Iron(III) fluorinated porphyrins: Greener chemistry from synthesis to oxidative catalysis reactions

Article abstract of DOI:10.3390/molecules21040481

: Iron(III) fluorinated porphyrins play a central role in the biomimetics of heme enzymes and enable cleaner routes to the oxidation of organic compounds. The present work reports significant improvements in the eco-compatibility of the synthesis of 5,10,15,20-tetrakis-pentafluorophenylporphyrin (H2 TPFPP) and the corresponding iron complex [Fe(TPFPP)Cl], and the use of [Fe(TPFPP)Cl] as an oxidation catalyst in green conditions. The preparations of H2 TPFPP and [Fe(TPFPP)Cl] typically use toxic solvents and can be made significantly greener and simpler using microwave heating and optimization of the reaction conditions. In the optimized procedure it was possible to eliminate nitrobenzene from the porphyrin synthesis and replace DMF by acetonitrile in the metalation reaction, concomitant with a significant reduction of reaction time and simplification of the purification procedure. The Fe(III)porphyrin is then tested as catalyst in the selective oxidation of aromatics at room temperature using a green oxidant (hydrogen peroxide) and green solvent (ethanol). Efficient epoxidation of indene and selective oxidation of 3,5-dimethylphenol and naphthalene to the corresponding quinones is observed.

Full text of DOI:10.3390/molecules21040481

molecules
Article
Iron(III) Fluorinated Porphyrins: Greener Chemistry
from Synthesis to Oxidative Catalysis Reactions
Susana L. H. Rebelo 1,*, André M. N. Silva 2, Craig J. Medforth 2 and Cristina Freire 1
1
REQUIMTE/LAQV, Departamento de Química e Bioquímica, Faculdade de Ciências,
Universidade do Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal; acfreire@fc.up.pt
REQUIMTE/UCIBIO, Departamento de Química e Bioquímica, Faculdade de Ciências,
2
Universidade do Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal;
andre.silva@fc.up.pt (A.M.N.S.); craig.medforth@fc.up.pt (C.J.M.)
*
Correspondence: susana.rebelo@fc.up.pt; Tel.: +351-220-402-586
Academic Editors: M. Graça P. M. S. Neves and M. Amparo F. Faustino
Received: 23 February 2016; Accepted: 5 April 2016; Published: 12 April 2016
Abstract: Iron(III) fluorinated porphyrins play a central role in the biomimetics of heme enzymes and
enable cleaner routes to the oxidation of organic compounds. The present work reports significant
improvements in the eco-compatibility of the synthesis of 5,10,15,20-tetrakis-pentafluorophenylporphyrin
(H2TPFPP) and the corresponding iron complex [Fe(TPFPP)Cl], and the use of [Fe(TPFPP)Cl]
as an oxidation catalyst in green conditions. The preparations of H2TPFPP and [Fe(TPFPP)Cl]
typically use toxic solvents and can be made significantly greener and simpler using microwave
heating and optimization of the reaction conditions. In the optimized procedure it was possible
to eliminate nitrobenzene from the porphyrin synthesis and replace DMF by acetonitrile in the
metalation reaction, concomitant with a significant reduction of reaction time and simplification of
the purification procedure. The Fe(III)porphyrin is then tested as catalyst in the selective oxidation of
aromatics at room temperature using a green oxidant (hydrogen peroxide) and green solvent (ethanol).
Efficient epoxidation of indene and selective oxidation of 3,5-dimethylphenol and naphthalene to the
corresponding quinones is observed.
Keywords: iron(III)porphyrin synthesis; microwave; green oxidation; catalysis; aromatics
1. Introduction
Fluorinated porphyrins have been attracting considerable attention as components of photonic
materials and in biological applications, such as imaging or photodynamic therapy, owing to their
versatile photophysics, electron withdrawing properties and resistance to oxidative degradation [
On the other hand, iron and manganese porphyrins have been successfully tested as biomimetics
of heme enzymes, including cytochrome P450 monooxygenases [ ], peroxidases [ ] or catalases [ 10].
1–5].
