Synthesis and functionalization of asymmetrical benzo-fused BODIPY dyes

Article abstract of DOI:10.1021/jo101164a

A series of asymmetrical benzo-fused BODIPY dyes were synthesized from the Sonogashira coupling and nucleophilic substitution reactions on the 3-halogenated benzo-fused BODIPY, generated from readily available 3-halogeno-1-formylisoindoles in a two-step synthetic procedure. This novel BODIPY platform provides an easy path for the linking of BODIPY fluorophore to various desired functionalities as demonstrated in this work. Most of the resulting BODIPY dyes show long-wavelength absorption and fluorescence emission, with good fluorescence quantum yields and long fluorescence lifetimes.

Full text of DOI:10.1021/jo101164a

pubs.acs.org/joc
applications in highly diverse fields,1 such as labeling rea-
Synthesis and Functionalization of Asymmetrical
Benzo-Fused BODIPY Dyes
gents,3-5 chemosensors,6,7 laser dyes,8 photosensitizers,9 and
fluorescence organic devices.10-12 The absorption and emission
wavelengths for classical BODIPY chromophore center at
470-530 nm. With regard to their various applications, it is
very necessary to have BODIPY dyes absorbing and emitting at
longer wavelengths. Recently, we and several other groups13-16
have achieved the red-shift of the absorption and fluorescence
Lijuan Jiao,* Changjiang Yu, Mingming Liu,
Yangchun Wu, Kebing Cong, Ting Meng, Yuqing Wang,
and Erhong Hao
Anhui Key Laboratory of Functional Molecular Solids,
College of Chemistry and Material Science, and Anhui Key
Laboratory of Molecular Based Materials, Anhui Normal
University, Wuhu, 241000, China
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Wang, J.; Cui, A.; Gao, Y. Org. Biomol. Chem. 2005, 3, 1387. (d) Baruah, M.;
jiao421@mail.ahnu.edu.cn
Received June 15, 2010
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A series of asymmetrical benzo-fused BODIPY dyes were
synthesized from the Sonogashira coupling and nucleophilic
substitution reactions on the 3-halogenated benzo-fused
BODIPY, generated from readily available 3-halogeno-1-
formylisoindoles in a two-step synthetic procedure. This
novel BODIPY platform provides an easy path for the
linking of BODIPY fluorophore to various desired function-
alities as demonstrated in this work. Most of the resulting
BODIPY dyes show long-wavelength absorption and fluor-
escence emission, with good fluorescence quantum yields and
long fluorescence lifetimes.
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Boradiazaindacenes, commonly known as BODIPY dyes, are
strongly UV-absorbing small molecules with high fluorescence
quantum yields, sharp fluorescence emissions, large molar
absorption coefficients, high photochemical stability, and low
sensitivity to the environment,1,2 and they have found wide
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DOI: 10.1021/jo101164a
r
Published on Web 08/09/2010
J. Org. Chem. 2010, 75, 6035–6038 6035
2010 American Chemical Society

Jiao et al.
JOCNote
TABLE 1. Synthesis of 3-Halogenated Benzo-Fused BODIPYs 4a-d
FIGURE 1. Syntheses of symmetrical benzo-fused BODIPYs B
from norbornane-derived pyrrole A.15c,d
X
R
product
yield (%)
Cl
Br
Cl
Br
H
H
CH3
CH3
4a
4b
4c
4d
63
67
53
45
2-halogenated acylpyrroles were further used under acid cata-
lyzed condition for the generation of asymmetrical BODIPYs,
complementary to their previous synthetic breakthrough in the
development13a and functionalization13b-d of a symmetrical
3,5-dichloro-BODIPY platform.6d
FIGURE 2. Benzo-fused BODIPY platform 4.
The resulting 3-halogeno-1-formylisoindoles 2 were used
for the condensation reactions with R-unsubstituted pyrroles
3 under POCl3 catalyzed condition. After subsequent treat-
SCHEME 1. Synthesis of 3-Halogeno-1-formylisoindoles 2a,b,
Using Vilsmeier Haack Reactions
ment with triethylamine and complexation with BF3 OEt2,
the desired benzo-fused BODIPYs 4a-d were generated in
45-67% yields as shown in Table 1.
