Some newly synthesized ferrocene based esters: Characterization, DNA interaction and DFT studies

Article abstract of DOI:10.1016/j.jorganchem.2016.07.027

A series of aromatic/aliphatic ferroceneyl-esters (E1–E10) was synthesized by condensation of 4-ferrocenyl benzoic acid (FB) with various alcohols (A1–A10). Structural elucidation of these esters was carried out by FT-IR,¹HNMR and UV–visible sp

Full text of DOI:10.1016/j.jorganchem.2016.07.027

Accepted Manuscript
Some newly synthesized ferrocene based esters: Characterization, DNA interaction
and DFT studies
Zaib un Nisa, Asghari Gul, Zareen Akhter, Muhammad Arif Nadeem, M. Nawaz Tahir,
Moiz Uddin Ahmed
PII:
S0022-328X(16)30320-5
10.1016/j.jorganchem.2016.07.027
JOM 19578
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 12 May 2016
Revised Date: 28 June 2016
Accepted Date: 29 July 2016
Please cite this article as: Z.u. Nisa, A. Gul, Z. Akhter, M.A. Nadeem, M.N. Tahir, M.U. Ahmed, Some
newly synthesized ferrocene based esters: Characterization, DNA interaction and DFT studies, Journal
of Organometallic Chemistry (2016), doi: 10.1016/j.jorganchem.2016.07.027.
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ACCEPTED MANUSCRIPT
Some newly synthesized ferrocene based esters: Characterization, DNA interaction and DFT
studies
aZaib un Nisa, bAsghari Gul, a*Zareen Akhter, aMuhammad Arif Nadeem, cM. Nawaz Tahir, dMoiz
Uddin Ahmed
aDepartment of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
bDepartment of Physics, COMSATS IIT, Islamabad, Pakistan.
cDepartment of Physics, University of Sargodha, Sargodha, Pakistan.
dDepartment of Computer Science, Allama Iqbal Open University, Islamabad, Pakistan
Graphical Abstract
(a) UV-Vis absorption spectra in Dichloromethane of representative ferrocenyl esters (b) UV-Vis
spectra of 10 µM E4 for DNA Binding Study: (a) 0.00 µM (b) 1.1 µM (c) 2.2 µM (d) 3.3 µM (e)
4.4 µM (f) 5.5µM at room temperature.
*Corresponding author
E-mail: zareenakhter@yahoo.com
1

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Ph. No. +925190642111
Some newly synthesized ferrocene based esters: Characterization, DNA interaction and
DFT studies
aZaib un Nisa, bAsghari Gul, a*Zareen Akhter, aMuhammad Arif Nadeem, cM. Nawaz Tahir, dMoiz
Uddin Ahmed
aDepartment of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
bDepartment of Physics, COMSATS IIT, Islamabad, Pakistan.
cDepartment of Physics, University of Sargodha, Sargodha, Pakistan.
dDepartment of Computer Science, Allama Iqbal Open University, Islamabad, Pakistan
Highlights
•
•
•
Ferrocenyl esters have been synthesized and characterized successfully.
DFT calculations were carried out to support the experimental data.
The interaction of these esters with double stranded chicken blood DNA was studied by cyclic
voltammetry and absorption spectroscopic methods.
2

ACCEPTED MANUSCRIPT
*Corresponding author
E-mail: zareenakhter@yahoo.com
Ph. No. +925190642111
Some newly synthesized ferrocene based esters: Characterization, DNA interaction and DFT
studies
aZaib un Nisa, bAsghari Gul, a*Zareen Akhter, aMuhammad Arif Nadeem, cM. Nawaz Tahir, dMoiz
Uddin Ahmed
aDepartment of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
bDepartment of Physics, COMSATS IIT, Islamabad, Pakistan.
cDepartment of Physics, University of Sargodha, Sargodha, Pakistan.
dDepartment of Computer Science, Allama Iqbal Open University, Islamabad, Pakistan
Synopsis
•
•
•
Synthesis and characterization of aromatic/aliphatic ferrocenyl ester.
Electrochemical study of the products.
UV spectroscopy and CV studies were planned in order to study their interaction with
double stranded chicken blood DNA.
3

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*Corresponding author
E-mail: zareenakhter@yahoo.comPh. No. +925190642111
Some newly synthesized ferrocene based esters: Characterization, DNA interaction and DFT
studies
a
aZaib un Nisa, bAsghari Gul, a*Zareen Akhter Muhammad Arif Nadeem, cM. Nawaz Tahir, dMoiz
Uddin Ahmed
aDepartment of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
bDepartment of Physics, COMSATS IIT, Islamabad, Pakistan.
cDepartment of Physics, University of Sargodha, Sargodha, Pakistan.
dDepartment of Computer Science, Allama Iqbal Open University, Islamabad, Pakistan
Abstract
A series of aromatic/aliphatic ferroceneyl-esters (E1-E10) was synthesized by condensation of 4-
ferrocenyl benzoic acid (FB) with various alcohols (A1-A10). Structural elucidation of these esters
1
was carried out by FT-IR, HNMR and UV-visible spectroscopic studies. Single crystal X-ray
analysis was used to investigate solid state structure of E1, E4 and E8. DFT calculations were
carried out at hybrid B3LYP level of theory using Density Gauss Double-Zeta with polarization
functions full-electron basis sets to support the experimental data. Calculated structural parameters
and FTIR vibrational frequencies of the optimized geometries were congruent to the experimental
data. The interaction of the esters with double stranded chicken blood DNA was studied by cyclic
voltammetry and absorption spectroscopic methods. Negative potential shift in cyclic
voltammetric and the hyperchromic shift in UV-vis spectroscopy suggested external interaction
4

