Porphyrin synthesis using mechanochemistry: Sustainability assessment

Article abstract of DOI:10.1142/S1088424619500755

Looking for sustainable synthetic methodologies, mechanochemistry as a new tool for one-step and two-step approaches for the synthesis of meso-substituted porphyrins was explored. The best results were obtained in a two-step procedure, under liquid-assisted grinding in the oxidation step using 2-methyltetrahydrofuran, an environmentally acceptable solvent, and MnO2 as a heterogeneous oxidant. The sustainability was assessed using two sustainability metrics, E-factor and EcoScale, which allow comparison between procedures and methods.

Full text of DOI:10.1142/S1088424619500755

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2019; 23: 1–9
DOI: 10.1142/S1088424619500755
Published at http://www.worldscinet.com/jpp/
Porphyrin synthesis using mechanochemistry: Sustainability
assessment
Carla Gomes, Mariana Peixoto and Marta Pineiro*◊
CQC and Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, Portugal
This paper is part of the 2019 Women in Porphyrin Science special issue.
Received 15 March 2019
Accepted 21 June 2019
ABSTRACT: Looking for sustainable synthetic methodologies, mechanochemistry as a new tool for
one-step and two-step approaches for the synthesis of meso-substituted porphyrins was explored. The
best results were obtained in a two-step procedure, under liquid-assisted grinding in the oxidation step
using 2-methyltetrahydrofuran, an environmentally acceptable solvent, and MnO2 as a heterogeneous
oxidant. The sustainability was assessed using two sustainability metrics, E-factor and EcoScale, which
allow comparison between procedures and methods.
KEYWORDS: porphyrin, synthesis, mechanochemistry, MnO2, porphyrinogen, sustainability.
of the word, are unquestionably compounds having
INTRODUCTION
unique properties which have led to their use in very
Sustainability has been a recurring theme in society
diverse applications, from cancer diagnosis and therapy,
and in chemistry. The preservation of the environment
to catalysis, to optical systems [4–16]. Moving from
and the quality of life of today’s society is undoubtedly
laboratory-scale to industrial production, for a wide
one of the great challenges of our society, in which
range of applications, leads to production of large
chemistry plays a crucial role. Synthetic chemists have
amounts of derivatives with different patterns of substi-
come a long way in the search for more sustainable
tution in the development phase and a large amount
processes, methods and techniques, seeking to imple-
of the same compound in the application phase. It has
ment the twelve principles that define the ideal of “Green
become necessary to look for more sustainable methods
Chemistry” [1]. Green Chemistry is focused on the
of porphyrin production, which has been carried out
design, development and implementation of chemical
by the chemists involved in their synthesis. Since the
products and processes, aiming at reducing pollution
work of Rothemund [17–19], synthesizing porphyrins
at its source by minimizing or eliminating the hazards
in pyridine, going through the recognized meritorious
of chemical feedstock, reagents, solvents and products
classical methodologies of Adler and Longo [20, 21],
[2, 3]. It assesses the solvent used in processes, explores
Lindsey [22–26] or Rocha Gonsalves [27–29], much of
the potential use of catalysts, promotes the incorporation
the philosophy has changed, and new tools for Green
of renewable feedstock, attempts to minimize energy
Chemistry are used every day in organic chemistry labs.
utilization and identifies materials that do not persist
Following the principles of Green Chemistry, several
or bioaccumulate. Porphyrins, in the broadest sense
methods for the synthesis of porphyrins have been
developed using alternative catalysts, reaction media
and new tools such as microwave irradiation [30–33].
◊SPP full member in good standing
Microwave irradiation is very well established as a
*Correspondence to: Marta Pineiro, Rua Larga, Department
tool that allows decreasing the amount of solvent used
and reducing the energy input, also decreasing the
reaction times. The use of microwave to afford the
of Chemistry, University of Coimbra, 3049-535 Coimbra,
Portugal, tel.: +351239857944, fax: +351239852080, email:
mpineiro@qui.uc.pt.
