New flavonoid-porphyrin conjugates via Buchwald-Hartwig amination: Synthesis and photophysical studies

Article abstract of DOI:10.1016/j.tetlet.2013.07.089

New flavonoid-porphyrin conjugates were synthesized using the cross-coupling Buchwald-Hartwig amination for the coupling of flavonoid and porphyrin moieties. A unique di-substituted flavone-porphyrin conjugate was also synthesized under similar reaction conditions for the first time. All the conjugates were fully characterized by NMR spectroscopy. The photophysical properties namely fluorescence and singlet oxygen production were evaluated considering their use for photodynamic therapy applications.

Full text of DOI:10.1016/j.tetlet.2013.07.089

Tetrahedron Letters 54 (2013) 5253–5256
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New flavonoid–porphyrin conjugates via Buchwald–Hartwig
amination: synthesis and photophysical studies
Sónia P. Lopes a, José C. J. M. D. S. Menezes a, Steffen Hackbarth b, Diana C. G. A. Pinto a,
,
⇑
Maria A. F. Faustino a, , Artur M. S. Silva a, Maria G. P. M. S. Neves a, Beate Röder b, José A. S. Cavaleiro a
⇑
a Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
b Institut für Physik, Photobiophysik, Humboldt-Universität zu Berlin, Newtonstrasse 15, 12489 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
New flavonoid–porphyrin conjugates were synthesized using the cross-coupling Buchwald–Hartwig ami-
nation for the coupling of flavonoid and porphyrin moieties. A unique di-substituted flavone–porphyrin
conjugate was also synthesized under similar reaction conditions for the first time. All the conjugates
were fully characterized by NMR spectroscopy. The photophysical properties namely fluorescence and
singlet oxygen production were evaluated considering their use for photodynamic therapy applications.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 4 June 2013
Revised 12 July 2013
Accepted 15 July 2013
Available online 23 July 2013
Keywords:
Flavonoids
Porphyrins
Buchwald–Hartwig
Photodynamic therapy
Singlet oxygen
Introduction
their interesting biological activities.8 Thus the conjugation of por-
phyrins to other important entities seems to be a good strategy to-
Porphyrin derivatives besides their important role in biological
systems are finding applications in different areas, namely in med-
icine.1 In the last two decades, the photodynamic therapy (PDT)
using porphyrin derivatives as photosensitizing biological chro-
mophores is considered as a non-invasive and efficient cancer ther-
apy.2 The medical application is the most popular example,
however, photodynamic inactivation of pathogenic microorgan-
isms is also gaining attention.3 Owing to their important applica-
tions various efforts to obtain new derivatives with improved
biological properties have been undertaken. In this perspective,
the synthesis of several porphyrin conjugates with other molecules
has been reported emphasizing that the final product has im-
proved properties with dual functions. For instance, glycoporphy-
rins, not only offer better solubility in an aqueous environment
but also improved targeting.4 Other examples can be mentioned,
like the porphyrin–ferrocene conjugates that reveal electron-trans-
fer from the ferrocene to porphyrin by changing their fluorescence
emission5 and the chalcone-porphyrin conjugates that appear to be
potential agents for cancer diagnosis wherein the chalcone moiety
induces a protective effect.6 In addition there are several reports
pointing out that flavonoids can be used in medical formulations7
and among them flavones are the most interesting ones due to
ward the discovery of new drugs. Recently we reported the
synthesis of novel flavone-dihydroporphyrin conjugates,9 there-
fore we decided to focus our interest in the synthesis of new
flavonoid–porphyrin conjugates. Considering that the Buchwald–
Hartwig palladium-catalyzed amination is a powerful approach
to conjugate porphyrin with other molecules via carbon–nitrogen
bonds,10 herein we describe the first application of this methodol-
ogy to obtain new molecules incorporating porphyrin and flavo-
noid moieties.
Results and discussion
The flavonoids used as starting compounds were synthesized by
previously reported procedures, wherein the aldol condensation of
20-hydroxyacetophenone with 4-bromobenzaldehyde afforded the
4-bromo-20-hydroxychalcone 1, which is transformed into 4-bro-
moflavone 2 by cyclodehydrogenation (Fig. 1).11 The amino por-
phyrins (2-amino-5,10,15,20-tetraphenylporphyrinato)-nickel(II)
3 and [5-(4-aminophenyl)-10,15,20-triphenylporphyrinato]zinc(II)
4, were also prepared according to known procedures12 in which
the 5,10,15,20-tetraphenylporphyrin (TPP)13 is used as the starting
porphyrin.
