Synthesis and characterization of novel 5-monocarbohydrate-10,20- bis -aryl-porphyrins

Article abstract of DOI:10.1142/S1088424619501049

The synthesis of derivatives bearing glucose or galactose units linked by an acrylate spacer to one free meso position of a bis-aryl-porphyrin macrocycle was developed and characterized by standard spectroscopic techniques. The new mono-substituted gluco- and galacto-porphyrin derivatives 5-8 present an alternative to the widespread tetra-aryl porphyrin functionalization. Singlet oxygen studies showed a comparable singlet oxygen production with TPP. Furthermore, the less bulky architectures here synthesized present an opportunity to enhance the PDT and PDI capabilities of glycoporphyrins with a simple synthetic modification at one of the meso positions.

Full text of DOI:10.1142/S1088424619501049

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2019; 23: 1–10
DOI: 10.1142/S1088424619501049
Published at http://www.worldscinet.com/jpp/
Synthesis and characterization of novel
5-monocarbohydrate-10,20-bis-aryl-porphyrins
Flávio Figueira*a,b, Leandro M. O. Lourençoa, Maria G. P. M. S. Nevesa,
José A. S. Cavaleiroa and João P. C.Toméa,c,*
aQOPNA&LAQV-Requinte and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
bCICECO — Aveiro Institute of Materials and Department of Chemistry, University of Aveiro, 3810-193 Aveiro,
Portugal
cCQE and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa,
Av. Rovisco Pais Nº1, 1049-001 Lisboa, Portugal
Dedicated to Professor Atsuhiro Osuka on the occasion of his 65th birthday.
Received 2 July 2019
Accepted 22 July 2019
ABSTRACT: The synthesis of derivatives bearing glucose or galactose units linked by an acrylate
spacer to one free meso position of a bis-aryl-porphyrin macrocycle was developed and characterized by
standard spectroscopic techniques. The new mono-substituted gluco- and galacto-porphyrin derivatives
5–8 present an alternative to the widespread tetra-aryl porphyrin functionalization. Singlet oxygen studies
showed a comparable singlet oxygen production with TPP. Furthermore, the less bulky architectures here
synthesized present an opportunity to enhance the PDT and PDI capabilities of glycoporphyrins with a
simple synthetic modification at one of the meso positions.
KEYWORDS: porphyrins, carbohydrates, glycoporphyrins, singlet oxygen, galactose, glucose.
been the subject of widespread research within this
INTRODUCTION
class of compounds [7–18]. Amongst these applications,
Porphyrin (Por) and carbohydrate (CH) derivatives
cancer photodynamic therapy (PDT) and microorganism
are present in many vital functions of life [1]. In fact,
photodynamic inactivation (PDI) have undoubtedly led
CHs are disseminated in all living organisms, appearing
to a major development in porphyrin related research
as monomers, oligomers, polymers and as components
[19–22]. The concept behind this driving force is based
of many other natural molecules, playing vital roles in
on the Pors ability to absorb light energy that can result
metabolic processes (e.g. cell–substrate and cell–cell
in an excited triplet state able to react with molecular
recognition, drug transport and energy storage) [2–5].
oxygen and produce reactive oxygen species such as
Also, countless organisms use CH polymeric derivatives
singlet oxygen and radical oxygen species [23, 24]. These
in cell walls and defensive coating [6]. Pors are present
very toxic oxygen species can destroy cancer cells and
in a vast range of biological processes including light
microorganisms, with special interest to the inactivation
harvesting in photosynthesis, electron transport in
of the antibiotic resistant ones [25].
respiration, and oxygen transport in the blood.
For better biocompatibility, recognition and selectivity
Porphyrin-based biological representatives include
of the Por core for the different cells, several synthetic
hemes, chlorophylls, cytochrome P450, and several others.
strategies have been explored. Pors bearing CH units
Several applications, such as photodynamic therapy
combine the unique Por photosensitizing properties with
(PDT), catalysis and supramolecular chemistry, have
those due to the carbohydrate ones [26]. Several tetra-aryl
glycoporphyrins are already well established throughout
the literature [26–30]. However, diarylporphyrins are
still rare, and in some cases have proven to be beneficial,
*Correspondence to: Flávio Figueira, email: ffigueira@ua.pt
and João P.C. Tomé, email: jtome@tecnico.ulisboa.pt.
Copyright © 2019 World Scientific Publishing Company

2
F. FIGUEIRA ET AL.
allowing higher uptakes and quicker clearance since
they are less bulky molecules with lower molecular
weights [31–34]. Herein, we present the use of a simple
strategy to append CH moieties into meso-formylated
diarylPors [35]. These compounds were firstly presented
at the ICPP-1 and later Aksenova et al. and our group
included them in a review and a book chapter on
glycoporphyrins [23, 36–38]. Still, the complete set of the
methodologies used in the synthesis and characterization
of these derivatives are insufficient in those publications.
Thereby, we present for the first time the complete
methodologies used to achieve such derivatives, and their
full characterization.
Synthesis
5,15-Bis(3-methoxyphenyl)porphyrin (1a) [40]. To a
dried CH2Cl2 solution (600 ml) containing 3-metho-
xybenzaldehyde (405.0 mg, 2.97 mmol), dipyrromethane
[41] (435.0 mg, 2.97 mmol) and 100 mL of TFA were
added dropwise. The mixture was stirred for 3 h at room
temperature under N2. Then DDQ (1.0 g, 4.45 mmol)
was added and the mixture was stirred for 30 min and
subsequently 3 mL of triethylamine (NEt3) were added. The
solution containing the reaction mixture was concentrated
and then chromatographed on silica gel column with
CH2Cl2:hexane(3:1)aseluent.Thepurpleporphyrinfraction
was collected and the solvent evaporated. Recrystallization
from CHCl3 and MeOH gave the pure target compound
1a as a purple powder (323.2 mg, 21%). mp > 300°C; 1H
NMR (300 MHz, Chloroform-d) d 10.31 (s, 2H, meso-H),
9.39 and 9.13 (2 d, J = 4.6 Hz, 8H, b-H), 7.88–7.84 (m, 4H,
5,15-Ar-o-H), 7.70 (t, J = 8.1 Hz, 2H, 5,15-Ar-p-H), 7.36
(dd, J = 8.1, 2.5 Hz, 2H, 5,15-Ar-m-H), 4.02 (s, 6H, OCH3),
-3.14 (s, 2H, NH); 13C NMR (125.76 MHz, Chloroform-d):
d 158.4, 147.2, 145.4, 142.8, 131.6 (b-C), 131.0 (b-C),
127.9 (5,15-Ar-p-C), 127.8 (5,15-Ar-o-C), 120.9 (5,15-
Ar-o-C), 118.9, 113.6 (5,15-Ar-m-C), 105.2 (meso-C),
55.6 (OCH3); HRMS (ESI) found: 523.2120, calcd for
C34H27N4O2: 523.2128 [M + H+]; UV-vis (DMF) lmax.