Copyright © 2019 World Scientific Publishing Company

2
C. GOMES, M. PEIXOTO AND M. PINEIRO
energy input for the synthesis of porphyrins further
allowed the development of new procedures such as the
use of heterogeneous catalysts or new oxidants such as
MnO2 [34].
Mechanochemistry, an ancient way to promote
reactions, has been widely used in the synthesis of
polymers and in inorganic chemistry [35–38]. More
recently, with the interest in reduction of the solvent in
organic processes, mechanochemistry has been used in
organic synthesis to promote reactions in the solid state
[39–41], however, so far only one report on the synthesis
of porphyrins under mechanical activation has been
described [42].
Following our previous work on the development of
sustainablemethodologiesforthesynthesisofporphyrins,
herein we present the use of mechanochemistry for
the synthesis of porphyrins in one or two steps and an
analysis of sustainability or greenness using two metrics,
E-factor and EcoScale, to allow comparison.
analysis of cyclization and oxidation in order to
maximize yield and sustainability. The porphyrinogen,
5,10,15,20-tetrakis-(4-methoxyphenyl)-5,10,15,20,22,24-
hexahydroporphyrin, precursor of 5,10,15,20-tetrakis-(4-
methoxyphenyl)porphyrin, chosen as model compound,
was prepared under mechanochemical activation from
the grinding of equimolar quantities of pyrrole and
4-methoxybenzaldehyde with p-toluenesulfonic acid
(20 mol%) in a stainless-steel grinding jar with two
stainless-steel balls for 30 min, adapting the conditions
previously described [42], Scheme 1.
Oxidation of the porphyrinogen was performed using
the classical conditions: 11 equivalents of DDQ in 50 mL
of chloroform at room temperature for 2 h [42], obtaining
of the desired porphyrin with 6% yield after column
chromatography, (entry 1, Table 1). Manganese (IV)
oxide is a green and cheap transition metal oxide with
low toxicity [43] that has been successfully used as
an effective heterogeneous oxidant of several organic
compounds [44] including hydroporphyrins [34]. The
oxidation of porphyrinogen under mechanical action
using MnO2 was tested using 10, 5 and 2.5 equivalents
in solventless conditions. The best balance between
porphyrin yield and simplicity of the purification process
was obtained using 5 equivalents of MnO2 yielding 3% of
porphyrin (entries 2–4, Table 1). The use of other green
oxidants such as iodine and hydrogen peroxide [45, 46]
only afford traces of the desired product (entries 5 and 6,
Table 1). It was previously observed than in liquid-
assisted grinding (LAG) mechanochemical reactivity
RESULTS AND DISCUSSION
Synthesis
Porphyrins were synthesized in one-step or two-
step procedures, i.e. separating or not the cyclization of
pyrrole and aldehyde to form porphyrinogen from its
oxidation to porphyrin. The studies were initiated using
a two-step approach, which facilitates the individual
OCH3
H
OCH3
pTsOH
))((
NH
HN
HN
H
(25 Hz, 30 min)
+
OCH3
H3CO
N
H
H
NH
H
CHO
OCH3
O
Table 1
OCH3
NH
N
N
OCH3
H3CO
HN
OCH3
Scheme 1. Two-step synthesis of 5,10,15,20-tetrakis-(4-methoxyphenyl)porphyrin, Photograph of the reaction product after
grinding pyrrole, 4-methoxybenzaldehyde and p-toluenesulfonylhydrazine. Symbols:)) ((mechanical activation; [O] oxidation
Copyright © 2019 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2019; 23: 2–9

PORPHYRIN SYNTHESIS USING MECHANOCHEMISTRY: SUSTAINABILITY ASSESSMENT
3
Table 1. Oxidation of 5,10,15,20-tetrakis-(4-methoxyphenyl)porphyrinogen
Entry
Activation method
Solvent/Oxidant
Temp. (°C)
Time (min)
Yield (%)
1
2
Stirring, room temp.
