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that our new method manages to reach a EcoScale value of
50.5 (Supporting Information), the highest value among the
analyzed methodologies for TPP preparation, and considered
as an acceptable synthesis, according to the EcoScale rank-
ing.[25] To our knowledge, this is the first method involving por-
phyrin synthesis that reaches such high sustainability values.
Notably, this new synthetic method produces almost no con-
tamination with the corresponding chlorin, as typically ob-
served in Adler–Longo methodology (as confirmed by HPLC,
see the Supporting Information).[15]
ported methods.[15,16,18] Among the meso-aryl substituted por-
phyrins, it is worth mentioning the (3:1) statistical condensa-
tion of 4-(2-ethylhexyloxy)benzaldehyde and 4-hydroxybenzal-
dehyde for the preparation of new unsymmetrical porphyrin 8,
obtained along with porphyrin 7 in 4% and 6% yields, respec-
tively. Porphyrin 8 has a low melting point (348–353 K) as well
as an hydroxyl functionality, opening the possibility for several
applications.[31] Additionally, we have also prepared com-
pound 8 in 14% yield by using directly 4-(2-ethylhexyloxy)-
benzaldehyde. Moreover, this method was extended to the
synthesis of other meso-alkyl substituted porphyrins 9 and 10,
which are generally more difficult to obtain than their aryl ana-
logues.[19,32] Using this procedure, porphyrins 9 and 10 were
prepared in 21% and 20% yields, respectively. However, the
yield of 10 could be increased to 30%, by further photo-oxida-
tion of the reaction mixture (Supporting Information). In both
cases, the yields obtained are substantially higher than those
reported in the literature.[19]
Furthermore, we carried out a larger-scale reaction (by
a factor of three) for the synthesis of this porphyrin. Using
a 35 mL MW vessel charged with 29 mmol of pyrrole and
29 mmol of benzaldehyde, mixed with 0.6 mL of water, it was
possible to obtain 1.071 g of TPP (24% yield). More than 1 g of
product was obtained using only 0.6 mL of water and produc-
ing as much as ~40 mL of residues after filtration of the
reaction crude (ethanol was added to help precipitation, simul-
taneously dissolving byproducts), which indisputably is an im-
provement when compared to other methodologies currently
available, including solvent-free methodologies or any meth-
ods involving catalyst recycling.
In conclusion, a new meso-substituted porphyrin synthetic
methodology is reported. Water, under microwave irradiation,
acts simultaneously as solvent, acid catalyst, and oxidant, al-
lowing the formation of meso-aryl- and meso-alkylporphyrins in
good yields, under very high concentrations (50m). The
method avoids the use of solvent and toxic, expensive acid
catalysts and oxidants. As a result, the E Factor for the prepara-
tion of TPP is 35, much closer to the goal of “zero” than all pre-
viously reported methodologies. Moreover, this is the first ap-
proach involving porphyrin synthesis to achieve more than 50
points on the EcoScale analysis.
In order to assess the scope of this reaction, our synthetic
methodology was extended to other differently substituted al-
dehydes for the preparation of meso-substituted porphyrins
(Table 3). Using optimized reaction conditions for TPP synthe-
sis, we performed a set of experiments using different aryl and
alkyl aldehydes to evaluate the effect of aldehyde structure on
the overall yield of the corresponding meso-substituted por-
phyrins (see the Experimental Section and the Supporting In-
formation) and the results are presented in Table 3.
Experimental Section
As expected, either the arylaldehyde electronic character or
the bulkiness of the ortho substituents gave similar or even
better results than the ones obtained so far by using classic re-
All starting materials (aldehydes and pyrrole) were bought from Al-
drich having the highest grade available and used as-received. Sol-
vents were purified by standard methods. In all reactions a CEM
Discover 600635 single-mode microwave reactor was used. All
spectroscopic data from synthesized porphyrins (all known com-
pounds) were confirmed (1H NMR) and are in agreement with liter-
ature reports. For TPP, for example, under optimal reaction condi-
tions (reaction conditions set-up is available in the Supporting In-
formation), a mixture of pyrrole (9.8 mmol; 0.68 mL), benzaldehyde
(9.8 mmol), and water (0.2 mL) were mixed in a 10 mL MW vessel.
The mixture was subjected to MW irradiation for 10 min at 473 K
and initial MW power of 300 W. After cooling, ethanol (15 mL) was
added to aid precipitation. The solid was then filtered, washed
with an additional 5 mL of ethanol, and dried, obtaining 430 mg of
TPP (27% yield) with less than 2% of chlorin.
Table 3. Scope of the method for meso-substituted porphyrin synthesis
using water as an additive, under microwave irradiation, at 473 K, 50m
concentration and 10 min of reaction time.
Compound Reagent
Product Yield [%][a]
1
2
3
4
5
6
7
8
R=R’=benzaldehyde
27
11
6
11
9
Acknowledgements
R=R’=3-hydroxybenzaldehyde
R=R’=4-fluorobenzaldehyde
R=R’=4-bromobenzaldehyde
R=R’=2,6-difluorobenzaldehyde
R=R’=2,6-dichlorobenzaldehyde
The authors thank CEM corporation for collaboration, FCT-Portu-
gal and the QREN/FEDER (COMPETE Programa Operacional Fac-
tores de Competitividade) for funding (PTDC/QUI-QUI/112913/
2009) and PEst-OE/QUI/UI0313/2014. NMR data were obtained at
the Nuclear Magnetic Resonance Laboratory of Coimbra Chemis-
POCI-2010). C.A.H. is grateful for his PhD grant SFRH/BD/84146/
2012, S.M.A.P. is grateful for her post-doctoral grant SFRH/BPD/
3
R=R’=4-(2-ethylhexyloxy)benzaldehyde 14
R=4-(2-ethylhexyloxy)benzaldehyde+
R’=4-hydroxybenzaldehyde (3:1)
R=R’=dodecyladehyde
4[b]
9
10
21
30
R=R’=butyraldehyde
[a] Isolated yield. [b] Compound 7 was also isolated in 6% yield.
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