Modifying the meso-phenyl with electron donating amino groups strongly enhances BODIPY's ability as good singlet oxygen photosensitizer

Article abstract of DOI:10.1016/j.dyepig.2017.10.018

We synthesized three 1,3,5,7-tetramethyl-BODIPY (1a, 2a, 3a) and three 3,5-dimethyl-BODIPY (1b, 2b, 3b) photosensitizers, in which the meso position was modified by different para-aminophenyl groups. The singlet oxygen generation and photophysical propert

Full text of DOI:10.1016/j.dyepig.2017.10.018

Accepted Manuscript
Modifying the meso-phenyl with electron donating amino groups strongly enhances
BODIPY's ability as good singlet oxygen photosensitizer
Wenbin Hu, Xian-Fu Zhang, Xulin Lu, Shuai Lan, Dandan Tian, Tingting Li, Liangxia
Wang, Siwen Zhao, Mingna Feng, Jing Zhang
PII:
S0143-7208(17)31613-3
10.1016/j.dyepig.2017.10.018
DYPI 6316
DOI:
Reference:
To appear in: Dyes and Pigments
Received Date: 27 July 2017
Revised Date: 10 October 2017
Accepted Date: 12 October 2017
Please cite this article as: Hu W, Zhang X-F, Lu X, Lan S, Tian D, Li T, Wang L, Zhao S, Feng M, Zhang
J, Modifying the meso-phenyl with electron donating amino groups strongly enhances BODIPY's ability
as good singlet oxygen photosensitizer, Dyes and Pigments (2017), doi: 10.1016/j.dyepig.2017.10.018.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Modifying the meso-phenyl with electron donating amino groups
strongly enhances BODIPY’s ability as good singlet oxygen
photosensitizer
Wenbin Hua, Xian-Fu Zhangb,*
Xulin Lua, Shuai Lana, Dandan Tiana, Tingting Lia, Liangxia Wanga, Siwen Zhaoa,
Mingna Fenga, Jing Zhanga
a
Department of Chemical Engineering, Hebei Normal University of Science and
Technology, Qinhuangdao, Hebei Province, China, 066004
b MPC Technologies, Hamilton, Ontario, Canada L8S 3H4
*Corresponding author
E-mail addresses: zhangxianfu@tsinghua.org.cn, zhangxf111@hotmail.com
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Abstract
We synthesized three 1,3,5,7-tetramethyl-BODIPY (1a, 2a, 3a) and three
3,5-dimethyl-BODIPY (1b, 2b, 3b) photosensitizers, in which the meso position was
modified by different para-aminophenyl groups. The singlet oxygen generation and
photophysical properties of the BODIPYs were studied by UV-vis absorption spectra,
fluorescence emission spectra methods in various solvents. It was found that these
BODIPY derivatives were environment-sensitive and fluorescent photosensitizers,
which show high efficiency for generating singlet oxygen in medium polar
environments but little photoactivity in polar and non polar solvents. In the mean time,
they are highly fluorescent in nonpolar solvents but much less emissive in polar
solvents, ICT emission occurs in medium polar solvents and correlated with singlet
oxygen formation efficiency. The results are explained by PCT (photoinduced charge
transfer) mechanism. The presence of the methyl groups at 1 and 7 positions disables
the rotation of the phenyl ring, and therefore, the corresponding BODIPY 1a, 2a, and
3a were characterized by significant higher singlet oxygen generation efficiency and
fluorescence quantum yield than that of BODIPY 1b, 2b, and 3b.
ò Key words: BODIPY; singlet oxygen; fluorescence; charge transfer
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1. Introduction
Environment-sensitive fluorescent BODIPYs (boron dipyrromethene complexes)
are attractive functional materials [1-9]. Their fluorescence properties are dependent
on the hydrophobicity and polarity of the environment. These BODIPY molecules
generally exhibit low fluorescence quantum yields in polar solvents, but became
highly emissive in nonpolar solution [3-9]. Photoinduced electron transfer (PET) and
photoinduced charge transfer (PCT) are widely acceptable mechanisms [3,10]. Take
PCT for example, upon photoexcitation, a BODIPY molecule generates charge
transfer state through the PCT mechanism, which makes the fluorescence of the
fluorophore quenched. However, charge transfer state can be very active state. For
example, by charge recombination intersystem crossing (CR ICT), charge transfer
state could generate excited triplet state (T1 state) [11-14], and T1 state can lead to
singlet oxygen formation and photochemical reactions [11,15-17]. The thought above
drove us to explore whether electron donor substituted BODIPYs, such as
amino-phenyl-BODIPY (electron donor-acceptor pair), could initiate T1 and hence
singlet oxygen (1∆g) formation which are key active species for photodynamic therapy
of tumor.
8-(para-amino) phenyl substituted BODIPYs are well known PCT-based
environment-sensitive fluorescence sensors [4,10,18,19], but have not been explored
for singlet oxygen formation. In this study, we synthesized a series of PCT-based
BODIPYs (1a, 2a and 3a) and the corresponding 1b, 2b and 3b to study their singlet
oxygen generation ability on the basis of our previous study [11, 15-17]. Because
singlet oxygen plays the main role to damage tumor tissues in photodynamic therapy
of tumor (PDT) [20], we hope this study may shed light on the novel PCT-based
BODIPY photosensitizers for photodynamic therapy and open a new avenue for the
development of more efficient BODIPY-type PDT agents.
