Synthesis of 5-(4-X-Phenyl)-10,15,20-tris(substituted phenyl) porphyrins using dipyrromethanes

Article abstract of DOI:10.3390/60600533

5-(4-X-Phenyl)-10,15,20-tris(substituted phenyl) porphyrins (4-6) were synthesized from meso-(substituted phenyl) dipyrromethanes (1-3), which in turn were prepared in yields of 75-92%. This synthetic pathway was compared with the binary mixed aldehyde an

Full text of DOI:10.3390/60600533

Molecules 2001, 6, 533-539
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of 5-(4-X-Phenyl)-10,15,20-tris(Substituted Phenyl)
Porphyrins Using Dipyrromethanes
Edgardo N. Durantini
Departamento de Química y Física, Universidad Nacional de Río Cuarto, Agencia Postal Nº 3, Río
Cuarto 5800, Argentina; e-mail: edurantini@exa.unrc.edu.ar
Received: 27 November 2000; in revised form 8 May 2001 / Accepted: 9 May 2001 / Published: 31 May
2
001
Abstract: 5-(4-X-Phenyl)-10,15,20-tris(substituted phenyl) porphyrins (4-6) were
synthesized from meso-(substituted phenyl) dipyrromethanes (1-3), which in turn were
prepared in yields of 75-92 %. This synthetic pathway was compared with the binary mixed
aldehyde and pyrrole condensation method. The reported dipyrromethane approach is
advantageous for porphyrins substituted by –OCH (4) and -F (6) groups (12-14 %), while
3
the yield of porphyrins bearing –N(CH ) (5) groups was similar (~0.3 %) by both methods.
3
2
Keywords: Porphyrin; dipyrromethane.
Introduction
Meso-substituted porphyrins are the great interest for the development of model systems in
biomimetic and materials chemistry [1]. Peripherally asymmetric AB -porphyrins, bearing three identical
3
substituted phenyl groups (B), can be covalently linked to other structures by the functional group
contained in the remaining phenyl substituent (A) [2,3]. These porphyrins bearing two different types of
meso-substituents can be prepared by a binary mixed aldehyde condensation [4,5]. However, this

Molecules 2001, 6
534
approach is statistical in nature and usually six porphyrins are formed [6]. Product isolation requires
careful and tedious chromatographic separations, the yield is very poor and it is not always possible to
isolate pure porphyrin. More direct approaches to trans-substituted porphyrins are provided by
condensation of dipyrromethane with aldehyde [7]. This route requires access to meso-substituted
dipyrromethane, which can be synthesized from the reaction of aldehyde with excess of pyrrole catalyzed
by acid [7,8]. In this paper, 5-(4-X-phenyl)-10,15,20-tris(substituted phenyl) porphyrins (4-6) were
synthesized from meso-(substituted phenyl) dipyrromethanes (1-3). The yields obtained using the
dipyrromethane approach are considerably higher for porphyrins substituted by –OCH (4) and -F (6)
3
groups than when the binary mixed aldehyde and pyrrole condensation method was used. However, in
spite of the fact that dipyrromethane 2 substituted by –N(CH ) was obtained with appreciable yield, it
3
2
does not present any advantage, as far as yield is concerned, for the synthesis of porphyrin 5.
Results and Discussion
Dipyrromethane formation.
The condensation of substituted benzylaldehyde with a large excess of pyrrole (1:45 aldehyde/
pyrrole mol ratio) catalyzed by trifluoroacetic acid affords meso-(4-substituted phenyl) dipyrromethanes
1-3 (Scheme 1). Under these conditions, pyrrole serves both as the reactant in excess and as the solvent
for the reaction. Complete consumption of the aldehyde was observed after stirring the mixture for 25
min at room temperature.
Scheme 1
R
F3CCOOH
R
H
2
+
C
Pyrrole
r.t., 20 min, Ar
75-92 %
N
H
O
NH HN
H
OCH3
F
F
F
F
(1) R:
(2) R:
N(CH3)2 (3) R:
F
OCH3
The dipyrromethanes 1, 2 and 3 were isolated by flash chromatography in 87, 75 and 92 % yields,
respectively. A mildly basic medium (n-hexane/ethyl acetate/triethylamine ~1%) was used as eluant to
prevent the decomposition of the dipyrromethane on the silica column used.

