Synthesis of meso-TPP revisited: Its "green-oriented" optimization under controlled microwave heating

Article abstract of DOI:10.1080/00397911.2010.520183

A practical and proecological improvement for synthesis of meso-tetraphenylporphyrin (meso-TPP) under microwave irradiation is described. A cyclocondensation reaction of benzaldehyde and pyrrole followed by oxidation of the porphyrinogen formed as an inte

Full text of DOI:10.1080/00397911.2010.520183

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Synthesis of meso-TPP Revisited: Its
“Green-Oriented” Optimization Under
Controlled Microwave Heating
Agnieszka Mikus a , Marta E. Bielińska a , Teodozja Lipińska a &
Stanisław Ostrowski a
a Institute of Chemistry, Uniwersytet Przyrodniczo–Humanistyczny w
Siedlcach, Siedlce, Poland
Accepted author version posted online: 30 Jun 2011.Published
online: 16 Jun 2011.
To cite this article: Agnieszka Mikus , Marta E. Bielińska , Teodozja Lipińska & Stanisław Ostrowski
(2011): Synthesis of meso-TPP Revisited: Its “Green-Oriented” Optimization Under Controlled
Microwave Heating, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:24, 3703-3713
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Synthetic Communications1, 41: 3703–3713, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.520183
SYNTHESIS OF meso-TPP REVISITED: ITS
‘‘GREEN-ORIENTED’’ OPTIMIZATION UNDER
CONTROLLED MICROWAVE HEATING
´ ´
Agnieszka Mikus, Marta E. Bielinska, Teodozja Lipinska,
and Stanisław Ostrowski
Institute of Chemistry, Uniwersytet Przyrodniczo–Humanistyczny w
Siedlcach, Siedlce, Poland
GRAPHICAL ABSTRACT
Abstract A practical and proecological improvement for synthesis of meso-tetraphenylpor-
phyrin (meso-TPP) under microwave irradiation is described. A cyclocondensation reaction
of benzaldehyde and pyrrole followed by oxidation of the porphyrinogen formed as an inter-
mediate in a small amount of propionic acid at 120 ꢀC (under controlled microwave heating)
resulted in conversion to meso-TPP in a reasonable yield (ca. 30%) in preparative-scale
experiments (300–500 mg). The influence of many parameters such as the concentration
of reagents, catalyst, solvent, temperature, reaction time, and oxidant on the reaction yield
was studied. The environmental motive in this improvement is reduction of solvent volume
(ca. 250 times). Also, some toxic reagents were eliminated from the procedure.
Keywords Green chemistry; microwave-assisted synthesis; optimization; porphyrins
INTRODUCTION
meso-Tetraphenylporphyrin (meso-TPP), synthesized for the first time by
Rothemund in 1935,[1] is a very useful starting material in many chemical transforma-
tions.[2] It leads to compounds of greater complexity that have potential biological
activity. Since this time, the synthesis has been intensively studied, and several pre-
parative improvements for meso-TPP have been described such as (a) Adler–Longo
methodology,[3] (b) Lindsey’s modification,[4] and (c) cyclocondensation promoted
Received March 24, 2010.
Address correspondence to Stanisław Ostrowski, Institute of Chemistry, Uniwersytet
Przyrodniczo–Humanistyczny w Siedlcach, ul. 3 Maja 54, 08-110 Siedlce, Poland. E-mail: stan@
uph.edu.pl
3703

3704
A. MIKUS ET AL.
by TiCl4.[5] However, these examples represent various difficulties and preparative incon-
veniences such as (1) poor or moderate yieds that are not reproducible, (2) high tempera-
ture, (3) problematic purification (e.g., difficult crystallization from propionic acid; see
Adler–Longo[3]), (4) large amounts of solvents (to produce a small quantity of the pro-
duct), (5) toxic reagents (BF3ꢁEt2O) and solvents (pyridine, CH2Cl2), (6) high-quality
substrates that require prior purification before the synthesis (e.g., Lindsey’s method),
and (7) time-consuming reactions (up to 2 days for reaction, work-up, and purification).
Because of these limitations, we have undertaken investigations to develop a
fast, straightforward, and inexpensive method for preparation of this key porphyrin.
This was a problem of great importance because meso-TPP is a crucial intermediate
and its derivatives are sought in many fields of chemistry, biology, medicine, and
novel materials.[6]
RESULTS AND DISCUSSION
In the past two decades, Lindsey’s method was a standard preparation tool that
was used many times in a number of laboratories all over the world. Recently, we tried
to develop an alternative method that would allow us to avoid using large amounts of
solvent and toxic reagents. We applied nonconventional reaction assistance by using
the microwave irradiation technique (MW), which usually accelerates the process
and=or improves its yield. The detailed investigations of many parameters (solvent,
temperature, catalyst, concentration of reagents, reaction time, type of oxidant)
resulted in practical improvement of the method for synthesis of meso-TPP
(Scheme 1), which was patented recently.[7]
Solvent and Catalyst
In the first experiments, the reagents were irradiated in CH2Cl2 and CHCl3 at
low temperature (35–50 ꢀC). The yields of these reactions were very poor, so we
Scheme 1.

