Extensive methodology screening of meso-tetrakys-(furan-2-yl)-porphyrin microwave-assisted synthesis

Article abstract of DOI:10.1039/c5nj02888d

Two novel microwave-assisted synthetic procedures for the preparation of meso-tetrakys-(furan-2-yl)-porphyrin are herein reported. A solvent-free method which uses solid supported reagents has been deeply investigated. However, yields were further improve

Full text of DOI:10.1039/c5nj02888d

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Extensive methodology screening of
meso-tetrakys-(furan-2-yl)-porphyrin
microwave-assisted synthesis†
Cite this:DOI: 10.1039/c5nj02888d
a
a
b
a
Federica Bosca, Silvia Tagliapietra, Claudio Garino, Giancarlo Cravotto* and
a
Alessandro Barge*
Two novel microwave-assisted synthetic procedures for the preparation of meso-tetrakys-(furan-2-yl)-
porphyrin are herein reported. A solvent-free method which uses solid supported reagents has been deeply
investigated. However, yields were further improved when working in dioxane under heterogeneous
catalysis. The reaction rate, yields and impurity profiles have been optimized as a function of all the main
parameters: temperature, microwave power, concentration, time and metal ions. The Zn(II) porphyrin
complex was obtained in acceptable yields after only 10 min of irradiation. Also included are preliminary
studies on Diels–Alder reactions with furanyl derivatives which aim to achieve further porphyrin derivatization.
Received (in Montpellier, France)
18th October 2015,
Accepted 12th January 2016
DOI: 10.1039/c5nj02888d
www.rsc.org/njc
1
7
number of studies reporting procedures. The main difficulties
stem from the intrinsic properties of porphyrins, such as their
Introduction
Porphyrins take their name from the Greek word ‘‘porphyra’’ low solubility and photo-stability, and from the separation,
which means ‘‘purple’’. The peculiarity of these compounds is purification and characterization of the final macrocyclic compound.
their intense purple colour which derives from their electronic Several methodologies have been studied over the years: the
absorption behaviour. Indeed, their UV-visible spectrum is char- Lindsey method, a two-step one-pot room temperature approach
acterized by a strong single band, from 400 to 460 nm (Soret or B to porphyrinogen macrocycle synthesis and further oxidation to
band), in the high energy region and a series of bands, from the final porphyrin, was one of the first methods working under
5
00 to 700 nm (Q bands), in the low energy region; metal ion gentle conditions. Similar procedures have been developed,
1
7
complexation can increase porphyrin stability and modulate firstly by Rothemund and then by Alder–Longo, but have
their optical properties. resulted in low product yields. Two step procedures, based on
Porphyrins are molecules of great interest because of their condensation between two pyrrole units and one aryl aldehyde
huge potential in a number of fields, including material chemistry, followed by condensation between two dipyrromethane units
catalysis, nanotechnology, supramolecular chemistry, and and two aryl aldehydes, have been separately studied by Lindsey
fluorescent probes furthermore they can be used as agents for and Dolphin in the hope of increasing reaction yields and
photo- and sono-dynamic therapy.
range of biological and pharmacological activities, as they show different way was followed by Vieira et al. who used a SiO
antitumoral and antioxidant
1,2
3
,4
5
6,7
1
7
8–13
Porphyrins possess a wide synthesizing asymmetric porphyrin derivatives. A completely
1
8
2
14,15
properties, and can potentially be support to form the macrocyclic backbone. Of all the enabling
applied in the treatment of atherosclerosis, and neurodegenerative technologies available in organic synthesis, microwaves (MWs)
1
6
diseases and as anti-aging products. Moreover, metallopor- are the most effective energy source in solvent-free reactions
1
9
phyrins show good antifungal and antiparasitic potential and with solid catalysts. Henriques et al. have reported an eco-
2
0
the presence of a metal ion can modify some physiological friendly procedure under MW which gives oxidized porphyrin.
