Regioselective stepwise bromination of boron dipyrromethene (BODIPY) dyes

Article abstract of DOI:10.1021/jo201754m

Halogenated BODIPYs are important synthetic precursors and potential sensitizers for photodynamic therapy (PDT). Electrophilic bromination of pyrrolic-unsubstituted BODIPYs using bromine regioselectively generated mono- to heptabromoBODIPYs in a stepwise

Full text of DOI:10.1021/jo201754m

Article
pubs.acs.org/joc
Regioselective Stepwise Bromination of Boron Dipyrromethene
(BODIPY) Dyes
Lijuan Jiao,* Weidong Pang, Jinyuan Zhou, Yun Wei, Xiaolong Mu, Guifeng Bai, and Erhong Hao*
Laboratory of Functional Molecular Solids, Ministry of Education; Anhui Laboratory of Molecule-Based Materials; School of
Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui, 241000, China
S
* Supporting Information
ABSTRACT: Halogenated BODIPYs are important synthetic precursors and
potential sensitizers for photodynamic therapy (PDT). Electrophilic bromination of
pyrrolic-unsubstituted BODIPYs using bromine regioselectively generated mono- to
heptabromoBODIPYs in a stepwise fashion in good to excellent yields. These
resultant bromoBODIPYs were applied for regioselective substitution and Suzuki
coupling reaction to generate BODIPYs 4, 5, 6, and 7 in good to excellent yields.
According to NMR and X-ray analysis results, the stepwise bromination first takes place at 2,6-, then at 3,5-, and eventually at 1,7-
positions, whereas the regioselective substitution occurs first at 3,5- then at 1,7-positions of the chromophore. The spectroscopic
properties of these resultant BODIPYs were studied, which shows the potential application of these bromoBODIPYs as
sensitizers for PDT.
cules,46−52 including long wavelength fluorescent dyes.
However, it is hard to control the halogen regiochemistry in
INTRODUCTION
The wide application of fluorescent dyes has led to the
■
these halogenated BODIPYs. It is achieved either through the
halogenation of the key synthetic precursor of BODIPY
(dipyrromethanes) during the course of BODIPY total
synthesis, or through the blocking effects of 1,3,5,7-tetraalkyl-
substituents. No direct regioselective halogenation on BODIPY
has been achieved until the recent disclosure of tetra- and
hexabromoBODIPYs by Churchill and co-workers53 and of 2,6-
dibromoBODIPYs by Shinokubo and co-workers.54 The first
case is achieved from the bromination of meso-thienyl BODIPY
using bromine, and the second one is obtained using N-
bromosuccinimide (NBS) at −78 °C. Therefore, the
regioselective halogenation of pyrrolic-unsubstituted BODIPYs
like 1a (Scheme 1) remains a challenge.
increased research interest in these molecules lately, especially
4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes, also known as
BODIPYs.1−6 BODIPYs have found wide applications in
diverse fields, for example, as labeling reagents,7,8 chemo-
sensors,9−11 and energy transfer cassettes,12−15 due to their
remarkable properties, including large molar absorption
coefficient, sharp fluorescence emissions, high fluorescence
quantum yields, and high photophysical stability.
Postmodification16−23 of some ready-made BODIPY frame-
works (such as halogenated BODIPYs A and B shown in Figure
Inspired by recent reports of the iridium-catalyzed
regioselective β-borylation of BODIPY 1a by Osuka55 and
regioselective nucleophilic substitution of BODIPY 1a by
Dehaen and Boens,56,57 respectively, herein we report the
preparation of mono- to heptabromoBODIPYs from the
regioselective stepwise bromination of pyrrolic-unsubstituted
BODIPYs 1 using bromine and the subsequent application of
these resultant bromoBODIPYs for the regioselective nucleo-
philic substitution and Suzuki coupling reactions. The stepwise
bromination was achieved through the variation of the amount
of bromine and the reaction time. As shown by NMR and X-ray
analysis results, this stepwise bromination first took place at 2,6-
, then at 3,5-, and eventually at 1,7-positions, whereas the
regioselective nucleophilic substitution occurred first at 3,5-
then at 1,7-positions of the chromophore.
Figure 1. Chemical structures of halogenated BODIPYs A and B.
1) is a convenient avenue for the facile functionalization of
BODIPYs. Among those, 3,5-chlorinated BODIPYs (A with X
= Cl), first developed by Boens et. al24 via total synthesis, have
been used for SNAr and palladium-catalyzed cross-coupling
reactions to generate the corresponding mono- and disub-
stituted BODIPYs.25−34 As complementary to Dehaen and
Boens’s chlorinated BODIPYs, our group35−37 recently has
developed 3-chloro- and 3,5-diiodoBODIPYs from the BF3
complexation of the corresponding halogenated dipyrrome-
thenes. 2,6-Halogenated BODIPYs B38 are potential sensitizers
for photodynamic therapy (PDT) using the heavy atom effect
of these halogen atoms39−45 and have also found wide
applications in the construction of many interesting mole-
Received: August 22, 2011
Published: November 13, 2011
© 2011 American Chemical Society
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electrophilic attack. Thus 2- or 2,6-brominated BODIPYs
would be the major products by carefully controlling the
amount of bromine. Treatment of BODIPY 1a with 1 equiv of
bromine (dropwise addition) in dichloromethane at room
temperature gave mono bromoBODIPY 2a. The monobromi-
nation occurred exclusively at the 2,6-position. No other
monobrominated BODIPY was obtained under this reaction
condition. Increasing the amount of bromine up to 2 equiv still
gave BODIPY 2a as the major product (Scheme 1). When the
amount of bromine was increased to 3 equiv, dibromoBODIPY
2b became the major product with a 93% isolated yield. Only
negligible amount of 2a or other brominated products were
obtained. The assignment of bromine regiochemistry in
BODIPYs 2a and 2b was based on 1H NMR results. Hydrogens
at different pyrrolic positions on BODIPY core show different
chemical shifts on the 1H NMR spectra, with the largest
chemical shift for 3,5-positional hydrogens and the smallest
chemical shift for 2,6-positional ones, as shown in a recent
Scheme 1. Syntheses of BODIPYs 2a−d
report.58 The comparison of the H NMR spectra before and
1
after the bromination reaction clearly showed the disappearance
of 2,6-protons on the BODIPY core. Thus, the bromine(s)
were present at 2- and 2,6-positions for BODIPYs 2a and 2b,
respectively.
