Synthesis and characterization of biocompatible bimodal meso-sulfonamide-perfluorophenylporphyrins

Article abstract of DOI:10.1016/j.jfluchem.2015.09.010

Herein we describe a synthetic strategy for preparing a set of meso-aryl sulfonamide-perfluorinated porphyrins by covalent binding in order to obtain new chemical entities that can potentially target bacteria and act both as bacteriostatic and photosensitizing agents. The conditions optimized allow to selectively obtain porphyrins containing the desired number of sulfonamide substituents. The new compounds showed a broad range of 1-octanol/water partition coefficients and singlet oxygen quantum yields from 0.59 to 0.74. Our results demonstrate that sulfonamide-perfluorinated porphyrins are a promising platform for biomedical applications, particularly in aPDT and medical imaging.

Full text of DOI:10.1016/j.jfluchem.2015.09.010

Journal of Fluorine Chemistry 180 (2015) 161–167
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and characterization of biocompatible bimodal
meso-sulfonamide-perfluorophenylporphyrins
a
b
a
b
´
´
Carolina S. Vinagreiro , Nuno P.F. Gonc¸alves , Mario J.F. Calvete , Fabio A. Schaberle ,
a
a,
*
´
Luıs G. Arnaut , Mariette M. Pereira
a CQC, Department of Chemistry, Faculty of Science and Technology, University of Coimbra, Coimbra 3004-535, Portugal
b
´
Luzitin, SA, Edifıcio Bluepharma, S. Martinho do Bispo, Coimbra 3045-016, Portugal
A R T I C L E I N F O
A B S T R A C T
Article history:
Herein we describe a synthetic strategy for preparing a set of meso-aryl sulfonamide-perfluorinated
porphyrins by covalent binding in order to obtain new chemical entities that can potentially target
bacteria and act both as bacteriostatic and photosensitizing agents. The conditions optimized allow to
selectively obtain porphyrins containing the desired number of sulfonamide substituents. The new
compounds showed a broad range of 1-octanol/water partition coefficients and singlet oxygen quantum
yields from 0.59 to 0.74. Our results demonstrate that sulfonamide-perfluorinated porphyrins are a
promising platform for biomedical applications, particularly in aPDT and medical imaging.
ß 2015 Elsevier B.V. All rights reserved.
Received 30 July 2015
Received in revised form 10 September 2015
Accepted 16 September 2015
Available online 21 September 2015
Keywords:
Porphyrins
Sulfonamides
Perfluorinated porphyrins
aPDT
Biocompatible
1. Introduction
compounds have been discovered and marketed [23,24], but they
have the major drawback of originating antibiotic-resistant bacteria
The presence of fluorine atoms in organic compounds with
potential application in pharmacology has been increasingly
exploited in recent years [1–4]. Notably, nearly 20% of pharma-
ceutical compounds contain at least one fluorine atom nowadays
[5], since it is well established that the replacement of a hydrogen
by an electronegative fluorine atom, with C–F bond energy of
105.4 kcal/mol, can significantly influence pharmacological out-
comes, metabolic stability, selectivity and physical properties.
[6,7,1] Thus, the development and optimization of new organic
molecules bearing fluorine atoms in their constitution is an area of
increasing interest in medicinal chemistry. In addition, in our
previous studies [8–10], we have demonstrated that the presence
of fluorine atoms in a sulfonamide-tetrapyrrolic macrocycles
originated photosensitizers with ideal PDT photophysical proper-
ties and/or remarkable photostability [11–21].
[25,26]. According to the World Health Organization, National data
obtained for E. coli, S. and K. pneumoniae, and S. aureus showed that
the proportion resistant to commonly used antibacterial drugs
exceeded 50% in many settings [27].
The development of new molecular entities capable of
promoting the inactivation of bacteria without developing drug
resistance depends on finding alternative mechanisms of action for
antibiotics. Antimicrobial photodynamic therapy (aPDT) [28,29] is
emerging as an alternative to classical antibiotics because aPDT is
not associated with the development of microorganism resistance
after treatment [30–32]. The most successful photosensitizing
agents used in aPDT are porphyrin derivatives. The appropriate
design and structural modulation of tetrapyrrolic macrocycles to
enhance membrane permeation in all classes of microbial cells,
along with appropriate photophysical properties, may drive aPDT
to a clinically acceptable alternative to antibiotics.
Sulfonamides are celebrated antibacterial agents since 1930,
owing to the discovery of Prontosil (Scheme 1) and the recognition
that sulfonamides can inhibit the enzyme dihydropteroate synthase
[22,23]. Numerous active antibiotics containing this class of
*
Corresponding author.
Scheme 1. In vivo metabolism of Prontosil.