Mechanical
Mechanical
Mechanical
Mechanical
Mechanical
Mechanical
Mechanical
Mechanical
Stirring
CHCl3 (50 mL)/DDQ (5 equiv.)
MnO2 (2.5 equiv.)
r.t.
r.t
120
30
30
30
30
30
30
30
30
120
10
5
6
traces
3
3
MnO2 (5 equiv.)
r.t
4
MnO2 (10 equiv.)
r.t
4
5
I2 (5 equiv.)
r.t
traces
traces
traces
3
6
H2O2 (5 equiv.)
r.t
7
Ethyl acetate (0.2 mL)/MnO2 (5 equiv.)
H2O (0.2 mL)/MnO2 (5 equiv.)
2MeTHF (0.2 mL)/MnO2 (5 equiv.)
2MeTHF (5 mL)/MnO2 (5 equiv.)
2MeTHF (2 mL)/MnO2 (5 equiv.)
Propionic acid/PhNO2
r.t
8
r.t
9
r.t
10
10
11
12
r.t.
80
200
19
MW
traces
5
MW
Table 2. One-step Synthesis of synthesis of 5,10,15,20-tetrakis-(4-methoxyphenyl)porphyrin
Entry
Activation method
MW
Solvent/oxidant
Water (0.2 mL)
Temperature (°C)
Time (min)
Yield (%)
1
2
3
4
5
200
120
r.t
10
10
75
75
75
14
20a
3
MW
Propionic acid/PhNO2 (5 mL)
p-toluenesulfonic acid, MnO2
p-toluenesulfonic acid, 2MeTHF/MnO2
Propionic acid/PhNO2 (0.2 mL)
Mechanical
Mechanical
Mechanical
r.t
5
r.t
traces
a Reference [57].
is induced or accelerated by near-stoichiometric or
substoichiometric amounts of a liquid in comparison to
solvent-free conditions [41, 47]. As the effect is highly
dependent on the solvent, we have chosen green solvents
with no specific danger regarding risk of explosion when
subjected to friction or mechanical shock, such as water,
2-methyltetrahydrofuran (2MeTHF) and ethyl acetate,
among the many possibilities [48, 49]. The addition of
0.2 mL ethyl acetate afforded only traces of the desired
compound (entry 7, Table 1). The addition of the same
amount of water yielded the porphyrin in similar yield
as when using solventless conditions (entry 8, Table 1).
However, the addition of 2MeTHF to the mechano-
chemical reaction improved the reaction yield to a
remarkable 10% yield (entry 9, Table 1), while longer
reaction times did not afford better yields.
By transferring the porphyrinogen prepared by mech-
anochemistry to a laboratory round glass vessel, adding
5 equivalents of MnO2 and 25 mL of 2MeTHF and keeping
the mixture under magnetic stirring at room temperature
for 120 min, 19% yield was obtained (entry 10, Table 1).
When performing the oxidation of the porphyrinogen
under microwave irradiation using MnO2 as oxidant, only
traces of the desired product resulted (entry 11, Table 1).
Furthermore, when the known mixture of propionic acid
and nitrobenzene was used, only 5% yield of the desired
porphyrin was obtained (entry 12, Table 1).
The synthesis of porphyrins in one-step under micro-
wave irradiation at 200°C for 10 min using pyrrole and
aldehyde and just a small amount of water has proven to be
a very sustainable method for the synthesis of porphyrins
and therefore a mark to compare other methods [31].
The synthesis under microwave irradiation with water
gave 5,10,15,20-tetrakis-(4-methoxyphenyl)porphyrin
with 14% yield after purification by precipitation and
recrystallization (entry 1, Table 2). The synthesis of
5,10,15,20-tetrakis-(4-methoxyphenyl)porphyrin under
microwave irradiation was performed following the
methodology we previously described, where propionic
acid and nitrobenzene were used as solvent and oxidant,
yielding 20% of porphyrin after purification by column
chromatography (entry 2, Table 2).