The synthetic strategy to prepare the new flavonoid–porphyrin
conjugates was based on the Buchwald–Hartwig palladium-cata-
⇑
Corresponding authors. Tel.: +351 234 401 407; fax: +351 234 401 470.
E-mail addresses: diana@ua.pt (D.C.G.A. Pinto), faustino@ua.pt (M.A.F. Faustino).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.089

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S. P. Lopes et al. / Tetrahedron Letters 54 (2013) 5253–5256
Figure 1. Flavonoid derivatives used in this study.
Scheme 2. Synthetic strategy to prepare flavonoid–porphyrin conjugates at meso-
position.
as the reagent the desired conjugate 10 was obtained in 65% yield.
Traces of a byproduct were also isolated from the reaction mixture.
The 1H NMR spectra indicated the presence of two flavone units
and showed the absence of the singlet due to the amino group
NH, furthermore a peak at 1131 [M+Å] in its MS spectra confirmed
that it was the di-substituted compound 11.17 Prolonged reaction
times (67 h vs 23 h) led to an inversion of the reaction mixture
composition, wherein the di-substituted derivative 11 was ob-
tained as the main product (45%) while the desired conjugate 10
was obtained in 11% yield (Scheme 2). It was possible to prepare
the di-substituted derivative 11 as the main product by the reac-
tion of conjugate 10 with 40-bromoflavone 2 under the same reac-
tion conditions. The above mentioned results indicate that
porphyrin 4 is slightly less reactive than porphyrin 3 but leads to
an unusual double amination.18
The structures of the new conjugates were confirmed by 1D and
2D NMR spectroscopy and mass spectrometry.16,17,19 The 1H NMR
spectra of conjugates 5 and 6 are similar and are consistent with
b-substituted porphyrins, showing the singlet of proton H-3 reso-
nance at d 8.42 and 8.37 ppm, respectively, and the other six b-pyr-
rolic proton resonances at d 8.54–8.71. Other important features
are the singlets due to the amino NH at d 6.57 and 6.55 ppm,
respectively for conjugates 5 and 6. Finally the characteristic sig-
nals due to the flavonoid moiety, which are: (i) the singlet due to
proton H-300 at d 6.74 and the double doublet due to proton H-500
at d 8.24, both distinctive of the flavone moiety; and (ii) the dis-
tinctive signals of the chalcone moiety, singlet due to the 200-OH
proton at d 12.89 and the vinylic system doublets at d 7.49 and
Scheme 1. Synthetic strategy to prepare flavonoid–porphyrin conjugates at b-
position.
lyzed amination, using the established conditions for the coupling
of porphyrins with bromobenzene derivatives.14
Accordingly the reactions of porphyrin 3 with 4-bromo-20-
hydroxychalcone 1 and 4-bromoflavone 2 were carried out in dry
toluene, in the presence of the catalytic system Pd(OAc)2, rac-BIN-
AP as the phosphine ligand, and using KOtBu as the base
(Scheme 1).15 The reactions were monitored by TLC and ended
after the consumption of the starting porphyrin. The reaction with
4-bromoflavone 2 gave the desired conjugate 5 in an overall yield
of 91%. The reaction with 4-bromo-20-hydroxychalcone 1 afforded
after a careful chromatographic separation the desired conjugate 6
in 51% and a secondary product in 15% yield. The mass spectrum of
this byproduct shows a peak at m/z 907 [M+Å] identical to the mass
observed for conjugate 6.16 However, the 1H NMR shows in the ali-
phatic region at d 5.42 a double doublet characteristic of a flava-
none H-200 and the two double doublets characteristic of the
flavanone H-300 protons at d 3.15 and 2.88 ppm. The coupling con-
stants (Jgeminal = 16.9 Hz, Jvicinal = 13.4 and 2.8 Hz) also point out the
presence of a flavanone moiety linked to the porphyrin as proposed
in structure 7 (Scheme 1). This byproduct formation can be due to
the known equilibrium between 20-hydroxichalcone and flavanone
nucleus that can be favored under the coupling conditions. At-
tempts to improve the outcome of chalcone coupling were not
successful.