(log e): 405 (5.11), 500 (4.28), 534 (3.75), 573 (3,72),
628 (3.17); Fluorescence (DMF): l(em. máx) = 631, 696 nm
(lexc = 405 nm).
EXPERIMENTAL SECTION
General considerations
1H and 13C solution NMR spectra were recorded
on Bruker Avance 300 (300.13 and 75.47 MHz), 500
(500.13 and 125.76 MHz) and 700 (700.13 and 175.03
MHz) spectrometers. CDCl3 and DMSO-d6 were used
as deuterated solvents and tetramethylsilane (TMS)
as internal reference; the chemical shifts are expressed
in ppm and the coupling constants (J) in Hertz (Hz).
Unequivocal 13C assignments were made using 2D
1
(HSQC H/13C). Mass spectra HRMS were recorded on
a LTQ Orbitrap XL mass spectrometer (Thermo Fischer
Scientific, Bremen, Germany) using CHCl3 or mixtures of
CHCl3:MeOH as solvents. UV-vis spectra were recorded
on an UV-2501PC Shimadzu spectrophotometer using
DMF as solvent. Preparative thin-layer chromatography
was carried out on 20:20 cm glass plates coated with silica
gel (0.5 mm thick). Column chromatography was carried
out using silica gel (Merck, 35–70 mesh). Analytical
TLC was carried out on pre-coated sheets with silica gel
(Merck 60, 0.2 mm thick).
(5,15-Bis(3-methoxyphenyl)porphyrinato)nickel(II)
(1b). The reaction between the free-base porphyrin 1a
(293.1 mg, 0.56 mmol) and nickel(II) acetate (418.0 mg,
1.68 mmol) was carried out in DMF at 120°C for 6 h.After
this period, the final product was precipitated with water
(3× 50mL). Filtrationoftheprecipitateandcrystallization
in CH2Cl2:MeOH yielded the desired product 1b
1
(305.3 mg, 94%). mp: >300°C; H NMR (300 MHz,
Chloroform-d): d 9.93 (s, 2H, meso-H), 9.18 and 8.98
(2 d, J = 4.7 Hz, 8H, b-H), 7.73–7.56 (m, 6H, 5,15-Ar-o
and p-H), 7.33–7.27 (m, 2H, 5,15-Ar-m-H), 3.96 (s, 6H,
OCH3); 13C NMR (126 MHz, Chloroform-d): d 158.1,
142.8, 142.6, 142.4, 132.5 (b-C), 132.1 (b-C), 127.8
(5,15-Ar-p-C), 126.2 (5,15-Ar-o-C), 119.8 (5,15-Ar-o-C),
118.1, 113.5 (5,15-Ar-m-C), 105.1 (meso-C), 55.5
(2 × OCH3); HRMS (ESI) found: 578.1241, calcd for
C34H24N4NiO2: 578.1253 [M+·]; UV-vis (DMF) lmax.
(log e): 399 (5.22), 513 (4.04), 545 (2.73).
5-Formyl-10,20-bis(3-methoxyphenyl)porphyrin(2a).
Trifluoroacetic acid (7 mL) and sulfuric acid (3 mL) were
added to 2b (100.0 mg, 0.16 mmol) (vide infra) under
nitrogen atmosphere. The mixture was stirred for 30 min
at rt, and CH2Cl2 (50 mL) and H2O (100 mL) were added.
Aqueous K2CO3 (sat.) was added dropwise to neutralize
the acid and the organic layer was separated. The organic
extracts were dried over Na2SO4 and concentrated. The
residue was crystallized in CH2Cl2:MeOH to yield 2a as
purple-red solid (56.3 mg, 62%). mp: >280°C; 1H NMR
All chemicals were used as supplied. Solvents
were purified or dried according to the literature
procedures [39].
Singlet oxygen generation
Astocksolutionofeachporphyrinderivativeat0.1mM
inDMFandastocksolutionof1,3-diphenylisobenzofuran
(DPiBF) at 10 mM in DMF were prepared. Aliquots
of 2 mL of a solution of each porphyrin (0.5 mM) and
1,3-diphenylisobenzofuran (DPiBF, 50 mM) in DMF
-2
.
were irradiated at an irradiance of 6.0 mW cm , in a
glass cuvette, at room temperature and under gentle
magnetic stirring, with a red LED array to prevent the
photodegradation of DPiBF. The LED array is composed
of a matrix of 5 × 5 LED that makes a total of 25 light
sources with an emission peak at 630 nm and a bandwidth
at half maximum of 20 nm. The absorption decay of
DPiBF at 425 nm was measured at irradiation intervals
up to 10 min.
Copyright © 2019 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2019; 23: 2–10

SYNTHESIS AND CHARACTERIZATION OF NOVEL 5-MONOCARBOHYDRATE-10,20-BIS-ARYL-PORPHYRINS
3
(300 MHz, Chloroform-d): d 12.59 (s, 1H, CHO), 10.25
(s, 1H, meso-H), 10.07 (d, J = 5.0 Hz, 2H, b-H), 9.28 (d,
J = 4.7 Hz, 2H, b-H), 9.11 (d, J = 5.0 Hz, 2H, b-H), 8.93 (d,
J = 4.7 Hz, 2H, b-H), 7.82–7.65 (m, 6H, 10,20-Ar-o and
p-H), 7.38 (m, 2H, 10,20-Ar-m-H), 4.02 (s, 6H, OCH3),
-2.48 (s, 2H, NH); 13C NMR (75 MHz, Chloroform-d):
d 195.3 (CHO), 158.1, 142.5, 128.1 (b-H), 127.8
(5,15-Ar-p-C), 127.5 (b-H), 121.9 (5,15-Ar-o-C), 120.5
(5,15-Ar-o-C), 113.8 (5,15-Ar-m-C), 109.9 (meso-C),
108.2, 55.6 (2 × OCH3); HRMS (ESI) found: 551.2069,
calcd for C35H27N4O3: 551.2078 [M + H+]; UV-vis; lmax.
nm in DMF: 420 (5.42), 518 (4.15), 556 (3.96), 590
(3.81), 646 (3.84); Fluorescence (DMF): l(em. máx) = 651,
716 nm (lexc = 420 nm).