6,
7
8
9,
The use of synthetic metaloporphyrin models has brought important insights into the mechanisms and
intermediates of the biological reactions [11]. In addition, biomimetic models are advantageous since
they are readily available and much easier to handle than the bio-catalytic systems, with halogenated
metaloporphyrins being among the first used, most efficient and robust catalytic systems [12,13].
In the last few decades, studies of catalytic oxidations using metaloporphyrins as P450 models
have led to new oxidation routes and new compounds that would otherwise be difficult to obtain, such
as multi-epoxides of polycyclic aromatic hydrocarbons [14
afforded novel synthetic methods for important chemicals with improved eco-compatibility [16
using green oxidants such as hydrogen peroxide [18 19] and mild conditions [20]. For example,
,
15]. Furthermore, metaloporphyrin catalysis
,17],
,
manganese porphyrins were used in the selective and mild oxidation of alkylphenols to p-quinones
using H2O2 at room temperature. This procedure was efficient in acetonitrile using ammonium
Molecules 2016, 21, 481; doi:10.3390/molecules21040481
www.mdpi.com/journal/molecules

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acetate as a co-catalyst (Figure 1a) [21]. Subsequently, iron fluorporphyrin systems were found to
show higher efficiency than manganese analogous for hydroxylation of aromatic rings in solvents
such as methanol:dichloromethane, namely during the oxidation of the herbicide mecoprop to
the p-hydroquinone derivative (Figure 1b) [22]. More recently, it was hypothesized that the high
efficiency observed in the biomimetic production of indigo dye, the color of blue jeans, was due to the
hydroxylation of indole in the presence of an Fe(III)porphyrin system (Figure 1c) [16].
Figure 1. Oxidations of aromatic compounds in the presence of Mn(III) or Fe(III)porphyrins:
(
a) oxidation of alkylphenols; (
b) oxidation of the herbicide mecoprop; (c) production of indigo
dye from indene oxidation.
One of the major drawbacks of these methodologies is the hazardous solvents used for the
porphyrin synthesis and metalation reactions and the long heating times for metalation reactions, which
reduce the eco-sustainability and feasibility of these procedures. For example, the commonly used
porphyrin 5,10,15,20-tetrakis-pentafluorophenyl porphyrin (H2TPFPP) that is the topic of this paper is
typically prepared by condensation of pyrrole and pentafluorobenzaldehyde in a refluxing mixture
of acetic acid and nitrobenzene followed by a complex purification procedure [23,24]. The Fe(III)
metalation procedure to produce [Fe(TPFPP)X] is generally based on the Adler method [25], which
consists of refluxing H2TPFPP with a large excess of the ferrous salt in N,N-dimethylformamide (DMF)
and pyridine for 48 h. Furthermore, in the case of H2TPFPP, this process results in the substitution of
the p-fluorine atoms by nucleophilic attack of dimethylamine, a product of DMF decomposition [26].
The partial or complete substitution of the p-fluorine atoms by 4-dimethylamine groups effectively
prevents functionalization by nucleophilic substitution, which is often an important synthetic pathway
for the modification of H2TPFPP [27] or its metal complexes, e.g., for anchoring them to solid supports
and for the preparation of hybrid materials for catalysis and photonic applications [28,29]. Although
other solvents have been used to replace DMF, all the methodologies were characterized by long
reaction times, the use of high temperatures and harmful or corrosive solvents.
Some microwave procedures have been reported to be efficient for the synthesis of
metaloporphyrins [30–32]. However, green procedures for halogenated porphyrins synthesis and
their metalation using Fe have not been described. Such methods are potentially of significant
interest given the environmentally hazardous procedures currently employed in the preparation of
fluorinated metaloporphyrins.
With the aim of demonstrating a more eco-compatible process from catalyst synthesis to oxidative
catalysis, the present work reports the optimization of the synthesis and metalation of H2TPFPP
using microwave heating. The study involves a systematic evaluation of the reaction solvent,

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time, temperature and reagent concentrations. Electrospray ionization Orbitrap mass spectrometry
(ESI-Orbitrap-MS) was used to characterize the iron(III) complexes [33] and evaluate nucleophilic
substitution of the p-fluorines by dimethylamine. The catalytic activity of the iron(III) complex was
then evaluated in the oxidation of indene, 3,5-dimethylphenol and naphthalene by a green oxidant
(H2O2) in a green solvent (ethanol) without other additives.