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Fig. 1. Chemical structures of the studied BODIPYs
2. Experimental section
2.1. Reagents and apparatus.
All reagents and solvents were obtained from Sigma - Aldrich, Acros Organics,
Merck or Fluka at the highest commercial grade and were used without further
purification. Thin layer chromatography (TLC) was performed on Merck silica-gel 60
F254 plates to monitor reactions. Chromatographic purifications were performed on
1
silica gel 60 (200-400 mesh) from Merck. H NMR and 13C NMR spectra were
1
carried out on a Bruker dmx NMR spectrometer (600 MHz for H NMR and 150
13
MHz for C NMR) using chloroform-d as solvent. Chemical shifts were reported in
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ppm. CDCl3 (1H: 7.26 ppm; 13C: 77.16) was used as reference. High resolution APCI
MS spectra were recorded on a LTQ Orbitrap XL APCI-TOF spectrometer.
2.2. General procedure for the synthesis of 8-(para-amino substituted)phenyl
BODIPYs 1a, 1b, 2a, 2b, 3a, and 3b
The synthesis follows the reported method in literature [3]. In an oven dried flask,
2,4-dimethylpyrrole (0.22 mL, 2.1 mmol) or 2-methylpyrrole (0.18 mL, 2.1 mmol)
and the corresponding aldehyde (1.0 mmol) were dissolved in absolute
dichloromethane (DCM, 20 mL). 50µL of TFA was added and the mixture was
stirred at room temperature for 20 hours. When TLC revealed disappearance of the
aldehyde, DDQ in dichloromethane (50 ml) was added to the solution, and stirred for
120 min. N,N-diisopropylethylamine (DIPEA, 5 mL) was added to the mixture and
stirred at room temperature for 20 min. Then boron trifluoride etherate (3 mL) was
added, and stirring was continued for 12 hours. The reaction mixture was washed
twice with water and saturated NaCl, and was dried by anhydrous MgSO4. The
solvent was filtered and removed under vacuum. The crude compound was purified
by silica gel flash chromatography using 30% DCM in petroleum ether to afford the
pure sample.
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Fig. 2. The synthetic path for the 8-(para-amino) phenyl substituted BODIPYs
10-(4-(dimethylamino)phenyl)-5,5-difluoro-1,3,7,9-tetramethyl-5H-dipyrrolo[1,2
1
-c:2',1'-f][1,3,2]diazaborinin-4-ium-5-uide (1a). Yield: 12%. Orange crystals. H
NMR (CDCl3, 600 MHz): δ 7.06 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.2 Hz, 2H), 5.97 (s,
2H), 3.02 (s, 6H), 2.55 (s, 6H), 1.48 (s, 6H). 13C NMR (CDCl3, 150 MHz): δ 154.72,
150.63, 143.28, 143.22, 132.20, 128.72, 122.15, 120.85, 112.32, 40.37, 14.74, 14.60.
11B NMR (CDCl3, 200 MHz): δ 0.83 (t, 1B). HRMS (APCI) m/z: 348.2031 [M-F]+
([M-F]+ calcd. 348.2047), m/z: 368.2089 [M+H]+ ([M+H]+ calcd. 368.2031)
10-(4-(dimethylamino)phenyl)-5,5-difluoro-3,7-dimethyl-5H-dipyrrolo[1,2-c:2',1
'-f][1,3,2]diazaborinin-4-ium-5-uide (1b). Yield: 11%. Red crystals. 1H NMR (CDCl3,
600 MHz): δ 7.44 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 4.0 Hz, 2H), 6.76 (d, J = 8.8 Hz,
13
2H), 6.26 (d, J = 4.0 Hz, 2H), 5.97 (s, 2H), 3.07 (s, 6H), 2.64 (s, 6H). C NMR
(CDCl3, 150 MHz): δ155.62, 151.83, 143.87, 134.29, 132.42, 130.04, 121.90, 118.64,
111.30, 40.23, 14.84. 11B NMR (CDCl3, 200 MHz): δ 1.00 (t, 1B). HRMS (APCI) m/z:
320.1721 [M-F]+ ([M-F]+ calcd. 320.1734), m/z: 340.1780 [M+H]+ ([M+H]+ calcd.
340.1718)
5,5-difluoro-1,3,7,9-tetramethyl-10-(4-(piperidin-1-yl)phenyl)-5H-dipyrrolo[1,2-
c:2',1'-f][1,3,2]diazaborinin-4-ium-5-uide (2a). Yield: 13%. Orange crystals. 1H NMR
(CDCl3, 600 MHz): δ 7.08 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 5.96 (s, 2H),
3.23 (t, J = 7.2, 6.3 Hz, 4H), 2.54 (s, 6H), 1.74 (m, J = 5.8 Hz, 4H), 1.61 (m, J = 6.0
Hz, 4H), 1.46 (s, 6H). 13C NMR (CDCl3, 150 MHz): δ154.90, 152.46, 143.28, 142.75,
11
132.01, 128.64, 124.82, 120.93, 116.28, 50.12, 25.66, 24.25, 14.69, 14.61. B NMR
(CDCl3, 200 MHz): δ 0.81 (t, 1B). HRMS (APCI) m/z: 388.2342 [M-F]+ ([M-F]+
calcd. 388.2360), m/z: 408.2401 [M+H]+ ([M+H]+ calcd. 408.2344)
5,5-difluoro-3,7-dimethyl-10-(4-(piperidin-1-yl)phenyl)-5H-dipyrrolo[1,2-c:2',1'-
1
f][1,3,2]diazaborinin-4-ium-5-uide (2b). Yield: 11%. Red crystals. H NMR (CDCl3,
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600 MHz): δ 7.42 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 4.0 Hz,
2H), 6.26 (d, J = 4.1 Hz, 2H), 5.96 (s, 2H), 3.32 (t, 4H), 2.64 (s, 6H), 1.72 (p, J = 5.6
13
Hz, 4H), 1.65 (p, J = 5.6 Hz, 4H). C NMR (CDCl3, 150 MHz): δ 155.98, 153.08,
143.50, 134.34, 132.23, 130.11, 123.72, 118.77, 114.40, 49.22, 25.57, 24.33, 14.87.
