Application of reductive amination reaction for preparation of ferrocene-modified porphyrins

Article abstract of DOI:10.1142/S1088424612501246

Porphyrin-modified ferrocenes were synthesized via the reductive amination reaction of ferrocenylpyrazolecarboxaldehydes and tetraphenylporphyrinamine. The steric hindrance of ferrocene moiety was found to play the key role in this reaction.

Full text of DOI:10.1142/S1088424612501246

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2012; 16: 1225–1232
DOI: 10.1142/S1088424612501246
Published at http://www.worldscinet.com/jpp/
Application of reductive amination reaction for preparation
of ferrocene-modified porphyrins
ElenaYu. Osipova*a, Alexey N. Rodionova, Alexander A. Simenela,b,
Yury A. Belousova, Oleg M. Nikitina,c and Vadim V. Kachalad
a A.N. Nesmeyanov Institute of Organoelement Compounds RAS, 28 Vavilov Str., Moscow 119991, Russian Federation
b Moscow State Mining University, 6 Leninsky Ave., Moscow 119991, Russian Federation
c Dept. of Chemistry, M.V. Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russian
Federation
d N.D. Zelynski Institute of Organic Chemistry RAS, 47 Leninsky Ave., Moscow 119991, Russian Federation
Received 26 January 2012
Accepted 13 July 2012
ABSTRACT: Porphyrin-modified ferrocenes were synthesized via the reductive amination reaction of
ferrocenylpyrazolecarboxaldehydes and tetraphenylporphyrinamine. The steric hindrance of ferrocene
moiety was found to play the key role in this reaction.
KEYWORDS: ferrocene, porphyrin, reductive amination, 5-(p-aminophenyl)-10,15,20-triphenyl-
porphyrin, electrochemistry.
coupling [23], linkage through conjugated spacers
INTRODUCTION
[24], linkage through saturated spacers [25], b-pyrrole-
For many years, porphyrins have been used in PDT
linked ferrocene-porphyrins [26, 27, 28] and ferrocene-
[1, 2]. They can act as radiosensitizers in thick tumors
porphyrin analogs [29].
[3], for photodynamic therapy of early esophageal
The difference of bounding ways in the ferrocene-
cancer [4]. At the same time, ferrocene-containing
porphyrin assemblies suggests the variety of application.
bioconjugates are a new class of biomaterials, in which
Their donor–acceptor properties have been employed
the organometallic ferrocene unit serving on the one
to study photoinduced electron transfer processes and
hand as a molecular substrate for the construction of an
to simulate photosynthesis active sites [30, 31]. Thus,
ordered structure via intramolecular hydrogen bonding,
on the other hand as a catalytic or redox-active site, etc.
[5]. Ferrocenylheterocyclic compounds have been found
to exhibit biological activities (e.g. antitumor [6] and
such structures have been employed as molecular sensors
[32] and for an increase of memory density that allowed
multibit information storage [33].
Previously, we have studied the reductive amination
antimicrobial [7]). Noteworthy, pyrazole moiety is the
reaction of ferrocenylpyrazolecarboxaldehydes with
core structure of numerous biologically active compounds
primary and secondary aliphatic and aromatic amines
[8]. Some pyrazole compounds have affinity for the human
[34]. Therefore, we used this reaction to produce
CRF-1 receptor [9], exhibit anti-viral/anti-tumor [10],
ferrocene-porphyrins.
antibacterial [11], anti-parasitic [12], antipyretic [13],
In our work, we synthesized a ferrocene-containing
anty-flammatory [11, 13, 14], analgesic [14], fungistatic
porphyrins, in which the ferrocene linked to porphyrin
[15], fungicidal [16], and anti-hyperglycemic [17] activity.
through the heterocycle (pyrazole, isoxazole). For these
Ferrocene and porphyrins have already been associated
by means of various synthetic methods. These include
direct connection [18, 19, 20–22] particularly via Suzuki
compounds, we carried out the reaction of reductive
amination of 5-(p-aminophenyl)-10,15,20-triphenyl-
porphyrin and ferrocenepyrazolecarboxaldehydes. Such
ferrocene-appended porphyrins are of interest for electro-
chemical studies.
*Correspondence to: ElenaYu. Osipova, email: anel-86@mail.ru
Copyright © 2012 World Scientific Publishing Company

1226 E.Y. OSIPOVA ET AL.
1-Phenyl-3-ferrocenyl-4-(4-chlorophenylamino-
EXPERIMENTAL
methyl)pyrazole (3b). Yellow-orange powder. Yield
1
60%, mp 150–151°C. H NMR (300 MHz, CDCl3): d,
Instrumental
ppm 4.13 (s, 5H, Cp); 4.32 (s, 2Ha, Cp); 4.40 (s, 2Hb,
Cp); 4.79 (s, 2H, CH2); 6.65 (d, 2H, o-Ph-NH, J = 9.0
Hz); 7.20 (d, 2H, m-Ph-NH, J = 9.0 Hz ); 7.46 (t, 3H, Ph,
J = 9.0 Hz); 7.69 (d, 2H, o-Ph, J = 9.0 Hz); 7.87 (s, 1H,
Pz). EI/MS: m/z (Ire, %) 467 (62) [M]+.
