MnO2 instead of quinones as selective oxidant of tetrapyrrolic macrocycles

Article abstract of DOI:10.1016/j.inoche.2009.12.032

Porphyrins and chlorins were generated through dehydrogenation of the corresponding porphyrinogen and bacteriochlorin precursors using activated manganese dioxide and focused microwave irradiation. The application of this inexpensive heterogeneous oxidant under microwave heating conditions, instead of the quinones usually employed in conventional methodologies, allowed short reaction times, simple overall work-ups and good yields.

Full text of DOI:10.1016/j.inoche.2009.12.032

Inorganic Chemistry Communications 13 (2010) 395–398
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Inorganic Chemistry Communications
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MnO2 instead of quinones as selective oxidant of tetrapyrrolic macrocycles
Bruno F.O. Nascimento a, António M.d’A. Rocha Gonsalves b, Marta Pineiro a,
*
a Department of Chemistry, University of Coimbra, Rua Larga 3004-535, Coimbra, Portugal
b Chymiotechnon, University of Coimbra, Rua Larga 3004-535, Coimbra, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Porphyrins and chlorins were generated through dehydrogenation of the corresponding porphyrinogen
and bacteriochlorin precursors using activated manganese dioxide and focused microwave irradiation.
The application of this inexpensive heterogeneous oxidant under microwave heating conditions, instead
of the quinones usually employed in conventional methodologies, allowed short reaction times, simple
overall work-ups and good yields.
Received 27 November 2009
Accepted 30 December 2009
Available online 6 January 2010
Keywords:
Porphyrin
Ó 2010 Elsevier B.V. All rights reserved.
Chlorin
Bacteriochlorin
Manganese dioxide
Microwave synthesis
Oxidation
Tetrapyrrolic macrocycles are crucial in a myriad of naturally-
occurring processes of fundamental importance in living organ-
isms [1]. Not surprisingly, these compounds attracted the interest
of several researchers of numerous scientific disciplines aiming to
mimic the role of these compounds in nature, understand the
mechanisms involved and, also, develop novel applications based
on the biological models [2]. However, the exploitation of these
applications has been somewhat limited by the existing methods
for the synthesis of some of these structures. Porphyrinogens, tet-
rahydroporphyrins, dihydroporphyrins and porphyrins are tetra-
pyrrolic macrocycles in different oxidation states with three
successive dehydrogenations steps between the porphyrinogen
and the porphyrin stages (Scheme 1).
The known methods for the synthesis of meso-substituted
hydroporphyrins followed a two-step procedure: synthesis of the
corresponding porphyrins followed by reduction. The reduction
step can be achieved with sodium in isoamilic alcohol [3–5],
through borohydration [6], photochemical reduction [7], catalytic
hydrogenation [8–10] or employing diimide [11]. This latter reduc-
tion method is undoubtedly the most used. It requires the genera-
tion of diimide in the reaction medium, using an excess of p-
toluenesulfonylhydrazide and base in refluxing pycoline or pyri-
dine, with reaction times ranging from 6 h to several days in order
to yield the chlorin or the bacteriochlorin, respectively. Usually the
chlorin is obtained contaminated with the corresponding bacterio-
chlorin and the purification involves re-oxidation of the bacterio-
chlorin using quinones, such as o-chloranil, as the oxidant.
The main methods for the synthesis of porphyrins starting from
pyrrole and an aldehyde are the Rothemund versions developed by
Adler et al. [12], Rocha Gonsalves et al. [13], and Lindsey et al. [14].
The first two methodologies follow a one-pot approach in which
the cyclization to the porphyrinogen and the oxidation to the cor-
responding porphyrin occur in the same medium. Adler used pro-
pionic acid as solvent and catalyst, oxygen being the only oxidizing
agent present. The yields obtained with aryl aldehydes are good in
some cases, but the high dilution of the reaction mixture requires
the use of a large amount of solvent and the porphyrin is usually
contaminated with variable quantities of the corresponding chlo-
rin, which is difficult to remove from the final product. Rocha Gon-
salves methodology uses acetic acid as solvent and catalyst and
nitrobenzene as oxidant. In this case, no contamination with chlo-
rin is observed and direct crystallization of the porphyrin from the
reaction medium often occurs. Lindsey reported the preparation of
several meso-tetraarylporphyrins using a two-step approach, the
cyclization step of which was firstly devised by Rocha Gonsalves
for the synthesis of meso-tetraalkylporphyrins [15]. The condensa-
tion of pyrrole and aldehyde is achieved in highly diluted solutions
of chloroform or dichloromethane and the porphyrinogen is subse-
quently oxidized with DDQ or o-chloranil.
Looking to make tetrapyrrolic macrocycles more accessible we
explored different synthetic approaches for the synthesis of bacte-
riochlorins, chlorins and porphyrins.
Aiming to obtain meso-substituted bacteriochlorins from the
corresponding porphyrin precursors [16], we decided to explore
the widely used diimide method reported by Whitlock and co-
workers for the preparation of hydroporphyrins [11]. In order to
shorten the long reaction times needed when using the classical
* Corresponding author. Tel.: +351 239 854479; fax: +351 239 827703.
E-mail address: mpineiro@qui.uc.pt (M. Pineiro).
1387-7003/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.inoche.2009.12.032