11B NMR (CDCl3, 200 MHz): δ 0.99 (t, 1B). HRMS (APCI) m/z: 360.2034 [M-F]+
([M-F]+ calcd. 360.2047), m/z: [M+H]+ 380.2094 ([M+H]+ calcd. 380.2031)
5,5-difluoro-1,3,7,9-tetramethyl-10-(4-morpholinophenyl)-5H-dipyrrolo[1,2-c:2',
1
1'-f][1,3,2]diazaborinin-4-ium-5-uide (3a). Yield: 13%. Orange crystals. H NMR
(CDCl3, 600 MHz): δ 7.12 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.1 Hz, 2H), 5.97 (s, 2H),
3.90 (t, J = 4.7 Hz, 4H), 3.23 (t, J = 4.8 Hz, 4H), 2.54 (s, 6H), 1.45 (s, 6H). 13C NMR
(CDCl3, 150 MHz): δ155.09, 151.59, 143.19, 142.25, 131.92, 128.86, 125.86, 121.03,
11
115.54, 66.78, 48.79, 14.69, 14.62. B NMR (CDCl3, 200 MHz): δ 0.80 (t, 1B).
HRMS (APCI) m/z: [M-F]+ 390.2137 ([M-F]+ calcd. 390.2153), m/z: [M+H]+
410.2195 ([M+H]+ calcd. 410.2137)
5,5-difluoro-3,7-dimethyl-10-(4-morpholinophenyl)-5H-dipyrrolo[1,2-c:2',1'-f][1
,3,2]diazaborinin-4-ium-5-uide (3b). Yield: 11%. Red crystals. 1H NMR (CDCl3, 600
MHz): δ 7.44 (d, J = 8.3 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 4.1 Hz, 2H),
6.27 (d, J = 4.1 Hz, 2H), 3.89 (t, J = 4.9 Hz, 4H), 3.29 (s, 4H), 2.64 (s, 6H). 13C NMR
(CDCl3, 150 MHz): δ156.47, 152.51, 143.01, 134.38, 132.07, 130.15, 125.05, 118.99,
11
114.18, 66.75, 48.16, 14.90. B NMR (CDCl3, 200 MHz): δ 0.98 (t, 1B). HRMS
(APCI) m/z: [M-F]+ 362.1826 ([M-F]+ calcd. 362.1840), m/z: [M+H]+ 382.1885
([M+H]+ calcd. 382.1824)
2.3. Photophysical measurements
The procedure for fluorescence and singlet oxygen measurements are similar to our
previous reports [11, 15-17].
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2.3.1. Absorption measurements.
Ground-state UV−vis absorption spectra were obtained on a Vary 8454
spectrometer from Agilent Technologies which was connected to a deuterium and
halogen lamp by Optical fiber using 1 cm matched quartz cuvettes at 20 ºC.
2.3.2. Fluorescence measurements.
The measurements on fluorescence spectra, fluorescence quantum yields, and the
fluorescence lifetimes were performed at 20 ºC. Steady state fluorescence studies
were performed with a FLS920 Fluorescence Spectrometer from Edinburgh
Instruments. The slit width was 0.5 nm for both excitation and emission. All spectra
were corrected for the sensitivity of the photomultiplier tube.
The fluorescence quantum yield (Φf) of each BODIPY derivative was obtained
by comparing the emission spectra of the test sample with that of a 10 mM PBS buffer
solution of 2,4,5,7-tetrabromo fluorescein excited at 475 nm, whose fluorescence
quantum yield is 0.24 according to the literature [21]. The sample and reference
solutions were prepared with the same absorbance (~0.090) at 475 nm. The
fluorescence quantum yield (Φf) was obtained according to the following equation:
(1)
where F denotes the integrated fluorescence intensity, s represents the sample, the
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subscript 0 stands for the reference compound, n denotes the refractive index of the
solvent, and A denotes the absorbance at the excitation wavelength. All solutions
were air saturated, and all spectra were recorded at 20 ºC.
2.3.3. Singlet oxygen quantum yield
Singlet oxygen quantum yield (Φ∆) determinations were measured by the
chemical trapping method [22]. The solvents were air saturated. The absorbance of a
solution of the BODIPYs is ca. 1.0 at 509 nm (close to the absorption maximum of
the BODIPY). The solution was irradiated at 509 nm by a LED light source. The
concentration of DPBF was decreased to 3×10−5 M in order to avoid the chain
reactions induced by DPBF in the presence of singlet oxygen. The degradation of
DPBF was monitored by UV−vis absorption spectra at 410 nm. The Φ∆ values were
calculated with the following equation:
(2)
Φ∆ref denotes the singlet oxygen quantum yield of solvent-independent standard
8-methylthio-2,6-diiodoBODIPY ( Φ∆ref ≈0.80) [23]. k and kref denote the
photobleaching rate constants of DPBF in the presence of samples and reference
compound, respectively. Ia and Iaref denote the light absorption rates at 509 nm of the
samples and reference compound. Their ratio can be calculated with the following
equation:
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ref
Iaref
Ia
1−10−A
1−10−A
509
=
(3)
509
ref
In which A509 and A509 denote the absorbance of at 509 nm of the BODIPY and
reference compound.