E-mail address: mmpereira@qui.uc.pt (M.M. Pereira).
http://dx.doi.org/10.1016/j.jfluchem.2015.09.010
0022-1139/ß 2015 Elsevier B.V. All rights reserved.

162
C.S. Vinagreiro et al. / Journal of Fluorine Chemistry 180 (2015) 161–167
The synthetic difficulties and scarce availability of natural
the nitrobenzene synthetic methodology [43]. NaY was used as
recoverable Lewis acid catalyst for the condensation of pyrrole
with pentafluorobenzaldehyde in an acetic acid/nitrobenzene
mixture [35], yielding the desired porphyrin 1 in 9% yield. Next,
the studies to selectively prepare the mono or tetra-substituted
fluorinated-sulfonamide porphyrins were carried out using the
commercially available methanesulfonamide as nucleophile
(Scheme 2).
As expected, the concentration of the reactants was crucial to
selectively obtain the mono vs tetrasubstituted compound. In a typical
experiment, the fluorinated porphyrin 1 was dissolved in dioxane
(5.1 ꢀ 10ꢁ3 M), mixed with six equivalents of methanesulfonamide
(2a) and six equivalents of cesium carbonate (Scheme 2, Method A).
Then, the reaction was kept at 100 8C for several hours. After work
up the crude was purified by silica gel column chromatography
(n-hexane:ethyl acetate 2:1), followed by preparative thin layer
chromatography, affording the 5-[20,30,50,60-tetrafluoro-40-methane-
sulfamoyl)phenyl]-10,15,20-tri-[(20,30,40,50,60-penta-fluoro)phe-
nyl]porphyrin 3a in 19% yield (entry 1, Table 1).
In order to prepare the tetrasubstituted compound, the reaction
conditions were changed by increasing the porphyrin concentra-
tion to 1.0 ꢀ 10ꢁ2 M and the ratio porphyrin:sulfonamide:base to
1:18:12 (Scheme 2, Method B). After 48 h at 100 8C, the initial
porphyrin completely disappeared, concomitantly with the
formation of a complex mixture of products observed by TLC. In
addition, we carried out another reaction, under the same
conditions, but increasing the concentration of porphyrin 1 to
1.5 ꢀ 10ꢁ2 M and, surprisingly, a dark solid precipitated out of the
reaction, upon room temperature cooling. After filtration, the solid
porphyrinoids [29,33,34], led to the use of meso-substituted
tetrapyrrolic macrocycles, easily obtained by sustainable synthetic
methods [12,35–38], as the main choice for the development of
new generations of PDT agents [8,9,39]. 5,10,15,20-Tetrakis(pen-
tafluorophenyl)porphyrin (TPFPP) is an interesting template to
functionalize via nucleophilic substitution reactions [40], making
use of nucleophiles such as amines, thiols, alcohols and nitrogen
heterocycles [41,42], to improve their avidity for bacteria.
However, to the best of our knowledge, the use of sulfonamides
as nucleophiles in this functionalization has not yet been
described.
This work presents new methods for the synthesis of bimodal
molecules that incorporate sulfonamides and 5,10,15,20-tetra-
kis(pentafluorophenyl)porphyrin in their structure, in order to
attain new chemical entities that can potentially target bacteria
and act both as bacteriostatic and photosensitizing agents.
Additionally, this work presents the fundamental photophysical
assessment of the new photosensitizers, namely in terms of their
electronic absorptions, singlet oxygen quantum yields and
1-octanol/water partition coefficients. Our results show that
sulfonamide TPFPPs are a promising platform for biomedical
applications, particularly in aPDT and medical imaging.
2. Results and discussion
In order to prepare meso-aryl fluorinated porphyrins containing
sulfonamide groups, we first synthesized 5,10,15,20-tetrakis(pen-
tafluorophenyl)porphyrin 1 following our recent improvement of
Scheme 2. Synthesis of mono and tetra substituted fluorinated-sulfonamide porphyrins. Reaction conditions: Method
[C] = 5.1 ꢀ 10ꢁ3 M; Method B – porphyrin/sulfonamide ratio 1:18, [C] = 1.54 ꢀ 10ꢁ2 M.
A – porphyrin/sulfonamide ratio 1:6,

C.S. Vinagreiro et al. / Journal of Fluorine Chemistry 180 (2015) 161–167
163
Table 1
Nucleophilic substitution of 5,10,15,20-pentafluorophenyl por-
phyrin 1 with N-methyl-p-toluenesulfonamide 2c (Scheme 3
yielded three products, namely 5-[(20,30,50,60-tetrafluoro-40-N-
methyl-p-toluenesulfamoyl)phenyl]-10,15,20-tri-[(20,30,40,50,60-
pentafluoro)phenyl]porphyrin 3c (3.1% yield), a mixture of 5,10-
[(20,30,50,60-tetrafluoro-40-N-methyl-p-toluenesulfamoyl)phenyl]-
15,20-dis-[(20,30,40,50,60-pentafluoro)phenyl]porphyrin 4c and
5,15-[(20,30,50,60-tetrafluoro-40-N-methyl-p-toluenesulfamoyl)phe-
nyl]-10,20-[(20,30,40,50,60-pentafluoro)phenyl]porphyrin 5c, (1.5%
yield) together with 5,10,15-tri-[(20,30,50,60-tetrafluoro-40-N-meth-
yl-p-toluenesulfamoyl)phenyl]-20-[(20,30,40,50,60-pentafluoro)phe-
nyl]porphyrin 6c (0.6% yield) (Table 1, entries 5–7).
