Selective functionalization of ferrocenyl compounds using a novel solvent free synthetic method for the preparation of bioactive unsymmetrical ferrocenyl derivatives

Article abstract of DOI:10.1002/aoc.4838

A novel solvent free synthetic method has been designed by using rice husk ash (RHA) as solid support for the selective functionalization of ferrocenyl derivatives and described the synthesis of a 1,1′-unsymmetrically bi-functionalized ferrocenyl compound

Full text of DOI:10.1002/aoc.4838

Received: 23 August 2018
DOI: 10.1002/aoc.4838
Revised: 4 January 2019
Accepted: 7 January 2019
F U L L P A P E R
Selective functionalization of ferrocenyl compounds using a
novel solvent free synthetic method for the preparation of
bioactive unsymmetrical ferrocenyl derivatives
Avishek Ghosh1 | Tulasi Barik1 | Smriti Dewangan1 | Paresh Kumar Majhi2 |
Takahiro Sasamori2 | Shaikh M. Mobin3
| Santanab Giri4 | Saurav Chatterjee1
1 Department of Chemistry, National
A novel solvent free synthetic method has been designed by using rice husk
ash (RHA) as solid support for the selective functionalization of ferrocenyl
derivatives and described the synthesis of a 1,1′‐unsymmetrically bi‐
functionalized ferrocenyl compounds for their biological evaluation. Single
crystal X‐ray structural evaluation showed some interesting intra‐molecular
hydrogen bonding interactions across the chains of the ferrocenyl molecule,
while DFT calculation revealed the significance of the orientation between
the two cyclopentadienyl rings for the hydrogen bonding interaction. Redox
and antibacterial properties have been studied to understand the electronic
and biological effect of different hydrazone system and their potential for
future application.
Institute of Technology Rourkela,
Rourkela 769008, India
2 Graduate School of Natural Sciences,
Nagoya City University, Nagoya, Aichi
467‐8501, Japan
3 Schools of Basic Science, Indian Institute
of Technology Indore, MP 452017, India
4 Theoretical Chemistry Laboratory,
Department of Chemistry, National
Institute of Technology Rourkela,
Rourkela 769008, India
Correspondence
Saurav Chatterjee, Department of
Chemistry, National Institute of
Technology Rourkela, Rourkela 769008,
India.
KEYWORDS
antibacterial, ferrocenyl, selective substitution, solvent free
Email: saurav@nitrkl.ac.in
Present Address
Santanab Giri, Department of Applied
Sciences, Haldia Institute of Technology,
ICARE Complex, Haldia‐721657, W.B,
India.
Funding information
Science and Engineering Research Board,
Department of Science and Technology,
India, Grant/Award Number: SB/S1/IC‐
30/2013
1 | INTRODUCTION
improved product synthesis, while solid supported reac-
tions involving organometallic fragments have been
Use of inorganic support in chemical synthesis has
attracted much attention due to their ability to perform
reactions under mild conditions, easy product isolation
procedures and higher yield.[1,2] Solid state, solvent free
reactions using organic substrates are widely used for
rarely studied.[3] During the last decade, functionalization
of ferrocene with biologically active moieties and their
study on different bioactivity have led to the immergence
of a new field of bio‐organometallic chemistry.[4] Investi-
gation on ferrocene substituted tamoxifen and ferrocenyl
Appl Organometal Chem. 2019;e4838.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4838

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GHOSH ET AL.
chloroquine derivatives are among the many examples
where systematic functionalization of ferrocene have
improved the activity of the drug.[4h–k] Replacement of
aromatic groups with ferrocenyl moieties in penicillin
and cephalosporine and introduction of various ferrocene
based chains reportedly enhances the antibacterial
potency of therapeutic drugs.[4l‐r] Moreover, the emer-
gence of bacterial resistance to commercial antibiotics
has compelled us to search for new class of antimicrobial
compounds with different mode of action to curb the
problem of multi‐resistant pathogens. Recently, ferrocene
based organometallic molecular entities have proved
their ability by showing inhibitory activities towards sev-
eral microbes.[4] We have also focused our study on the
biological aspects of various ferrocene based molecular
systems ranging from ferrocenyl hydrazones, hetero‐
bimetallic ferrocenyl chalcones, ferrocene based cluster
compounds, ferrocenyl dithiocarboxylates and multi‐
ferrocenyl compounds and reported their significant
biological properties.[5] Recently, bi‐functionalization of
ferrocene in the form of 1,1′‐unsymmetrically di‐
substituted derivatives (Figure 1, Type C) have shown
remarkable sensor based, biological and catalytic
properties.[5a,6] However, selective synthesis of these
unsymmetrically disubstituted ferrocenyl derivatives has
been a challenge due to the formation of symmetrical
di‐substituted product (Type A) in major amount,
resulting in either very low yield or non formation of
the required unsymmetrical derivative of the type B. As
a result, ferrocenyl compounds containing unsymmetrical
substitution (Type C) are far less known than their sym-
metrical analogue. Nevertheless, we could able to isolate
1,1′‐ unsymmetrically bi‐functionalized ferrocenyl com-
pounds (Type C) involving a two step solution based reac-
tion process,[5a] and observed interesting sensing and
electro‐communication properties, but the overall yield
of the compounds has been significantly less for any prac-
tical application. The low yield has been mainly due to
the non‐selective reaction process resulting in reduced
formation of the unsymmetrical product (Type B). There-
fore, we continued our investigation to find an ideal sys-
tem where one of the cyclopentadienyl (Cp) rings of a
ferrocenyl fragment can be selectively substituted with
respect to the other ring. A range of different bi‐
functionalized unsymmetrical compounds can be pre-
pared once the first substitution is achieved selectively,
followed by an easier second substitution at the pendant
Cp ring. Such selective substitution has been a challenge
for system like diacetyl‐ and dialdehyde ferrocene which
are widely used as precursor for a variety of ferrocene
based functional products.[7] This prompted us to investi-
gate a process involving solid state synthetic method for
the selective substitution of Cp rings in diacetyl and
dialdehyde ferrocene compounds and understand their
potential for the synthesis of bi‐functional molecules.
In our study we have chosen Rice husk ash (RHA) as
solid support due its high silica content, wide availability
and to understand its usage in synthetic reactions. RHA is
obtained when rice husk is burnt during their use as fuel
in the rice mills and left unused.[8] Efforts are going on in
global research to use this RHA in several fronts.[9] To
the best of our knowledge Rice Husk Ash (RHA)
has never been studied extensively for their role to
support/mediate chemical reactions. In this report, we
describe the use of RHA in supported condensation reac-
tions for selective functionalization of diacetyl and
dialdehyde ferrocenyl compounds and report the synthesis
of novel bifuntionalized unsymmetrical ferrocenyl deriva-
tive and their high antibacterial activity. Structural charac-
terization of the two unsymmetrically substituted
ferrocenyl compounds have been carried out and their
hydrogen bonding features and conformational orientations
were investigated. Cyclic voltammetric studies and DFT cal-
culation have also been reported to understand their redox
system, bonding features and future application.
2 | RESULTS AND DISCUSSION
Reaction of 1,1′‐diacetylferrocene (135 mg, 0.5 mmol)
with respective hydrazides (0.5 mmol) in presence of rice
husk ash (RHA, 1gm) as solid support gave selectively
single mono‐functionalized products, 1,1′‐[CH3C(O)(η5‐
C5H4)Fe{(η5‐C5H4)C(CH3)═N‐N(H)C(O)‐R}] {R = C6H5
(1a), C6H4‐OH (1b), CH2CN (2)} in high yield with excep-
tional selectivity (Scheme 1). Table 1 shows the selectivity
for the formation of mono‐ functionalized product with
increasing amount of hydrazide ratio up to 5 equivalents.
FIGURE
1
Type A: Symmetrical substitution, Type B:
Unsymmetrical substitution, Type C: Bi‐functional unsymmetrical
substitution