Thesolventsweredehydratedbyconventionalmethods
directly before use. 3-(5-(p-Aminophenyl)-10,15,20-
triphenylporphyrin)-5-ferrocenyl-1-phenylpyrazole
(4b), 1,5-diphenyl-4-(5-(p-aminophenyl)-10,15,20-trip-
henylporphyrin)pyrazole (8a) 1,3-diphenyl-4-(5-(p-ami-
nophenyl)-10,15,20-triphenylporphyrin)pyrazole (8b)
were synthesized according to the method described
[35]. Mass spectra (MS) were obtained on a “FINNIGAN
POLARIS Q” spectrometer using electron ionization
method and on a “LCQ Advantage” spectrometer using
electro spray ionization. High resolution mass spectrum
was obtained on a Bruker “micro TOF II” spectrometer
using electro spray ionization. NMR spectra were
registeredonan“AVANCE”spectrometerwithoperational
frequency 300 MHz and on a “Bruker DRX-500”
spectrometer with operational frequencies 500.13 MHz
1-Phenyl-5-ferrocenyl-4-(4-chlorophenylamino-
methyl)pyrazole (3c). Yellow-orange oil. Yield 38%.
1H NMR (300 MHz, CDCl3): d, ppm 4.06 (s, 5H, Cp);
4.07 (s, 2Ha, Cp); 4.08 (s, 2Hb, Cp); 4.49 (s, 2H, CH2);
6.59 (d, 2H, Ph, J = 9.0 Hz); 6.70 (d, 2H, Ph, J = 9.0 Hz);
7.09 (d, 2H, Ph, J = 9.0 Hz); 7.29–7.33 (m, 5H, Ph); 8.31
(s, 1H, Pz). EI/MS: m/z (Ire, %) 467 (48) [M]+.
1-(Naphtalen-1-yl)-3-ferrocenyl-4-(4-chloropheny-
laminomethyl)pyrazole (3d). Yellow-orange powder.
1
Yield 58%, mp 188–189 °C (dec). H NMR (300 MHz,
CDCl3): d, ppm 4.15 (s, 5H, Cp); 4.35 (s, 2Ha, Cp); 4.44
(s, 2Hb, Cp); 4.83 (s, 2H, CH2); 6.68 (d, 2H, o-Ph-NH,
J = 9.0 Hz); 7.21 (d, 2H, m-Ph-NH, J = 9.0 Hz); 7.48–
7.52 (m, 3H, Nf); 7.88–7.93 (m, 5H, Nf,); 8.01 (s, 1H);
8.11 (s, 1H). 13C NMR (126 MHz, CDCl3): d, ppm 39.4,
67.3, 68.9, 69.4, 113.9, 115.6, 118.1, 122.5, 125.7, 126.9,
127.4, 127.8, 129.5, 131.7, 133.7, 146.5. EI/MS: m/z (Ire,
%) 517 (90).
3-(5-(p-Aminophenyl)-10,15,20-triphenylporph-
yrin)-5-ferrocenyl-1-izoxazole(6a).Violetpowder.Yield
51%. UV-vis (CH2Cl2): lmax, nm 285, 420, 518, 648.
1H NMR (500 MHz, CDCl3): d, ppm -2.61 (s, 2H, NH),
4.19 (s, 5H, Cp), 4.44 (s, 2Hb, Cp), 4.67 (s, 2H, CH2),
4.79 (s, 2Ha, Cp), 6.30 (s, 1H, Izo), 7.07 (d, 2H, o-Ph-NH,
J = 10.0 Hz), 7.75–7.79 (s, 9H, Ph), 8.06 (d, 2H, m-Ph,
J = 10.0 Hz), 8.84–8.85 (m, 6H, 6CH), 8.96 (d, 2H, J =
5.0 Hz). 13C NMR (126 MHz, CDCl3): d, ppm 40.6, 67.2,
69.9, 97.28, 111.5, 119.7, 120.9, 126.7, 127.7, 132.09,
134.6, 135.8, 142.2, 147.1, 162.6. ESI/MS: m/z (Ire %)
895 (100) [M + H]+.
3-(5-(p-Aminophenyl)-10,15,20-triphenylporph-
yrin)-5-ferrocenyl-1-(4-methylphenyl)pyrazole (6b).
Violet powder. Yield 53%. UV-vis (CH2Cl2): lmax, nm
263, 420, 518, 649. 1H NMR (500 MHz, CDCl3): d, ppm
-2.61 (s, 2H, NH), 4.13 (c, 5H, Cp), 4.25 (s, 2Ha, Cp),
4.27 (c, 2Hb, Cp), 4.70 (s, 2H, CH2), 6.62 (s, 1H, Pz),
7.14 (d, 2H, o-Ph-NH, J = 10.0 Hz), 7.38 (d, 2H, Ph, J =
5.0 Hz), 7.48 (d, 2H, Ph, J = 5.0 Hz), 7.75–7.80 (m, 9H,
Ph), 8.08 (d, 6H, Ph, J = 10.0 Hz), 8.82–8.86 (m, 6H),
9.00 (d, 2H, J = 10.0 Hz). ESI/MS: m/z (Ire %) 984 (100)
[M + H]+.