Molecules 2001, 6
535
Dipyrromethanes 1-3 are stable in the purified form if stored at 0°C under nitrogen atmospheres and
in the absence of light. The results show that this condensation reaction is compatible with aromatic
aldehydes bearing -OCH , -N(CH ) and –F groups, widening the broad scope of these reactions [7,8].
3
3 2
Synthesis of porphyrins
Porphyrins 4-6 were synthesized by the acid-catalyzed condensation of dipyrromethanes 1-3 and the
corresponding benzaldehyde derivatives in chloroform at room temperature (Scheme 2).
Scheme 2
R
H
R
NH HN
.
. BF O(Et) /CHCl
3 2
3
1
+
NH
N
N
O
r.t., 80 min.
R
C
R
X
H
+
2. DDQ, r.t., 60 min, Ar
HN
O
H
X
C
R
OCH3
F
F
F
F
(4) R:
(5) R:
N(CH3)2 (6) R:
F
OCH3
X: NHCOCH3
X: NHCOCH3
X: COOCH3
Mixed-benzaldehyde dipyrromethane condensations were performed using about [2.2:1.4:1] molar
ratios of dipyrromethane, 4-X-benzaldehyde and substituted benzaldehyde. These amounts of reactants
lead to better yields of the selected AB -porphyrins. Under the experimental conditions used the acid-
3
catalyzed fragmentation of dipyrromethane leads to an increase in the formation of symmetric
porphyrins. Consequently, this side reaction was minimized by adding a small excess of the 4-X
benzaldehyde with respect to the substituted benzaldehyde. After this adjustment, the reaction mixture
was subjected to oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The porphyrins
were separated in high purity by flash chromatography using dichloromethane/methanol or acetone
mixtures as eluants. In all these cases, the first purple band corresponds to the meso-tetra(substituted
phenyl) porphyrin and the second is the desired AB -porphyrins (4-6), which were obtained in yields of
3
14, 0.3 and 12 %, respectively. In each case, the corresponding symmetrical porphyrins were formed in
yields of 12, 0.5 and 10 %, respectively.
Another way of preparing these porphyrins, bearing two different types of meso-substituents, is a
binary mixed aldehyde condensation. Thus, porphyrin 4 was synthesized using this procedure by heating

Molecules 2001, 6
536
a mixture of 4-acetamidobenzaldehyde, 3,5-methoxybenzaldehyde and pyrrole in propionic acid at 90 ºC
for 1 h. The reaction workup was not simple due to the difficulty of removing the propionic acid and the
tars present. Porphyrin 4 was separated by slow column chromatography to yield 2.6 % of the desired
compound. Porphyrin 5 was also prepared under similar conditions using a mixture of 4-
acetamidobenzaldehyde, 4-N,N-dimethylaminobenzaldehyde and pyrrole yielding the desired product in
a yield of ~0.4 % after a lenghty purification procedure [4]. The synthesis of porphyrin 6 via a
modification of Lindsay’s method was previously reported in the literature [5]. The reaction of
pentafluorbenzaldehyde, 4-carbomethoxybenzaldehyde and pyrrole was performed in chloroform using
trifluoracetic acid as catalyst to yield ~1.5 % of porphyrin 6.
In conclusion, the reported results expand the scope of the AB -porphyrin synthesis using dipyrro-
3
methane/benzaldehyde mixtures [8]. This method considerably increases the yields of porphyrins 4 and 6
in comparison with the binary mixed aldehyde condensation procedures. However, this pathway does not
present any advantage in the synthesis of porphyrin 5, substituted by –N(CH ) groups. In this case, the
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2
presence of a high level of side products was detected. The amine group apparently produces an increase
in the formation of open-chain oligomers, which complicate the porphyrin purification and the yield is
considerably diminished. Trifluoroacetic acid, an alternative catalyst of these reactions instead of
.
BF O(Et) , could diminish the acidolysis of 1,9-unsubstituted dipyrromethanes and the amount of
3
2
oligomers formed [9]. Finally, the resulting amido porphyrins 4-6 can be hydrolyzed to the correponding
amino porphyrins, which are interesting starting materials for preparing supramolecules linked by amide
bond [1].
Acknowledgments
The author is grateful to the Consejo Nacional de Investigaciones Científicas y Técnicas
(CONICET), Fundación Antorchas and Agencia Nacional de Promoción Científica y Tecnológica of
Argentina for financial support. E.N.D. is a scientific member of CONICET.
Experimental
General
Absorption spectra were recorded on a Shimadzu UV-2401PC. NMR spectra were recorded on a
Varian Gemini spectrometer at 300 MHz. Mass spectra were taken with a Varian Matt 312 operating in
EI mode at 70 eV. All the chemicals were received from Aldrich and were used without further
purification. Solvents (Merck, GR grade) were redistilled. Chloroform was stored over 4Å molecular
sieves.