properties, such as cytotoxicity and antitumoral activity. In general, the preparation of symmetric meso-aryl-porphyrin,
The synthesis of porphyrins that bear differently functionalized and in particular the synthesis of meso-tetrakis(furan-2-yl)porphyrin
dangling arms is still an onerous, but exciting, task despite the (Fig. 1), has shown several drawbacks and limitations. This fact
prompted us to investigate alternative eco-friendly protocols
a
Dipartimento di Scienza e Tecnologia del Farmaco, University of Turin,
under MW irradiation. Moreover, in an attempt to better under-
stand the role of specific experimental variables, we have
investigated the influence of several reaction parameters on
the reaction behaviour. The parameters considered include
Via P. Giuria 9, 10125 – Torino, Italy. E-mail: giancarlo.cravotto@unito.it
alessandro.barge@unito.it; Tel: +39 0116707684, +39 0116707080
b
Dipartimento di Chimica, University of Turin, Via P. Giuria 7, 10125 – Torino,
Italy
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nj02888d reactant concentration, reaction time, reaction temperature,
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the MW oven cavity. The cavity was then hermetically sealed
and the inner pressure increased to 50 bar by nitrogen. The
reaction mixture was subsequently subjected to a temperature
controlled MW irradiation (max power of 1000 W) for the
required time, as described in the discussion section, at 170 1C.
After cooling to room temperature, the compact solid was
ground in a mortar and subjected to a first rough separation.
The finely grained solid was packed into the top of a flash
chromatographic pre-column cartridge containing 4 g of silica
gel and eluted using dichloromethane. The isolated fraction
was directly oxidized because of the presence of porphyrinogen-
like species (HPLC-MS analysis) with 2,3-dichloro-5,6-dicyano-
Fig. 1 Structure of meso-tetrakys-(furan-2-yl)-porphyrin.
1,4-benzoquinone (DDQ). To this purpose, the solvent was
removed under vacuum, the residue weighted and re-dissolved
in 30 mL of dichloromethane. DDQ (1.5 equivalents calculated
considering a residue made up of only the porphyrinogen
derivative) was added to the solution and heated to reflux for
the acid catalyst, the metal ion used and the homogeneous/
heterogeneous reaction strategy.
4
h. Reaction progress was monitored by HPLC-MS. The mixture
Experimental
Materials and methods
was then washed with water (3 Â 20 mL), the organic layer was
dried with anhydrous Na SO and the solvent was removed
2
4
All reagents and solvents were purchased from Sigma-Aldrich
under reduced pressure. The final meso-porphyrin derivative
was obtained by preparative HPLC-MS separation (more details
are described in the ESI†). In all cases the isolated yield was
lower than 1%.
(Milan, Italy) and used without further purification. Pyrrole and
furfural were distilled under vacuum prior to use. MW-assisted
reactions were carried out in a multimode reactor SynthWave
(
Milestone Srl, Italy) equipped with a full monitoring system of
General solution protocol for the preparation of
meso-tetrakys-aryl-porphyrins
temperature, pressure and power inputs. The CombiFlash
RfTeledyne (ISCO) purification system was used to purify all
crude reactions on silica gel. Analytical and Preparative HPLC-MS
was performed using a Fraction Link autopurification system
A solution of pyrrole and aryl-aldehyde in dioxane (12.5 mL,
concentration of both reagents from 1 M to 0.1 M) was placed
in a Pyrex test tube of 20 mm in diameter and stirred for 15 min
at room temperature. Amberlyst 15 (2 mg), a strongly acidic
resin, was added to the mixture and immediately subjected to a
temperature controlled MW irradiation (max power of 1000 W),
at 50 bar (air was not removed before increasing pressure
(Waters) equipped with a 2996 photo-diode array detector and a
Micromass ZQ detector (ESCI hybrid ionization source). IR
spectra were recorded on a FT-IR Spectrum BXII (Perkin Elmer)
with KBr dispersion and diffuse reflectance apparatus DRIFT
ACCY. NMR spectra were recorded on an Avance 300 spectro-
meter (Bruker) operating at 7 T, in deuterated THF. Chemical
shifts were referenced according to solvent residual signals. MS
spectra were obtained using electrospray ionization (ESI) or by
atmospheric pressure chemical ionization (APCI), in positive
ion mode, on a Micromass ZQ spectrometer (Waters). UV-Vis
absorption and photoemission spectra were recorded in THF
solution at ambient temperature. Absorption spectra were acquired
on an Agilent Cary 60 UV-Vis spectrometer, while photoemission
spectra were obtained on a Horiba Jobin Yvon FluoroLog 3 spectro-
fluorimeter (Horiba Ltd, Minami-Ku Kyoto, Japan), equipped with a
with N ), for variable reaction temperatures and times, as
2
previously described. The catalyst was filtered off and washed
with dichloromethane. The solvent was removed under reduced
pressure and the residue was roughly purified by isocratic flash
chromatography (silica, dichloromethane). The HPLC-MS analyses
of the isolated fraction confirmed the presence of the final meso-
porphyrin which was directly purified by preparative HPLC-MS.