3
As shown in Figure S1 (Supporting Information), BODIPYs
4 showed a narrow absorption band centered between 542 and
562 nm, with a considerably weaker, broad absorption band
centered at around 320 nm, similar to those previously reported
BODIPY dyes. In addition, BODIPYs 4 gave high molar ab-
sorption coefficients (log ε 4.68-5.10) and favorably good
fluorescence quantum yields in dichloromethane (around 0.6,
Table 2). In comparison with those nonbenzo-fused BODIPY
analogue C19 shown in Figure 2, the fusion of a benzene ring at
the pyrrolic position of BODIPYs 4c-d leads to more than
63 nm red-shift in both the absorption and fluorescence emission
maxima in dichloromethane. No significant solvatochromic
shifts were observed in the absorption and emission maxima for
BODIPYs 4 as shown in Table S1 (Supporting Information).
BODIPYs 4 have valuable halogenated substituents
(chloro- or bromo-) at the 3-position of the BODIPY core,
which provides a facile path for the efficient introduction of
various functionalities to the BODIPY core via coupling or
nucleophilic substitution reactions, bringing spectral changes,
for example the desired red-shift of the spectra or functional
materials. To demonstrate the good reactivity of the 3-haloge-
nated substituent, BODIPY 4c was applied in Sonogashira
coupling reactions with various arylethynyl derivatives as
shown in Scheme 2, from which several asymmetrical benzo-
fused BODIPYs 5 were generated in 53-64% yields within
3 h at 65 °C. In comparison with BODIPY 4c, 4d gave a
similar yield for the generation of BODIPY 5a.
emission maxima via the chemical modification of the ready-
made BODIPY core with aryl, vinyl, styryl, and arylethynyl
substituents, or with a rigid ring fused to the pyrrolic position of
the core. Among those, the rigid ring fused constrain molecules
such as benzo-fused BODIPYs B shown in Figure 1 generally
possess more favorable fluorescence characteristics than those of
the unconstrained dyes.
Currently, the main synthetic approach for the benzo-fused
BODIPYs is the retro-Diels-Alder reaction15c,d of norbornane-
derived pyrroles A developed by Ono et al. as shown in Figure 1,
in which high temperature is required, and less than a handful of
benzo-fused BODIPYs have been reported.
Herein we report the expedious construction of a 3-haloge-
nated benzo-fused BODIPY platform 4 as shown in Figure 2.
The fusion of a benzene ring leads to the increased conjuga-
tion, while the installation of a halogenated substituent at the
3-position provides BODIPY 4 a facile way for the further func-
tionalizations, as demonstrated in this work via Sonogashira
coupling and nucleophilic substitution reactions, from which a
series of asymmetrical benzo-fused BODIPY dyes have been
obtained.
As the key synthetic precursors for BODIPY 4, 3-halogeno-1-
formylisoindoles 2 were synthesized from the readily available
isoindolin-1-one in 40-68% yields using a modified literature
procedure18 as shown in Scheme 1, involving the Vilsmeier-
Haack and the subsequent hydrolysis reactions. While we were
making progress in this project, Dehaen et al.17 reported the
efficient conversion of pyrroles to 2-halogenated acylpyrroles
from the in situ acylation of 2-halogenated pyrroles. These
BODIPYs 5 showed typical absorption and emission
features of BODIPY dyes in dichloromethane as shown in
Figure 3, with strong absorption and emission maxima cen-
tered at 612-618 and 625-633 nm, respectively. In compari-
son with BODIPY 4c, the newly installed arylethynyl groups in
BODIPYs 5a-e caused red-shifts of the absorption and fluore-
scence emission maxima up to 57 and 61 nm, respectively, as
summarized in Table 2. Similar to the starting BODIPY 4c, no
(17) Leen, V.; Braeken, E.; Luckermans, K.; Jackers, C.; Van der
Auweraer, M.; Boens, N.; Dehaen, W. Chem. Commun. 2009, 4515.
(18) Bonnett, R.; McManus, K. A. J. Chem. Soc., Perkin Trans. 1 1996,
2461.