Reaction products of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin
1 with
sulfonamides 2a–c.
Entry
R2
F
R3
F
R4
R5
Yield (%)
1
2
3
4
5
6
7
3a
7a
3b
F
NHSO2Me
NHSO2Me
NHSO2PhMe
19a
70b
4.5a
0.7a
3.1a
1.5a
0.6a
NHSO2Me NHSO2Me
NHSO2Me
F
F
F
F
F
F
4b,5b F
NHSO2PhMe NHSO2PhMe
NMeSO2PhMe
NMeSO2PhMe NMeSO2PhMe
3c
F
F
F
F
4c,5c
6c
NMeSO2PhMe NMeSO2PhMe NMeSO2PhMe
a
Synthesized by Method A (porphyrin/sulfonamide ratio 1:6, [C] = 5.1 ꢀ 10ꢁ3 M).
b
Synthesized
by
Method
B
(porphyrin/sulfonamide
ratio
1:18,
[C] =1.5 ꢀ 10ꢁ2 M).
As selected example the 19F NMR spectra of the hydrophilic
porphyrin 7a is presented in Fig. 1.
As expected, 19F NMR aromatic signals appeared as double
was washed with acetone, dissolved in water and purified via
ultra-filtration membrane, using a 1 kDa Amicon membrane. After
solvent evaporation and drying, we obtained 5,10,15,20-tetra-
[(20,30,40,50,60-methanesulfamoyl)phenyl]porphyrin 7a in 70% yield
(entry 2, Table 1).
doublets around
d
ꢂ ꢁ144.71 and ꢁ152.19 ppm, corresponding to
the symmetric substitution pattern present in porphyrin 7a. These
narrow intense peaks shown by 19F NMR allow them to be
potential probes for 19F MRI. These fluorinated amphiphilic
compounds may find use as 19F MRI probes for cancer detection
because the fluorine atom has 100% NMR active isotope with
intrinsic high sensitivity in biological systems [44], and it is well
established that porphyrins preferentially accumulate in tumors
[45].
We also evaluated the effect of the number of sulfonamide
substituents on the 1-octanol/water partition coefficients using a
minor modification of the shake-flask method [46–48]. The desired
sulfonamide porphyrin was dissolved in 1-octanol saturated with
phosphate buffer (PBS). This solution was then added to a PBS
solution saturated with 1-octanol. The mixture of the two solvents
was vigorously stirred, centrifuged and the solvents were
separated. An appropriate volume of each phase was taken and
a volume of pure 1-octanol should be added keeping equal
dilutions of organic and water parts containing the compound.
Optical absorption of the 1-octanol and of the PBS fractions were
used to determine the logarithm of the partition coefficient,
log POW = log (A1-oct/APBS). Additionally, a correlation curve be-
tween experimental [10] and computational data of LogP was
constructed for a family of sulfonamide-substituted porphyrins
and their derivatives. The computational approach was made using
the program Marvin Sketch 14.10.6.0. The results are presented in
Table 2.
Our methodology to selectively synthesize the mono or the
tetrasubstituted compounds required careful adjustment of the
concentrations of the reactants and of the porphyrin/sulfonamide
ratio. The monosubstituted compound was obtained as the major
product when the reaction was carried out with a porphyrin
concentration of 5.1 ꢀ 10ꢁ3 M and an excess of six equivalents of
sulfonamide was used (Scheme 2, Method A). The tetrasubstituted
product required an excess of 18 sulfonamide equivalents and a
porphyrin concentration of 1.54 ꢀ 10ꢁ2 M (Scheme 2, Method B).
Based on the conditions previously optimized for the preparation
of monosubstituted sulfonamide porphyrin (5.1 ꢀ 10ꢁ3 M), we
enlarged the reaction scope using p-toluenesulfonamide 2b and
N-methyl-p-toluenesulfonamide 2c as nucleophiles. These sulfona-
mides were prepared in 48% and 94% isolated yields, respectively
(Scheme 3 and Table 1, entries 3–7) by reacting p-toluenesulfonyl
chloride with the corresponding amines.