The synthesis of the reference compound under
mechanical activation was performed using MnO2 as
oxidant, mixing pyrrole, 4-methoxybenzaldehyde,
p-toluenesulfonic acid and MnO2 in a stainless-steel
grinding jar along with two stainless-steel balls, for
75 min. Samples were taken at 30 and 45 min, and the
Copyright © 2019 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2019; 23: 3–9

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C. GOMES, M. PEIXOTO AND M. PINEIRO
Table 3. Values for each of the parameters evaluated in EcoScale
EcoScale Penalty Points
Entry
Activation method/Solvent/
Oxidant
1. Yield
2. Price
3. Safety 4. Technical setup 5. Temp./Time
6. Workup
and Isolation
Two-step procedures
1
2
3
4
5
6
Stirring/CHCl3/DDQ
47
23
18
18
21
23
21
21
13
13
17
17
22
2
2
2
2
2
2
1
0
0
0
1
2
10
1
Mechanical/MnO2
48.5
48.5
45
Mechanical/H2O/MnO2
Mechanical/2MeTHF/MnO2
Stirring/2MeTHF/MnO2
MW/Propionic acid/PhNO2
1
1
40.5
47.5
1
10
One-step procedures
7
8
9
MW/ Propionic acid/PhNO2
40
16
8
17
7
2
2
2
2
2
0
10
1
MW/Water
43
Mechanical/2MeTHF/MnO2
47.5
23
17
1
formation of the porphyrin was controlled by UV-vis
spectroscopy. After filtration over celite and column
chromatography, a 3% yield was obtained (entry 3,
Table 2). In an independent experiment, by adding
0.2 mL of 2MeTHF to the initial mixture, 5% yield of
porphyrin was obtained (entry 4, Table 2). Comparing
this result with the oxidation in two-steps with MnO2,
which yielded 10%, this could be explained by the
negative influence of the solvent in the cyclization
step. The use of a propionic acid/nitrobenzene mixture
as acid catalyst and oxidant under mechanochemistry
conditions did not afford the desired product (entry 5,
Table 2).
and also economic issues and therefore considers not
only greenness but also sustainability.
Calculation of the E-factor was determined using
Equation 1. Calculation of the EcoScale was achieved
by subtracting, from the 100 initial points the six
parameters in Table 3 represented in Fig. 1. The values
of both metrics are collected in Table 4 and represented
in Fig. 2.
E-factor = g of Waste / g of Product =
((g of Reactants + g of Solvents + g of Oxidant)
– g of Product) / g of Product
(1)
The E-factor for the two-step procedures includes
the reactants needed for the first-step, the porphy-
rinogen synthesis, i.e. 2.5 mmol of pyrrole and
p-methoxybenzaldehyde and 0.5 mmol of p-toluene-
sulfonic acid, which gave a constant value of 0.60 g.
