Optimized synthesis of tetrakis(4-methoxyphenyl)porphin-Co(II)

Article abstract of DOI:10.1080/00397910802574617

Detailed kinetic investigation of Rothemund synthesis of porphyrins was conducted in different solvents. A one-pot synthesis of tetrakis(4- methoxyphenyl)porphin-Co(II) from pyrrole, anisic aldehyde, and cobalt acetate was developed that gave 35% isolated yield. Chlorobenzene was found to be the best solvent for the reaction. The synthesis can be done with either propionic or chloroacetic acid as catalyst with about the same yield. Cobalt prevents the synthesis of the porphyrin, so it has to be added in the reaction mixture only after the synthesis of the free porphyrin is finished. Optimum time is 2-2.5h at a temperature of 130C. Lower temperatures reduce the yield. Potentially, these dependencies can be applied to synthesis of other analogous porphyrins. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802574617

Synthetic Communications1, 39: 1679–1689, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802574617
Optimized Synthesis of Tetrakis
(4-methoxyphenyl)porphin–Co(II)
Alexei A. Gridnev and Gregorii A. Nikiforov
Institute of Biochemical Physics of the Russian Academy of Sciences,
Moscow, Russia
Abstract: Detailed kinetic investigation of Rothemund synthesis of porphyrins
was conducted in different solvents. A one-pot synthesis of tetrakis(4-methoxy-
phenyl)porphin–Co(II) from pyrrole, anisic aldehyde, and cobalt acetate was
developed that gave 35% isolated yield. Chlorobenzene was found to be the best
solvent for the reaction. The synthesis can be done with either propionic or chlor-
oacetic acid as catalyst with about the same yield. Cobalt prevents the synthesis of
the porphyrin, so it has to be added in the reaction mixture only after the synth-
esis of the free porphyrin is finished. Optimum time is 2–2.5 h at a temperature of
130ꢀC. Lower temperatures reduce the yield. Potentially, these dependencies can
be applied to synthesis of other analogous porphyrins.
Keywords: Cobalt porphyrine, porphine, synthesis, tetrakis(4-methoxyphenyl)-
porphin, tetraphenylporphin
Cobalt porphyrins catalyze chain transfer to monomer in radical
polymerization.[1] Although not the most active ones, cobalt porphyrins
are less sensitive to catalytic poisons in catalyzed chain transfer
(CCT).[2] The high cost of porphyrins seems to preclude their usage in
commercial applications. This work aimed to optimize synthesis of the
one of the most prominent candidates among porphyrins as a commer-
cial CCT catalyst, tetrakis(4-methoxyphenyl)porphine, also known as
tetraanisylporphin (TAP). TAP can be obtained conveniently from
Received October 8, 2008.
Address correspondence to Gregorii A. Nikiforov, Institute of Biochemical
Physics of the Russian Academy of Sciences, Kosygin St., 4, Moscow, Russia.
E-mail: aagridnev@gmail.com
1679

