0.16 ꢁ 0.13
q
range, deg
3.17e25.00
2.94e24.99
3.01e25.00
3.00e24.98
Index ranges
ꢀ14 < h < 14, ꢀ12 < k < 12,
ꢀ15 < l < 15
ꢀ9 < h < 9, ꢀ20 < k < 22,
ꢀ25 < l < 25
19,145/2820 [R(int) ¼ 0.0496]
ꢀ12 < h < 11, ꢀ15 < k < 15,
ꢀ27 < l < 21
ꢀ25 < h < 25, ꢀ20 < k < 25,
ꢀ8 < l < 8
Reflections collected/
unique
12,573/2869 [R(int) ¼ 0.0305]
22,098/2855 [R(int) ¼ 0.0666]
12,301/2849 [R(int) ¼ 0.0420]
Data/restraints/
parameters
2869/0/231
2820/0/218
2855/0/222
2849/0/216
Goodness-of-fit on F2
1.063
1.051
0.956
1.083
Final R indices [I > 2
R indices (all data)
s
(I)]
R1 ¼ 0.0304, wR2 ¼ 0.0832
R1 ¼ 0.0346, wR2 ¼ 0.0867
0.236
ꢀ0.179
R1 ¼ 0.0387, wR2 ¼ 0.0939
R1 ¼ 0.0478, wR2 ¼ 0.1011
0.319
ꢀ0.381
R1 ¼ 0.0356, wR2 ¼ 0.0787
R1 ¼ 0.0591, wR2 ¼ 0.0849
0.266
ꢀ0.276
R1 ¼ 0.0322, wR2 ¼ 0.0809
R1 ¼ 0.0350, wR2 ¼ 0.0832
0.387
ꢀ0.408
Largest diff. peak and hole,
e Åꢀ3

V. Tirkey et al. / Journal of Organometallic Chemistry 732 (2013) 122e129
125
O
CH3
CH3
N
O
Mn
OC
OC
CO
N
H
EtOH
RT
Y
X
+
Mn
OC
OC
O
CO
NHNH2
4 : Y = C-OH, X = H
5 : Y = CH, X = N
6 : Y = CH, X = H
7 : Y = N, X = CH
X
Y
ꢂ
ꢀ
Fig. 2. ORTEP diagram of 5. Selected bond lengths (A) and bond angles ( ): N(2)e
C(5) ¼ 1.280(3), N(1)eN(2) ¼ 1.391(3), N(1)eC(4) ¼ 1.340(3), O(4)eC(4) ¼ 1.221(3),
O(1)eC(1) ¼ 1.144(4), C(5)eN(2)eN(1) ¼ 116.3(2), C(4)eN(1)eN(2) ¼ 118.3(2).
Scheme 1.
O
2.8. Antibacterial activity
CH3
CH3
N
O
Compounds 4, 5, 6, 8, 9 and 10 were screened for their anti-
bacterial activity in vitro following the protocol described else-
where [41]. The antibacterial effect was assayed against both Gram
positive bacteria viz., Staphylococcus aureus, Bacillus subtilis and
Gram negative bacteria viz., Escherichia coli, Pseudomonas aerugi-
nosa and Klebsiella pneumoniae by the agar well diffusion method
[41]. The compounds were dissolved in DMSO at different con-
Fe
N
H
X
EtOH
RT
Fe
R
O
R
NHNH2
(8) R = OH, X = H
(9) R = H, X = N
centrations ranging from 500 to 15.625 mg/ml. Mueller Hinton-agar
X
(containing 1% peptone, 0.6% yeast extract, 0.5% beef extract and
0.5% NaCl, at pH 6.9e7.1) plates were prepared and 0.5 e McFarland
culture (1.5 ꢁ 108 cells/ml) of the test organisms were swabbed
onto the agar plate. 9 mm wells were made in the LB agar petri
Scheme 2.
dishes. 100 ml of each of the compound with decreasing concen-
compounds (salicyloyl hydrazide, isonicotinyl hydrazide, benzoyl hy-
drazide and nicotinyl hydrazide) (Scheme 1). All the compounds have
been isolated and purified by preparative chromatography and char-
acterized by spectroscopic techniques.
trations was added to separate wells. DMSO was used as the
negative control and Ampicillin was used as positive control. The
plates were incubated at 37 ꢂC and observed for zones of inhibition
around each well after 24 h. The results were compared with the
activity of Ampicillin at identical concentrations. The MIC, defined
as the lowest concentration of the test compound, which inhibits
the visible growth, was determined visually after incubation for
24 h at 37 ꢂC.