2. Results and Discussion
2.1. Optimization of the Microwave Synthesis of H2TPFPP
A study of microwave synthesis was performed in order to achieve a faster and greener route
to the preparation of H2TPFPP. The optimization of the procedure started from previous reports of
metaloporphyrin synthesis [23,30] and involved a systematic evaluation of the reaction conditions.
In the method of Gonsalves et al. [23,24], nitrobenzene was used simultaneously as a co-solvent
and oxidant (to decrease the formation ofreduced macrocycles, which brings additional difficulties
to the chromatographic separation). Is this synthesis, conventional heating (at reflux) of a mixture of
acetic acid and nitrobenzene (2:1) containing pentafluorobenzaldehyde and pyrrole (0.1 mol )
dm´3
¨
for 1 h yielded 17% H2TPFPP as quantified by UV-Vis analysis (Figure 2). However, under these
conditions the porphyrin did not precipitate directly from the reaction mixture, as reported for other
meso-tetraphenylporphyrins, and it is necessary to separate the H2TPFPP from an abundance of
polymeric material by column chromatography. After purification the isolated yield of H2TPFPP
was ~11%.
Figure 2. Synthesis of H2TPFPP in conventional heating conditions and screening of the microwave
(MW) reaction conditions. The reference conditions were used and (
) propionic acid as solvent with 5, 10, 15 min as reaction times; ( ) acetic acid:nitrobenzene mixture
as solvent with 5, 10, 15 min as reaction times; ( ) different reaction temperatures; ( ) different
concentrations of reagents. The yields were determined by UV-Vis spectroscopy.
a–c) 5, 10, 15 min reaction times;
(d
–f
g–i
j
–
n
o–p
A reference set of microwave˝conditions was first developed (Figure 2): 0.1 mol
¨
dm´3 reagents
heated in acetic acid (AcOH) at 120 C for 10 min [30]. In order to compare the efficiency of the modified
reactions, yields were evaluated by UV-Vis analysis of the reaction mixture. Different solvents were
studied, acetic acid (AcOH), propionic acid (PrOH, allowing a higher reflux temperature) and a mixture
of acetic acid and nitrobenzene (AcOH:PhNO2) and various reaction times were tested (5, 10 and
15 min) (Figure 2, conditions a–i).
In all solvents the highest yields were obtained for 15 min reactions. Higher yields were obtained
in AcOH:PhNO2 relative to other solvents, although a good yield was also achieved for the reaction
in pure AcOH. The worst result after 15 min was obtained for the reaction in PrOH. This may be
due to the higher pka of PrOH (4.87) relatively to AcOH (4.75) leading to lower efficiency in the acid
catalyzed formation of porphyrinogen. Furthermore, the reaction in AcOH (conditions c) shows a
slightly higher amount of probably a reduced macrocycle form; as detected by the presence of the

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electronic band near 730 nm (the UV-Vis spectra can be seen in Supplementary Materials, Figure S1a).
However, it was observed that the H2TPFPP precipitated when the AcOH reactions were set aside
for 72 h. After filtration, washing with hexane and recrystallization from dichromethane:n-hexane
mixture, pure H2TPFPP was recovered as verified by TLC analysis and mass spectrometry (Figure 3a).
This solved the purification problems associated with chlorin formation and established AcOH as the
most eco-compatible solvent.
Figure 3. High Resolution ESI mass spectra analysis of H2TPFPP (a) and of iron complexes obtained
under the experimental conditions described in Table 1, Entry 2 ( ); Entry 3 (
b
c
); Entry 4 ( ); Entry 5 ( ).
d
e,f
Table 1. Reaction conditions for the metalation reactions using conventional and microwave heating.
Entry
Heating
Solvent
Temperature
Time
FeCl2:H2TPFPP a
1
2
3
4
5
conventional
conventional
microwave
microwave
microwave
DMF, Py
DMF, Py
DMF
CH3CN
DMF
155 ˝C
120 ˝C
48 h
48 h
24 h
3 h b
3 h b
200
200
100
20
120 ˝C
120 ˝C b
160 ˝C b
20
a
Molar ratio of “iron salt:H2TPFPP” at the end of reaction; b After addition of each FeCl2 aliquot, the reaction
was stirred for 1 h at room temperature before heating (the reaction times shown refer to the total time,
agitation + heating time).