Therefore, the differences obtained in the final value
are due to the different oxidation procedures. The
rational use of the solvent has an important influence
on the E-factor. In fact, the use of large quantities of
solvents led to very high E-factor values, on the order
of thousands and hundreds (entries 1 and 6, Table. 4)
while lower values were obtained when reducing the
quantity of solvent, both under conventional stirring
conditions and under mechanical activation (entries
2–5, Table 4). The lowest value was obtained for the
liquid-assisted mechanochemical oxidation with MnO2
(entry 4, Table 4) where the increase of waste using
Sustainability assessment
The development of metrics for comparing the
greenness and sustainability of competing methodologies
is still a field in development [50, 51]. To compare the
methods in this study, we chose two metrics. One was
the E-factor, one of the original mass-based metrics
focused on the elimination of waste, i.e. the efficiency of
source utilization [52]. Mass-based metrics gave a rapid
and clear assessment of the efficiency of the reaction,
but failed in the consideration of the nature of raw
materials and waste energy efficiency, and economical
aspects. Therefore, a metric with a more global analysis
was also used, the EcoScale, developed by Van Aken
and co-workers [53]. This was one of the first metrics
developed which includes all the environmental factors
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PORPHYRIN SYNTHESIS USING MECHANOCHEMISTRY: SUSTAINABILITY ASSESSMENT
5
Fig. 1. Penalty points of each of the six parameters evaluated in EcoScale for one- and two-step synthesis of porphyrins
Table 4. E-factor and EcoScale values obtained for the one- and two-step procedures
Entry
Activation method/Solvent/Oxidant
Yield (%)
E-factor
EcoScale
1
2
3
4
5
6
7
Stirring/CHCl3/DDQ
6
3
2800
62
-4
Mechanical/MnO2
17.5
17.5
14
Mechanical/H2O/MnO2
Mechanical/2MeTHF/MnO2
Stirring/2MeTHF/MnO2
MW/Propionic acid/PhNO2
MW/Propionic acid/PhNO2
3
77
10
19
5
22
58
15.5
-4.5
13
121
19
20
8
9
MW/Water
14
5
8
37
Mechanical/ 2MeTHF/MnO2
32
9.5
minimal amounts of solvent is balanced by the increase
in the reaction yield.
increased from 22 to 32 and the EcoScale decreased from
14 to 9.5 as a consequence of the decrease in the reaction
yield. Therefore, the use of mechanical activation does
not bring any improvements in sustainability.
In any case, under mechanical activation the E-factor
values are higher, while EcoScale values lower than
those obtained in the microwave methods using water
as solvent (entry 8, Table 4), which once again gave the
best sustainability values, an EcoScale value of 37 and
E-factor of 8, the closest values to 100 (ideal value of
EcoScale) and to 0 (ideal value of E-factor).
Analyzing the EcoScale parameters, it is obvious that
the biggest contribution to the loss of points is the low
yield. The use of MnO2 and greener solvents instead
of hazardous solvents and oxidants such as DDQ,
CHCl3 or nitrobenzene led to fewer penalty points in
safety. The use of reaction conditions that allow the
isolation of the porphyrin by filtration, avoiding column
chromatography, gave fewer penalty points in the workup
and purification parameter. The above described factors
led to higher EcoScale values when MnO2 was used as
oxidant (entries 2–5, Table 4).
Scope of two-step liquid-assisted mechanochemical
procedure
Comparing the one-step method (entry 9, Table 4) with
the two-step method, using MnO2 and 2MeTHF (entry 4,
Table 4), where the same quantities of pyrrole, aldehyde,
acid catalyst, solvent and oxidant were used, the E-factor
Considering the use of mechanical activation, the more
adequateprocedurefromtheviewpointofsustainabilityis
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6
C. GOMES, M. PEIXOTO AND M. PINEIRO
Fig. 2. Panel (a) E-factor and Panel (b) EcoScale values for one- and two-step methods for the synthesis of porphyrins at Table 4
Scheme 2. Scope of the two-step mechanical synthesis of porphyrins
the two-step liquid-assisted mechanochemical procedure,
where the oxidation is performed with MnO2 in the
presence of 2MeTHF. Using these reaction conditions,
5,10,15,20-tetrakis-(3,4-dimethoxyphenyl)porphyrin,
5,10,15,20-tetraphenylporphyrin, 5,10,15,20-tetrakis-(2-
chlorophenyl)porphyrin and 5,10,15,20-tetrakis-(3,5-
dichlorophenyl)porphyrin were obtained with 17, 18, 27
and 7% yield, respectively, indicating the applicability
of mechanochemistry to the synthesis of porphyrins,
Scheme 2.
received. Pyrrole (Fluorochem, 99%) was used as
received or, when necessary, distilled under vacuum for
purification prior to use.