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(groove binding). Interaction of ferrocenyl esters with DNA were found electrostatic in nature.
Free energies of ferrocenyl esters-DNA complexes indicated spontaneity of their binding.
Keywords
Characterization, DFT calculations, Electrochemistry, Ferrocenyl esters, Synthesis, Thermal
behavior
*Corresponding author
E-mail: zareenakhter@yahoo.com,
Ph. No. +925190642111
1.
Introduction
Discovery of bis(cyclopentadienyl) iron(II) has significantly influenced research in the advanced
organometallic chemistry. Diverse coordination number, geometries, bonding modes, thermal
stability, applications in catalysis, organic synthesis, and industry makes ferrocene (Cp2Fe) most
widely studied versatile compound in many research areas. It has also been investigated
extensively for potential biological and medicinal applications from the beginning.[1-6]
In recent years, bio-organometallic chemistry has evolved as a rapidly emerging area which links
classical organometallic chemistry to biology, molecular biotechnology and subsequently, with the
preparation of novel peptide mimetic models and unnatural drugs. The oxidized species of
ferrocene, ferrocenium (Cp2Fe+) was reported to be responsible for the cytotoxic properties on
DNA mediated through its capacity to generate oxygen-free radical species. Presence of the
ferrocenyl moiety enhances activity due to its relatively low reversible redox behavior.[6-11] This
property is responsible for generating reactive oxygenated species under physiological conditions
resulting in increase in anti-cancer activity as well as cell permeability due to its lipophilic
nature.[12] Ferrocene has been recently reported to have antitumor properties due to the metabolic
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formation of ferrocenium ions which induces oxidative damage to DNA. As a result, many
functionalized ferrocenes have been prepared and tested in cancer cells.[7-12]
We report, herein, synthesis, structural characterization (experimental and calculated) of some
newly synthesized ferrocenyl-esters. Different aliphatic and aromatic ferrocenyl esters were
designed to study the effect of the presence of these groups on the DNA binding ability of the
compounds, [7] which was performed using cyclic voltammertry and Uv-visible spectroscopic
techniques.
2.
Material and Methods
Materials and Reagents
2.1
Ferrocene (172.5 °C), hexadecyltrimethylammonium bromide sodium hydroxide (318 °C), N,N-
dicyclohexylcarbodiimide (DCC, 34 °C), 4-N,N-dimethylaminopyridine (DMAP, 110-113 °C), 4-
aminobenzoic acid (187–189 °C), sodium nitrite (271 °C), octadecan-1-ol (170-171 °C),
hexadecan-1-ol (b.p. 150°C to 154), m-cresol (11 °C), decan-1-ol and conc. H2SO4 (10 °C) were
purchased from Fluka, Switzerland and used without further purification. Anhydrous MgSO4 (dec.
1124 °C) and benzoyl chloride were purchased from Panreac, Spain. 1-Napthol (95 to 96 °C),
propan-1-ol (97 to 98 °C), propan-2-ol, silica gel 60-HF254 were obtained from Merck, Germany.
NaHCO3 and conc. HCl were obtained from Riedel-deHaen, Germany. The solvent
dichloromethane purchased from Sigma Aldrich used were purified according to the
standard reported method.
2.2
Synthesis
2.2.1 4-Ferrocenyl benzoic acid (FB)
FB was synthesized following a reported procedure out lined in the scheme 1. [14, 15]
2.2.2
Synthesis of Ferrocenyl Ester Derivatives (E1-E10)
1.306 mmol 4-ferrrocenyl benzoic acid and 1.306 mmol alcohols (A1-A10, scheme 1) were added
to a three- necked round-bottom flask fitted with reflux condenser, magnetic stirrer and inert gas
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inlet/outlet. 50 ml anhydrous CH2Cl2 was added to the flask with constant stirring. After that a
solution containing 0.296 g (1.436 mmol) N,N-dicyclohexylcarbodiimide (DCC) and a catalytic
amount of N,N-dimethylaminopyridine (DMAP) in 10 ml anhydrous CH2Cl2 was added to the
flask under N2 atmosphere. The reaction mixture was stirred for 4 hours at room temperature. The
dicyclohexylurea was filtered off and the solvent was removed under reduced pressure. The
obtained products were purified by passing through a column of silica gel (ethyl acetate: n-
hexanes), and then recrystallized from chloroform/ n-hexane (1:9).
2.2.3 Synthesis of phenyl 4-ferrocenyl benzoate (E1)
The ferrocenyl ester phenyl 4-ferrocenyl benzoate was synthesized and purified by above
mentioned general method using phenol (0.122 g; 1.306 mmol). The product was purified by
passing through a column of silica gel (ethyl acetate: n-hexane = 1:5).
1
2
8
9
5
O
C
2' 1'
O
7
3'
4'
Fe
3
4
6
E1
1
Yield; 54.0%, m.p. 129oC. H NMR (300 MHz, DMSO-d6): δ 8.309 ( 2H, d, J = 8.4 Hz, 2,4),
7.754 ( 2H, d, J = 8.4 Hz, 1,3), 7.488 ( 2H, m, 5,9), 7.347-7.283 ( 3H, m, 6-8), 4.996 { 2H, t, J =
1.8 Hz, 1’4’ (η5-C5H4)}, 4.487 { 2H, t, J = 1.8 Hz, 2’,3’ (η5-C5H4)}, 4.057 { 5H, s, (η5-C5H5)}.
UV/vis (CH2Cl2): λmax 461 (ε=1500), 368 (ε=3000) nm. C23H18FeO2 Calcd: C, 72.251, H, 4.712;
Found; C, 71.39; H, 4.02.
2.2.4 Synthesis of n-propyl 4-ferrocenyl benzoate (E2)
n-Propyl 4-ferrocenyl benzoate was prepared by the procedure described above using (0.078 g;
1.306 mmol) propane-1-ol. Obtained ester was purified by passing through a column of silica gel
(ethyl acetate: n-hexane = 1:6).
1
2
O
C
2'
1'
3'
O C3H7
4'
Fe
3
4
E2
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Yield; 52.0%. 1H NMR (300 MHz, DMSO-d6): δ 8.163 ( 2H, d, J = 8.4 Hz, 2,4), 7.981 ( 2H, d, J =
8.4 Hz, 1,3), 4.736 {2H, t, J = 1.8 Hz, 1’,4’(η5-C5H4)}, 4.413 { 2H, t, J = 1.8 Hz, 2’,3’ (η5-C5H4)},
4.060 {5H, s, (η5-C5H5)}, 4.127 ( 2H, t, J = 7.2 Hz, -OCH2), 1.836 ( 2H, m, -CH2-), 1.069 ( 3H, t,
J = 7.2 Hz, -CH3). UV/vis (CH2Cl2): λmax 455 (ε=2360), 344 (ε=9280) nm. 344. C20H20FeO2
Calcd: C, 68.96, H, 5.747; Found; C, 67.88; H, 4.98.
2.2.5 Synthesis of ethyl 4-ferrocenyl benzoate (E3)
Ethyl 4-ferrocenyl benzoate was synthesized by above mentioned procedure using (0.060 g; 1.306
mmol) ethanol, obtained product was purified by passing through a column of silica gel (ethyl
acetate: n-hexane = 1:5).
1 2
O
C
2'
4'
1'
Fe
O C2H5
3'
E3
3 4
Yield; 53.0%, m.p. 88oC. 1H NMR (300 MHz, DMSO-d6): δ 7.871 ( 2H, d, J = 8.4 Hz, 2,4), 7.669
( 2H, d, J = 8.4 Hz, 1,3), 4.909 { 2H, t, J = 1.8 Hz, 1’,4’(η5-C5H4)}, 4.452 { 2H, t, J = 1.8 Hz,
2’,3’(η5-C5H4)}, 4.034 { 5H, s, (η5-C5H5)}. 4.313 ( 2H, q, J = 7.2 Hz, -OCH2), 1.332 ( 3H, t, J =
7.2 Hz, -CH3). UV/vis (CH2Cl2): λmax 455 (ε=2630), 361 (ε=7890) nm. C19H18FeO2 Calcd: C,
68.26, H, 5.38; Found; C, 67.88; H, 5.08.
2.2.6 Synthesis of 1-naphthyl 4-ferrocenyl benzoate (E4)
1-Naphthyl 4-ferrocenyl benzoate was synthesized by the procedure outlined in scheme 1 by
using (0.18 g; 1.306 mmol) 1-napthol. Ferrocenyl ester obtained was purified by passing through a
column of silica gel (ethyl acetate: n-hexane = 1:5).
10 9
11
8
7
1
2
O
C
2'
1'
O
3'
4'
Fe
6
3 4
5
E4
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Yield; 56.0%, m.p. 181-182oC. 1H NMR (300 MHz, DMSO-d6): δ 8.169 ( 2H, d, J = 8.4 Hz, 2,4),
7.811 ( 2H, d, J = 8.4 Hz, 1,3), 8.070-7.476 ( 7H, m, 5-11), 4.991 { 2H, t, J = 1.8 Hz, 1’,4’(η5-
C5H4)}, 4.507 { 2H, t, J = 1.8 Hz, 2’,3’(η5-C5H4)}, 4.089 { 5H, s, (η5-C5H5)}. UV/vis (CH2Cl2):
λmax 460 (ε=2000), 370 (ε=6550) nm. C27H20FeO2 Calcd: C, 75.0, H, 4.62; Found; C, 73.88; H,
4.08.
2.2.7 Synthesis of methyl 4-ferrocenyl benzoate (E5)
The specie methyl 4-ferrocenyl benzoate was prepared using (90.041 g; 1.306 mmol) methanol by
the above mentioned procedure. Purification of resulting ester was done by column of silica gel
(ethyl acetate: n-hexane = 1:7).
1
2
O
C
1'
2'
O
CH3
3'
4'
Fe
3
4
E5
1
Yield; 55.0%, m.p. 100-101oC. H NMR (300 MHz, DMSO-d6): δ 7.64 ( 2H, d, J = 8 Hz, 2,4),
7.43 ( 2H, d, J = 8 Hz, 1,3), 4.21 { 2H, t, J = 1.8 Hz, 1’,4’(η5-C5H4)}, 4.061 { 2H, t, J = 1.8 Hz,
2’,3’(η5-C5H4)}, 3.79 {5H, s, (η5-C5H5)} 4.13 ( 3H, s, -OCH3). UV/vis (CH2Cl2): λmax 455
(ε=2360), 361 (ε=6910) nm. C18H16FeO2 Calcd: C, 67.5, H, 5.00; Found; C, 66.4; H, 4.88.
2.2.8 Synthesis of n-octadecanyl 4-ferrocenyl benzoate (E6)
The n-octadecanyl 4-ferrocenyl benzoate was synthesized by general procedure described above
using (0.325 g; 1.306 mmol) n-octadecanol. Obtained product was purified by passing through a
column of silica gel (n-hexane).
1
2
O
C
2' 1'
CH2 CH3
17
O
3'
4'
Fe
3 4
E6
Yield; 65.0%, m.p. 66oC. 1H NMR (300 MHz, 13CHCl3): δ 7.970 ( 2H, d, J = 8.4 Hz, 2,4), 7.530 (
2H, d, J = 8.4 Hz, 1,3), 4.726 { 2H, t, J = 1.8 Hz, 1’,4’(η5-C5H4)}, 4.403 { 2H, t, J = 1.8 Hz,
2’,3’(η5-C5H4)}, 4.049 { 5H, s, (η5-C5H5)}, 4.324 ( 2H, t, J = 6.6 Hz, -OCH2-), 1.785 ( 2H, m, -
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CH2-), 1.311-1.269 ( 30H, m, -CH2-), 0.849 ( 3H, t, -CH3). UV/vis (CH2Cl2): λmax 455 (ε=3440),
361(ε=9078) nm. C35H50FeO2 Calcd: C, 75.26, H, 8.96; Found; C, 74.4; H, 8.08.
2.2.9 Synthesis of isopropyl 4-ferrocenyl benzoate (E7)
Isopropyl 4-ferrocenyl benzoate was prepared by using (0.078 g; 1.306 mmol) 2-propanol
following the general procedure mentioned above. Obtained ferrocenyl ester was purified by
passing through a column of silica gel (ethyl acetate: n-hexane = 1:6).
2
1
O
C
2'
1'
H
O
C
CH3
3'
2
4'
Fe
4
3
E7
1
Yield; 57.0%, m.p. 71-73oC. H NMR (300 MHz, DMSO-d6): δ 7.873 ( 2H, d, J = 8.4 Hz, 2,4),
7.667 ( 2H, d, J = 8.4 Hz, 1,3), 4.904 {2H, t, J = 1.8 Hz, 1’,4’ (η5-C5H4)}, 4.450 { 2H, t, J = 1.8
Hz, 2’,3’(η5-C5H4)}, 4.032 { 5H, s, (η5-C5H5)} 4.345 ( 1H, m, -OCH-), 1.329 ( 6H, d, -CH3).
UV/vis (CH2Cl2): λmax 454 (ε=2520), 362 (ε=6360) nm. Calcd: C, 68.96, H, 5.747; Found; C, 67.4;
H, 5.08. C20H20FeO2 Calcd: C, 68.96, H, 5.747; Found; C, 67.4; H, 5.08
2.2.10 Synthesis of (3-methyl)-phenyl 4-ferrocenyl benzoate (E8)
(3-Methyl)-phenyl 4-ferrocenyl benzoate was synthesized by above mentioned general procedure
using m-cresol (0.140 g; 1.306 mmol), the produced ferrocenyl ester was purified by passing
through a column of silica gel (ethyl acetate: n-hexane = 1:7).
1
2
8
5
2' 1'
O
C
7
O
3'
6
4'
Fe
E8
4
3
CH3
1
Yield; 58.0%, m.p. 109-110oC. H NMR (300 MHz, 13CHCl3): δ 8.184 ( 2H, d, J = 8.7 Hz, 2,4),
7.605 ( 2H, d, J = 8.7 Hz, 1,3), 7.284-7.061 ( 4H, m, 5-8), 4.781 { 2H, t, J = 1.8 Hz, 1’,4’(η5-
C5H4)}, 4.452 { 2H, t, J = 1.8 Hz, 2’,3’(η5-C5H4)}, 4.160 { 5H, s, (η5-C5H5)}, 2.420 ( 3H, s, -CH3).
UV/vis (CH2Cl2): λmax 459 (ε=1070), 363 (ε=2893) nm. C20H20FeO2 Calcd: C, 72.72, H, 5.05;
Found; C, 71.4; H, 4.98.
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2.2.11 Synthesis of n-decanyl 4-ferrocenyl benzoate (E9)
n-Decanyl 4-ferrocenyl benzoate was synthesized by above mentioned general method using
(0.248 g; 1.306 mmol) n-decanol. ferrocenyl ester obtained was purified by passing through a
column of silica gel (n-hexane).
1
2
1'
2'
O
C
CH2 CH3
9
O
3'
4'Fe
4
3
E9
Yield; 64.0%. 1H NMR (300 MHz, 13CHCl3): δ 7.898 ( 2H, d, J = 8.4 Hz, 2,4), 7.527 ( 2H, d, J =
8.4 Hz, 1,3), 4.729 { 2H, t, J = 1.8 Hz, 1’,4’(η5-C5H4)}, 4.407 { 2H, t, J = 1.8 Hz, 2’,3’(η5-C5H4)},
4.052 { 5H, s, (η5-C5H5)}, 4.326 ( 2H, t, J = 6.6 Hz, -OCH2-), 1.784 ( 2H, m, -CH2-), 1.279-1.251
( 14H, m, -CH2-), 0.849 ( 3H, t, -CH3). UV/vis (CH2Cl2): λmax 455 (ε=2350), 369 (ε=3990) nm.
C21H34FeO2 Calcd: C, 67.37, H, 9.09; Found; C, 66.92H, 8.99.
2.2.12 Synthesis of n-hexadecanyl 4-ferrocenyl benzoate (E10)
The n-hexadecanyl 4-ferrocenyl benzoate benzoate was prepared by above mentioned procedure
using (0.315 g; 1.306 mmol) n-hexadecanol. Obtained product was purified by passing through a
column of silica gel (n-hexane).
1
2
1'
O
C
2'
CH2 CH3
15
3'
O
4'
Fe
3
4
E10
Yield; 68.0%, m.p. 73oC. 1H NMR (300 MHz, 13CHCl3): δ 7.971 ( 2H, d, J = 8.4 Hz,2,4), 7.529 (
2H, d, J = 8.4 Hz, 1,2), 4.727 { 2H, t, J = 1.8 Hz, 1’,4’(η5-C5H4)}, 4.404 { 2H, t, J = 1.8 Hz, 2’,3’
(η5-C5H4)}, 4.050 { 5H, s, (η5-C5H5)}, 4.325 ( 2H, t, J = 6.6 Hz, -OCH2-), 1.784 ( 2H, m, -CH2-),
1.315-1.270 ( 26H, m, -CH2-), 0.894 ( 3H, t, -CH3). UV/vis (CH2Cl2): λmax 455 (ε=2380), 368
(ε=4920) nm. C33H46FeO2 Calcd: C, 74.70, H, 8.73; Found; C, 72.4; H, 7.98. Calcd: C, 74.71, H,
8.67; Found; C, 72.4; H, 7.98
2.3
Characterization
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1H NMR spectral analysis was carried out using Bruker Avance 300 MHz NMR instrument (in
DMSO-d6). Fourier transform infrared spectra were recorded on a FTIR instrument, Nicolet 6700,
Thermoscientific company, USA using solid state analysis. Melting temperature of the esters was
determined on a melting point apparatus, Mel-Temp., Mitamura Riken Kogyo, Inc., Tokyo, Japan,
using open capillary tubes. Thermal characterization was carried out using Perkin-Elmer
o
instrument TGA7 thermobalane, at a heating rate of 20-25 C/min under N2 atmosphere upto
maximum temperature of 600 oC. Single crystal X-ray studies were performed at 150(2) K on a
Bruker Apex II CCD diffractometer using MoKα radiation (λ= 0.71073Ao). The cyclic
voltammetry studies of representative ferrocene based esters were performed using Eco Chemie
Auto lab. PGSTAT 12 potentiostat/galvanostat instrument with three electrode cells, glassy carbon
(GC, 0.071 cm2), Pt wire (0.1 cm thickness) and saturated calomel electrode (SCE)/ 3 M KCl were
employed as working, counter and reference electrode respectively, using tetrabutylammonium
perchlorate (TBAP) as a supporting electrolyte. The working electrode was polished with
powdered α-alumina on a polishing pad and washed with doubly distilled water prior to each
experiment. Absorption spectra of the esters were recorded on shimadzu 1700 spectrophotometer,
Kyoto Japan. Purity of the product was monitored by TLC using pre-coated kieselgel 60-HF TLC
platter using the eluent system that gave the best separation. Flash column chromatography was
carried out using a forced flow of the indicated solvent on Kieselgel using pre-coated kieselgel 60-
HF (0.02−0.045 mm).
3.
Results and discussion
FB was synthesized following the reported method given in the scheme 1. It was then esterified
with the aromatic and aliphatic alcohols (A1-A10, Scheme 1) producing ferrocenyl esters (E1-
E10). The process was carried out in anhydrous dichloromethane using N,N-
dicyclohexylcarbodiimide (DCC) and catalytic amount of 4-N,N-dimethylaminopyridine (DMAP).
12