GHOSH ET AL.
3 of 15
the RHA using BET and FESEM techniques. BET
surface analysis reveals a pore size diameter of around
40 Å (Figure S26) and an average surface area of
126 m2/g. The mesoporous nature of the particles has also
been revealed by the BET adsorption isotherm analysis
(Figure S27). The FESEM image shows the presence of
nanosized particles in the range 30–60 nm with highly
porous surface morphology (Figure S25). The remarkable
surface properties of RHA with high porosity, nanosize
particles and acidic nature of silica may have been
responsible for the selective interaction of the substrate
giving rise to selective functionalization. Compounds 1a
and 1b were isolated and their spectral data was
compared with the previously reported data,[5a] while 2,
as per our knowledge, is a newly synthesized compound
and has been characterized by IR, NMR and Mass spec-
troscopy. Infrared spectrum of 2 shows the presence of
SCHEME 1 Synthesis of 1a, 1b and 2
‐C≡N and keto groups at 2246 cm−1 and 1696 cm−1
,
1668 cm−1 regions respectively, while ‐C═N vibration
1
peak has been observed at 1622 cm−1. H NMR spectral
analysis shows two methyl peaks at δ 2.14 and δ 2.37
and one peak at δ 3.84 corresponding to methylene pro-
ton. Peaks for ferrocenyl protons have been observed
between δ 4.43 – δ 4.79 region while a peak at δ 8.59
has been attributed to NH group present in the molecule.
13C NMR spectral analysis reveals the presence of peaks
at δ 14.35, δ 24.73 and δ 27.69 region corresponding to
methyl and methylene carbon, while cyclopentadienyl
carbon peaks has been found between δ 84.04 ‐ δ 68.62
region. The spectrum also shows peaks in the downfield
region at δ 114.38, δ 151.19, δ 164.64 and δ 201.65 regions
which may corresponds to –C=N, ‐C=O and ‐C≡N
groups respectively. Mass spectral analysis of compound
2 shows the presence of [M + 1]+ peak at m/z 352.8.
In our earlier report, we observed the formation of 1a and
1b in much lower yields along with a major amount of
symmetrically di‐substituted ferrocenyl compound by
solution based method in weakly acidic condition.[5a]
The mono‐functionalized compound of the type A are
the key precursor for the synthesis of 1,1′‐ unsymmetri-
cally bi‐functionalized ferrocenyl compounds (Type C)
which have interesting sensing and electro‐
communication properties.[5a,6] However, the use of rice
husk ash (RHA) as solid support gave highly selective
substitution at one of the cyclopentadienyl ring of the
ferrocenyl system to obtain compounds 1a, 1b and 2. To
understand the selectivity of the reaction obtained under
RHA condition, we investigated the surface properties of
TABLE 1 Selectivity and yields for the formation 1a, 1b and 2
[H2NNC(O)R]
R = C6H5, C6H4OH,
CH2CN
Yields‐Mono‐
functionalized
Product
Yields‐Di‐
functionalized
Product (Type A)
Reaction
condition
[Fe{(η5‐C5H4)(COCH3)}2]
Selectivity
0.5 mmol (135 mg)
0.5 mmol
6 hrs., 50 °C
186 mg (1a)
194 mg (1b)
172 mg (2)
Negligible
Negligible
nil
~99% (1a)
~99% (1b)
~100% (2)
0.5 mmol(135 mg)
0.5 mmol (135 mg)
0.5 mmol (135 mg)
1 mmol
6 hrs., 50 °C
6 hrs., 50 °C
6 hrs., 50 °C
182 mg (1a)
190 mg (1b)
173 mg (2)
Negligible
Negligible
nil
~99%(1a)
~99% (1b)
~100% (2)
1.5 mmol
2 mmol
180 mg (1a)
186 mg (1b)
168 mg (2)
10 mg
12 mg
Negligible
~96% (1a)
~95% (1b)
~98% (2)
177 mg (1a)
185 mg (1b)
166 mg (2)
12 mg
13 mg
Negligible
~95% (1a)
~95% (1b)
~98% (2)
N.B.: The yields of the product have been calculated on the basis of the amount of reactant consumed.

4 of 15
GHOSH ET AL.
FIGURE 2 Molecular structure of 1a. Selected bond lengths (Å)
and bond angles (°): N(1)‐C(13) = 1.297(6), N(1)‐N(2) = 1.390(6),
O(2)‐C(15) = 1.231(12), O(1)‐C(6) = 1.220(7), Fe(1) –
C(1) = 2.051(4), N(1)‐N(2)‐C(15) = 113.66(1), C(13)‐N(1)‐
N(2) = 115.46(0), C(1)‐C(6)‐C(7) = 117.24(1)
FIGURE 4 Molecular structure of 2. Selected bond lengths (Å)
and bond angles (°): N(1)‐C(13) = 1.291(1), N(1)‐N(2) = 1.387(0),
O(2)‐C(15) = 1.238(0), O(1)‐C(6) = 1.216(0), N(3)‐C(17) = 1.141(0),
Fe(1) – C(1) = 2.038(4), N(1)‐N(2)‐C(15) = 117.9(0), C(13)‐N(1)‐
N(2) = 117.65(0), C(1)‐C(6)‐C(7) = 117.12(0), C(16)‐C(17)‐
N(3) = 117.21(0)
Molecular structure of 1a confirms the presence of a
–COCH3 group attached to one of the cyclopentadienyl
ring of the ferrocenyl fragment, while the other ring is
linked to a hydrazone unit via a ‐C═N bond (Figure 2).
The structural analysis confirms a double bond character
of C(13)‐N(1) bond with a bond length of 1.297(6) Å,
while N(1)‐N(2) corresponds to single bond character
(1.390(6) Å). The two ferrocenyl cyclopentadienyl rings
are oriented in eclipsed conformation with a dihedral
angle of 0.6° between the two substitutions at C1 and
C8 position. The plane of the phenyl ring is perpendicular
to the Cp ring in contrast to the earlier structure of the
pyridyl derivative, 1,1′‐[CH3C(O)(η5‐C5H4)Fe{(η5‐C5H4)C
(CH3)═NN(H)C(O)(C5H4N)}].[5a] The C‐O bond length
corresponding to the ketonic group of the hydrazone
chain is slightly longer (C(15)‐O(2) = 1.231(12) Å) than
the ketonic group linked to the other Cp ring (C(6)‐
O(1) = 1.220(7) Å). Packing diagram reveals three inter‐
molecular hydrogen bonding interactions between O2 …
H‐C7, O2 … H‐N2 and O2 … H‐C14 with the formation
of a linear polymeric chain with alternate molecular units
(Figure 3).
Molecular structure of 2 confirms the structural integrity
with the presence of a ferrocenyl moiety attached to an ace-
tyl group at one of the cyclopentadienyl ring and a
hydrazone chain of the type –C (CH)3NN(H)C(O)CH2CN
at the other ring as shown in Figure 4. The hydrazone chain
contains an active methylene group in contrast to aromatic
group present in compound 1a. The molecule shows both
inter‐ and intra‐molecular hydrogen bonding as shown in
Figure 5. The intra‐molecular hydrogen bonding has been
observed between the CH2 proton of the hydrazone chain
and the oxygen atom of the acetyl group attached to the
other Cp ring of the same ferrocenyl moiety. The presence
FIGURE 3 Inter‐molecular Hydrogen‐bonding interactions in 1a

