Ethyl 5-ferrocenyl-1H-pyrazolecarboxylates: The synthesis and redox properties

Article abstract of DOI:10.1007/s11172-014-0731-3

Redox potentials of isomeric ethyl 5-ferrocenyl-1H-pyrazole-3-carboxylates 2 and ethyl 5-ferrocenyl-1H-pyrazole-4-carboxylates 4 were measured and their dependences on the acidity of the medium were determined. The structures of various conformers of neut

Full text of DOI:10.1007/s11172-014-0731-3

Russian Chemical Bulletin, International Edition, Vol. 63, No. 10, pp. 2255—2259, October, 2014
2255
Ethyl 5ꢀferrocenylꢀ1Hꢀpyrazolecarboxylates: the synthesis and redox properties*
V. N. Kulikov,a,b O. M. Nikitin, Yu. A. Borisov, A. S. Makarov, A. N. Rodionov,
a
a
a
a
R. S. Nikulin,a,b L. V. Kovalenko, and Yu. A. Belousov
b
a
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
8 ul. Vavilova, 119991 Moscow, Russian Federation.
2
Fax: +7 (499) 135 5085. Eꢀmail: belyur@ineos.ac.ru
D. Mendeleyev University of Chemical Technology of Russia,
b
9
Miusskaya pl., 125047 Moscow, Russian Federation.
Fax: +7 (495) 609 2964. Eꢀmail: kulikov_v_n@mail.ru
Redox potentials of isomeric ethyl 5ꢀferrocenylꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylates 2 and ethyl
ꢀferrocenylꢀ1Hꢀpyrazoleꢀ4ꢀcarboxylates 4 were measured and their dependences on the acidity
5
of the medium were determined. The structures of various conformers of neutral molecules and
corresponding radical cations were calculated by the B3LYP/6ꢀ31G* method. The results of
calculations for neutral molecules were confirmed by Xꢀray data.
Key words: ferrocene, ferrocenylazoles, voltammetry, quantum chemical calculations,
density functional theory, B3LYP method, ferricinium radical cation.
Ferrocenylazoles exhibit antitumor,1—3 antibacteriꢀ
Thus, it is clearly seen that ferrocene derivatives are
al,4—8 and fungicidal activity. Ferrocene derivatives are
of low toxicity and can be used as pharmaceuticals. For
instance, Ferroceron, a ferroceneꢀcontaining stimulator
of erythropoiesis,1 is included in the State Pharmacoꢀ
poeia of the Russian Federation. A number of ferrocene
derivatives are under clinical trials for antitumor and antiꢀ
malarial activity.11
4,9
promising for solving problems in medicinal chemistry.
Also, knowledge of the electrochemical properties of these
compounds and their dependence on the environmental
conditions is required for rational design of ferroceneꢀ
containing drugs and for modelling their distribution and
metabolism in living organisms.
0
Medicinal applications of ferrocene derivatives are
based on unique properties of the ferrocene nucleus, viz.,
stability in biological media,12 lipophilicity that favors easy
penetration through cell membranes, as well as aromatic
character and a small size typical of aromatic hydroꢀ
carbons. Besides, ferrocene exhibits ideal electrochemiꢀ
cal properties, namely, a low redox potential and high
chemical stability of the oxidized and reduced forms
Experimental
Ethyl 5ꢀferrocenylꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylates (2) and ethyl
5ꢀferrocenylꢀ1Hꢀpyrazoleꢀ4ꢀcarboxylates (4) were synthesized
The physicochemical parameters of comꢀ
pounds 2 and 4 agree with the published data. Acetonitrile was
purified immediately prior to use following a known procedure,
HBF and [Bu N]OH (Acros Organics) were utilized in the form
1
4,15
as reported earlier.
1
6
4
4
of aqueous solutions.
(
ferricinium and ferrocene, respectively) and a high
The oxidation potentials of substrates were measured with
an IPC_Win digital potentiostat/galvanostat. Cyclic voltammoꢀ
grams (CVs) were recorded in a 10ꢀmL electrochemical cell at
a concentration of 1 mM under argon in deoxygenated acetoꢀ
nitrile solution containing 0.05 M [Bu N]BF4 as supporting
elelctrolyte at 20 C. The potential scan rate was 0.1 V s
A platinum stationary disk electrode (S = 0.1 cm ) and a platiꢀ
num auxiliary electrode were used. Electrolysis at a controlled
potential was performed using a Pꢀ5827 M potentiostat in an
electrochemical cell with separated anodic and cathodic comꢀ
rate of electron transfer between them, which favors not
only enhanced membranotropicity, but also facilitates
transport in cell cytoplasm. Yet another important facꢀ
tor is the interaction of the ferrocene—ferricinium sysꢀ
tem with the plasma membrane. This system spans from
the interface into membrane interior and thus proꢀ
vides with coupled transmembrane electron and ion
transport which leads to changes in the membrane polarꢀ
ization.13
4
–
1
.
2
2
partments. The working electrode (S = 0.6 cm ) and the auxiliaꢀ
ry electrode were Pt plates. In all measurements, the reference
electrode was a saturated chlorineꢀsilver electrode (Ag/AgCl/
KCl (sat.), the potential is 0.48 V vs. Fc/Fc in MeCN). The
measured potential values were recalculated taking into account
ohmic losses.
*
Dedicated to Academician of the Russian Academy of Sciences
Yu. N. Bubnov on the occasion of his 80th birthday and to the
0th anniversary of the foundation of A. N. Nesmeyanov Institute
of Organoelement Compounds of the Russian Academy of Sciences.
+
6
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2255—2259, October, 2014.
066ꢀ5285/14/6310ꢀ2255 © 2014 Springer Science+Business Media, Inc.
1

