Iodine-catalyzed one-pot synthesis of unsymmetrical meso-substituted porphyrins

Article abstract of DOI:10.1016/j.tet.2010.01.055

The wide range use of 5-(4-nitrophenyl)-10,15,20-triphenylporphyrin is well established, but its synthesis requires two steps and is not very practical. This article describes an iodine-catalyzed one-pot synthesis of this unsymmetrical porphyrin that uses

Full text of DOI:10.1016/j.tet.2010.01.055

Tetrahedron 66 (2010) 1994–1996
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iodine-catalyzed one-pot synthesis of unsymmetrical meso-substituted
porphyrins
Benjamin Boe¨ns, Pierre-Antoine Faugeras, Julien Vergnaud, Romain Lucas,
*
Karine Teste, Rachida Zerrouki
´
Laboratoire de Chimie des Substances Naturelles EA1069, Faculte des Sciences et Techniques, 123 Avenue Albert Thomas, F-87060 Limoges, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The wide range use of 5-(4-nitrophenyl)-10,15,20-triphenylporphyrin is well established, but its syn-
thesis requires two steps and is not very practical. This article describes an iodine-catalyzed one-pot
synthesis of this unsymmetrical porphyrin that uses commercial reagents and reactants as such, without
prior distillation. Unsymmetrical mono functionalized porphyrins with various functional groups have
also been obtained to validate this method. The influence of electronic effects of functional groups (donor
or acceptor) has also been studied.
Received 7 December 2009
Received in revised form 8 January 2010
Accepted 14 January 2010
Available online 20 January 2010
Keywords:
Unsymmetrical porphyrins
Iodine catalysis
Ó 2010 Published by Elsevier Ltd.
Microwave-assisted synthesis
Pyrrole
1. Introduction
or the reduction of the latter to amino group.9 However, obtaining
this porphyrin is not an easy task. Indeed, several publications
Porphyrins are key biological compounds. Their photo-electro
and biochemical properties opened a wide field of applications in,
e.g., electronic/electro-optical and nonlinear optics,1 selective ca-
talysis,2 or material chemistry.3 One of these applications is the
well-known use of porphyrins as photosensitizers in photodynamic
therapy,4 which accounts for the importance of these dyes in bio-
conjugation chemistry.5
mention a two-step synthesis, which begins with the preparation of
meso-tetraphenylporphyrin, followed by a selective nitration10 at the
para position of one of the phenyl groups. These two steps, conducted
in restrictive conditions, require intermediate product purification,
and lead to the final product with 20–30% global yield.
On the other hand, molecular iodine has emerged as a really in-
teresting, inexpensive, and readily available catalyst for carrying out
numerous organic reactions.11 Iodine catalysis has been recently
used in selective and efficient conjugate additions of pyrrole to
Since the ‘Fischer era’,6 organic chemists have built a huge ‘cat-
alogue’ of porphyrins. This amazing diversity results from the use of
a number of imaginative synthetic routes but, very often, overall
reaction yields are matters of concern. For example, the synthesis of
unsymmetrical porphyrins presents a real challenge especially
when practicable yields are needed. The well-known Little’s mixed
aldehyde method7 leads to mono functionalized meso-substituted
porphyrins in low yields (4–7%). Although reactants are mixed in
stoichiometric amounts, the symmetrical meso-tetraarylporphyrin
is obtained as the main product.
Recently, a particular attention has been given to the mono
functionalized 5-(4-nitrophenyl)-10,15,20-triphenylporphyrin which
paves the way to valuable intermediates in the synthesis of
substituted porphyrins, thanks to the vicarious nucleophilic sub-
stitution (VNS)8 of hydrogen in ortho position of the nitro group and/
nitroolefins or a,b
-unsaturated ketones.12 These two reactions take
advantage of the mild Lewis-acidity of molecular iodine, which first
activates the carbonyl group. Mechanistic similarities between these
reactions and porphyrinogen formation suggest that iodine could
catalyze the condensation of pyrrole with aldehyde. Recent work in
this field13 confirms this hypothesis, and thus allows avoidance of
the traditional BF3/Et2O or propionic acid systems. This paper reports
an iodine-catalyzed, one-pot synthesis of 5-(4-nitrophenyl)-
10,15,20-triphenylporphyrin, a method that, contrary to the Little’s
protocol, does not require prior reactant or solvent distillation.
2. Results and discussion
The synthesis of meso-tetraphenylporphyrin (Scheme 1) was
performed as a preliminary test of iodine catalysis. Various concen-
trations of reactants and catalyst were assayed. Dichloromethane,
pyrrole, and benzaldehyde were used without prior distillation.
* Corresponding author. Tel.: þ33 5 55 45 72 24; fax: þ33 5 55 45 72 02.
E-mail address: rachida.zerrouki@unilim.fr (R. Zerrouki).
0040-4020/$ – see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.01.055