All commercially-acquired solvents were purified
according to literature procedures prior to use [54],
with the following exceptions: 2-methyltetrahydrofuran
anhydrous (Sigma–Aldrich, ≥ 99.0%), deuterated chloro-
form (Sigma–Aldrich, 99.9% D, 0.03% v/v TMS (Trim-
ethylsilane); Euriso-Top, 99.8% D, 0.03% v/v TMS),
propionic acid (Acros Organics, 99.0%) and nitrobenzene
(Acros Organics, 99.0%); these were used as purchased.
Microwave-assisted reactions were performed in
a CEM Discover S-Class single-mode microwave
reactor featuring continuous temperature, pressure and
microwave power monitoring.
EXPERIMENTAL
General
Automated sample grinding was carried out using a
Retsch Mixer Mill MM400 in a stainless-steel grinding
jar (10 mL volume) along with two stainless steel balls
(7 mm diameter, 1.38 g). TLC-monitoring of the reactions
was performed using SiO2 60 F254-coated aluminum
plates (Merck). 1H NMR spectra were registered at
room temperature on a Bruker Avance III spectrometer
operating at 400 MHz. TMS (Trimethylsilane) was the
internal standard used. Chemical shifts (d) and coupling
constants (J) are indicated in ppm and Hz, respectively.
Benzaldehyde (Riedel deHaën, 99.0+%), p-anisal-
dehyde (Acros Organics, 99.0+%), 3,4-dimethoxybenz-
aldehyde (Sigma–Aldrich, 99.0%), 3,4-dihydroxybenz-
aldehyde (Sigma–Aldrich, 97.0%), 3,5-dichlorobenz-
aldehyde (Alfa Aesar, 97.0%), 2-chlorobenzaldehyde
(Sigma–Aldrich, 99.0%), p-tolu-enesulfonic acid mono-
hydrate (Sigma–Aldrich, 98.5%), activated manganese
(IV) oxide (Alfa Aesar, 90.0%), 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone(Sigma–Aldrich, 98%) and
SiO2 60A 30–70 micron (Fluorochem) were used as
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PORPHYRIN SYNTHESIS USING MECHANOCHEMISTRY: SUSTAINABILITY ASSESSMENT
7
UV-vis absorption spectra were obtained on a Shimadzu
UV-2100 spectrometer.
jar (10 mL volume) along with two stainless-steel balls
(7 mm diameter). The mixture was ground in a Retsch
MM400 mill at a frequency of 25 Hz for 30 min.
Preparation of porphyrin under mechanical activ-
ation. Pyrrole (2.5 mmol, 0.17 mL) and 4-methoxy-
benzaldehyde (2.5 mmol) were combined with
p-toluenesulfonic acid (0.5 mmol, 95.1 mg) and the
appropriate oxidant, and placed in the stainless-steel
grinding jar (10 mL volume) with two stainless-steel
balls (7 mm diameter). The mixture was ground in a
Retsch MM400 mill at a frequency of 25 Hz for 75 min.
Synthesis
Preparation of porphyrinogen under conventional
procedure. In a 500 mL round-bottom flask, 250 mL
of dichloromethane and 4-methoxybenzaldehyde
(2.5 mmol) were added and the solution was bubbled
with nitrogen and magnetically stirred at room
temperature for 15 min. Then, pyrrole was added
(2.5 mmol, 0.17 mL) under nitrogen atmosphere and
the solution stirred magnetically for a few minutes
before the addition of boron trifluoride diethyl etherate
(0.2 mmol, 31 μL). The reaction was kept, with stirring,
at room temperature under nitrogen atmosphere for 4 h.
Preparation of porphyrinogen under mechanical
activation. Pyrrole (2.5 mmol, 0.17 mL) and 4-methoxy-
benzaldehyde (2.5 mmol) were combined with p-toluene-
sulfonic acid (0.5 mmol, 95.1 mg) in a stainless-steel
grinding jar (10 mL volume) along with two stainless-
steel balls (7 mm diameter). The mixture was ground in a
Retsch MM400 mill at a frequency of 25 Hz for 30 min,
yielding a pink solid.