1
and 125.76 MHz for H and 13C respectivelly, in CDCl3
and DMSO-d6. Two-dimensional spectra COSY, HSQC
and HMBC were registered using the gradient method.
The UV-vis spectral measurements were carried out with
a “Carl Zeiss Jena” model Specord M40 spectrometer in
200–1000 nm region. Voltammetric experiments were
performed with IPC-Win potentiostat, one compartment
cell of 10 mL with a platinum wire counter electrode
and Ag/AgCl/KCl aq. reference electrode. All potentials
below refer to this reference electrode. Working electrode
was Pt disk.
Synthesis
General procedure 1. Ferrocenylformylpyrazole 1
mmol and 1.2 mmol of 5-(p-aminophenyl)-10,15,20-tri-
phenylporphyrin (or p-chloranilin, were mixed in
1,2-dichloroethane (35 mL) for 1 h. at rt and treated with
1.4 mmol of sodium triacetoxyborohydride. The mixture
was refluxed for 1 h. The reaction mixture was quenched
byaddingaqueoussaturatedNaHCO3,andtheproductwas
extracted with 2 × 30 mL dichloromethane. The organic
layers combined and washed with brine. After drying
over Na2SO4 the solvent was evaporated. The residue
was purified by means of column chromatography (SiO2,
eluent CHCl3-MeOH 9/1 for p-chloranilin derivatives
and hexane-ethylacetate 3/1 for ferroceneporphyrins).
1-Phenyl-5-ferrocenyl-3-(4-chlorophenylamino-
methyl)pyrazole (3a). Yellow-orange powder. Yield
1
63% mp 150–151 °C. H NMR (300 MHz, CDCl3): d,
3-(5-(p-Aminophenyl)-10,15,20-triphenylporph-
yrin)-5-ferrocenyl-1-(4-tert-butylphenyl)pyrazole
ppm 4.05 (s, 5H, Cp); 4.14 (s, 2Ha, Cp); 4.19 (s, 2Hb,
Cp); 4.38 (s, 2H, CH2); 6.46 (c, 1H, Pz); 6.67 (d, 2H,
o-Ph-NH, J = 9.0 Hz); 7.15 (d, 2H, m-Ph-NH, J = 9.0 Hz);
7.34–7.46 (m, 5H, Ph). 13C NMR (75 MHz, CDCl3): d,
ppm 42.3, 68.7, 69.8, 74.6, 105.2, 114.3, 122.2, 126.1,
128.2, 128.9, 140.2, 142.9, 146.7, 150.5. EI/MS: m/z
(Ire, %) 467 (80) [M]+.
(6c). Violet powder. Yield 55%. UV-vis (CH2Cl2): lmax
,
nm 276, 420, 516, 557, 649. 1H NMR (500 MHz, CDCl3):
d, ppm -2.61 (s, 2H), 4.13 (s, 5H, Cp), 4.25 (s, 2Ha, Cp),
4.25 (s, 2Hb, Cp), 4.70 (s, 2H, CH2), 6.62 (s, 1H, CH,
Pz), 7.14 (d, 2H, o-Ph-NH, J = 10.0 Hz), 7.38 (d, 2H, Ph,
J = 5.0 Hz) 7.48 (d, 2H, Ph, J = 10.0 Hz), 7.75–7.80
Copyright © 2012 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2012; 16: 1226–1232

APPLICATION OF REDUCTIVE AMINATION REACTION FOR PREPARATION OF FERROCENE-MODIFIED PORPHYRINS 1227
(m, 9H, Ph), 8.08 (d, 6H, Ph, J = 5.0 Hz), 8.24 (d, 6H, Ph,
J = 5.0 Hz), 8.82–8.87 (m, 6H, 6CH), 9.00 (d, 2H, 2CH,
J = 5.0 Hz). 13C NMR (126 MHz, CDCl3): d, ppm 31.4,
42.5, 68.7, 69.9, 74.3, 105.1, 115.5, 125.7, 125.8, 126.7,
127.6, 134.6, 135.8, 142.4, 151.4. ESI/MS: m/z (Ire %)
1025 (100) [M + H]+.
powder. Yield 95%. UV-vis (CH2Cl2): lmax, nm 297
(12000), 424 (112500), 552 (6000), 598 (3000). 1H NMR
(500 MHz, CDCl3): d, ppm 4.16 (s, 5H, Cp); 4.25 (s,
4Ha,b, Cp); 4.55 (s, 2H); 6.60 (s, 1H, Pz); 6.97–6.98
(d, 2H, o-Ph-NH, J = 10.0 Hz), 7.74–7.78 (m, 9H, Ph),
8.02–8.05 (d, 2H, m-Ph-NH, J = 10.0 Hz), 8.25–8.24 (d,
6H, Ph, J = 5.0 Hz), 8.93 (s, 6H), 9.07 (d, 2H, J = 5.0
Hz). 13C NMR (126 MHz, CDCl3): d, ppm 68.7, 69.9,
75.0, 105.4, 111.5, 119.6, 119.9, 121.3, 126.6, 127.6,
128.1, 128.9, 131.5, 134.6, 135.8, 140.4, 142.3, 142.4,
142.9, 147.8, 150.9. ESI/MS: m/z 1032 [M]+. Anal.