B. Boe¨ns et al. / Tetrahedron 66 (2010) 1994–1996
1995
Scheme 2. Synthesis of 5-(4-nitrophenyl)-10,15,20-triphenylporphyrin.
Scheme 1. One-pot synthesis of meso-tetraphenylporphyrin 1.
Iodine as an acid promoter in catalytic amount was the key of this
reaction, because it avoided inconvenient conditions, such as the use
of propionic acid. At the same time, we investigated the influence of
several microwave activation conditions. Results summarized in
Table 1 show that iodine as catalyst afforded the final product (except
for entry 2); a high concentration of pyrrole and benzaldehyde
(>10ꢀ1 mol/L) did not lead to any product (entry 2), and finally an
excessive power of activation (ꢁ400 W) favored a significant poly-
merization of pyrrole instead of the expected tetraphenylporphyrin
(entry 5).
Table 3
Comparison of global yields
Entry
Global Yield (%)
Little synthesis (1 step)a
Mononitration (2 steps)
I2 at rt (1 step)a
w7%
w46–56%
12%
I2 with M.W. (1 step)a,b
22%
a
Conditions: pyrrole (1 equiv), benzaldehyde (0.75 equiv),4-nitrobenzaldehyde
(0.25 equiv).
b
Activation: 100 W, 30 ꢂC, 15 min.
into account a previous work,12 activation by microwave irradiation
resulted in a significant yield increase (22%). These two results
confirm that iodine as Lewis acid catalyzes the synthesis of 5-(4-
nitrophenyl)-10,15,20-triphenylporphyrin in good yield after
purification, and show the possible effect of microwave on the se-
lectivity of this reaction (Table 3).
In order to confirm this interesting result, we applied this method
to the synthesis of a variety of mono functionalized porphyrins, –OH
3, –OMe 4, –COOMe 5, and –Cl 6. The presence of these substituents
allows the conjugation of porphyrins with a wide range of mole-
cules: hydroxyl group permits a Williamson alkylation, carboxylic
acid can be obtained by hydrolysis of methoxycarbonyl group, and
chlorine can take part in aromatic nucleophilic substitution.17 In
similar conditions of reaction, all these porphyrins have been
obtained in suitable yields, ranging from 8 to 27% (Table 4).
Interestingly, these results show a possible influence of elec-
tronic effects of each substituent on the reactivity of the carbonyl
group. As a matter of fact, electro acceptor groups, such as –NO2 or
–COOMe tend to increase reaction yields (22% and 27%) whereas,
electro donor groups like –OH or –OMe have the opposite effect (8%
and 11%). This could be interpreted as an increase of the carbonyl
group reactivity induced by electro acceptors via an increase of the
partial positive charge of the carbonyl carbon. This result was
confirmed by a reaction realized with para-tolualdehyde, in which
the electro donor effect is low compared to hydroxyl or methoxy
Table 1
Most significant results for this method
Entry I2
Reagent
Activation
Activation time
first; second (min) (%)
Yield
(equiv) concentration conditions
(mol Lꢀ1
)
1
2
3
4
5
0.2
0.2
0.05
0.1
0.2
5.10ꢀ2
2.10ꢀ1
10ꢀ1
30 ꢂC to 100 W 10; 1
43
0
28
47
18
30 ꢂC to 100 W 30; d
30 ꢂC to 100 W 8; 1
30 ꢂC to 100 W 20; 1
40 ꢂC to 400 W 1/12; 1/6
10ꢀ2
10ꢀ1
The use of excess iodine, expected to directly oxidize por-
phyrinogen, resulted in the vanishing of the benzaldehyde spot,
although a black polymer was produced instead of the desired final
compound. Optimum conditions (entry 4, Table 1) present several
interesting advantages in comparison to other synthesis methods
(Table 2): it is very easy to implement, it uses undistilled reagents
and solvent and gives the final product within a short reaction time
with good yields (47%).
This method was then used to obtain unsymmetrical porphyrins
especially 5-(4-nitrophenyl)-10,15,20-triphenylporphyrin (Scheme 2).
We first compared the synthesis of 2 with the classical Little
pathway and with the mononitration of meso-tetraphenylpor-
phyrin (which requires prior synthesis of tetraphenylporphyrin 1).
Results summarized in Table 3 show that addition of molecular
iodine at room temperature instead of another acid system led to
the final product with a sensible yield (12%). Furthermore, taking
groups. 5-(4-Methylphenyl)-10,15,20-triphenylporphyrin
7 was
obtained with a reference yield of 14%, similar to the 15% yield
Table 2
Synthesis of TPP, comparison with well-known methods
Rothemund14
Pyridine
Adler15
Lindsey16
I2/M.W.
Solvent
(I) Propionic
Acid
Dichloromethane
Chloroform
Dichloromethane
(II) Acetic Acid
Temperature
Catalyst
220 ꢂC
(I) 141 ꢂ
C
25 ꢂ
TFA
C
30 ꢂ
I2
C
(II) 120 ꢂC
Solvolysis
d
BF3, Et2O
BF3, Et2O/EtOH
DDQ or p-chloranil
0.001–0.1 mol Lꢀ1
Oxidant
d
3.6 mol Lꢀ1
O2
p-Chloranil
Reactants
concentration
Reaction time
Synthesis
Purification
Yield
0.3–1 mol Lꢀ1
0.1 mol Lꢀ1
48 h
1 step
Recrystallization
<10%
0.5–1 h
1 step
Filtration
w20%
1 h
2 steps
Chromatography
Up to 45%
21 min
One-pot
Filtration
47%

