1,3-dioxopyrrolo[3,4- b ]porphyrins: Synthesis and chemistry

Article abstract of DOI:10.1021/ol102691s

A novel 1,3-dioxopyrrolo[3,4-b]porphyrin (2) has been synthesized in 70% yield following a [4 + 2] cycloaddition reaction of pyrrolo[3,4-b]porphyrin 1 with ¹O₂. The new imide was used as a template to other 1,3-dioxopyrrolo[3,4-b]por

Full text of DOI:10.1021/ol102691s

ORGANIC
LETTERS
2011
Vol. 13, No. 1
130-133
1,3-Dioxopyrrolo[3,4-b]porphyrins:
Synthesis and Chemistry
Carla M. B. Carvalho,† Maria G. P. M. S. Neves,*,† Augusto C. Tome´,*,†
Filipe A. Almeida Paz,‡ Artur M. S. Silva,† and Jose´ A. S. Cavaleiro†
Department of Chemistry, QOPNA, UniVersity of AVeiro, 3810-193 AVeiro, Portugal, and
Department of Chemistry, CICECO, UniVersity of AVeiro, 3810-193 AVeiro, Portugal
actome@ua.pt; gneVes@ua.pt
Received November 8, 2010
ABSTRACT
A novel 1,3-dioxopyrrolo[3,4-b]porphyrin (2) has been synthesized in 70% yield following a [4 + 2] cycloaddition reaction of pyrrolo[3,4-
b]porphyrin 1 with O2. The new imide was used as a template to other 1,3-dioxopyrrolo[3,4-b]porphyrins and to the corresponding open
1
counterparts. The UV/vis absorption spectra of the new compounds show significant red-shifts when compared with those of the nonsubstituted
analogues. The structure of an imide derivative was confirmed by single-crystal X-ray diffraction.
The development of new synthetic strategies concerning the
functionalization of porphyrins has attracted the interest of many
research groups due to the remarkable photo- and biochemical
properties of this type of compound. The structural modification
of porphyrins at their ꢀ-pyrrolic positions is probably the most
versatile approach to obtain new compounds with improved
properties for a particular application.1 Our research group has
been particularly focused on the development of synthetic
methodologies to functionalize ꢀ-pyrrolic positions of meso-
tetraarylporphyrins by cycloaddition reactions.2-5 In particular,
we have described a novel approach to N-alkylpyrrolo[3,4-b]-
porphyrins via 1,5-electrocyclization of porphyrinic azomethine
ylides generated from the reaction of (2-formyl-5,10,15,20-tet-
raphenylporphyrinato)nickel(II) with N-substituted glycines.6 This
methodology is an important alternative to the synthetic approach
described by Smith and co-workers to obtain similar compounds.7
The Knapp8 and Smith groups9,10 found that the exocyclic
pyrrole unit of the pyrroloporphyrins can act as a diene in
Diels-Alder reactions with acetylenedicarboxylates. Here we
describe that pyrrolo[3,4-b]porphyrin 1 can be converted into
the corresponding 1,3-dioxopyrrolo[3,4-b]porphyrin 2 in excel-
lent yield. We also show that this novel derivative can be further
modified to give access to other 1,3-dioxopyrrolo[3,4-b]por-
phyrins or porphyrin-2,3-dicarboxamide derivatives.
(3) (a) Silva, A. M. G.; Tome´, A. C.; Neves, M. G. P. M. S.; Silva,
A. M. S.; Cavaleiro, J. A. S. Chem. Commun. 1999, 1767. (b) Silva,
A. M. G.; Tome´, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.; Cavaleiro,
J. A. S.; Perrone, D.; Dondoni, A. Tetrahedron Lett. 2002, 43, 603. (c)
Silva, A. M. G.; Tome´, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.;
Cavaleiro, J. A. S. J. Org. Chem. 2005, 70, 2306.
(4) Silva, A. M. G.; Lacerda, S. S. P.; Tome´, A. C.; Neves, M. G. P. M.
S.; Silva, A. M. S.; Cavaleiro; Makarova, E. A.; Lukyanets, E. A. J. Org.
Chem. 2006, 71, 8352.
(5) Oliveira, K. T.; Silva, A. M.S.; Tome´, A. C.; Neves, M. G. P. M.
S.; Neri, C. R.; Garcia, V. S.; Serra, O. A.; Iamamoto, Y.; Cavaleiro, J. A. S.
Tetrahedron 2008, 64, 8709.
