Tuning photosensitized singlet oxygen generation efficiency of novel Aza-BODIPY dyes

Article abstract of DOI:10.1021/ol102562k

Novel aza-BODIPY derivatives substituted with heavy atoms such as bromine and iodine were synthesized, and their triplet and singlet oxygen generation efficiencies have been investigated. These derivatives showed absorption in the NIR region with high mol

Full text of DOI:10.1021/ol102562k

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5720-5723
Tuning Photosensitized Singlet Oxygen
Generation Efficiency of Novel
Aza-BODIPY Dyes
Nagappanpillai Adarsh, Rekha R. Avirah, and Danaboyina Ramaiah*
Photosciences and Photonics, Chemical Sciences and Technology DiVision,
National Institute for Interdisciplinary Science and Technology, CSIR,
TriVandrum -695 019, Kerala, India
rama@niist.res.in; d_ramaiah@rediffmail.com
Received October 22, 2010
ABSTRACT
Novel aza-BODIPY derivatives substituted with heavy atoms such as bromine and iodine were synthesized, and their triplet and singlet oxygen
generation efficiencies have been investigated. These derivatives showed absorption in the NIR region with high molar extinction coefficients.
The dye substituted with four iodine atoms showed yields of ΦT ) 0.78 and Φ(1O2) ) 0.70, which are the highest values so far obtained for
the aza-BODIPY derivatives.
Photosensitized generation of singlet oxygen O2(a1∆g) is a
well studied phenomenon, which has found numerous
applications from synthetic organic chemistry to wastewater
treatment to photodynamic cell death.1 Triplet sensitization
have inherent intersystem crossing efficiency and thereby
good singlet oxygen generation efficiency viz. phthalocya-
nines, chlorins, bacteriochlorins, and related systems.4 Re-
cently, Wu et al.4b have reported di(perylenebisimide)s with
exceptional intersystem crossing efficiency. In contrast, the
design of sensitizers such as squaraine5 and BODIPY6 dyes
with high triplet quantum yields has been quite challenging
for their potential applications.
-
of molecular oxygen O2(X3Σg ) is the most commonly
employed method for generating singlet oxygen.2 The energy
transfer to molecular oxygen, yielding the singlet oxygen,
occurs most efficiently from the triplet state of the sensitizer.
The probability of the intersystem crossing, S1 f T1, in the
sensitizer can be enhanced through spin-orbit perturbations
by incorporating heavy atoms.3 A number of organic ligands
The 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes, abbrevi-
ated as BODIPYs, hold great promise as ideal sensitizers
owing to their favorable properties such as high stability,
absorption, and emission in the NIR region; high extinction
coefficients and fluorescence quantum yields; and negligible
(1) (a) DeRosa, M. C.; Crutchley, R. J. Coord. Chem. ReV. 2002,
233-234, 351–357, and references therein. (b) Greer, A. Acc. Chem. Res.
2006, 39, 797–804.
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(b) Koziar, J. C.; Cowan, D. O. Acc. Chem. Res. 1978, 334–341.
(3) Sauerwein, B.; Schuster, G. B. J. Phys. Chem. 1991, 95, 1903–1906.
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J. Phys. Chem. Lett. 2010, 1, 2499–2502.
10.1021/ol102562k  2010 American Chemical Society
Published on Web 11/19/2010

photobleaching.7 Because of these reasons, in recent years
there has been increased interest in the derivatization of the
BODIPY dyes for various applications.8-10 Recent works
by various research groups have demonstrated that aza-
BODIPY dyes can generate singlet oxygen and thus act as
efficient photodynamic therapeutic agents.11 However, the
triplet quantum yields and the singlet oxygen generation
efficiency of those dyes were found to be relatively low.
Herein, we report the synthesis and photophysical charac-
terization of novel boron complexes of aza-dipyrromethenes
(aza-BODIPYs) substituted with heavier halogen atoms such
as bromine and iodine. By heavy atom substitution, we have
been able to obtain a triplet quantum yield of 0.78 and singlet
oxygen generation efficiencies as high as 70%. As far as we
know these values are the highest reported so far for aza-
BODIPY derivatives.
Scheme 1. Synthesis of Aza-BODIPY Derivatives
Scheme 1 summarizes the synthetic strategy adopted for
the synthesis of various aza-BODIPY derivatives 4a-b and
5b. The compounds 4a-b were synthesized in a facile three-
step route starting from the chalcones 1a-b. Addition of
nitromethane to the chalcone in the presence of diethylamine
gave the addition products 2a-b in ca. 75-80% yields.