SYNTHESIS OF meso-TPP REVISITED
3705
selected a solvent that allows investigation within a wide temperature range. We tried
to avoid using BF3ꢁEt2O Lewis acid in case the applied solvent would also play the
role of acid catalyst. Similar to the Adler–Longo method, carboxylic acid of high
boiling point was selected for further studies, and all the experiments were carried
out in propionic acid (bp 141 ꢀC). The only exception was MW irradiation of the
reaction mixture with professional microwave reactor at controlled temperature
(max. power, 300 W, 2450 MHz) and high concentration of the reagents.
Concentration of the Reagents
For the first goal, the reaction was carried out at high concentration [20 mmol=
mL, in a 40-mmol scale; all the concentrations are given in millimoles (mmol) per
1 mL of solvent]. The temperature was also relatively high (120 ꢀC), and the reaction
time was very short (3 min). After purification, the desired product was isolated in a
poor yield (4.3%). The conditions of this reaction were similar to those described in
the same time in the literature.[8] However, we could not reproduce the reported
yields. On the other hand, the information provided in the literature was very enig-
matic (e.g., the authors did not comment concerning the applied MW power).
Additionally, we observed that the reactions at this concentration of substrates were
extremely vigorous, sometimes even self-igniting. Consequently, we decided to con-
tinue our investigations under the initially arranged conditions in the MW reactor.
However, in all the remaining experiments, the concentration decreased by up to
0.7 mmol=mL.
We found the maximum yield at the concentration of 4.0 mmol=mL (13.8%; see
Table 1 and Fig. 1). The poor yields at higher concentrations can be rationalized by
Table 1. Optimal concentration of substrates for synthesis of meso-TPP (Scheme 1; the reactions were
performed in 2 mL of propionic acid, temperature 120 ꢀC)
Benzaldehyde
Pyrrole
(mmol)
Concentrationa
(mmol=mL)
Reaction
time (min)
(mg)
(mmol)
(mg)
meso-TPP (mg)
Yield (%)
140
424
1.32
4.00
90
270
1.34
4.02
0.7
2.0
5
5
5
5
5
5
5
5
5
5
3
14
53
6.9
8.6
565
710
5.32
6.69
360
450
5.37
6.71
2.7
3.4
111
140
170
178
147
160
150
138
263
13.6
13.6
13.8b
12.7
9.6
849
970
8.00
9.14
537
620
8.00
9.24
4.0
4.6
1061
2122
2650
3185
4245
10.00
20.00
24.97
30.01
40.00
671
10.00
20.20
25.00
30.03
40.01
5.0
1347
1677
2015
2684
10.0
12.5
15.0
20.0
5.2
3.9
3.0
4.3c
aConcentration is given in millimoles [mmol] per 1 mL of the solvent (in all tables and in Experimental
Section).
bThe reaction conditions in which the greatest yields of meso TPP were obtained are marked in gray (in
all tables).
cUnder the reaction conditions described in the literature.[8]

3706
A. MIKUS ET AL.
Figure 1. meso-TPP yield as a function of reactants concentration (also see Table 1).
oligomerization, polymerization, formation of larger rings, and other competitive
reactions or degradation processes. Interestingly, the published data[8] claims ca.
40% yield in conditions that in our study produced only 4.3% of the desired product.
However, our results fit very well with the data listed in Table 1 (and in Fig. 1).
For the found by us optimal concentration of substrates, we investigated the
influence of further parameters on the reaction yield.
Influence of Reaction Time on Yield
In the next step, the yields of meso-TPP from the experiments carried out at a
fixed concentration of reactants of 4.0 mmol=mL (mentioned previously) were fol-
lowed as a function of reaction time (Table 2). In this set of experiments, we changed
the time of microwave irradiation of the reaction mixture between 5 min and
100 min. The maximum yield (23.1%) was found to occur at 50 min. Prolonging
MW irradiation in these experiments caused a small decrease in yield. This can be
easily explained by subsequent degradation of the product during longer exposure
to irradiation.
The optimal time was applied to investigate the influence of temperature and
external oxidant on the reaction yield.
Optimal Reaction Temperature
Next we investigated the temperature parameter. The yields from the experi-
ments performed between 70 ꢀC and 130 ꢀC, under the optimal reaction time
(50 min) and optimal concentration (C ¼ 4.0 mmol=mL), are listed in Table 3. The
experiments at higher temperature were limited by the boiling point of the solvent
(141 ꢀC).

