[a]-Phenanthrene-fused BF2 azadipyrromethene (AzaBODIPY) dyes as bright near-infrared fluorophores

Article abstract of DOI:10.1021/acs.joc.7b01803

A new substitution pattern of BF₂ azadipyrromethene (azaBODIPY) dyes was obtained by phenanthrene fusion through a key palladium-catalyzed intramolecular C-H activation reaction. These [a]-phenanthrene-fused azaBODIPYs have a near planar struct

Full text of DOI:10.1021/acs.joc.7b01803

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Article
[a]-Phenanthrene-Fused BF2 Azadipyrromethene
(azaBODIPY) Dyes as Bright Near-Infrared Fluorophores
Wanle Sheng, Jiuen Cui, Zheng Ruan, Lifeng Yan, Qinghua
Wu, Changjiang Yu, Yun Wei, Erhong Hao, and Lijuan Jiao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01803 • Publication Date (Web): 13 Sep 2017
Downloaded from http://pubs.acs.org on September 14, 2017
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[a]ꢀPhenanthreneꢀFused BF2
Azadipyrromethene (azaBODIPY) Dyes as
Bright NearꢀInfrared Fluorophores
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†
†
‡
‡
†
†
†
Wanle Sheng, Jiuen Cui, Zheng Ruan, Lifeng Yan, Qinghua Wu, Changjiang Yu, Yun Wei,
†
†
Erhong Hao* and Lijuan Jiao*
†
Laboratory of Functional Molecular Solids, Ministry of Education; Anhui Laboratory of
MoleculeꢀBased Materials (State Key Laboratory Cultivation Base) and School of Chemistry and
Materials Science, Anhui Normal University, No.1 East Beijing Road, Wuhu, 241000, China.
‡
CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences
at the Microscale, iChEM, and Department of Chemical Physics, University of Science and
Technology of China, Jinzai Road 96#, Hefei, 230026 Anhui, China.
*
To whom correspondence should be addressed.
Eꢀmail: haoehong@ahnu.edu.cn, jiao421@ahnu.edu.cn
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Abstract Graphic
Br
Br
N
B
Pd cat.
N
B
Pd cat.
N
B
Br
Br
C-H activation
N
N
C-H activation
N
N
N
N
Ar
F
F
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Ar
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-
phenanthrene-fused
azaBODIPY
2
Abstract: A new substitution pattern of BF azadipyrromethene (azaBODIPY) dyes
was obtained by phenanthrene fusion through a key palladiumꢀcatalyzed
intramolecular CꢀH activation reaction. These [a]ꢀphenanthreneꢀfused azaBODIPYs
have near planar structure of the phenanthreneꢀfused azadipyrromethene core in the
crystalline state. The chromophore absorbs (log ε > 5) and fluoresces (φ = 0.32ꢀ0.38)
strongly above 700 nm with excellent photostability, and may be used as an attractive
bright NIR bioimaging agent.
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INTRODUCTION
New design strategies for functional organic chromophores, especially those
absorbing and/or emitting in the nearꢀinfrared (NIR) spectroscopic window (700ꢀ1000
nm) are of great interest for the continuous development of highꢀcontrast bioꢀimaging
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agent, optical recording material, NIR laser filter, photographic material and
1
photosensitizers for solar cells. BF
2
azadipyrromethenes (azaBODIPYs) firstly
2
ꢀ4
reported by O’Shea et al. have received extensive research interests due to their
remarkable photophysical properties, such as the inherent strong long wavelength
absorption (around 650 nm) and easy accessibility. Several elegant researches have
been performed to further red shift their absorption and emission bands to NIR
regions, including the installation of electronꢀdonating and/or electronꢀwithdrawing
5,6
substituents to the parent π−conjugated framework (via “pushꢀpull” effect), and the
installation
of
six
member
ring(s)
to
rigidify
3,5ꢀaryls
(via
7,8
“
conformationalꢀrestriction” strategy, Chart S1 in the supporting information) .
1
3ꢀ14
Figure 1. Reported synthesis of [a]ꢀbenzoꢀfused azaBODIPYs
(a) and the
synthetic strategies for [a]ꢀphenanthreneꢀfused azaBODIPYs in this work (b).
On the other hand, direct annulations of azaBODIPYs with aromatic rings at the
peripheral positions of the chromophore bring the desired structure rigidity and NIR
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absorption.
The recently reported benzo/pyrazineꢀfused azaBODIPYs and lately
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disclosed unsymmetrical benzoꢀfused azaBODIPYs by Shen and coworkers using
phthalonitrile as the starting material (Figure 1a) are the only examples to achieve
[
a]ꢀringꢀfused azaBODIPYs.
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Recently, we reported [b]ꢀbisphenanthreneꢀfused azaBODIPYs from a key
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intramolecular oxidative aromatic coupling reaction mediated by iron(III) chloride.
These [b]ꢀbisphenanthreneꢀfused azaBODIPYs showed decreased fluorescence and
interesting semiconducting properties. Herein, we report a novel method to synthesize
three [a]ꢀphenanthreneꢀfused azaBODIPYs (Figure 1b) via the bromination, Suzuki
coupling in concert with the key palladiumꢀcatalyzed intramolecular CꢀH activation
1
3
reaction. The Xꢀray structures, electronic and optical properties of these resultant
dyes were investigated and compared with corresponding [b]ꢀbisphenanthreneꢀfused
azaBODIPYs .
RESULTS AND DISCUSSION
Syntheses
The starting azaBODIPY 1 was prepared in 35% overall yield over three steps from
commercially available 4ꢀmethoxyacetophenone and 3,4,5ꢀtrimethoxybenzaldehyde
(
Scheme S1 in the supporting information). Bromination of 1 with 2.3 equiv. of liquid
bromine afforded 2,6ꢀdibromoazaBODIPY 1Br in 78% yield. Subsequent Suzuki
coupling on 1Br with 4ꢀtertꢀbutylphenylboronic acid provided
hexaphenylazaBODIPY 2 in 75% yield (Scheme 1). We rationalized that the
installation of the three methoxy directing groups on 1,7ꢀphenyls of azaBODIPY 2
would be able to activate this site to participate in the oxidativeꢀringꢀclosure reaction
to achieve [a]ꢀphenanthreneꢀfused azaBODIPY 4a. Interestingly, the application of 2
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3 2 2 3 2
for the oxidativeꢀringꢀfusion reaction with 10 equiv. of FeCl in CH Cl /CH NO at
room temperature still generated exclusively [b]ꢀannulated 3 as a slightly polar
12
product in 87% yield (Scheme 1). Similar to previous report, azaBODIPY 3 showed
a 103 nm redꢀshift in the absorption (centered at 797 nm) with respect to 2 (centered
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at 694 nm) in toluene. This indicates the successive ring fusion on the chromophore.