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The viscous products obtained were further purified using flash column chromatography. FTIR,
13C and 1H-NMR analyses were carried out in order to confirm the syntheses of Es.
In FTIR spectra a broad band of carboxylic group (–COOH, 3500-2200 cm-1) disappeared with the
appearance of an intense carbonyl (C=O) peak at 1700-1740 cm-1 indicating the formation of ester
linkage.[5,6] Typical Fe-Cp stretching vibration was found in range 470-490 cm-1. The
representative FTIR spectra are given in supporting information (SI). In order to support the
experiental data, IR frequencies were calculated by using hybrid B3LYP with DFT-optimized
DGDZVP basis sets. These frequencies were scaled according to the reported method and are
given in supplementary information.[15]
1H-NMR spectroscopic analysis of FB and ferrocenyl esters was carried out using TMS as an
internal reference to support the FTIR results. Relevant peaks for FB [14] were found in the
1
spectrum. H-NMR spectra of Es were consistent with the proposed structures. Characteristic
signals associated with the proton of ferrocene moiety were present in all spectra in the form of
one upfield singlet 4.01-4.07 ppm and two downfield triplets [13] corresponding to unsubstituted
and substituted cp ring protons respectively. Disappearance of signal because of carboxylic group
(12.95 ppm) and appearance of signals due to aliphatic and aromatic substituents confirmed the
formation of esters. Signals in 13C-NMR spectra of all the synthesized compounds were in
appropriate regions and confirmed the successful synthesis and purity of esters. [5-8] Their
representative NMR spectra are given in SI. Single crystals suitable for X-ray analysis of E1, E4
and E8 were grown by slow evaporation from the solution. The data suggested that the compound
E1 was crystallized in the monoclinic space group P21/c. The Fe1-C bond lengths for η5 (C5H4)
ring of E1 were in the range of 2.030(2) -2.051(2) Å (calc. 2.041-2.63 Å), similar to the η5 (C5H5)
ring, with a range of 2.017(3)-2.051(3) Å (calc. 2.023-2.059 Å). The cyclopentadienyl C-C bond
lengths were in the range of 1.406(3)– 1.432(3) Å (calc. 1.411-1.441 Å) for η5 (C5H4) ring whilst
13