Further increasing the amount of bromine to 6 equiv resulted
only in tetrabromoBODIPY 2c in a 98% isolated yield. As
shown in the X-ray structure (Figure 2), the four bromine-
RESULTS AND DISCUSSION
■
Synthesis. As an electrophilic substitution reaction, bromi-
nation would prefer to occur at the least positively charged
positions of the BODIPY core. According to the mesomeric
structures1 of the BODIPY core, 2,6-(β-)positions bear the least
positive charge. Therefore, they should be most susceptible to
Figure 2. X-ray structures of BODIPYs 2c,d, 3a−e, and 4c.
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Figure 3. Chemical structures and isolated yields of bromoBODIPYs 3a−d.
substituents were present at the 2,3,5- and 6-positions of the
BODIPY core. Although the formation of tribromoBODIPY
could be detected on TLC during the reaction process, it was
difficult to isolate in a pure form because of the similar
polarities of these bromoBODIPYs. In addition, because of the
similar reactivity between 3- and 5-positions of the BODIPY
core, we were unable to get it as a major product.
this reaction because of the poor solubility of BODIPYs in
these solvents.
This stepwise bromination reaction was further applied to
meso-(4-methoxyphenyl) BODIPY 1b, and gave a similarly high
regioselectivity. In comparison with meso-phenyl BODIPY 1a,
BODIPY 1b showed an enhanced reactivity in this
regioselective stepwise bromination reaction and generally
required a shorter reaction time. This may be attributed to the
higher electron density in the BODIPY core of BODIPY 1b
due to the existence of methoxy-substituent at the meso-aryl
position. By varying the amount of bromine, the desired mono-,
di-, and tetrabromoBODIPYs 3a−c were obtained in good to
excellent yields (Figure 3). The structures of these
bromoBODIPYs were confirmed by NMR and X-ray analysis
results (Figure 2). The disappearance of the proton signals for
BODIPYs 3a and 3b followed a similar order to that of
BODIPYs 2a and 2b, which supports our previous assignment
of the bromine regiochemistry in BODIPYs 2a and 2b based on
1H NMR results.
Unlike that of the meso-phenyl BODIPY 1a, at varying
amounts of bromine, meso-(4-methoxyphenyl)BODIPY 1b
failed to generate the desired hexabromoBODIPY. With 40
equiv of bromine, tetrabromoBODIPY 3c was still obtained as
the major product plus pentabromoBODIPY 3d (Figure 3),
which was obtained in a 23% isolated yield. Further increasing
the amount of bromine leads to the yield decrease of 3c and
increase of 3d and to the appearance of heptabromoBODIPY
3e. However, it is difficult to isolate 3d in pure form because of
the similar polarity of 3d and 3e. When the amount of bromine
was increased to 400 equiv, only 3e was obtained in an 81%
yield (Scheme 2). On the other hand, Lakshmi and Ravikanth
The further bromination at 1,7-positions of BODIPY 1a
required a large excess amount (300 equiv) of bromine and
gave hexabromoBODIPY 2d in an 86% isolated yield. The
regiochemistry of bromine was confirmed by X-ray analysis as
shown in Figure 2. The requirement of a large excess amount of
bromine indicates that 1,7-positions are the least reactive sites
toward electrophilic substitution reaction. This may be
attributed to both the electronic and the steric hindrance
effects: among the six pyrrolic positions, these two positions
bear the most positive charge and have a meso-substituent in
their adjacent position. During the course of the reaction, the
formation of pentabromoBODIPY was detected on TLC and
confirmed by mass spectra (MALDI-TOF) with a [M − F]+
peak at 642.3 (calcd. 642.3). Because of the similar reactivity
between 1- and 7-positions, we were unable to get the
pentabromoBODIPY as the major product. The attempt to
isolate it in a pure form also failed because of the close polarity
of these bromoBODIPYs. Our experiment showed that these
bromoBODIPYs were formed in a stepwise manner and that
the bromination first occurred at the 2,6- instead of the 3,5-
positions proposed by the literature.53
That the bromination occurs in a stepwise manner was
1
consistent with H NMR results, in which there is a stepwise
disappearance of pyrrolic protons in the order of 2,6-, 3,5-, and
1,7-protons. Interestingly, our stepwise bromination occurs in a
similar order to that of Knoevenagel condensations18,22 on
1,3,5,7-tetramethylBODIPYs using aromatic aldehydes (first at
3,5- then at 1,7-positional methyl-substituents).
Scheme 2. Synthesis of HeptabromoBODIPY 3e
Although the electronic effect on pyrrolic positions of the
BODIPY core plays a crucial role, solvent is also important in
this regioselective stepwise bromination reaction. Among the
solvents studied, dichloromethane gave the best result. Carbon
tetrachloride is a poor solvent for this reaction because it
requires longer reaction time and gives poor regioselectivity,
especially for the generation of mono- and dibromoBODIPYs.