HPLC separation methods
HPLC-MS analyses were carried out on a Waters SunFire (4.6 Â
4
50 W xenon lamp and a Hamamatsu R928 photomultiplier.
150, 5 mm) C18 column, using 0.1% trifluoroacetic acid (TFA)
The spectral response was corrected for the spectral sensitivity
of the photomultiplier and the fluorescence emission recording
range was from 500 to 850 nm with slits at 3 nm.
aqueous solution (A) and 0.1% TFA in methanol (B) as eluents.
The flow rate was 1 mL min and gradient timetables were as
follows.
À1
Method 1 (min, B%): 0, 50%; 7.50, 50%; 22.50, 100%;
2.50, 100%.
The product purity was calculated as the area ratio at 430 nm
Procedure for the solid-support preparation of
meso-tetrakys-(furan-2-yl)-porphyrin
3
Pyrrole (360 mL, 5.2 mmol) and furfural (431 mL, 5.2 mmol) were and MS TIC traces.
mixed and stirred at room temperature in a Pyrex test tube of Method 2 (min, B%): 0, 65%; 15.00, 65%; 27.50, 100%;
0 mm in diameter. After 15 min stirring, 620 mg of silica 42.50, 100%.
or alumina; SiO /Al in 1 : 1, 1 : 2, 1 : 3 ratio; Al 0.1% The product purity was calculated as the area ratio at 428 nm
AcOH) was added to the mixture and the tube was placed in and MS TIC traces.
2
(
2
2
O
3
2 3
O
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Method 3 (min, B%): 0, 50%; 7.50, 50%; 25.00, 100%;
5.00, 100%.
H NMR (300 MHz, CDCl
3
, d 7.26 ppm) d 8.93 (d, J = 8.31 Hz,
+
3
8H), 8.79 (d, J = 8.31 Hz, 8H) 8.63 (s, 8H); APCI-MS : m/z calcd
Preparative HPLC separations were carried out using a for C H N O , 794.19; found 795.26 [M + H ]; l (from
max
+
4
4
26
8
8
Phenomenex Gemini C18 (21.2 Â 100, 5 mm, 110 Å) column, HPLC-MS analysis, MeOH–TFA, H O–TFA) = 418 nm.
2
using water (A) and methanol (B) as eluents. The flow rate was
À1
24
20 mL min and gradient timetables were as follows.
meso-Tetrakys-(4-methoxyphenyl)-porphyrin (5)
Method 4 (min, B%): 0, 70%; 2.80, 70%; 4.30, 100%;
.50, 100%.
Method 5 (min, B%): 0, 70%; 4.30, 100%; 7.50, 100%.
Method 6 (min, B%): 0, 80%; 7.00, 100%; 10.00, 100%.
The general solution protocol was followed using freshly distilled
pyrrole (0.1 M in dioxane) and 4-methoxybenzaldehyde (0.1 M in
dioxane), at 170 1C for 20 min. Amberlyst 15 (2 mg), a strongly
acidic resin, was added to the mixture. After purification, the
8
desired product was recovered as a solid (yield 3%).
2
1
meso-Tetrakys-(furan-2-yl)-porphyrin (1)
1
H NMR (300 MHz, THF-d , d 1.73 ppm) d 8.84 (s, 8H),
8
+
meso-Tetrakys-(furan-2-yl)-porphyrin was obtained according to 8.11 (m, 8H) 7.34 (m, 8H), 1.29 (s, 12H); APCI-MS : m/z calcd
+
38 4 4
the solid-support procedure with yields lower than 1%. The for C48H N O , 734.29; found 735.39 [M + H ]; lmax (from
solution protocol was also used and gave better results. A HPLC-MS analysis, MeOH–TFA, H
2
O–TFA) = 447 nm.
green solid was obtained, at yields up to 3.8%, after HPLC-MS
purification (method 4).