Infrared spectral analysis for compounds 4e7 reveals the
presence of terminal metal carbonyl groups in the region 1923e
2019 cmꢀ1 and peaks corresponding to C]O and C]N in the
range 1601.5e1669 cmꢀ1 1H NMR spectra shows the presence of
.
protons corresponding to substituted cyclopentadienyl unit,
methyl group, NH and aromatic ring protons for each of the four
cymantrenyl hydrazone compounds. Compound 4 also shows a
3. Results and discussion
broad peak at
d 11.66 corresponding to eOH proton. Mass spectral
Cymantrenyl based hydrazone compounds, [(CO)3Mn{(
C(CH3)]NeN(H)C(O)eC6H4eOH}] (4), [(CO)3Mn{(
5-C5H4)C(CH3)]
NeN(H)C(O)eC6H4N-p}] (5), [(CO)3Mn{(
5-C5H4)C(CH3)]NeN(H)
C(O)eC6H5}] (6), and [(CO)3Mn{(
5-C5H4)C(CH3)]NeN(H)C(O)e
C6H4N-o}] (7) were synthesized by the room temperature reaction
of [Mn(CO)3{(
5-C5H4)COCH3}] with the appropriate hydrazide
h
5-C5H4)
analysis for 4 shows the characteristic molecular ion peak (Mþ) at
m/z 381 whereas for compounds 6 and 7, ESI-MS peaks are
observed at m/z 365 [(M þ 1)þ] and 366 [(M þ 1)þ] respectively.
Single crystal X-ray diffraction studies have been successfully
carried out for 4 and 5 with the respective single crystals, grown from
dichloromethane:n-hexane solvent mixture at ꢀ10 ꢂC. The
h
h
h
h
ꢂ
ꢀ
Fig. 3. ORTEP diagram of 8. Selected bond lengths (A) and bond angles ( ): N(1)e
N(2) ¼ 1.380(2), N(2)eC(8) ¼ 1.284(3), N(1)eC(7) ¼ 1.340(3), O(2)eC(7) ¼ 1.229(3),
ꢂ
ꢀ
Fig. 1. ORTEP diagram of 4. Selected bond lengths (A) and bond angles ( ): N(1)e
C(9) ¼ 1.273(3), N(1)eN(2) ¼ 1.372(2), N(2)eC(11) ¼ 1.338(3), O(4)eC(11) ¼ 1.227(2),
C(9)eN(1)eN(2) ¼ 116.39(16), C(11)eN(2)eN(1) ¼ 120.80(16).
C(7)eN(1)eN(2)
C(9) ¼ 124.7(2).
¼
119.46(18), O(2)eC(7)eN(1)
¼
122.4(2), N(2)eC(8)e

126
V. Tirkey et al. / Journal of Organometallic Chemistry 732 (2013) 122e129
the corresponding disubstituted hydrazone compound, [Fe{(h5
-
C5H4)C(CH3)]NeN(H)C(O)eC6H4(OH)}2] (10) (Scheme 2). The
above synthesis and purification procedure for compounds 8 and
10 involves slightly modified reaction and work-up conditions from
the previously reported literature on the synthesis of the same
compounds in thermal reaction condition [27,43]. We have been
able to confirm the molecular structure for compound 8 by X-ray
crystallography from a single crystal grown by evaporation tech-
niques with ethanol/diethylether solvent mixture. Infrared spectra
for 8 and 10 shows peaks at 1607, 1628, 1606, 1633 cmꢀ1 corre-
sponding to C]N and C]O groups. Presence of ferrocenyl protons
Fig. 4. ORTEP diagram of 9. Water molecule has been removed for clarity. Selected
have been confirmed by 1H NMR spectral data in the range
d 4.23e
ꢂ
ꢀ
bond lengths (A) and bond angles ( ): N(1)eN(2) ¼ 1.391(3), N(2)eC(3) ¼ 1.355(4),
N(1)eC(1) ¼ 1.291(4), O(1)eC(3) ¼ 1.232(4), C(1)eN(1)eN(2) ¼ 115.5(2), O(1)eC(3)e
N(2) ¼ 124.2(3), N(1)eC(1)eC(2) ¼ 127.1(3).