The reaction of TPFPP with p-toluenesulfonamide 2b
(Scheme 3) at 100 8C for several hours afforded 5-[(20,30,50,60-
tetrafluoro-40-p-toluenesulfamoyl)phenyl]-10,15,20-tri-[(20,30,40,50,
60-pentafluoro)phenyl]porphyrin 3b in 4.5% isolated yield and a
mixture of 5,10-[(20,30,50,60-tetrafluoro-40-p-toluenesulfamoyl)phe-
nyl]-15,20-dis-[(20,30,40,50,60-penta-fluoro)phenyl]porphyrin 4b and
5,15-[(20,30,50,60-tetrafluoro-40-p-toluenesulfamoyl)phenyl]-10,20-
[(20,30,40,50,60-pentafluoro)phenyl]porphyrin 5b in 0.7% isolated
yields, after preparative thin layer chromatography.
Upon analysis of the correlation curve, we could observe that
the compounds presenting lower LogP (less lipophilic) were
derivatives 3a and 7a. The determination of their experimental
Scheme 3. Synthesis of substituted fluorinated-sulfonamide porphyrins.

164
C.S. Vinagreiro et al. / Journal of Fluorine Chemistry 180 (2015) 161–167
Fig. 1. 19F NMR spectrum of the porphyrin 7a in DMSO.
LogP gave values of LogP > 4 and LogP = 0.94, respectively, reason
why we did not perform the experimental determination of the
LogP values for the other compounds, since our LogP determina-
tion method is limited to values of LogP ꢃ 4.
The phototoxicity of porphyrin photosenstizers is mostly due to
energy transfer from the porphyrin excited triplet state to molecular
oxygen,withtheformationofsingletoxygen[10]. Thiselectronically
excited state of molecular oxygen can oxidize
a variety of
The log POW values of porphyrins 3a and 7a show that the
number of methanesulfonamide fragments is crucial to modulate
the amphiphilicity of the compounds. Whereas porphyrin 3a
(bearing just one sulfonamide substituent) displays a log POW > 4,
meaning that the compound is very hydrophobic, porphyrin 7a
shows a value of log POW of 0.94 suggesting that this compound is
the most biocompatible photosensitizer of the series.
biomolecules and trigger cell death mechanisms [50]. Hence, we
measured the singlet oxygen quantum yields (LD) of the porphyrins
synthesized in this work to assess their potential as PDT photo-
sensitizers. The values of LD were obtained by comparing the
intensities of singlet oxygen emission at 1270 nm in an air-
equilibrated samples containing a given sensitizer against the
intensity obtained from an optically matched sample containing a
reference sensitizer, as a function of the pulsed laser excitation
energy [11]. We used phenalenone as a reference and used its
literaturevalue for thesingletoxygen quantumyieldintoluene, 0.98
[51]. All the compounds showed suitable singlet oxygen quantum
yield for photosensitization applications, although the tertiary
amines seemed to have lower LD values.
The ground state absorption spectrum of sulfonamide porphyr-
ins, recorded at room temperature in toluene (compounds 3–6)
and DMSO (7a) is presented in Fig. 2. The spectrum shows the
characteristic bands from free base porphyrins with the D2h
symmetry, described by Gouterman’s four orbitals model [49]. The
intense Soret band is observed around 410 nm and four bands
between 500 and 650 nm are assigned to the Qx and Qy (0,0) bands
and their (1,0) vibronic progressions (Table 2). Using the measured
absorbance for several concentrations, the molar absorption
coefficients were determined using Beer’s law. Their absorption
band maxima and corresponding molar absorption coefficients are
presented in Table 3. As expected, the compounds display their
maxima peaks around similar wavelengths as well as similar molar
absorption coefficient.
3.0x105
3b
2.5x105
4/5b
3c
4/5c
6c
3a
2.0x105
1.5x105
1.0x105
Table 2
Partition coefficients (log POW) in 1-octanol/water of sulfonamide porphyrin
derivatives: theoretical, experimental, and values obtained from correlation curve
(+CC).
Sulfonamide
derivatives
LogP theoretical
LogP +CC
LogP
5.0x104
0.0
experimental
3a
11.26
14.19
14.4
6.09
7.69
7.80
8.09
8.32
8.84
2.49
>4
–
3b
3c
–
400
500
600
700
4b/5b
4c/5c
6c
14.92
15.34
16.29
4.68
–
Wavelength / nm
–
–
Fig. 2. Absorption spectra of the porphyrin derivatives here described, recorded in
7a
0.94
toluene.

C.S. Vinagreiro et al. / Journal of Fluorine Chemistry 180 (2015) 161–167
165
Table 3
Absorption coefficients and singlet oxygen quantum yields for selected porphyrin derivatives.