HPLC-MS: (method 1) Rt = 14.71 min, purity 80%; H NMR
300 MHz, THF-d , d 1.73 ppm) d 9.18 (s, 8H), 8.25 (br s, 4H),
.39 (br s, 4H), 7.08 (br s, 4H), À2.55 (s, 2H); APCI-MS :
General procedure for the Diels–Alder reaction
1
Zn(II)-meso-tetrakys-(furan-2-yl)-porphyrin (7 mg, 0.011 mmol)
and ethyl crotonate (11 mL, 0.088 mmol) were dissolved in THF
(
7
8
+
2
(4 mL) and anhydrous ZnCl (3 mg) was added as the catalyst.
+
m/z calcd for C36
22 4 4
H N O , 574.16; found 575.48 [M + H ];
The mixture was heated to reflux for 2 days. The reaction
was monitored by HPLC-MS which was set up to detect the
mono-Diels–Alder derivative (6) and the disappearance of the
starting materials. The solvent was removed and the desired
lmax (THF) = 430 nm.
Zn(II)-meso-tetrakys-(furan-2-yl)-porphyrin (2)
The general solution protocol was followed and freshly distilled product was isolated by preparative HPLC-MS (method 6) in a
pyrrole (0.4 M in dioxane) and furfural (0.4 M in dioxane) were 30% yield.
1
used, while Zn(AcO)
.13 M, at 140 1C for 10 min. Amberlyst 15 (2 mg), a strongly CDCl
acidic resin, was added to the mixture. After purification 7.03–6.87 (br-m, 6H), 6.08 (m, 2H), 5.38 (m, 1H), 4.25 (m, 2H),
HPLC-MS method 5), the desired product was recovered as a 3.85 (br-m, 2H), 2.81 (m, 3H), 2.02 (t, J = 4.30 Hz, 3H);
2
was added to give a final concentration of
HPLC-MS: (method 3) Rt = 27.39 min; H NMR (300 MHz,
0
3
, d 7.26 ppm) d 7.52–7.33 (m, 8H), 7.12–703 (br-m, 3H)
(
+
violet-blue solid (yield 5.2%).
30 4 6
HRMS (APCI ): m/z calcd for C42H N O Zn, 750.1457; found
+
HPLC-MS: (method 2) Rt = 31.22 min, purity 83%; IR (KBr) 751.1540 [M + H] ; lmax (from HPLC-MS analysis, MeOH–TFA,
À1
1
3122, 2801, 1676, 1200, 1144, 797, 724 cm
;
H NMR
H O–TFA) = 426 nm.
2
(
7
C
300 MHz, CDCl , d 7.26 ppm) d 8.60 (s, 8H), 8.37 (s, 4H),
3
+
.82 (d, J = 2.94 Hz, 4H), 7.20 (s, 4H); APCI-MS : m/z calcd for
+
Results and discussion
Structure design
36
H
2o
N
4
O
4
Zn, 636.08; found 637.60 [M + H ]; lmax (from
HPLC-MS analysis, MeOH–TFA, H O–TFA) = 428, 564, 610 nm.
2
2
2
Specific porphyrin applications require their conjugation or grafting
to a variety of substrates, such as nanoparticles, dendrimers,
polymers, fullerene, graphene or carbon nanotubes, as well as a
variety of small molecules. Porphyrin structural modification,
via the insertion of one or more specific dangling arms, is
therefore an important task. The synthetic target often involves
the protection and deprotection of many functional groups in
order to display the selected functionality. The introduction of
a reactive group which is orthogonal to the most common
functional groups on the porphyrin surface may make the
conjugation of a further dangling arm easier and furan may
meso-Tetrakys-(phenyl)-porphyrin (3)
The general solution protocol was followed and freshly distilled
pyrrole (0.1 M in dioxane) and benzaldehyde (0.1 M in dioxane)
were used at 170 1C for 20 min. Amberlyst 15 (2 mg), a strongly
acidic resin, was added to the mixture. After purification, the
desired product was recovered as a brownish solid (yield 5%).