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 10, October, 2014
Kulikov et al.
Quantum chemical calculations were carried out within the
framework of the density functional theory (DFT) by the Becke—
Electrochemical studies. A series of ferrocenylpyrazoles
with different substituents in the pyrazole ring was studied
by cyclic voltammetry. The influence of the ester group
position and the nature of substituent at the heteroatom in
the pyrazole ring on the electrochemical properties of
ferrocenylpyrazoles was elucidated. Measurements were
carried out in a threeꢀelectrode cell. The concentration of
solutes under study was 1 mmol L . The cyclic voltꢀ
ammograms of all compounds studied exhibit oneꢀelecꢀ
tron reversible oxidation peaks (Fig. 1) whose potentials
are listed in Table 1.
The introduction of aromatic substituents into posiꢀ
tion 1 of the pyrazole ring causes the oxidation potential of
the ferrocene moiety to increase by 60—110 mV compared
to the oxidation potentials of unsubstituted pyrazoles 2a
and 4a. Variation of substituents at the nitrogen atom has
almost no effect on the oxidation potential of the subꢀ
strate. This is most probably due to the absence of conjuꢀ
gation between the aromatic substituent and the pyrazole
1
7,18
Lee—Yang—Parr (B3LYP) method
set using the GAUSSIANꢀ98 program. Closedꢀshell systems
were calculated by the RB3LYP method and openꢀshell systems
with the 6ꢀ31G* basis
1
9
20
(
radical cations) were calculated by the UB3LYP method.
Results and Discussion
–
1
Synthesis. Condensation of hydrazine hydrate and
monosubstituted hydrazines with ethyl ester of ferroꢀ
1
4
cenoylpyruvic acid (1) results in ethyl 5ꢀferrocenylꢀ1Hꢀ
pyrazoleꢀ3ꢀcarboxylates (2) in 65—90% yields (Scheme 1).
If the reaction is conducted in ethanol in the presence of
catalytic amounts of AcOH, only one possible regioisomer
is formed.
Scheme 1
I/mA
0
0
.02
.01
0
2
1
R = H (a),
(b),
(c),
(d),
(e)
i. RNHNH , EtOH, AcOHcat, Ar, .
2
Ethyl 5ꢀferrocenylꢀ1Hꢀpyrazoleꢀ4ꢀcarboxylates (4)
were obtained by condensation of ethyl (Z,E)ꢀ3ꢀ(dimethylꢀ
0
200
400
600
800
E/mV
amino)ꢀ2ꢀferrocenoyl acrylate (3) with monosubstituted
Fig. 1. Cyclic voltammograms of 1 mM solutions of compounds 2e
hydrazines and hydrazine hydrate (Scheme 2).1
4,15
The
(
[
1) and 4e (2) obtained in acetonitrile solution containing 0.05 M
reactions also occur regioselectively and their yields vary
in the range from 65 to 95%.
Bu N]BF4 as supporting electrolyte (Pt working electrode
4
–
1
(vs. Ag/AgCl/KCl (sat.)); potential scan rate was 100 mV s ).
Scheme 2
Table 1. Oxidation potentials (E, E/mV) of ferrocenylpyrꢀ
azoles under study
Comꢀ
pound
E
E
Comꢀ
pound
E
E
2
2
2
2
2
a
b
c
d
e
560
645
630
670
625
60
60
60
60
60
4a
4b,c
4d
4e
4f
530
595
625
590
595
60
70
60
60
70
Note: determined at a concentration of compounds of
mmol L–1 using a Pt working electrode (vs. Ag/AgCl/
KCl (sat.)) in acetonitrile solution containing 0.05 M
1
R = H (a),
(b),
(c),
(d),
(e),
(f)
[
Bu N]BF4 as supporting electrolyte at a potential scan
4
–
1
i. RNHNH , EtOH, AcOHcat, Ar, .
rate of 100 mV s .
2