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A. A. Gridnev and G. A. Nikiforov
unsubstituted pyrrole and corresponding arylaldehyde in a one-pot,
two-step synthesis as indicated in Scheme 1,[3] also referred to by some
authors as the Rothemund synthesis of prophyrins.
Condensation of CH acids with carbonyl compounds is catalyzed by
bases as well as by acids. Earlier, condensation shown in Scheme 1 was
carried out under basic catalytic conditions.[4,5] Thus heating of pyrrole
with benzaldehide in pyridine in the presence of zinc acetate gave rise
to mezo-tetraphenylporphine (TPP) at maximum yield of 18%.[6]
Further investigation of this reaction was carried out by Adler et al.,
who showed that condensation of pyrroles with aldehydes is more
effective under acid catalysis.[7,8] With the use of an air stream as an
oxidizer, the yield of substituted TPP can reach 40% (spectrophotometric
estimation).[9] However, this same author showed that real yield of TPP is
no more than 20% if the condensation occurs in boiling propionic acid.[8]
TPP is separated easily by filtration after cooling of the reaction mixture.
Washing crystals with methanol gave TPP containing no more than 1%
of porphinogene.
Acid-catalyzed synthesis of TPP and its derivatives became a leading
method in recent years. Acetic,[7,9] propionic,[8,10] chloro- and trichloro-
aceticacids,[7,11,12] trifluoroacetic acid,[11,13] p-nitrobensoic acid,[14] and
Lewis acids (BF3ꢀEt2O,[15] AlCl3[16]) are used as acids. Stronger acids
(F3CCOOH, Cl3CCOOH, ClCH2COOH) can also be used, but it is
necessary to process reaction mixture with NH4OH.[17]
EXPERIMENTAL
All reagents (Reakhim, Russian Federation) were KhCh grade and were
used without further purification. Pyrrole and anisic aldehyde were dis-
tilled and kept in a refrigerator. In a typical procedure, solvent and acidic
catalyst (ꢁ60 ml total) were warmed up to slow reflux. Then an equi-
molar mixture of pyrrole with anisic aldehyde (0.0145 mol) was added
during ꢁ10 min, maintaining the reaction temperature at 127–130ꢂC.
Scheme 1. Reaction of pyrrole with aldehydes.

Tetrakis(4-methoxyphenyl)porphin–Co(II)
1681
Small samples (0.5 ml) of reaction mixture were taken at the indicated
amount of time. Optical density of the taken samples was determined
at Specord UV–vis (DDR) by the band of protonated form of MeO-
TPP at 658 nm after dilution with propionic acid. When nitrobenzene
was used as oxidizer, the process was carried out either under argon or
with a slow stream of air passing through the reaction mixture.
After the reaction was over, reaction mixture was chilled down to
room temperature, and after 30 min precipitated crystals of TAP were fil-
tered off, washed with methanol and ether, and dried under vacuum.
Purity of porphyrin was determined by thin-layer chromatography
(TLC) on Merk plastic 20=20 panels (silica gel 60 F254) in chloroform.
All yields given in the figures are spectral ones.
RESULTS AND DISCUSSION
We chose TAP as a target for this work because its Co complex is more
soluble in common organic solvents than the corresponding TPP com-
plex. Two methods attracted our attention most. The first was Adler’s
method of refluxing in propionic acid, because of simplicity.[8] The
second, as suggested by Semeikin,[11] was usage of xylene with chloro-
acetic acid with simultaneous azeotropic removal of water. Results of
our experiments are summarized in Table 1. Yields including the accom-
panying chlorine derivative are given in Table 1.
As was expected, Adler’s method provided about 20% yield of TAP
and high (99%) purity. Replacement of propionic acid with acetic acid
reduced yields by half (entries 1–4). Semeikin’s approach also was repro-
duced with TAP instead of TPP at about double the yield. Xylene was
one of the best solvents among those tested, and water removal was
found to be crucial (entries 5–9). Besides p-xylene, chlorobenzene is
another good solvent for the Rothemund reaction (entries 10–12).
Oxygen is the mostly used oxidizer of porphyrogen.[8,11,17] Other
oxidizers can be used, such as chloroanil[13,18–20] and nitrobenzene.[21,22]
Nitrobenzene is especially attractive for large-scale applications because
unlike other oxidizers, nitrobenzene is liquid.
In all cases, with either p-xylene or chlorobenzene as solvents, the
highest yields were reached in about 2.5 h (Fig. 1). Some researchers
suggested that reaching equilibrium in porphinogen formation vs. linear
oligomers may be beneficial in the Scheme 1 synthesis.[15] In our experi-
ments, we found that oxidizing prophinogen right at the very beginning
of condensation rather than waiting for the equilibrium to set gave better
yields. Thus, addition of the nitrobenzene half an hour after the addition
of pyrrole and aldehyde slightly reduced the yield (Fig. 2).