† QOPNA, University of Aveiro.
‡ CICECO, University of Aveiro.
(6) Silva, A. M. G.; Faustino, M. A. F.; Tome´, A. C.; Neves, M. G. P. M.
S.; Silva, A. M. S.; Cavaleiro, J. A. S. J. Chem. Soc., Perkin Trans. 1 2001,
2752.
(1) The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guillard,
R., Eds.; Academic Press: San Diego, 2000; Vol. 6.
(2) (a) Tome´, A. C.; Lacerda, P. S. S.; Neves, M. G. P. M. S.; Cavaleiro,
J. A. S. Chem. Commun. 1997, 1199. (b) Silva, A. M. G.; Tome´, A. C.;
Neves, M. G. P. M. S.; Cavaleiro, J. A. S.; Kappe, C. O. Tetrahedron Lett.
(7) Jaquinod, L.; Gros, C.; Olmstead, M. M.; Antolovich, M.; Smith,
K. M. Chem. Commun. 1996, 1475.
(8) Knapp, S.; Vasudevan, J.; Emge, T. J.; Arison, B. H.; Potenza, J. A.;
Schugar, H. J. Angew. Chem., Int. Ed. 1998, 37, 2368.
2005, 46, 4723
.
10.1021/ol102691s  2011 American Chemical Society
Published on Web 12/03/2010

The first evidence that 1,3-dioxopyrrolo[3,4-b]porphyrin 2
can be obtained by oxidation of pyrrolo[3,4-b]porphyrin 1
occurred when we attempted the synthesis of fused diporphyrins
by Diels-Alder reaction of 1 (diene) with meso-tetrakis(pen-
tafluorophenyl)porphyrin (dienophile). The experiment was
carried out by refluxing a toluene solution of both porphyrins.
After 72 h, the TLC analysis revealed the formation of a new
compound, in small amount, with an Rf value smaller than those
of the starting porphyrins and with an intense green color. After
the workup and purification, the mass spectrum of that
compound showed a base peak with a m/z value at 753 not
corresponding to the expected adduct. Based on the mass
spectrum and NMR studies, we were able to establish the
structure of the green compound as 2 (Scheme 1). The 1H NMR
Table 1. Formation of Compounds 2 and 3 using Different
Reaction Conditionsa
recovered yield of yield of
conditions
1 (%)
2 (%)
3 (%)
i
ii
toluene, reflux, 72 h
o-dichlorobenzene,
150 °C, 72 h
60
27
5
28
-
-
iii o-dichlorobenzene,
19
65
-
34
6
-
21
35
-
reflux, 72 h
iv
v
o-dichlorobenzene,
rt, irradiation, 1.5 h
TPP, o-dichlorobenzene,
rt, irradiation, 1.5 h
1. TPP, o-dichlorobenzene,
rt, irradiation, 1.5 h;
2. reflux, 16 h
15
53
vi
-
vii 1. TPP, o-dichlorobenzene,
-
70
-
Scheme 1. Synthesis of Porphyrins 2, 2a, and 3
rt, irradiation, 1.5 h;
2. DDQ, reflux, 30 min
viii o-dichlorobenzene, reflux, N2
99
99
-
-
-
-
ix
o-dichlorobenzene,
reflux, shielded from light
a All reactions were exposed to air, except viii.
Refluxing a toluene solution of 1 for 3 days, in an open system,
affords 2 in 5% yield only (60% of 1 is recovered). However,
in o-dichlorobenzene (o-DCB), at 150 °C, the yield increases
to 28% while in refluxing o-DCB (180 °C) it reaches 34%. In
a control experiment, an o-DCB solution of porphyrin 1 was
heated at reflux under a nitrogen atmosphere. After 3 days
porphyrin 1 was totally recovered, confirming that oxygen is
the oxidant in this reaction. Suspecting that singlet oxygen (1O2)
could have an important role in the oxidation process, an
additional experiment was carried out. An o-DCB solution of
pyrroloporphyrin 1 was heated at reflux for 3 days, in an open
system, but protected from ambient light. Also in this case,
pyrroloporphyrin 1 was completely recovered. This result
confirms that singlet 1O2 is the ultimate oxidant. Based on this
result, it is expected that the yield of 2 may be greatly improved
if the experimental conditions used favor the 1O2 formation.12
The role of 1O2 as dienophile in Diels-Alder reactions is well
established, leading to dioxetane adducts. Usually these adducts
are unstable and convert to carbonyl derivatives.