found % C, 74.11; H, 4.28; Fe, 5.47; N, 9.60. Calcd. for
C63H43FeN7Zn%: C, 74.24; H, 4.25; Fe, 5.48; N, 9.62.
CuII[3-(5-(p-Aminophenyl)-10,15,20-triphenyl-
porphyrin)-5-ferrocenyl-1-phenylpyrazole] 9b. Crim-
son powder. Yield 97%. UV-vis (CH2Cl2): lmax, nm 289
(12000), 417 (112500), 542 (9000), 589 (6000). ESI/
MS: m/z 1031 [M]+. Anal. found % C, 73.97; H, 4.28; Fe,
5.46; N, 9.59. Calcd. for C63H44CuFeN7%: C, 74.37; H,
4.26; Fe, 5.49; N, 9.64.
3-(5-(p-Aminophenyl)-10,15,20-triphenylporph-
yrin)-5-ferrocenyl-1-(2-chlorophenyl)pyrazole (6d).
Violet powder. Yield 42%. UV-vis (CH2Cl2): lmax, nm
1
285, 420, 518, 557, 648. H NMR (500 MHz, CDCl3):
d, ppm -2.61 (s, 2H, NH), 4.16 (s, 5H, Cp), 4.26 (s, 2Ha,
Cp), 4.28 (s, 2Hb, Cp), 4.70 (s, 2H, CH2), 6.70 (s, 1H, Pz),
7.14 (d, 2H, o-Ph-NH, J = 10.0 Hz), 7.34–7.39 (m, 4H,
Ph), 7.72–7.80 (m, 9H, Ph), 8.07 (d, 2H, m-Ph-NH, J =
10.0 Hz), 8.23 (d, 6H, Ph, J = 5.0 Hz), 8.85 (s, 6H, 6CH),
8.99 (d, 2H, J = 5.0 Hz). 13C NMR (126 MHz, CDCl3):
d, ppm 42.5, 68.9, 69.9, 74.6, 106.3, 111.5, 116.7, 119.6,
119.9, 121.2, 124.0, 126.1, 126.7, 127.6, 128.0, 129.7,
131.6, 134.5, 135.8, 141.2, 142.3, 147.7, 151.4. ESI/MS:
m/z (Ire %) 1021(80) [M + H]+.
3-(5-(p-Aminophenyl)-10,15,20-triphenylpor-
phyrin)-5-ferrocenyl-1-(3-chlorophenyl)pyrazole
MnII[3-(5-(p-Aminophenyl)-10,15,20-triphenyl-
porphyrin)-5-ferrocenyl-1-phenylpyrazole] 9c. Green
powder. Yield 98%. UV-vis (CH2Cl2): lmax, nm 287
(12000), 419 (112500), 548 (8000), 590 (6000). ESI/
MS: m/z 1022 [M]+. Anal. found % C, 74.74; H, 4.32; Fe,
5.52; N, 9.68. Calcd. for C63H43FeMnN7 %: C, 75.00; H,
4.30; Fe, 5.54; N, 9.72.
(6e). Violet powder. Yield 45%. UV-vis (CH2Cl2):
1
l
max, nm 279, 421, 517, 556, 649. H NMR (500 MHz,
CDCl3): d, ppm -2.61 (s, 2H, NH), 4.13 (s, 5H, Cp), 4.24
(s, 4Ha,b, Cp), 4.71 (s, 2H, CH2), 6.69 (s, 1H, Pz), 7.15–
7.16 (d, 2H, o-Ph-NH, J = 5.0 Hz), 7.75–7.79 (m, 9H,
Ph), 8.08 (d, 2H, m-Ph-NH, J = 5.0 Hz), 8.24 (d, 6H, Ph,
J = 5.0 Hz), 8.85 (s, 6H, 6CH), 8.99 (d, 2H, J = 5.0 Hz).
13C NMR (126 MHz, CDCl3): d, ppm 42.5, 68.7, 69.9,
105.5, 111.6, 126.2, 126.6, 127.6, 128.2, 128.8, 134.6,
135.8, 142.4, 147.8, 150.9. ESI/MS: m/z (Ire %) 1003
(100) [M + H]+.