4.69 for both the compounds and peaks at
d
11.84 (OH),
d
11.16 (NH)
2.16 (CH3)
and 2.23 (CH3) for 8 and 11.58 (OH), 11.14 (NH) and
d
d
d
d
for 10 reveals the presence of other functional protons. The NMR
spectral analysis also reveals the presence of two hydrazone units
attached to each of the ferrocenyl Cp ring in compound 10,
whereas in 8 one of the ferrocenyl Cp ring is linked to a
hydrazone chain. The infrared and 1H NMR spectra of compound
9 were compared with the reported values [28].
molecular structure of compound 4 and 5 confirms the presence of a
cymantrenyl unit linked to the hydrazone chain, [C]NN(H)C(O)eR]
involving a C]N bond (Figs. 1 and 2). In the molecule of 4, the
cyclopentadienyl and phenyl rings are almost coplanar, whereas in
compound 5 the cyclopentadienyl ring and the pyridyl rings are
perpendicular to each other forming a dihedral angle of around 72ꢂ
between the cyclopentadienyl and pyridyl plane. The C]N bond
The molecular structures of 8 and 9 have been confirmed by
single crystal X-ray analysis using crystals grown from ethanol/
diethylether solvent mixture at ꢀ5 ꢂC. Structure of compound 8
shows a ferrocenyl unit in which one of the Cp ring is attached to a
hydrazone chain, [C]NN(H)C(O)C6H4eOH] via C]N linkage
ꢀ
ꢀ
distances for 4 and 5 are 1.279(2) A and 1.280(3) A respectively,
which are comparable to that in ferrocenyl Schiff base compounds,
ꢀ
[(
h
5-C5H5)Fe{(
h
5-C5H4)C(H)]NN(H)C(O)C6H5}] (1.277(4) A) [10]
and [Fe{(h5-C5H4)C(CH3)]NN]C(C5H4N)}2] (1.241 (7)e1.300(7) A)
(Fig. 3). The C]N bond distance is 1.284(3) A which is slightly longer
ꢀ
ꢀ
than that in [(h h
5-C5H5)Fe{( 5-C5H4)C(H)]NN(H)C(O)C6H5}]
ꢀ
[42]. The N1eN2 single bond distance in 4 (1.377(2) A) is shorter
5-C5H5)Fe{(
h
5-C5H4)C(H)]
(1.277(4) A) [10] and comparable to that present in [Fe{(
h
5-C5H4)
ꢀ
ꢀ
than that in 5 (1.391(3) A) and in [(
h
ꢀ
C(CH3)]NN]C(C5H4N)}2] (1.241 (7)e1.300(7) A) [42].
NN(H)C(O)C6H5}] [10]. In both the structures of 4 and 5, the C]O and
NeH bonds are trans to each other.
The molecular structure for 9 reveals the presence of a ferrocenyl
unit linked to an isonicotinyl hydrazone chain [C]NN(H)C(O)C5H4N]
by a Schiff base type C]N linkage (Fig. 4). The NeH and C]O bonds
in the hydrazone fragment are in the opposite direction forming an
E-isomer. The C1eN1 and C3eO1 bonds reveal double bond char-
Monosubstituted ferrocenyl hydrazone compounds, [(
h
h
5-C5H5)
5-C5H5)
Fe{(
Fe{(
h
h
5-C5H4)C(CH3)]NeN(H)C(O)C6H4(OH)}] (8) and [(
5-C5H4)C(CH3)]NeN(H)C(O)(C5H4N)}] (9) have been ob-
tained by a room temperature reaction of an ethanol solution of
salicyloyl hydrazide or isonicotinyl hydrazide with monoacetyl
ferrocene. Both the compounds have been isolated in pure form by
preparative TLC using 80:20 (v/v) n-hexane:ethanol solvent
mixture for characterization and antibacterial studies. Analogous
reaction at room temperature was performed with 1,10-diac-
etylferrocene and two equivalents of salicyloyl hydrazide to obtain
ꢀ
ꢀ
acter with a bond distance of 1.291(4) A and 1.232(4) A respectively.
Unsymmetrically 1,10-disubstituted ferrocenyl compounds have
been of interest due to their multifunctional properties with unique
structural features and tunable electrochemical responses. In the
current study, we have been able to synthesize unsymmetrically
1,10-disubstituted ferrocenyl compounds containing two different
O
CH3
N
O
CH3
N
O
N
H
O
N
H
CH3
X
R
N
Fe
EtOH
RT
Fe
NH NH2
R
Fe
+
X
O
O
R
N
CH3
N
H
CH3
CH3
X
O
X = N, R = H
X = CH, R = OH
11
10: R = OH, X = CH
2
O
O
NH NH2
NH NH2
RT, EtOH
RT, EtOH
N
OH
O
CH3
N
O
CH3
N
N
H
N
H
N
N
Fe
Fe
O
O
OH
N
N
N
H
N
H
CH3
CH3
12
N
13
Scheme 3.