SYNTHESIS OF meso-TPP REVISITED
3707
Table 2. Influence of the reaction time on the yield of synthesis
of meso-TPP (Scheme 1; the reactions were performed at
C ¼ 4.0 mmol=mL, T ¼ 120 ꢀC; in 2 mL of C2H5CO2H)
Time (min)
meso-TPP (mg)
Yield (%)
5
30
40
45
50
55
60
70
75
90
100
170
209
234
237
284
233
228
227
204
225
211
13.8
17.0
19.0
19.3
23.1
19.0
18.5
18.5
16.6
18.3
17.2
An analysis of the results in Table 3 allowed us to find the greatest yield at
120 ꢀC (23.1%). We observed the same maximum when the yield of meso-TPP was
investigated as a function of the reaction time (see Table 2). At low temperature,
we changed the solvent in an attempt to increase the yield obtained in propionic acid
(1.3% at 70 ꢀC). The experiment was carried out in CHCl3=C2H5CO2H mixture
(10:1) at 45 ꢀC. The temperature was established ca. 15 ꢀC below the boiling point
of CHCl3 to avoid overheating the reaction mixture. In the post-reaction residue,
we detected a considerable amount of the unchanged substrates and only traces of
meso-TPP. Thus, we confirmed that the conversion of the reactants at temperature
less than 70 ꢀC under these conditions is very poor.
The External Oxidant: Reinvestigation of the Reaction Conditions in
the Presence of para-Chloranil
All the experiments were performed in open vessels; therefore they were exposed
to air. No external oxidant was used, thus allowing oxidation by atmospheric oxygen
only. One could assume the addition of an external oxidant of considerable E1=2 such
Table 3. Optimal temperature for synthesis of meso-TPP
(Scheme 1; the reactions were performed at C ¼ 4.0 mmol=mL,
t ¼ 50 min; in 2 mL of C2H5CO2H)
Temperature (ꢀC)
meso-TPP (mg)
Yield (%)
70
90
16
168
194
202
215
284
258
237
1.3
13.7
15.8
16.4
17.5
23.1
21.0
19.3
100
110
115
120
125
130

3708
A. MIKUS ET AL.
as 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) or para-chloranil would accelerate
the reaction and increase its yield, so we decided to study the reactions, under MW
irradiation, using these types of effective oxidants. The first attempts at using DDQ
(E1=2 ¼ þ0.51 V)[9] were unsuccessful. The reactions carried out under the previously
discovered optimal conditions (C ¼ 4.0 mmol=mL, T ¼ 120 ꢀC, t ¼ 50 min) occurred
very rapidly, and a strong exothermic effect was detected (in some experiments fol-
lowed by inflammation). No formation of the product was observed. It is known that
DDQ is a rather strong oxidant, and it likely was too strong for this process. Finally,
when the time was reduced to 10 min in conjunction with the addition of DDQ 5 min
after the reaction began, we could isolate small amounts of meso-TPP (only 9.5%).
In the remaining experiments, under the same optimal concentration and
optimal temperature, a more gentle oxidant, para-chloranil (E1=2 ¼ þ0,01 V),[9] was
applied. The reaction time was changing stepwise between 5 min and 50 min. The
greatest yield (30.3%, average from three experiments) was observed for 30 min
(Table 4).
The results obtained show that applying external oxidant under MW
irradiation shortens reaction time and increases process yield. It is worth mentioning
that in some single experiments, we observed greater yields (compared to the average
of 30.3%), sometimes reaching 40%.
At the end of our study to identify optimal conditions for straightforward and
inexpensive method for synthesis of meso-TPP, we performed a reference experiment
by applying conventional heating. Under the best conditions found (but without
MW irradiation) the yield obtained was very poor (7.7%). Consequently, we can con-
clude that MW assistance plays an important role in this preparative modification.
In some reactions, small amounts of meso-triphenylcorrole were detected (less
than 1%). The formation of corroles, which usually accompany main products in the
synthesis of porphyrins, was reported several times in the literature.[10]
Finally, we applied the optimal conditions to check their effectivenes for
synthesis of analagous porphyrin, namely 5,10,15,20-tetrakis(3-methoxyphenyl)
Table 4. Influence of the reaction time on the yield of meso-TPP
[in the process carried out in the presence of the oxidant, para-
chloranil (PCA); Scheme 1; C ¼ 4.0 mmol=mL, T ¼ 120 ꢀC, in
2 mL of C2H5CO2H), mPCA ¼ 1475 mg (6.0 mmol); average yields
from 2–3 experiments are given]
Time (min)
meso-TPP (mg)
Yield (%)
5
10
15
20
25
27.5
30
35
40
45
50
114
143
166
262
259
290
373
288
248
295
280
9.3
11.6
13.5
21.3
21.0
23.6
30.3
23.4
20.2
24.0
22.8