Entry
Porphyrin
Absorption/nm (
B(0-0)
e )
/Mꢁ1 cmꢁ1
Qy(1,0)
Qy(0,0)
Qx(1,0)
Qx(0,0)
LD
1
2
3
4
5
6
7
3a
411 (2.4 ꢀ 105)
411 (2.1 ꢀ 105)
411 (2.7 ꢀ 105)
412 (1.7 ꢀ 105)
412 (2.3 ꢀ 105)
413 (2.9 ꢀ 105)
413 (5.8 ꢀ 104)
505 (1.4 ꢀ 104)
506 (1.7 ꢀ 104)
505 (1.7 ꢀ 104)
506 (1.2 ꢀ 104)
506 (1.8 ꢀ 104)
506 (1.7 ꢀ 104)
509 (6.6 ꢀ 103)
Shoulder
Shoulder
Shoulder
Shoulder
Shoulder
Shoulder
Shoulder
582 (4.5 ꢀ 103)
583 (5.4 ꢀ 103)
582 (5.3 ꢀ 103)
583 (4.0 ꢀ 103)
583 (5.7 ꢀ 103)
583 (5.6 ꢀ 103)
585 (2.8 ꢀ 103)
636 (6.6 ꢀ 102)
637 (8.2 ꢀ 102)
636 (8.3 ꢀ 102)
644 (1.3 ꢀ 103)
642 (1.1 ꢀ 103)
640 (9.6 ꢀ 102)
638 (6.3 ꢀ 102)
0.74
0.70
0.66
0.71
0.63
0.59
0.70
3b
3c
4b/5b
4c/5c
6c
7a
3. Conclusions
observed by TLC (thin layer chromatography) plates (4–5 h). The
sulfonamides precipitates from the reaction medium and were
isolated by filtration. The solid was dissolved in dichloromethane,
washed with a saturated solution of sodium bicarbonate (4ꢀ) and
then with water (4ꢀ) and dried over anhydrous Na2SO4. The
solvent was evaporated, affording the title compounds.
Sulfonamides of perfluorophenylporphyrins can be prepared in
large yields. It is specially noteworthy that adequate choices of the
concentration of the starting perfluorophenylporphyrin and of the
porphyrin/sulfonamide ratio can lead to very high isolated yields of
mono or tetrasubstituted sulfonamide perfluorophenylporphyrins.
The ability to control the degree of substitution is particularly
useful to modulate the amphiphilicity of these photosensitizers.
Surprisingly, the tetrasubstituted sulfonamide perfluorophenyl-
porphyrin combines water solubility with a log POW = 0.94, which
are desirable for intravenous administration in biocompatible
solvents and for tumor localization.
4.2.1. p-Toluenesulfonamide
(2b): Yield 48% (0.88 g); 1H NMR (400 MHz, CD3OD): ppm,
d
2.42 (s, 3H), 7.35 (d, J = 7.8 Hz, 2H), 7.78 (d, J = 7.8 Hz, 2H); 13C NMR
(101 MHz, MeOD): ppm, d 21.5, 127.2, 130.6, 144.2; MS ESI-TOF, m/
z: calcd. for C7H10NO2S 172.0427 [M + H]+; found 172.0422; the
data is in agreement with the literature [52].
The spectroscopic properties of these new sulfonamide per-
fluorophenylporphyrins are comparable to those of other porphy-
rin-based photosensitizers. The singlet oxygen quantum yields of
the secondary sulfonamide perfluorophenylporphyrins are re-
markably high. The high LD of these compounds, the large number
of fluorine atoms in their structure, the presence of a variable
number of sulfonamide groups and the possibility of using
biocompatible solvents to administer them, make this class of
compounds an interesting starting point for new molecular
templates for aPDT and medical imaging.
4.2.2. N-Methyl-p-toluenesulfonamide
(2c): Yield 94% (1.87 g). 1H NMR(400 MHz, CDCl3): ppm,
d
2.43
(s, 3H), 2.63 (d, J = 5.3 Hz, 3H), 4.59 (s, 1H), 7.31 (d, J = 8.1 Hz, 2H),
7.75 (d, J = 8.1 Hz, 2H); 13C NMR (101 MHz, CDCl3): ppm,
21.5,
29.3, 127.28, 129.7, 135.7, 143.5; MS ESI-TOF, m/z: calcd. for
C8H12NO2S 186.0583 [M + H]+; found 186.0575; the data is in
agreement with the literature [53].
d
4.3. Synthesis of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (1)
4. Experimental
The porphyrin 5,10,15,20-tetrakis(pentafluorophenyl)por-
phyrin (1) was synthesized accordingly to our recent methodology
[35]. In a typical experiment, 18 g of catalyst (NaY) was introduced
into a 1 l round flask, previously filled with a glacial acetic acid/
nitrobenzene mixture (340 ml/190 ml) and pentafluorobenzalde-
hyde (0.04 mol). Addition of equimolar amount of pyrrole
(0.04 mol) was carried out drop wise under stirring and heating
of the suspension (ꢂ120 8C). After complete addition, the
suspension was heated further to attain the reflux temperature
(ꢂ130 8C) and maintained at this temperature for ca. 2 h. The hot
suspension was filtered and the resulting solid material washed
with chloroform and tetrahydrofuran until no colored material
was collected on the supernatant. The volume of supernatant was
then reduced by rotoevaporation (enough volume to remove the
added washing solvents). The crude was purified by silica gel
column chromatography using hexane/dichloromethane (10:1) as
eluent and successive precipitations. The resulting crystals were
dried under vacuum (yield = 9.1%, 0.953 g).