7.87 ppm due to H-a and H-b, respectively showing a coupling
constant of J 15.4 Hz, consistent with a trans configuration. Besides
that, 13C NMR spectra of conjugates 5 and 6 also exhibit signals at d
178.3 and 193.7 ppm due to the carbonyl resonances of the flavone
and chalcone moieties. The 1H NMR spectra of conjugates 8 and
1019 which are linked at the 4-position of meso-phenyl group of
the porphyrin are very similar. In addition to the characteristic sig-
nals of the flavone and chalcone moieties, the eight b-pyrrolic pro-
tons appear at d 8.95–9.05 as well as a broad singlet due to NH
proton at d 6.47 and 6.39 ppm. The most significant feature, the
AB system due to the protons of the para-substituted 5-phenyl
The methodology was extended to the zinc(II) porphyrin 4 bear-
ing the amino group as the meso-phenyl substituent. The inner
core of the macrocycle was protected by zinc in order to avoid met-
allation by palladium. The reaction with chalcone 1 afforded the
expected conjugate 8 in 31% yield (Scheme 2). The formation of
the flavanone–porphyrin conjugate 9 (ꢀ5% yield), was also ob-
served as in the case of b-aminoporphyrin derivative 3, which
was confirmed by its 1H NMR spectra and a peak at m/z 913
[M+Å] in the mass spectrum. When 40-bromoflavone 2 was used
group, in which the ortho-protons resonated at
d 8.20 and
8.18 ppm and the meta at d 7.58 and 7.53 ppm was observed.

S. P. Lopes et al. / Tetrahedron Letters 54 (2013) 5253–5256
5255
To be considered for use in any photodynamic procedure the
ability of the compound to generate singlet oxygen (1O2) is essen-
tial taking into account that the 1O2 is the main reactive oxygen
species (ROS) responsible for cell death.22 Therefore, fluorescence
quantum yields (Ufl) and singlet oxygen quantum yields (UD) were
determined. The methods used—steady state absorption and fluo-
rescence as well as time resolved singlet oxygen luminescence
detection have been described.23 The steady state fluorescence
spectra were measured in DMF solutions under normal air condi-
tions with an OD = 0.02 at kexc = 550 and 580 nm for all conjugates
with the flavonoids linked at the meso- or b-pyrrolic positions of
the porphyrin macrocycle, respectively. The fluorescence emission
spectra of the conjugates are characterized by two emission bands
(Fig. 2). The fluorescence maxima of flavonoid–porphyrin appear at
around 610 nm for the zinc derivatives and around 660 nm for all
free bases (M = 2H).
Figure 2. Representative normalized absorption (solid) and fluorescence spectra
(dotted) (kexc = 550 nm, OD = 0.02) of flavonoid–porphyrin conjugate 17 in DMF.
The fluorescence quantum yields for the meso-substituted free-
base conjugates 15–18 reach values between 14% and 19%, for the
Zn(II) conjugates 8–11 between 2% and 8%. The coupling of the fla-
vone moiety to the meso-position of the porphyrin macrocycle
leads to an increased fluorescence (TPP, Ufl = 11%).24 Moreover,
the lower Ufl of the Zn(II) complexes has already been observed
in other Zn derivatives.25 The conjugates with flavonoid moieties
linked at the b-position 12–14 show low fluorescence emission
(4–5%) compared with those in the meso position.
The ability of all conjugates to generate singlet oxygen was also
evaluated in DMF using TPP as a standard. TPP is known to be a
good singlet oxygen generator (UD = 68% in DMF).26 From the re-
sults obtained (Fig. 3), we can see that all conjugates are capable
to generate singlet oxygen, although the coupling of the flavonoid
units to the porphyrin induced different effects. For instance, the
presence of the chalcone or flavanone moieties, in both positions,
reduced the ability of these derivatives to produce singlet oxygen
resulting in the UD values of 22–56%. Otherwise, the coupling of
the flavone moiety, particularly in the meso-position, increases
the UD to values between 67% for the flavone–porphyrin conjugate
17 and 83% for conjugate 10.