The effect of different reaction temperatures on the reaction in AcOH for 10 min were then
investigated (conditions j, l, m and n). The yield increases with temperature but the difference between

Molecules 2016, 21, 481
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˝
˝
140 C (17.6%) and 200 C (18.9%) was small. Doubling the concentration of the reagents had a negative
effect on the yield (conditions o and p), although the decrease in yield was small enough that the
´3
amount of porphyrin produced was considerably higher at a concentration of 0.2 mol¨ dm
.
These results demonstrate a significant reduction of reaction time and increased eco-compatibility
for microwave synthesis using acetic acid and 0.1 mol
dm´3 reagent concentrations, with H2TPFPP
¨
being isolated in 13% yield by precipitation from the reaction mixture after 72 h. This greener route
compares very favorably with the 17% yield obtained by conventional heating in AcOH:PhNO2 for
much longer periods, and the subsequent laborious chromatographic separation leading to a final
yield of ~11%. Further evidence of the advantage of microwave heating was obtained by comparing
the isolated yields for two reactions performed in acetic acid at 120 ˝C for 1 h using conventional
heating and for 10 min in microwave heating, 5% and 14%, respectively (Figure S1b).
2.2. Optimization of the Iron Insertion Reaction Using Microwave Heating Conditions
The application of Adler’s procedure [25] to the preparation of Fe(III) and Mn(III) complexes of
H2TPFPP often leads to uncontrolled substitution of the p-fluorine atoms of the pentafluorophenyl
rings due to nucleophilic attack by dimethylamine arising from decomposition of DMF [26].
The DMF decomposition probably occurs by a thermal degradation mechanism, [34] although
DMF can also be hydrolyzed by water present in the solvent. The resulting Fe(III)porphyrin
complexes are depicted in Figure 4. Compound
tetrakis(2,3,4,5,6-pentafluorophenyl)porphyrinate] iron(III) complex. Compound
I
is the desired unsubstituted chloro [5,10,15,20-
is the chloro
V
[5,10,15,20-tetrakis(4-dimethylamino-2,3,5,6-tetrafluorophenyl)porphyrinate] iron(III) where all of the
p-fluorine groups have been replaced by dimethylamine groups. Further nucleophilic substitution of
the p-phenyl positions of compound
V is hampered and consequently its derivatization is limited [29].
Figure 4. Complexes of [Fe(TPFPP)X] obtained during metalation reactions by heating DMF and
pyridine mixtures for long reaction periods.
Compound
V is the main complex obtained using an experimental procedure based on the Adler
method. This consists of refluxing a solution of H2TPFPP in DMF and pyridine (10:1 v/v) using
conventional heating and adding 10 molar equivalents of FeCl2. The reaction is monitored by TLC
and addition of the same amounts of iron salt and pyridine continued until full conversion of the
H2TPFPP was achieved (Table 1, Entry 1). The resulting product was analyzed by mass spectrometry
(Supplementary Materials, Figure S2). The most intense peak m/z 1128.2 corresponded to the ion
[M ´ Cl]+ from the tetra-substituted derivative [Fe(TF4NMe2PP)Cl] (V).

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The optimization studies started by comparing the iron insertion procedure at a lower reaction
˝
temperature (120 C) using conventional and microwave heating (Table 1, Entries 2 and 3, respectively).
In the microwave heating reaction, pyridine was eliminated from the reaction mixture. The reaction
using conventional heating (Entry 2), lasted 48 h and the ratio of iron salt: H2TPFPP was 200. For the
microwave reaction (Entry 3), the final reaction time and the iron salt to H2TPFPP where decreased to
24 h and 100, respectively.
The resulting compounds were analyzed by high resolution mass spectrometry with electrospray
ionization in the positive mode (ESI+-MS). The data is shown in Figure 3. The spectrum of product
obtained using conditions on Entry 2 (Figure 3b), shows the molecular ions [M
´
Cl]+ of all five possible
metaloporphyrins ( ). However, the most intense peaks are seen for the mono- and di-substituted
I–V
derivatives II (m/z 1053.03023) and III (m/z 1078.08144).