For example, in order to generate the desired tetra- and
hexabromoBODIPYs 2c and 2d in a comparative yield to that
in dichloromethane, a longer reaction time and larger amount
of bromine were required. Also, in the preparation of mono-
and dibromoBODIPYs 2a and 2b, it gave a poor selectivity,
which made it difficult to get them in a pure form. Other
common organic solvents, such as N,N-dimethylmethanamide,
carbon disulfide, and tetrahydrofuran, were also not suitable for
recently have disclosed the preparation of the corresponding
hexabromoBODIPY in 24% yield via the BF3 complexation of
hexabromodipyrromethene, which was generated through NBS
bromination of suitable dipyrromethane in THF and the
subsequent oxidation with DDQ.59 The structures of BODIPYs
3d and 3e were confirmed by NMR and X-ray analysis results
(Figure 2). meso-Aryl groups in BODIPYs 3d and 3e are nearly
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perpendicular to the planes of the BODIPY core (87° for
BODIPY 3d and 90° for BODIPY 3e), consistent with that of
the hexabromoBODIPY (88°) reported in the literature.59
Nucleophilic Substitution and Suzuki Coupling of
BromoBODIPYs. SNAr reactions on 3-chloro- or 3,5-dichlor-
oBODIPYs A have been used as an efficient method for the
functionalization of the BODIPY core with various function-
alities for various applications. With these bromoBODIPYs in
hand, we then studied their applications in the nucleophilic
substitution reactions. Our bromoBODIPYs 2c and 2d showed
a similar reactivity to that of 3,5-dihalogenated BODIPYs A26 in
this nucleophilic substitution reaction. As shown in Schemes 3
(Scheme 5). Our result is consistent with a recent report of the
disubstitution of 1,7-dichloroBODIPY by Dehaen and Boens,
Scheme 5. Syntheses of BODIPYs 6a−b
Scheme 3. Syntheses of BODIPYs 4a−c
in which the authors attributed this lowering of the reactivity of
the 1,7-compared to the 3,5-positions to their smaller HOMO
coefficients.60
By carefully controlling the amount of thiol nucleophile and
the reaction time, we were also able to synthesize the
corresponding 3,5-disubstituted product 6a in high yield. On
the other hand, all attempts to introduce substitutions at 2,6-
positions of BODIPYs 2c and 2d failed, even using a large
excess amount of thiol nucleophilies with extended reaction
time. Substitution positions for BODIPYs 4c, 6a, and 6b were
confirmed by X-ray analysis results (Figures 2 and 4), whereas
substitution positions for BODIPYs 4a, 4b, 5a, and 5b were
Scheme 4. Syntheses of BODIPYs 5a−b
1
based on the H NMR results in light of X-ray structures for
these mono-, di-, and tetrasubstitutedBODIPYs 4c, 6a, and 6b.
TetrabromoBODIPY 2c was used as an example to study the
performance of our bromoBODIPYs in Suzuki coupling
reaction. BODIPY 2c showed a similarly excellent reactivity
in Suzuki coupling reaction in comparison to that of
hexabromoBODIPY reported in the literature.59 This Pd-
catalyzed cross-coupling reaction of tetrabromoBODIPY 2c
with benzene boronic acid was proceeded in refluxing toluene
using Pd(PPh3)4 as a catalyst in the presence of aqueous
Na2CO3, from which tetra-coupling BODIPY 7 was generated
in high yield (Scheme 6). In contrast to that of nucleophilic
substitution reactions, the 2,6-positions of BODIPY 2c showed
a good reactivity in this Pd-catalyzed reaction.
X-ray Structure Analysis. Crystals suitable for X-ray
analysis were obtained via slow diffusion of hexane into
dichloromethane solutions of bromoBODIPYs under atmos-
pheric pressure. Most of these BODIPYs (Figures 2 and 4)
show an almost planar structure for the BODIPY core (the
central six-membered ring with two adjacent five-membered
rings). The plane defined by F−B−F atoms for these BODIPY
molecules is perpendicular to that of BODIPY core as usual.
The B−N distance for these BODIPYs is within 1.54−1.60 Å,
which indicates the usual delocalization of the positive charge.
The average dihedral angles between meso-aryl-substituents
and the BODIPY core are 45°, 51°, 50°, and 51° for BODIPYs
2c and 3a−c, respectively. In contrast, larger dihedral angles are
observed for BODIPYs 2d (85°), 3d (87°), 3e (90°), 4c (84°),
6a (77°), and 6b (76°). This may be attributed to the steric
hindrance effect from 1,7-dibromo-substituents of the BODIPY
and 4, treatment of tetra- and hexabromoBODIPYs 2c and 2d
with various nucleophiles smoothly generated BODIPYs 4 and
5 in good yields under mild reaction conditions.
Similar to that of the 3,5-positions in 3,5-dihalogenated
BODIPY dyes, the electron density at 1,7-positions are rather
poor for hexabromoBODIPY 2d. Thus, we rationalized that
1,7-positions would show similar reactivity to that for 3,5-
positions. However, all attempts to substitute 1,7-positional
bromines of BODIPYs 2d failed, even using a large excess
amount of oxygen and nitrogen nucleophiles. In contrast, a
strongly nucleophilic thiolate anion was able to participate in
this 1,7-disubstitution reaction with hexabormoBODIPY 2d to
generate the corresponding tetrathioether 6b in excellent yield
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Figure 4. X-ray structures of BODIPYs 6a and 6b.
Scheme 6. Synthesis of BODIPY 7 via Suzuki Coupling
Reaction
core. Interestingly, in BODIPY 4c, the intermolecular hydrogen
bonding between two F atoms and the NH proton (2.42 and
2.53 Å) makes the aniline ring almost perpendicular to the
BODIPY core, with a dihedral angle of 78°.
Figure 5. Normalized absorption (solid lines) and emission (dashed
lines) spectra of BODIPYs 1a (black), 2a (red), 2b (green), 2c (pink),
and 2d (blue) in dichloromethane.
In the solid state, most of these bromoBODIPYs form
multiple C−H···F intermolecular hydrogen bonds due to the
strong electron negativity of the F atom.61−63 Multiple
intermolecular hydrogen bonds between F atoms and various
hydrogen atoms (phenyl, pyrrolic, and methyl hydrogens) are
formed with the H···F hydrogen bond distance in the range of
2.31−2.77 Å (Supporting Information, Figures S1−S10).