59 8 3 2
HRMS (APCI) showed a parent ion peak at m/z 998.4348 (calcd. for C60H O N BF
+
[
M+H] 998.4358) for this compound, indicating that only four protons have been
1
removed from this reaction. This loss of four protons was further confirmed by H
NMR spectra.
MeO
MeO
OMe
MeO
Br
OMe
OMe
OMe MeO
N
OMe MeO
N
MeO
MeO
MeO
O
H
OMe MeO
35% yield
over 3 steps
2.3 equiv Br2
Br
N
N
N
N
B
0 oC, 15 min
B
F
F
F F
O
1
1Br
MeO
7
8%
MeO
OMe
MeO
equiv
OMe
Pd(PPh3)4
Na2CO3
80 oC, 12 h
tꢀBu
B(OH)2
4
MeO
MeO
OMe
OMe
OMe MeO
N
MeO
OMe
OMe
OMe MeO
N
MeO
10 equiv FeCl3
tꢀBu
tꢀBu
tꢀBu
N
N
tꢀBu
N
N
B
5 min, rt
B
F
F
F
F
3
2
MeO
87%
OMe
75%
MeO
OMe
20 equiv Br2,
0 oC, 5 min
MeO
OMe
OMe
MeO
MeO
OMe
OMe
OMe MeO
OMe MeO
MeO
Pd(OAc)2
PPh3
K2CO3
Br
Br
N
N
B
tꢀBu
tꢀBu
toluene tꢀBu
tꢀBu
N
N
N
N
B
20 oC, 32 h
1
F
F
F F
4
a
2
Br
MeO
4
6%
OMe
MeO
OMe
82%
Scheme 1. Synthesis of [a]ꢀphenanthreneꢀfused azaBODIPYs 3 and 4a.
We thus turned to develop a new method for regioselective synthesis of [a]ꢀfused
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azaBODIPY 4a (Scheme 1) through an intramolecular CꢀH activation reaction of
azaBODIPY 2Br, in which Br groups were installed on 2 positions of 1,7ꢀphenyl
groups. By taking advantage of the three electronꢀrich directing methoxy groups on
the 1,7ꢀphenyls of azaBODIPY 2, dibromohexaphenylazaBODIPY 2Br was obtained
regioselectively in 82% yield from the bromination of hexaphenylazaBODIPY 2 with
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0 equiv. of liquid bromine. [a]ꢀAnnulated isomer 4a was successfully synthesized in
6% yield from dibromohexaphenylazaBODIPY 2Br through intramolecular CꢀH
4
2
activation reaction using Pd(OAc) as catalyst under anhydrous airꢀfree conditions
1
13
(
Scheme 1). The formation of 4a was confirmed by H and C NMR and HRMS with
+
a parent ion peak at m/z 998.4350 (calcd. for C H O N BF m/z 998.4358 [M+H] ).
6
0
59
8
3
2
Compound 4a showed a 51 nm redꢀshift in the absorption (centered at 745 nm) with
respect to 2 (centered at 694 nm) in toluene. Fortunately, the [a]ꢀphenanthreneꢀfused
azaBODIPY 4a was unambiguously confirmed via the Xꢀray crystallographic analysis
(Figure 2d).
With the successful syntheses of [a]ꢀphenanthreneꢀfused azaBODIPY 4a, we next
attempted to further apply the above developed method to synthesize
[
a]ꢀphenanthreneꢀfused
4b.
3
,5ꢀDiꢀ(4ꢀmethoxyphenyl)ꢀ1,7ꢀdiꢀ(2ꢀbromopheny)azaBODIPY 5, as the key precursor
for [a]ꢀphenanthroꢀazaBODIPYs was generated in 30% overall yield in three steps
(Scheme S2 in the supporting information) from commercially available
2ꢀbromobenzaldehyde and 4ꢀmethoxyacetophenone. AzaBODIPY 6 was then
synthesized from the Suzuki reaction between 4ꢀtertꢀbutylbenzeneboronic acid and 5
in 92% yield (Scheme 2). The oxidative ringꢀfusion reaction of 6 under FeCl
3
in
CH Cl and other conditions was failed, probably due to the poor stability of target
2
2
[a]ꢀphenanthreneꢀfused 4b under the reaction condition. Thus, treatment of 6 with
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liquid bromine afforded the 6Br in 72% yield. The palladium catalyzed
intramolecular CꢀH activation of 6Br successfully gave the mixture of
[
(
a]ꢀphenanthreneꢀfused azaBODIPYs 4b and 4c in 27% and 38% yields, respectively
Scheme 2). All these resulting azaBODIPYs were characterized by NMR and HRMS,
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and [a]ꢀphenanthreneꢀfused azaBODIPY 4c was further characterized by Xꢀray
crystallographic analysis (Figure 2c).
tꢀBu
O
O
H
Br
N
B
Br
4 equiv
B(OH)2
30% yield
over 3 steps
Br
N
N
F
F
Pd(PPh3)4
2
OMe
Na CO3
8
0 oC, 12 h
5
MeO
OMe
N
4
equiv Br2
N
B
0 oC, 5 min
tꢀBu
Br
Br
N
N
N
B
N
tꢀBu
tꢀBu
tꢀBu
F
F
F F
6
6Br
72%
92%
MeO
FeCl3
OMe
MeO
OMe
Pd(OAc)2
90 oC,
PPh3
decompose
8 h
Na2CO3
N
N
B
N
B
N
N
N
F
tꢀBu
tꢀBu
tꢀBu
tꢀBu
F
F
F
4
38%
c
4b
27%
MeO
OMe
MeO
OMe
Scheme 2. Synthesis of [a]ꢀphenanthreneꢀfused azaBODIPYs 4b and 4c.
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X-ray Structure
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Figure 2. Top (and side) views of the Xꢀray crystal structures of (a) 2, (b) 2Br, (c) 4c
and (d) 4a. Thermal ellipsoids were shown at 50 % probability. The grayꢀ, blueꢀ, redꢀ,
pinkꢀ, olivine and orangeꢀcolored atoms represent C, N, O, B, F and Br, respectively.
Hydrogen atoms are omitted for clarity.