Considering the potential application of these new flavonoid–
porphyrin conjugates in medicine, namely in PDT, we carried out
the decomplexation of all synthesized compounds (Scheme 1 and
2).20 For this, conjugates 5 and 6 which are linked at the b-pyrrolic
position of the Ni(II) porphyrin were treated with 10% concen-
trated sulfuric acid in chloroform and the desired free bases 12
and 13 were obtained in 89% and 39% yields, respectively. It is
worth mentioning that during the decomplexation of conjugate 6
the formation of the corresponding flavanone–porphyrin conjugate
14 was observed in 29% yield (Scheme 1). The demetallation of zinc
ion from the flavonoid–porphyrin conjugates 8 and 10, was
achieved using 5% of trifluoroacetic acid in chloroform. In this case
the desired derivatives 15 and 17 were obtained in 70% and 82%
yields, respectively, and the formation of the flavanone–porphyrin
conjugate 16 was also observed (9%) (Scheme 2). The decomplex-
ation of the conjugate 11 obtained led to the formation of conju-
gate 18 in 91% yield. The structure of these free base derivatives
was confirmed by various means. In UV–Vis spectroscopy, all free
base derivatives present four Q bands (Fig. 2). The 1H NMR analysis
showed the inner NH of the macrocycle confirming the removal of
the metal ion from the inner core. Besides that the samples were
also analyzed by mass spectrometry.21
In summary, this work successfully accomplished for the first
time the coupling of flavonoid and porphyrin moieties and a novel
di-substituted flavone–porphyrin conjugate using the cross-cou-
Figure 3. Plot of the singlet oxygen quantum yield (UD) of the flavonoid–porphyrin conjugates versus their fluorescence quantum yield (Ufl) in DMF. The interception of the
dotted lines represents the value of the standard (TPP).

5256
S. P. Lopes et al. / Tetrahedron Letters 54 (2013) 5253–5256
J = 15.4 Hz, H-b), 7.81–7.78 (m, 1H, 20-H-p-Ph), 7.75–7.72 (m, 2H, 20-H-m-Ph),
7.67–7.64 (m, 9H, 5,10,15-H-m,p-Ph), 7.53 (d, 2H, J = 8.7 Hz, H-30,50), 7.49 (d,
pling Buchwald–Hartwig amination. The study of the photophysi-
cal properties reveals that most of the conjugates present fluores-
cence and good capacity to generate singlet oxygen, making these
compounds possible candidates to be used as photosensitizers in
PDT or in fluorescence diagnosis. Further design and investigation
of new flavonoid–porphyrin conjugates in biological systems will
be performed to validate these preliminary results.
1H, J = 15.4 Hz, H-a
), 7.46–7.44 (m, 1H, H-4000), 7.01 (dd, 1H, J = 8.4, 1.1 Hz, H-
3000), 6.91 (ddd, 1H, J = 8.1, 7.1, 1.1 Hz, H-5000), 6.87 (d, 2H, J = 8.7 Hz, H-20,60),
6.55 (br s, 1H, NH); 13C NMR (CDCl3, 125.77 MHz): d 193.7 (C-100), 163.7 (C-2000),
145.4 (C-b), 145.2, 144.1, 143.30, 143.26, 143.16, 142.7, 142.6, 142.1, 141.7,
141.2, 140.9, 140.8, 139.9, 135.9 (C-4000), 133.7, 133.6, 133.57, 133.5, 132.9,
132.6, 132.1, 132.0, 131.72, 131.70, 131.0, 130.6, 129.5 (C-6000), 128.9, 128.5,
127.86, 127.83, 126.79, 127.1, 126.93, 126.91, 127.0, 120.5, 120.2 (C-1000), 118.9,
118.7 (C-5000), 118.6 (C-3000), 116.9 (C-
a), 116.7, 115.8, 115.7, 114.5 (C-3); UV–
Vis (DMF), kmax (log e): 277 (4.3), 414 (5.1), 538 (4.2), 585 (4.4) nm; HRMS ESI:
Acknowledgments
m/z calcd for C59H39N5NiO2 [M+Å]: 907.2457; found: 907.2452.