Procedure for the oxidation of the porphyrinogen
under microwave irradiation with propionic acid/
nitrobenzene. The porphyrinogen and propionic acid/
nitrobenzene (7:3 v/v, 2 mL) were thoroughly mixed in
an appropriate 10 mL thick-walled glass vial. The glass
vial was tightly sealed with a Teflon cap and the reaction
mixture was stirred and heated at 200°C for 5 min, under
microwave irradiation, with an initial power setting
of 250 W.
Procedure for the oxidation of the porphyrinogen
under microwave irradiation with MnO2. The porphy-
rinogen and 5 equivalents of MnO2 in 2 mL of 2-methyl-
tetrahydrofuran (2MeTHF) were thoroughly mixed in
an appropriate 10 mL thick-walled glass vial. The glass
vial was tightly sealed with a Teflon cap and the reaction
mixture was stirred and heated at 80°C for 10 min, under
microwave irradiation, with an initial power setting of
250 W.
General procedure for the oxidation of the
porphyrinogen under conventional stirring conditions.
The porphyrinogen and 5 equivalents of MnO2 in 25 mL
of 2MeTHF were thoroughly mixed in a 50 mL round-
bottom flask, and stirred magnetically at room temperature
for 2 h. Alternatively, the porphyrinogen and 2,3-dichloro-
5,6-dicyanobenzoquinone (DDQ) (11.19 mmol, 2.54 g) in
50 mL of chloroform were thoroughly mixed in a 100 mL
round-bottom flask and stirred magnetically at room
temperature for 2 h.
Porphyrin yields
Porphyrin yields were determined by UV-vis spectro-
scopy using calibration curves from pure porphyrins in
2MeTHF. Aliquots of the reaction mixture (2 mg) were
dissolved in 3 mL of 2MeTHF and diluted until the
maximum of the Soret band was observable in the interval
of the corresponding calibration curves. The yield of the
porphyrin was determined by the intensity of the Soret
band measured from the apex to the base of the red edge of
the band to avoid the contribution of polypyrromethanes
[26]. The Soret band absorption coefficients in 2MeTHF
for 5,10,15,20-tetrakis-(4-methoxyphenyl)porphyrin,
5,10,15,20-tetraphenylporphyrin, 5,10,15,20-tetrakis-
(3,4-dimethoxyphenyl)porphyrin, 5,10,15,20-tetrakis-(2-
chlorophenyl)porphyrin and 5,10,15,20-tetrakis-(3,5-
-1
dichlorophenyl)porphyrin were 3.1 × 105 M-1 cm ; 1.1 ×
.
105 M-1 cm ; 2.4 × 10 M cm ; 1.0 × 10 M cm and
-1
5
-1
-1
5
-1
-1
.
.
.
-1
2.1 × 105 M-1 cm , respectively.
.
Porphyrin purification was achieved by washing with
ethanol and filtration over celite. When necessary, the
reaction mixture was dissolved in 2MeTHF, neutralized
with triethylamine and then porphyrin purified by flash
column chromatography using 2MeTHF/ethyl acetate
(10:1 v/v) as eluent.
The 1H-NMR of the obtained compounds are in good
agreement with the those previously described.
5,10,15,20-Tetrakis-(4-methoxyphenyl)porphyrin.
1H-NMR (400 Mz, CDCl3), d (ppm) = d (ppm) = -2.8
(2H, s), 4.05 (12H, s), 7.28 (8H, d, J = 8.8 Hz), 8.12 (8H,
d, J = 8.8 Hz), 8.85 (8H, s) [4].
5,10,15,20-Tetraphenylporphyrin. 1H-NMR (400 Mz,
CDCl3), d (ppm) = -2.82 (2H, s), 7.68 (12H, m), 8.17
(8H, m), 8.80 (8H, s) [29].