ACCEPTED MANUSCRIPT
for η5 (C5H5) ring, these ranges from 1.371(3)–1.410(4) Å (calc. 1.383-1.421 Å). The
representative bond length and angles are given in table 1.
The cyclopentadienyl rings were deviated slightly from an eclipsed geometry in E1. The alkyl
benzoate chain is attached with the cyclopentadienyl ring in almost linear fashion as evidenced by
the torsion angle of C9-C10-C11-C12, the value of which was 3.7(3)° (calc. 3.9). However,
disposition of terminal phenyl (C6H5) ring, which gave a C17-O2-C18-C23 torsion angle of
126.9(2)° (calc. 127) mean that the phenyl moiety in E1 was significantly out of the benzoate CO2
plane. Analysis of hydrogen bonding in E1 showed only two interactions, involving the un
substituted ring and the ester O=C group as η5-(C5H5) C-H....O=C (2.651 Å, calc. 2.682)
interactions, together with Csp2-H…..π(C5H5) interactions. The molecules were arranged as one
dimensional column along a-axis through π…..π stacking interactions of two phenyl rings in the
ester chain. The compound E4 crystallized in the monoclinic space group P21/n. The Fe1-C bond
lengths for η5 (C5H4) ring of E4 were in the range of 2.025(3)-2.048(2) Å (calc. 2.031-2.049 Å),
similar to the η5 (C5H5) ring, with a range of 2.027(3)-2.044(3) Å (calc. 2.029-2.051 Å), figure 1.
The cyclopentadienyl C-C bond lengths were in the range of 1.399(5)– 1.428(4) Å (calc. 1.40-
1.431 Å) for η5 (C5H4) ring whilst for η5 (C5H5) ring, these ranged from 1.395(4)– 1.416(4) Å
(calc. 1.41-1.45 Å). Unlike E1, the cyclopentadienyl rings were in almost eclipsed geometry in E4.
Similarly, unlike E1, the alkyl benzoate chain attached with the cyclopentadienyl ring was out of
plane as evidenced by the torsion angle of C9-C10-C11-C12, the value of which was 148.1(3)°
(calc. 149.2).
Similarly, disposition of terminal phenyl (C6H5) ring, which gave a C17-O2-C18-C23 torsion
angle of 119.9(3)° (calc. 119.9), meant that the phenyl moiety in E4 was also significantly out of
the benzoate CO2 plane. Analysis of hydrogen bonding in E4 showed only two types of
interactions, involving the un substituted ring and the ester O=C group as η5-(C5H5)C-H....O=C
(2.552 Å) interactions together with C-H…..π interactions. Due to these intermolecular attractions,
14