Subsequently, the condensation products 3a-b were gener-
ated by refluxing 2a-b with ammonium acetate in ethanol
for 48 h. The product precipitated during the course of the
reaction was filtered and recrystallized to yield 3a-b
(40-50%) with a violet metallic luster. The azadipyr-
romethenes 3a-b were subsequently converted to the
targeted aza-BODIPY derivatives 4a-b by modifying the
reported procedure.6d This was achieved by refluxing 3a-b
with boron trifluoride diethyl etherate and triethyl amine in
toluene for 5 h to give 4a-b in quantitative yields (75-80%)
after purification through column chromatography.
With the goal of improving the intersystem crossing
efficiency and hence the singlet oxygen generation by the
aza-BODIPY derivatives, we introduced heavy atoms such
as iodine in the pyrrole ring. This was achieved by reacting
4b with 4.5 equiv of N-iodosuccinimide in a 3:1 mixture of
chloroform/acetic acid at 25 °C for 10 h. The reaction
mixture after evaporation of the solvent was subjected to
column chromatography to yield the iodo substituted aza-
BODIPY derivative 5b in 65% yield. All these derivatives
were characterized by various spectral and analytical tech-
niques (Figures S1-S5, Supporting Information).
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George, M. V. Photochem. Photobiol. 1997, 65, 783–790. (b) Jyothish, K.;
Avirah, R. R.; Ramaiah, D. Org. Lett. 2006, 8, 111–114. (c) Jyothish, K.;
Arun, K. T.; Ramaiah, D. Org. Lett. 2004, 6, 3965–3968. (d) Jisha, V. S.;
Arun, K. T.; Hariharan, M.; Ramaiah, D. J. Am. Chem. Soc. 2006, 128,
6024–6025. (e) Salice, P.; Arnbjerg, J.; Pedersen, B. W.; Toftegaard, R.;
Beverina, L.; Pagani, G. A.; Ogilby, P. R. J. Phys. Chem. A 2010, 114,
2518–2525. (f) Ramaiah, D.; Eckert, I.; Arun, K. T.; Weidenfeller, L.; Epe,
B. Photochem. Photobiol. 2004, 79, 99–104. (g) Arun, K. T.; Epe, B.;
Ramaiah, D. J. Phys. Chem. B 2002, 106, 11622–11627. (h) Arun, K. T.;
Ramaiah, D. J. Phys. Chem. A 2005, 109, 5571–5578.
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Soc. 2005, 127, 12162–12163. (c) Gorman, A.; Killoran, J.; O’Shea, C.;
Kenna, T.; Gallagher, W. M.; O’Shea, D. F. J. Am. Chem. Soc. 2004, 126,
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16361.
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references therein.
Aza-dipyrromethenes 3a-b are characterized by their
intense absorption in the near-infrared region of the visible
spectrum. The free ligands 3a-b showed a distinct absorp-
tion band in the 610-620 nm region with molar extinction
coefficients in the range (3-7) × 104 M-1 cm-1 (Figure S6,
Supporting Information). The incorporation of Lewis acid
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T.; Dehaen, W.; Boens, N. Org. Lett. 2005, 7, 4377–4380. (b) Haefele, A.;
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.
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Pagliuca, C.; Zhu, Z.-J.; Menichetti, S.; Rotello, V. M. J. Am. Chem. Soc.
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Wortmann, R.; Ny, T.; Johansson, L. B.-A. J. Am. Chem. Soc. 2002, 124,
+
BF2 to the ligand caused a bathochromic shift in the
absorption spectra of the aza-BODIPY derivatives 4a-b by
50-60 nm (Figure 1A). The absorption spectrum of the
compound 5b with iodo-substitution at the peripheral phenyl
rings as well as at the core showed a maximum at 666 nm.
Figure 1B shows the fluorescence spectra of 4b and 5b in
DMSO. The azadipyrromethene 3b has an emission maxi-
mum at 655 nm (Figure S7, Supporting Information), while
the aza-BODIPYs 4a-b and 5b exhibited emission in the
690-710 nm region with Stoke shifts in the range 30-40
196–204
.
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4065–4067. (b) Guliyev, R.; Coskun, A.; Akkaya, E. U. J. Am. Chem. Soc.
2009, 131, 9007–9013. (c) Bonardi, L.; Kanaan, H.; Camerel, F.; Jolinat,
P.; Retailleau, P.; Ziessel, R. AdV. Funct. Mater. 2008, 18, 401–413
.