On the other hand, the first microwave procedure that is described in Entry 3 led not only to the
reduction of reaction time and amount of iron salt but also avoided the substitution of p-fluorine atoms
by dimethyl amino groups (Figure 3c). The species observed in the mass spectrum corresponded to
complex
I
[M
´
X]+ as adducts with DMF (m/z 1101.02949), or with CH3CN (m/z 1069.00285) or the
X + CH3CN]+ is also observed in other
complex without solvent (m/z 1027.97393). The peak [M
´
analysis of this compound when the solvent used to dissolve the sample is CH3CN [33].
Subsequent studies led to a significant improvement of the reaction conditions. The reaction
described on Entry 4 of Table 1 considered the use of acetonitrile as the reaction solvent replacing DMF
and pyridine. Furthermore, the initial reaction mixture was stirred at room temperature for 1 h before
microwave heating at 120 ˝C for 30 min. After monitoring the reaction by TLC, the procedure was
repeated with addition of a second aliquot of iron salt (10 molar equivalents relative to H2TPFPP),
followed by the stirring at room temperature and microwave heating procedures. After this second
addition, the metalation of H2TPFPP was complete. These conditions led to a significant reduction of
the reaction time (finished in 3 h, considering the agitation and heating periods) and amount of iron
salt required to achieve complete metalation (Entry 4). The effect of stirring the reaction mixture prior
to heating is probably due to the fact that coordination of iron to the porphyrin occurs more readily in
the ferrous state, and upon heating of the reaction mixture the ferric state is easily produced and the
metalation rate is significantly reduced.
The mass spectrum in the positive mode (ESI+) of the compound resulting from the reaction
conditions in Entry 4 (Figure 3d) shows two significant peaks, the peak [M
´
X]+ from complex
I
[Fe(TPFPP)X] (m/z 1027.98005) and its adduct with acetonitrile (m/z 1069.01076). Nucleophilic
substitution is also avoided under these conditions and derivative I is obtained selectively.
˝
The microwave synthesis was performed at 160 C in DMF (Entry 5) in an attempt to determine if
it was possible to achieve complete substitution of the p-fluorine atoms by dimethylamine groups to
produce compound
V. However, only the non-substituted derivative I was obtained in the form of its
adduct with DMF (Figure 3e). The dimethylamine is probably only formed when there is prolonged
heating of DMF.
Finally, the same compound was also analyzed using ESI mass spectrometry in the negative
mode (ESI´), and the spectrum is shown in Figure 3f. The most intense peak corresponds to the ion
´
[Fe(TPFPP)Cl2] , which is complex I with two chlorine atoms as the axial ligands (Figure 3f).
The methodology developed for the synthesis [Fe(TPFPP)Cl] embodies a significant improvement
in the preparation of the iron complexes of fluorinated porphyrins. As far as we are aware, these are
the first studies to use microwave heating for the synthesis of [Fe(TPFPP)Cl].
2.3. Green Oxidation of Aromatic Compounds Using [Fe(TPFPP)Cl]
The [Fe(TPFPP)Cl] prepared using the reaction described in Entry 4 of Table 1 was then tested in the
oxidation of aromatic compounds using green conditions. The oxidation of indene (1), 3,5-dimethylphenol
(3) and naphthalene (5) was studied using hydrogen peroxide as a green oxidant at room temperature.
Ethanol was used as the solvent system without the presence of other additives (Figure 5).

Molecules 2016, 21, 481
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Figure 5. Catalytic oxidation of aromatic compounds in the system [Fe(TPFPP)Cl]/EtOH/H2O2.
Using 0.3 mol % of catalyst, indene (1) is oxidized to indene oxide (2) with full conversion and
94% selectivity in a reaction time of 2 h (Figure S3). Epoxidation at the 1,2-position, preferential
to the hydroxylation reaction, can be related to the alkene character present at this position [14,15].
The other products all show higher retention times than indene oxide, with their amounts increasing for
higher reaction temperatures. These compounds probably result from epoxide ring opening reactions.
The predominance of the epoxidation pathway indicates a mechanism proceeding through a high
valent iron porphyrin species rather than the generation and attack of hydroxyl radicals [11,16].