ACCEPTED MANUSCRIPT
each molecule was linked with neighboring three molecules and arranged in zigzag fashion
forming three dimensional supra-molecular architecture (figure 2).
The compound E8 crystallized in the monoclinic space group P21/n. The Fe1-C bond lengths for
η5 (C5H4) ring of E8 were in the range of 2.018(3) -2.036(2) Å (calc. 2.11-2.04 Å), similar to the
η5 (C5H5) ring, with a range of 2.009(3)-2.035(3) Å (calc. 2.010-2.041 Å). The cyclopentadienyl
C-C bond lengths were in the range of 1.403(4) – 1.423(4) Å (calc. 1.410-1.438 Å) for η5 (C5H4)
ring whilst for η5 (C5H5) ring, these ranges from 1.363(5)– 1.416(6) Å (calc. 1.371-1.422 Å).
Unlike E1, the cyclopentadienyl rings were in almost eclipsed geometry in E8. The alkyl benzoate
chain attached with the cyclopentadienyl ring was slightly out of plane as indicated by the torsion
angle of C6-C10-C11-C12, the value of which was 13.0(4)° (calc. 13.3). However, disposition of
terminal phenyl (C6H5) ring, which gave a C17-O2-C18-C23 torsion angle of 88.1(3)° (calc. 88.7)
means that the phenyl moiety in E8 wass almost at right angle to the benzoate CO2 plane. Analysis
of hydrogen bonding in E8 showed two types of interactions, involving the CH3 substituted on
phenyl ring and the ester O=C group as (Csp3)C-H....O=C (2.692 Å, calc. 2.71 Å) interactions
together with C-H….C-H and C-H…..π interactions between (C6H5) C-H and η5-(C5H5) of
neighboring molecules. The molecules were arranged as one dimensional column along b-axis,
table 2. The geometric parameters of E1, E4 and E8 calculated by using hybrid B3LYP
With DFT-optimized DGDZVP basis set were found in the usual ranges.[15] ] The X-ray data
suggests that the bond angles and bond lengths are comparable with the previous reports on
ferrocene derivatives. For example, Hongwei used FB for the synthesis of one dimensional
coordination polymers and the FB showed similar structural features as E1, E4 and E8 [16].
Similarly, Gandrath synthesized some ferrocene esters and carboxylates, the C-C, Fe-C bond
lengths and bond angles are comparable with their structural data [17]. Recently, Guoxiong
synthesized errocenylphosphonofluoridodithioate derivatves and the data is again in agreement
with the our ferrocene moety [18].
15