RESULTS AND DISCUSSION
The synthesis of these ferrocenyl porphyrins involved
the reductive amination reaction, using 5-(p-aminoph-
enyl)-10,15,20-triphenylporphyrin and ferrocenyl formyl
pyrazoles as starting materials. The porphyrin precursor
1 could be prepared by well-known method derived from
5,10,15,20-tetraphenylporphyrin [36]. Formyl ferrocene
[37] 2a, ferrocenyl formyl heterocyclic compounds
(1-phenyl-5-ferrocenyl-3-formylpyrazole [38] 2b,
1-phenyl-5-ferrocenyl-4-formylpyrazole [39] 2c,
1-aryl-3-ferrocenyl-4-formylpyrazoles [35, 40] 2d) and
phenylformylpyrazoles (1-phenyl-5-ferrocenyl-4-pyra-
zolecarboxaldehyde [41] 8a, and 1-phenyl-3-ferrocenyl-
4-pyrazolecarbaldehyde [42] 8b) were obtained by
methods described in literature.
To predict the reaction of ferrocenylheterocycles
with 5-(p-aminophenyl)-10,15,20-triphenylporphyrin,
we at first carried out the model reduction amination
reaction with ferrocenylpyrazolecarbaldehydes where
p-chloraniline was taken as amino component. Thus,
ferrocene derivatives of p-chloroaniline 3b-e were
synthesized with yields up to 63% (Scheme 1). The
maximal yield was reached in the case with 1-phenyl-5-
ferrocenyl-3-formylpyrazole in which the minimal steric
hindrance between ferrocene and formyl group took
place.
3-(5-(p-Aminophenyl)-10,15,20-triphenylpor-
phyrin)-5-ferrocenyl-1-(4-fluorophenyl) pyrazole (6f).
Violet powder. Yield 66%. UV-vis (CH2Cl2): lmax, nm 280
(12000), 421 (103500), 518 (16000), 558 (3000), 649
1
(1500). H NMR (500 MHz, CDCl3): d, ppm -2.61 (s,
2H), 4.14 (s, 5H, Cp), 4.22 (s, 2Ha, Cp), 4.25 (s, 2Hb, Cp),
4.69 (s, 2H, CH2), 6.67 (s, 1H, Pz), 7.14–7.17 (m, 4H, Ph,
J = 15.0 Hz), 7.41–7.44 (m, 2H, Ph), 7.74–7.79 (m, 9H,
Ph), 8.07 (d, 2H, m-Ph-NH, J = 10.0 Hz), 8.23 (d, 6H,
Ph, J = 5.0 Hz), 8.85 (s, 6H, 6CH), 8.99 (d, 2H, 2CH, J =
5). 13C NMR (126 MHz, CDCl3): d, ppm 42.5, 68.7, 69.9,
74.6, 105.6, 111.5, 115.7, 119.6, 119.9, 121.2, 126.6,
127.6, 127.9, 131.5, 134.6, 135.8, 136.4, 142.3, 143.1,
147.8, 151.0. ESI/MS: m/z (Ire %) 988 (100) [M + H]+.
General procedure 2. To the solution of 1 mmol of
ferrocenylporphyrin4b in CHCl3 the saturated methanolic
solution of 10 fold excess of corresponding metal acetate
was added. The resulted mixture was refluxed with TLC
monitoring. After reaction was complete the mixture was
cooled to the room temperature and washed with water.
After drying over Na2SO4 solvents were removed under
reduced pressure.
ZnII[3-(5-(p-aminophenyl)-10,15,20-triphenyl-
porphyrin)-5-ferrocenyl-1-phenylpyrazole] 9a. Violet
As we can see the different substituents at the
heterocyclic fragment does not affect the yield of the
Copyright © 2012 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2012; 16: 1227–1232

1228 E.Y. OSIPOVA ET AL.
O
O
O
O
N
N
N
N
N
N
N
N
Fe
Fe
Fe
Fe
2d
2c
2e
2b
H2N
Cl
C2H4Cl2
NaB(OAc)3H
Cl
HN
HN
Cl
HN
H
Cl
N
Cl
N
N
N
N
N
N
N
N
Fe
Fe
Fe
Fe
3b
3c
38
3d
3e
Yield% =
60
63
58
Scheme 1. The reductive amination of ferrocene compounds with p-chloroaniline
reaction. The main idea is in the difference between
the relative position of formyl and ferrocenyl groups in
heterocycle (pyrazole). Thus we assumed that the reaction
with bulky aminoporphyrin would proceed more readily
in the case of 1-phenyl-5-ferrocenyl-3-formylpyrazole.
In the reaction of ferrocenylpyrazolecarbaldehydes
with
5-(p-aminophenyl)-10,15,20-triphenylporphyrin
the target product was obtained only from 1-phenyl-
5-ferrocenyl-3-formylpyrazole, with the 62% yield
(Scheme 2). The verifying of reaction time and
O
O
O
N
N
N
N
N
N
O
Fe
Fe
Fe
Fe
2d
2a
2c
2e
+
NH
N
N
N
H
O
HN
N
N
N
N
NH
N
NaB(OAc)3H
NH2
Fe
Fe
+
HN
N
C2H4Cl2
2b
4b
1
Scheme 2. The reductive amination of ferrocene compounds with TPP-NH2
Copyright © 2012 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2012; 16: 1228–1232

APPLICATION OF REDUCTIVE AMINATION REACTION FOR PREPARATION OF FERROCENE-MODIFIED PORPHYRINS 1229
conditions for another aldehydes led only to traces of the
target products. We assume that in contrast to the reaction
of ferrocenylcarboxaldehydes with p-chloroaniline, in
the case of bulky aminoporphyrin fragment the presence
namely of ferrocene near the CO group in pyrazole
prevents the interaction with amine.