Using the same conditions, 3,5-dimethylphenol (3) was completely and selectively oxidized to
3,5-dimethyl-1,4-benzoquinone (4) (Figures S4–S6). No traces of the 1,2-benzoquinone are observed in
the 1H-NMR and 13C APT NMR spectra of the total reaction mixtures (Figures S5 and S6), which only
show the signals expected for the more symmetrical 1,4-benzoquinone. The oxidation of naphthalene
(5) using the same conditions but 1 mol % of catalyst afforded 1,4-naphthoquinone (6) in quantitative
yield after a reaction time of 6 h (Figures S7 and S8). The selectivity for the 1,4-naphthoquinone (6)
increases in comparison with reactions catalyzed by manganese porphyrins [35]. The hydroxylation
reaction can also be explained by the action of the high valent ironporphyrin species, as has been
reported both for metaloporphyrin models [11,16,22] and P-450 mutants [36]. Control experiments
involving oxidation of the three substrates (1, 3, and 5) using the above conditions but in the absence
of catalyst were performed and the conversions were always below 5%. For indene oxidation the GC
chromatograms of the oxidation reactions in the presence and absence of catalyst are shown in the
supporting material (Figure S9).
3. Materials and Methods
All the reagents and solvents were used as received without further purification. Pyrrole (98%),
indene (98%), 3,5-dimethylphenol (>99%) and naphthalene (99%) were purchased from Aldrich
(St. Louis, MO, USA), and pentafluorobenzaldehyde (98%) was purchased from Acros Organics-Fisher
Scientific (Porto Salvo, Portugal). N,N-dimethylformamide (DMF), ethanol (EtOH), acetonitrile, acetic
acid (AcOH), propionic acid (PrOH), nitrobenzene (PhNO2), chloroform, n-hexane and FeCl2.4H20
were of p.a. grade. Hydrogen peroxide was 30% w/w (Pedrogen, Aldrich).

Molecules 2016, 21, 481
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3.1. Physical Measurements
UV-visible absorption spectra were recorded on a UV-3600 Spectrophotometer (Shimadzu
Corporation, Kyoto, Japan). High-resolution electrospray ionization mass spectra (ESI-MS) were
obtained using a LTQ-Orbitrap XL mass spectrometer (Thermo Scientific, Bremen, Germany), externally
calibrated with a standard kit provided by the manufacturer. Samples were dissolved in acetonitrile
´1
and directly infused into the electrospray ion source at 10
µL
¨
min utilizing the syringe pump in the
mass spectrometer. The spectrometer was operated in the positive or negative ionization mode with
the capillary voltage set to +3.1 kV or 1.7 kV, respectively, sheath gas flow to 6 and the temperature
´
˝
of the ion transfer capillary to 275 C.
NMR spectra and attached proton test (APT) experiments of the compounds and total reaction
mixtures were recorded using a Advance III spectrometer (Brucker, Billerica, MA, USA) operating
1
at a frequency of 400 MHz and 100 MHz for H and 13C experiments, respectively, with sample
˝
temperatures of 22 C.
Analyses using gas chromatography with flame ionization detection (GC-FID) were performed
using a CP-3380 gas chromatograph (Varian, Palo Alto, CA, USA) with helium as the carrier gas and
a fused silica Varian Chrompack capillary column CP-Sil 8 CB Low Bleed/MS (30 m
0.25
m film thickness). The temperature program was: 70 ˝C (1 min), 20 ˝C min´1, 200 ˝C (5 min).
The injector temperature was 200 C and the detector temperature 250 C.
ˆ
0.25 mm i.d.;
µ
¨
˝
˝
Analyses using gas chromatography-mass spectrometry (GC/MS) were performed using a
Finnigan Trace GC/MS Thermo Quest (CE instruments, Lancashire, UK) and helium as the carrier
gas (35 cm/s). The capillary column and the temperature program were the same as described for the
GC-FID analyses.
3.2. Preparation of Metaloporphyrin Catalysts
Microwave syntheses were carried out using a Discover LabMate reactor (CEM Corporation,
Matthews, NC, USA) with a temperature control system equipped with a reaction vessel of 10 mL.
The reaction mixture was constantly irradiated in a closed system, at the desired temperature, using
up to 300W of power.