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In order to study the reactions, electrostatic potential V(r) maps were calculated which are known
for the identification of the electronic charge distribution around molecular surface and
subsequently to predict sites for the reactions. These maps were calculated by using the same basis
set as for IR frequencies. Attempt was made to predict the site for electrophilic/nucleophillic
attacks. It can be seen that the FB is stable having almost uniform distribution of charge density,
figure 3. However, oxygen and nitrogen atoms are surrounded by a greater negative charge
surface, making these sites potentially more favorable for electrophilic attack (red). On the other
hand the electrostatic potential map calculated for phenol showed positive (blue) mesh around OH
group; however the aromatic ring seems neutral in terms of electron density. Thus distribution of
potential in both esters is in favor of the esterification reaction. [15]
UV-visible spectroscopic technique was used to study the interaction (range 300-600 nm) and the
binding mode of esters with double strand chicken blood DNA. It was found that the esterification
of FB with various alcohols resulted in red shift with respect to the ferrocene due to the electron
withdrawing nature of the ester linkage. [19] When compared to FB the aliphatic Es exhibited blue
shift (hypsochromic effect, E2, E3, E5, E6, E7, E9 and E10) whereas aromatic compounds showed
red shift (bathochromic effect, E1, E4, and E8) which was in accordance with the literature that the
increase in conjugation results in the better overlap of π-orbitals and consequently decreases in the
energy gap.
DNA binding study using UV-Vis spectroscopy between E4-DNA was investigated by studying
interaction between 10 µM E4 and various concentrations (0.0–5.5 µM) of DNA, figure 4. It was
found that there was an increase in absorbance (hyperchromism; figure. 4) with the increase in the
concentration of DNA, based on the expected conformational changes of cyclopentadienyl rings in
E4. [20,21] From literature it is known that NFC (4-nitrophenylferrocene), which is a potential
anticancer drug exhibit similar behavior with DNA. NFC–DNA interactions reduce the face to
face base stacking, causing extension and subsequently uncoiling of the DNA double helical
16

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structure [7,8] or external interaction (groove binding or electrostatic) resulting in hyperchromic
shift.[12,23] Therefore E4 is expected to exhibit groove binding with DNA. Binding constants for
Es-DNA were determined at room temperature employing Benesi-Hildebrand equation.[24]
Different solvent mixture were used to calculate these constants depending upon the solubility of
the products like DMSO/H2O (9:1) mixture for E4, E7 DMF/ H2O (9:1) mixture for E10, E6 and
EtOH/ H2O (9:1) mixture for the remaining Es. The binding energy data for Es was found in range
6.21 × 105 M-1 to 2.48 × 103 M-1, table 3, figure 5 which was in agreement with the literature which
5
-1
showed that the typical range is between 102 -10 M for ferrocenl esters. Negative ꢀG values
found in range -17.74 to −30.27 kJ/mol signified the spontaneity of interaction.
Electrochemical study was carried out to study redox behavior of the reactions. Cyclic
voltammograms and approximately one value of Ipc/Ipa for all esters indicated reversible redox
behavior. The selected CV data of the Es is given in table 4 and representative cyclic
voltamograms are given in figure 9. The investigation carried out at different scan rates revealed
that oxidation and reduction peaks showed a negligible shift in peak potential with the increase in
scan rate (figure 7) which is a particular behavior related to reversible redox electro-active specie.
[25,26] The Randles-Sevcik equation was used to calculate the diffusion coefficient values (D),
Kochi’s formula was used to calculate charge transfer coefficient(α) and Nicholson, Kochi method
was used to calculate the Heterogeneous rate constant (table 5). Calculated α value, approximately
0.5 (figure 8, table 5) indicated reversibility of the redox process for E1-E10. [27] A straight line
was obtained from the plot of peak current versus square root of scan rate (figure 8). This linear
relationship suggested that processs is diffusion controlled.
DNA binding study using CV was used to elucidate the mechanism of their interaction with
double strand chicken blood DNA in vivo figure 9, [28-30] the addition of various concentrations
of DNA on fixed concentrations of E1 resulted in decrease in the current reduction peak values.
Also a negative peak potential shift (cathodic shift) in the CV was observed which was attributed
17