Crystals of 2, 2Br, 4a and 4c suitable for Xꢀray analysis were obtained from the
slow diffusion of anhydrous ethanol or hexane into their dichloromethane solutions
(within one week) at room temperature. These azaBODIPYs showed small
pyrroleꢀpyrrole dihedral angle (<7.1°, Table S1 in the supporting information), with
typical BꢀN and BꢀF bond lengths (1.54ꢀ1.57 Å and 1.35ꢀ1.39 Å, respectively, Table
S2). AzaBODIPY 4a showed a small phenanthreneꢀphenanthrene dihedral angle
o
(
8.37 ). The bond lengths of CꢀC, pyrrolic and nonpyrrolic CꢀN within the
azadipyrromethene framework of 4a showed no clear distinction between the single
and double bonds (Table S2 in the supporting information). Thus, the annulations of
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phenanthrene moieties to the azaBODIPY core cause little structural disruption of the
planarity of the core structure. On the other hand, it greatly affected the dihedral
angles between the azadipyrromethene framework and the aryl substituents (PaꢀPc)
(Table S3 in the supporting information). For example, the dihedral angles between
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azadipyrromethene framework and 1,7/2,6ꢀphenyls (Pa and Pc) are between 45ꢀ54°
for 2 and 2Br, respectively. These dihedral angles were significantly decreased to less
than 16° in 4a. By contrast, a gradually increased dihedral angle between 3,5ꢀphenyls
(Pb) and the azadipyrromethene framework was observed for 4a (78°) with respect to
2
and 2Br (61 and 65°, respectively). Similar trends were clearly observed in the
unsymmetrical azaBODIPY 4c (Table S4 in the supporting information), in which the
dihedral angles between azadipyrromethene framework and 1,7ꢀ or 3,5ꢀphenyls are
3
.5° (Pa), 34° (Pa’), 33° (Pb) and 86° (Pb’), respectively.
Spectroscopic properties
The absorption spectra of 3 and 4a in toluene were compared with the parent 2 to
evaluate the impact of different fusion positions on extending the conjugation of the
system (Figure 3a and Table 1). AzaBODIPYs 3 and 4a each showed a typical narrow
absorption band similar to most azaBODIPYs, with the absorption maximum centered
at 797 and 745 nm, respectively. The larger redꢀshifted absorption was observed for 3
over 4a (103 and 51 nm, respectively) with respect to 2, indicating [b]ꢀfusion may be
14a
more efficient in extending the πꢀconjugation and reducing the HOMOꢀLUMO gap.
ꢀ1
ꢀ1
In addition, [b]ꢀfusion doubled the molar absorptivity (ε = 162700 M cm for 3) with
ꢀ1
ꢀ1
respect to 2 (ε = 79500 M cm ), while a smaller enhancement was observed for
ꢀ1
ꢀ1
[
a]ꢀisomer 4a (ε = 124700 M cm ).
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Wavelength (nm)
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(b)
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4
a
0.5
0.0
7
00
750
800
850
900
Wavelength (nm)
Figure 3. Overlaid absorption (a) and normalized fluorescence emission (b) spectra of
2, 3 and 4a in toluene.
Similar modulations in the fluorescence behaviour were also observed with the
variation of the fusion positions (Figure 3b). A 45 and 84 nm redꢀshifted fluorescence
max
emission was observed for 3 and 4a (λem
= 810 and 771 nm, respectively) with
respect to 2, respectively. Interestingly, [a]ꢀannulated 4a showed intense fluorescence
φ = 0.35) in toluene, while its isomer 3 showed very weak fluorescence emission
(
14
comparable to that of parent 2. The origin of the weak fluorescence for 2 may
associated with the internal conversion due to the rotation of six aryl groups. This
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remarkablely intense fluorescence was also observed for [a]ꢀphenanthreneꢀfused
azaBODIPYs 4b and 4c. 4b and 4c showed emission maxima at 741 and 723 nm with
fluorescent quantum yields of 0.32 and 0.38, respectively. More importantly, both
annulated dyes 3 and 4a showed comparably good photostabilities with that of parent
1,3,5,7ꢀtetraphenylazaꢀBODIPY in toluene (Figure S15 in the supporting
information).
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Table 1. Photophysical properties of azaBODIPYs 1-4 at room temperature in
toluene.
Stokesꢀshift
max
max
ꢀ1
ꢀ1
a
dyes
λ
abs
(nm)
λ
em
(nm)
ε (M cm )
Φ
ꢀ1
(
cm )
1
698
689
694
706
797
745
716
701
724
723
726
740
810
771
741
723
91900
0.24
0.002
0.04
514
1
2
2
3
Br
72700
683
635
651
201
453
471
434
79500
Br
65800
0.08
162700
124700
147700
100400
0.05
4a
0.35
4
b
0.32
4
c
0.38
a
fluorescence
,7ꢀdiphenylꢀ3,5ꢀdimehoxyphenylꢀazadipyrromethene (
reference compound for 1, 1Br, 2, 2Br, 4b, 4c and Indocyanine Green (ICG) (φ =
quantum
yields
were
obtained
by
using
1
Φ = 0.36 in chloroform) as
0
.12 in DMSO) for 3 and 4a. The standard errors are less than 10%.
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DFT calculations
To elucidate the influence of fusion positions on the electronic and optical
properties of these phenanthreneꢀannulated azaBODIPYs, cyclic voltammetry of these
dyes was studied (Figure S16 and Table S5 in the supporting information).
AzaBODIPYs 1ꢀ4 each displayed a reversible or quasiꢀreversible reduction wave,
with a reversible or quasiꢀreversible oxidation wave. [a]ꢀAnnulation in 4a mainly
increased the HOMO energy level to ꢀ5.28 eV from ꢀ5.40 eV for 2, which were
calculated from their onset potential of the first oxidation and reduction waves. This
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3
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0
9
,11
result is similar to most reported aromaticꢀring annulated chromophores , in which
the decrease of bandgaps were generally achieved via the increase of HOMO energy
levels. By contrast, the overall decreased bandgap observed for [b]ꢀannulated 3
(relative to 4a) not only came from the increased HOMO energy level to ꢀ5.29 eV
from ꢀ5.40 eV for 2, but also came from the decreased LUMO energy level to ꢀ4.07
eV from ꢀ3.91 eV for 2. The HOMOꢀLUMO energy gap of 3 is smaller than that of 4a,
which is in good agreement with the absorption spectra shown in Figure 3a.
Figure 4. Frontier molecular orbitals and the energies of 2, 3 and 4a.