1682

Tetrakis(4-methoxyphenyl)porphin–Co(II)
1683
Figure 1. Kinetics of TAP synthesis: 1, PhCl, 2.5% chloroacetic acid, 130ꢂC, air;
2, p-xylene, 2.5% chloroacetic acid, 130ꢂC, air; and 3, p-xylene, 25% propionic
acid, 130ꢂC, air.
The best results with the chlorobenzene=propionic acid mixture were
obtained when concentration of the acid in the reaction mixture was
more than 20%. Greater concentrations of the propionic acid do not
improve the yield further (Fig. 3). Found conditions of TAP synthesis
Figure 2. Dependence of TAP yield on reaction time: 1, PhCl=EtCOOH ¼ 3:1
(vol.), under Ar, oxidizer PhNO2; after 30 min of stirring: Pyr=ArCHO=PhNO2 ¼
1:1:1 (mol), Pyr=EtCOOH ¼ 1:15 (mol), 130ꢂC. 2, PhCl, PhCl=CH3CH2COOH ¼
3:1 (vol), oxidizer PhNO2=O2 (simultaneous introduction of Pyr-ArCHO=
PhNO2), Pyr=ArCHO=PhNO2 ¼ 1:1:1 (mol), Pyr=EtCOOH ¼ 1:15 (mol), 130ꢂC.

1684
A. A. Gridnev and G. A. Nikiforov
Figure 3. Dependence of TAP yield on concentration of CH3CH2COOH. PhCl,
Pyr=ArCHO=PhNO2 ¼ 1:1:1, under Ar. An oxidizer, PhNO2, was added after
30 min of stirring; 130ꢂC, 2 h.
in chlorobenzene provide robustness toward concentrations of pyrrole
and aldehyde in the reaction mixture (Fig. 4).
For oxidation of porphinogen into porphin, theoretically, three
oxygen atoms are required. However, only two oxygen atoms from
nitrobenzene were enough for successful conversion of porphinogen
into porphin according to Fig. 5, where equimolar concentrations of
nitrobenzene provided the highest yields. We would not like to speculate
Figure 4. Dependence of TAP yield on the ratio of Pyr=EtCOOH (mol=mol).
PhCl=EtCOOH ¼ 3:1 (v=v), Pyr=ArCHO=PhNO2 ¼ 1:1:1 (mol=mol); oxidizer
PhNO2=O2, 130ꢂC, 2 h.

Tetrakis(4-methoxyphenyl)porphin–Co(II)
1685
Figure 5. Dependence of TAP yield on ratio of Pyr=PhNO2 (mol=mol). PhCl=
RCOOH ¼ 3:1 (v=v), Ar, Pyr=ArCHO ¼ 1:1 (mol=mol), Pyr=Et COOH ¼ 1:15
(v=v). An oxidizer, PhNO2, was added after 30 min of stirring; 130ꢂC, 2 h.
on the mechanism of the oxidation at this point. Possibly, excess
hydrogen atoms in the Scheme 1 synthesis were transferred to the
reaction by-products or to azobenzene that may form in reduction of
nitrobenzene.
Insertion of metal atoms into prophyrin cavity requires an additional
step. Generally, metal insertion requires porphyrin to be dissolved in a
solvent or mixture of solvents that solubilizes both the poprhyrin and
the metal salt. The problem is that the first one is hydrophobic and the
second one is hydophilic. Known solvents appropriate for porphyrin
metallation are dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
and mixtures or chloroform with methanol.
One of the reasons for playing with different solvents in the Scheme 1
synthesis was our desire to combine both steps, poprhyrin synthesis
and metallation, into a one-pot reaction. Chlorobenzene at elevated
temperatures turned out to be the best choice for this one-pot synthesis
of metalloporphyrin. It dissolves both poprhyrin and cobalt acetate
well.
Cobalt acetate should be added only after synthesis of porphyrin
is complete. It is clearly shown in Fig. 6. The optimal amount of
cobalt salt was found to be 40–50% of the theoretical amount (Fig. 7).
These numbers correlate with yield of porphyrin in the reaction in
Scheme 1.
Table 2 data indicate that optimal temperature for synthesis of both
TAP and TAP-Co is not less that 130ꢂC. It cannot be discounted that the
yields would be greater at greater temperatures, but different solvents