GHOSH ET AL.
5 of 15
FIGURE 5 Hydrogen bonding interactions in 2
of intra‐molecular hydrogen bonding interaction across the
two side chains of the Cp rings may have been responsible
for the formation of a non‐eclipsed type orientation of the
Cp rings with a torsional angle of 59.6°. The staggered
conformational feature of 2 is new in contrast to 1a and
some earlier reported similar type of mono‐functionalized
compounds with eclipsed conformation.[5a] Across the chain
hydrogen bonding interactions has been well established in
some significant ferrocene ‐ peptide conjugates for their
analogy with several biomolecular system. To establish the
basis of the hydrogen bonding interaction across the chains
in compound 2, DFT calculation was carried out, the results
of which has been depicted later.
In another solvent free reaction of 1,1′‐
ferrocenylcarboxyaldehyde with the respective hydrazides
involving Rice husk ash (RHA) as solid support gave
selectively mono‐substituted product, 1,1′‐[CH(O)(η5‐
C5H4)Fe{(η5‐C5H4)C(H) = NN(H)C(O)R}] {R = C6H5
(3a), C6H4‐OH (3b)} in high yields (Scheme 2). Com-
pounds 3a, 3b were characterized using IR, NMR and
mass spectroscopic techniques. Infrared spectra for com-
pounds 3a, 3b show peaks corresponding to C=O and
C=N stretching frequency in the range 1681–1607 cm−1
region. 1H NMR spectra of 3a and 3b reveals the presence
of four triplet (or broad) peaks at δ 4.48–4.89 region cor-
responding to eight substituted ferrocenyl Cp protons
and a multiplet at δ 6.92–8.09 region for phenyl protons
in each of the two compounds. One singlet peak at δ
9.94 region has been observed for both 3a and 3b due to
SCHEME 2 Synthesis of 3a, 3b and 4

6 of 15
GHOSH ET AL.
the presence of aldehyde proton. A singlet peak at down-
field region (δ 11.92) shows the presence of ‐OH proton in
compound 3b. NH protons have also been observed at δ
9.27 and δ 9.55 for compounds 3a and 3b respectively.
Mass spectral analysis of compounds 3a shows the pres-
ence of [M + 1]+ peak at m/z 362.
ferrocenyl dialdehyde and an active methylene substrate
using rice husk ash as support.
Solvent free solid supported reaction of ferrocenyl
dialdehyde with acetophenone 2‐cyanoacetohydrazone
(5) or 1‐(coumarin‐3‐yl)ethylidene 2‐cyanoacetohydrazone
(6) using RHA gave selectively unsymmetrically mono‐
substituted product (7, 8) (Scheme 3). To the best of our
knowledge, this is a first report on the selectivity of
Knoevenagel type condensation on ferrocenyl system. In
comparison, solution based Knoevenagel condensation of
ferrocenyl dialdehyde with 5 or 6 using piperidine gave
di‐substituted product in major amount. Both the com-
pounds, 5 and 6 have been prepared using a modified pro-
cedure involving RHA as solid support and characterized
using IR and NMR spectroscopic technique. The spectra
were matched with that in the previously reported litera-
ture.[10] The unsymmetrically mono‐functionalized com-
pounds, 7 and 8, was also obtained by a solid state one
pot reaction condition using acetophenone or acetyl cou-
marin, 2‐cyanoacetohydrazide, ferrocenyl dialdehyde and
RHA. Characterization of compounds 7 and 8 with IR,
NMR and mass spectroscopic technique confirmed their
structural features. Infrared spectra for both 7 and 8 showed
bands at 2214 cm−1 due to the presence of C≡N group and
at 1730–1663 cm−1 region for the presence of ketonic
groups. 1H NMR spectral analysis for 7 and 8 show methyl
peaks at δ 2.42 and δ 2.43 region respectively and peak
for olefinic proton has been observed at δ 8.24 ‐ δ 8.27
region. Ferrocene based cyclopentadienyl protons have
been observed between δ 4.68 – δ 5.11 region while peaks
at δ 7.32 – δ 8.25 (multiplet) corresponds to aromatic
protons for phenyl and coumarin moieties. A singlet peak
at δ 9.91 and δ 9.89 has been observed for 7 and 8
respectively due to the presence of aldehyde proton and
peaks at δ 9.26 and δ 9.36 shows the presence of ‐NH proton
for compounds 7 and 8 respectively. Mass spectral
analysis of compound 8 shows the presence of [M + 1]+
peak at m/z 494.
Further reaction of 3a with acetophenone 2‐
cyanoacetohydrazone (5) under solvent free condition
using RHA as solid support gave a bi‐functionalized
unsymmetrically substituted compound 4 in substantial
yield as shown in Scheme 2. This shows that the solid
RHA also catalyzes Knoevenagel type condensation reac-
tion between an aldehyde group and active methylene
unit. Effort to undergo a multi‐component reaction in
one pot condition using ferrocenyl dialdehyde, benzoic
hydrazide and 5, also gave compound 4 without the need
for isolation of 3a. Compound 4 was characterized by IR,
NMR and Mass spectrometry. The infrared spectral data
for 4 show bands corresponding to C≡N, ketonic and
C=N units at 2210 cm−1, 1651 cm−1, and 1606 cm−1
regions respectively. 1H NMR spectra reveals the presence
of CH3 protons at δ 2.31 and substituted ferrocenyl Cp
peaks at δ 4.44, δ 4.79, δ 4.94, δ 5.13 regions, while peaks
for phenyl protons have been observed at δ 7.40–8.06
(multiplet) region. Two singlet peaks corresponding to
olefinic protons have been observed at δ 7.76 and δ 8.16
regions and ‐NH protons have also been observed at δ
9.26 and δ 9.78 region. Mass spectral analysis showed
[M + 1]+ peak at m/z 544 region. Formation of com-
pound 4 revealed that RHA can also be used as support
for Knoevenagel condensation. Attempts to prepare 4
using different solution based method were not success-
ful. Therefore, we directed our study on the selectivity
of Knoevenagel based condensation reactions involving
2.1 | Redox properties study
The electrochemical properties of compounds 2, 3a, 3b, 4,
7 and 8 were examined in acetonitrile solution (0.1 M
TBAP) by cyclic voltammetry (CV) and differential
pulse voltammetry. Compound 2, involving a ferrocenyl
moiety and linked to one cyanoacetohydrazide group
exhibited a reversible redox process at +0.66 V (E1/2
)
due to the Fe (II)/Fe (III) redox couple which is slightly
lower than the redox peak observed for compound 1a
(E1/2 = 0.69 V), while the potential value is similar to
that of compound 1b (E1/2 = 0.66 V) (Figure 6).[5a] Both
the compounds 3a and 3b showed the corresponding
SCHEME 3 Synthesis of 7 and 8