SYNTHESIS OF meso-TPP REVISITED
3709
Figure 2.
porphyrin (3), from 3-methoxybenzaldehyde and pyrrole. The reaction occurred very
vigorously; thus, the process time was shortened to 15 min. In this case, the desired
product was also obtained in satisfactory yield (27%).
CONCLUSIONS
In this microwave-assisted method, the products can be synthesized very
quickly on an unlimited scale with a small amount of solvent. The greatest
yield was obtained in the reaction carried out at 120 ꢀC at the concentration of
4.0 mmol=mL of the substrates during 30 min (in the presence of para-chloranil as
an external oxidant). The yield obtained is less than that reported in the literature;[4]
however, this method has significant advantages: (a) The reaction time was reduced
many times, (b) the amount of solvent used was about 250 times less, (c) the
reactants used were of commercial grade without prior purification, (d) the use of
toxic BF3-etherate was avoided.
This variant of meso-TPP synthesis is competitive with the previously described
methods.[1,3–5] It allows very fast production of meso-TPP and its derivatives, which
are key substrates in the synthesis of porphyrin systems of greater complexity.[2,11]
We believe these factors make this modification valuable, and it will receive future
attention in the synthesis of these types of compounds. The modification also follows
green chemistry principles.
EXPERIMENTAL
The reactions were carried out in a Synthwave 402 Prolabo microwave reactor with an
open rotating system of reaction vessel [max. power, 300 W (frequency, 2450 MHz)],
coupled with a computer equipped with software allowing for continuous temperature
regulation. All the reactions were monitored by thin-layer chromatography (TLC,
aluminium foil plates precoated with silica gel, 60 F 254, Merck; CHCl3=n-hexane,
2:1). The structure of meso-TPP was confirmed by 1H NMR, ultraviolet=visible
(UV=vis), and mass spectrographic (MS) spectra. They were identical to those
described in earlier literature.[12]