For the studies on the synthesis of H2TPFPP, 6 mL of the reaction solvent were introduced into the
reaction vessel, or when a solvent mixture was used, acetic acid (4 mL) and nitrobenzene (2 mL) were
added to the reaction vessel. The reagents were added to the microwave reactor immediately before
the reactions we´re4 heated. For the reactions performed at reagent conc´en4 trations of 0.1 mol
to the reaction vessel and the mixture agitated using a magnetic stirrer for the chosen temperature and
time (Figure 2). The completed reactions were promptly analyzed using UV-Vis spectroscopy using
solutions diluted with chloroform.
¨
dm´3
,
pyrrole (6.0
ˆ
10 mol; 41.6
µ
L) and pentafluorobenzaldehyde (6.0
ˆ
10 mol; 74.1 µL) were added
In the reactions performed in acetic acid, after 72 h a porphyrin precipitate was observed.
The reaction mixture was filtered, the precipitate washed with n-hexane and recrystallized from
dichloromethane:n-hexane.
For the studies of the preparation of the iron complex [Fe(TPFPP)Cl], the reaction vessel was
charged with 5 mL of the reaction solvent and 50 mg of H2TPFPP and the vessel irradiated using
the conditions described in Table 1. For the reactions described in Entries 4 and 5, the initial reaction
mixture was agitated for 1 h outside of the microwave apparatus prior to irradiation.
The iron insertion reactions were evaluated by thin layer chromatography (TLC) using silica
plates with chloroform as eluent to determine if metalation was complete. The solvent was then
evaporated and the reaction mixture dissolved in chloroform and washed several times with deionized
water. After evaporation of chloroform, the metaloporphyrin was dissolved in dichloromethane and
reprecipitated by the addition of n-hexane. The precipitate was filtered and washed with n-hexane.

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3.3. Catalysis Experiments
In a typical experiment, the substrate (0.3 mmol) and the metaloporphyrin (1 or 3
µ
mol) were
dissolved in 2 mL of ethanol and stirred at 22 ˝C. Aqueous hydrogen peroxide (30% w/w) diluted in
ethanol (1:10) was added to the reaction mixture at a rate of 0.6 mL/h through a syringe pump. Control
experiments in the absence of catalyst were also performed. The indene reactions were monitored by
GC-FID using decane as an internal standard and 1,2-indene oxide produced by a reference method [19
for product identification. The naphthalene reactions were monitored by thin layer chromatography
(silica gel 60 DGF254) using CH2Cl2 as the eluent. At the reaction end, the 1,4-naphthoquinone ( ) was
isolated by TLC and its structure confirmed by 1H- and 13C-NMR and GC-MS analysis with electronic
impact ionization (EI). The oxidation reactions of 3,5-dimethylphenol ( ) were analyzed by removing
]
6
3
the solvent using a rotavapor keeping the water bath at room temperature. The total reaction mixtures
were analyzed then by MS-ESI and NMR (1H and APT).
3.4. Analytical Data for Compounds
(Metalo)porphyrins
H2TPFPP: MS (ESI+) m/z: 975.0652 [M + H]+, calculated: 975.0659, ∆m: 0.7 ppm.
Compound I: MS (ESI+) m/z:. 1027.97880 [Fe(TPFPP)]+, calculated: 1027.97790, ∆m: 0.9 ppm.
Compound II: MS (ESI+) m/z: 1053.03023 [M ´ Cl]+, calculated: 1053.02952, ∆m: 0.7 ppm
Compound III: MS (ESI+) m/z: 1078.08144 [M ´ Cl]+, calculated: 1078.08114, ∆m: 0.3 ppm.
Compound IV: MS (ESI+) m/z: 1103.13287 [M ´ Cl]+, calculated: 1103.13277, ∆m: 0.1 ppm.
Compound V: MS (ESI+) m/z: 1128.18457 [M ´ Cl]+, calculated: 1128.18439, ∆m: 0.2 ppm.
Indene oxide (2) MS (ESI+) m/z: 133.06441 [M + H]+, calculated: 133.06479, ∆m: 2.9 ppm.