2.4. Laser flash photolysis for excited triplet state
Transient absorption spectra were recorded in THF solution with an Edinburgh
LP920 laser flash photolysis system. An OPO laser (500 nm and 4 ns FWHM, 2 mJ)
was used as excitation source. The analyzing light was from a pulsed xenon lamp. The
laser and analyzing light beams perpendicularly passed through a quartz cell with an
optical path length of 1 cm. The signal was displayed and recorded on a Tektronix
TDS 3012B oscilloscope and an R928B detector. The laser energy incident at the
sample was attenuated to ca. 2 mJ per pulse. Time profiles at a series of wavelengths
from which point by-point spectra were assembled were recorded with the aid of a Pc
controlled kinetic absorption spectrometer. The concentrations of the target
compounds were typically 20 µM providing A500 = 1.0 in a 10 mm cuvettes.
2.5. Quantum chemical computation
The calculations were carried out using density functional theory (DFT) method
as implemented in the Gaussian 09 package. The B3LYP exchange-correlation
functional was chosen together with a 6-31G(d) basis set for structural optimization.
The solvent effect was modeled using the Polarizable Continuum Model (CPCM)
method. In all the cases frequency analysis was made after geometry optimization to
ensure the convergence to an energy minimum.
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3. Results and discussion
The six compounds were prepared by the well established synthetic procedure for
BODIPYs. NMR and HRMS data are well consistent with the structures as given in
the experimental section. These BODIPY derivatives are well soluble in both non
polar and polar solvents, such as benzene, n-hexane, toluene, DCM, chloroform, ethyl
acetate, THF, acetone, acetonitrile, DMF, DMSO, ethanol and methanol and so on.
Therefore seven solvents (n-hexane, ethyl acetate, THF, pinacolone, acetone,
methanol and acetonitrile) ranging from nonpolar, medium polar and high polar
were selected to measure their singlet oxygen generation ability.
3.1. Ground state UV-Vis absorption
Table 1 and Figure 3 show the UV−vis absorption properties of the BODIPY
derivatives in several solvents. Their spectra showed the typical absorption bands of
BODIPY chromophore, in which a strong absorption band is located around 500 nm
with a shoulder at 480 nm. The spectral shape of 1a, 2a, and 3a are only slightly
affected by either para-substitutents of the phenyl or the solvents used. With the
increase in solvent polarity, the shape of the absorption spectra is slightly broadened
due to the weak ground state charge transfer interaction. The peak maximum values
are blue shifted by only 4 nm, which is also in line with the general behavior of
BODIPYs. Therefore, in the ground-state configuration there are two independent π
systems within each compound 1a, 2a, and 3a: the phenyl group and the
perpendicular BODIPY core, which have little electronic coupling and form a
donor−acceptor pair. The BODIPY core is the fluorophore and acts as an electron
acceptor. The attached amino phenyl group acts as an electron donor. A detailed
inspection of the spectra of 1b, 2b, and 3b shows that a weak shoulder at 550 nm
exists, which became more obvious when the polarity of solvents is increased. This
indicates that the weak band at 550 nm is due to charge transfer [5]. Compared to 1a,
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2a, and 3a, the two methyls at 1 and 7 positions of BODIPY are absent in compound
1b, 2b, and 3b, which makes the phenyl and the attached BODIPY core are not
perpendicular but have a dihedral angle ca. 60o. This angle increases the electron
cloud overlapping between the amino phenyl and the BODIPY core, and makes the
charge transfer from the amino phenyl to the attached BODIPY core easier.
The absorption maximum of 1b, 2b, 3b are 6-10 nm larger than that of 1a, 2a, 3a.
This is due to the inductive effect +I of the methyl groups, which raise up the energy
of the LUMO state with regard to that of the HOMO. This results in a slight increase
in the energy gap between both states, and therefore causes the hypsochromic shifts
[13].
Table 1. The photophysical characteristics of BODIPY 1-3 in several solvents
abs
max
em
max
λ
λ
∆λ
solvent
Φf
Φ∆
(nm) (nm) (nm)
n-hexane
EtOAc
THF
0.441 0.102 500
0.011 0.412 498
0.014 0.623 499
511
510
513
511
510
511
508
519
513
517
512
515
11
12
14
15
14
19
12
12
9
Pinacolone 0.015 0.490 496
BODIPY 1a
Acetone
MeOH
CH3CN
n-hexane
EtOAc
THF
0.009 0.114 496
0.003 0.073 492
0.005 0.062 496
0.376 0.230 507
0.013 0.171 504
0.011 0.321 506
11
7
BODIPY 1b
Pinacolone 0.024 0.439 505
Acetone
0.006 0.087 504
11
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MeOH
CH3CN
n-hexane
EtOAc
THF
0.030 0.019 503
0.008 0.052 503
0.384 0.058 500
0.006 0.511 498
0.008 0.612 499
511
511
511
515
515
516
515
514
511
520
518
514
523
517
518
519
511
517
514
520
516
514
511
520
8
8
11
17
16
20
20
17
15
14
13
10
17
11
14
15
13
19
14
25
26
20
15
12
Pinacolone 0.024 0.644 496
BODIPY 2a
Acetone
MeOH
CH3CN
n-hexane
EtOAc
THF
0.002 0.145 495
0.010 0.037 497
0.005 0.083 496
0.341 0.258 506
0.005 0.220 505
0.008 0.401 504
Pinacolone 0.004 0.457 506
BODIPY 2b
Acetone
MeOH
CH3CN
n-hexane
EtOAc
THF
0.002 0.099 506
0.003 0.046 504
0.002 0.057 504
0.450 0.120 498
0.029 0.676 498
0.011 0.535 500
Pinacolone 0.063 0.588 495
BODIPY 3a
Acetone
MeOH
0.001 0.192 490
0.002 0.038 494
0.001 0.083 496
0.388 0.225 508
CH3CN
n-hexane
BODIPY 3b
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EtOAc
THF
0.008 0.290 506
0.004 0.338 507
520
528
530
517
521
534
14
21
24
12
16
29
Pinacolone 0.002 0.281 506
Acetone
MeOH
CH3CN
0.002 0.100 505
0.005 0.008 505
0.020 0.033 505
Φf: the fluorescence quantum yield, Φ∆: the quantum yield for singlet oxygen
abs
em
formation, λ : the UV−vis absorption maximum, λ : the fluorescence emission
max
max
maximum, ∆λ: the Stokes shift.