GHOSH ET AL.
7 of 15
FIGURE 6 Cyclic voltammograms (—) and differential pulse voltammograms (…) of compounds 2, 3a, 3b, 4, 7 and 8 in Acetonitrile/0.1 M
TBAP at 298 K
TABLE 2 Cyclic voltammetric data
at one of the cyclopentadienyl ring of the ferrocenyl frag-
Epa
(V)
Epc
(V)
E1/2 (V)
(ΔE (mV))
dpv
(V)
ment (Table 2). However, functionalization of a Cp ring
with acetophenone cyanoacetohydrazone in 7 exhibited
a much higher redox couple at +0.845 V, which shows
a better electron withdrawing property of the hydrazone
chain and the presence of a donor‐acceptor type of
system in the molecule. Compound 8 with a coumarin
fragment attached to the hydrazone chain also shows a
redox couple at the oxidative potential of +0.85 V.
However, The potential value of both 7 and 8, are
slightly lower than the redox couple of Fe (II)/Fe (III)
Compounds
Ref.
1a
0.717
0.69
0.695
0.72
0.72
0.72
0.88
0.88
0.89
0.657
0.633
0.633
0.676
0.68
0.69 (60)
0.66 (57)
0.664 (62)
0.698 (44)
0.7 (40)
0.66
0.634
0.642
0.67
0.687
0.65
0.83
0.82
0.83
[5a]
1b
[5a]
2
‐
‐
‐
‐
‐
3a
3b
4
0.65
0.685 (70)
0.845 (70)
0.85 (50)
0.855 (70)
7
0.81
in dialdehyde ferrocene (E1/2
= +0.855 V). The
8
0.83
‐
[10]
bifunctionalized unsymmetrical compound 4, exhibited
a reversible redox process at +0.685 V (E1/2) due to the
Fe (II)/Fe (III) couple which is higher than that in 1
and 2 but lower than 3, 7 and 8 (Table 2). This reveals
that the electron withdrawing behaviour of the
hydrazone chain is lower than that of a cyanovinyl link-
age, which have similar electron withdrawing tendency
as a –CHO group.
Fc (CHO)2
0.82
In acetonitrile at a scan rate of 50 mv s−1. E1/2 (V) = (Epa + Epc)/2,
where Epa and Epc are the anodic and cathodic peak potentials respectively.
ΔEp (mV) = Epa‐Epc
.
Fe (II)/Fe (III) redox couple at higher potential
(E1/2 = +0.7 V) due to the presence of an aldehyde group

8 of 15
GHOSH ET AL.
the orientation with θ = 59.6° is 0.18 eV more stable
than the fully staggered geometry with higher torsional
angle of 144°, but slightly less stable (0.032 eV) than that
for the eclipsed orientation. Solution phase calculation
with dichloromethane and ethanol solvents also showed
similar energy behavior. Calculation using both B3LYP
and M06‐2X functional reveals the presence of intramo-
lecular hydrogen bonding interaction between the
ketonic oxygen and methylene hydrogen group across
the two Cp rings for θ = 59.6° orientation in gas phase
as well as in solution phase. The hydrogen bond dis-
tances, calculated in gas phase is always shorter
(2.04 Å) than that calculated in dichloromethane and
ethanol solvent phases (2.072, 2.089 Å). In contrast, the
orientations with θ = 0°, and 144° does not show –
CH...O=C‐ intramolecular hydrogen bonding interac-
tions across the Cp rings. On the contrary, a different
intramolecular hydrogen bonding interaction between
the NH group of the hydrazone chain and ketonic oxy-
gen of the other chain with a distance of 2.45 Å has been
observed for the eclipsed conformation with θ = 0°. The
hydrogen bonding distances and the energies for differ-
ent orientations have been depicted in Table 3. Among
the two solvents, energy calculation of ethanol solution
in 0°, 59.6° and 144° orientation showed 0.075 eV,
0.082 eV and 0.012 eV more stable than that in dichloro-
methane phase respectively, probably due to the higher
polarity of ethanol which may have increased the hydro-
gen bonding interactions with the solvent molecules
(Table 3).
2.2 | DFT study
DFT calculation was carried out with fully optimized
geometry of compound 2 in gas and solution phase for
different orientation of ferrocenyl system using B3LYP
and M06‐2X functionals. Energy calculation was carried
out with the optimized geometry of three different
orientations of compound 2: One with the geometry of
the X‐ray crystal data having a torsional angle (θ)
between the two Cp rings of 59.6°, another with
eclipsed geometry (torsional angle θ = 0°) and an addi-
tional with the fully staggered geometrical orientation
having a torsional angle (θ) of 144°. The single crystal
structure of compound 2 with non ‐eclipsed conforma-
tion shows intra‐ molecular hydrogen bonding in –
between the two side chains of the same ferrocenyl
moiety. This type of intra‐molecular H‐bonding has
not been observed with analogous compounds, 1a and
1b. This prompted us to look into the details of the basis
of the hydrogen bonding interaction across the side
chains. Hydrogen bonding interactions play a vital role
in several biomolecules and have been observed recently
in some disubstituted ferrocenyl‐peptide molecular
system.[11] These ferrocene based peptide molecule also
shows intra ‐ molecular hydrogen bonding interactions
across the peptide side chain, comparable to that in
biomolecules. In our study, we anticipated that the H‐
bonding interaction across the side chain in compound
2 was due to a specific orientation of the two Cp rings.
To understand the details of the interaction we carried
out energy calculation with the optimized geometry of
three different orientations of compound 2: One with
the geometry of the X‐ray crystal data having a torsional
angle (θ) between the two Cp rings of 59.6°, another
with eclipsed geometry (torsional angle θ = 0°) and an
additional with the geometrical orientation having a
torsional angle (θ) of 144°. Figure 7 depicts the DFT
optimized structure of different orientation having
θ = 0°, 59.6° and 144° respectively. Gas phase calcula-
tion using M06‐2X functional shows that the energy for
Molecular orbital diagram for 2 were generated to
understand the involvement of different moieties and
their possibility for any electronic conjugation within
the hydrazone chain. Molecular orbital calculation for
the three orientations (θ = 0°, 59.6°, 144°) shows that
the Highest occupied molecular orbital (HOMO) of the
ferrocenyl system with θ = 59.6° shows the involvement
of metal d‐orbitals and the hydrazone chain, while the
LUMO is localized on the ketonic group of the pendant
acetyl fragment (Table S1, S2).
FIGURE 7 Optimized structure of 2 with θ = 0°, 59.6° and 144°