3710
A. MIKUS ET AL.
1H NMR spectra were recorded with a Varian Gemini-200 spectrometer oper-
ating at 200 MHz. Mass spectra were measured with an AMD 604 (AMD Intectra
GmbH, Germany) spectrometer (EI method). UV=vis spectra were measured with
a Beckman DU-68 spectrometer. Silica gel, 230–400 mesh (Merck AG), was used
for column chromatography.
Synthesis of meso-TPP (2) in Microwave-Assisted Reactions
All the reactions were performed in cylindrical-shaped Pyrex glass vessels
(/ ¼ 2.5 cm, l ¼ 12 cm), in the microwave reactor.
Procedure A: Investigation of the Influence of Reagents Concentration
on the Yield of meso-TPP (Experiment Under the Optimal Concentration). A
solution of benzaldehyde (849mg, 8.0 mmol) and pyrrole (537mg, 8.0 mmol) in
propionic acid (2 mL) was placed in a cylindrical vessel. It was irradiated at 120 ꢀC dur-
ing 5 min. After cooling, the reaction mixture was dissolved in CHCl3 (15 mL) and
moved to an extractor; then water was added (50 mL). After separation, the water phase
was extracted with CHCl3 (2 ꢁ 30mL). The combined organic layers were washed with
water (3 ꢁ 50mL) and dried with MgSO4=Na2CO3. After evaporating the solvent on a
rotary evaporator, the crude residue was chromatographed on a column using
chloroform=n-hexane mixture (2:1) as eluent to obtain pure meso-TPP (170mg, 13.8%).
All the remaining experiments were carried out according to this procedure.
The amounts of the reagents (benzaldehyde and pyrrole), volume of solvent
(C2H5COOH), reaction conditions, and the yields obtained of the desired product
are listed in Table 1.
Procedure B: Investigation of the Influence of Reaction Time on the
Yield of meso-TPP (Experiment Under Optimal Conditions). As in procedure
A, the reagents were irradiated at 120 ꢀC during 50 min. After work-up and purifi-
cation, 284 mg of meso-TPP was obtained (23.1%).
All the remaining experiments were carried out according to this procedure.
The reaction time was changing between 5 min and 100 min. The amounts of the
desired product obtained and the yields are detailed in Table 2.
Procedure C: Investigation of the Influence of Temperature on the Yield
of meso-TPP. All the experiments were carried out according to procedure A. The
reagents were irradiated during 50 min, changing the temperature between 70 ꢀC and
130 ꢀC range. The amounts of the desired product obtained and the yields are
detailed in Table 3.
Procedure D: Investigation of the Influence of the External Oxidant on
the Yield of meso-TPP. All the experiments were carried out according to pro-
cedure A. Additionally, portions of para-chloranil (1475 mg, 6.0 mmol) were added
to the solution in each of the reactions.
In this series of experiments, the irradiation time was changing between 5 min
and 50 min. After work-up, the product was purified to give the following amounts:
5 min – 112 mg (9.1%), 130 mg (10.6%), 101 mg (8.2%);
10 min – 125 mg (10.2%) 168 mg (13.7%), 135 mg (11.0%);

SYNTHESIS OF meso-TPP REVISITED
3711
15 min – 179 mg (14.6%), 155 mg (12.6%), 165 mg (13.4%);
20 min – 284 mg (23.1%), 227 mg (18.5%), 274 mg (22.3%);
25 min – 251 mg (20.4%), 266 mg (21.6%);
27.5 min – 290 mg (23.6%);
30 min – 381 mg (31.0%), 389 mg (31.6%), 349 mg (28.4%);
35 min – 300 mg (24.4%), 275 mg (22.4%);
40 min – 256 mg (20.8%), 236 mg (19.2%), 252 mg (20.5%);
45 min – 295 mg (24.0%);
50 min – 316 mg (25.7%), 243 mg (19.8%).
The average yields of product 2 from the respective experiments are given in
Table 4.
In the reaction carried out under the same conditions in which DDQ (1362 mg,
6.0 mmol) was added instead of para-chloranil, meso-TPP was obtained in 9.5%
yield. In this experiment, DDQ was added to the reaction mixture 5 min after the
process began, and the reaction continued for another 5 min.
Reference experiment (Carried Out Under Conventional Heating When
Applying the Conditions in Which the Highest Yield Was Obtained). In a
round-bottomed flask equipped with a reflux condenser, a solution of benzaldehyde
(849 mg, 8.0 mmol), pyrrole (537 mg, 8.0 mmol), and para-chloranil (1475 mg,
6.0 mmol) in propionic acid (2 mL) was preheated to 120 ꢀC, and it was kept at this
temperature for 30 min. After work-up according to procedure A, 95 mg of meso-
TPP was obtained (yield – 7.7%).
Synthesis of 5,10,15,20-tetrakis(3-methoxyphenyl)porphyrin (3)
A solution of 3-methoxybenzaldehyde (1090 mg, 8.0 mmol), pyrrole (537 mg,
8.0 mmol), and para-chloranil (984 mg, 4.0 mmol) in propionic acid (2 mL) was
placed in a cylindrical vessel. It was irradiated at 120 ꢀC for 15 min. After cooling,
the reaction mixture was dissolved in CHCl3 (15 mL) and moved to an extractor con-
taining 35 mL of water. After separation, the water phase was additionally extracted
with CHCl3 (3 ꢁ 15 mL). The combined organic layers were washed with water
(2 ꢁ 50 mL) and dried with MgSO4=Na2CO3. After evaporating the solvent, the
crude product was purified by column chromatography (eluent: chloroform=n-
hexane, 1:1) to give pure 5,10,15,20-tetrakis(3-methoxyphenyl)porphyrin (397 mg, 27%).
The spectral data obtained for this product are in agreement with those
described earlier.[13]
ACKNOWLEDGMENT
This work was supported by the Ministry of Science and Higher Education,
Grant N N204 218535 (2008–2011).
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