(5-Formyl-10,20-bis(3-methoxyphenyl)porphyrinato)
nickel(II) (2b). A solution of 1b (100.0 mg, 0.17 mmol)
in dried CH2Cl2 (20.0 mL) under N2 was cooled to 0°C
and a mixture of POCl3 (1.2 mL) and DMF (1.2 mL)],
previously prepared, was added dropwise. The mixture
was stirred at 40°C for 12 h. Saturated aqueous sodium
carbonate solution (30 mL) was carefully added and
the mixture was stirred for 3 h at room temperature.
The solution was extracted three times with CH2Cl2,
the extracts were washed with H2O, dried over Na2SO4
and evaporated in a vacuum system to give a brown
oil. This was purified by flash chromatography (silica:
eluent CH2Cl2:MeOH; 98:2) to give the desired product
2b in 79% (81.5 mg), after evaporation of the solvent in
vacuum and recrystallization from CH2Cl2:hexane. mp:
235–237°C; 1H NMR (300 MHz, Chloroform-d): d 12.11
(s, 1H, CHO), 9.84 (d, J = 5.2 Hz, 2H, b-H), 9.72 (s, 1H,
meso-H), 9.03 (d, J = 5.2 Hz, 2H, b-H), 8.93 (d, J = 4.8
Hz, 2H, b-H), 8.77 (d, J = 4.8 Hz, 2H, b-H), 7.64–7.51
(m, 6H, 5,15-Ar-p and m-H), 7.29 (s, 2H, 5,15-Ar-m-H),
3.95 (s, 6H, OCH3); 13C NMR (75 MHz, Chloroform-d):
d 193.1 (CHO), 158.2, 144.2, 144.0, 141.8, 141.2, 141.0,
135.3 (b-C), 133.2 (b-C), 132.4 (b-C), 130.5 (b-C), 128.0
(5,15-Ar-p-C), 126.5(5,15-Ar-o-C), 120.2(5,15-Ar-o-C),
119.6, 113.7 (5,15-Ar-m-C), 108.5 (meso-C), 106.3,
55.5 (2 × OCH3); HRMS (ESI) found: 606.1187, calcd
for C35H24N4NiO3: 606.1196 [M·+]; UV-vis (DMF) lmax.
(log e): 415 (5.28), 539 (4.41) 585 (4.56).
J = 4.7 Hz, 4H, b-H), 7.84–7.64 (2 m, 6H, 10,20-Ar-m
and o-H), 7.41–7.33 (m, 2H, 10,20-Ar-p-H), 6.74 (d,
J = 15.6 Hz, 1H, CH=CHCO2tBu), 4.02 (s, 6H, OCH3),
1.74 (s, 9H, CH3), -2.91 (s, 2H, NH); 13C NMR (75 MHz,
Chloroform-d): d 165.6, 158.1, 145.0 (CH=CHCO2tBu),
142.9, 133.8 (CH=CHCO2tBu), 131.5 (b-C), 131.4 (b-C),
129.1 (b-C), 127.8 (10,20-Ar-p-C) 127.7 (10,20-Ar-o-C)
120.1 (10,20-Ar-o-C), 113.6 (10,20-Ar-m-C), 106.0
(meso-C), 55.6 (2 × OCH3), 28.4 (OtBu); HRMS (ESI)
found: 649.2797, calcd. for: C41H37N4O4: 649.2809 [M +
H+]; UV-vis; UV-vis (DMF) lmax. (log e): 418 (5.48), 514
(4.21), 550 (3.93), 590 (3.73), 649 (3.59); Fluorescence
(DMF): l(em. máx) = 659, 719 nm (lexc = 418 nm).
5-[2-(Tert-butoxycarbonylethylene)]-10,20-bis(3-
methoxyphenyl)porphyrin nickel(II)(3b). Compound 3
was prepared in 95% yield using the procedure described
above for compound 3a, using as starting material
2b, albeit with 24 h of reaction time. The residue was
chromatographed on silica gel using CH2Cl2 as eluent and
a pale red colored band was collected to yield 3b as a dark
blue solid after recrystallization from CH2Cl2/MeOH.
1
mp: 246–248°C; H NMR (700 MHz, Chloroform-d):
d 9.85 (d, J = 15.7 Hz, 1H, CH=CHCO2tBu), 9.68 (s,
1H, meso-H), 9.40 (d, J = 4.9 Hz, 2H, b-H), 9.04 (d,
J = 4.7 Hz, 2H, b-H), 8.89 (d, J = 4.9 Hz, 2H, b-H),
8.83 (d, J = 4.7 Hz, 2H, b-H), 7.61–7.57 (m, 4H,
10,20-Ar-o-H), 7.54 (m, 2H, 10,20-Ar-m-H), 7.29–7.27
(m, 2H, 10,20-Ar-p-H), 6.27 (d, J = 15.7 Hz, 1H,
CH=CHCO2tBu), 3.94 (s, 6H, OCH3), 1.66 (s, 9H,
CH3); 13C NMR (75 MHz, Chloroform-d): d 165.6,
158.2, 142.9, 142.6, 142.4, 141.8, 141.7, 141.2, 133.9
(CH=CHCO2tBu), 133.3 (b-H), 132.7 (b-H), 132.5 (b-H),
131.2 (b-H), 127.9 (5,15-Ar-p-C), 126.7 (5,15-Ar-o-C),
119.7 (5,15-Ar-o-C), 118.7, 113.6 (5,15-Ar-m-C), 110.8,
105.5 (meso-C), 81.0, 55.5 (2 × OCH3), 28.4 (OtBu);
HRMS (ESI) found: 705.1998, calcd for C41H35N4NiO4:
705.2006 [M + H+]; UV-vis; lmax. nm in DMSO: 417
(5.13), 530 (4.25) 551 (4.24).