H NMR (300 MHz, CDCl , d 7.26 ppm) d 8.61 (s, 4H), 8.57
s, 8H), 7.98 (m, 16H); APCI-MS : m/z calcd for C H N ,
1
3
+
(
6
4
4
30 4
+
14.25; found 615.40 [M + H ]; lmax (from HPLC-MS analysis,
MeOH–TFA, H
2
O–TFA) = 433 nm.
2
5
be a useful reactive group in Diels–Alder reactions or as a
precursor to an aldehyde carbonyl. For these reasons, we have
2
3
meso-Tetrakys-(4-nitrophenyl)-porphyrin (4)
The general solution protocol was followed using freshly dis- considered a porphyrin bearing four exposed furanyl moieties
tilled pyrrole (0.1 M in dioxane) and 4-nitrobenzaldehyde (0.1 M on its surface (Fig. 1). This structure could be applied in the
in dioxane), at 170 1C for 20 min. Amberlyst 15 (2 mg), a strongly synthesis of more complicated porphyrins or used for its hydro-
acidic resin, was added to the mixture. After purification, the phobicity and luminescence behaviour in a number of application
desired product was recovered as a solid (yield 2%).
fields. So far, the reported syntheses of this particular porphyrin
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2
1,22,26
did not give satisfactory yields (1–2.1%),
and higher yields maximum absorption value for porphyrin, but it is a good
(
10%) could be achieved with a time consuming (5 min + compromise to monitor the signals of porphyrin-like species
2
1
overnight stirring) and multi-step procedure. Moreover, none and impurities alike (Fig. 3).
of the published procedures report the purity of the isolated
HPLC profiles were conveniently divided into three regions
porphyrin. This study explores the preparation of symmetrical (see Fig. S9 in the ESI†) in order to rationalize the HPLC data
meso-tetrakys-(furan-2-yl)-porphyrin by the acid catalysed con- and extract some general information on impurities. The area
densation of four furfural and four pyrrole derivatives. Two with a retention time higher than porphyrin like species (Rt2),
different routes have been investigated. They are both in the the area which includes porphyrin-like species and the area
heterogeneous phase, one over a solid support and the other in with lower retention times than porphyrin (Rt1). The number of
solution (Scheme 1). In the former, the solid support also plays impurity peaks and the distribution profile are different when
the role of an acid catalyst, while in the solution protocol the the solid support composition changes from silica to alumina.
catalyst is an acidic polymeric resin. From both protocols, the The Rt2 impurity peak area decreases when the amount of
desired porphyrin was obtained after only 10 min of MW irradiation alumina in the solid support is increased, whereas the opposite
under pressure. Fast HPLC purification (8.5 min long) gave meso- is observed for Rt1 impurities. Interestingly, the chromato-
tetrakys-(furan-2-yl)-porphyrin with a purity of 80%.
graphic profile is characterized by a very clear Rt2 region when
Furthermore, preliminary investigations on the photophysical acid doped alumina is used.
properties of meso-tetrakys-(furan-2-yl)-porphyrin and Zn(II)-meso-
The impurities could reasonably be ascribed to different
tetrakys-(furan-2-yl)-porphyrin were carried out.
kinds of variably sized linear condensation products on the
basis of these experimental data. This impurity distribution
may be related to the different types of interactions that exist
Solid-support synthesis
2
0
Six different solid supports, silica gel, neutral alumina, a between the reagents/products, the solid supports and oxygen.
mixture of the two (SiO /Al = 1 : 1; 1 : 2; 1 : 3) and acetic acid Finally, the reaction time was also investigated and we can
0.1% w/w) on alumina, have been investigated. All reactions were conclude that 20 min is the optimal value to minimize the
carried out under the same conditions: MW irradiation, 30 min, amount of both starting materials and side-products in the
70 1C, support/pyrrole/aldehyde ratio = 119/1/1 (w/mol/mol). final reaction mixture.
meso-Tetrakys-(furan-2-yl)-porphyrin was obtained after the In summary, we can assert that, under these reaction conditions
oxidation of the crude material with 2,3-dichloro-5,6-dicyano- (MW irradiation, 20 min, 170 1C, support/pyrrol/aldehyde
,4-benzoquinone (DDQ). ratio = 119/1/1 g/mol/mol) the best solid support, in terms of
Porphyrinogen, partially oxidized porphyrinogen and porphyrin porphyrin/porphyrinogen like ratio and impurity quantity, is
2
2 3
O
(
1
1
were detected by HPLC-MS analysis in all reactions before the 0.1% acetic acid treated alumina.