(19) Vos de Wael, E.; Pardon, J. A.; van Koevering, J. A.; Lugtenburg, J.
Recl. Trav. Chim. Pays-Bas 1977, 96, 306.
6036 J. Org. Chem. Vol. 75, No. 17, 2010

Jiao et al.
JOCNote
TABLE 2. Photophysical Properties of BODIPYs 4a-d, 5a-e, and 6a-f in Dichloromethane at Room Temperature
λmax (nm)
log εmax
λem (nm)
Φa
Stokes shift (cm-1
)
τb (ns)
kr (107 s-1
)
knr (107 s-1
)
4a
4b
4c
4d
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
6f
542
542
562
562
612
612
616
618
612
546
574
576
526
548
518
4.68
4.84
4.70
5.10
4.69
4.77
4.53
4.15
4.97
4.87
4.86
4.61
4.41
4.20
4.21
562
562
572
573
629
625
633
631
628
564
588
591
583
586
559
0.62
0.66
0.62
0.63
0.89
0.90
0.63
0.44
0.80
0.65
0.39
0.49
0.61
0.55
0.20
657
657
311
342
442
340
436
333
416
585
415
441
1859
1183
1416
8.23
7.34
8.83
7.15
7.97
7.16
6.91
6.16
7.76
7.97
8.20
11.39
4.82
6.75
5.66
7.5
9.0
7.0
8.8
11.2
12.6
9.1
7.1
10.3
8.2
4.8
4.3
12.7
8.1
4.6
4.6
4.3
5.2
1.3
1.4
5.4
9.1
2.6
4.3
7.4
4.5
8.0
6.7
14.1
3.5
aFluorescence quantum yields for BODIPYs 4a-d (λex = 520 nm) and 6a-e (λex = 520 nm) were calculated with Rhodamin B (0.49 in EtOH)21 as the
reference, while those for BODIPYs 5a-e (λex = 580 nm) and 6f (λex = 490 nm) were calculated with methylene blue22 (0.03 in MeOH) and fluorescein
(0.95 in 0.1 M NaOH)23 as the standard, respectively. bτ represents the fluorescence lifetimes.
SCHEME 2. Synthesis ofAsymmetricalBenzo-Fused BODIPYs
5a-e from the Derivation of 3-Chloro-Benzo-Fused BODIPY 4c,
Using Sonogashira Coupling Reactions
FIGURE 3. Normalized UV-vis (a) and fluorescence (b, λex=580 nm)
spectra of BODIPYs 5a (black), 5b (red), 5c (blue), 5d (magenta), and5e
(green) in dichloromethane at 25 °C.
SCHEME 3. The Application of 3-Chloro-Benzo-Fused BODIPY
4c in the Nucleophilic Substitution Reactions To Generate BODIPYs
6a-f
significant solvatochromic shifts of the spectra were observed
for BODIPYs 5 as summarized in Table S2 (Supporting Infor-
mation). Most of BODIPYs 5 showed high fluorescence quan-
tum yields (between 0.6 and 0.9) in dichloromethane except
BODIPY 5d (0.44) as shown in Table 2. The relatively lower
fluorescence quantum yield observed in BODIPY 5d may be
attributed to a fast intramolecular charge-transfer (ICT) process
from the electron-rich 2-ethynylthiophene to the BODIPY
acceptor similar to those described in the literature.16c,20 The
fluorescence lifetime, which is described by a single exponential,
variety of nucleophiles, including oxygen-centered, sulfur-cen-
parallels the fluorescence quantum yield value, with a lifetime
tered, and nitrogen-centered ones as shown in Scheme 3, from
of ca. 6-8 ns.
which BODIPYs 6 were obtained in 60-95% isolated yields.
BODIPY 4c also showed good reactivity in the nucleo-
In comparison with the monosubstitution reaction on the 3,5-
philic substitution reactions at room temperature with a
dichloroBODIPY,13a BODIPY 4c showed comparable reacti-
vity in reacting with various nucleophiles. The introduction of
(20) (a) Bozdemir, O. A.; Guliyev, R.; Buyukcakir, O.; Selcuk, S.; Kolemen,
S.; Gulseren, G.; Nalbantoglu, T.; Boyaci, H.; Akkaya, E. U. J. Am. Chem. Soc.