1.0
1.0
0.8
0.6
0.4
0.2
0.0
MeCN
MeOH
MeCN
MeOH
0.8
0.6
0.4
0.2
0.0
Acetone
Pinacolone
THF
EtOAC
n-hexane
Acetone
Pinacolone
THF
EtOAC
n-hexane
350 400 450 500 550 600 650 700 750 800
350 400 450 500 550 600 650 700 750 800
Wavelength (nm)
Wavelength (nm)
1a
1b
1.0
1.0
MeCN
MeCN
MeOH
MeOH
0.8
0.6
0.4
0.2
0.0
0.8
0.6
0.4
0.2
0.0
Acetone
Pinacolone
THF
EtOAC
n-hexane
Acetone
Pinacolone
THF
EtOAC
n-hexane
350 400 450 500 550 600 650 700 750 800
350 400 450 500 550 600 650 700 750 800
Wavelength (nm)
Wavelength (nm)
2a
2b
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1.0
0.8
0.6
0.4
0.2
0.0
1.0
MeCN
MeOH
Acetone
Pinacolone
THF
EtOAC
n-hexane
MeCN
MeOH
0.8
Acetone
Pinacolone
THF
EtOAC
n-hexane
0.6
0.4
0.2
0.0
350 400 450 500 550 600 650 700 750 800
350 400 450 500 550 600 650 700 750 800
Wavelength (nm)
Wavelength (nm)
3a
3b
Fig. 3. Normalized absorption spectra of 1 - 3 in different solvents.
3.2. Fluorescence studies
The fluorescence emission of the BODIPYs is strongly solvent dependent. With
the increase in solvent polarity, new emission bands appear for all the amino
phenyl-BODIPYs, but not for Ph-TMBDP. The new band is broad and structureless,
which shows the typical feature of charge transfer emission (CT emission).
Apparently the presence of amino groups is responsible for the charge transfer. The
CT band intensity is 1a < 2a< 3a and 1b < 2b< 3b, which is consistent with the
ranking of the electron donating ability of the amino groups attached on the phenyl.
The fluorescence quantum yield (Φf) values of Ph-TMBDP are 0.57±0.04 in
different solvents, which is little affected by the solvent polarity. The Φf of any amino
phenyl substituted BODIPY (Table 1) in any solvent is always smaller than that of
Ph-TMBDP, in particular in polar solvents. This indicates that amino phenyl unit
quenches the S1 state of the attached TMBDP unit, due to charge transfer process
from S1 state (1BODIPY-Donor → BODIPY[δ−]-Donor[δ+]) [24]. In addition, Φf of the
BODIPYs is very dependent on the solvent polarity. The values of Φf decrease with
increasing solvent polarity from n-hexane to acetonitrile. To explain the solvent
effects on the phenomenon above, we can view the BODIPYs as electron
donor/acceptor pairs. The intramolecular charge transfer (ICT) occurs upon light
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irradiation and leads to the formation of the excited state with a large dipole moment.
The intramolecular charge transfer (ICT) is favored by high polar solvents [25-27].
Therefore, increasing the solvent polarity leads to a faster decay of the S1 and a lower
fluorescence quantum yield. In medium polar solvents, the intramolecular charge
transfer causes a red-shifted new emission band [13]. In highly polar solvents, the
red-shifted emission is so weak that it can hardly be detected due to the fast charge
recombination of the ICT state [5,13]. 2a and 3a showed the stronger ICT emission,
probably because the six member ring (or the γ atoms of the six member ring) may
stabilize the positive charge and create additional charge transfer [28].
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
MeCN
MeOH
MeCN
MeOH
Acetone
Pinacolone
THF
EtOAC
n-hexane
Acetone
Pinacolone
THF
EtOAC
n-hexane
450
500
550
600
650
700
750
800
450
500
550
600
650
700
750
Wavelength (nm)
Wavelength (nm)
1a
1b
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
MeCN
MeOH
Acetone
Pinacolone
THF
MeCN
MeOH
Acetone
Pinacolone
THF
EtOAC
n-hexane
EtOAC
n-hexane
450
500
550
600
650
700
750
800
850
450
500
550
600
650
700
750
800
850
Wavelength (nm)
Wavelength (nm)
2a
2b
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1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
MeCN
MeOH
MeCN
MeOH
Acetone
Pinacolone
THF
0.6
Acetone
Pinacolone
THF
EtOAC
n-hexane
0.4
0.2
0.0
EtOAC
n-hexane
450
500
550
600
650
700
750
800
850
450
500
550
600
650
700
750
800
850
Wavelength (nm)
Wavelength (nm)
3a
3b
Fig. 4. Normalized fluorescence emission spectra of the BODIPYs in different
solvents with excitation at 475 nm
The fluorescence quantum yields for 1a - 3a were greater than those for the
corresponding 1b - 3b. Because 1b - 3b are not substituted by methyl groups at the 1
and 7 positions, the phenyl ring has greater freedom of rotation, which increases the
amount of energy loss via non radiative decay.