4.1. Materials and characterization
All solvents were dried according to standard procedures. All
reagents were obtained commercially from Sigma–Aldrich and
Fluorochem and used without further purification. The spectra of
proton nuclear magnetic resonance (1H), carbon (13C) and fluorine
(
19F) were recorded on a spectrometer 400 Bruker Avance (400,
101 and 376.5 MHz, respectively), using tetramethylsilane
(
(
d
d
= 0.00 ppm) as internal standard for 1H and 13C and TFA
= ꢁ76.55 ppm) for 19F NMR. The MALDI-TOF mass spectra were
acquired using a Bruker Daltonics flex Analysis apparatus. UV–vis
spectra were recorded on Hitachi U-2001 or Shimadzu 2100 spec-
trophotometers. The third harmonic of a Spectra-Physics Quanta-
Ray GCR-130 Nd–YAG laser was used for the excitation of the
photosensitizers in the determination of singlet oxygen quantum
yields and phenalenone was used as a reference. Singlet oxygen
phosphorescence was collected at 1270 nm through a Hamamatsu
R5509-42 photomultiplier, cooled to 193 K in a liquid nitrogen
chamber using a filter (Newport model 10LWF-1000-B) to block
the porphyrins fluorescence.
1H NMR (400 MHz, CDCl3): ppm,
NMR (376 MHz, CDCl3) ppm,
d
ꢁ2.91 (s, 2H), 8.92 (s, 8H); 19
F
d
ꢁ160.14 to ꢁ160.28 (m, J = 22.7,
7.6 Hz, 8F), ꢁ150.06 to ꢁ150.16 (t, J = 20.8 Hz, 4F), ꢁ135.35 to
ꢁ135.43 (dd, J = 23.3, 7.7 Hz, 8F); the data is in agreement with the
literature [35].
4.2. General synthesis of sulfonamides
4.4. Synthesis of meso-sulfonamide perfluorophenylporphyrins using
Method A
In a round bottom flask containing p-toluenesulfonyl chloride
(2 g; 0.011 mol) and 200 ml of dichloromethane, the desired amine
(1.2 mol) was added. The reaction mixture was stirred at room
temperature until complete consumption of starting material was
In a round bottom flask containing 5,10,15,20-tetrakis(penta-
fluorophenyl)porphyrin (100 mg; 1.02 ꢀ 10ꢁ4 mol)(1) and the

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C.S. Vinagreiro et al. / Journal of Fluorine Chemistry 180 (2015) 161–167
desired sulfonamide (2a–c) (porphyrin/sulfonamide 1:6 mol) was
dissolved in dioxane (20 ml) and cesium carbonate
(6.15 ꢀ 10ꢁ4 mol) was added. The reaction mixture was stirred
at 100 8C along 2–4 days until no further evolution reaction by TLC.
The crude was washed with a saturated solution of sodium
bicarbonate (6ꢀ) and then with water (6ꢀ) and dried over
anhydrous Na2SO4. The solvent was evaporated in a rotary
evaporator and the resulting solid dissolved in dichloromethane
and purified by silica gel column chromatography using hexane/
ethyl acetate (2:1) as eluent, followed by preparative silica gel thin
layer chromatography (PrepTLC).
CDCl3): ppm,
d
ꢁ161.25 to ꢁ161.35 (m, 4F), ꢁ151.19 (t, J = 20.7 Hz,
2F), ꢁ142.9 (d, J = 12.9 Hz, 4F), ꢁ136.79 (dd, J = 23.4, 10.5 Hz, 4F),
ꢁ136.50 (d, J = 16.1 Hz, 4F); MS(MALDI-TOF): m/z calcd. for
C
60H30F18N6O4S2 1304.1477 [M]+; found 1304.1485.