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M. J.; Killoran, J.; O’Shea, D. F. Br. J. Cancer 2005, 92, 1702–1710. (b)
Byrne, A. T.; O’Connor, A. E.; Hall, M.; Murtagh, J.; O’Neill, K.; Curran,
K. M.; Mongrain, K.; Rousseau, J. A.; Lecomte, R.; McGee, S.; Callanan,
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Org. Lett., Vol. 12, No. 24, 2010
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Figure 1
. (A) Absorption and (B) emission spectra of the aza-
BODIPY derivatives. Excitation wavelength, 630 nm.
Figure 2. Transient absorption spectra of 5b following 355 nm
Table 1. Photophysical Properties of Various Derivativesa b
,
laser pulse excitation; time-resolved absorption spectra recorded
at (a) 0.1, (b) 0.4, (c) 1, (d) 2, (e) 4, and (f) 10 µs. Inset shows the
decay of the transient at 510 nm.
compound
λab, nm
ε, 104 M-1 cm-1
λem, nm
3a
3b
4a
4b
5b
619
617
681
664
666
7.05
3.57
5.97
3.84
6.99
c
655
772
701
694
was found to be 0.07 with a lifetime of 44 µs. Notably, when
the pyrrole ring as well as the peripheral phenyl ring was
substituted with iodine atoms, as in 5b, we could observe
significant enhancement in the triplet quantum yield to 0.78
( 0.02 with a lifetime of 1.6 µs. We have monitored the
transient absorption of 5b at 320 nm to estimate the efficiency
of the energy transfer from BODIPY to ꢀ-carotene, and this
is the highest triplet quantum yield reported so far in the
case of the aza-BODIPY derivatives.
Singlet oxygen is considered to be the main cytotoxic agent
in photodynamic therapy, and hence we have examined the
efficiency of the photosensitized singlet oxygen generation.
Quantum yields for singlet oxygen generation were deter-
mined by monitoring the dye-sensitized photooxidation of
1,3-diphenylisobenzofuran (DPBF).13 For this, a solution of
the aza-BODIPY derivative and DPBF was irradiated using
630 nm long pass over a time period of 6-600 s and the
decrease in the absorption band (e10%) of DPBF was
monitored. Yields for the generation of singlet oxygen was
calculated using the standard, methylene blue (MB), by
plotting the ∆OD of DPBF against the irradiation time
(Figure 3B).
a Average of more than two experiments. b DMSO. c Negligible
fluorescence.
nm (Table 1). Due to the presence of heavy atoms like
bromine and iodine, these derivatives have fluorescence
quantum yields less than 0.1. All the aza-BODIPY deriva-
tives have high extinction coefficients in the NIR region and
good solubility in common organic solvents such as CHCl3,
CH3CN, THF, DMSO, and DMF.
Since the photodynamic activity of the photosensitizers
is expected to involve the generation of cytotoxic agents such
as singlet oxygen, it is important to study the excited state
properties of the synthesized compounds. To characterize
the transient intermediates such as triplet excited states in
these systems, we have carried out nanosecond laser flash
photolysis studies of the aza-BODIPY derivatives in THF
solution. Figure 2 shows the transient absorption spectra of
5b. Excitation of 5b by 355 nm laser pulses (10 ns, 50 mJ/
pulse) led to the formation of transient absorption having
peaks at 320 and 510 nm with a bleach in the region
corresponding to the ground state absorption. The transient
absorption at 510 nm, which is formed within the laser pulse,
decays by a first-order process and leads to the recovery of
the ground state absorption (inset of Figure 2), indicating
negligible formation of any permanent products. This
transient absorption is readily quenched by dissolved oxygen,
suggesting that the absorption may be due to the triplet
excited state formation.5a,12a Similar transients were obtained
for 4a and 4b at 450 and 430 nm, respectively.
The azadipyrromethenes 3a-b have negligible singlet
oxygen generation efficiency. Upon complexation with BF2,
we could observe a singlet oxygen generation quantum yield
of 0.009 for the nonohalogenated aza-BODIPY, 4a (Figure
S8, Supporting Information). By the incorporation of two
bromine atoms, we could observe an increase in the quantum
(12) (a) Joseph, J.; Eldho, N. V.; Ramaiah, D. J. Phys. Chem. B 2003,
107, 4444–4450. (b) Jisha, V. S.; Arun, K. T.; Hariharan, M.; Ramaiah, D.