Redox properties of 5ꢀferrocenylꢀ1Hꢀpyrazoles
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 10, October, 2014
2257
ring, as was confirmed by the results of quantum chemical
calculations and by Xꢀray data. Therefore, only the elecꢀ
tronꢀwithdrawing –Iꢀeffect of the sp ꢀhybridized carbon
Table 2. Oxidation potentials (E, E/mV) of ferrocene
derivatives
2
Comꢀ
pound
Neutral
medium
HBF4
(2 eq.)
[Bu N]OH
atom appears to be valuable.
4
(2 eq.)
Variation of position of the ester group in the pyrazole
ring led to an unexpected result, namely, the oxidation
potential of the ferrocene unit is shifted by 35—50 mV
toward the cathodic potential region on going from comꢀ
pounds 2 to compounds 4. That is, the oxidation occurs
easier when the electronꢀwithdrawing substituent in the
pyrazole ring is close to the ferrocene moiety. This can be
explained by electronic interaction between the carboxylic
oxygen and the iron atom. A Fe3+ ion formed upon oxidaꢀ
tion is stabilized through coordination to oxygen atom of
the COOH group. An Xꢀray study revealed a short contact
between the iron atom and the carboxylic group in esꢀ
ters 4b (3.59 Å) and 4d (3.74 Å).*
Е
Е
E
Е
E
2
4
2
4
a
a
e
e
560
530
625
590
60
60
60
60
640
595
625
605
60
60
60
60
315
340
330
340
Note: determined at a concentration of compounds of
mmol L using a Pt working electrode (vs. Ag/AgCl/KCl
–1
1
(
sat.)) in acetonitrile solution containing 0.05 M [Bu N]BF
4 4
as supporting electrolyte at a potential scan rate of 100 mV s–1.
The addition of HBF (2 eq.) to solutions of substitutꢀ
Quantum chemical calculations. To determine the reaꢀ
son for the decrease in the oxidation potential on going
from isomers 2 to isomers 4, we carried out quantum chemꢀ
ical calculations of the molecular structures of neutral
ferrocenylpyrazoles and corresponding radical cations
within the framework of the density functional theory. It
was shown that for one of the possible conformers of comꢀ
pounds 4 the distance between the iron atom and the carbꢀ
onyl oxygen atom in the ester group lies in the range from
3.64 to 3.77 Å (Fig. 2)
The short contact between the carbonyl oxygen atom
and iron atom was also found in the structures of correꢀ
sponding radical cations of compounds 4. Moreover, the
radical cations are characterized by about 0.2 Å shorter
distances between the iron and oxygen atoms (Table 3).
This makes transfer of positive charge from the iron atom
in the ferricinium moiety to the oxygen carboxylic atom
possible and leads to a decrease in the oxidation potential.
In compounds 2, such a coordination is impossible owing
to the long distance between the ferrocene iron atoms and
oxygen atoms in the ester group (Fig. 3). The results of
4
ed ferrocenylpyrazoles causes no changes in their oxidaꢀ
tion potentials, whereas those of the unsubstituted pyrꢀ
azoles 2a and 4a increase by 60 to 75 mV (Table 2) as
a result of the protonation of pyrazole and enhanceꢀ
ment of its electronꢀwithdrawing properties compared to
ferrocene. The basicities of the substituted pyrazoles
seem to be too low for protonation to occur under these
conditions.
In a basic medium, the oxidation potential of ferrocene
remains almost unchanged; however, a new peak in the
region of 315—340 mV appears in the CV curve. Carrying
out a potentiostatic electrolysis of 2e and 4e at the corꢀ
responding oxidation potentials in the presence of
[
Bu N]OH led to a gradual decrease in the concentrations
4
of the starting compounds. The reaction mixtures turned
darkꢀbrown. No ferrocene derivatives were found in the
mixtures after electrolysis. By analogy with the results of
a recent study21 one can suggest that electrolysis in basic
media causes the ferrocene nucleus to decompose to form
inorganic iron and cyclopentadiene polymers.
a
b
c
3
.46 Å
3
.64 Å
3
.59 Å
Fig. 2. Pyrazole 4b: molecular structure from DFT calculations for neutral molecule (a) and radical cation (b) and from Xꢀray data (c).
Cambridge Structural Database System, Version 5.35, 2014, CCDC 1013395 (2b), 1013396 (4b), 1013397 (4d).
*