GHOSH ET AL.
9 of 15
TABLE 3 Energy calculation of 2
Gas Phase
Calculation
(eV)
Solution Phase Calculation
Intra‐molecular H‐bond
Distance (C‐H … O‐C‐)
Ethanol (eV)
CH2Cl2 (eV)
θ = 0°
−29814.84a,
−29803.21b
−29815.49a
−29803.84b
−29815.41a,
−29803.77b
C‐H … O‐C‐ type intra‐molecular H‐bonding
not observed
b
θ = 59.6°
−29814.88a
−29803.18b
−29815.52a
−29803.82b
−29815.44a
−29803.7366b
2.123 Åa, 2.040 Å (in gas phase)
2.187 Åa, 2.072 Åb (in CH2Cl2)
2.213 Åa, 2.089 Åb (in EtOH)
θ = 144°
−29814.75a,
−29803.00b
−29815.50a,
−29803.72b
−29815.40a
−29803.7367b
C‐H … O‐C‐ type intra‐molecular H‐bonding
not observed
aCalculated using B3LYP functional,
bCalculated using M06‐2X functional.
activity with lower MIC values against all the studied bac-
terial strains. Presence of a cyanovinyl chain with a phe-
nyl substituent, in compound 7, also showed lower MIC
values against B. subtilis, E. coli and P. aeruginosa. Our
earlier reports showed moderate antibacterial activity
with ferrocenyl hydrazone and enone based compounds,
but the inhibitory properties shown by the ferrocenyl
bi‐functionalized compound (4) and cyanovinyl based
compounds (7, 8) are significantly high revealing their
potential as medicinal agent. Significant antibacterial
activity for the reported organometallic compounds could
possibly be due to the presence of functionalized ferro-
cene based fragment which are supposed to play a vital
role in increasing the cell permeability and lipophilicity
of the compounds. Factors like electron delocalization
and blocking of metal binding sites of the enzyme of
microorganism are also responsible for the high inhibi-
tion activity in these compounds.
TABLE 4 Minimum inhibitory concentration (MIC) value in
μg/ml
Compounds B. subtilis E. coli P. aeruginosa V. cholerae
2
NS
3.9
3.9
3.9
1.9
1.9
3.9
3.9
3.9
NS
NS
3.9
‐‐
3a
3b
4
NS
NS
1.9
15.6
7.8
NS
1.9
7
1.9
3.9
1.9
8
15.6
1.9
Vancomycin 31.3
Ampicillin 15.6
31.3
15.6
31.3
7.8
1.9
NS: Inhibitory activity not shown
2.3 | Antibacterial activity
In summary, we have used Rice Husk Ash sup-
ported, solvent‐free synthetic strategy for the selective
functionalization of diacetyl – and dialdehyde‐ ferro-
cene which has been further reacted to obtain 1,1′‐
unsymmetrically bifunctionalized ferrocenyl deriva-
tives. The ferrocene based compounds showed revers-
ible one electron oxidative redox processes in varied
potential range depending upon the chain attached to
the cyclopentadienyl rings of the ferrocene moiety.
Single crystal X‐ray study showed a unique intra‐
molecular hydrogen bonding interaction across the
functionalized Cp rings potentially due to a specific
conformational orientation as supported by DFT calcu-
lation. Some of the functionalized compounds showed
Antibacterial study was carried out for compounds 2, 3a,
3b, 4, 7 and 8 against Gram positive B. subtilis and Gram
negative E. coli, P. aeruginosa, V. cholerae bacterial
strains. All the compounds showed high inhibition activ-
ity against the bacterial strains as shown in Table 4. Com-
pounds 2, 3a and 3b containing a mono‐functionalized
ferrocenyl hydrazone chain shows very similar inhibition
behavior against E. coli, P. aeruginosa, V. cholerae bacte-
rial strains, while no inhibitory response was observed
against B. subtilis. In contrast, compound 4 with bi‐
functionalized chains showed good inhibitory effect
against B. subtilis and P. aeruginosa bacterial strains.
Compound 8 with a coumarin moiety attached to a
ferrocenyl cyanovinyl chain showed high antibacterial