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to the electrostatic interaction of the positively charged ferrocene of E1 with polyanionic DNA
molecule. The substantial diminution in peak current was due to the formation of slowly diffusing
E1-DNA complex which lowered the concentration of free E1. The cathodic shift in peak also
indicated that Fe (II) of E1 was easier to oxidize in the presence of DNA as its oxidized form was
more strongly bound to DNA than its reduced form. [31-35] Using different concentrations of
DNA, the binding constants, Kb for all the Es-DNA complexes were calculated at room
temperature (25oC), (figure 10, table 6). The binding energy data for Es was found in range 6.41 ×
105 to 2.71 × 103. Kb and ꢀG valves obtained from CV were in good agreement with the ones
obtained from UV-vis techniques (table 6 and table 3 respectively).
4. Conclusion
A series of aromatic and aliphatic ferrocenyl ester E1-E10 was synthesized and characterized using
standard protocols/procedures. Calculated bond distances, angles and vibrational IR frequencies
showed excellent correlation with the experimental data. Their DNA interaction through UV-vis
spectroscopy and Cyclic voltammetry were utilized in order to investigate their potential activity to
be used as drugs. The observed hperchromism and cathodic shifts in peak potential suggested their
different modes of interaction with DNA. Electrochemical studies showed that all the synthesized
ester follow diffusion controlled one electron reversible redox behavior and formal potential
values of compounds can be tailored by changing the substituent attached to the ferrocenyl moiety.
Hence Es could be considered as a potential material for drugs. Among all, E3 showed greatest
binding constant as well as Gibbs free energy thus it has greatest potential to be used as drug.
Acknowledgements
Department of Chemistry, Quaid-i-Azam University is greatly acknowledged for the laboratory
facilities.
Supplementary Information
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CCDC number for the compounds C23H18FeO2, C27H20 FeO2 and C24 H20FeO2 are 1053011,
1053012 and 1053013 respectively.
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[35] N. K. Janjua, Z. Akhter, F. Jabeen, B. Iftikhar, J. Korean Chem. Soc., 58 (2014) 2.
List of scheme
1. Scheme: 1 Synthesis of 4-Ferrocenyl benzoic acid (FB) and 4-Ferrocenyl alkyl benzoate.
List of tables
1. Table 1. Selected bond lengths and bond angles of E1, E4 and E8
2. Table 2. Crystallographic data and structure refinement results.
3. Table 3. Binding constant and free energy values for ferrocenyl esters-DNA complexes
from UV-spectrophotometric data at room temperature.
4. Table 4. Selected CV data for compounds in mentioned solvents using KCl/TBAP vs
Ag/AgBr: scan rate= 100mV/s
5. Table 5. Kinetic parameters calculated from CV data (Effect of scan rate on Es) of the
compounds
6. Table 6. Binding constant and free energy values for ferrocenyl esters-DNA complexes
from voltametric data at room temperature.
List of figures
1. Figure 1. A packing diagram of E4 molecule.
2. Figure 2. A diagram showing intermolecular attraction between E8 molecules.
3. Figure 3. Electrostatic potential maps of phenol (A1), ferrocenyl benzoic acid (FB) and
respective ferrocenyl ester (E1).
4. Figure 4. UV-Vis absorption spectra in dichloromethane of representative ferrocenyl esters.
5. Figure 5. UV-Vis spectra of 10 µM E4 for DNA Interaction Study: (a) 0.00 µM (b) 1.1 µM
(c) 2.2 µM (d) 3.3 µM (e) 4.4 µM (f) 5.5µM at room temperature.
6. Figure 6. Plot of Ao / A-Ao vs 1/ [DNA] for 10 µM E4 with varying concentration of DNA
to calculate the binding constant (using UV-Vis spectroscopy).
7. Figure 7. Cyclicvoltamograms of Representative Esters at Scan rate 100 mv/s (a) E1 (1.3
mmol) (b) E3 (1mmol)
8. Figure 8. Effect of scan rate (using CV) on current-voltage profile of 1mM E1 at Pt disk
electrode in10% aqueous ethanol and room temperature were: (a) 100 (b) 200 (c) 300 (d)
400 (e) 500 (f) 600 (g) 700 mV
9. Figure 9. Plot of I vs ν1/2 for the determination of diffusion coefficient of 1mM E1(using
CV)
10. Figure 10. Effect of DNA on CV behaviour of 1mM E1 at 100mV/s: (a) 0.00 µM (b) 0.74
µM (c) 1.48 µM (d) 2.22 µM (e) 2.96 µM (f) 3.7µM (g) 5.55µM DNA
21

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11. Figure 11. Plot of Ip2 vs Ipo2- Ip2 /[DNA] for calculation of binding constant (using CV) of
1mM E1-DNA adduct at room temperature.
22

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H2N
NaNO2
COOH
HCl
0-5oC
N
2
COOH
HCl
PTC
Diethyl ether
Fe
COOH
FB
Fe
DCC
ROH
/DMAP
1
CH2Cl2
2
COOR
4
Fe
R=
3
where
H2
C
8
9
7
H3C CH2
E3
H3C C
H2
5
E1
6
9
E2
10
8
11
H2
C
CH3
H3C
H3C
7
16
5
6
E4
E5
E6
H2
7
8
5
H3C
C
6
H3C
8
H3C
H3C
E8
E7
E9
H2
C
14
E10
Scheme: 1 Synthesis of 4-Ferrocenyl benzoic acid (FB) and 4-ferrocenyl alkyl benzoate
23

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Table 1. Selected bond lengths and bond angles of E1, E4 and E8
Important bond lengths and bond angles of E1(C23H18FeO2)
Bond
Bond length Aº
Bond angle
Bond angle
Measurement (º)
40.41 (13)
Fe1—C1
Fe1—C6
Fe1—C10
Fe1—C4
2.017 (3)
2.030 (2)
2.046 (2)
2.051 (3)
C1—Fe1—C5
C5—Fe1—C7
C17—O2—C18
Fe1—C1—H1
125.80 (13)
120.22 (18)
124.6
C3—C4
1.374 (4)
1.399 (3)
C4—C5—Fe1
71.37 (16)
−165.9 (2)
O2—C18
C7—Fe1—C2—C1
C4—H4
0.9300
C19—C20—C21—
C22
C18—O2—C17—O1
0.0 (4)
3.0 (3)
C21—C22 1.367 (4)
C18—C23 1.369 (3)
C13—C14—C17—O1 3.7 (3)
C11—C16 1.391 (3)
Fe1—C8—H8
126.5
Important bond lengths and bond angles of E4
(C27H20FeO2)
Bond
Bond length Aº
Bond a gle
Bond angle
Measurement (º)
Fe1—C6
2.025 (3)
C10—C6—H6
126.2
24

