Functionalization of 3,5,8-trichlorinated BODIPY dyes

Article abstract of DOI:10.1021/jo501969z

Catalytic hydrogenation of dibenzyl 5-dipyrroketone-2,9-dicarboxylates followed by decarboxylative iodination affords a 2,9-diiododipyrroketone which gives a 2,5,9-trichlorodipyrromethene hydrochloride after nucleophilic addition/elimination, with adventitious chloride to replace the two iodide groups. Treatment with BF₃·Et₂O gives a 3,5,8-trichloro-BODIPY that readily undergoes regioselective Stille coupling at the 8-position, or homo/mixed couplings at the 3,8- or 3,5- and 8-positions. Stepwise and controlled replacement of the 3,5- and 8-chlorine atoms using Stille reagents results in formation of a completely unsymmetrical trisubstituted BODIPY. Several examples of unsymmetrical BODIPYs were synthesized and characterized using this methodology. Structure features of new BODIPYs are discussed within the context of 14 new X-ray structures, and photophysical parameters of all new BODIPY compounds are reported and discussed.

Full text of DOI:10.1021/jo501969z

Article
pubs.acs.org/joc
Functionalization of 3,5,8-Trichlorinated BODIPY Dyes
Haijun Wang, Frank R. Fronczek, M. Graca̧ H. Vicente, and Kevin M. Smith*
Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, United States
S
* Supporting Information
ABSTRACT: Catalytic hydrogenation of dibenzyl 5-dipyrro-
ketone-2,9-dicarboxylates followed by decarboxylative iodina-
tion affords a 2,9-diiododipyrroketone which gives a 2,5,9-
trichlorodipyrromethene hydrochloride after nucleophilic
addition/elimination, with adventitious chloride to replace
the two iodide groups. Treatment with BF3·Et2O gives a 3,5,8-
trichloro-BODIPY that readily undergoes regioselective Stille
coupling at the 8-position, or homo/mixed couplings at the
3,8- or 3,5- and 8-positions. Stepwise and controlled replacement of the 3,5- and 8-chlorine atoms using Stille reagents results in
formation of a completely unsymmetrical trisubstituted BODIPY. Several examples of unsymmetrical BODIPYs were synthesized
and characterized using this methodology. Structure features of new BODIPYs are discussed within the context of 14 new X-ray
structures, and photophysical parameters of all new BODIPY compounds are reported and discussed.
BODIPY core at the 3,5-positions significantly affects the
spectroscopic and photophysical properties, and this strategy
has been exploited for the synthesis of a variety of
functionalized BODIPYs, from 3,5-dichloro- or 3,5-diiodo-
BODIPY precursors.13,14,17−21 On the other hand, a very useful
method for facile transformation of dipyrroketones into 5-
chlorodipyrromethene salts using phosgene was developed by
Fischer and Orth27 and has since been exploited by others28,29
and ourselves.30 The resulting 8-chloro-BODIPYs are reactive
toward palladium-catalyzed cross-coupling reactions and to
nucleophilic aromatic substitutions using N-, O-, and S-based
nucleophiles. Palladium-catalyzed Suzuki, Stille, Sonogashira,
and Heck cross-coupling reactions have all been performed on
3,5-chloro-BODIPY, while Suzuki, Stille, and Sonogashira
reactions have been achieved at the 8-position. Among these,
the milder Stille reaction conditions, using Pd(PPh3)4 and a
organotin reagent in toluene, in the absence of a base, gave 8-
aryl, -alkyl, and -ethynyl-BODIPYs in yields >93%,30 making it
a highly efficient methodology for the functionalization of
chloro-BODIPYs. Herein we report the synthesis of a
symmetrical 3,5,8-trichloro-BODIPY (5) and describe both its
global and regioselective functionalization using Stille coupling
reactions to afford both symmetric and unsymmetric BODIPY
dyes with extended π-conjugated systems. The spectroscopic
properties of the 19 new BODIPY derivatives synthesized and
structurally characterized, including 14 X-ray structures, are
compared and discussed.