4.4.3.3. 5,10,15-Tri-[(20,30,50,60-tetrafluoro-40-N-methyl-p-toluene-
sulfamoyl)phenyl]-20-[(20,30,40,50,60-pentafluoro)phenyl]porphyr-
in(6c), yield = 0.6% (4 mg). 1H NMR (400 MHz, CDCl3): ppm,
d
ꢁ2.89
(s, 2H), 2.51 (s,9H), 3.51 (s, 9H), 7.47 (d, J = 8.0 Hz, 6H), 7.96 (d,
J = 8.1 Hz, 6H), 8.96 (s, 8H); 19F NMR (376 MHz, CD3COCD3): ppm,
d
ꢁ161.14 to ꢁ161.26 (m, 2F), ꢁ152.05 (s, 1F), ꢁ141.52 (dd, J = 23.2,
10.0 Hz, 6F), ꢁ136.95 to ꢁ137.07 (m, 6F), ꢁ136.57 (dd, J = 23.2,
7.1 Hz, 2F); MS(MALDI-TOF): m/z calcd. forC68H40F17N7O6S3
1469.1925 [M]+; found 1469.1946.
4.4.1. Methanesulfonamide derivatives
5-[20,30,50,60-Tetrafluoro-40-methanesulfamoyl)phenyl]-
10,15,20-tri-[(20,30,40,50,60-pentafluoro)phenyl]porphyrin
(3a),
yield = 19% (20.3 mg).
4.5. Synthesis of meso-sulfonamide perfluorophenylporphyrins using
Method B
1H NMR (400 MHz, CDCl3): ppm,
d
ꢁ2.92 (s, 2H), 3.53 (s, 3H),
8.93 (brs, J = 13.5 Hz, 8H); 19F NMR (376 MHz, CDCl3): ppm,
d
ꢁ161.26 to ꢁ161.37 (m, 6F), ꢁ151.22 (td, J = 20.9, 7.1 Hz, 3F),
ꢁ147.82 (dd, J = 23.7, 10.7 Hz, 2F), ꢁ136.54 (d, J = 7.3 Hz, 2F),
ꢁ136.47 (dd, J = 15.3, 7.9 Hz, 6F); MS(MALDI-TOF): m/z calcd. for
In a round bottom flask, 5,10,15,20-tetrakis(pentafluorophe-
nyl)porphyrin (30 mg; 3.07 ꢀ 10ꢁ5 mol) (1) and methanesulfona-
mide (porphyrin/sulfonamide 1:18 mol equivalents) (2a) were
C
45H14F19N5O2S 1049.05593 [M]+; found 1049.05487.
dissolved
in
dioxane
(2 ml)
and
cesium
carbonate
(3.69 ꢀ 10ꢁ4 mol) was added. The reaction mixture was stirred
at 100 8C for 2 days until complete consumption of starting
material was observed by TLC. The crude was washed with acetone
and the resulting precipitate was purified using the Amicon device
(10 kDa membranes).
4.4.2. p-Toluenesulfonamide derivatives
4.4.2.1. 5-[(20,30,50,60-Tetrafluoro-40-p-toluenesulfamoyl)phenyl]-
10,15,20-tri-[(20,30,40,50,60-pentafluoro)phenyl]porphyrin(3b),
yield = 4.5% (15.7 mg). 1H NMR (400 MHz, CDCl3): ppm,
d
ꢁ2.89 (s,
2H), 2.51 (s, 3H), 7.08 (s, 1H), 7.47 (d, J = 8.2 Hz, 2H), 8.05 (d,
J = 8.2 Hz, 2H), 8.94 (s, 8H); 19F NMR (376 MHz, CD3COCD3): ppm,
4.5.1. 5,10,15,20-Tetra-[(20,30,50,60-tetrafluoro-40-
d
methanesulfamoyl)phenyl]porphyrin (7a), yield = 70% (27 mg).
1H NMR (400 MHz, DMSO-d6): ppm,
d
ꢁ3.01 (s, 2H), 2.94 (s,
12H), 9.08 (s, 8H); 19F NMR (376 MHz, DMSO-d6): ppm,
ꢁ152.19
(d, 19.1, 8F), ꢁ144.71 (d, 17.7, 8F); MS(MALDI-TOF): m/z calcd. for
48H26F16N8O8S4 1274.0496 [M]+; found 1274.0478.
ꢁ159.35 (td, J = 22.8, 7.5 Hz, 6F), ꢁ150.20 to ꢁ150.34 (m, 3F),
ꢁ142.13 (dd, J = 67.3, 33.5 Hz, 2F), ꢁ135.45 (dd, J = 102.1, 51.0 Hz,
2F), ꢁ134.73 (dd, J = 21.8, 5.1 Hz, 6F); MS(MALDI-TOF): m/z calcd.
for C51H18F19N5O2S 1125.08723 [M]+; found 1125.08694.