5-(2-Carbonylethylene)-10,20-bis(3-methoxyphenyl)
porphyrin (4). A solution of 3a (50 mg, 84.9 mmol) in
formic acid (10 mL) was kept at room temperature under
vigorous stirring for 7 h. After this period, the reaction
was quenched with H2O, neutralized with a saturated
solution of sodium carbonate and the organic phase
extracted with CH2Cl2. The organic extracts were dried
over Na2SO4 and concentrated. The final product 4 was
obtained as a dark blue solid after recrystallization from
CH2Cl2/hexane (41 mg, 91%). mp: 250–252°C; 1H NMR
(300 MHz, Chloroform-d): d 10.47 (d, J = 15.5 Hz, 1H,
CH=CHCO2H), 10.21 (s, 1H, meso-H), 9.57 (d, J = 4.9
Hz, 2H, b-H), 9.31 (d, J = 4.7 Hz, 2H, b-H), 9.06 (dd,
J = 4.9 Hz, 2H, b-H), 9.02 (d, J = 4.7 Hz, 2H, b-H),
7.87–7.59 (2 m, 6H, 10,20-Ar-m and o-H), 7.37 (d, J =
8.2 Hz, 2H, 10,20-Ar-p-H), 6.88 (d, J = 15.5 Hz, 1H,
CH=CHCO2H), 4.03 (s, 6H, OCH3), -2.84 (s, 2H, NH);
13C NMR (75 MHz, Chloroform-d): d 168.9, 158.1, 148.7
(CH=CHCO2H), 142.8, 131.6, 130.0 (CH=CHCO2H),
(5-[2-(Tert-butoxycarbonylethylene)]-10,20-bis(3-
methoxyphenyl)porphyrinato) (3a). To a solution of 2a
(100.0mg, 0.18mmol)dissolvedinCH2Cl2 (10mL), (tert-
butoxycarbonylmethylene)triphenylphosphorane (304.5
mg, 0.81 mmol, 4.5 eq.) was added and then refluxed.
After 6.5 h, the reaction was cooled and quenched with
H2O and extracted with CH2Cl2. The organic extracts
were dried over Na2SO4 and concentrated. The residue
was chromatographed on silica gel using CH2Cl2 as
eluent, and a brown-red color band was collected to
yield 3a as dark blue solid after recrystallization from
1
CH2Cl2/MeOH (112.8 mg, 96%). mp: 175–178°C; H
NMR (300 MHz, Chloroform-d): d 10.23 (d, J = 15.6 Hz,
1H, CH=CHCO2tBu), 10.19 (s, 1H, meso-H), 9.55 (d, J =
4.7 Hz, 2H, b-H), 9.30 (d, J = 4.6 Hz, 2H, b-H), 9.02 (t,
Copyright © 2019 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2019; 23: 3–10

4
F. FIGUEIRA ET AL.
129.0,127.8,127.7(10,20-Ar-p-H),120.6(10,20-Ar-o-H),
120.4 (10,20-Ar-o-H), 113.7 (10,20-Ar-m-H), 112.0,
106.5 (meso-H), 55.6 (2 × OCH3); HRMS (ESI) found:
593.2172, calcd for: C37H29N4O4: 593.2183 [M + H+];
UV-vis UV-vis (DMF) lmax. (log e): 417 (5.42), 513
(4.25), 549 (3.96), 590 (3.79), 647 (3.60); Fluorescence
(DMF): l(em. máx) = 657, 718 nm (lexc = 420 nm).
5-[2-(2,3,4,6-tetra-O-acetyl-a,b-D-glucopyrano-
syloxycarbonyl)ethylene]-10,20-bis(3-methoxyphenyl)
porphyrins 5 (b isomer) and 6 (a isomer). To a solution
of Por 4 (30 mg, 50.6 μmol) in dry DMF (5 mL) was added
1-bromo-2,3,4,6-tetra-O-acetyl-a-D-glucopyranose
(41.5 mg, 0.11 mmol) and a large excess of potassium
carbonate (100 mg). The reaction was carried out during
24 h at room temperature. Evaporation of the excess of
DMFandpurificationoversilicagelwithCH2Cl2 provided
compounds 5 (b isomer) and 6 (a isomer) as a mixture in
88% yield (40.7 mg). Purification over preparative TLC
plates with ethyl acetate hexanes (2:1) provided pure 5
and 6 in a ratio of 3:1 (62 and 20%, respectively). The
more polar compound was the b isomer (5) and the less
polar was the a isomer (6).
-2.81 (s, 2H, NH); 13C NMR (75 MHz, Chloroform-d):
d 170.7, 170.3, 169.9, 169.5, 163.9, 158.1, 149.0, 142.8,
132.1, 131.6, 129.3, 128.7, 127.8, 120.7, 113.6, 111.5,
106.8, 89.7 (Glu-C1), 70.1 (Glu-C3), 69.5 (Glu-C2), 68.0
(Glu-C4), 61.5, 55.6 (OCH3), 20.8 (OAc), 20.7 (OAc),
20.6 (OAc); UV-vis. lmax. nm in DMSO: 420 (5.26) 515
(4.11), 554 (3.88), 591 (3.68), 649 (3.46); Fluorescence
(DMF): l(em. máx) = 663, 721 nm (lexc = 420 nm).
[5-[2-(1,2:3,4-Di-O-isopropylidene-a-D-galacto-
pyranosyloxycarbonyl)ethylene]-10,20-bis(3-methoxy-
phenyl)porphyrin (7). To a solution of 4 (35.0 mg, 0.05
mmol) and 1,2:3,4-Di-O-isopropylidene-a-D-galacto-
pyranose (76.6 mg, 0.25 mmol, 5 eq.) in dry CH2Cl2
(5 mL) under N2, 1-ethyl-3-(3-dimethylaminopropyl)
.