396
B.F.O. Nascimento et al. / Inorganic Chemistry Communications 13 (2010) 395–398
Scheme 3. Selective heterogeneous oxidation of bacteriochlorin.
as minor products, with yields ranging from 65% to 90% and recov-
ered mass up to 85% [18] (Table 2).
Our recently published microwave-assisted synthetic strategy
for the preparation of meso-tetraarylporphyrins [19] was revisited
using a single-mode microwave reactor [26] instead of the domes-
tic microwave oven previously utilized (Scheme 4). Porphyrins
(1a–g) were obtained in 5-min reactions, with yields ranging from
5% to 55% [16] (Table 3).
Scheme 1. Tetrapyrrolic macrocycles.
In an attempt to incorporate the advantages of heterogeneous
oxidation in the synthesis of meso-substituted porphyrins we used
meso-tetraphenylporphyrin (TPP, 1a) as the model molecule and
prepared the porphyrinogen through the method described by
Lindsey et al. [14]. The porphyrinogen was then oxidized to the
porphyrin utilizing activated MnO2 under different reaction condi-
tions (Scheme 4). After 16 h at 40 °C, the porphyrinogen was oxi-
dized to porphyrin 1a in 32% yield. Under microwave irradiation
the concentrated solution of the porphyrinogen was irradiated at
50 °C for 10 min, yielding 20% of TPP. A microwave-assisted sol-
vent-free strategy was also studied using SiO2 60 doped with
MnO2. After 30 min at 100 °C, 22% of TPP was attained.
Activated MnO2 has been successfully used in the oxidation of
several organic compounds, including dehydrogenation and oxida-
tive aromatization reactions, both under conventional heating and
microwave irradiation conditions [20–25]. It is an inexpensive het-
erogeneous oxidant, which greatly simplifies the isolation and
purification processes and has never been used for the oxidation
of tetrapyrrolic macrocycles.
Hence, a series of differently substituted meso-tetraarylbacte-
riochlorins was efficiently prepared by microwave heating in only
25 min, using minimum amounts of reagents and organic solvents
and an undemanding workup procedure, therefore, reducing the
waste products and the costs involved in the synthetic process
comparatively to the conventional heating diimide method. The
corresponding meso-tetraarylchlorins were also cost-effectively
prepared under microwave irradiation in a 3-min reaction. The
replacement of o-chloranil, an extremely toxic and expensive oxi-
dizing agent, by the much cheaper and user-friendly manganese
dioxide proved to be an advantageous modification to the classical
Scheme 2. Bacteriochlorin synthesis under microwave irradiation.
conditions we performed the reaction under microwave irradiation
(MW) (Scheme 2). The target bacteriochlorins (2a–g) were ob-
tained in 25 min, slightly contaminated with the corresponding
chlorins as minor products, with 90–96% of recovered mass and
yields between 65% and 85%, except in the case of compound 2g
[17] (Table 1) (see Supplementary material).
In a new approach to obtain meso-substituted chlorins, a mix-
ture of the selected bacteriochlorin (2a–g, 23–24 mg) and activated
manganese dioxide (50 equiv.) in 2 mL of 1,4-dioxane was heated
at 90 °C for 3 min again under focused microwave irradiation
(Scheme 3). Dilution of the cooled crude product mixture with
an appropriate organic solvent, followed by filtration through a
plug of SiO2 60 and evaporation, yielded the desired chlorins
(3a–g), slightly contaminated with the corresponding porphyrins
Table 1
Table 2
Yields of bacteriochlorins (2a–g) synthesized under microwave irradiation.
Yields of chlorins (3a–g) synthesized under microwave irradiation.
Compound
Recovered
mass (%)
Isolated mass
(mg)
Yield (%) (bacteriochlorin/
chlorin ratio)a
Compound Recovered
mass (%)
Isolated mass
(mg)
Yield (%) (chlorin/
porphyrin ratio)a
2a
2b
2c
2d
2e
2f
96
92
95
93
95
92
90
24
23
24
23
24
23
23
75/25
85/15
85/15
80/20
3a
3b
3c
3d
3e
3f
92
85
93
88
90
88
86
23
21
23
22
22
22
21
80/20
75/25
90/10
65/35
90/10
85/13
70/30
65/35
65/35
2g
45/30/25b
3g
Accessed by the 1H NMR spectroscopy data of the isolated compounds.
Bacteriochlorin/chlorin/porphyrin ratio (%)
a
a
Accessed by the 1H NMR spectroscopy data of the isolated compounds.
b