INTRODUCTION
■
4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (known as BODI-
PY) is a class of very versatile fluorophores that has been widely
recognized and exploited in the last several decades. These dyes
have found various applications as labeling agents, chemical
sensors, photosensitizers, and energy-related cassettes and in
luminescent devices.1−4 BODIPY dyes have advantages
compared with other fluorophores, including large molar
absorption coefficients and high fluorescence quantum yields,
redox active, relatively high thermal and photochemical
stability, and easy functionalization that enables the tuning of
their properties, such as absorption/emission wavelengths,
charge-transfer, and amphiphilicity.5−7 Due in part to their
relatively low molecular weight, BODIPYs and their conjugates
usually show good permeability across the membranes of living
cells, making them suitable for biological and medical
applications.4−10
Various methods have been developed for the functionaliza-
tion of BODIPYs to change their photophysical, hydrophobic,
and charge-transfer properties. These methods include, but are
not limited to, electrophilic and nucleophilic substitutions,
palladium-catalyzed cross-couplings, aromatic ring fusion, and
Knoevenagel condensations.5−7 Among these, aromatic ring
fusion7,11,12 and cross-coupling reactions13−16 are particularly
useful for inducing bathochromic shifts of the BODIPY optical
transitions via extension of π-conjugation, while substitution
reactions17−21 are often used to modify the molecular
amphiphilicity upon introduction of heteroatom-based groups,
and for bioconjugations. Halogenated BODIPYs are particularly
versatile substrates for functionalization purposes via both
cross-coupling and nucleophilic substitution reactions, and all
halogens (fluoride, chloride, bromide, and iodide) have been
introduced into the pyrrolic positions of BODIPY (or a
dipyrromethane or pyrrole precursor), mainly using electro-
philic substitution.5,6,22−26 In particular, functionalization of the
RESULTS AND DISCUSSION
■
Syntheses. 3,5,8-Trichloro-BODIPY 5, bearing two methyl
propanoate groups that could subsequently be used for
bioconjugation, was prepared as shown in Scheme 1.
Received: August 25, 2014
© XXXX American Chemical Society
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Scheme 1. Synthesis of Halogenated BODIPYs by
a
Phosgenation of Dipyrroketone 2
Figure 1. X-ray structures of BODIPYs 5 and 7, with 50% ellipsoids.
Both molecules have essentially C2 symmetry, with 7 lying on
a crystallographic 2-fold axis, and 5 having nearly the same
conformation. The torsion angle about the CH2−CH2 bonds of
the methyl propanoate substituents is −66.1° in 7, while in 5,
the two torsion angles differ by 21.2°, but their mean value,
−66.2°, closely matches that in 7. The central C3N2B ring is
slightly more twisted in 5, with N atoms lying 0.11 Å out of
the C3B plane, compared to 0.05 Å in 7. The N2B and BF2
planes form a dihedral angle of 89.2° in 5 and 89.9° in 7.
Because, as mentioned above, the milder palladium-catalyzed
Stille cross-coupling reaction33,34 gave the highest yields of
functionalized BODIPYs,30 in this study we investigated Stille
couplings, using four different stannane reagents, in increasing
order of reactivity: tributylphenyltin, trimethyl-
[(tributylstannyl)ethynyl]silane, tributyl(1-ethoxyvinyl)tin, and
2-(tributylstannyl)thiophene, to produce 8-mono-, 3,8-di-, and
3,5,8-trisubstituted BODIPYs, as shown in Schemes 2−5.
Anticipating regioselectivity in the reactions of the 3,5,8-
trichloro-BODIPY 5, we first addressed the global Stille
coupling to demonstrate that functionalization at the 3,5,8-
positions of BODIPY 5 can be performed in one step. A typical
procedure involved refluxing a toluene mixture of 3,5,8-
trichloro-BODIPY 5 and excess organotin reagent (4.5
equiv), in the presence of Pd(PPh3)4, for 5−24 h. The global
Stille reactions proceeded in moderate to good yields,
producing the corresponding 3,5,8-trisubstituted BODIPYs
8−10 in 42−83% yields (Scheme 2). The least reactive tin
reagent used, the tributylphenyltin, required the longest time
refluxing in toluene for 24 h, and gave the lowest yield of
product. Products 8−10 showed red-shifted absorptions
compared with the starting material 3,5,8-trichloro-BODIPY
5, which absorbs at λmax 538 nm; BODIPY 10 showed the most
red-shifted absorption (λmax 648 nm), followed by BODIPY 8
(λmax 594 nm) and 9 (λmax 546 nm) (see Table 1). This is a
result of a nearly perpendicular orientation of the phenyl
groups on the trisubstituted BODIPYs 9, particularly the 8-
phenyl, which prevents orbital interactions, whereas the linear
trimethylsilylethynyl group lies in the plane of the BODIPY
core, efficiently extending its π-conjugation (see Figure 2). In
addition, in the case of the electron-rich thienyl group, the
a
Reaction conditions: (i) Br2, Et2O; (ii) MeOH, Δ (70% yield, two
steps); (iii) Pb(OAc)4/PbO2, (60%); (iv) Pd/C, H2, THF, (92%); (v)
I2, NaHCO3, MeOH/H2O, (75%); (vi) COCl2 (toluene soln); (vii)
BF3·Et2O, DIEA, (5, 55%), (6, 11%), (7, 5%).