last oxidative step. The ratio between porphyrin and the sum of
reduced species depends on the support used; it was 0.6 with
silica gel and decreased to 0.3 in the case of alumina. When
silica and alumina were mixed, the ratio was markedly lower
than with neat alumina (namely 0.1 for the two higher SiO2/
Al O ratio and 0.2 for SiO /Al O = 1 : 3, Fig. 2). The ratio
In-solution synthesis
Solid support reaction optimization did not give gratifying
results in terms of yield. Therefore we decided to try a new
approach which combines some aspects of solid-support synthesis
with others from solution synthesis. We took the heterogeneous
acid catalyst and MW irradiation from supported syntheses and
all the advantages of a homogeneous reaction medium from
solution synthesis.
Surprisingly, the in-solution synthesis carried out directly
gave meso-tetrakys-(furan-2-yl)-porphyrin in higher yield values.
This major improvement in aldehyde-pyrrole condensation
reduces the required synthetic steps, as the intermediate species
is immediately oxidised. This phenomenon may be due to
in-solution oxygen diffusion which is enhanced by the high
pressure conditions set for all the experiments performed.
2
3
2
2 3
reaches the value of 0.9 in acetic acid adulterated alumina.
If the various supports have an effect on the distribution of
porphyrin like species, it does not affect the reaction yield.
Indeed, preparative HPLC-MS purification of the final compound
always gave an overall yield of about 1% after DDQ oxidation. This
behaviour (Fig. 2) may be explained by the acidity of the support
and its morphology after heating. Silica gel is more acidic than
neutral alumina, but it shows a more vitreous morphology after
heating than alumina which has a spongy appearance. Both the
acidity and sponginess are lost when the two substances are
combined. Optimal conditions are reached enhancing the soft
and springy nature of the support by acidity. This is the case of
acetic acid tainted alumina. Silica gel is unfavourable to oxygen
diffusion into the mass, whereas neutral alumina is less acidic All in-solution reactions were carried out using Amberlyst 15,
Catalyst
2
7
but can boast of the morphology that facilitates oxygen diffusion a strongly acidic cation exchanger resin, as the solid acid
and thus porphyrin formation. catalyst. The resin was activated by washing with HCl 2 M
Another interesting aspect to study, beside the formation of and dried before each use. Preliminary catalyst amount screening
porphyrin/porphyrinogen like species, is the impurity profile. showed that the reaction yield and the impurity profile did not
The impurity amount and distribution were evaluated by HPLC change with the catalyst amount, so we decided to use a fixed
analysis at 254 nm. This wavelength does not correspond to the amount of 2 mg.
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Scheme 1 Two different protocols for meso-aryl-porphyrin synthesis.
Temperature
(nitrogen atmosphere) was set to 50 bar. The HPLC-MS analysis
Initially, solid-support conditions were directly transferred to of the crude product showed the absence of all porphyrinogen
the solution protocol. The temperature was set to 170 1C, the like species, because residual oxygen present is sufficient for
reaction time to 20 min and the reagent concentration was the oxidizing process. Furthermore, the peak area for the
fixed at 1 M. The boiling point of dioxane is lower than the 254 nm trace in the Rt2 region is close to zero. The overall
reaction temperature, hence a pressurized MW reactor was yields were again lower than 1% after the final purification by
selected to carry out solution reactions and the pressure preparative HPLC-MS. No improvement was observed, either in
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Fig. 4 Porphyrin yield vs. reactant concentration. MW enhanced reac-
tions carried out in dioxane, 50 bar (N
70 1C (black square).
2
), 20 min, 140 1C (red circle) and
1
Yield behaviour was very similar at the two different tem-
peratures. Yield does not depend on temperature (between
40 and 170 1C) at higher concentrations, but an improvement
is observed in reactions carried out at 170 1C at the lower
1
Fig. 2 Porphyrin/porphyrinogen like species ratio vs. solid support concentration.
composition.