10 of 15
GHOSH ET AL.
high antibacterial activity and can be useful for their
application as potential drug candidate. We are pres-
ently focusing our research on the Donor‐Acceptor
property of the bi‐functionalized molecular system to
understand their influence in biological moieties for
their therapeutic use.
colored compound, 1,1′‐[CH3C(O)(η5‐C5H4)Fe{(η5‐C5H4)
C (CH3)=NN(H)C(O)R}] {R = C6H5 (1a), C6H4‐OH (1b),
‐CH2CN (2)}. (Yields: 1a: 186 mg (96%); 1b: 194 mg
(96%); 2: 172 mg (98%)).
1a: Anal. calcd. (found): C, 64.97 (65.12); H, 5.19
(5.05); N, 7.22 (7.34). IR(ν, cm−1,CH2Cl2): 1666 (vs),
1
1650 (vs, br), 1603 (m), 1581 (m). H NMR (δ, CDCl3):
2.09 (s, 3H, CH3), 2.29 (s, 3H, CH3), 4.33 (t, 2H,
η5‐C5H4), 4.44 (t, 2H, η5‐C5H4), 4.75 (t, 2H, η5‐C5H4),
4.80 (t, 2H, η5‐C5H4), 7.42–7.86 (m, 5H, ‐C6H4). MS
(ESI): m/z 389 (M + 1)+.
3 | EXPERIMENTAL SECTIONS
3.1 | General procedures
1b: Anal. calcd. (found): C, 62.40 (62.58); H, 4.99
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 2 spec-
trometer as CH2Cl2 solution and NMR spectra on a
400 MHz Bruker spectrometer in CDCl3. Elemental analy-
ses were performed on a Vario El Cube analyzer. Mass
spectra were obtained on a SQ‐300 MS instrument operat-
ing in ESI mode. Cyclic voltammetric and differential
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 sol-
ute concentration was ~10−3 M. The scan rate used was
50–200 mV s−1. All electrochemical experiments were car-
ried out under a nitrogen atmosphere and are uncorrected
for junction potentials. TLC plates (20x20 cm, Silica gel
60 F254) were purchased from Merck. [Fe(η5‐
C5H4COCH3)2], [Fe(η5‐C5H4CHO)2], [H2NN(H)C(O)R],
(R = ‐C6H4‐OH, C6H4N‐p, C6H5, C6H4N‐o, CH2CN) were
prepared following reported procedures.[12–14]
(4.86); N, 6.93 (6.84). IR(ν, cm−1,CH2Cl2): 3086 (br),
1
1665 (vs), 1643 (s), 1605 (m), 1552 (s, br). H NMR (δ,
CDCl3): 2.21 (s, 3H, CH3), 2.38 (s, 3H, CH3), 4.45 (t, 2H,
η5‐C5H4), 4.54 (t, 2H, η5‐C5H4), 4.84 (t, 2H, η5‐C5H4),
4.87 (t, 2H, η5‐C5H4), 6.93–7.56 (m, 4H, ‐C6H4), 11.89 (s,
1H, OH). MS (ESI): m/z 405 (M + 1)+.
2: Anal. calcd. (found): C, 58.14 (58.36); H, 4.88 (4.74);
N, 11.97 (12.14). IR(ν, cm−1,CH2Cl2): 2248 (m), 1694 (vs),
1
1668 (vs), 1621 (m), 1455 (m). H NMR (δ, CDCl3): 2.07
(s, 3H, CH3), 2.34 (s, 3H, CH3), 3.80 (s, 2H, CH2), 4.41
(t, 2H, η5‐C5H4), 4.50 (t, 2H, η5‐C5H4), 4.67 (t, 2H,
η5‐C5H4), 4.77 (t, 2H, η5‐C5H4), 8.59 (s, 1H, ‐NH).
13C NMR (δ, CDCl3): 14.35 (‐CH3), 24.73 (‐CH3),
27.69 (‐CH2), 68.62 (η5‐C5H4), 70.78 (η5‐C5H4), 71.78
(η5‐C5H4), 73.40 (η5‐C5H4), 80.19 (η5‐C5H4), 84.04
(η5‐C5H4), 114.38 (‐C=N), 151.19 (‐CO), 164.64 (‐CO),
201.65 (‐CN). MS (ESI): m/z 352.8 (M + 1)+.
3.3 | Synthesis of 1,1′‐[CH(O)(η5‐C5H4)
Fe{(η5‐C5H4)C(H)=NN(H)C(O)R}]
{R = C6H5 (3a), C6H4–OH (3b)}
In a two neck round bottomed flask 1 gm of powdered
Rice Husk Ash (RHA) was taken and dichloromethane
solution of 1,1′‐ ferrocenyl carboxyladehyde (0.5 mmol,
121 mg) and the respective hydrazide (0.5 mmol) was
added. The mixture was evaporated to dryness using vac-
uum to obtain a solid mixture and stirred continuously
for six hours at room temperature. After the reaction,
the solid mixture was extracted in dichloromethane sol-
vent, filtered and dried in vacuum. The residue was then
dissolved in dichloromethane and purified using a short
column chromatography. Rapid elution with 15%
ethylacetate:n‐hexane solvent mixture afforded an orange
colored compound, 1,1′‐[CH(O)(η5‐C5H4)Fe{(η5‐C5H4)
C(H)=NN(H)C(O)R}] {R = C6H5 (3a), C6H4–OH (3b)}.
(Yield: 3a: 162 mg (90%); 3b: 173 mg (92%)).
3.2 | Synthesis of 1,1′‐[CH3C(O)(η5‐C5H4)
Fe{(η5‐C5H4)C(CH3)=NN(H)C(O)R}]
{R = C6H5 (1a), C6H4‐OH (1b), ‐CH2CN (2)}
In a two neck round bottomed flask 1 gm of powdered
Rice Husk Ash (RHA) was taken. Dichloromethane solu-
tion of 1,1′‐diacetylferrocene (0.5 mmol, 135 mg) and
respective hydrazide (0.5 mmol) was added and the mix-
ture was evaporated to dryness using vacuum to obtain
a solid mixture. The reaction mixture was then stirred
continuously at 50 °C for six hours. After the reaction,
the solid mixture was extracted in dichloromethane sol-
vent, filtered and dried in vacuum. The residue was then
dissolved in dichloromethane and purified using a short
column chromatography. Rapid elution with 15%
ethylacetate:n‐hexane solvent mixture afforded an orange
3a: Anal. calcd. (found): C, 63.36 (63.51); H, 4.48 (4.57);
N, 7.78 (7.64). IR(ν, cm−1, CH2Cl2): 1678.5 (s), 1651 (vs),
1608 (s), 1557 (m). 1H NMR (δ, CDCl3): 4.48 (s, 2H,