This strong intermolecular hydrogen bonding helps the
establishment of the crystal packing structure and leads to the
formation of various interesting hydrogen bonding networks
(Supporting Information, Figures S1−S10). In these crystal
packing structures, most of bromoBODIPYs are nearly parallel
to each other in a head-to-tail orientation except BODIPYs 3a
and 4c as shown in Figure 5, which show unusual partially
parallel packing in a head-to-head orientation.
Photophysical Properties. The photophysical properties
of these resultant BODIPYs are summarized in Table 1. Most
of BODIPY analogues showed strong absorption bands at 530
± 30 nm and weaker absorption bands at around 350 nm,
whereas longer wavelength absorption and emission were
observed for BODIPYs 6a, 6b, and 7. In comparison to the
starting BODIPYs, the installation of bromo-substituent(s)
onto the BODIPY core lead to an up to 56 nm red-shift of the
absorption maximum and an up to 52 nm red-shift of the
emission maximum as shown in Figure 5, similar to those
reported bromoBODIPYs.26,53,59,60
Similar to literature results,24−26,30,31,60,64 the installation of
new substituents on the BODIPY core greatly affects the
spectroscopic characteristics of the chromophore. Among
those, oxygen and nitrogen nucleophiles cause an up to 53
nm blue-shift of the absorption with little effect on the emission
spectra. In addition, nitrogen nucleophiles generally gave broad
spectra. In contrast, thiol nucleophile shows an up to 74 and 72
nm red-shift of the absorption and emission spectra,
respectively. Interestingly, the installation of benzene rings on
the BODIPY core in BODIPY 7 not only results in a 30 and 50
nm red-shift of the absorption and emission spectra
respectively, but also causes a restore of fluorescence of the
chromophore.
Consistent with the literature,65,66 BODIPYs 1a and 1b gave
low fluorescent quantum yields. These low emission yields
found in these two aryl-substituted BODIPYs bearing no
internal steric hindrance may be attributed to a facile S1-excited-
state nonradiative decay channel that is restricted when internal
steric constraints are imposed or in the absence of a meso-aryl-
substituent. On the other hand, the low fluorescence quantum
yields of bromoBODIPYs 2−5 could be partially attributed to
the heavy atom effect, which facilitates the S1 → T1 intersystem
crossing process. This heavy atom effect indicates the potential
application of these resultant bromoBODIPYs as sensitizers for
PDT.39−45
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otherwise. All reactions were performed in oven-dried or flame-dried
glassware unless otherwise stated and were monitored by TLC using
Table 1. Photophysical Properties of BODIPYs 1−7 in
Dichloromethane at Room Temperature
1
0.25 mm silica gel plates with UV indicator (60F-254). H and 13C
Stokes shift
NMR were obtained on a 300 MHz NMR spectrometer at room
temperature. Chemical shifts (δ) are given in ppm relative to CDCl3
(7.26 ppm for 1H and 77 ppm for 13C) or to internal TMS (0 ppm for
1H). High-resolution mass spectra were obtained using EI-TOF in
positive mode. MALDI-TOF mass spectra were obtained in positive
mode using cyano-4-hydroxycinnamic acid as matrix.
UV−vis absorption spectra and fluorescence emission spectra were
recorded on a commercial spectrophotometer (190−1100 nm scan
range). The slit width was set at 2.5 nm for excitation and 5.0 nm for
emission. Relative quantum efficiencies of fluorescence of BODIPY
derivatives were obtained by comparing the areas under the corrected
emission spectrum of the test sample with fluorescein (0.95 in 0.1 M
NaOH aqueous solution) and Rhodamin B (0.49 in EtOH),68
respectively. Non-degassed, spectroscopic-grade solvents and a 10 mm
quartz cuvette were used. Dilute solutions (0.01 < A < 0.05) were used
to minimize the reabsorption effects. Quantum yields were determined
using the following equation:69
a
BODIPY λmax (nm) log εmax λem (nm)
Φ
(cm−1
)
(nm)
1a
2a
2b
2c
2d
1b
3a
3b
3c
3d
3e
4a
4b
4c
5a
5b
6a
6b
7
500
516
538
554
551
498
514
533
550
551
554
534
501
534
549
549
606
625
584
4.52
4.53
4.14
4.99
4.83
4.68
4.61
4.92
5.08
5.00
4.52
4.53
4.53
4.79
4.94
5.01
4.83
4.47
4.77
527
547
569
578
562
521
542
562
572
573
567
580
565
561
573
576
634
630
628
0.03
0.08
0.08
0.03
0.13
0.05
0.10
0.07
0.13
0.03
0.04
0.01
0.02
0.02
0.02
0.02
0.001
0.003
0.40
1025
1098
1013
750
27
31
31
24
11
23
28
29
22
22
13
46
64
27
24
27
28
5
355
886
1005
968
699
697
414
1485
2261
901
763
854
where ΦS stands for the reported quantum yield of the standard, I
stands for the integrated emission spectra, A stands for the absorbance
at the excitation wavelength, and n stands for the refractive index of
the solvent being used (n = 1 when the same solvent was used for both
the test sample and the standard). X subscript stands for the test
sample, and S subscript stands for the standard.
Crystals of BODIPYs 2c−d, 3a−e, 4c, and 6a−b suitable for X-ray
analysis were obtained by slow diffusion of hexane into their
dichloromethane solutions. The vial containing this solution was
placed, loosely capped, to promote the crystallization upon hexane
diffusion. The structure was solved by the direct method using the
SHELXS-974 program and refined by the least-squares method on F2,
SHELXL-97,70 incorporated in SHELXTL V5.10.71
Syntheses and Characterizations of Compounds. BODIPY
2a. To BODIPY 1a (29 mg, 0.11 mmol) in 40 mL of dry CH2Cl2 was
slowly added liquid bromine (13 μL, 0.24 mmol) in dry CH2Cl2 (10
mL) over a period of 6 h. This reaction was tracked by TLC. The
reaction mixture was washed with an aqueous solution of sodium
thiosulfate. Organic layers were combined, extracted by CH2Cl2, dried
over Na2SO4, and evaporated to dryness under vacuum. Purification
was performed by column chromatography on silica gel using hexane/
ethyl acetate (6:1, v/v) as eluent, from which the desired product 2a
was obtained as a red solid in 80% yield (30 mg): 1H NMR (300 MHz,
CDCl3) δ 8.01 (s, 1H), 7.80 (s, 1H), 7.56 (s, 5H), 7.02 (s, 1H), 6.89
(s, 1H), 6.61 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 147.2, 146.2,
144.1, 142.2, 135.4, 134.3, 133.2, 131.1, 130.4, 130.3, 128.6, 119.6,
105.9; HRMS (EI) Calcd. for C15H10B79BrF2N2 [M+] 346.0088, found
346.0094; HRMS (EI) Calcd. For C15H10B81BrF2N2 [M+] 348.0068,
found 348.0067.