spectrum of 2 is extremely simple, corresponding to a highly
symmetric molecule: one singlet at δ 3.03 ppm (N-CH3), two
doublets (δ 8.56 and 8.73 ppm) and a singlet (δ 8.63 ppm)
corresponding to the ꢀ-pyrrolic protons and several multiplets
corresponding to the phenyl protons. The 13C NMR spectrum
shows a distinctive signal at δ 163.0 ppm corresponding to the
two carbonyl carbons. These data are compatible with an imide-
fused porphyrin. The demetalation of 2 with a mixture of
sulfuric acid in dichloromethane afforded quantitatively the
corresponding metal-free porphyrin 2a. The UV/vis spectrum
of compound 2a (Figure 2) shows a broad absorption band
centered at 700 nm, which makes this compound a potential
candidate for PDT applications.11
The unusual structure of porphyrin 2, and the anticipated
possibility of using the imide function for the construction of
novel porphyrin derivatives, prompted us to study new experi-
mental conditions in order to improve the yield of such
compound. In fact, after some modifications on the experimental
conditions, we were able to obtain compound 2 in 70% yield
(Table 1). As shown in Table 1 (entries i-iii), the oxidation of
1 to 2 is strongly dependent on the reaction temperature.
An efficient 1O2 production requires, in addition to molecular
oxygen, visible light and a photosensitizing agent (PS). Because
porphyrins are excellent PS,12 probably when porphyrin 1 is
exposed to ambient light, it converts molecular oxygen (3O2)
1
into O2 which then reacts with the porphyrin itself affording
imide 2. This reasoning prompted us to carry out the two
following experiments: (i) irradiation of an o-DCB solution of
1 with artificial white light and (ii) irradiation of an o-DCB
solution of 1 containing an additional PS, namely meso-
tetraphenylporphyrin (TPP). This last strategy was adopted
because our pyrroloporphyrin 1 is a Ni(II) complex and this
type of complexes are usually associated to an inadequate
(9) Vicente, M. G. H.; Jaquinod, L.; Khoury, R. G.; Madrona, A. Y.;
Smith, K. M. Tetrahedron Lett. 1999, 40, 8763.
(10) Liu, W.; Fronczek, F. R.; Vicente, M. G. H.; Smith, K. M.
Tetrahedron Lett. 2005, 46, 7321.
(11) Nyman, E. S.; Hynninen, P. H. J. Photochem. Photobiol. B: Biol.
2004, 73, 1.
(12) DeRosa, M. C.; Crutchley, R. J. Coord. Chem. ReV. 2002, 233-234,
351.
Org. Lett., Vol. 13, No. 1, 2011
131

12
1
production of O2. Both experiments were carried out by
stirring the solutions for 1.5 h at room temperature under
artificial white light (500 W halogen lamp, 350 W m-2) (Table
1, entries iv and v). In both cases an unexpected drastic change
in color (from green to red) was observed. After the workup
and purification compound 2 (obtained in 6 and 15% yield under
conditions iv and v, respectively) was accompanied by a novel
major red compound (21 and 35% under conditions iv and v,
respectively) that was identified as porphyrin 3 (Scheme 1).
Other minor red compounds were also observed by TLC,
mainly when the reaction was carried out in the presence of
TPP, but their characterization was not possible as a result of
their instability in silica gel. Comparing the results of both
experiments, the beneficial effect of the additional PS is evident.
A higher conversion was obtained and the combined yield of 2
plus 3 almost doubled when compared with the reaction without
Another interesting modification of 2 involved its reaction
with pentylamine or 2-aminoethanol in refluxing toluene;
porphyrins 6 and 8 were obtained in quantitative yields (Scheme
3). These porphyrin-2,3-dicarboxamides undergo efficient ring-
Scheme 3. Synthesis of Porphyrins 6-9, 6a, and 8a
1
TPP. The H NMR spectrum of porphyrin 3 shows in the
aliphatic region, in addition to the singlet at δ 3.03 ppm, a
doublet at δ 5.76 ppm corresponding to the resonance of one
proton. This doublet is converted into a singlet by D2O addition.
The mass spectrum of 3 (m/z ) 755, two units higher than 2)
is also in agreement with the proposed structure. Refluxing the
crude reaction mixture obtained under conditions v of Table 1
for 16 h resulted in the complete oxidation of 3 to 2, which
was isolated in 53% yield (Table 1, entry vi). This process is
much faster and efficient if DDQ is added to the reaction
mixture (Table 1, entry vii). In that way, imide 2 is obtained in
70% yield after irradiation for 1.5 h at room temperature
followed by refluxing for 30 min with DDQ.
closure to the corresponding imides 7 and 9 when heated at
reflux in 1,2,4-trichlorobenzene in the presence of La(TfO)3.