carbodiimide hydrochloride (EDC HCl) (55.0 mg, 0.30
mmol, 6 eq.) and DMAP (43.1 mg, 0.31 mmol, 6 eq.),
were stirred at 40°C for 12 h. The reaction was quenched
with diluted HCl, and the product was extracted with
CH2Cl2. The organic layer was washed with H2O and
dried over Na2SO4. Purification by silica gel column
1
chromatography (CH2Cl2) afforded 7 in 82%. H NMR
(700 MHz, Chloroform-d): d 10.36 (d, J = 15.7 Hz, 1H,
CH=CHCO2), 10.19 (s, 1H, meso-H), 9.53 (d, J = 4.6 Hz,
2H, b-H), 9.30 (d, J = 4.6 Hz, 4H, b-H), 9.02 (m, 4H,
b-H), 7.85–7.65 (m, 6H, 10,20-Ar-o and m-H), 7.37 (d,
J = 8.6 Hz, 2H, 10,20-Ar-p-H), 6.86 (d, J = 15.7 Hz, 1H,
CH=CHCO2), 5.65 (d, J = 4.9 Hz, 1H, Gal-H1), 4.72 (dd,
J = 7.9, 2.5 Hz, 1H), 4.68 (dd, J = 11.4, 4.8 Hz, 1H), 4.60
(dd, J = 11.4, 7.7 Hz, 1H), 4.44 (dd, J = 8.0, 1.8 Hz, 1H),
4.41 (dd, J = 5.0, 2.4 Hz, 1H), 4.32 (dd, J = 7.0, 4.8 Hz,
1H), 4.02 (s, 6H, OCH3), 1.62 (s, 3H, CH3), 1.42 (s, 3H,
CH3), 1.37 (s, 3H, CH3), 1.25 (s, 3H, CH3), -2.88 (s, 2H,
NH); 13C NMR (75 MHz, Chloroform-d): d 166.1, 158.1,
146.8, 142.9, 131.0, 127.7, 120.6, 120.2, 113.7, 109.8,
108.9, 96.4, 71.3, 70.8, 70.6, 66.3, 64.0, 55.6 (OCH3),
26.2 (CH3), 26.1 (CH3), 25.0 (CH3), 24.58 (CH3); HRMS
(ESI) found: 835.3323, calcd. for C49H47N4O9: 835.3337
[M + H+]; UV-vis (DMF) lmax. (log e): 419 (5.27), 514
(4.09), 550 (3.86), 589 (3.60), 648 (3.42); Fluorescence
(DMF): l(em. máx) = 659, 718 nm (lexc = 419 nm).
5:mp:249–250°C;1HNMR(300MHz,Chloroform-d):
d 10.43 (d, J = 15.7 Hz, 1H, CH=CHCO2H), 10.18 (s, 1H,
meso-H), 9.54 (d, J = 4.9 Hz, 2H, b-H), 9.28 (d, J = 4.6
Hz, 2H, b-H), 9.04 (d, J = 4.9 Hz, 2H, b-H), 9.00 (d,
J = 4.6 Hz, 2H, b-H), 7.84–7.77 (m, 4H, 10,20-Ar-o-H),
7.69 (t, J = 7.8 Hz, 2H, 10,20-Ar-m-H), 7.37 (dd, J =
8.4, 2.6, 1.1 Hz, 2H, 10,20-Ar-p-H), 6.79 (d, J = 15.7 Hz,
1H, CH=CHCO2Glu), 6.11 (d, J = 7.8 Hz, 1H, Glu-H1),
5.53–5.41 (m, 2H, Glu-H6), 5.30 (t, J = 9.4 Hz, 1H, Glu-
H4), 4.45 (dd, J = 12.6, 4.3 Hz, 1H, Glu-H3), 4.28 (dd,
J = 12.5, 2.1 Hz, 1H, Glu-H5), 4.09 (m, 1H, Glu-H2),
4.02 (s, 6H, OCH3), 2.16 (m, 6H, 2 × OAc), 2.10 (s, 3H.
OAc), 2.09 (s, 3H, OAc), -2.83 (s, 2H, NH2). 13C NMR
(75 MHz, Chloroform-d): d 170.8, 170.2, 169.6, 169.5,
163.7, 158.1, 149.3, 142.8, 132.1, 131.6, 129.1, 128.8,
127.8, 120.6, 120.6, 113.7, 111.5, 106.8, 92.4 (Glu-
C1), 73.0 (Glu-C2), 72.8 (Glu-C3), 70.5 (Glu-C4), 68.0
(Glu-C5), 61.6 (Glu-C6), 55.6 (OCH3), 20.9 (OAc), 20.8
(OAc), 20.7 (OAc), 20.6 (OAc); HRMS (ESI) found:
923.3139, calcd for C51H47O13N4: 923.3144 [M + H+];
UV-vis. lmax. nm in DMSO: 421 (5.21), 516 (4.10), 554
(3.84), 591 (3,64), 650 (3.61); Fluorescence (DMF):
l(em. máx) = 663, 722 nm (lexc = 421 nm).
[5-[2-(a/b-Galactopyranosyloxycarbonyl)ethylene]-
10,20-bis(3-methoxyphenyl)porphyrin (8). Por 7 (20.0
mg, 3.95 μmol) was stirred at room temperature during
6 h inTFA/water (2.8:0.2 mL). The mixture was quenched
with CH2Cl2 and neutralized with aqueous K2CO3 and
the product was extracted with CH2Cl2/MeOH (10%).