Molecules 2001, 6
537
Synthesis of dipyrromethane derivative.s
meso-(3,5-Dimethoxyphenyl)dipyrromethane (1).- A solution of 3,5-dimethoxybenzaldehyde (1.33 g, 8
mmol) and pyrrole (25 mL 360 mmol) was degassed by bubbling with argon for 15 min, then
trifluoroacetic acid (154 µL, 2 mmol) was added. The solution was stirred for 25 min at room
temperature, at which point no starting aldehyde was evident by TLC analysis (cyclohexane/ethyl
acetate/triethylamine; 80:20:1). The mixture was diluted with dichloromethane (50 mL), washed with
aqueous 0.1 M NaOH (50 mL) and then washed with water. The organic phase was dried with Na SO ,
2
4
filtered and the solvent was removed under reduced pressure. The unreacted pyrrole was removed by
vacuum distillation at room temperature. Flash chromatography (silica gel, cyclohexane/ ethyl
acetate/triethylamine; 80:20:1) yielded 1.96 g (87 %) of the pure dipyrromethane 1. TLC (silica gel) Rf
1
(
cyclohexane/ethyl acetate/triethylamine 80:20:1) = 0.40. H-NMR (CDCl , TMS) δ [ppm] 3.85 (s, 6H);
3
5
.41 (s, 1H, meso-H); 5.90 (m, 2H, pyrrole-H); 6.15 (q, 2H, pyrrole-H); 6.69 (m, 2H, pyrrole-H); 6.87 (t,
+
1H, J=2.4 Hz); 7.38 (t, 2H, J=2.4 Hz); 7.92 (s, brs, 2H, pyrrole-NH). MS [m/z] 282 (M ). Anal. Calcd.
for C H N O : C 72.32, H 6.42, N 9.92; found C 72.27, H 6.46, N 9.98.
1
7
18
2
2
meso-(4-N,N-Dimethylaminophenyl)dipyrromethane (2)-.
A
sample of 4-N,N-dimethylamino
benzaldehyde (1.19 g, 8 mmol) was processed as described for dipyrromethane 1, affording 1.60 g (75
%
) of the pure dipyrromethane 2. TLC (silica gel) R (cyclohexane/ethyl acetate/triethylamine 80:20:1) =
f
1
0
.26. H-NMR (CDCl , TMS) δ [ppm] 2.90 (s, 6H); 5.35 (s, 1H, meso-H); 5.91 (m, 2H, pyrrole-H); 6.12
3
(
q, 2H, pyrrole-H); 6.66 (m, 2H, pyrrole-H); 7.06 (d, 2H, J=8.5Hz); 7.41 (d, 2H, J=8.7Hz); 7.97 (s, brs,
+
2
H, pyrrole-NH). MS [m/z] 265 (M ). Anal. Calcd. for C H N : C 76.95, H 7.22, N 15.84; found C
1
7
19
3
76.89, H 7.28, N 15.88.
meso-(Pentafluorophenyl)dipyrromethane (3).- A sample of pentafluorobenzaldehyde (1.57 g, 8 mmol)
was processed as described for dipyrromethane 1, affording 2.30 g (92 %) of the pure dipyrromethane 3.
1
TLC (silica gel) R (cyclohexane/ethyl acetate/triethylamine 80:20:1) = 0.46. H-NMR (CDCl , TMS) δ
f
3
5
.88 (s, 1H, meso-H); 6.00 (m, 2H, pyrrole-H); 6.15 (q, 2H, pyrrole-H); 6.74 (m, 2H, pyrrole-H); 8.10 (s,
+
brs, 2H, pyrrole-NH). MS [m/z] 312 (M ). Anal. Calcd. for C H N F : C 57.70, H 2.91, N 8.97; found C
1
5
9
2 5
5
7.79 H 2.83, N 8.90.
Synthesis of meso-substituted porphyrins
-(4-Acetaminophenyl)-10,15,20-tris(3,5-dimethoxyphenyl) porphyrin (4).- A solution of 3,5-
5
dimethylbenzaldehyde (257 µL, 1.55 mmol), 4-acetamidobenzaldehyde (350 mg, 2.15 mmol) and
dipyrromethane 1 (974 mg, 3.45 mmol) in 250 mL of chloroform was purged with argon for 15 min.
.
Then BF O(Et) (1.05 mmol, 0.42 mL of 2.5 M stock solution in chloroform) was added. The solution
3
2