Symmetrical dipyrromethane 1 was obtained by treatment of
benzyl 4-(2-methoxycarbonylethyl)-3,5-dimethylpyrrole-2-car-
boxylate on a 10−20 g scale with 1 equiv of bromine in
diethyl ether, followed by heating in methanol. It was then
oxidized with Pb(OAc)4/PbO2 in acetic acid31 to give the
corresponding dipyrrylketone 2 in 60% yield. Unlike our
previously reported tetra- and hexaalkyldipyrrylketones,30 the
electron-deficient dipyrrylketone 2 could not be converted into
the corresponding 5-chlorodipyrromethene hydrochloride by
reaction with phosgene. Therefore, dipyrrylketone 2 was
subjected instead to palladium-catalyzed debenzylation in a
hydrogen atmosphere, followed by decarboxylative iodination
to provide the 3,5-diiododipyrrylketone 3 in 69% overall
yield.32 Upon treatment with excess phosgene, the 3,5-
diiododipyrrylketone 3 was converted into the fully conjugated
meso-chlorodipyrromethene hydrochloride 4 which was not
isolated but immediately complexed with BF3·Et2O in situ
under basic conditions, to afford BODIPY 5 as the major
product in 55% yield from 3. BODIPYs 6 and 7 were also
isolated as minor byproducts, obtained in 11% and 5% yields
from 3, respectively, after chromatographic separation. The
trans-halogenation of 3,5-diiododipyrrylketone 3 to give 4 is
probably a result of nucleophilic addition/elimination by
chloride during the process, as nucleophilic substitutions at
the 3,5- and 8-positions of the BODIPY have been shown to
occur in the presence of a variety of nucleophiles.17,28,30 On the
other hand, byproducts 6 and 7 likely resulted from
dehalogenation of the 3- and 3,5-positions, respectively,
under the reaction conditions. The structures of BODIPYs 5
and 7 were unequivocally identified by their X-ray structures,
shown in Figure 1.
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Scheme 2. Global Stille Coupling Reactions of 3,5,8-Trichloro-BODIPY 5 To Give BODIPYs 8−10
Table 1. Spectroscopic Properties of BODIPYs in
a
Dichloromethane Solution at Room Temperature
abs λmax
(nm)
emission λmax
Stokes shift
BODIPY
(nm)
(cm−1
)
Φf
ε
5
538
534
528
594
546
648
548
534
584
560
609
574
594
636
601
616
645
555
559
550
549
547
649
576
660
559
544
597
591
616
629
600
702
634
625
679
587
597
406
512
658
1427
954
280
359
344
372
936
186
1524
168
1478
866
234
776
982
1138
0.58
0.45
0.30
0.10
0.43
0.01
0.24
0.86
0.03
0.27
0.22
0.45
0.34
0.08
0.05
0.21
0.05
0.53
0.67
112200
60300
38000
43700
29500
88000
77600
69200
67600
17800
89100
38900
47900
29500
38900
46800
29500
33300
13000
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
a
Fluorescence quantum yields (Φf) were calculated as follows:
rhodamine 6G was used as the standard for compounds 5−9 and
for compounds 11 and 12; rhodamine B was used as the standard for
compounds 13, 14, 16, 17, 22, and 23; methylene blue was used as the
standard for compounds 10, 15, 18−21.
thiophene tends to decrease the HOMO−LUMO gap,
therefore increasing the absorbance wavelength relative to the
phenyl analogue (vide infra).35 Figure 2 shows the X-ray
structures of BODIPYs 8 and 10.
Unlike the structures of 5 and 7 (Figure 1), both 8 and 10
have their propanoate substituents extended, with torsion
angles about their CH2−CH2 bonds 170.4° and 179.7° for 8,
157.7° and 179.7° for 10. All three of the thiophenes in 8
exhibit disorder by 2-fold rotation about the C−C bonds
joining them to the rest of the molecule, with only the major
conformers shown in Figure 2. The central C3N2B ring in both
molecules has a slight boat distortion, with B and the C
opposite it lying, respectively, 0.18 and 0.04 Å on the same side
of the plane formed by the other four atoms for 8, 0.19 and
0.04 Å for 10. The N2B and BF2 planes form a dihedral angle of
89.8° in both 8 and 10. The 12-atom BODIPY core of 8 makes
a dihedral angle of 89.6° with the 8-thiophene plane and 68.1°
and 39.9° with the other two.
Figure 2. X-ray structures of BODIPYs 8 and 10, with 50% ellipsoids.
described above for the synthesis of 8−10, but in a 1:1 ratio to
the BODIPY rather than in excess. We anticipated mono-
substitution at the most electrophilic 8-position of the
BODIPY.23 The coupling reaction with 2-(tributylstannyl)-
thiophene in refluxing toluene for 5 h gave the monothienyl-
BODIPY 11 as the sole product, in 72% yield (Scheme 3).