Compound 8 was then purified by preparative TLC
with ethyl acetate and crystalized from CH2Cl2/MeOH,
6: mp: 248–249°C; 1H NMR (300 MHz, Chloroform-
d): d 10.48 (d, J = 15.6 Hz, 1H, CH=CHCO2H), 10.21 (s,
1H, meso-H), 9.55 (d, J = 4.9 Hz, 2H, b-H), 9.31 (d, J =
4.7 Hz, 2H, b-H), 9.08 (d, J = 4.9 Hz, 2H, b-H), 9.02 (d,
J = 4.7 Hz, 2H, b-H), 7.86–7.77 (m, 4H, 10,20-Ar-o-H),
7.69 (dd, J = 8.3, 7.4 Hz, 2H, 10,20-Ar-m-H), 7.38 (dd,
J = 8.3, 2.6, 1.1 Hz, 2H, 10,20-Ar-p-H), 6.89 (d, J =
15.6 Hz, 1H, CH=CHCO2Glu), 6.74 (d, J = 3.6 Hz, 1H,
Glu-H1) 5.80–5.68 (m, 1H, Glu-H4), 5.34–5.26 (m, 2H,
Glu-H6), 4.43–4.32 (m, 2H, Glu-H5 and H2), 4.27–4.17
(m, 1H, Glu-H5), 4.02 (s, 6H, OCH3), 2.18 (s, 3H, OAc),
2.14 (s, 3H, OAc), 2.08 (s, 3H, OAc), 2.05 (s, 3H, OAc),
1
furnishing 15.6 mg of porphyrin 8 (78%). H NMR
(300 MHz, DMSO-d6): d 10.54 (s, 1H, meso-H), 10.26 (d,
J = 15.7 Hz, 1H, CH=CHCO2), 9.65 (d, J = 4.9, Hz, 2H,
b-H), 9.58 (d, J = 4.7 Hz, 2H, b-H), 9.00 (m, 4H, b-H),
7.84–7.73 (m, 6H, 10,20-Ar-o and m-H), 7.56–7.40 (m,
2H, 10,20-Ar-p-H), 6.83 and 6.81 (2 d, 1H, CH=CHCO2
and CH=CHCO2, respectively), 6.70 (d, 0.39H, 6.7 Hz,
Gal-b-H), 6.36 (d, J = 4.7 Hz, 0.59H, Gal-a-H), 5.36–
5.24 (m, 0.22H, Gal-H) 5.06 (d, J = 4.6, Hz, 0.64 H,
Copyright © 2019 World Scientific Publishing Company
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SYNTHESIS AND CHARACTERIZATION OF NOVEL 5-MONOCARBOHYDRATE-10,20-BIS-ARYL-PORPHYRINS
5
1
Gal-H), 4.85–4.73 (m, 1.72 H, Gal-H), 4.63 (d, J = 5.5
1a
2a
3a
Hz, 0.53 H, Gal-H), 4.51 (t, J = 5.8 Hz, 1.67H, Gal-H),
4.44–4.28 (m, 1.62H, Gal-H), 3.99 (s, 6H, OCH3), 3.92
0.8
0.6
0.4
0.2
0
4
5
6
7
8
(d, J = 4.5 Hz, 1.07 H, Gal-H), 3.85–3.77 (m, 0.63H, Gal-
H), 3.76–3.57 (m, 1.41H, Gal-H), -3.08 (s, 2H, NH); 13C
NMR (75 MHz, DMSO-d6): d 165.2, 157.9, 145.5, 142.0,
128.1, 127.4, 120.4, 119.8, 113.8, 112.5, 97.5, 92.8, 73.1,
71.9, 69.5, 69.1, 68.6, 67.9, 55.4 (OCH3); HRMS (ESI)
found: 755.2700, calcd. for C43H39N4O9: 755.2711) [M +
H+]; UV-vis (DMF) lmax. (log e): 418 (5.11) 514 (3.62),
553 (3.40), 591 (3.19), 650 (2.99); Fluorescence (DMF):
l(em. máx) = 659, 720 nm (lexc = 418 nm).
450 500 550 600 650 700
300
400
500
600
700
800
RESULTS AND DISCUSSION
Wavelength (nm)
The synthetic strategy giving access to the mono
substituted gluco- and galacto-porphyrin derivatives
5–8 is summarized in Schemes 1–3. The synthesis of
5,15-bis(3-methoxyphenyl)porphyrin(1a)startedwiththe
preparation of the meso-unsubstituted dipyrromethane by
amethoddescribedintheliterature[42].Thecondensation
of this dipyrromethane with 3-methoxybenzaldehyde
in presence of trifluoroacetic acid (TFA) furnished
1a after oxidation of the intermediary porphyrinogen
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
(Scheme 1, Figs S1–S5) [43, 44].
Then, before the formylation step, porphyrin 1a was
metallated with nickel acetate in DMF at 120°C for 6 h.
After completion, the UV-vis profile showed the expected
Soret band at 400 nm and two Q bands at 513 and
545 nm (Fig. 1). This data is consistent with an increase
in symmetry of the final product 1b corresponding to a
metallated porphyrin.
1
1b
2b
3b
0.8
0.6
0.4
0.2
0
450
500
550
600
650
700
300
400
500
600
800
Wavelength (nm)
Fig. 1. UV-vis Spectra of compounds 1a to 8
Subsequently, 1b was submitted to Vilsmeier
conditions (POCl3/DMF), accessing formyl porphyrin
2b in 79% (Scheme 2). The reaction only took place
at one meso-position judging by the spectroscopic data
(Figs S14–S18). Important features are the presence of a
resonance at 193.1 ppm in 13C NMR spectrum due to the
formyl carbon and the existence in the 1H NMR spectrum
of two distinctive singlets, one at 12.11 ppm, due to the
formyl proton, and the other at 9.72 ppm, due to the meso
proton (Figs S14–S16). Por 2b also gave the expected
+
(CH2O)n
i)
N
OCH3
H
molecular ion peak upon HRMS (ESI) analysis, M+·
=
606.1187 (Figs S17 and S18).After the introduction of the
formyl group, 2b was demetallated in the presence of TFA
and sulphuric acid, retaining the formyl functionalization
and structural integrity of the macrocycle in about 66%
yield. UV-vis analysis showed the split of the Q bands
from two to four bands, consistent with the complete
demetallation of 2a (Fig. 1; the emission profile of this
and other free-bases is illustrated in Fig. S51). Other
attempts have been made to remove the nickel from 2b
such, as the use of sulphuric acid in CH2Cl2 at variable
ratios. Nevertheless, these attempts proved unsuccessful
and provided lower yields than expected. HRMS (ESI)
analysis showed the correspondent molecular ion peak
for 2a at m/z = 551.2069 (Figs S12 and S13).
NH HN
OCH3
N
N
N
N
ii)
M
1a, M = 2H
1b, M = Ni
CHO
iii)
H3CO
i) TFA, 60ºC, 5 min., N2
ii) a) TFA, CH2Cl2, rt, 3 h; b) DDQ, 30min., rt
iii) Ni(OAc)2, DMF, 120ºC, 6h
Scheme 1. Synthesis of porphyrins 1a and 1b
Copyright © 2019 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2019; 23: 5–10

6
F. FIGUEIRA ET AL.
R
M
6.27 ppm (Fig. S24). There is a singlet at d 1.74 and 1.66
ppm related to the resonances of the CH3 of the t-Bu
for 3a and 3b, respectively. The HRMS (ESI) analysis
gave the expected protonated molecular ion peaks at m/z
649.2797 (Figs S22 and S23) for 3a and for 3b at m/z
705.1998 (Figs S27 and S28).