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DFT calculations indicate that the HOMO orbitals are mainly delocalized over both
the central azadipyrromethene framework and the phenanthrene moieties for both 3
and 4a, while the HOMO coefficients are mainly located on the central
azadipyrromethene framework and 3,5ꢀ phenyls for 2 (Figure 4). The LUMO
coefficients are mainly located on the central azadipyrromethene framework and 3,5ꢀ
phenyls for both 2 and [b]ꢀannulated 3, while, in contrast, the LUMO orbitals are
mainly located on the central azadipyrromethene framework and 1,7ꢀ phenyls for
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[
b]ꢀannulated 4a (Figure 4). In comparison with 2, both annulated isomers showed
destabilized calculated HOMO energy levels, while only [b]ꢀisomer also showed
stabilized LUMO energy levels. The calculated HOMO and LUMO energy levels are
in good agreement with those collected by cyclic voltammetry. The modulation of the
fusion positions from [b] to [a] led to the increased calculated LUMO levels from
ꢀ3.30 eV (3) to ꢀ3.16 eV (4a), while the calculated HOMO energy levels remain
nearly unchanged (ꢀ5.15 and ꢀ5.14 eV for 3 and 4a, respectively).
1
.0
Total
1
1
0
.2
.0
.8
S0→S1
S0→S4
S0→S14
S0→S20
0.8
0
0
0
.6
.4
.2
0.6
0
0
0
.4
.2
.0
0.0
800
3
00
400
500
600
700
Wavelength (nm)
Figure 5. TDDFT predicted absorption spectra of azaBODIPY 4a. The contributions
from the transitions whose strengths are larger than 0.1 have been depicted. The unit
5
ꢀ1
ꢀ1
for molar absorption coefficient is 10 M cm .
In addition, the computed absorption spectra for azaBODIPYs 2, 3 and 4a are in
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2
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2
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agreement with the experimental ones, with the absorption maximum for all these
dyes mainly contributed from the HOMO to the LUMO transition (Table S6 in the
supporting information). The TDDFT predicted absorption spectra of azaBODIPY 4a
(Figure 6) shows an intense peak contributed from S0 → S1 transition with excitation
0
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2
3
4
5
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0
1
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0
energy of 695 nm and oscillator strength of 0.901. Relatively small still significant
absorption peak around 670 nm is mainly from S0 → S4 transition with calculated
excitation energy of 565 nm and oscillator strength of 0.150). Similarly, azaBODIPY
3
also has an shoulder peak which is contributed from S0 → S3 transition with
calculated excitation energy of 611 nm and oscillator strength of 0.138), along with an
intense peak contributed from S0 → S1 transition with excitation energy of 714 nm
and oscillator strength of 0.701. Parent azaBODIPY 2 shows a S0 → S1 transition
with excitation energy of 646 nm and a S0 → S3 transition with excitation energy of
5
83 nm. These two excited states both contribute to the maximum absorption of 2,
resulting its broad absorption peak observed from 600ꢀ7590 nm (Figure 3a).
Cytotoxicity and bioimaging studies
[a]ꢀFused azaBODIPY 4a was chosen for biological evaluation in human HEp2
cells and the results are summarized in Figures 6. The biocompatibility of 4a was
evaluated via MTT assays. As shown in Figure 6a, there is no evident cell death even
at a high concentration of 10 ꢁM 4a, indicating nontoxicity of the compound to cells
under present condition.
AzaBODIPY 4a was readily taken up by the human HEp2 cells and the images
taken by fluorescence microscope were shown in Figure 6. After incubation of HEp2
cells with 4a for 8 h, this dye proved to be membrane permeable and strong red
fluorescence was observed in the cytoplasm (Figure 6c). The fluorescence of 4a in
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cells shows an attractive bright NIR bioimaging property which is potential for further
application in vitro and in vivo.
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Figure 6. Cell viability of HepG2 cells incubated with 4a for 24 h (a); fluorescence
images of HepG2 cells stained with 4a (5.0 ꢁM) and DAPI (1.67 ꢁg/ml): (b) DAPI
fluorescence, (c) 4a fluorescence, (d) Merged image (b) and (c); scale bar was 10 uM.
Conclusion
In summary, we have developed a novel method to synthesize unprecedented
[
a]ꢀphenanthreneꢀfused azaBODIPYs via the bromination, Suzuki coupling in concert
with the key palladiumꢀcatalyzed intramolecular CꢀH activation reaction on parent
azaBODIPY chromophore. The Xꢀray structures, electronic and optical properties of
these πꢀextended systems were investigated. DFT calculation and cyclic voltammetry
studies indicated, in comparison with parent hexaphenylazaBODIPY 2, the
corresponding [b]ꢀphenanthreneꢀfused azaBODIPY 3 showed destabilized HOMO
energy levels and stabilized LUMO energy levels, while [a]ꢀphenanthreneꢀfused
azaBODIPY 4a mainly showed destabilized HOMO energy levels. TDDFT
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2
2
2
2
2
2
2
2
2
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calculation indicated the absorption maximum for all these dyes mainly contributed
from the HOMO to the LUMO transition. Compared with corresponding
hexaphenylazaBODIPY 2, [a]ꢀphenanthreneꢀfused azaBODIPYs not only show
strong redꢀshifted NIR absorption, but also have high fluorescent quantum yields. The
0
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1
2
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4
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7
8
9
0
max
strong NIR absorption (λabs
= 745 nm, log ε = 5.1) and fluorescence emission
max
(λ
em
= 771 nm, φ = 0.35) made [a]ꢀphenanthreneꢀfused azaBODIPY 4a an
attractive bright NIR bioimaging agent.
Experimental Section
General. NMR data were obtained on a 300/500 MHz NMR spectrometer at room
temperature. Chemical shifts (δ) are given in ppm relative to TMS. Highꢀresolution
mass spectra were obtained using APCIꢀTOF in positive mode. Absorption and
fluorescence emission spectra were recorded on commercial spectrophotometers at
room temperature. Relative fluorescence quantum efficiencies of these dyes were
obtained by comparing the areas under their emission spectra with that of the
reference compound. Nonꢀdegassed, spectroscopic grade solvents and a 10 mm quartz
cuvette were used. Dilute solutions (0.01<A<0.05) were used to minimize the
reꢀabsorption effects. Quantum yields were determined using the following
15
equation :
−
A (λ
)
)
r
ex
ex
2
Fx 1−10
nx
Φ = Φ ×
×
×
x
r
−A (λ
2
x
Fr
1−10
nr
The subscripts x and r refer respectively to our sample x and reference (standard)
fluorophore r with known quantum yield in a specific solvent, F stands for the
Φ
r
spectrally corrected, integrated fluorescence spectra, A(λ ) denotes the absorbance at
ex
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the used excitation wavelength λex, and n represents the refractive index of the solvent
(in principle at the average emission wavelength).