2010, 132, 8029. (b) Atilgan, S.; Ozdemir, T.; Akkaya, E. U. Org. Lett. 2008, 10,
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4065. (c) Baruah, M.; Qin, W.; Vallee, R. A. L.; Beljonne, D.; Rohand, T.;
Dehaen, W.; Boens, N. Org. Lett. 2005, 7, 4377.
(21) Casey, K. G.; Quitevis, E. L. J. Phys. Chem. 1988, 92, 6590.
(22) Olmsted, J. J. Phys. Chem. 1979, 83, 2581.
(23) Fery-Forgues, S.; Lavabre, D. J. Chem. Educ. 1999, 76, 1260.
J. Org. Chem. Vol. 75, No. 17, 2010 6037

Jiao et al.
JOCNote
of water, and extracted with 30 mL of CH2Cl2. Organic layers were
combined, and solvent was removed under vacuum. The crude
product was purified by chromatography (silica gel, hexane/
CH2Cl2 = 2/1, v/v) to give the desired compound 4c as a brown
powder in 53% yield (800 mg): 1H NMR (300 MHz, CDCl3) δ7.78
(d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.3 Hz,
1H), 7.36 (t, J= 7.5 Hz, 1H), 7.10 (s, 1H), 5.88 (s, 1H), 2.39 (s, 3H),
2.29 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.9, 140.3, 139.8,
134.3, 132.4, 130.6, 128.5, 126.8, 126.0, 121.7, 119.1, 118.3, 117.1,
14.6, 11.3; HRMS calcd for C15H12BClF2N2 [M]þ 304.0750, found
304.0757.
BODIPYs 5a. To a 50 mL dry Schlenk flask were added
BODIPY 4c (61 mg, 0.2 mmol), Pd(PPh3)2Cl2 (22 mg, 3 mmol %),
and CuI (13 mg, 7 mmol %) in 5 mL of freshly distilled THF. After
freeze-thaw three times, Et3N (0.4 mL) and phenylacetylene
(110 μL, 1.0 mmol) in 1 mL of THF were added through a syringe
into the mixture, respectively. The mixture was stirred at 65 °C for
3 h, cooled to room temperature, and filtrated through Celite, then
the cake was washed with CH2Cl2 (3ꢀ 20 mL). Organic layers were
combined, washed with brine, and dried over anhydrous MgSO4,
then the solvent was removed under vacuum. The crude product
was purified by chromatography (silica gel, hexane/CH2Cl2 =
5/2, v/v) to give the desired compound 5a as dark blue solid
in 55% yield (41 mg): 1H NMR (300 MHz, CDCl3) δ 8.17 (d, J=
7.8 Hz, 1H), 8.05-8.00 (m, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.75-7.69
(m, 2H), 7.51-7.15 (m, 4H), 6.92 (s, 1H), 6.03 (s, 1H), 2.58 (s, 3H),
2.29 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 139.1, 138.3, 136.5,
129.6, 129.5, 129.0, 128.4, 127.7, 126.3, 125.3, 124.5, 123.9, 119.6(3),
119.5(8), 119.4, 118.8, 117.8, 116.1, 115.3, 14.6, 11.3; HRMS (EI)
calcd for C23H17BF2N2 [M]þ 370.1453, found 370.1451.
FIGURE 4. Normalized UV-vis (a) and fluorescence (b, λex=520 nm)
spectra of BODIPYs 4c (orange), 6a (black), 6b (red), 6c (blue), 6d
(magenta), 6e (green), and 6f (cyan) in dichloromethane at 25 °C.
various electron donating groups without aryl-spacer to the
3-position of the BODIPY core, such as di(2-pyridylmethyl)-
amine (DPA) as a good metal chelating ligand in BODIPY 6e
and the 6-aminocaproic acid as a conjugation site to biomole-
cules in BODIPY 6f, provides these resulting BODIPYs with
great potential as a selective fluorescent sensor or as a fluor-
escent labeling reagent for biomolecules.