OMe
1b
2b
2a
H
Ni
i)
Ni
CHO
CHO
N
N
N
N
ii)
R
M
2H
2H
The removal of the ester group in 3a with a formic
acid solution at room temperature for 24 h provided 4 in
96% yield. The disappearance of the signal at 1.74 ppm
iii)
iii)
O
3a
3b
OtBu
O
1
(Fig. S29), attributed to the tert-butyl group in the H
Ni
NMR spectrum of 3a, and the presence of the protonated
molecular ion at m/z 593.21729 ((M + H)+ in the mass
spectrum confirmed the success of this deprotection step
(Figs S32 and S33).
MeO
1-4
OtBu
O
iv)
4
2H
i) a) POCl3/DMF, dry CH2Cl2,
OH
reflux, 12 h; b) K2CO3 (sat.), r.t., 3 h;
Reaction of
4 with 2,3,4,6-tetra-O-acetyl-a-D-
glucopyranosyl bromide in the presence of potassium
carbonate afforded the target compounds 5 and 6 in a
combined yield of 90% (Scheme 3).
ii) H2SO4 (conc.)/TFA, CHCl3, 30 min; iii) Ph3P=CHCO2C(CH3)3,
CH2Cl2, reflux, 6-24 h; iv) HCO2H, r.t., 7 h.
Although the initial purification of these anomers
performed over preparative TLC plates with CH2Cl2
revealed only one band, the 1H NMR evaluation showed
several overlapped peaks providing an initial insight that
a mixture of these isomers was present (Fig. 2). HRMS
(ESI) of this mixture provided a single molecular ion peak
at 923.3139 ((M + H)+), confirming the isomeric nature
of the compounds (Fig. S37). The ratio between the two
isomers was easily quantified (ca. 3:1) by comparing the
1H NMR signals of the anomeric protons at d 6.11 ppm
assigned to the major compound 5 (b-isomer) and at d
6.74 ppm attributed to the minor a-isomer (compound 6).
This allowed assignment of the inner NH protons that
appear at d -2.82 ppm to compound 5, and at d -2.81 ppm
to compound 6, while the CH=CHCO2R protons of the
ethylene spacer appear at d 6.79 ppm for compound 5
and at d 6.89 ppm for compound 6, with J = 15.7 and
15.6 Hz, respectively, as illustrated by the insets in Fig. 2.
The corresponding CH=CHCO2R protons are at d 10.43
and 10.48 ppm.
Scheme 2. Synthesis of porphyrins 1–4.
Theappendedformylgroupwasthenusedtosynthesize
derivatives 3a and 3b in almost quantitative yields
(97–100%), by reacting porphyrins 2a and 2b with tert-
butoxycarbonylmethylene)triphenylphosphorane under
Wittig conditions. The UV-vis analysis of compounds 2a
and 2b showed a slight red shift when compared with the
initial precursors (1a and 1b). This is due to the extended
p conjugation acquired with the conjugated appended
formyl group (Fig. 1).
The H and 13C NMR of 3a and 3b confirmed the
1
introduction of the ethylene spacer at position 5. The
signals attributed to these protons appear as two duplets
at d 10.23 (CH=CHCO2t-Bu) and 6.74 (CH=CHCO2t-Bu)
ppm with a coupling constant of J = 15.6 Hz in compound
3a (Fig. S19). Compound 3b exhibits the same coupling
constant and the signals are located at d 9.85 and
R
OMe
OAc
OAc
OAc
O
AcO
O
O
AcO
AcO
AcO
AcO
+
AcO
AcO
Br
AcO
AcO
NH
N
N
6 (α - isomer)
5 (β - isomer)
i)
O
HN
OR
O
ii)
HO
OH
O
O
O
iii)
O
O
O
MeO
O
HO
O
OH
OH
O
4 R = H
O
7
8
i) K2CO3, DMF, rt, 8 h; ii) EDI, DMAP, CH2Cl2, reflux, 24 h; iii) TFA/H2O (9:1), 6 h.
Scheme 3. Synthesis of compounds 5–8
Copyright © 2019 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2019; 23: 6–10

SYNTHESIS AND CHARACTERIZATION OF NOVEL 5-MONOCARBOHYDRATE-10,20-BIS-ARYL-PORPHYRINS
7
The ratio between isomers 5 and 6 of approximately
3:1 seems to indicate that the reaction proceeds mainly
through a SN2 nucleophilic substitution, where the
inversion of the anomeric carbon configuration occurs
predominantly. Nevertheless, rapid anomerization of the
b-substituted derivative takes place during the reaction,
originating a mixture of a (6) and b (5) isomers.
work-up and purification, the expected conjugate in
excellent yield (82%). The structure of this derivative
was unambiguously established by spectroscopic data,
namely NMR spectroscopy and mass spectrometry
techniques (Figs S41–S45). The removal of the
isopropylidene-protecting groups in 7 was performed
with acid hydrolysis (TFA/H2O, 9:1) at room temperature,
affording 8 after purification over preparative TLC plates
in 83% yield.
Additional purification of isomers 5 and 6 over
preparative TLC plates provided 62 and 20% of b (5)
(Figs. S34–S36) and a (6) (Figs S38–S40) isomers,
respectively. These values are in full agreement with the
In this case, 1H NMR spectra can be quite informative
in terms of the general view of the molecule since the
deprotection step performed in compound 7 results in a
much more complex 1H NMR spectrum (Figs 3 and S46).
The presence of many unresolved peaks from the
saccharide unit can be seen due to the presence of the
two anomers. In general, in glycan analysis, with the
1
ratio calculated by H NMR spectroscopy (Fig. 2). The
protons at axial positions (b-isomer) of carbohydrate
derivatives are known to resonate at higher magnetic
1
field frequencies in H NMR than the ones positioned
at equatorial positions (a-isomer) due to the anisotropic
effect [45]. For instance, the anomeric protons, in 5 (b)
and 6 (a) are displayed at d 6.11 and 6.74 ppm, with
coupling constants Jaa around 8.0 Hz and Jea around 3.7
Hz, respectively (Fig. 2). This feature provides assurance
about the final attributed structures for 5 and 6 [45].