The presence of PCT within amino phenyl-TMBDP is also supported by the
HOMO/LUMO distribution of the compounds (Fig. 5). For example, the LUMO of 1a
is located on the TMBDP moiety, while its HOMO is on the dimethylamino phenyl
unit. This means that upon photoexcitation, electron charge will be relocated from one
unit to another attached moiety, i.e. PCT occurs. For Ph-TMBDP, however, both
LUMO and HOMO are located on the TMBDP moiety, no PCT is possible. This
result shows that the dimethylamino substitution on the phenyl unit has a remarkable
positive effect on PCT, since it increases the electron donating ability of the phenyl
and makes PCT more likely, and causes the fluorescence quenching of TMBDP and
the enhancement on T1 and singlet oxygen formation.
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Fig. 5. Top: the HOMO-1, HOMO, and LUMO of compound Ph-TMBDP in MeCN.
Bottom: the HOMO-1, HOMO, and LUMO of compound 1a in MeCN.
3.3. Singlet oxygen formation
The singlet oxygen generation capacity of the BODIPYs was measured in several
organic solvents. 1,3-diphenyl-iso-benzofuran (DPBF) was used since it is the widely
known quantitative and specific singlet oxygen trapper for the determination of the
formation quantum yield of singlet oxygen. The light irradiations at 510 nm were used
since it is absorbed by BODIPYs but not by DPBF. The absorption band of DPBF at
410 nm was gradually reduced with the light irradiation up to 30 minutes in the
presence of a BODIPY, but BODIPYs did not show any absorption change (Fig. 6).
The absorbance change of DPBF is linearly correlated to time t (Fig. 7). In the
absence of either the BODIPY or light, no DPBF degradation occurred, indicating that
the BODIPYs indeed produced singlet oxygen and caused the oxidation of DPBF.
1.4
1.1
0
1.2
1.0
0.8
0.6
0.4
0.2
0.0
1.5 min
3.0 min
4.5 min
6.0 min
7.5 min
9.0 min
10.5 min
12 min
1.0
0.9
0.8
0.7
0.6
0.5
13.5 min
300
350
400
450
500
550
0
2
4
6
8
10
12
14
Time (min)
Wavelength (nm)
Fig. 6. The change of absorption Fig. 7. The plot of DPBF absorbance at
spectrum of DPBF in the presence of 3a 410 nm against time and the fitting
in EtOAc with irradiation at 510 nm
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The singlet oxygen formation quantum yields (Φ∆) of the Ph-TMBDP are
0.040±0.02 in the solvents studied. In contrast, the Φ∆ of any amino phenyl substituted
BODIPY (Table 1) is always much higher than that of Ph-TMBDP in polar solvents
EtOAc, THF, pinacolone and acetone (Φ∆ can be as high as close to 0.70). This
indicates that the amino presence significantly enhances the formation of singlet
oxygen which is coincident with the fluorescence quenching due to charge transfer
－
＋
process from S1 state (1BODIPY-Donor → BODIPY[δ ]-Donor[δ ]). We then conclude that
－
＋
]
3
the charge transfer causes the T1 formation (BODIPY[δ ]-Donor[δ → BODIPY-Donor),
since T1 is the precursor of singlet oxygen (3BODIPY-Donor + O2 → BODIPY-Donor +
1O2)
.
Fig. 8. The dependence of Φ∆ on the solvent polarity (dielectric constant ε).
Fig. 8 shows the dependence of Φ∆ on solvent polarity (represented by the
dielectric constant ε). The highest Φ∆ was obtained when ε is about 15. Fig. 8 also
tells the effect of the electron-donating ability of the amino phenyl substituent on the
quantum yields. Φ∆ of 2b is slightly higher than that of 1b, while Φ∆ of 1b is higher
than that of 3b. Φ∆ of 2a in most cases is higher than that of 3a and 1a. The
performance of 2b and 2a indicates that the substitutents with medium electron
donating ability are better. Also noted is that the Φ∆ of BODIPY 1b-3b are lower than
those of BODIPY 1a-3a. This is due to the free rotation of the phenyl units of 1b-3b
(because of the absence of 1,7-dimethyl compared to that in 1a-3a), which causes
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ACCEPTED MANUSCRIPT
more S1 states going back to S0 by heat releasing rather than charge transfer.
For each compound, observing Φ∆ values in Table 1 and ICT emission intensity
(IICT) of Fig. 4 in different solvents, it is clear that the higher the IICT is, the higher the
Φ∆ value is. This close relationship also indicates that the singlet oxygen generation
ability depends on the ICT state. In other words, triplet state T1 is from ICT state
(process 1-6 below), since singlet oxygen comes from energy transfer of T1 state.
1. BODIPY-Donor + hν → 1BODIPY-Donor,
light absorption to form excited state.