d
C
4.4.2.2. Mixture of 5,10-[(20,30,50,60-tetrafluoro-40-p-toluenesulfa-
moyl)phenyl]-15,20-dis-[(20,30,40,50,60-penta-fluoro)phenyl]porphyrin
(4b) and 5,15-[(20,30,50,60-tetrafluoro-40-p-toluenesulfamoyl)phenyl]-
10,20-[(20,30,40,50,60-penta-fluoro)phenyl]porphyrin (5b), yield = 0.7%
4.6. 1-Octanol/water partition coefficients
1-Octanol/water partition coefficients were measured fol-
lowing shake-flask method with minor modifications [46–
48]. Equal volumes of PBS and 1-octanol were mixed and left
overnight. A volume of 5 ml of 1-octanol saturated with PBS was
taken from the previous mixture and used to dissolve a sample of
7a until the solution turned into a light color. Then 5 ml of PBS
saturated with 1-octanol was taken from the mixture and added
to the solution of 7a in 1-octanol saturated with PBS. The solvent
mixture was then shaken vigorously. This solution was
centrifuged at 3700 rpm to obtain clear phase separation. A
volume of 2 ml of water part containing the compound was
taken, mixed with 0.5 ml of 1-octanol and evaporated at 50 8C.
After evaporation, a volume of pure 1-octanol was added
keeping equal dilutions of organic and water parts containing
the compound. Optical absorption of the 1-octanol and the PBS
fractions were used to determine the logarithm of the partition
coefficient.
(2.7 mg). 1H NMR (400 MHz, CDCl3): ppm,
6H), 6.86 (s, 2 H), 7.46 (d, J = 7.9 Hz, 2H), 8.01(d, J = 8.1 Hz, 2H), 8.89
(s, 8H); 19F NMR (376 MHz, CDCl3): ppm,
d
ꢁ2.94 (s, 2H), 2.51 (s,
d
ꢁ159.34 (td, J = 22.3,
6.8 Hz, 4F), ꢁ150.24 (t, J = 20.4 Hz, 2F), ꢁ142.01 (dd, J = 23.3,
10.4 Hz, 4F), ꢁ135.27 (dd, J = 23.4, 10.4 Hz, 4F), ꢁ134.73 (dd,
J = 23.2, 7.1 Hz, 4F); MS(MALDI-TOF): m/z calcd. for
C
58H26F18N6O4S2 1276.11640 [M]+; found 1276.11649.
4.4.3. N-Methyl-p-toluenesulfonamide derivatives
4.4.3.1. 5-[(20,30,50,60-Tetrafluoro-40-N-methyl-p-toluenesulfamoyl)-
phenyl]-10,15,20-tri-[(20,30,40,50,60-pentafluoro)phenyl]porphyrin
(3c), yield = 3.1% (15 mg). 1H NMR (400 MHz, CDCl3): ppm,
d
ꢁ2.91
(s, 2H), 2.51 (s, 3H), 3.50 (s, 3H), 7.47 (d, J = 8.1 Hz, 2H), 7.97 (d,
J = 8.2 Hz, 2H), 8.92 (s, 8H); 19F NMR (376 MHz, CDCl3): ppm,
d
ꢁ160.15 to ꢁ160.26 (m, 6F), ꢁ150.12 (t, J = 20.6 Hz, 3F), ꢁ141.80
(dd, J = 23.7, 10.9 Hz, 2F), ꢁ135.69 (dd, J = 23.7, 10.9 Hz, 2F),
ꢁ135.40 (dd, J = 23.2, 7.3 Hz, 6F); MS(ESI-TOF): m/z calcd. for
4.6.1. Computational determination of the LogP
C
52H21F19N5O2S 1140.1107 [M + H]+; found 1140.1078.
A correlation curve between experimental [10] and computa-
tional data of LogP was constructed for a family of sulfonamide-
substituted porphyrins and their derivatives. The computational
approach was made using the program Marvin Sketch
14.10.6.0 available in http://www.chemaxon.com. All computation-
al data was run using the same initial conditions in the simulation.
From the fitting curve given in Fig. 3, a good approximation of the
LogP value can be obtained through the equation: [LogP(Theor)-
0.12]/1.83.
4.4.3.2. Mixture of 5,10-[(20,30,50,60-tetrafluoro-40-N-methyl-p-tolue-
nesulfamoyl)phenyl]-15,20-dis-[(20,30,40,50,60-pentafluoro)phenyl]-
porphyrin(4c)
and
5,15-[(20,30,50,60-tetrafluoro-40-N-methyl-p-
toluenesulfamoyl)phenyl]-10,20-[(20,30,40,50,60-pentafluoro)phenyl]-
porphyrin (5c), yield = 1.5% (8 mg). 1H NMR (400 MHz, CDCl3): ppm,
d
ꢁ2.90 (s, 2H), 2.51 (s, 3H), 3.50 (s, 6H), 7.47 (d, J = 7.5 Hz, 4H), 7.96
(d, J = 7.6 Hz, 4H), 8.85 (d, J = 51.6 Hz, 8H); 19F NMR (376 MHz,

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This work was financially supported by Portuguese Science
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