J. Phys. Chem. B 2010, 114, 5912–5919. (c) Kumar, C. V.; Qin, L.; Das,
P. K. J. Chem. Soc., Faraday Trans. 2 1984, 80, 783–793. (d) Joseph, J.;
Eldho, N. V.; Ramaiah, D. Chem.sEur. J. 2003, 9, 5926–5935. (e)
Hariharan, M.; Joseph, J.; Ramaiah, D. J. Phys. Chem. B 2006, 110, 24678–
24686.
The triplet quantum yields of these aza-BODIPY deriva-
tives were determined using triplet-triplet energy transfer
to ꢀ-carotene using a tris(bipyridyl)ruthenium(II) complex
as the reference.5a,12 The nonhalogenated dye 4a has a low
triplet quantum yield of 0.01 with a lifetime of 28 µs, and
the bromo derivative 4b showed a higher triplet yield which
(13) (a) Rossi, L. M.; Silva, P. R.; Vono, L. L. R.; Fernandes, A. U.;
Tada, D. B.; Baptista, M. S. Langmuir 2008, 24, 12534–12538. (b) Morone,
M.; Beverina, L.; Abbotto, A.; Silvestri, F.; Collini, E.; Ferrante, C.; Bozio,
R.; Pagani, G. A. Org. Lett. 2006, 8, 2719–2722. (c) Mirenda, M.; Strassert,
C. A.; Dicello, L. E.; Roman, E. S. Appl. Mater. Interfaces 2010, 2, 1556–
1560.
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Org. Lett., Vol. 12, No. 24, 2010

Figure 3. (A) Absorption spectra of DPBF upon irradiation in the
presence of 5b for 8 s: (a) 0 s to (b) 8 s (recorded at 2 s interval).
(B) Plot of change in absorbance of DPBF at 418 nm vs irradiation
time (λirr ) 630 nm) in the presence of 5b against methylene blue
(MB) as the standard in DMSO.
Figure 4. Relative bar diagram showing the singlet oxygen
generation quantum yields of aza-BODIPY derivatives and MB.
properties. All these derivatives showed a strong NIR
absorption in the 620-680 nm region with good molar
extinction coefficients ((3-7) × 104 M-1 cm-1). The
substitution of heavy atoms at the core as well as the
peripheral positions resulted in a significant enhancement in
the excited state properties of these derivatives. The triplet
state characteristics and singlet oxygen generation studies
suggest that the derivative 5b can act as a potential candidate
for PDT applications as well as in waste treatment plants.
The triplet quantum yield of 78% and singlet oxygen
generation efficiency of 70% exhibited by 5b are the highest
triplet and singlet oxygen generation quantum yields reported
for the aza-BODIPY derivatives. Further studies are in
progress to understand the cellular localization of various
aza-BODIPY dyes and their potential PDT applications.
yield to 0.012 for the dye 4b (Figure S9, Supporting
Information). Interestingly, we observed a significant de-
crease (e10%) in the absorption bands of DPBF (Figure 3A)
in the presence of iodinated derivative 5b within 6 s, while
the standard MB (Φ(1O2) ) 0.52) showed the corresponding
changes in 10 s (Figure S10, Supporting Information). As
evident from Figure 3B, both of the plots followed linearity.
The presence of four iodine atoms significantly enhanced
the singlet oxygen generation quantum yield, Φ(1O2), of 5b
and was calculated to be 0.70 ( 0.03. In contrast to the aza-
BODIPY derivatives reported earlier,6 5b showed the highest
singlet oxygen generation efficiency of 70%.
The resistance of these dyes to photobleaching was
investigated by irradiating an oxygen saturated solution of
5b for 2 h. We observed negligible changes in its absorption
spectrum (Figure S11, Supporting Information) confirming
the stability of the dye toward photobleaching. Figure 4
shows the relative singlet oxygen generation quantum yields
of the various azadipyrromethene and aza-BODIPY deriva-
tives. As can be seen, the derivative 5b shows the maximum
singlet oxygen generation quantum yields among the aza-
BODIPY derivatives synthesized.
Acknowledgment. This work was supported by the
Department of Science and Technology (DST), Government
of India and the National Institute for Interdisciplinary
Science and Technology (NIIST), CSIR, Trivandrum. This
is Contribution No. PPG-308 from NIIST, Trivandrum.
Supporting Information Available: Experimental details
and Figures S1-12 showing 1H NMR and spectroscopic data
of the dyes. This material is available free of charge via the
Internet at http://pubs.acs.org.
In conclusion, we have developed a few novel NIR
absorbing aza-BODIPY dyes through a high yielding syn-
thetic route and investigated their excited state photophysical
OL102562K
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