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Fe1—C10
Fe1—C4
O1—C17
O2—C18
C4—H4
C2—C3
C1—C2
C3—H3
2.033 (3)
2.038 (3)
1.183 (3)
1.413 (3)
0.9300
Fe1—C6—H6
125.9
C6—C7—H7
125.8
Fe1—C7—H7
126.4
C11—C12—H12
O1—C17—O2
O2—C17—C14
C10—Fe1—C7—C6
C6—C7—C8—Fe1
119.2
122.8 (3)
112.1 (2)
38.19 (19)
−58.7 (2)
1.416 (4)
1.395 (4)
0.9300
C23—C24 1.411 (4)
C1—C5 1.405 (4)
C10—Fe1—C1—C5
−121.09 (19)
−1.9 (5)
C23—C22—C27—
C26
Important bond lengths and bond angles of E8
(
C
24
H
20FeO )
2
Bond
Bond length Aº Bond angle
Bond angle
Measurement
(º)
Fe1—C10
Fe1—C4
O2—C17
C2—H2
2.018 (3)
2.035 (3)
1.352 (3)
0.9300
C1—Fe1—C10
C10—Fe1—C6
C10—Fe1—C4
C17—O2—C18
C5—C1—Fe1
C3—C2—C1
C1—Fe1—C10
41.22 (10)
158.43 (14)
117.9 (2)
69.8 (2)
C6—C7
1.415 (4)
1.396 (4)
1.351 (6)
0.9600
C11—C12
C20—C21
C24—H24C
O2—C18
C14—C17
Fe1—C9
108.9 (4)
127.0
C5—C1—H1
Fe1—C8—H8
O1—C17—O2
O2—C17—C14
C7—Fe1—C8—C9
126.4
1.396 (4)
1.480 (4)
2.029 (3)
122.1 (3)
111.9 (3)
119.8 (3)
25

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Table 2 Crystallographic data and structure refinement results
E1
E4
E8
Empirical formula
C23H18FeO2
C27H20FeO2
C24H20FeO2
Formula weight
382.22
296 K
432.28
396.25
Temperature
296 K
296 K
Crystal system
Monoclinic
P21/c
Monoclinic
P21/n
Monoclinic
P21/n
Space group
a / Å
5.8859 (2)
21.1780 (9)
13.9737 (5)
90°
12.4697 (4)
14.2173 (5)
12.8412 (4)
90°
11.4841 (5)
8.8836 (4)
18.7976 (8)
90°
b / Å
c / Å
α
98.353(2)°
90°
118.243 (1)°
90°
98.471 (2)°
90°
β
Γ
Volume / Å3
1723.37 (11)
4
2005.53 (11)
4
1896.81 (14)
4
Z
Density Mg m-3
1.473
1.432
1.388
S
1.05
1.04
1.02
F(000)
792
896
824
Limiting indices
-7 ≤ h ≤ 5
-24 ≤ k ≤ 25
-14 ≤ l ≤ 16
3109
-14 ≤ h ≤ 14
-17 ≤ k ≤ 17
-15 ≤ l ≤ 15
3620
-14 ≤ h ≤ 14
-10 ≤ k ≤ 7
-23 ≤ l ≤ 23
3718
Reflections number
Rint
0.027
0.041
0.024
Tmax
25.3°
25.3°
26.0°
wR(F2)
0.086
0.104
0.121
26

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Table 3. Binding constant and free energy values for ferrocenyl esters-DNA complexes
from UV-spectrophotometric data at room temperature.
*Binding Constant *Free energy
Compounds
†(Kb) M-1
2.51 × 105
1.87 × 105
6.21 × 105
1.83 × 105
1.09 × 105
8.22 × 103
1.58 × 104
8.62 × 104
2.48 × 103
5.20 × 103
(-ꢀG= −RT ln K) KjM
E1
E2
E3
E4
E5
E6
E7
E8
E9
E10
28.22
27.55
30.27
27.50
26.33
20.46
22.01
25.79
17.74
19.42
Table 4. Selected CV data for compounds in mentioned solvents using KCl/TBAP vs Ag/AgBr:
scan rate= 100mV/s
٭Eo (mV)
331
a
c
Compounds Ep (V) Ep (V)
†ꢀEp (mV)
242
E1 (Ethanol) 0.452
E2 (Ethanol) 0.352
E3 (Ethanol) 0.422
E4 (DMSO) 0.582
E5 (Ethanol) 0.291
0.210
0.170
0.207
0.468
0.198
0.428
0.268
0.248
0.258
0.448
261
182
314
215
525
113
244
93
E6 (DMF)
0.502
465
74
E7 (DMSO) 0.382
E8 (Ethanol) 0.321
E9 (Ethanol) 0.392
E10 (DMF) 0.572
325
114
499
73
325
134
510
124
a
c
a
c
٭Eo = Ep + Ep / 2 ,
†ꢀEp = Ep -Ep
27

ACCEPTED MANUSCRIPT
Table 5. Kinetic parameters calculated from CV data (Effect of scan rate on Es) of the compounds
†Diffusion coefficient †Charge transfer
†Heterogeneous rate constant
Ks,h(cms-1)
Compounds
D (cm2s-1)
coefficient α
E1
E2
E3
E4
E5
E6
E7
E8
E9
E10
1.66 × 10-5
0.500
1.2 × 10-3
1.23 × 10-5
1.549 × 10-5
1.11× 10-7
1.03 × 10-5
2.5 × 10-6
2.7 × 10-7
2.62 × 10-6
2.62 × 10-6
4.6 × 10-6
0.501
0.497
0.499
0.494
0.500
0.500
0.499
0.500
0.500
1.74 × 10-3
9.4× 10-2
1.05× 10-3
4.0 × 10-3
2.3 × 10-3
5.26 × 10-4
2.4 × 10-3
8.4 × 10-4
1.48 × 10-3
c
a
c
† D1/2
=
ip________
,
† α = E1/2 - EP / Ep - EP
,
† Ks,h = 2.18 [ανnFDo/RT]1/2 exp[- α2nF ꢀEp]
(269,000)n3/2A Cν1/2
RT
28

ACCEPTED MANUSCRIPT
Table 6. Binding constant and free energy values for ferrocenyl esters-DNA complexes from
voltametric data at room temperature
Binding constant Freee energy
Compounds
†٭Kb (M-1)
(-ꢀG=RTlnK) Kj M-1
E1
E2
E3
E4
E5
E6
E7
E8
E9
2.81 × 105
28.55
2.07 × 105
6.41 × 105
1.99 × 105
1.29 × 105
8.40 × 103
1.75 × 104
8.82 × 104
2.71 × 103
27.86
30.44
27.77
26.79
20.57
22.24
25.92
17.99
19.57
E10
5.42 × 103
†٭ Ip 2
=
1
(Ip02 - Ip2 ) + Ip02 – [DNA]
Kb[DNA]
Figure 1. A packing diagram of E4 molecule.
29