To confirm our prepositions that the reductive
amination reaction proceeds with only 1-aryl-5-
ferrocenyl-3-formylazoles 5a–5f and aryl moieties
didn’t affect the reaction we carried the one with various
aromatic substituents at nitrogen in pyrazole ring along
with ferrocenylformylisoxazole (Scheme 3).
As result we got a number of ferrocene derivatives
where porphyrin moety connects to heterocycle via
amino spacer.
According to these results one may conclude that
yields little depend on electronic effects of substituents
in phenyl ring due to at first the remoteness of the phenyl
substituent from carbonyl group and at the second
noncoplanarity of the phenyl and pyrazole prohibiting
the conjugation between carbonyl group and the
substituent in phenyl radical. UV-visible spectroscopy
data have familiar values confirming the fact about no
investigations of substituents in phenyl ring in general
molecular behavior.
To confirm our suggestion about the steric hindrance
caused by the ferrocenyl group, we carried out the
reaction of aminoporphyrin with 1,5-diphenyl-4-pyra-
zolecarbaldehyde 7a, and 1,3-diphenyl-4-pyrazolec-
arbaldehyde 7b.
In contrast to the ferrocene analogs, diphenylaldehydes
7a and 7b entered into in this reaction. Diphenyl-
pyrazoleporphyrins were synthesised with yields up to
45% (Scheme 4).
NH
N
N
N
H
O
HN
NH
N
N
N
N
NaBH(OAc)3
C2H4Cl2
X
X
NH2
+
Fe
Fe
HN
5a-f
1
6a-f
N
N
N
N
N
Cl
X =
O
Cl
CH3
H3C CH3
F
CH3
53
51
55
42
45
66
Yield % =
Scheme 3. The reductive amination of 5-ferrocenylazole-4-carboxaldehyds with TPP-NH2
O
NH
N
N
HN
N
HN
N
N
N
7a
8a
NH
N
N
NH2
+
C2H4Cl2
HN
NH
N
N
O
N
H
1
N
HN
N
N
N
8b
7b
Scheme 4. The synthesis of diphenylpyrazoleporphyrins by the reductive amination of diphenylpyrozoles with TPP-NH2
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1230 E.Y. OSIPOVA ET AL.
(CH3COO)M2+
CHCl3/MeOH
NH
N
N
N
N
N
N
N
N
H
M
H
N
N
HN
N
N
Fe
Fe
M2+: Zn2+, Cu2+, Mn2+
9a-c
4b
Scheme 5. The metalation reaction of 3-(5-(p-aminophenyl)-10,15,20-triphenylporphyrin)-5-ferrocenyl-1-phenylpyrazole
Fig. 1. CVA curves of Fc-TPP (a) and Fc-TPP-Cu (b) (1 mM, CH3CN, 0.05 M Bu4NBF4, Pt, 100 mV/s)
Metalloporphyrins
Porphyrin-modified ferrocene 4b was entered in the
reaction with three metal salts of Zn(II), Cu(II), Mn(II)
(Scheme 5). The resulted products were obtained with
quantitative yields. 1H NMR spectrum was obtained only
for diamagnetic complex of zinc. Copper and manganese
complexes were characterized by ESI MS.
Electrochemistry
The measurements were carried out in acetonitrile
solution in the presence of 0.05 M Bu4NBF4 at a platinum
workingelectrode.Allinvestigatedcompoundsdemonstrate
of redox activity in the cathodic and anodic potential area.
Electrochemical oxidation of Fc-TPP revealed three
peaks at the potentials of 640/560, 920 and 1130 mV
Fig. 2. CVA curves of Fc-TPP and Fc-TPP-Met (Met = Cu, Mn,
Zn) (1 mM, CH3CN, 0.05 M Bu4NBF4, Pt, 100 mV/s)
(Fig. 1). The first peak is one-electron and reversible.
It likely corresponds to the oxidation of the ferrocene
fragment. The second and third peaks are also one-
electron and are attributed to the oxidation of the
porphyrin ring. The oxidation potentials of Fc-TPP are in
good agreement with literature data for unsubstituted TPP
[43] (Table 1). The similarity of the oxidation potentials
observed for the complex with the oxidation potentials
of its individual fragments indicates a weak electronic
interaction between porphyrin and ferrocene parts.