Cyclic voltammograms were measured in dichloromethane solution, containing
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60
0
.1 M TBAPF as the supporting electrolyte, glassy carbon electrode as a working
6
electrode, Pt wire as a counter electrode, and saturated calomel electrode (SCE) as
ꢀ1
reference electrode at 100 mV s of scanning rate at room temperature.
Crystals of azaBODIPYs 2 (CCDC 1445434), 2Br (CCDC 1445436), 4a (CCDC
1
445439) and 4c (CCDC 1556933) suitable for Xꢀray analysis were obtained by slow
diffusion of anhydrous ethanol into their dichloromethane solutions (within one week
period) at room temperature. A suitable crystal was chosen and mounted on a glass
fiber using grease. Data were collected using a diffractometer equipped with a
graphite crystal monochromator situated in the incident beam for data collection at
16
room temperature. Cell parameters were retrieved using SMART software and
17
refined using SAINT on all observed reflections. The determination of unit cell
parameters and data collections were performed with Mo Kα radiation (λ) at 0.71073
Å. Data reduction was performed using the SAINT software, which corrects for Lp
and decay. The structure was solved by the direct method using the SHELXSꢀ974
2
18
program and refined by least squares method on F , SHELXLꢀ97, incorporated in
19
SHELXTL V5.10.
Ground state geometries for azaBODIPYs 1ꢀ4 were optimized using
2
0
TimeꢀDependent Density Functional Theory (TDꢀDFT) method at B3LYP/6ꢀ31G
21
(d) level . The same method was used for vibrational analysis to verify that the
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5
5
6
optimized structures correspond to local minima on the energy surface. TDꢀDFT
computations were used to obtain the vertical excitation energies and oscillator
strengths at the optimized ground state equilibrium geometries under the
B3LYP/6ꢀ31G (d) theoretical level. The geometry optimizations for these dyes in
dichloromethane were performed using the SelfꢀConsistent Reaction Field (SCRF)
method and Polarizable Continuum Model (PCM). All of the calculations were
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0
22
carried out by the methods implemented in Gaussian 09 package.
Synthesis.
(E)-1-(4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-propenone (S1): Compound
S1 was synthesized from the condensation of 3,4,5ꢀtrimethoxybenzaldehyde (1.96 g,
10 mmol) with 4ꢀmethoxyacetophenone (1.50 g, 10 mmol) in the presence of KOH
(0.8 g, 14 mmol) in anhydrous ethanol (30 mL). The reaction mixture was stirred at
room temperature for 30 min. Precipitate was collected, washed with water, and
extracted with dichloromethane. Organic layers were combined, and dried over
anhydrous Na
yellowish green solid in 91% yield (2.98 g). mp 132ꢀ133 C. H NMR (300 MHz,
CDCl ) δ 8.03 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 15.6 Hz, 1H), 7.41 (d, J = 15.6 Hz,
H), 6.97 (d, J = 8.7 Hz, 2H), 6.85 (s, 2H), 3.91 (s, 6H), 3.88 (d, J = 4.5 Hz, 3H), 3.87
2 4
SO . Solvent was removed under vacuum to afford compound S1 as a
o
1
3
1
13
(s, 3H). C NMR (CDCl , 75 MHz) δ 188.7, 163.4, 153.4, 144.1, 140.1, 130.8, 130.6,
3
1
21 5
21.2, 113.8, 105.4, 114.0, 61.0, 56.2, 55.5. HRMS (APCI) calcd. for C19H O
+
[M+H] 329.1384, found 329.1379.
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1
-(4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-4-nitro-butan-1-one (S2): To S1
(3.28 g, 10 mmol) in anhydrous ethanol (30 mL) was added diethylamine (15 mL) and
nitromethane (5.4 mL, 0.10 mol). The reaction mixture was heated under reflux for 24
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11
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13
14
15
16
17
18
19
20
21
22
23
24
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52
53
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55
56
57
58
59
60
hrs. Solvent was removed under vacuum to give compound S2 as a white solid in 95%
o
1
yield (3.70 g). mp 118ꢀ119 C. H NMR (300 MHz, CDCl
3
) δ 7.90 (d, J = 8.7 Hz,
2
4
H), 6.92 (d, J = 8.7 Hz, 2H), 6.46 (s, 2H), 4.85ꢀ4,79 (m, 1H), 4.70ꢀ4.63 (m, 1H),
13
.22ꢀ4.04 (m, 1H), 3.86 (s, 3H), 3.83 (s, 6H), 3.80 (s, 3H), 3.48ꢀ3.14 (m, 1H). C
3
NMR (CDCl , 75 MHz) δ 195.4, 163.8, 153.5, 135.0, 130.3, 130.8, 129.4, 113.9,
1
04.4, 105.4, 79.5, 60.8, 56.1, 55.5, 41.2, 39.7. HRMS (APCI) calcd. for C H NO
20 24
7
+
[
M+H] 390.1547, found 390.1543.
1,7-di(3,4,5-trimethoxylphenyl)-3,5-di(4-methoxylphenyl)azaBODIPY
(1):
AzaBODIPY 1 was synthesized from the reaction of S2 (3.89 g, 10 mmol) with
o
CH
3
CO
2
NH
4
(11.6 g, 0.15 mol, 15 equiv) in acetic acid (20 mL) at 120 C for 8 h.
The reaction mixture was then cooled down to room temperature. The precipitate was
filtered, washed with water and dried under vacuum. It was directly applied for the
.
subsequent boron complexation with triethylamine (10 mL, 72 mmol) and BF
3
Et
2
O
o
(15 mL, 0.14 mol) in toluene. The reaction mixture was stirred at 65 C for 0.5 h,
2 4
diluted with dichloromethane, dried over anhydrous Na SO , filtered and evaporated
under vacuum. The crude product was purified by column chromatography on silica
gel (petroleum/ dichloromethane = 3 / 10, v/ v) to give 1 as a red powder in 40% yield
o
1
(1.47 g). mp > 220 C. H NMR (300 MHz, CDCl
3
) δ 8.09 (d, J = 8.8 Hz, 4H), 7.19
(s, 4H), 7.01 (d, J = 8.7 Hz, 4H), 6.96 (s, 2H), 3.92 (s, 6H), 3.89 (s, 6H), 3.77 (s,
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2
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4
4
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1
3
1
1
2H). C NMR (CDCl
3
, 75 MHz) δ 161.9, 157.9, 153.2, 145.2, 143.3, 139.2, 128.2,
2 3 8
24.1, 118.5, 114.2, 106.5, 61.0, 56.0, 55.4. HRMS (APCI) calcd. for C40H39BF N O
+
[
M+H] 738.2793, found 738.2790.