1686
A. A. Gridnev and G. A. Nikiforov
Figure 6. Dependence of yield of TAP-Co on time of Co(OAc)2 ꢀ 4 H2O addition
into reaction mixture; 127ꢂC; Pyr=ArCHO=PhNO2 ¼ 1:1:1 (mol); Pyr=Co(OAc)2 ꢀ
4 H2O ¼ 8:1 (mol=mol); PhCl=EtCOOH ¼ 3:1 (v=v); # the addition time of
Co(OAc)2 ꢀ 4 H2O.
then are required because the mixture of chlorobenzene and propionic
acid boils at this temperature.
Table 2 data correlate with the Fig. 6 data that show that cobalt
suppresses formation of porphyrin, although it is not clear whether
Figure 7. Dependence of the yield of Co-MeO–TPP on ratio of pyrrole=
Co(OAc)2 ꢀ 4 H2O; 127–130ꢂC; 2.5 h; Pyr=ArCHO=PhNO2 ¼ 1:1:1 (mol); PhCl=
EtCOOH ¼ 3:1 (ml): Pyr=EtCOOH ¼ 1:15 (ml).

Tetrakis(4-methoxyphenyl)porphin–Co(II)
1687
Table 2. Isolated yield of TAP and TAP-Co at different temperatures
T (ꢂC)
Yield of TAP-Co (%)
Yield of TAP (%)
130
120
110
34
26
17
38
28
20
cobalt prevents oxidation of porphinogen or cyclization of pyrrol=
aldehyde adducts.
Optimized Synthesis of TAP–Co
A mixture of 1 ml (0.0145 M) of pyrrole, 2.75 ml (0.0145 M) of anisic
aldehyde, and 1.5 ml (0.0145 M) of nitrobenzene was added dropwise
during about 5 min to a stirred solution of 15 ml (0.2 M) of propionic acid
in 45 ml of chlorobenzene at 130ꢂC. The mixture was stirred for 2 h at
127–130ꢂC while azeotrope was distilled off under airflow (10–15ml=min
under the reaction mixture surface). Then, a solution of 1.8 g (0.0073 M)
Co(OAc)2 ꢀ 4 H2O in 10ml of propionic acid was added dropwise while
maintaining the temperature warmer than 125ꢂC. The mixture was stirred
for 30min at 127–130ꢂC, chilled to 18–20ꢂC, stirred additionally for
30min, and filtered. Shiny purple crystals were washed with 10 ml of
MeOH and 5 ml of ether. After drying in a vacuum, 0.98g of TAP-Co
was obtained, which is 34% isolated yield at 97–98% purity (TLC).
CONCLUSIONS
One-pot high-yield synthesis of TAP-Co has been developed. Chloroben-
zene is a promising solvent for the porphyrin synthesis, providing slightly
better yields. Presumably, better stability of chlorobenzene toward oxida-
tion reactions makes it more preferable than xylenes in the Rothemund
synthesis of porphins. Apparently, this approach can be used in synthesis
of other TPP derivatives and other metal complexes, as well. Cobalt does
not work as a template in the synthesis of porphyrins from pyrrole and
aldehydes. Moreover, it has profound negative impact on it. The amount
of cobalt is not to be more than 100–120% of the amount of porphyrin
synthesized in the first step. Finally, we would like to add that our
one-pot synthesis of TAP-Co was reproduced by other chemists at
different laboratories with isolated yields in the 32–35% range.

1688
A. A. Gridnev and G. A. Nikiforov
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