－
＋
]
2. 1BODIPY-Donor → BODIPY[δ ]-Donor[δ
,
ICT process.
－
＋
]
3. BODIPY[δ ]-Donor[δ → 3BODIPY-Donor, charge recombination (CR) to form T1 state.
－
＋
]
4. BODIPY[δ ]-Donor[δ → BODIPY-Donor+ heat, CR to form ground state.
－
＋
]
5. BODIPY[δ ]-Donor[δ → BODIPY-Donor+ hν’, CR to luminescence (ICT emission).
6. 3BODIPY-Donor + O2 → BODIPY-Donor + 1O2, energy transfer to from singlet oxygen.
7. 1O2 + DPBF → decomposed product.
Based on the mechanism above, we can explain why the emission spectra for
EtOAc and THF are very different from those in other solvents (Fig 4 in which IICT is
higher for THF and EtOAc). Increasing solvent polarity enhances both process 2 and
－
＋
]
process 4, but enhancing process 2 makes more BODIPY[δ ]-Donor[δ and so ICT
emission should becomes higher. However, enhancing process 4 consumes more
－
＋
]
BODIPY[δ ]-Donor[δ by heat releasing, so ICT emission becomes lower. When the
solvent polarity is too high, process 4 (heat releasing) will dominate, ICT emission
and singlet oxygen formation become very weak. On the other hand, if the solvent
polarity is too low, process 2 will be absent and no ICT state is formed, therefore no
ICT emission and the associated triplet state formation. EtOAc and THF have
medium polarity, PCT process 2 is fast while heat releasing process is still slow, so
that ICT emission and the associated triplet state formation yield are high.
Laser flash photolysis (LFP) technique was used to examine the formation of
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ACCEPTED MANUSCRIPT
excited triplet state with excitation at 500 nm (4 ns pulse) in air saturated THF
solutions. The transient absorption spectra (TAS) and the triplet decay curves are
shown in Fig. 9. The positive absorption bands were observed at about 430 nm for 1a
and 2a. No significant signal was detected for Ph-TMBDP. The band shape and
positions are similar to the reported T1-Tn absorption of other BODIPY analogues [16,
17]. The lifetime is 0.37 and 0.43 µs in air saturated THF for 1a and 2a respectively,
but it became much longer, i.e. 36 and 39 µs in argon saturated THF respectively.
These results show that excited triplet state was indeed formed for the amino phenyl
substituted BODIPYs.
Fig. 9. µs scaled transient absorption spectra (Left) and the decay of positive transient
absorbance (Right) in air saturated THF solution (20 µM), excitation wavelength is
500 nm (2 mJ, 4 ns OPO pulsed laser). Top: 1a, Bottom: 2a.
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The photophysical processes proposed above can be shown in Fig. 10. Upon
photoexcitation, 8-(para-amino) phenyl substituted BODIPYs generate charge
transfer state, and charge transfer state forms excited triplet state (T1 state), ICT
emission and ground state by charge recombination (backward electron transfer). T1
state causes the energy transfer to molecular oxygen to form singlet oxygen.
Table 1 summarized the Φ∆ results. Apparently the BODIPYs showed efficient
generation of singlet oxygen in medium polar environments but little photo active in
polar and non polar solvents. In non polar solvent, no ICT state is formed, therefore
no T1 state and singlet oxygen formation. In high polar solvent, process 4 (heat
releasing) is very fast and predominant, so that process 3 (T1 formation) and 5 (ICT
emission) are not competent.
BODIPY 1a, 2a, and 3a exhibited higher singlet oxygen generation efficiency
than the corresponding 1b, 2b, and 3b, since the presence of the methyl groups at the
1, and 7 positions of the s-indacene ring causes the large steric hindrance for the
rotation of the phenyl group, and reduces heat releasing.
Based on the mechanism above, the experimental results of the studied
BODIPYs could be explained below.
1. In non polar solvent, the energy of S1 is mainly released as light emission.
2. With the increase in solvent polarity, the intramolecular charge transfer
becomes more and more favored, and the number of molecules in charge transfer state
increases.
3. In medium polar solvents, charge transfer state produces excited triplet state,
which leads to the formation of singlet oxygen. DPBF is then decomposed by singlet
oxygen.
4. In high polar solvents, the energy of charge transfer state is mainly released as
－
＋
]
heat: BODIPY[δ ]-Donor[δ → BODIPY-Donor+ heat. Process 3 (T1 formation) and
5 (ICT emission) are not competent and negligible.
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ACCEPTED MANUSCRIPT
5. The methyl groups at the 1 and 7 positions of the s-indacene ring hinders the
rotation of the phenyl rings and results in significantly higher fluorescence quantum
yields and the quantum yields of singlet oxygen formation.
Fig. 10. Photophysics and energy level for T1 formation by PCT mechanism.
4. Conclusions
We synthesized six 8-para-amino phenyl substituted BODIPY photosensitizers.
These BODIPYs showed the efficient generation of singlet oxygen in medium polar
environments. Φf and Φ∆ of the BODIPYs are related to both the structure of the
donor moiety and solvent polarity due to PCT (photoinduced charge transfer)
mechanism. Incorporating methyl groups at the 1 and 7 positions of the BODIPY core
decreases the degree of rotational freedom, which leads to the increase in the quantum
yield for both fluorescence and singlet oxygen formation, while Φf is decreased with
the increase in solvent polarity. These novel photosensitizers based on PCT
mechanism indicate their potential application in photodynamic therapy of cancer.