17. Conjugate 11: 1H NMR (CDCl3, 300.13 MHz): d 9.07 and 9.02 (AB, 4H, J = 4.7 Hz,
H-bpyrrolic), 8.96 (s, 4H, H-bpyrrolic), 8.26–8.19 (m, 10H, 5,10,15,20-H-o-Ph and
2 ꢁ H-500), 8.01 (d, 4H, J = 8.9 Hz, 2 ꢁ H-30,50), 7.80–7.75 (m, 9H, 10,15,20-H-
m,p-Ph), 7.75–7.70 (m, 2H, 2 ꢁ H-700), 7.62–7.58 (m, 4H, 5-H-m-Ph and 2 ꢁ H-
800), 7.57 (d, 4H, J = 8.9 Hz, 2 ꢁ H-20,60), 7.46-7.41 (m, 2H, 2 ꢁ H-600), 6.80 (s, 2H,
Thanks are due to Fundação para a Ciência e a Tecnologia (FCT,
Portugal), European Union, QREN, FEDER, and COMPETE for fund-
ing the QOPNA research unit (project PEst-C/QUI/UI0062/2013).
JCJMDS Menezes thanks QOPNA for a research grant.
13
2 ꢁ H-300); C NMR (125.77 MHz, CDCl3) d 177.2 (C-400), 167.3 (C-200), 150.3,
145.6 (C-900), 134.5, 133.7 (C-700), 132.2, 132.12, 132.1, 131.6, 127.9, 127.5 (C-
500), 126.6 (C-600), 125.2; 124.0 and 123.97 (C-800 and C-1000), 123.8, 121.3,
121.27, 118.0, 106.6 (C-300), 103.6; UV–Vis (DMF), kmax (log
e): 306 (4.5), 426
References and notes
(5.7), 559 (4.4), 600 (4.1) nm; HRMS ESI: m/z calcd for C74H45N5O4Zn [M+Å]:
1131.2750; found: 1131.2758.
1. Milgrom, L. R. The Colours of Life: An Introduction to the Chemistry of Porphyrins
and Related Compounds; Oxford University Press, 1997.
18. The converse process using bromo substituted TPP with disubstituted amine
has been reported (a) Gao, G.-Y.; Chen, Y.; Zhang, X. P. J. Org. Chem. 2003, 68,
6215–6221; (b) Gao, G.-Y.; Ruppel, J. V.; Allen, D. B.; Chen, Y.; Zhang, X. P. J. Org.
Chem. 2007, 72, 9060–9066.
2. (a) Yano, S.; Hirohara, S.; Obata, M.; Hagiya, Y.; Ogura, S.; Ikeda, A.; Kataoka, H.;
Tanaka, M.; Joh, T. J. Photochem. Photobiol. C 2011, 12, 46–67; (b) Nyman, E. S.;
Hynninen, P. H. J. Photochem. Photobiol. B: Biol. 2004, 73, 1–28; (c) Allison, R. R.;
Downie, G. H.; Cuenca, R.; Hu, X.; Childs, C. J. H.; Sibata, C. H. Photodiagn.
Photodyn. Ther. 2004, 1, 27–42; (d) Ethirajan, M.; Chen, Y.; Joshi, P.; Pandey, R.
K. Chem. Soc. Rev. 2011, 40, 340–362.
3. Almeida, A.; Cunha, A.; Faustino, M. A. F.; Tomé, A. C.; Neves, M. G. P. M. S.
Porphyrins as Antimicrobial Photosensitizing Agents. In Photodynamic
Inactivation of Microbial Pathogens: Medical and Environmental Applications;
Hamblin, M. R., Jori, G., Eds.; Royal Society of Chemistry: London, 2011.
4. Cavaleiro, J. A. S.; Faustino, M. A. F.; Tomé, J. P. C. Carbohydr. Chem. 2009, 35,
199–231.
5. Shetti, V. S.; Ravikanth, M. Eur. J. Org. Chem. 2010, 494–508.
6. Vaz-Serra, V.; Camões, F.; Vieira, S. I.; Faustino, M. A. F.; Tomé, J. P. C.; Pinto, D.
C. G. A.; Neves, M. G. P. M. S.; Tomé, A. C.; Silva, A. M. S.; da Cruz e Silva, E. F.;
Cavaleiro, J. A. S. Acta Chim. Slov. 2009, 56, 603–611.