The introduction of electron-donating substituents on the
3-position of the BODIPY core has a great effect on the
photophysical properties of the BODIPY fluorophore as
shown in Figure 4. In comparison with the starting BODIPY4c,
most of BODIPYs 6 showed shifts in the absorption and
emission spectra, and reduced fluorescence quantum yields in
various solvents studied as summarized in Table 2 and Table S3
(Supporting Information). Among those, the installation of
nitrogen-centered nucleophiles in BODIPYs 6c-dgave a broad-
er absorption band with a larger Stokes shift in dichloromethane
(41-57 nm) and the other solvents investigated (up to 69 nm).
The Stokes shift for most of BODIPYs 6 was greatly affected by
the polarity of the solvents as summarized in Table S3
(Supporting Information): polar solvents like DMSO, MeCN,
and MeOH generally gave larger Stokes shift in comparison
with nonpolar solvents like toluene and hexane.
BODIPYs 6a. To a 50 mL dry Schlenk flask were added
BODIPY 4c (40 mg, 0.13 mmol) and phenol (61 mg, 0.65 mmol)
in 10 mL of CH2Cl2. Then K2CO3 (138 mg, 1 mmol) was added
and the reaction mixture was stirred at room temperature for
10 min, poured into water, and extracted with CH2Cl2 (3ꢀ 20 mL).
Organic layers were combined, solvent was removed under
vacuum, the crude product was purified by chromatography
(silica gel, hexane/CH2Cl2 = 2/1, v/v), and the desired com-
1
pound 6a was obtained as a powder in 85% yield (41 mg): H
In summary, we have developed a novel 3-halogenated
benzo-fused BODIPY 4 platform, easily synthesized from
readily available 3-halogeno-1-formylisoindoles 2 and fea-
tured with an active reacting site at the 3-position. The
application of this platform in Sonogashira coupling and
nucleophilic substitution reactions generates a series of
asymmetrical benzo-fused BODIPY dyes, allowing the effi-
cient linking of the BODIPY unit to various substituents of
interest as demonstrated in this work. Most of the resulting
BODIPY dyes show long-wavelength absorption and fluor-
escence emission, with good fluorescence quantum yields
and long fluorescence lifetimes.
NMR (300 MHz, CDCl3) δ 7.70 (d, J=7.8 Hz, 1H), 7.37 (d,
J=6.6 Hz, 2H), 7.28 (d, J=7.8 Hz, 3H), 7.19 (s, 1H), 6.94 (t,
J = 7.5 Hz, 2H), 6.50 (d, J = 8.1 Hz, 1H), 5.89 (s, 1H), 2.45
(s, 3H), 2.20 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.6, 149.1,
136.7, 134.7, 130.8, 130.2, 126.5, 125.4, 123.5, 123.2, 120.2,
120.0, 119.5, 116.2, 114.9, 14.2, 11.2; HRMS (EI) calcd for
C21H17BF2N2O [M]þ 362.1402, found 362.1406.
Acknowledgment. This work is supported by the National
Nature Science Foundation of China (Grants 20802002
and 20902004), Anhui Province (Grants 090416221 and
KJ2009A130), Scientific Research Foundation for Returned
Overseas Chinese Scholars, State Education Ministry, and
Doctoral Fund of Ministry of Education of China (Grant
20093424120001).
Experimental Section
BODIPY 4c. To compound 2a (895 mg, 5 mmol) in 10 mL of
CH2Cl2 was added 2,4-dimethylpyrrole (620 μL, 5 mmol) in 1 mL
of CH2Cl2 and POCl3 (470 μL, 5 mmol) in 1 mL of CH2Cl2, respec-
tively, at ice-cold condition under argon. The reaction mixture was
stirred at ice-cold condition for 30 min, and Et3N (7 mL) was
added into the reaction mixture. The mixture was further stirred
Supporting Information Available: General experimental
methods, experimental procedures, compound characterization
data and copies of 1H NMR, 13C NMR spectra and exact mass
spectra for all new compounds, and UV-vis and fluorescence
spectra data. This material is available free of charge via the
Internet at http://pubs.acs.org.
for 10 min, then BF3 OEt2 (7 mL) was added through a syringe.
3
The reaction mixture was left stirring for 10 h, poured into 50 mL
6038 J. Org. Chem. Vol. 75, No. 17, 2010