V. Tirkey et al. / Journal of Organometallic Chemistry 732 (2013) 122e129
127
Compounds 11e13 have been characterized by IR and 1H NMR
spectroscopy. Infrared spectra for compounds 11e13 show peaks
corresponding to C]O and C]N stretching frequency in the range
1601e1659 cmꢀ1, 1595e1642 cmꢀ1 and 1600e1659 cmꢀ1 respec-
Table 2
Cyclic voltammetric data for 8, 9, 10 and 13.
Compounds
Epa
Epc
E1/2 (V) (DEp (mV))
8
9
10
13
0.332
0.534
0.656
0.660
0.260
0.465
0.548
0.547
0.296(72)
0.499(69)
0.602 (108)
0.604(113)
tively. 1H NMR spectra for 11 show peaks at
sponding to two different methyl protons,
for disubstituted ferrocenyl Cp protons, 7.87 and
protons and 10.94 for NH proton of the hydrazone unit. Presence of
CH3, disubstituted ferrocenyl and pyridyl protons for compound 12
have been confirmed from their corresponding peaks at 2.29,
4.61e4.81and 7.84e8.81 respectively. Proton NMR spectra for
compound 13 shows two methyl peaks at 2.28 and 2.15 region,
four peaks in the range 4.43e4.79 corresponding to eight ferrocenyl
protons and phenyl and pyridyl protons are observed in the range
d
2.21 and
4.49e4.81 (four peaks)
8.92 for pyridyl
d 2.32 corre-
d
d
d
In DMF at a scan rate of 50 mV sꢀ1. E1/2 (V) ¼ (Epa þ Epc)/2, where Epa and Epc are the
d
anodic and cathodic peak potentials Vs. Ag/AgCl respectively.
DEp (mV) ¼ Epa ꢀ Epc
.
d
d
d
hydrazone units by using simple synthetic methodology involving
selective transformation of one of the Cp substituent. Reaction of
1,10-diacetylferrocene with one equivalent of isonicotinyl hydrazide
d
d
d
results in the formation of [{(h h
5-C5H4)COCH3}Fe{( 5-C5H4)
d
6.52e7.82 as multiplet. ESI mass spectral analysis for 13 reveals the
C(CH3)]NeN(H)C(O)(C5H4N)}] (11) in which one of the Cp ring
of the ferrocenyl moiety is attached to a hydrazone chain while the
other Cp ring remains unchanged with an acetyl group (eCOCH3)
(Scheme 3). To understand its reactivity, we added equivalent
amount of isonicotinyl hydrazide to an ethanol solution of 11 under
inert atmosphere to isolate the symmetrically disubstituted de-
presence of Mþ fragment at 523 m/z region. To our knowledge 1,10-
unsymmetrically substituted ferrocenyl mixed hydrazone com-
pounds are novel and the synthetic method described here can be
used to prepare a varied range of ferrocenyl hydrazone compounds
containing unsymmetrically Cp substituted side chains.
rivative [Fe{(h
5-C5H4)C(CH3)]NeN(H)C(O)(C5H4N)}2] (12). This
reveals that the pendant acetyl group attached to one of the Cp ring
in compound 11 is taking part in the reaction to form Schiff base
type hydrazone linkage. Therefore, we carried out similar reaction
technique to prepare 1,10 unsymmetrically disubstituted ferrocenyl
compounds containing two different hydrazone units. Thus, com-
pound 11 was reacted with equivalent amount of salicyloyl hy-
drazide to obtain a new ferrocene containing mixed hydrazone
3.1. Electrochemical properties
The electrochemical properties of compounds 8, 9, 10 and 13
have been examined in DMF solution (0.1 M TBAP) by cyclic vol-
tammetry. Compounds 8 and 9 showed reversible responses in the
potential range 0.26e0.54 V involving single electron Fe(II)eFe(III)
oxidation when scanned in the positive potential side. The one-
electron nature of these oxidations has been tentatively estab-
lished by comparing its current height with that of the standard
compound [Fe{(
C(CH3)]NeN(H)C(O)eC6H4eOH}] (13) (Scheme 3).
h h
5-C5H4)C(CH3)]NeN(H)C(O)(C5H4N)}{( 5-C5H4)
Fig. 5. Cyclic voltammograms (d) and differential pulse voltammograms (.) of compounds (a) 9, (b) 10 and (c) 13 in DMF/0.1 M TEAP at 298 K. Ferrocene/ferrocenium was used as
the standard.