1996
B. Boe¨ns et al. / Tetrahedron 66 (2010) 1994–1996
Table 4
4.2. General procedure for porphyrin synthesis
Yield comparison between literature and I2/M.W. methods
Substituted aldehydes (0.25 mmol), benzaldehyde (76
0.75 mmol), molecular iodine (25 mg, 0.1 equiv), then pyrrole (70
m
m
L,
L,
Compounds
Aldehydes
Ref. 18 (%)
This study (%)
8
1 mmol) were added successively to 10 mL CH2Cl2, without particular
precautions. After the first activation (100 W, 30 ꢂC), TLC showed the
total conversion of benzaldehyde. para-Chloranil (0.75 equiv,184 mg)
was then added and a second activation was performed (100 W,
30 ꢂC). The reaction mixture was evaporated on florisil and purified
by flash chromatography (eluent gradient: EP/CHCl3, 8/2–1/9).
3
7
4
5
6
7.4
15
5
11
15
27
4.3. Spectroscopic data
All physicochemical properties coincided with literature
data.10,13,18
Acknowledgements
obtained with the synthesis of 5-(4-chlorophenyl)-10,15,20-tri-
phenylporphyrin; the latter attests for the competition between the
two possible effects of the chlorine group, which is at the same time
electro donor and acceptor.
The authors thank Dr. Michel Guilloton for his help in manu-
script editing.
References and notes
3. Conclusions
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4. Experimental section
4.1. General methods
All the solvents and chemicals were commercially available and,
unless otherwise stated, were used as received. Benzaldehyde
(99%), pyrrole (98%), and p-anisaldehyde (98%) were purchased
from Aldrich, and tolualdehyde (98%) was purchased from Alfa
Aesar. Reactions were monitored by thin-layer chromatography
(TLC) on precoated 0.2 mm silica gel 60 F254 (Merck) plates and
visualized with an ultraviolet light source at 254 nm. Microwave
irradiations were performed by the means of an Ethos 1600
MicroSynth reactor from Milestone. Temperature was measured
with a fiber optic thermometer (ATC-FO)/Ethos. 1H NMR spectra
were recorded at 400.13 MHz with a Bru¨ker DPX spectrometer.
Chemical shifts (d) are expressed in parts per million with Me4Si as
an internal standard (
shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet, and br, broad), coupling constants (Hz) and assignment.
d
¼0). Data are reported as follows: chemical