729
127
1200
44
a
The fluorescence quantum yields (Φ) were calculated using
Rhodamine B in anhydrous ethanol (Φ = 0.49) for 2b−d, 3b−e,
5a,b, and 7; fluorescein in 0.1 N NaOH aqueous solution (Φ = 0.90)
for 1a,b, 2a, 3a, and 4a−c; or cresyl violet perchlorate in anhydrous
methanol (Φ = 0.54) for 6a,b as the standard.
To demonstrate their potential application as sensitizers for
PDT, a photooxidation study was performed for bromoBODI-
PYs 2c and 2d using methylene blue as a comparative
reference.44 This was achieved by monitoring the light-induced
degradation of 1,3-diphenylisobenzofuran (DPBF) with reac-
tive oxygen species (ROS) generated by sensitizers (bromo-
BODIPYs 2c and 2d or methylene blue). Following a literature
procedure,67 the toluene solution of each of these sensitizers (1
× 10−7 M) and DPBF (initial concentration of 5 × 10−5 M)
was irradiated, and the disappearance of the absorbance band of
DPBF at 415 nm over a period of time was recorded. The
comparison of DPBF degradation profiles of these sensitizers
clearly shows that bromoBODIPYs 2c and 2d can efficiently
generate ROS with a DPBF degradation profile comparable to
that of methylene blue (Supporting Information, Figure S30).
CONCLUSIONS
■
BODIPY 2b. To BODIPY 1a (30 mg, 0.11 mmol) in 40 mL of dry
CH2Cl2 was added dropwise liquid bromine (18 μL, 0.34 mmol) in
CH2Cl2 (5 mL) over a period of 1 h. The mixture was left stirring for
an additional 2 h, washed with an aqueous solution of sodium
thiosulfate, and extracted by CH2Cl2. Organic layers were combined,
dried over Na2SO4, and evaporated to dryness. Purification was
performed by column chromatography on silica gel using hexane/ethyl
acetate (7:1, v/v) as eluent, from which the desired product 2b was
In summary, we have developed a highly regioselective stepwise
electrophilic bromination of BODIPYs, from which a series of
mono- to heptabromoBODIPYs have been prepared in good to
excellent yields. These resultant bromoBODIPYs have been
applied for further functionalization via nucleophilic substitu-
tion and Suzuki coupling reactions. The regiochemistry has
been confirmed by NMR and X-ray analysis results. This
regioselective stepwise bromination and its applications for the
regioselectively nucleophilic substitution reaction presented in
this work provide another dimension for the regioselective
functionalization of BODIPY derivatives.
1
obtained as red solid in 93% yield (44 mg): H NMR (300 MHz,
CDCl3) δ 7.85 (s, 2H), 7.64−7.53 (m, 5H), 6.96 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 147.0, 144.2, 134.6, 132.8, 131.7, 131.5, 130.3,
128.8, 107.2; HRMS (EI) Calcd. for C15H9B79Br2F2N2 [M+] 423.9294,
found 423.9189; HRMS (EI) Calcd. for C15H9B81Br2F2N2 [M+]
427.9153, found 427.9117.
EXPERIMENTAL SECTION
BODIPY 2c. To BODIPY 1a (27 mg, 0.1 mmol) in 16 mL of dry
CH2Cl2 was added liquid bromine (35 μL, 0.6 mmol) in CH2Cl2 (4
mL). The mixture was left stirring for 2 h at room temperature,
washed with an aqueous solution of sodium thiosulfate, and extracted
■
General Methods. Reagents were purchased as reagent-grade and
used without further purification unless otherwise stated. Solvents
were used as received from commercial suppliers unless noted
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The Journal of Organic Chemistry
Article
by CH2Cl2. Organic layers were combined, dried over Na2SO4, and
evaporated to dryness under vacuum. Purification was performed by
column chromatography on silica gel using CH2Cl2 as eluent, from
which the desired product 2c was obtained as red solid in 98% yield
(57 mg): 1H NMR (300 MHz, CDCl3) δ 7.64−7.47 (m, 5H), 6.91 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 142.8, 135.1, 134.7, 131.6, 131.5,
131.4, 130.3, 128.9, 112.0; MALDI-TOF Calcd. for C15H7BBr4F2N2
[M+] 583.73, found 583.43. Anal. Calcd. for C15H7BBr4F2N2: C, 30.87;
H, 1.21; N, 4.80. Found: C, 30.62; H, 1.31; N, 4.81.