GHOSH ET AL.
11 of 15
η5‐C5H4), 4.65 (t, 2H, η5‐C5H4), 4.87 (t, 4H, η5‐C5H4), 7.47–
8.09 (m, 5H, ‐C6H4), 9.27 (s, 1H, ‐NH), 9.94 (s, 1H, ‐CHO).
13C NMR (δ, CDCl3): 69.92 (η5‐C5H4), 70.88 (η5‐C5H4),
71.79 (η5‐C5H4), 74.35 (η5‐C5H4), 79.78 (η5‐C5H4), 79.81
(η5‐C5H4), 127.35 (Ar), 128.77 (Ar), 132.04 (Ar), 133.23
(Ar), 148.58 (‐C(H)=), 164.03 (‐C=O), 194.42 (‐C=O). MS
(ESI): m/z 362 (M + 1)+.
3b: Anal. calcd. (found): C, 60.66 (60.79); H, 4.29
(4.16); N, 7.45 (7.52). IR(ν, cm−1,CH2Cl2): 3394 (br),
3100 (br), 1681 (vs), 1656 (vs), 1607 (vs), 1491 (m), 1456
(m). 1H NMR (δ, CDCl3): 4.50 (s, 2H, η5‐C5H4), 4.66
(s, 2H, η5‐C5H4), 4.89 (br, 4H, η5‐C5H4), 6.92–7.52
(m, 4H, ‐C6H4), 9.55 (s, 1H, ‐NH), 9.94 (s, 1H, ‐CHO),
11.92 (s, 1H, ‐OH). 13C NMR (δ, CDCl3): 69.58
(η5‐C5H4), 71.01 (η5‐C5H4), 72.02 (η5‐C5H4), 74.45
(η5‐C5H4), 79.34 (η5‐C5H4), 79.69 (η5‐C5H4), 113.52 (Ar),
118.65 (Ar), 118.99 (Ar), 126.19 (Ar), 134.68 (Ar), 149.53
(Ar), 161.72 (‐C(H)=), 166.29 (‐C=O), 194.61 (‐C=O).
The dried residue was dissolved in dichloromethane and
purification was done using a short column chromatogra-
phy. Elution with 25% ethylacetate:n‐hexane solvent mix-
ture afforded a violet colored compound, 1,1′‐[{(C6H5)
C(CH3)=NN(H)C(O)C(CN)=CH}(η5‐C5H4)Fe(η5‐C5H4)
{CH═NN(H)C(O)C6H5}] (4). (Yield: 103 mg (76%)).
4: Anal. calcd. (found): C, 66.31 (66.47); H, 4.64 (4.57);
N, 12.89 (12.77). IR(ν, cm−1,CH2Cl2): 2210 (m), 1651 (vs),
1606 (m), 1581 (s), 1554 (m). 1H NMR (δ, CDCl3): 2.31 (s,
3H, CH3), 4.44 (s, 2H, η5‐C5H4), 4.79 (s, 2H, η5‐C5H4), 4.94
(s, 2H, η5‐C5H4), 5.13 (s, 2H, η5‐C5H4), 7.40–8.06 (m, 10H,
‐C6H5), 7.76 (s, 1H, ‐CH=), 8.16 (s, 1H, ‐CH=), 9.26
(s, 1H, NH), 9.78 (s, 1H, NH). 13C NMR (δ, CDCl3):
29.71 (‐CH3), 70.29 (η5‐C5H4), 72.11 (η5‐C5H4), 72.60
(η5‐C5H4), 74.85 (η5‐C5H4), 76.14 (η5‐C5H4), 118.02 (Ar),
126.77 (Ar), 127.51 (Ar), 128.40 (Ar), 128.59 (Ar), 130.01
(Ar), 131.78 (Ar). MS (ESI): m/z 544 (M + 1)+.
3.5 | Synthesis of [(CN)CH2C(O)N(H)N=C
(CH3)(Ar)], {Ar = C6H5 (5), C9H5O2 (6)}
3.4 | Synthesis of 1,1′‐[{(C6H5)C
(CH3)=NN(H)C(O)C (CN)=CH}(η5‐C5H4)
Fe(η5‐C5H4){CH═NN(H)C(O)C6H5}] (4)
In a two neck round bottomed flask, acetophenone
(0.5 mmol, 0.06 ml) or 3‐acetyl coumarin (0.5 mmol,
94 mg) and 2‐cyanoacetohydrazide (0.5 mmol, 50 mg)
was added to 1 gm of powdered Rice Husk Ash (RHA).
The mixture was stirred continuously at 50 °C for eight
hours. After the reaction, the solid mixture was extracted
in dichloromethane solvent, filtered and dried in vacuum.
The residue was then dissolved in dichloromethane and
purification was done using column chromatography.
Elution with 25% ethylacetate:n‐hexane solvent mixture
afforded a colorless compound, [(Ar)C (CH3) = NN(H)
C(O)CH2CN] {Ar = C6H5 (5), C9H5O2 (6)}. (Yield: 5:
92 mg (92%); 6: 113 mg (84%)).
(a) Reaction of 3a with [(C6H5)C (CH3)=NN(H)C(O)
CH2CN](5)
Powdered Rice Husk Ash (RHA) (1gm) was taken in a
two neck round bottomed flask and dichloromethane solu-
tion of 3a (0.25 mmol, 90 mg) and 1 N‐phenylethylidene‐2‐
cyanoacetohydrazide (5) (0.25 mmol, 50 mg) was added.
The mixture was evaporated to dryness to obtain a solid
mixture and stirred continuously at 50 °C for eight hours.
After the reaction, the solid mixture was extracted in
dichloromethane solvent, filtered and dried in vacuum.
The residue was then dissolved in dichloromethane and
purification was done using a short column chromatogra-
phy. Elution with 25% ethylacetate:n‐hexane solvent mix-
ture afforded a violet colored compound, 1,1′‐[{(C6H5)C
(CH3)=NN(H)C(O)C(CN)=CH}(η5‐C5H4)Fe(η5‐C5H4)
{CH═NN(H)C(O)C6H5}] (4). (Yield: 113 mg (83%))
5: IR (νCO, cm−1, CH2Cl2): 2222 (m), 1693 (vs), 1640
1
(s), 1632 (m). H NMR (δ, CDCl3): 2.29 (s, CH3, 3H),
3.93(s, CH2, 2H), 7.42–7.73(m, 5H), 9.23 (s, NH, 1H).
6: IR (ν, cm−1,CH2Cl2): 2263 (m), 1727 (s), 1694 (vs),
1684 (s), 1607 (m). 1H NMR (δ, CDCl3): 2.29 (s, 3H,
CH3), 3.83 (s, 2H, ‐CH2‐), 7.33–7.62 (m, 4H, ‐C9H5O2),
8.07 (s, 1H, ‐C9H5O2), 8.81 (s, 1H, NH).
Spectral data of 5 and 6 has been matched with those
(b) One pot three component reaction
previously reported.[10]
Dichloromethane solution of 1,1′‐ ferrocenyl
carboxyladehyde (0.25 mmol, 61 mg), benzoic hydrazide
(0.25 mmol, 34 mg) and 5 (0.25 mmol, 50 mg) was added
to 1 gm of powdered Rice Husk Ash (RHA) in a two neck
round bottomed flask. The mixture was evaporated to
dryness to obtain a solid mixture and stirred initially for
4 hours at room temperature and then at 50 °C for eight
hours. After the reaction, the solid mixture was extracted
in dichloromethane solvent, filtered and dried in vacuum.
3.6 | Synthesis of 1,1′‐[HC(O)(η5‐C5H4)
Fe{(η5‐C5H4)CH=C (CN)C(O)N(H)N=C
(CH3)R] {R = C6H5 (7), C9H5O2 (8)}
(a) One pot method
Acetophenone (0.5 mmol, 0.06 ml) or 3‐acetyl
coumarin (0.5 mmol, 94 mg) and 2‐cyanoacetohydrazide