Time
Our attention moved to reaction time at a single temperature
value (140 1C). Four different reaction times (10, 20, 40, and
0 min) were considered for two different reactant concentrations
0.1 and 0.2 M). The yield increases incrementing the reaction time
6
(
from 10 to 40 min, with the same trend for both concentration
values. After this maximum, the curve decreases rapidly to very low
yields (Fig. 5). Simultaneously, the impurity amount increases after
40 min as observed in HPLC-MS profiles.
Metal template synthesis
A further improvement in the synthetic protocol was achieved
by exploiting the template ability of the Zn(II) ion. The cyclo-
condensation of four aldehydes and four pyrroles is a favourable
Fig. 3 Impurity peak area (% calculated at 254 nm) in the Rt1 region (black process in the presence of zinc acetate.
square) and the Rt2 region (red circle) vs. solid support composition.
In contrast to previously observed results (Fig. 4), the cyclization
reaction, in the presence of Zn(II) ions, is less favourable at
terms of yield or impurity profile, when the reaction temperature
was reduced to 140 1C and all the other conditions were
maintained constant.
Concentration
It is well known that cyclization reactions take advantage of
high dilution conditions. Hence, this meso-tetrakys-(furan-2-yl)-
porphyrin synthesis was studied at four different reactant
concentrations (from 1 to 0.1 M) at 170 1C and 140 1C. As
depicted in Fig. 4, the reaction yield, calculated as the isolated
product (by preparative HPLC-MS), increases when reactant
concentrations decrease, giving a maximum value of 4% at
0.1 M and 170 1C. Further dilutions do not improve the reaction
yield, since the extremely low amount of reagent contained in
the low volume tubes employed does not allow for the yield to
be correctly evaluated.
Fig. 5 Porphyrin yield vs. reaction time (min). MW enhanced reactions
carried out in dioxane, 50 bar (N
(purple sphere).
2
), 140 1C, 0.1 M (green triangle) and 0.2 M
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and concentration are similar to those observed for meso-tetrakys-
(furan-2-yl)-porphyrin, but the isolated yields are slightly lower.
With these three aldehydes, the purification of cyclocondensation
products was more difficult, affecting negatively the overall yield.
Preliminary study of a two step procedure (MacDonald 2 + 2
2
4
method )
As described in the literature, the MacDonald 2 + 2 method is
used to synthesize meso substituted porphyrins, and especially
for obtaining asymmetric derivatives. This method consists of
a first step which generates the dipyrromethane intermediate, a
further condensation with an aldehyde to give the meso-substituted
porphyrinogen and the final oxidation to meso-porphyrin (Scheme 2).
In theory, the procedure described in this paper could also
be employed to obtain the dipyrromethane intermediate, if the
ratio between pyrrole and aryl aldehyde is set at 2 : 1. This first
preliminary study leads us to conclude that the intermediate is
converted to porphyrinogen and then immediately to porphyrin.
This last oxidation step involves ring aromatization and so
moves the reaction to meso-tetra-aryl-porphyrin formation.
Fig. 6 Zn-porphyrin yield vs. reaction time (min). MW enhanced reactions
2 2
carried out in dioxane in the presence of Zn(AcO) (0.13 M), 50 bar (N ),
1
40 1C, reactant concentration 0.4 M.
170 1C than at 140 1C. The trend depicted in Fig. 6 shows a
faster reaction rate with a maximum yield of 5% after only
0 min. The role of Zn(II) is not only related to the synthetic
1
procedure (higher yield, shorter time, and one step reaction),
but also to the stability of these delicate and frail compounds
which is improved by the formation of the metal complex.
Analogous results, in terms of kinetics, were observed with
different metals (Cu(II), Fe(III), and Mn(II)) but markedly lower
reaction yields were obtained.
Preliminary investigation on the photo-physical properties of
meso-tetrakys-(furan-2-yl)-porphyrin and Zn(II)-meso-tetrakys-
(
furan-2-yl)-porphyrin
2
8
As previously reported by Santosh and Ravikanth, replacing
the six-membered aryl groups with the five-membered furyl groups
at the meso-positions considerably alters porphyrin electronic
properties. The absorption spectrum of meso-tetrakys-(furan-2-yl)-
porphyrin, recorded in toluene, shows three clear Q-bands (526,
571, 605 (shoulder), and 670 nm) and one Soret band (433 nm).