5,10,15,20-Tetrakis-(3,4-dimethoxyphenyl)
porphyrin. 1H-NMR (400 Mz, CDCl3), d (ppm) = -2.75
(2H, s), 3.98 (3H, s), 4.17 (3H, s), 7.26 (4H, d, J = 4.5
Hz), 7.74 (4H, d, J = 4.5 Hz), 7.78 (4H, s), 8.90 (8H,
s) [29].
5,10,15,20-Tetrakis-(4-chlorophenyl)porphyrin.
1H-NMR (400 MHz, CDCl3), d (ppm) = -2.66 (2H, s),
7.62–7.90 (8H, m), 8.12–8.30 (8H, m), 8.70 (8H, s) [55].
5,10,15,20-Tetrakis-(3,5-dichlorophenyl)porphyrin.
1H-NMR (400 Mz, CDCl3), d (ppm) = -2.80 (2H, s), 7.84
(4H, t, J = 2 Hz), 8.11 (8H, d, J = 2 Hz), 8.89 (8H, s) [56].
General procedure for the oxidation of the
porphyrinogen under mechanical activation. A mixture
of the porphyrinogen and 5 equivalents of MnO2 with
0.2 mL of the appropriate solvent, 2MeTHF, water or
ethyl acetate, was placed in a stainless-steel grinding
Copyright © 2019 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2019; 23: 7–9

8
C. GOMES, M. PEIXOTO AND M. PINEIRO
Chemistry, Physics, Materials Science, Engineer-
ing, Biology and Medicine — Volume 10: Catalysis
and Bio–Inspired Systems; World Scientific, 2010.
11. Kadish KM, Smith KM and Guilard R., Eds. Hand-
book of Porphyrin Science: With Applications to
Chemistry, Physics, Materials Science, Engineer-
ing, Biology and Medicine — Volume 12: Applica-
tions; World Scientific, 2011.
12. Kadish KM, Smith KM and Guilard R., Eds. Hand-
book of Porphyrin Science: With Applications to
Chemistry, Physics, Materials Science, Engineer-
ing, Biology and Medicine — Volume 18: Applica-
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13. Kadish KM, Smith KM and Guilard R., Eds. Hand-
book of Porphyrin Science: With Applications to
Chemistry, Physics, Materials Science, Engineer-
ing, Biology and Medicine — Volume 33: Applica-
tions — part II; World Scientific, 2014.
14. Kadish KM, Smith KM and Guilard R., Eds. Hand-
book of Porphyrin Science: With Applications to
Chemistry, Physics, Materials Science, Engineer-
ing, Biology and Medicine — Volume 39: Towards
Diagnostics and Treatment of Cancer; World Scien-
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CONCLUSION
The use of mechanochemistry for the one-step and
two-step synthesis of porphyrins allowed us to obtain
meso-tetrasubstituted porphyrins in good yields and
short reaction times. Using greener solvent and oxidant
alternatives such as 2-methyltetrahydrofuran and mang-
anese (IV) oxide it was possible to achieve sustainability
scores, from E-factor and EcoScale calculations, of the
same order of magnitude obtained using overheated
water under microwave irradiation, which is a serious
improvement when compared with the approach used in
classical methodologies.
Acknowledgments
The authors acknowledge FCT (Fundação para a
CiênciaeaTecnologia,I.P.)projectUID/QUI/00313/2019
for funding. This work was performed under the project
“SunStorage — Harvesting and storage of solar energy,”
with reference POCI-01-0145-FEDER-016387, funded
by the European Regional Development Fund (ERDF),
through COMPETE 2020 — Operational Programme
for Competitiveness and Internationalization (OPCI),
and by national funds, through FCT — Fundação para a
Ciência e a Tecnologia I.P. Carla S. Gomes thanks FCT
and PhD program CATSUS for PhD grant FCT- PD/
BD/135531/2018.
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