These imides were isolated in 38 and 32% yields, respectively
(some imide 2 is also formed in both cases). In the absence of
the Lewis acid catalyst, most part of the dicarboxamides is
recovered and the imides are formed in very low yields (∼2%).
Derivative 7 was successfully crystallized from a mixture of
dichloromethane and hexane, which allowed the isolation of
large crystals whose structure was unveiled from single-crystal
X-ray diffraction.13 The asymmetric unit is composed of a
whole molecular unit as depicted in Figure 1. The porphyrin
ring is distorted with the average planes containing each pyrrole
unit subtending mutual dihedral angles which vary between ca.
22.3 and 27.7° (Figure 1). Noteworthy, these distortions fall
within the expected values for Ni2+ porphyrins, has already been
observed (in several degrees of distortion) for a handful of
related structures10,14 as revealed by a search in the Cambridge
Structural Database15 and by the conformational analysis of
Shelnutt.16 Nevertheless, despite these ring distortions, the
central Ni2+ cation has an almost regular {NiN4} square
planar coordination geometry [Ni-N bond lengths ranging
from 1.9199(15)-1.9328(14) Å; cis and trans angles in the
Once established a fast and efficient procedure for the
conversion of pyrroloporphyrin 1 into imide 2, we decided to
use this imide as precursor for other porphyrin-2,3-dicarboxylic
acid derivatives. Hydrolysis of the imide group with KOH in
propan-2-ol resulted in the formation of the red 3-(methylcar-
bamoyl)porphyrin-2-carboxylic acid 4 in 84% yield (Scheme
2). Several attempts to obtain the porphyrin-2,3-dicarboxylic
Scheme 2. Synthesis of Porphyrins 4, 4a, 5, and 5a
(13) Crystal data: C51H37N5NiO3, M ) 810.55, triclinic, space group
j
P1, Z ) 2, a ) 11.5233(5) Å, b ) 12.9680(5) Å, c ) 13.3977(5) Å, R )
101.394(2)°, ꢀ ) 94.514(2)°, γ ) 99.229(2)°, V ) 1924.56(13) Å3, red
plate with crystal size of 0.18 × 0.12 × 0.04 mm3. Of a total of 75 694
reflections collected, 10 222 were independent (Rint ) 0.0428). Final R1 )
0.0413 [I > 2σ (I)] and wR2 ) 0.1208 (all data). CCDC 780286. See
Supporting Information for further details on the crystal solution and
refinement.
acid by complete hydrolysis of 2 or 4, both in basic and acid
conditions, and either under classical or microwave heating
conditions, were all unsuccessful. When compound 2 was
heated at reflux in DMSO a decarboxylation occurred affording
(14) (a) Alonso, C. M. A.; Serra, V. I. V.; Neves, M. G. P. M. S.; Tome´,
A. C.; Silva, A. M. S.; Paz, F. A. A.; Cavaleiro, J. A. S. Org. Lett. 2007,
9, 2305. (b) Vicente, M. G. H.; Rezzano, I. N.; Smith, K. M. Tetrahedron
1
amide 5 in 52% yield. The H NMR spectrum of 5 shows a
singlet at δ 8.90 ppm which is correlated (3J) with a carbonyl
carbon in the 1H-13C HMBC spectrum suggesting the loss of
CO2. The mass spectrum, with a peak at m/z ) 727, is also
consistent with structure 5.
Lett. 1990, 31, 1365
.
(15) (a) Allen, F. H. Acta Cryst. B 2002, 58, 380. (b) Allen, F. H.;
Motherwell, W. D. S. Acta Cryst. B 2002, 58, 407.
(16) Jentzen, W.; Song, X.-Z.; Shelnutt, J. A. J. Phys. Chem. B. 1997,
101, 1684.
132
Org. Lett., Vol. 13, No. 1, 2011

Figure 2. UV/vis spectra of the free-base derivatives (3 µM) in CHCl3.
The spectrum of TPP is shown as reference.
observed in the UV/vis spectra of the nickel derivatives
(Figure S44, Supporting Information) are less relevant than
those observed in the spectra of the corresponding free-base
porphyrins, supporting a less pronunced distortion of the
macrocycle due to the presence of the metal.