128
V. Tirkey et al. / Journal of Organometallic Chemistry 732 (2013) 122e129
Table 3
fragments have been synthesized. Methodology has been designed
Minimum inhibitory concentration (MIC) value in mg/ml.
to obtain unsymmetrically substituted ferrocenyl hydrazone com-
pounds. Study of their electrochemical properties by cyclic vol-
tammetric techniques shows responses corresponding to ferrocene-
ferrocenium couple. Reactions were carried out to isolate four
cymantrenyl hydrazone compounds and have been structurally
characterized by single crystal X-ray studies. We explored the
antibacterial activity for some ferrocenyl and cymantrenyl com-
pounds against, B. subtilis, E. coli, S. aureus, K. pneumoniae and P.
aeruginosa and MIC values have been reported. Among all, com-
pounds 6, 9 and 10 were found to have good antibacterial activity
in vitro against the bacterial strains. These ferrocenyl and cyman-
trenyl Schiff base compounds are further suited for complexation
reaction to obtain multimetallic compounds and various modifica-
tion for their application in the field of bioorganometallic chemistry.
We are currently engaged in the synthesis and reactivity of a variety
of Cp based organometallic compounds and exploring their possi-
bility for effective medicinal properties.
Compounds B. subtilis E. coli
S. aureus K. pneumoniae P. aeruginosa
4
5
6
8
9
10
125
250
e
250
125
62.5
250
62.5
125
e
e
125
250
62.5
e
125
e
31.25
250
62.5
e
31.25
15.62
15.62
e
125
e
e
e
e
62.5
62.5
Ampicillin
31.25
15.62
31.25
ferrocene/ferrocenium couple under the same experimental con-
ditions. The one electron oxidation process at the positive potential
for compound 9 shifted towards more positive side as compared to
compound 8. This may be due to the presence of a pyridyl group in
9 which makes the Fe(II)/Fe(III) oxidation more difficult than that in
8. Disubstituted ferrocenyl compounds 10 and 13 showed irre-
versible oxidation steps in the positive potential range 0.547e
0.660 V, which are higher than those for monosubstituted ferro-
cenyl compounds (8, 9). The potential data are listed in Table 2, and
some voltammograms are shown in Fig. 5.
Acknowledgements
S.C. and S.M. are grateful to the Council of Scientific and In-
dustrial Research, India, for research funding. VT is grateful to UGC
for research fellowship under Rajiv Gandhi National Fellowship
scheme. The authors thank Dr. Rupam Dinda, NIT Rourkela for
discussions related to the article. VT, SM and SC also gratefully
acknowledge the use of ESI-Mass spectrophotometer purchased
from the DST-FIST Grant.
3.2. Antibacterial activity
Antibacterial study was carried out for six of the synthesized
compounds, 4, 5, 6, 8, 9 and 10. All of them showed potential in-
hibition activity against the bacterial strains as shown in Table 3.
Compound 10, having two salicyloyl hydrazone chains attached to a
ferrocene unit, showed promising antibacterial activity against
B. subtilis and P. aeruginosa as compared to other compounds
containing only one hydrazone chain linked to either cymantrenyl
or ferrocenyl fragments. Among the cymantrenyl hydrazones,
compound 6 has better MIC against E. coli and P. aeruginosa bac-
terial strain whereas cymantrenyl isonicotinyl hydrazone (5)
showed better result when tested with K. pneumoniae. Ferrocenyl
isonicotinyl hydrazone (9) is more active against B. subtilis and E.
coli compared to the cymantrenyl analogue, whereas the later is
more active in case of K. pneumoniae. Comparison of the inhibition
activity for these ferrocenyl and cymantrenyl compounds with the
reported antimicrobial properties of their organic analogue reveals
increased inhibitory activity for the compounds containing organ-
ometallic fragments [44]. For example, the MIC for the hydrox-
yphenyl benzoylhydrazone, [(OH)C6H4CH]NNHC(O)Ph] has been
found in the range 125e500, much higher than that for the ferro-
cenyl and cymantrenyl analogues [2]. Isonicotinic hydrazide and
their hydrazone derivative, ] [C6H4N(CH3)C(O)C═NNHC(O)C5H4N]
Appendix A. Supplementary material
CCDC 882042, 882043, 882044 and 905674 contain the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Appendix B
http://dx.doi.org/10.1016/j.jorganchem.2013.02.020.
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