12 of 15
GHOSH ET AL.
(0.5 mmol, 50 mg) was added to 1 gm of powdered Rice
Husk Ash (RHA) taken in a round bottom flask The mix-
ture was stirred continuously at 50 °C temperature for
eight hours. After the reaction, dichloromethane solution
of 1,1′‐ ferrocenyl carboxaldehyde (0.5 mmol, 121 mg)
was added. The solid mixture was dried and stirred
continuously at room temperature for twelve hours. On
completion of the reaction, the solid mixture was
extracted in dichloromethane solvent, filtered and dried
in vacuum. The residue was dissolved in dichlorometh-
ane and purification was done using a short column chro-
matography. Elution with 25% ethylacetate: n‐hexane
solvent mixture afforded a violet colored compound,
1,1′‐[HC(O)(η5‐C5H4)Fe{(η5‐C5H4)CH=C (CN)C(O)N(H)
N=C(CH3)R] {R = C6H5 (7), C9H5O2 (8)}. (Yields: 7:
174 mg (82%); 8: 180 mg (73%)).
In a two neck round bottomed flask 1 gm of powdered
Rice Husk Ash (RHA) was taken and dichloromethane
solution of 1,1′‐ ferrocenyl carboxaldehyde (0.5 mmol,
121 mg) and 5 or 6 (0.5 mmol) was added. The mixture
was evaporated to dryness to obtain a solid mixture and
stirred continuously at room temperature for twelve
hours. After the reaction, the solid mixture was extracted
in dichloromethane solvent, filtered and dried in vacuum.
The residue was then dissolved in dichloromethane
and purification was done using a short column chroma-
tography. Elution with 25% ethylacetate: n‐hexane
solvent mixture afforded a violet colored compound,
1,1′‐[HC(O)(η5‐C5H4)Fe{(η5‐C5H4)CH=C(CN)C(O)N(H)
N=C(CH3)R], {R = C6H5 (7), C9H5O2 (8)}. (Yield: 7:
183 mg (86%); 8: 192 mg (78%))
7: Anal. calcd. (found): C, 64.96 (65.12); H, 4.50 (4.41);
N, 9.88 (9.97). IR (ν, cm−1,CH2Cl2): 2214 (m), 1682 (vs),
1663(vs), 1589 (s), 1527 (m), 1455 (m). 1H NMR (δ, CDCl3):
(b) Reaction of Ferrocenyl dialdehyde with 5 or 6.
TABLE 5 Crystal data and structure refinement parameters for compounds 1a and 2
1a
2
Empirical formula
Formula weight
Crystal system
Space group
a, Å
C21H20FeN2O2
388.24
C17H17FeN3O2
351.18
Orthorhombic
Pca21
Monoclinic
P21/n
8.6622(9)
9.6048(9)
41.472(4)
90°
8.8762(2)
22.3127(6)
15.3692(5)
90°
b, Å
c, Å
α deg
β deg
900
95.582(2)°
90°
γ deg
90°
V, Å3
3450.5(6)
8
3029.47(15)
8
Z
Dcalcd, Mg m−3
abs coeff, mm−1
F(000)
1.495
1.540
0.892
1.009
1616
1456
Cryst size, mm
θ range, deg
index ranges
0.208 x 0.207 x 0.070
2.892° to 30.482°
0.170 x 0.030 x 0.020
1.825 to 26.000°
−12 < =h < =9, −13 < =k
< =13, −58 < =l < =58
−10 < =h < =10, −27 < =k
< =27, −18 < =l < =18
reflections collected/unique
data/restraints/parameters
goodness‐of‐fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
60946/10004 [R (int) = 0.0337]
10004/471/460
53105/5627 [R (int) = 0.1158]
5627/0/419
1.087
1.080
R1 = 0.0442, wR2 = 0.1127
R1 = 0.0517, wR2 = 0.1253
1.835
R1 = 0.0467, wR2 = 0.0738
R1 = 0.0988, wR2 = 0.0953
0.476
largest diff peak
and hole, eÅ−3
−0.623
−0.478

GHOSH ET AL.
13 of 15
2.42 (s, 3H, CH3), 4.69 (s, 2H, η5‐C5H4), 4.79 (s, 2H,
η5‐C5H4), 4.90 (s, 2H, η5‐C5H4), 5.12 (s, 2H, η5‐C5H4),
7.44–7.89 (m, 4H, ‐C6H5), 8.26 (s, 1H, ‐CH=), 9.26 (br,
1H, NH), 9.91 (s, 1H, ‐CHO). 13C NMR (δ, CDCl3): 13.34
(‐CH3), 71.37 (η5‐C5H4), 72.37 (η5‐C5H4), 72.52 (η5‐C5H4),
74.64 (η5‐C5H4), 74.79 (η5‐C5H4), 80.93 (η5‐C5H4), 126.29
(Ar), 126.86 (Ar), 128.54 (Ar), 130.00 (Ar), 130.36
(‐CH=), 137.33 (‐CH=), 154.33 (‐CN), 154.84 (‐C=O),
192.31 (‐C=O). MS (ESI): m/z 426.9 (M + 1)+.
3.9 | Crystal structure determination for
1a and 2
Single crystal X‐ray structural studies of 1a and 2 were
performed on a CCD Oxford Diffraction XCALIBUR‐S
diffractometer equipped with an Oxford Instruments
low‐temperature attachment. Data were collected at
150(2) K using graphite‐monochromated Mo Kα radiation
(λα = 0.71073 Å). The strategy for the data collection
was evaluated by using the CrysAlisPro CCD software.
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 F 2.[18]
The positions of all the atoms were obtained by
direct methods. All non‐hydrogen atoms were refined
anisotropically. The crystallographic details are summa-
rized in Table 5.
8: Anal. calcd. (found): C, 63.31 (63.47); H, 3.88 (3.72);
N, 8.52 (8.64). IR (ν, cm−1,CH2Cl2): 2214 (m), 1730 (vs),
1
1714 (vs), 1682 (vs), 1607 (s), 1494 (s), 1456 (s). H NMR
(δ, CDCl3): 2.43 (s, 3H, CH3), 4.68 (s, 2H, η5‐C5H4), 4.79
(s, 2H, η5‐C5H4), 4.89 (s, 2H, η5‐C5H4), 5.11 (s, 2H,
η5‐C5H4), 7.32–8.23 (m, 5H, C9H5O2), 8.24 (s, 1H,
‐CH=), 9.36 (s, 1H, NH), 9.89 (s, 1H, ‐CHO). MS (ESI):
m/z 494.11 (M + 1)+.
3.7 | Computational details
Geometry optimization of compound 2 in different con-
formers were carried out by using density functional the-
ory (DFT) at B3LYP and M06‐2X level of theory using
LANL2DZ basis sets.[15,16] In addition to optimization,
energy calculation in gas and solution phase was carried
out at the same level of basis sets. The natural frontier
molecular orbitals (FMO) have been analyzed.
ACKNOWLEDGEMENTS
S.C. is grateful to the Department of Science and Technol-
ogy (SERB), Government of India, for research funding
(No. SB/S1/IC‐30/2013). We are thankful to Soliel Oilex
Pvt Ltd, WB, India, for providing us with Rice Husk
and Rice Hush ash for the reaction purposes.
3.8 | Antibacterial activity
ORCID
Shaikh M. Mobin https://orcid.org/0000-0003-1940-3822
Saurav Chatterjee https://orcid.org/0000-0002-6290-4342
Compounds 2, 3a, 3b, 4, 7 and 8 were screened for their
antibacterial activity in vitro following the protocol
described elsewhere.[17] The antibacterial effect was
assayed against both Gram positive bacteria Bacillus
subtilis and Gram negative bacteria, Escherichia coli and
Pseudomonas aeruginosa and Vibrio cholarae by the agar
well diffusion method.[17] The compound was dissolved
in 2% DMSO at different concentrations ranging from
62.5 to 1.0 μg/ml. Mueller Hinton‐agar (containing 1%
peptone, 0.6% yeast extract, 0.5% beef extract and 0.5%
NaCl, at pH 6.9–7.1) plates were prepared and 0.5 –
McFarland culture (1.5 X 108 cells/ml) of the test organ-
isms were swabbed onto the agar plate. 9 mm wells were
made in the LB agar petri dishes. 100 μl of each of the
compound with decreasing concentrations was added to
separate wells. DMSO was used as the negative control
and Ampicillin and Vancomycin was taken as positive
control. The plates were incubated at 37 °C and observed
for zones of inhibition around each well after 24 hrs. The
MIC, defined as the lowest concentration of the test com-
pound, which inhibits the visible growth, was determined
visually after incubation for 24 hr at 37 °C.
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How to cite this article: Ghosh A, Barik T,
Dewangan S, et al. Selective functionalization of
ferrocenyl compounds using a novel solvent free
synthetic method for the preparation of bioactive
unsymmetrical ferrocenyl derivatives. Appl
Organometal Chem. 2019;e4838. https://doi.org/
10.1002/aoc.4838
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