3,5-dimethyl-1,4-benzoquinone (
H-2,6). 13C-NMR (DMSO-d6, 100 MHz, APT)
(C-1,4). MS (ESI+) m/z: 137.05918 [M + H]+, calculated: 137.05971, ∆m: 3.9 ppm.
4
) 1H-NMR (DMSO-d6, 400 MHz)
(ppm): 16.2 (–CH3), 133.4 (C-2,6), 146.1 (C3,5), 188.4
δ (ppm): 1.98 (s, 6H, –CH3), 6.66 (s, 2H,
δ
1,4-naphthoquinone (6 δ (ppm): 6.98 (s, 2H; H-2,3), 7.74-7.79 (m; 2H; H-6,7),
) 1H-NMR (CDCl3, 400 MHz)
8.07-8.11 (m; 2H; H-5,8). 13C-NMR (CDCl3, 100 MHz, APT): 126.4 (C-5,8), 132.0 (C-4a,5a), 134.0 (C-6,7),
138.7 (C-2,3), 185.1 (C-1,4). EM (EI) m/z (%): 158 (M+‚; 100); 130 (30).
4. Conclusions
The syntheses of H2TPFPP and [Fe(TPFPP)Cl] have been optimized using microwave methods
to allow the production of these important fluorinated porphyrins in a more eco-sustainable manner,
and the use of the prepared [Fe(TPFPP)Cl] has been investigated in green catalytic oxidation reactions.
The synthesis of H2TPFPP in 13% isolated yield was achieved by microwave heating of 0.1 M pyrrole
˝
and pentafluorobenzaldehyde in acetic acid at 120 C for 15 min. The H2TPFPP then precipitates
from the reaction mixture after 72 h and is isolated by filtration, washing and recrystallization.
The metalation of H2TPFPP to form the corresponding iron complex [Fe(TPFPP)Cl] was achieved by
stirring H2TPFPP for 1 h with 10 equivalents of FeCl2 in acetonitrile at room temperature, followed by
microwave heating of the reaction mixture for 30 min at 120 ˝C and repeating once the addition of
FeCl2 procedure and heating. The [Fe(TPFPP)Cl] is isolated in quantitative yield, whereas the standard
metal insertion procedure using DMF produces varying amounts of porphyrins where the para-fluorine
groups have undergone nucleophilic substitution by dimethylamine produced by decomposition of the
solvent. The oxidation of indene (1), 3,5-dimethylphenol (3) and naphthalene (5) at room temperature
using a green oxidant (hydrogen peroxide) and solvent (ethanol) was then investigated. High selectivity
(>90%) was observed for the formation of indene oxide (2), 3,5-dimethyl-1,4-benzoquinone (4) and
1,4-naphthoquinone (6) using 0.1 and 0.3 mol % of catalyst and reaction times of 2–6 h.

Molecules 2016, 21, 481
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Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
4/481/s1.
Acknowledgments: The work was financed under the financing program of Portuguese Research Units with
references REQUIMTE/LAQV (UID/QUI/50006/2013) and REQUIMTE/UCIBIO (UID/MULTI/04378/2013)
with financial support from FCT/MEC (Fundação para a Ciência e a Tecnologia / Ministério da Educação e
Ciência) through national funds and co-financed by FEDER (Fundo Europeu de Desenvolvimento Regional), under
the Partnership Agreement PT2020. S.L.H. Rebelo also thanks FCT for the Post-Doctoral Grant SFRH/101281/2014
and C.J. Medforth acknowledges a 2013 FCT investigator Award (IF/00873/2013). The authors acknowledge
Miss Márcia Silva for the preliminary studies on the porphyrin synthesis using microwave heating. ESI-MS and
NMR studies were performed at Centro de Materiais da Universidade do Porto (CEMUP), Porto, Portugal.
Author Contributions: S.L.H.R. conceived the work and performed the experiments on metaloporphyrin
synthesis and catalytic reactions; A.M.N.S. analyzed the ESI mass spectrometry data; S.L.H.R., C.J.M. and
C.F. wrote the paper.
Conflicts of Interest: The authors declare no conflicts of interest. The founding sponsors had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the
decision to publish the results.
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Sample Availability: Samples of the compounds H2TPFPP and [Fe(TFPPP)Cl] are available from the authors.
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2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
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