BODIPY 2d. To BODIPY 1a (31 mg, 0.11 mmol) in 16 mL of dry
CH2Cl2 was added liquid bromine (2 mL, 36 mmol) in CH2Cl2 (4
mL). The mixture was left stirring for 2 h at room temperature,
washed with an aqueous solution of sodium hydroxide, and extracted
by CH2Cl2. Organic layers were combined, dried over Na2SO4, and
evaporated to dryness under vacuum. Purification was performed by
column chromatography on silica gel using CH2Cl2 as eluent, from
which the desired product 2d was obtained as red solid in 86% yield
(73 mg): 1H NMR (300 MHz, CDCl3) δ 7.55 (br, 3H), 7.26 (br, 2H);
13C NMR (75 MHz, CDCl3) δ 142.8, 135.2, 131.4, 130.5, 129.6, 129.5,
128.5, 123.9, 117.7; MALDI-TOF Calcd. for C15H5BBr6FN2 [M − F]+
720.56, found 720.24. Anal. Calcd. for C15H5BBr6F2N2: C, 24.30; H,
0.68; N, 3.78. Found: C, 24.03; H, 0.74; N, 4.01.
mL). The mixture was left stirring at room temperature for 4.5 h,
washed with an aqueous solution of sodium thiosulfate, and extracted
by CH2Cl2. Organic layers were combined, dried over Na2SO4, and
evaporated to dryness under vacuum. Purification was performed by
column chromatography on silica gel using hexane/ethyl acetate (8:1,
v/v) as eluent, from which the desired product 3d was obtained as red
1
solid in 25% yield (18 mg): H NMR (300 MHz, CDCl3) δ 7.26 (s,
2H), 7.03 (d, J = 8.1 Hz, 2H), 6.75 (s, 1H), 3.91 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 161.9, 143.1, 136.5, 135.7, 133.9, 132.7, 132.2,
131.3, 122.5, 122.3, 116.6, 114.3, 112.4, 55.5; MALDI-TOF Calcd. for
C16H8BBr5FN2O [M − F]+ 670.66, found 670.07. Anal. Calcd. for
C16H8BBr5F2N2O: C, 27.75; H, 1.16; N, 4.04. Found: C, 27.92; H,
1.37; N, 4.22.
BODIPY 3e. To BODIPY 1b (31 mg, 0.10 mmol) in 16 mL of dry
CH2Cl2 was added liquid bromine (2.23 mL, 0.04 mol) in CH2Cl2 (4
mL). The mixture was left stirring at room temperature for 30 min,
washed with an aqueous solution of sodium hydroxide, and extracted
by CH2Cl2. Organic layers were combined, dried over Na2SO4, and
evaporated to dryness under vacuum. Purification was performed by
column chromatography on silica gel using hexane/ethyl acetate (2:1,
v/v) as eluent, from which the desired product 3e was obtained as red
1
solid in 81% yield (71 mg): H NMR (300 MHz, CDCl3) δ 7.46 (s,
1H), 7.17 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.01 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 157.9, 140.7, 135.5, 133.6, 131.5, 129.3,
123.8, 122.6, 117.8, 112.7, 112.5, 56.4; MALDI-TOF Calcd. for
C16H6BBr7FN2O [M − F]+ 828.48, found 828.04. Anal. Calcd. for
C16H6BBr7F2N2O: C, 22.60; H, 0.71; N, 3.29. Found: C, 22.83; H,
0.87; N, 3.43.
BODIPY 4a. To BODIPY 2c (30 mg, 0.05 mmol) in 50 mL of
CH3CN was added aniline (10 μL, 0.1 mmol). The mixture was left
stirring at room temperature for 3 h and evaporated to dryness under
vacuum. The crude product was further purified by column
chromatography on silica gel using hexane/ethyl acetate (8:1, v/v)
as eluent, from which 4a was obtained as a green solid in 89% yield
(28 mg): 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.51−7.26 (m,
10H), 7.01 (s, 1H), 6.52 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
155.3, 137.5, 135.4, 133.0, 132.8, 131.8, 130.2, 130.1, 129.2, 128.6,
127.6, 126.0, 123.2, 119.3, 116.4, 105.8, 101.8; HRMS (EI) Calcd. for
C21H13B79Br3F2N3 [M+] 592.8721, found 592.8723.
BODIPY 4b. To BODIPY 2c (31 mg, 0.05 mmol) in 50 mL of
CH3CN was added N-phenylethylenediamine (15 μL, 0.11 mmol) in
CH3CN (1 mL). The mixture was left stirring at room temperature for
2 h and evaporated to dryness under vacuum. The crude product was
further purified by column chromatography on silica gel using hexane/
CH2Cl2 (1:1, v/v) as eluent, from which 4b was obtained as a pink
solid in 83% yield (28 mg): 1H NMR (300 MHz, CDCl3) δ 7.50−7.38
(m, 6H), 7.26−7.20 (m, 2H), 6.93 (s, 1H), 6.80 (t, J = 7.2 Hz, 1H),
6.73 (d, J = 6.9 Hz, 2H), 6.60 (s, 1H), 6.40 (s, 1H), 4.20 (q, 2H), 3.57
(t, J = 5.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 157.4, 147.2, 135.5,
133.1, 132.7, 132.5, 130.5, 130.2, 129.7, 129.5, 128.5, 121.1, 118.9,
116.8, 113.7, 105.1, 103.8, 43.9, 43.7; HRMS (EI) Calcd. for
C23H18B79Br3F2N4 [M+] 635.9143, found 635.9150.
BODIPY 4c. To BODIPY 2d (26 mg, 0.03 mmol) in 50 mL of
CH3CN was added aniline (8 μL, 0.08 mmol). The mixture was left
stirring at room temperature for 30 min and evaporated to dryness
under vacuum. The crude product was further purified by column
chromatography on silica gel using CH2Cl2 as eluent, from which 4c
was obtained as a red solid in 90% yield (23 mg): 1H NMR (300 MHz,
CDCl3) δ 8.24 (s, 1H), 7.50−7.26 (m, 10H); 13C NMR (75 MHz,
CDCl3) δ 154.7, 135.2, 133.2, 131.0, 130.7, 130.0, 129.7, 129.3, 129.0,
128.7, 128.0, 126.4, 119.6, 119.3, 113.5, 111.8, 107.1; MALDI-TOF
Calcd. for C21H11BBr5F2N3 [M+] 754.69, found 754.42. Anal. Calcd.
for C21H11BBr5F2N3: C, 33.47; H, 1.47; N, 5.58. Found: C, 33.62; H,
1.31; N, 5.81.