7. Voskresensky, O. N.; Levitsky, A. P. Curr. Med. Chem. 2002, 9, 1367–1383.
8. Verma, A. K.; Pratap, R. Nat. Prod. Rep. 2010, 27, 1571–1593.
9. Sousa, R. M. S.; Pinto, D. C. G. A.; Silva, A. M. S.; Vaz Serra, V.; Barros, A. I. R. N.
A.; Faustino, M. A. F.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. Eur. J. Org. Chem.
2012, 132–143.
19. Conjugate 10: 1H NMR (CDCl3, 300.13 MHz): d 9.05 and 8.96 (AB, 4H, J = 4.7 Hz,
H-bpyrrolic), 8.95 (br s, 4H, H-bpyrrolic), 8.25–8.21 (m, 6H, 10,15,20-H-o-Ph), 8.20
(d, 2H, J = 8.4 Hz, 5-H-o-Ph), 8.15 (dd, 1H, J = 7.9, 1.5 Hz, H-500), 7.96 (d, 2H,
J = 8.8 Hz, H-30,50), 7.79–7.75 (m, 9H, 10,15,20-H-m,p-Ph), 7.72–7.66 (m, 1H, H-
700), 7.61–7.56 (m, 1H, H-800), 7.58 (d, 2H, J = 8.4 Hz, 5-H-m-Ph), 7.47 (d, 2H,
J = 8.8 Hz, H-20,60), 7.43–7.38 (m, 1H, H-600), 6.70 (s, 1H, H-300), 6.47 (br s, 1H,
NH); 13C NMR (CDCl3, 75.47 MHz): d 179.4 (C-400), 164.8 (C-200), 156.3, 150.2,
150.13, 150.1, 147.9, 143.5, 143.4, 140.5 (C-900), 137.7, 135.7, 134.6, 134.0 (C-
700), 131.7, 128.3, 127.3, 126.4, 125.43 (C-600), 125.35 (C-500), 123.7 (C-1000),
121.7, 120.7, 120.3, 120.1 (C-800), 118.1, 117.6, 115.8, 104.6 (C-300); UV–Vis
(DMF), kmax (log e): 302 (4.5), 428 (5.6), 560 (4.3), 600 (4.2) nm; HRMS (ESI): m/
z calcd for C59H37N5O2Zn [M+Å]: 911.2239; found: 911.2233.
20. General procedure: To a CHCl3 solution of each metallo-conjugate was added
10% H2SO4 [for Ni(II) complex] or 5% TFA [for Zn(II)] and stirred at room
temperature for about 20–30 min. The reaction mixture was poured into cold
water, neutralized with a saturated aqueous solution of NaHCO3, washed
several times with water, and extracted with CHCl3. The organic layer was
dried over Na2SO4 and the solvent removed under reduced pressure. Further
purification using preparative TLC, using a mixture of light petroleum and
chloroform (1:2) as a solvent, afforded the desired free base conjugates.
21. Conjugate 12: 1H NMR (CDCl3, 300.13 MHz): d 8.86 (AB, 1H, J = 4.9 Hz, H-
bpyrrolic), 8.82 (AB, 1H, J = 4.9 Hz, H-bpyrrolic), 8.79 (AB, 1H, J = 4.9 Hz, H-bpyrrolic),
8.76 (s, 2H, H-bpyrrolic), 8.62 (AB, 1H, J = 4.9 Hz, H-bpyrrolic), 8.43 (s, 1H, H-3),
8.25–8.17 (m, 9H, 5,10,15,20-H-o-Ph and H-500), 8.00–7.93 (m, 1H, 20-H-p-Ph),
7.92–7.87 (m, 2H, 20-H-m-Ph), 7.86 (d, 2H, J = 8.8 Hz, H-30,50), 7.80–7.73 (m,
9H, 5,10,15-H-m,p-Ph), 7.72–7.67 (m, 1H, H-700), 7.57 (dd, 1H, J = 8.4, 0.94 Hz,
H-800), 7.42 (ddd, 1H, J = 8.0, 7.0, 0.9 Hz, H-600), 7.04 (d, 2H, J = 8.8 Hz, H-20,60),
6.82 (br s, 1H, NH), 6.76 (s, 1H, H-300), ꢂ2.63 (br s, 2H, H-21 and H-23); 13C NMR
(CDCl3, 75.47 MHz): d 178.4 (C-400), 163.4 (C-200), 156.2 (C-900), 145.5, 142.6,
142.1, 141.8, 140.8, 134.5, 134.4, 134.2, 133.5 (C-700), 133.2, 129.9, 129.2, 128.6,
127.9, 127.8, 127.7, 126.9, 126.8, 126.7, 125.7, 125.0 (C-500), 124.0 (C-600), 123.0
(C-1000), 121.4, 120.2, 118.2, 117.9 (C-800), 116.4, 115.7, 105.6 (C-3); UV–Vis
10. Menezes, J. C. J. M. D. S.; Pereira, A. M. V. M.; Neves, M. G. P. M. S.; Silva, A. M. S.;
Santos, S. M.; Martinez, S. T.; Silva, B. V.; Pinto, A. C.; Cavaleiro, J. A. S.