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2
,6-dibromo-1,7-di(3,4,5-trimethoxylphenyl)-3,5-di(4-methoxylphenyl)azaBODIP
Y (1Br): 2,6ꢀDibromoazaBODIPY 1Br was synthesized from dropwise addition of
the dichloromethane (10 mL) solution of liquid bromine (370 mg, 2.3 mmol, 2.3
equiv) to 1 (737 mg, 1 mmol) in dry dichloromethane (150 mL). The reaction mixture
was stirred at iceꢀcold condition for 15 min. The crude product was purified by
column chromatography on silica gel (petroleum ether/dichloromethane = 1/5, v/v) to
o
1
give 1Br as a red powder in 78% yield (697 mg). mp > 220 C. H NMR (300 MHz,
CDCl
3
) δ 7.75 (d, J = 8.7 Hz, 4H), 7.10 (s, 4H), 6.99 (d, J = 8.7 Hz, 4H), 3.94 (s, 6H),
13
3
.87 (s, 6H), 3.68 (s, 12H). C NMR (CDCl
3
, 75 MHz) δ 161.7, 157.5, 152.6, 144.0,
141.9, 139.3, 132.4, 126.1, 121.7, 113.6, 109.4, 108.2, 61.0, 55.9, 55.3. HRMS
+
(
APCI) calcd. for C H BBr F N O [M+H] 894.1004, found 894.0998.
40
37
2
2
3
8
1,7-di(3,4,5-trimethoxylphenyl)-2,6-di(4-t-butylphenyl)-3,5-di(4-methoxylphenyl)
azaBODIPY (2): To a dried Schlenk flask were added 1Br (890 mg 1 mmol),
palladium tetrakis(triphenylphosphine) (121 mg, 0.1 mmol), 4ꢀtertꢀbutylphenylbronic
acid (712 mg, 4 mmol, 4 equiv). This mixture was degassed via three
freeze-pump-thaw cycles. To the mixture was added dry toluene (10 mL) and the
2 3
aqueous solution (8 mL) of Na CO (0.85 g, 8 mmol) via syringe. The reaction
mixture was further degassed via three freezeꢀpumpꢀthaw cycles and purged with
o
argon. The Schlenk flask was sealed and heated to 80 C for 12 h, cooled down to
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room temperature, washed with brine. Organic layers were combined and dried over
2 4
anhydrous Na SO . Solvent was removed under vacuum. The reside was purified via
column chromatograph on silica gel (petroleum ether/dichloromethane = 1:4) to
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53
54
55
56
57
58
59
60
o
1
afford compound 2 as a red solid in 75% yield (748 mg). mp > 220 C. H NMR (300
MHz, CDCl ) δ 7.46 (d, J = 8.6 Hz, 4H), 7.25 (d, J = 6.9 Hz, 4H), 6.95 (d, J = 8.1 Hz,
H), 6.78 (d, J = 8.7 Hz, 4H), 6.65 (s, 4H), 3.86 (s, 6H), 3.79 (s, 6H), 3.32 (s, 12H),
3
4
1
1
3
1
1
3
3
.27 (s, 18H). C NMR (CDCl , 75 MHz) δ 160.8, 158.0, 152.2, 150.3, 145.2, 140.1,
38.0, 133.1, 132.6, 130.6, 130.3, 127.2, 125.4, 122.9, 113.3, 108.3, 60.9, 55.3, 55.2,
+
4.6, 31.3. HRMS (APCI) calcd. for C H BF N O [M+H] 1002.4671, found
60 63
2
3
8
002.4663.
[b]-Fused azaBODIPY 3: To 2 (50 mg, 0.05 mmol) in dichloromethane (30 mL) was
dropwise added FeCl (84 mg, 0.5 mmol) in CH NO (2 mL) via syringe. The reaction
3
3
2
mixture was stirred for 5 min and was quenched by adding water (50 mL). The
mixture was extracted with CH Cl . Organic layers were combined and dried over
2
2
anhydrous Na
2 4
SO . Solvent was removed under vacuum to afford 3 as a red solid in
o
1
8
7% yield (43 mg).mp > 220 C. H NMR (300 MHz ,CDCl ) δ 9.47 (d, J = 6.0 Hz,
3
2H), 8.35 (s, 2H), 8.06 (d, J = 9.0 Hz, 2H), 7.99 (s, 2H), 7.38 (d, J = 9.0 Hz, 4H), 6.78
13
(
s, 4H), 4.10 (s, 6H), 4.02 (s, 6H), 3.65 (s, 12H), 1.43 (s, 18H). C NMR (75 MHz,
CDCl ) δ 162.2, 152.7, 150.7, 150.1, 148.7, 138.3, 138.1, 137.8, 132.4, 128.5, 128.3,
3
1
26.7, 125.7, 125.5, 125.3, 120.0, 117.5, 114.5, 108.9, 108.4, 61.0, 56.1, 55.7, 35.1,
+
31.3. HRMS (APCI) calcd. for C60
H59BF
2
N
3
O
8
[M+H] 998.4358, found 998.4348.
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1
,7-di(2-bromo-3,4,5-trimethoxylphenyl)-2,6-di(4-t-butylphenyl)-3,5-di(4-methox
ylphenyl)azaBODIPY (2Br): To 2 (200 mg, 0.2 mmol) in dried dichloromethane
100 mL) was dropwisely added liquid bromine (639 mg, 4.0 mmol, 20 equiv) in
(
0
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7
8
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2
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8
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dried dichloromethane (10 mL). The reaction mixture was stirred at iceꢀcold condition
for 5 min. The crude product was purified by column chromatography on silica gel
(petroleum ether : dichloromethane = 1:1) to give 2Br as a red powder in 82% yield
o
1
(223 mg). mp > 220 C. H NMR (500 MHz, CDCl
3
) δ 9.62 (s, 2 H ), 9.08 (s, 2H ),
7
4
1
.20 (d, J = 8.4 Hz, 4H), 7.41ꢀ7.33 (m, 4H), 7.05 (d, J = 8.7 Hz, 4H), 4.13 (s, 6H),
13
.04 (s, 6H), 3.99 (s, 6H), 3.92 (s, 6H), 1.42 (s, 18H). C NMR (126 MHZ, CDCl ) δ
3
61.1, 158.2, 152.2, 150.9, 150.1, 144.9, 143.0, 140.9, 135.3, 132.6, 129.9, 129.5,
129.1, 124.8, 123.2, 113.4, 111.8, 110.8, 61.1, 60.8, 56.3, 55.2, 34.5, 31.2. HRMS
+
(APCI) Calcd. for C60
61
H O
8
N
3
BBr
2
F
2
[M+H] 1160.2861 found 1160.2859.