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 10, October, 2014
Kulikov et al.
a
b
c
6
.69 Å
6
.26 Å
6
.17 Å
Fig. 3. Pyrazole 2b: molecular structure from DFT calculations for neutral molecule (a) and radical cation (b) and from Xꢀray data (c).
calculations for neutral molecules were confirmed by
Xꢀray data.
Table 3 lists the results of calculations. It follows that
the adiabatic ionization potentials of pyrazoles 2 are
Iad/eV
2
6
.3
.2
R = 0.961
2
b
0
.27—0.32 eV higher than those of isomeric pyrazoles 4.
2e
6
This agrees with the results of electrochemical measureꢀ
ments. No correlation was found between the oxidation
potentials, E, and the calculated gasꢀphase adiabatic ionꢀ
ization potentials, I, of compounds 2a and 4a. This seems
to be due to the absence of aromatic substituents at the
nitrogen atom. Ignoring compounds 2a and 4a, one gets
a linear correlation between the experimental and calcuꢀ
lated gasꢀphase adiabatic oxidation potentials of the comꢀ
pounds studied (Fig. 4).
6.1
4
b
6
.0
4e
590
600
610 620 630
640 650 (E )/mV
ox
Summing up, we have shown that ethyl 5ꢀferroꢀ
cenylpyrazolecarboxylates are readily oxidized in neutral
media (E = 530—645 mV). Electrolysis in the presence of
a base leads to the decompositon of the ferrocene nucleus;
Fig. 4. Correlation between calculated gasꢀphase adiabatic
ionization potentials (I ) and experimental oxidation potentials
ad
(
E ) in solution for compounds 2b,e and 4b,e.
ox
HBF has no effect on the oxidation of Nꢀsubstituted pyraꢀ
zoles, whereas the oxidation of unsubstituted pyrazoles 2a
4
The correlation found between the calculated adiabatꢀ
ic ionization potentials of the molecules studied and the
experimentally determined oxidation potentials of the subꢀ
stituted ferrocene derivatives makes it possible to estimate
the redox potentials of other ferrocene derivatives using on
the results of calculations.
and 4a in the presence of HBF is much more difficult
4
(
oxidation potential increases by 60—75 mV). The short
contact between the carbonyl oxygen atom and the iron
atom of the ferrocene nucleus in compounds 4 causes their
oxidation potentials to decrease by 30—50 mV compared
to those of isomeric compounds 2.
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos 14ꢀ03ꢀ00980
and 14ꢀ03ꢀ31469).
Table 3. Vertical (I ) and adiabatic (I ) ionization potentials of
v
ad
neutral molecules and radical cations derived from them
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