Two one-electron reversible peaks (-1120/-1050 and
-1450/-1350 mV) (Fig. 2) corresponding to the reduction
of the porphyrin ring can be observed in CV curve of
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J. Porphyrins Phthalocyanines 2012; 16: 1230–1232

APPLICATION OF REDUCTIVE AMINATION REACTION FOR PREPARATION OF FERROCENE-MODIFIED PORPHYRINS 1231
Table 1. The oxidation potentials of the complexes of Fc-TPP-X (X = Cu2+, Mn2+, 2H) (CH3CN, 0.05
M Bu4NBF4, Pt, 100 mV/s)
Substance
E1Ox, mV E2Ox, mV
E3Ox, mV
E4Ox, mV
-E1Red, mV
-E2Red, mV
Fc-TPP
640/560
630/550
650/550
920
960
1130
1160
—
1420
1380
—
1120/1050
1190/1130
1100/1020
1110/1020
1450/1350
1530/1450
1430/1320
1460/1350
Fc-TPP-Cu
Fc-TPP-Mn
920
1120
p-CH3-C6H4-Fc-TPP 610/520
H2TPP
930
920<44>
1140
1130<44>
1780 /1650* 2120/2010*
* In solution 0.2 M Bu4NPF6 in CH2Cl2. Platinum electrode, referred to Fc/Fc+ [45].
Fc-TPP in the anodic potentials area. Reduction potentials
as one similar to the literature data [43] for the TPP.
The introduction of metals (Cu2+ or Mn2+) in the
porphyrin ring confirms the argument of the weak
electronic interaction of the ferrocene and the porphyrin
unit of the complex, namely the oxidation potentials
of Fc-TPP-Cu 9b (640/560 mV) and Fc-TPP-Mn 9c
(630/550 mV) are very close to the potential of Fc-TPP
(650/ 550 mV). (Table 1).
The introduction of electron-donating fragment in
the ferrocene unit of the complex has no effect on the
oxidation and reduction potentials of the porphyrin
fragment and the oxidation potential of ferrocene are
slightly shifted in the cathode area.
5. Moriuchi T and Hirao T. Top. Organomet. Chem.
2006; 17: 143–175.
6. Snegur LV, Simenel AA, Nekrasov YuS, Morozova
EA, Starikova ZA, Peregudova SM, Kuzmenko
YuV, Babin VN, Ostrovskaya LA, Bluchterova NV
and Fomina MM. J. Organomet. Chem. 2004; 689:
2473–2479.
7. Damljanović IS, Vukićević MD, Radulović NS,
Palić R, Ellmerer E, Ratković Z, Joksović MD and
Vukićević RD. Bioorg. Med. Chem. Lett. 2009; 19:
1093–1096.
8. Elguero J, Goya P, Jagerovic N and Silva AMS.
Targets Heterocycl. Syst. 2002; 6: 52–98.
9. Wustrow DJ, Capiris T, Rubin R, Knobelsdorf JA,
Akunne H, Davis MD, MacKenzie R, Pugsley TA,
Zoski K, Heffner T and Wise L. Bioorg. Med. Chem.
Lett. 1998; 8: 2067–2070.
CONCLUSION
10. Park HJ, Lee K, Park SJ, Ahn B, Lee JC, Cho H
and Lee KI. Bioorg. Med. Chem. Lett. 2005; 15:
3307–3312.
11. Bekhit AA, Fahmy HTY, Rostom SAF and Baraka
AM. Eur. J. Med. Chem. 2003; 38: 27–36.
12. Rathelot P, Azas N, El-Kashef H, Delmas F, Di
Giorgio C, Timon-David P, Maldonado J and
Vanelle P. Eur. J. Med. Chem. 2002; 37: 671–679.
13. Eid AI, Kira MA and Fahmy HH. J. Pharm. Belg.
1978; 33: 303–311.
We first obtained the ferrocenylheterocyclic por-
phyrin by means of the reductive amination reaction
and optimized the reaction conditions. It was revealed
that the reaction proceeded only with those ferrocenyl-
formaldehydes, that lacked steric hindrances between
substituents in the pyrazole unit. Biological tests of
obtained ferrocene-porphyrin 3a are carrying out.
Aknowledgements
This work was partially supported by the Russian
Academy of Sciences (Presidium Program “Fundamental
Sciences — for Medicine”), by the Department of
Chemistry and Materials Science (Project OX-09), and
by the Russian Foundation for Basic Research (RFBR
No. 09-03-00535).
14. Menozzi G, Mosti L, Fossa P, Mattioli F and Ghia
M. J. Heterocyclic. Chem. 1997; 34: 963–968.
15. Sridhar R, Perumal PT, Etti S, Shanmugam G,
Ponnuswamy MN, Prabavathy VR and Mathivanan
N. Bioorg. Med. Chem. Lett. 2004; 14: 6035–6040.
16. Rich S and Horsfall JG. Phytopathology 1952; 42:
457–460.
17. Bebernitz G, Argentiery G, Battle B, Brennan C,
Balkan B, Byrkey B, Eckhardt M, Gao J, Kapa P,
Strohschein R, Schuster H, Wilson M and Xu D. J.
Med. Chem. 2001; 44: 2601–2608.
18. Loim NM, Abramova NV and Sokolov VI.
Mendeleev Commun. 1996; 46–47.