Thus, the number of Q-bands is reduced from four to three and
the Soret and Q-bands are red shifted and broadened as compared
to tetrakys-arylporphyrins. In a similar way, the emission spectrum
of meso-tetrakys-(furan-2-yl)-porphyrin displays one band (697 nm)
that is red shifted with regard to the two emission bands of meso-
tetrakys-arylporphyrins.
Scheme 2 Schematic representation of the MacDonald 2 + 2 procedure.
2
9
Upon metalloporphyrin formation, the Q bands in the
visible region collapse into essentially two bands (565 and
615 nm) due to the higher D4h symmetry, while the Soret band
is not affected (see ESI,† Fig. S5). Upon Soret band excitation,
Zn(II)-meso-tetrakys-(furan-2-yl)-porphyrin displays one emission
band at 655 nm that is blue shifted as compared to the emission
band of the free base.
Preliminary study of different meso substitutions
In order to fully exploit the peculiarity of the solution procedure
(170 1C, 50 bar, 40 min, 0.1 M), three other aldehydes were
considered; benzaldehyde, p-nitro-benzaldehyde and p-methoxy-
benzaldehyde. Similarly to the previous procedures, HPLC-MS
profiles do not show the presence of porphyrinogen like species,
Scheme 3 Schematic representation of porphyrin derivatization using
but only the desired final porphyrins. The impurity distribution the Diels–Alder reaction.
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Indeed, dipyrromethane was not present in the chromatogram and
only the final compound was detected in remarkable amounts.
6 M. Wathier and M. W. Grinstaff, J. Am. Chem. Soc., 2008,
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C. M. Drain, A. Varotto and I. Radivojevic, Chem. Rev., 2009,
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New application paths of meso-tetrakys-(furan-2-yl)-porphyrin
1
A Diels–Alder reaction between ethyl crotonate and Zn(II)-meso-
tetrakys-(furan-2-yl)-porphyrin was investigated as a means to
evaluate the possibility of further functionalizing meso-tetrakys-
2
004, 11, 349.
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(
furan-2-yl)-porphyrin (Scheme 3). The Zn(II) porphyrin complex
1
1
1
1
1
was chosen because of its higher stability as compared to the
free metal. Following the reaction by HPLC-MS analysis, it was
possible to observe the disappearance of the starting material
and the sole formation of the mono derivate of the Diels–Alder
cycloaddition with a yield of about 34% (by HPLC-MS).
Although this reaction still requires optimisation, a wide portfolio
of multifunctional porphyrin derivatives is in the offing.
2
2
4 N. A. Antonova, V. P. Osipova, M. N. Kolyada, N. O. Movchan,
E. R. Milaeva and Y. T. Pimenov, Macroheterocycles, 2010,
Conclusions
3
(2–3), 139.
Two novel MW-assisted synthetic protocols for the preparation of
meso-tetrakys-(furan-2-yl)-porphyrin have been investigated. The
solvent-free method was carried out using solid supported reagents
to give moderate yields and required an oxidation step. Better
results were achieved in dioxane under heterogeneous catalysis.
The few published synthetic procedures entail time-consuming
multi-steps and laborious purifications, moreover they only refer
to the reaction yield omitting product purity. The advantages of the
reported procedure are the short reaction time (10–20 min), the
one step conversion (no further porphyrinogen oxidation is
required) and the efficient, fast and relatively easy purification of
1
1
1
5 M. Yuasa, K. Oyaizu, H. Murata, Y. Sahara, T. Hatsugai and
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Chem., 1967, 32(2), 476.
2
crude porphyrin. The presence of Zn(AcO) in the reaction mixture
1
8 L. F. Vieira Ferreira, D. P. Ferreira, A. S. Oliveira, R. Boscencu,
R. Socoteanu, M. Ilie, C. Constantin and M. Neagu, Dyes Pigm.,
increases the reaction rate giving the corresponding metallo-
porphyrin. Furanyl moieties on the porphyrin surface were
functionalized by the Diels–Alder reaction.
In conclusion, these promising results and the fast synthesis
of meso-tetrakys-(furan-2-yl)-porphyrins may pave the way for
their decoration and grafting onto nanomaterials.
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