Acknowledgements
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This work is supported by the Natural Science Foundation of Hebei Province
(Contract B2016407084 and B2014407080), Youth Talent Program of Hebei High
School (Contract BJ2017028), and Technology Foundation for Selected Overseas
Chinese Scholar of Hebei Province (Contract C2015003046). We also thank the
financial support from Hebei Provincial Hundred Talents Plan (Contract
E2013100005) and HBUST (Contract CXTD2012-05).
References
[1] Zhao J, Xu K, Yang W, Wang Z, Zhong F. Chem Soc Rev. 2015;44(24):8904-39.
[2] Zhao J, Huang L, Cui X, Li S, Wu H. J. Mater. Chem. B, 2015; 3:9194-9211.
[3] H. Sunahara,Y. Urano, H. Kojima, T. Nagano, J. Am. Chem. Soc., 2007, 129,
5597-5604.
[4] M. Baruah , W. Qin , N. Basarić , W. M. De Borggraeve , N. Boens, J. Org. Chem.,
2005, 70, 4152-4157.
[5] A. Filarowski, M. Kluba, K. Cieslik-Boczula, A. Koll, A. Kochel, L. Pandey,
W. M. De Borggraeve, M. Van der Auweraer, J. Catalanc, N. Boens, Photochem.
Photobiol. Sci., 2010, 2010, 996-1008.
[6] P. Bukowska, J. Piechowska, R. Loska, Dyes and Pigments, 2017, 137, 312-321.
[7] R. I. Roacho, A. Metta-Magaña, M. M. Portillo, E. Peña-Cabrera, K. H. Pannell, J.
Org. Chem., 2013, 78, 4245−4250.
[8] C. Yu, Q. Wu, Z. Tian, T. Li, E. Hao, L. Jiao, J. Porphyrins Phthalocyanines, 2016,
2016, 1–15.
[9] E. V. Antina, N. A. Bumagina, A. I. V'yugin, A. V. Solomonov, Dyes and Pigments,
2017, 136, 368-381.
[10] W. Qin, M. Baruah, M. Van der Auweraer, F. C. De Schryver, N. Boens, J. Phys.
Chem. A, 2005, 109, 7371-7384.
24

ACCEPTED MANUSCRIPT
[11] X.-F. Zhang, N. Feng, Chem. Asian J., 2017, 12, 2447-2456.
[12] S. H. Park, A. Roy, S. Beaupré, S. Cho, N. Coates, J. S. Moon, D. Moses, M.
Leclerc, K. Lee, A. J. Heege, Nature Photon. 2009, 3, 297-302.
[13] P. Janssen, S. H.W. Wouters, M. Cox, B. Koopmans, Org. Electron. 2014, 15,
743–750.
[14] W. Chang, D. N. Congreve, E. Hontz, M. E. Bahlke, D. P. McMahon, S. Reineke,
T. C. Wu, V. Bulović, T. Van Voorhis, M. A. Baldo, Nat. Commun., 2015, 6,
6415.
[15] X.-F. Zhang, X. Yang, B. Xu, Phys. Chem. Chem. Phys. 2017, 19(36),
24792-804.
[16] X.-F. Zhang, Dyes and Pigments. 2017,146, 491-501.
[17] X.-F. Zhang, X. Yang, J. Phys. Chem. B, 2013, 117, 9050−9055.
[18] M. Kollmannsberger, K. Rurack, U. Resch-Genger, J. Daub, J. Phys. Chem. A,
1998, 102, 10211-10220.
[19] K. Rurack, M. Kollmannsberger, U. Resch-Genger, J. Daub, J. Am. Chem. Soc.,
2000, 122, 968-969.
[20] L. B. Josefsen, R. W. Boyle, Met Based Drugs., 2008, 2008, 276109.
[21] X.-F. Zhang, J. Zhang, L. Liu, J. Fluoresc. 2014, 24, 819–826.
[22] T. Nyokong, Coord. Chem. Rev. 2007, 251, 1707-1722.
[23] N. Epelde-Elezcano, V. Martinez-Martinez, E. PeÇa-Cabrera, C. F. A.
Gjmez-Duran, I. L. Arbeloa, S. Lacombe, RSC Adv. 2016, 6, 41991-
41998.
[24]M. Kollmannsberger, K. Rurack, U. Resch-Genger, W. Rettig, J. Daub, Chem.
Phys. Lett. 2000, 329, 363-369.
[25]P. Van Haver, N. Helsen, S. Depaemelaere, M. Van der Auweraer, F. C. De
25

ACCEPTED MANUSCRIPT
Schryver, J. Am. Chem. Soc., 1991, 113(18), 6849-6857.
[26]A. Onkelinx, G. Schweitzer, F. C. De Schryver, H. Miyasaka, and M. Van der
Auweraer , T. Asahi, H. Masuhara, and H. Fukumura , A. Yashima, K. Iwai, J.
Phys. Chem. A 1997, 101, 5054-5062.
[27]J. Herbich. A. Kapturkiewicz, Chem. Phys. 1991, 158, 143-153.
[28]G. B.Clemans, M. Alemayehu, Tetrahedron Lett., 1993, 34(10), 1563-1566.
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Highlights
ò Six 8-(para-amino) phenyl substituted BODIPY photosensitizers were prepared.
ò They can efficiently generate singlet oxygen in medium polar environments.
ò They exhibit high fluorescence quantum yields in nonpolar solvents but low
fluorescence quantum yields in polar solvents.
ò Both quantum yields for singlet oxygen formation and fluorescence are increased
by the methyl in 1 and 7 positions of the BODIPY core.