The synthesis of 7 was initially attempted from
4 with the protected 6-iodo-galactopyranose. In this
case, the reaction required high temperatures and the
low yields achieved hampered further investigation
to obtain 7. Nonetheless, the synthesis of 7 was
subsequenty performed with direct conjugation with 1,2:
3,4-Di-O-isopropylidene-a-D-galactopyranose mediated
by activation of the carboxylic acid with 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide (EDI) in the
presence of 4-dimethylaminopyridine (DMAP). Under
these conditions, we were able to obtain, after the
1
exception of the H-signals belonging to the anomeric
protons that resonate at downfield region of the spectra
(usually located somewhere between d 5.0 and 7.0
ppm depending on the deuterated solvent used for the
characterization), all other ring protons from the most
monosaccharide types resonate squeezedly between 3.0
1
and 5.0 ppm. This can be seen through the H NMR
spectrum in solution of the galactopyranose derivative
8. Furthermore, it is possible to note a complete
disappearance of the isopropylidene moieties (d between
1.25 and 1.62) and that the a and b anomers appear in a
ratio of 6:4. The doublet signal at d 6.36 ppm (J = 4.7 Hz)
corresponds to the isomer a, and the doublet at d 6.70
ppm (J = 6.7 Hz), belongs to the equatorial H-1 of the b
derivative. The two doublets with J = 15.7 Hz at d 6.83
and 6.81 ppm are attributed to the CH=CHCO2R protons
1
Fig. 2. H NMR spectra of compounds 5 and 6. Insets: expansions where is possible to note the mixture between a and b
derivatives
Copyright © 2019 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2019; 23: 7–10

8
F. FIGUEIRA ET AL.
Fig. 3. 1H NMR spectra of compound 8. Insets: expansions where is possible to note the presence of the a and b derivatives
continuously over the course of irradiation in the presence
of 5, 6 and 8.
The singlet oxygen capabilities of compounds 5, 6
and 8 were compared against 5,10,15,20-tetraphenyl
porphyrin (TPP). While compounds 5 and 6 provided
less photo-bleaching of DPiBF than TPP, no differences
between the two isomers can be observed concerning the
singlet oxygen production. Galactose derivative 8 seems
to be slightly less efficient in singlet oxygen production
when compared with the glucose congeners 5 and 6;
however, these values only differ in 5% over the course
of 10 min.
CONCLUSION
Fig. 4. Photodecomposition of 1,3-diphenylisobenzofuran
(DPiBF) by singlet oxygen generated by porphyrin derivatives
5, 6 and 8 after irradiation with red light (6 mW/cm2), in
DMF. TPP (5,10,15,20-tetraphenylporphyrin) was used for
comparison
In conclusion, we have synthesized and characterized
new bis-aryl-porphyrins bearing in one of the meso
positions an acrylate unit linked to glucose or galactose
moieties. All the new products were obtained in
good yields. The presence of CH moieties linked at
the meso position of the porphyrinic framework and
the methodologies herein implemented open new
perspectives concerning their use in different areas of
materials research.
of both isomers (total 1 proton), with both CH=CHCO2R
protons (total 1 proton) being located under the same
doublet at d 10.26 ppm. The remaining signals, located
at down field, are attributed, as before, to the porphyrinic
framework.
The ability of the glycoporphyrins 5, 6 and 8 to
generate singlet oxygen under light irradiation was
evaluated by monitoring the photo-oxidation of
1,3-diphenylisobenzofuran (DPiBF). In this indirect
method, the decrease in the DPiBF absorption is directly
correlated to the singlet oxygen production. As shown
in Fig. 4, the DPiBF absorption at 425 nm decreased
Acknowledgments
We wish to thank Fundação para a Ciência e a
Tecnologia (FCT, Portugal), the European Union,
QREN, FEDER through Programa Operacional Factores
de Competitividade (COMPETE), QOPNA (FCT UID/
QUI/00062/2019) and CQE (FCT UID/QUI/0100/2019)
research units, financed by national funds through the
Copyright © 2019 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2019; 23: 8–10

SYNTHESIS AND CHARACTERIZATION OF NOVEL 5-MONOCARBOHYDRATE-10,20-BIS-ARYL-PORPHYRINS
9
FCT/MEC and when appropriate co-financed by FEDER
under the PT2020 Partnership Agreement. The research
contracts of F. Figueira (REF. -168-89-ARH/2018)
is funded by national funds (OE), through FCT —
Fundação para a Ciência e Tecnologia, I.P., in the scope
of the framework contract foreseen in the numbers 4, 5
and 6 of the article 23, of the Decree-Law 57/2016, of
August 29, changed by Law 57/2017, of July 19.
15. Castro KADF, Figueira F, Mendes RF, Almeida Paz
FA, Neves MdGPMS, Cavaleiro JAS, Nakagaki S,
Tomé JPC and Simões MMQ. Polyhedron 2019;
158: 478–484.
16. Pereira CF, Liu Y, Howarth A, Figueira F, Rocha
J, Hupp JT, Farha OK, Tomé JPC and Almeida
Paz FA. ACS Appl. Nano Mater. 2019; 2:
465–469.
17. Pereira CF, Figueira F, Mendes RF, Rocha J, Hupp
JT, Farha OK, Simões MMQ, Tomé JPC and Paz
FAA. Inorg. Chem. 2018; 57: 3855–3864.
18. Castro KADF, Figueira F, Mendes RF, Cavaleiro
JAS, Neves MdGPMS, Simões MMQ, Almeida-
Paz FA, Tomé JPC and Nakagaki S. ChemCatChem
2017; 9: 2939–2945.
Supporting information
Spectral analysis of compounds 1-8 (Figs S1–S52)
are given in the supplementary material. This material is
available free of charge via the Internet at http://www.
worldscinet.com/jpp/jpp.shtml.
19. Vieira C, Gomes ATPC, Mesquita MQ, Moura
NMM, Neves MGPMS, Faustino MAF andAlmeida
A. Front. Microbiol. 2018; 9: 2665–2665.
20. Alves E, Faustino MAF, Neves MGPMS, Cunha Â,
Nadais H and Almeida A. J. Photochem. Photobiol.
C 2015; 22: 34–57.
21. Fernández L, Lin Z, Schneider RJ, Esteves VI,
Cunha  and Tomé JPC. ChemPhotoChem 2018; 2:
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