BODIPY 3a. To BODIPY 1b (31 mg, 0.10 mmol) in 40 mL of dry
CH2Cl2 was slowly added liquid bromine (9 μL, 165 μmol) in dry
CH2Cl2 (6 mL) over a period of 4 h at 0 °C. TLC was used to track
this reaction. The mixture was washed with an aqueous solution of
sodium thiosulfate and extracted by CH2Cl2. Organic layers were
combined, dried over Na2SO4, and evaporated to dryness under
vacuum. Purification was performed by column chromatography on
silica gel using hexane/ethyl acetate (7:1, v/v) as eluent, from which
the desired product 3a was obtained as a red solid in 85% yield (33
mg): 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.77 (s, 1H), 7.54
(d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.4 Hz, 3H), 6.93 (s, 1H), 6.61 (s,
1H), 3.92 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.5, 146.2, 144.3,
140.4, 134.2, 133.2, 131.9, 131.5, 129.1, 124.8, 118.3, 113.3, 104.7,
54.6; MALDI-TOF Calcd. for C16H12BBrF2N2O [M+] 378.01, found
377.97. Anal. Calcd. for C16H12BBrF2N2O: C, 50.97; H, 3.21; N, 7.43.
Found: C, 51.08; H, 3.04; N, 7.17.
BODIPY 3b. To BODIPY 1b (33 mg, 0.11 mmol) in 50 mL of dry
CH2Cl2 was added dropwise liquid bromine (17 μL, 325 μmol) in
CH2Cl2 (6 mL) over a period of 2 h at 0 °C. The mixture was left
stirring until most of the starting material had been converted to the
desired product, washed with an aqueous solution of sodium
thiosulfate, and extracted by CH2Cl2. Organic layers were combined,
dried over Na2SO4, and evaporated to dryness under vacuum.
Purification was performed by column chromatography on silica gel
using hexane/ethyl acetate (7:1, v/v) as eluent, from which the desired
product 3b was obtained as metallic brown solid in 69% yield (35 mg):
1H NMR (300 MHz, CDCl3) δ 7.82 (s, 2H), 7.53 (d, J = 8.7 Hz, 2H),
7.07 (d, J = 8.7 Hz, 2H), 6.99 (s, 2H), 3.92 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 162.9, 147.1, 143.4, 134.5, 132.6, 131.5, 125.4, 114.5,
106.9, 54.7; MALDI-TOF Calcd. for C16H11BBr2F2N2O [M+] 455.93,
found 455.79. Anal. Calcd. for C16H11BBr2F2N2O: C, 42.15; H, 2.43;
N, 6.14. Found: C, 41.96; H, 2.28; N, 6.04.
BODIPY 3c. To BODIPY 1b (31 mg, 0.10 mmol) in 16 mL of dry
CH2Cl2 was added liquid bromine (37 μL, 0.63 mmol) in CH2Cl2 (4
mL). The mixture was left stirring for 1.5 h at room temperature,
washed with an aqueous solution of sodium thiosulfate, and extracted
by CH2Cl2. Organic layers were combined, dried over Na2SO4, and
evaporated to dryness under vacuum. Purification was performed by
column chromatography on silica gel using hexane/ethyl acetate (2:1,
v/v) as eluent, from which the desired product 3c was obtained as red
solid in 95% yield (60 mg): 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J
= 8.1 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 6.95 (s, 2H), 3.92 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 161.7, 142.0, 133.7, 133.1, 131.3, 130.4,
123.1, 113.6, 110.7, 54.6; MALDI-TOF Calcd. for C16H9BBr4F2N2O
[M+] 613.75, found 613.56. Anal. Calcd. for C16H9BBr4F2N2O: C,
31.31; H, 1.48; N, 4.56. Found: C, 31.56; H, 1.57; N, 4.73.
BODIPY 3d. To BODIPY 1b (31 mg, 0.10 mmol) in 16 mL of dry
CH2Cl2 was added liquid bromine (242 μL, 4.1 mmol) in CH2Cl2 (4
BODIPY 5a. To BODIPY 2c (32 mg, 0.06 mmol) in 50 mL of
CH3CN was added 4-methoxyphenol (6 mg, 0.05 mmol). The mixture
was left stirring at room temperature for 5 min in the presence of
K2CO3, filtrated to remove excess amount of K2CO3, and washed with
CH3CN. Organic layer was washed with brine and evaporated to
dryness under vacuum. The crude product was further purified by
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The Journal of Organic Chemistry
Article
column chromatography on silica gel using hexane/ethyl acetate (6:1,
H]+ 573.2308, found 573.2291; HRMS (EI) Calcd. for C39H27BFN2
v/v) as eluent, from which 5a was obtained as a red solid in 60% yield
[M − F]+ 553.2246, found 553.2235;
1
(21 mg): H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 6.6 Hz, 5H),
7.13 (s, 2H), 7.00 (s, 1H), 6.89 (s, 2H), 6.76 (s, 1H), 3.81 (s, 3H); 13
C
ASSOCIATED CONTENT
■
NMR (75 MHz, CDCl3) δ 160.1, 156.2, 147.5, 140.3, 137.0, 134.2,
132.7, 131.0, 129.9, 129.3, 127.8, 127.6, 127.5, 118.9, 113.7, 108.1,
97.3, 54.6; MALDI-TOF Calcd. for C22H14BBr3FN2O2 [M − F]+
606.87, found 606.59. Anal. Calcd. for C22H14BBr3F2N2O2: C, 42.15;
H, 2.25; N, 4.47. Found: C, 41.90; H, 2.13; N, 4.21.
S
* Supporting Information
Copies of NMR, UV−vis, and fluorescence spectra for all new
compounds and crystallographic information files (CIFs) for
compounds 2c−d, 3a−e, 4c, and 6a−b. This material is
available free of charge via the Internet at http://pubs.acs.org.