REFERENCES
1. Kalka K, Merk H and Mukhtar H. J. Am. Acad.
Dermatol. 2000; 42: 389–413.
2. The Porphyrin Handbook, Kadish KM, Smith KM and
Guilard R. (Eds.) Academic Press: Amsterdam, 2003.
3. Schwartz S, Absolon K and Vermund H. Univ.
Minnesota Med. Bull. 1955; 27: 7–13.
19. Wollmann RG and Hendrickson DN. Inorg. Chem.
1977; 16: 3079–3089.
4. Filonenko EV, Sokolov VV, Chissov VI, Lukyanets
EA and Vorozhtsov GN. Photodiagn. Photodyn.
Ther. 2008; 5: 187–190.
20. Nemykin VN, Rohde GT, Barrett CD, Hadt RG,
Sabin JR, Reina G, Galloni P and Floris B. Inorg.
Chem. 2010; 49: 7497–7509.
Copyright © 2012 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2012; 16: 1231–1232

1232 E.Y. OSIPOVA ET AL.
21. Nemykin VN, Galloni P, Floris B, Barrett CD, Hadt
RG, Subbotin RI, Marrani AG, Zanoni R and Loim
NM. Dalton Trans. 2008; 4233–4246.
22. Auger A and Swartz JL. Organometallics 2007; 26:
102–109.
23. Bakar MA, Sergeeva NN, Juillard T and Senge MO.
Organometallics 2011; 30: 3225–3228.
24. Schmidt ES, Calderwood TS and Bruice TC. Inorg.
Chem. 1986; 25: 3718–3720.
36. Ascarov KA, Berezin BD, Evstygneeva RP,
Enykolopyan NS, Kirillova GV, Koyfman OI,
Mironov AF, Ponomarev GV, Semeikin AS and
Helevina OG. Porphyrins. Structure, Synthesis,
Properties — M.: Nature. — 1985; pp 332 (in Russ.).
37. Perevalova EG, Reshetova MD and Grandberg KI.
Methods of Elementoorganic Chemistry, Organoiron
Compounds. Ferrocene, Moscow: Nauka, 1983; pp
544 (in Russ.).
25. Beer PD and Kurek SS. J. Organomet. Chem. 1987;
336: C17–C21.
26. Burrell AK, Campbell WM and Officer DL.
Tetrahedron Lett. 1997; 38: 1249–1252.
38. Rodionov AN, Simenel AA, Korlyukov AA,
Kachala VV, Peregudova SM, Zherebker KYa and
Osipova EYu. J. Organomet. Chem. 2011; 696:
2108–2115.
27. Burrell AK, Campbell WM, Officer DL, Scott SM,
Gordon KC and McDonald MR. J. Chem. Soc.,
Dalton Trans. 1999; 3349–3354.
39. Rodionov AN, Anufrieva NV, Simenel AA and
Korlyukov AA. Appl. Organomet. Chem. 2012; in
press.
28. Bucher C, Devillers CH, Moutet JC, Royal G and
Saint-Aman E. Chem. Commun. 2003; 888–889.
29. Bucher C, Devillers CH, Moutet JC, P´ecaut J,
Royal G, Saint-Aman E and Thomas F. Dalton
Tran. 2005; 22: 3620–3631.
30. Wasielewski MR. Chem. Rev. 1992; 92: 435–461.
31. Gust D, Moore TA and Moore AL. Acc. Chem. Res.
1993; 26: 198–205.
32. Beer PD, Gale PA and Chen GZ. Coord. Chem. Rev.
1999; 185–186, 3–36.
33. Liu Z, Yasseri AA, Lindsey JS and Bocian DF.
Sciences 2003; 302: 1543–1545.
40. Joksović M, Ratković Z,Vukiėević M andVukiėević
D. Synlett. 2006; 16: 2581–2585.
41. Menozzi G, Mosti L, Fossa P, Matiolli F and Ghia
M. J. Chet. Chem. 1997; 34: 963–968.
42. Rathelot P, Azas N, El-Kashef H, Delmas F, Giorgio
CD, Timon-David P, Maldonado J and Vanelle P.
Eur. J. Med. Chem. 2002; 37: 671–679.
43. Tezuka M, Ohkatsu Y and Osa T. Bull. Chem. Soc.
Jpn 1976; 49: 1435–1436.
44. Brown GM, Hopf FR, Ferguson JA, Meyer TJ
and Whitten DG. J. Am. Chem. Soc. 1973; 95:
5939–5942.
34. RodionovAN, SimenelAA, NekrasovYuS, Kachala
VV, Osipova EYu and Zherebker KYa. Russ. Chem.
Bull., Int. Ed. 2010; 59: 405–410.
45. Paul-Roth C, Rault-Berthelot J, Simonneaux G,
Poriel C, Abdalilah M and Letessier J. J. Electroan.
Chem. 2006; 597: 19–27.
35. Osipova EYu, Rodionov AN, Simenel AA,
Konovalova NV and Kachala VV. Macrohetero-
cycles 2011; 4: 124–126.
Copyright © 2012 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2012; 16: 1232–1232