B.F.O. Nascimento et al. / Inorganic Chemistry Communications 13 (2010) 395–398
397
In summary, the advantages of using activated MnO2 in por-
phyrinogen dehydrogenation reactions relatively to the traditional
quinone oxidants are, along with the use of a much more inexpen-
sive oxidizing agent, the absence of contamination with the corre-
sponding chlorin in the final product and the very straightforward
isolation workup. Hence, no lengthy chromatographic purifications
are required to separate the porphyrin from the chlorin contami-
nant, the excess of DDQ or o-cloranil and their reduction by-prod-
N
H
CH2Cl2, BF3.Et2O
N2, rt, 16 ºC)
HN
NH
PhCHO
+
N
H
H
N
ucts. Using MnO2
a
simple filtration and subsequent
recrystallization is enough to obtain the porphyrins in high purity.
Microwave irradiation lead to a pronounced decrease of the
amount of solvents used and drastically reduced the reaction time,
although slightly lower yields were obtained. It is our opinion that
these results are quite promising and further studies on these syn-
thetic methodologies are currently being addressed at our labora-
tories and will be presented in due time.
SiO2 60, MnO2
CH2Cl2, MnO2
CH2Cl2, MnO2
MW
(50 ºC, 10 min)
20%
MW
(100 ºC, 30 min)
22%
40 ºC, 16 h
32%
Acknowledgments
Financial support provided by Fundação para a Ciência e Tecno-
logia (SFRH/BD/41472/2007 Ph.D. Grant received by Bruno F.O.
Nascimento) and Chymiotechnon is gratefully acknowledged. The
authors also wish to thank Dr. Alexandra Rocha Gonsalves for the
mass spectrometry studies, the Nuclear Magnetic Resonance Labo-
ratory of the Coimbra Chemistry Center, Universidade de Coimbra
(supported in part by Grant REEQ/481/QUI/2006 provided by Fun-
dação para a Ciência e Tecnologia, POCI-2010 and FEDER) for the
proton nuclear magnetic resonance spectroscopy data and Dr.
Arménio C. Serra for the helpful insights and proficient discussions.
N
H
N
N
H
N
1a
Scheme 4. Selective heterogeneous oxidation of porphyrinogen.
Table 3
Yields of porphyrins (1a–g) synthesized under microwave irradiation.
Appendix A. Supplementary material
Compound
Yield (%)
Yield a(%)
Isolated mass (mg)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.inoche.2009.12.032.
1a
1b
1c
1d
1e
1f
46
5
20
4
710
110
550
615
920
715
1150
30
36
50
30
55
15
12
20
12
25
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chlorin compounds, thus avoiding the numerous and tedious
extraction processes and the rather complex chromatographic sep-
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the oxidation of the bacteriochlorin can be clearly seen in the syn-
thesis of chlorin 3g. From a mixture with a ratio of bacteriochlorin/
chlorin/porphyrin of 45/30/25 the chlorin was obtained in a mix-
ture of 70/30 with the corresponding porphyrin contaminant.
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nation, showing that all the bacteriochlorin was oxidized to the
corresponding chlorin, without the oxidation of the chlorin to the
porphyrin taking place.
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acetate 9:1 v/v (1c) or methylene chloride/ethyl acetate 1:1 v/v (1d). The red

398
B.F.O. Nascimento et al. / Inorganic Chemistry Communications 13 (2010) 395–398
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vessel is then tightly sealed with a Teflon cap and the reaction mixture is
magnetically stirred and heated at 90 °C for 3 min under focused microwave
irradiation with an initial power setting of 100 W. After cooling to room
temperature, the crude product mixture is diluted with methylene chloride or
ethyl acetate (50 mL) and filtered through a plug of SiO2 60 in order to remove
the excess MnO2. The liquid filtrate is then evaporated under reduced pressure
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corresponding chlorin (major product) and porphyrin (minor product) as a
dark purple solid (3a–g).
a
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potassium carbonate (100 equiv.) and p-toluenesulfonylhydrazide (100 equiv.)
are added to 1,4-dioxane (2 mL) and thoroughly mixed in an appropriate
thick-walled glass vial. The reaction vessel is then tightly sealed with a Teflon
cap and the reaction mixture is magnetically stirred and heated at 120 °C for
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homogenized with distilled water (50 mL) and neutralized by the drop-wise
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