BODIPY 5b. To BODIPY 2c (29 mg, 0.05 mmol) in 50 mL of
CH3CN was added 4-methoxyphenol (14 mg, 0.11 mmol). The
mixture was left stirring at room temperature for 30 min in the
presence of K2CO3, filtrated to remove excess amount of K2CO3, and
washed with CH3CN. Organic layer was evaporated to dryness under
vacuum and the crude product was further purified by column
chromatography on silica gel using CH2Cl2 as eluent, from which 5b
was obtained as a red solid in 65% yield (22 mg): 1H NMR (300 MHz,
CDCl3) δ 7.54 (d, J = 10.2 Hz, 5H), 7.07 (d, J = 9.0 Hz, 4H), 6.87−
6.83 (t, 6H), 3.78 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 158.1,
156.4, 149.3, 141.4, 132.1, 131.9, 130.6, 130.2, 128.6, 127.2, 119.0,
114.5, 95.3, 55.5; HRMS (EI) Calcd. for C29H21B79Br81BrF2N2O4
[M+] 669.9910, found 669.9940.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jiao421@mail.ahnu.edu.cn, haoehong@mail.ahnu.edu.
cn.
ACKNOWLEDGMENTS
■
This work is supported by the National Nature Science
Foundation of China (Grants 20802002, 20902004, and
21072005), Anhui Province (Grants 090416221 and
KJ2009A130), and Ministry of Education of China (Grant
20093424120001). We thank Dr. Frank R. Fronczek and Prof.
Shuangliu Zhou for the help with X-ray analysis. We also thank
Prof. Gaosheng Yang for the help with NMR experiments.
BODIPY 6a. To a solution of BODIPY 2d (32 mg, 0.04 mmol) in
acetonitrile (20 mL) were added triethylamine (14 mg, 0.14 mmol)
and p-thiocresol (16 mg, 0.13 mmol). This mixture was left stirring for
5 min at room temperature, washed with brine, and extracted by
CH2Cl2. Organic layers were combined, dried over Na2SO4, and
evaporated to dryness. Purification was performed by column
chromatography on silica gel using hexane/ethyl acetate (7:1, v/v)
as eluent, from which the desired product 6a was obtained in 84%
yield (30 mg): 1H NMR (300 MHz, CDCl3) δ 7.53 (br, 3H), 7.41 (d,
J = 7.4 Hz, 4H), 7.29 (br, 2H), 7.13 (d, J = 7.5 Hz, 4H), 2.34 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 151.6, 141.1, 138.7, 132.4, 131.3, 130.6,
130.1, 129.3, 129.0, 128.0, 123.9, 119.3, 21.3; HRMS (EI) Calcd. for
C29H19B79Br4BrF2N2S2 [M − F]+ 804.7795, found 806.7799; HRMS
(EI) Calcd. for C29H19B79Br381BrF2N2S2 [M − F]+ 806.7774, found
806.7771; HRMS (EI) Calcd. for C29H19B79Br281Br2F2N2S2 [M − F]+
808.7754, found 808.7746; HRMS (EI) Calcd. for
C29H19B79Br281Br2F2N2S2 [M − F]+ 810.7733, found 810.7720.
BODIPY 6b. To a solution of BODIPY 2d (33 mg, 0.05 mmol) in
acetonitrile (2 mL) were added triethylamine (47 mg, 0.46 mmol) and
p-thiocresol (58 mg, 0.47 mmol). The mixture was left stirring for 5 h
at 70 °C, washed with brine, and extracted by CH2Cl2. Organic layers
were combined, dried over Na2SO4, and evaporated to dryness.
Purification was performed by column chromatography on silica gel
using hexane/ethyl acetate (6:1, v/v) as eluent, from which the desired
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1
product 6b was obtained in 78% yield (32 mg): H NMR (300 MHz,
CDCl3) δ 7.34 (d, J = 7.4 Hz, 4H), 7.22 (br, 3H), 7.09 (d, J = 7.3 Hz,
6H), 6.93 (d, J = 7.3 Hz, 4H), 6.68 (d, J = 7.4 Hz, 4H), 2.31 (s, 6H),
2.25 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 151.6, 140.9, 138.1,
137.7, 136.1, 135.5, 132.2, 132.1, 131.6, 130.0, 129.9, 129.5, 129.0,
128.8, 128.7, 128.1, 123.1, 21.2, 21.0; HRMS (EI) Calcd. for
C44H34B79Br81BrF2N2S4 [M + H]+ 915.0007, found 914.9981;
HRMS (EI) Calcd. for C44H33B79Br81BrFN2S4 [M − F]+ 894.9945,
found 894.9936; HRMS (EI) Calcd. for C44H33B79Br2FN2S4 [M − F]+
892.9959, found 892.9965.
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BODIPY 7. BODIPY 2c (60 mg, 0.1 mmol) was dissolved in
toluene (2 mL), followed by the addition of benzene boronic acid (57
mg, 0.47 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol, 10%), and aqueous
Na2CO3 (1 mL of a 1 M solution). The resulting mixture was refluxed
under argon for 4 h, washed with brine, and extracted by CH2Cl2.
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dryness. Purification was performed by column chromatography on
silica gel using hexane/ethyl acetate (6:1, v/v) as eluent, from which
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Akkaya, E. U. Org. Lett. 2009, 11, 4644.
1
the desired product 7 was obtained in 75% yield (44 mg): H NMR
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2009, 74, 7525.
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(300 MHz, CDCl3) δ 7.70 (d, J = 6.4 Hz, 2H), 7.59 (d, J = 6.8 Hz,
3H), 7.49 (d, J = 6.4 Hz, 4H), 7.32 (d, J = 6.8 Hz, 6H), 7.16 (s, 6H),
7.02 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 156.4, 143.8, 134.6,
134.3, 133.7, 131.6, 130.6, 130.3, 129.0, 128.5, 128.3, 128.2, 128.0,
127.7, 126.8, 125.4, 116.8; HRMS (EI) Calcd. for C39H28BF2N2 [M +
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9995
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