Tetrahedron 2012, 68, 8330–8339.
11. The starting flavonoids 1 and 2 were prepared according to known procedures:
(a) Silva, A. M. S.; Tavares, H. R.; Barros, A. I. N. R. A.; Cavaleiro, J. A. S. Spectrosc.
Lett. 1997, 30, 1655–1667; (b) Barros, A. I. N. R. A.; Silva, A. M. S. Monatsh. Chem.
2006, 137, 1505–1528.
12. The starting porphyrins
3 and 4 were prepared according to known
procedures: (a) Richeter, S.; Jeandon, C.; Gissilbrecht, J.-P.; Graff, R.; Ruppert,
R.; Callot, H. Inorg. Chem. 2004, 43, 251–263; (b) Hombrecher, H. K.; Gherdan,
V. M.; Ohm, S.; Cavaleiro, J. A. S.; Neves, M. G. P. M. S.; Condesso, M. F.
Tetrahedron 1993, 49, 8569–8578; (c) Luguya, R.; Jaquinod, L.; Fronczek, F. R.;
Vicente, M. G. H.; Smith, K. M. Tetrahedron 2004, 60, 2757–2763.
13. TPP was prepared according to known procedures: De Paula, R.; Pinto, D.;
Faustino, M. A. F.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. J. Heterocycl. Chem.
2008, 45, 453–459.
(DMF), kmax (log e): 306 (4.3), 414 (5.3), 459 (4.8), 523 (4.4), 599 (4.0), 656 (3.5)
nm; HRMS (ESI): m/z calcd for C59H40N5O2 [M+H]+: 850.3173; found: 850.3177.
22. Bonnett, R. Chemical Aspects of Photodynamic Therapy; Gordon and Breach
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14. Pereira, A. M. V. M.; Alonso, C. M. A.; Neves, M. G. P. M. S.; Tomé, A. C.; Silva, A.
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15. General procedure: To a mixture of porphyrin:flavonoid in the ratio (1:2)
dissolved in dry toluene were added Pd(OAc)2 (0.29 equiv), rac-BINAP
(0.25 equiv), and KOtBu (2.13 equiv). The mixture was stirred at 95–110 °C
until all porphyrin derivatives were consumed. The mixture was filtered
through a CeliteÒ-545 column, extracted with CHCl3, washed, and dried over
anhydrous sodium sulfate. The residue obtained was chromatographed by
preparative thin layer chromatography (TLC) using CHCl3 as solvent.
16. Conjugate 6: 1H NMR (CDCl3, 500.13 MHz): d 12.89 (br s, 1H, OH), 8.6812 and
8.6809 (AB, 2H, J = 5.0 Hz, H-bpyrrolic), 8.66 and 8.61 (AB, 2H, J = 5.0 Hz, H-
bpyrrolic), 8.64 and 8.54 (AB, 2H, J = 4.9 Hz, H-bpyrrolic), 8.37 (s, 1H, H-3), 8.00–
7.95 (m, 8H, 5,10,15,20-H-o-Ph), 7.90 (dd, 1H, J = 8.1, 1.7 Hz, H-6000), 7.87 (d, 1H,
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