[a]-Fused azaBODIPY 4a: To 2Br (58 mg, 0.05 mmol) in toluene (5 mL) was added
Pd(OAc) (3.4 mg, 0.015 mmol), PPh (8.0 mg, 0.03 mmol) and K CO (21 mg, 0.15
2
3
2
3
o
mmol, 3 equiv). The resulting suspension was stirred at 120 C for 32 h under argon.
The crude product was purified by column chromatography on silica gel (petroleum
ether/ dichloromethane = 1/1, v/v) to give 4a as a blue chip powder in 46% yield (27
o
1
3
mg). mp > 220 C. H NMR (300 MHz, CDCl ) δ 7.52 (d, J = 8.5 Hz, 4H), 7.06 (d, J
= 3.0 Hz, 4H), 6.82 (d, J = 9.0 Hz, 4H), 6.73 (d, J = 8.5 Hz, 4H), 6.45 (s, 2H), 3.85 (s,
13
6
H), 3.82 (s, 12H), 3.72 (s, 6H), 1.22 (s, 18H). C NMR (126 MHz, CDCl
3
) δ 160.9,
156.1, 153.7, 152.8, 149.2, 145.5, 141.8, 131.3, 130.3, 125.6, 125.5, 125.0, 124. 8,
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24.4, 124.2, 123.1, 122.5, 114.1, 106.6, 61.6, 60.5, 57.1, 55.3, 35.2, 31.5. HRMS
+
(APCI) Calcd. for C60
59
H O
8
N
3
BF
2
[M+H] 998.4358 found 998.4350.
(E)-1-(4-methoxyphenyl)-3-(2-bromophenyl)-propenone (S3) was obtained as a
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60
yellow solid from 2ꢀbromobenzaldehyde (1.85 g, 10 mmol) and
4
8
1
7
ꢀmethoxyacetophenone (1.50 g, 10 mmol) following the same procedure as S1 in
o
1
3
4% yield (2.65 g). mp 75ꢀ76 C. HꢀNMR (300 MHz, CDCl ) δ 8.14 (d, J = 15.0 Hz,
H), 8.05 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.47 ꢀ
13
.34 (m, 2H), 7.25 ꢀ 7.01 (m, 1H), 7.00 (d, J = 8.3 Hz, 2H), 3.90 (s, 3H). CꢀNMR
(
75 MHz, CDCl ) δ 188.6, 163.5, 142.4, 135.3, 133.5, 131.1, 131.0, 130.1, 127.9,
3
+
1
27.7, 125.8, 125.0, 113.8, 55.5. HRMS (APCI) calcd. for C16
317.0172, found 317.0170.
-(4-methoxyphenyl)-3-(2-bromophenyl)-4-nitro-butan-1-one (S4) was obtained as
H
13BrO
2
[M+H] :
1
a yellow oil from S3 (3.17 g, 10 mmol) following the same procedure as S2 in 90%
1
yield (3.4 g). H NMR (300 MHz, CDCl ) δ 7.91 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.0
3
Hz, 1H), 7.27 ꢀ 7.25 (m, 2H), 7.14 ꢀ 7.11 (m, 1H), 6.91 (d, J = 9.1 Hz, 2H), 4.86 ꢀ
13
4
.83 (m, 2H), 4.69 ꢀ 4.64 (m, 1H), 3.85 (s, 3H), 3.46 (d, J = 7.3 Hz, 2H). C NMR
(75 MHz, CDCl
3
) δ: 195.2, 163.9, 138.0, 133.8, 130.4, 129.3, 129.2, 128.1, 128.0,
+
1
24.5, 113.9, 77.7, 55.6, 39.7, 38.3. HRMS (APCI) calcd. for C17
378.0336, found 378.0334.
,7-di(2-bromophenyl)-3,5-di(4-methoxylphenyl)azaBODIPY (5) was obtained as
a gray solid from S4 (3.77 g, 10 mmol) following the same procedure as 1 in 39%
4
H17BrNO [M+H]
1
o
1
3
yield (1.29 g). mp > 220 C. HꢀNMR (300 MHz, CDCl ) δ: 8.06 (d, J = 8.3 Hz, 4H),
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8
1
.60 (d, J = 7.3 Hz, 4H), 7.26 – 7.20 (m, 4H), 7.14 (d, J = 8.4 Hz, 2H), 6.97 (d, J =
1
3
3
.5 Hz, 4H), 3.84 (s, 6H). CꢀNMR (75 MHz, CDCl ) δ 162.1, 157.6, 146.0, 142.2,
33.8, 133.5, 132.7, 131.9, 129.7, 126.7, 123.9, 123.3, 114.4, 55.5. HRMS (APCI)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
calcd. for C H BF Br N O [M+H] 715.0402, found 715.0383.
34
25
2
2
3
2
1
,7-di(2-(4-t-butylphenyl)-phenyl)-3,5-di(4-methoxylphenyl)azaBODIPY (6) was
obtained from 5 (185 mg, 0.26 mmol) and 4ꢀtertꢀbutylphenylbronic acid (153 mg,
o
1
.04 mmol) following the same procedure as 2 in 92% yield (196 mg). mp > 220 C.
1
H NMR (500 MHz, CDCl
3
) δ 8.02 (d, J = 7.3 Hz, 2H), 7.61 (d, J = 8.8 Hz, 4H), 7.46
ꢀ
(
7.40 (m, 10H), 7.25 (d, J = 9.7 Hz, 4H), 6.83 (d, J = 8.9 Hz, 4H), 5.87 (s, 2H), 3.83
13
3
s, 6H), 1.38 (s, 18H). C NMR (126 MHz, CDCl ) δ 162.0, 157.2, 150.5, 146.4,
143.6, 142.9, 139.4, 133.2, 131.7, 131.4, 130.7, 129.8, 129.1, 127.3, 125.5, 124.7,
+
1
23.4, 114.3, 55.7, 35.0, 31.8. HRMS (APCI) Calcd. for C54
822.4042 found 822.4039.
,6-dibromo-1,7-di(2-(4-t-butylphenyl)-phenyl)-3,5-di(4-methoxylphenyl)azaBO
51 2 3 2
H O N BF [M+H]
2
DIPY (6Br) was obtained from 2e (205 mg, 0.25 mmol) and liquid bromine (160 mg,
o
1
mmol) following the same procedure as 2Br in 72% yield (176 mg). mp > 220 C.