Molecules 2001, 6
538
was stirred for 80 min at room temperature. Then, DDQ (510 mg, 2.25 mmol) was added and the mixture
was stirred for an additional 1 h at room temperature. The solvent was removed under reduced pressure
and flash column chromatography (silica gel, dichloromethane/acetone 5 %) gives 185 mg (14 %) of the
pure desired porphyrin 5 as the second moving band. TLC (silica gel) R (dichloromethane/acetone 5%)
f
-
1
-1
=
0.33. UV-visible λmax (dichloromethane) [nm] (ε [M cm ]) 422 (475,000), 516 (20,900), 551 (7,500),
1
5
92 (6,300) and 650 (3,800). H-NMR (CDCl , TMS) δ -2.79 (s, 2H, brs, pyrrole N-H); 3.96 (s, 18H, Ar-
3
OCH ); 6.89 (t, 3H, J=2.4Hz,10,15,20-Ar); 7.39 (t, 6H, J=2.4Hz, 10,15,20-Ar); 7.48 (brs, 1H, Ar-
3
NHCO); 7.87 (d, 2H, J=8.0Hz, 5-Ar); 8.17 (d, 2H, J=8.0Hz, 5-Ar); 8.90-8.95 (m, 8H, pyrrole-H). MS
+
[
m/z] 851 (M ). Anal. Calcd. for C H N O : C 73.31, H 5.32, N 8.22; found C 73.40, H 5.39, N 8.15.
5
2
45
5
7
Porphyrin 4 was also synthesized from a mixture of 3,5-dimethoxylbenzaldehyde (1.5 g, 9 mmol) and
-acetamidobenzaldehyde (490 mg, 3 mmol) in propionic acid (100 mL) stirred at 90 °C. Then, 1.1 mL
4
of pyrrole (16 mmol) was slowly added. The resulting mixture was allowed to reflux for one hour at
which time it was poured into 350 mL of water (containing 10 g of NaCl). The precipitated material
(green mass) was collected by vacuum filtration. The precipitate was dried under vacuum at 60 ºC for 48
hours to remove propionic acid. The resulting material was dissolved in chloroform/ methanol (5%) and
filtered on short column of alumina. This procedure was repeated using silica gel. The solvents were
removed under reduced pressure and treated with DDQ (908 mg, 4 mmol) in 150 mL of chloroform for 2
hours. The solvent was evaporated and the residual was pulverized to a fine powder. Slow
chromatography column (silica gel, chloroform/methanol gradient) afforded 66 mg (2.6 %) of the pure
desired porphyrin 4 as the second moving band.
5-(4-Acetaminophenyl)-10,15,20-tris(4-N,N-dimethylaminophenyl) porphyrin (5).- A sample of 4-N,N-
dimethylaminobenzaldehyde (231 mg, 1.55 mmol), 4-acetamidobenzaldehyde (350 mg, 2.15 mmol) and
dipyrromethane 2 (914 mg, 3.45 mmol) was processed as described for porphyrin 4. The solution was
treated water (100 mL) and the organic phase was extracted with dichloromethane. The solvent was
removed under reduced pressure. The residue was purified by flash chromatography
(dichloromethane/methanol 1%). This procedure was repeated to yield 4 mg (0.3%) of the pure selected
porphyrin 5 as second moving band. TLC (silica gel) R (dichloromethane/ methanol 3%) = 0.46. MS
f
+
[
m/z] 800 (M ). Spectroscopic data for porphyrin 5 were previously reported [4].
5-(4-Carbomethoxyphenyl)-10,15,20-tris(pentafluorophenyl) porphyrin (6).- A sample of penta-
fluorobenzaldehyde (353 mg, 1.8 mmol), 4-carboxymethylbenzaldehyde (410 mg, 2.5 mmol) and
dipyrromethane 3 (1.25 g, 4.0 mmol) was processed as described for porphyrin 4. Purification by flash
chromatography afforded 203 mg (12%) of the pure porphyrin 6 as the second moving band. TLC (silica
+
gel) R (dichloromethane) = 0.61. MS [m/z] 942 (M ). Spectroscopic data for porphyrin 6 were identical
f
to those previously reported [5].

Molecules 2001, 6
539
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Sample Availability: Samples are available from the author.
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