Figure 1. Schematic top and side representations of the molecular
unit of compound 7. Non-hydrogen atoms are represented as thermal
ellipsoids drawn at the 80% probability level, and hydrogen atoms
are represented as small spheres with arbitrary radius (see Figure S41
in the Supporting Information for a detailed atom labeling and specific
bond lengths and angles of the {NiN4} coordination environment).
For clarity, only one location of the pendant pentyl chain is represented.
Pyrroloporphyrin 1 is unstable to acidic conditions6 and,
therefore, cannot be demetalated. However, using the data for
a free-base pyrroloporphyrin reported in the literature,7 we can
see that the lower energy absorption Q-band of compound 2a (700
nm) is 38 nm red-shifted relatively to the corresponding absorption
band of that compound (662 nm). Again, this effect is not so
noticeable when we compare the UV/vis spectra of the nickel
complexes 1 and 2 (Q-bands at 615 and 608 nm, respectively).
In summary, a novel 1,3-dioxopyrrolo[3,4-b]porphyrin (2)
was obtained in excellent yield by a new synthetic approach.
The formation of 2 involves a [4 + 2] cycloaddition reaction
89.64(6)-90.46(6)° and 174.72(6)-175.05(6)° ranges,
respectivelyssee Figure S41 in the Supporting Information].
Crystal packing is essentially mediated by the need to
effectively fill the available space (Figure S42 in the
Supporting Information). Indeed, the combined effect of the high
distortion degree of the ring with the steric impediment of the
pendant aliphatic chain, do not allow the occurrence of significant
supramolecular contacts between neighboring species.
The distortion due to the presence of 1,3-dioxopyrrole
substituent group must be particularly relevant in the free-base
series. In fact, when the UV/vis spectra of compounds 2a, 4a,
5a, and 6a, with different combinations of electron-withdrawing
groups, are compared with the UV/vis spectrum of TPP, the
most remarkable red-shift is observed for porphyrin 2a (Figure
2, see also the UV/vis spectra of the corresponding nickel
complexes in Figure S44, Supporting Information). Comparing
the lower energy absorption Q-band of TPP with the corre-
sponding absorption band of 5a (one electron-withdrawing
group in a ꢀ-pyrrolic position), only a 5 nm red-shift is observed.
Slightly higher red-shifts (ca. 11 nm) are observed for porphy-
rins 4a and 6a (both with two electron-withdrawing groups in
ꢀ-pyrrolic positions).17 This means that the remarkable red-
shift (56 nm) observed for porphyrin 2a cannot be justified by
the presence of two electron-withdrawing groups but mainly
to the enhanced macrocycle distortion18-20 caused by the
presence of the 1,3-dioxopyrrole unit. The differences
1
between pyrrolo[3,4-b]porphyrin 1 (the diene) and O2 (the
dienophile). The novel compound exhibits spectral features (a
Q-band at 700 nm) which are suitable for its potential use in
PDT. Furthermore compound 2 can be used as an adequate
template to other 1,3-dioxopyrrolo[3,4-b]porphyrins or to the
corresponding open counterparts.
Acknowledgment. Thanks are due to the Universidade de
Aveiro, Fundac¸a˜o para a Cieˆncia e a Tecnologia (FCT) for
specific funding toward the purchase of the single-crystal
diffractometer and FEDER for funding the Organic Chemistry
Research Unit and the Project PTDC/QUI/74150/2006. C.M.B.C.
thanks FCT for the PhD grant SFRH/BD/38611/2007.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
Details on the crystal data collection, solution and refinement
of compound 7. Additional drawings of the crystal packing
and asymmetric unit of 7, showing the atomic labeling and
selected bond lengths and angles of the Ni2+ environment.
Crystal structure in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL102691S
(17) It is well established that the presence of electron-withdrawing
substituents in ꢀ-pyrrolic positions promote the contraction of the HOMO-
LUMO gap that is reflected by red-shifts in absorption bands (refs 18-20).
(18) Takeuchi, T.; Gray, H. B.; Goddard, W. A. J. Am. Chem. Soc. 1994,
(19) Shelnutt, J. A.; Song, X.-Z.; Ma, J.-G.; Jia, S.-L.; Jentzena, W.;
Medfortha, C. J. Chem. Soc. ReV. 1998, 27, 31.
(20) Parusel, A. B. J.; Wondimagegn, T.; Ghosh, A. J. Am. Chem. Soc.
2000, 122, 6371.
116, 9730
.
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