1
H NMR (300 MHz, CDCl
3
) δ 7.64 (d, J = 8.8 Hz, 2H), 7.58 ꢀ 7.51 (m, 4H), 7.50 ꢀ
7
.37 (m, 6H), 7.20 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 6.94 ꢀ 6.88 (m, 6H),
13
6.71 (d, J = 8.2 Hz, 2H), 3.83 (s, 6H), 1.26 (s, 18H). C NMR (126 MHz, CDCl ) δ
3
1
62.0, 157.1, 149.9, 149.5, 145.1, 144.9, 143.4, 143.3, 142.9, 138.8, 132.7, 132.5,
131.8, 130.5, 130.3, 129.8, 129.6, 129.3, 129.2, 126.8, 126.6, 125.3, 125.0, 122.2,
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49 2 3 2
13.9, 55.7, 34.9, 34.8, 31.7, 31.6. HRMS (APCI) Calcd. for C54H O N BBr BrF
+
[
M+H] 980.2227 found 980.2245.
[
a]-Fused azaBODIPYs 4b and 4c: To a stirred solution of 6Br (50 mg, 0.05 mmol)
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60
in toluene (5 mL) was added Pd(OAc) (3.4 mg, 0.015 mmol), PPh (8.0 mg, 0.03
2
3
o
2 3
mmol) and Na CO (16 mg, 0.15 mmol). The resulting suspension was stirred at 90 C
for 8 h under argon. The crude product was purified by column chromatography on
silica gel (petroleum ether / dichloromethane = 3/1, v/v) to give 4b (12 mg, 27 %) and
o
1
4
c (19 mg, 38%). 4b: mp > 220 C. H NMR (300 MHz, CDCl
3
) δ 9.73 (d, J = 7.8 Hz,
2
H), 8.60 (d, J = 8.2 Hz, 2H), 8.53 (d, J = 8.9 Hz, 2H), 7.88 ꢀ 7.68 (m, 2H), 7.65 (d, J
=
8.6 Hz, 2H), 7.58 (d, J = 6.9 Hz, 4H), 7.50 (s, 2H), 7.10 (d, J = 8.7 Hz, 2H), 3.91 (s,
+
4H), 1.12 (s, 18H). HRMS (APCI) Calcd. for C54
H
47
O
2
N
3
BF
2
[M+H] 818.3724
o
1
found 818.3702. 4c: mp > 220 C. H NMR (300 MHz, CDCl
1H), 8.59 ꢀ 8.52 (m, 2H), 8.17 (d, J = 7.5 Hz, 1H), 7.70 ꢀ 7.54 (m, 11H), 7.43 (d, J =
.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.7 Hz,
3
) δ 9.43 (d, J = 7.7 Hz,
8
1
3
2H), 5.89 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 1.37 (s, 9H), 1.13 (s, 9H). C NMR (126
MHz, CDCl ) δ 161.9, 161.3, 157.3, 157.2, 150.6, 146.0, 143.4, 143.0, 142.8, 139.3,
133.4, 133.2, 131.7, 131.6, 131.4, 131.3, 130.8, 129.9, 129.2, 129.1, 128.9, 128.0,
27.9, 127.7, 127.5, 127.4, 126.6, 125.6, 124.9, 124.6, 123.8, 123.4, 122.7, 120.9,
114.6, 114.3, 55.9, 55.7, 35.0, 31.8, 31.3. HRMS (APCI) Calcd. for C H O N BF
3
1
54
49
2
3
2
+
[
M+H] 820.3886 found 820.3881.
Cell culture
The HepG2 cancer cells (a human hepatocellular carcinoma cell line) from ATCC
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(
American Type Culture Collection) were cultured in Dulbecco's Modified Eagle's
medium (DMEM, Invitrogen, Carlsbad, CA) with 10 % fetal bovine serum (FBS,
ExCell Bio, Shanghai, China) at 37 °C with 5 % CO2.
0
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Cytotoxicity determined by MTT method
The HEp2 cells were plated at 3000 cells per well in a 96ꢀwell plate in DMEM
medium and allowed to grow for 24 h. A gradient concentration of azaBODIPY 4a
from 2 to 10 ꢁM in fresh medium was added as a replacement and the cells were
incubated for 24 h. The working solutions were then removed and the cells were
−1
washed with PBS buffer three times. 20 ꢁL MTT (1.5 mg mL ) was added into each
well, and the cells further incubated at 37 ºC for 4 h in a 10% CO humidified
2
atmosphere. Then the medium was removed and 150 ꢁL DMSO was added. The plate
was shaken for 10 minutes and the absorbance was measured at 490 nm using a
microplate reader.
Cell incubation and imaging
1
00, 000 HepG2 cells were seeded into a 6ꢀwell plate with the same procedure above.
AzaBODIPY 4a solution in medium (5 ꢁM) was added to the above cells and
incubated for another 8 h. The cells were then washed with PBS three times and fixed
by 4% formaldehyde for 15 mins. Organelle tracer DAPI (1.67 ꢁg/ml) was added
subsequently and incubated for 30 min to stain the nucleus. The above solution in
each well was removed and the cells were washed with PBS buffer three times before
imaging. After replacement of medium, cells were imaged using a fluorescence
microscope with a 20×objective lens.
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Supplementary Information (SI) available: Crystal structure data and CIF files,
additional photophysical data and spectra, copies of NMR spectra, high resolution
mass spectra and additional computational data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgements
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This work is supported by the National Nature Science Foundation of China
(21402001, 21372011 and 21672006) and Anhui Province (1508085J07). The
calculations have been done on the supercomputing system in the Supercomputing
Center of USTC.
Reference:
(1) (a) Chen, H.; Dong, B.; Tang, Y.; Lin, W. Acc. Chem. Res. 2017, 50, 1410. (b)
Pansare, V. J.; Hejazi, S.; Faenza, W. J.; Prud’homme, R. K. Chem. Mater. 2012,
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Zhang, Z.; Zhang, H.; Wang, Y. Org. Lett. 2014, 16, 880. (h) Hiruta, Y.; Koiso, H.;
Ozawa, H.; Sata, H.; Hamada, K.; Yabushita, S.; Citterio, D.; Suzuki, K. Org. Lett.
2015, 17, 3022.
(
2) (a) Killoran, J.; Allen, L.; Gallagher, J. F.; Gallagher, W. M.; O’Shea, D. F. Chem.
Commun. 2002, 1862. (b) McDonnell, S. O.; Hall, M. J.; Allen, L. T.; Byrne, A.;
Gallagher, W. M.; O’Shea, D. F. J. Am. Chem. Soc. 2005, 127, 16360. (c)
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