Under similar conditions, BODIPY 13 was also obtained in a
reasonable yield (65%) along with trace amount of the
corresponding 3,8-disubstituted product. Using the least
Regioselective coupling reactions were performed on the
3,5,8-trichloro-BODIPY 5 using the same organotin reagents as
C
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Scheme 3. Regioselective Stille Coupling Reactions of BODIPY 5 at the 8-Position To Give BODIPYs 11−13
Figure 3. X-ray structures of BODIPYs 11−13, with 50% ellipsoids.
reactive tin reagent, BODIPY 12 was obtained in only 21%
yield; however, the yield of 12 was increased to 57% when 2
equiv (rather than 1) of organotin were used, and no
disubstitution product was detected. The 1,7-propanoate
groups likely lead to an increased dihedral angle between the
BODIPY core and the phenyl group, resulting in blue-shifted
absorption and emission bands. The X-ray structures of
BODIPYS 11−13 are shown in Figure 3.
Both 11 and 12 have two independent molecules in the
crystal (only one shown in Figure 3), and the thiophene in both
molecules of 11 is disordered. The propanoate substituents of
all three molecules are extended, with torsion angle magnitudes
in the range 175.9−179.8° for 11, 170.0−176.6° for 12, and
178.5° and 179.8° for 13. In the central C3N2B ring of all three
molecules, only the B atom is distinctly out of plane, by a mean
distance of 0.10 Å for 11, 0.14 Å for 12, and 0.12 Å for 13. In all
three molecules, the BN2 and BF2 planes form dihedral angles
of 89.7° to 89.8°. The 12-atom BODIPY core of 11 forms
dihedral angles of 89.3° and 90.0° with the thiophene planes in
the two independent molecules. The BODIPY core of 12 forms
dihedral angles with the phenyl rings of 86.5° and 87.8° for the
two independent molecules.
For the three new 8-substituted BODIPYs 11−13, different
functional groups were introduced at the 3,5-positions by Stille
coupling reactions using 2.4 equiv of selected organotin
reagents, as shown in Scheme 4. Specifically, the 8-thienyl-
BODIPY 11 was functionalized at the 3,5-positions with phenyl
and trimethylsilylethynyl groups to provide BODIPYs 14 and
15, the 8-phenyl-BODIPY 12 was functionalized with thienyl
and trimethylsilylethynyl groups to give BODIPYs 16 and 17,
and BODIPY 13 was functionalized with phenyl and thienyl
groups to produce BODIPYs 18 and 19. These double Stille
reactions proceeded in good yields (51−78%), the highest
obtained using the most reactive 2-(tributylstannyl)thiophene
reagent and the lowest using the least nucleophilic
tributylphenyltin. Five of these differentially substituted
BODIPY compounds (specifically 15−19) were also charac-
terized by single crystal X-ray crystallography, shown in Figure
4.
Of the thiophene-containing molecules, 15 has its thiophene
ordered, 18 has one ordered and the other disordered, and 16
has both disordered. BODIPY 19 has disorder both in the
phenyl and COOMe conformations. Only the major con-
formers are shown in Figure 4. All five molecules have their
methyl propanoate substituents extended, with torsion angle
magnitudes about the CH2−CH2 bonds in the range 168.9−
179.3°. There is some variation in the conformations of the
central C3N2B rings. BODIPY 16 has the B atom 0.19 Å out of
the best plane of the other five atoms, while in the two
independent molecules of 19, the deviations are 0.19 and 0.35
Å. BODIPYs 15 and 17 have the slight boat distortion, with
deviations 0.12 (for B) and 0.05 Å (for C) in 15, and 0.22 and
0.04 Å, respectively, for 17. The central C3N2B ring of 18
differs from the others, having a twist conformation with the B
atom 0.07 Å and a N atom 0.13 Å on opposite sides of the
plane of the other four atoms. The BN2/BF2 dihedral angles in
15, 16, 17, and 19 are all 89.6−90.0°, while that of 18 is slightly
smaller, 88.9°. In 15, the BODIPY core forms a dihedral angle
of 77.0° with the thiophene plane. In 16 and 17, respectively,
the BODIPY core forms a dihedral angle of 87.6° and 80.0°
with the phenyl plane. In 18, the BODIPY core forms dihedral
angles of 58.1° and 44.9° with the two thiophene planes. In 19,
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Scheme 4. Double Stille Coupling Reactions of BODIPYs 11−13 To Give Differentially Functionalized BODIPYs 14−19
the BODIPY core forms dihedral angles in the range 60.5−
74.9° (mean value 70.5°) with the phenyl planes in the two
independent molecules.
consecutive Stille reactions using different organotin reagents,
to produce a completely asymmetric BODIPY. The phenyl
group was first regioselectively introduced at the most reactive
8-position to give the 8-phenyl BODIPY 12. Next, thiophene
was introduced at the 3-position of BODIPY 12 using 1 equiv
of 2-(tributylstannyl)thiophene, resulting in the isolation of
asymmetric BODIPY 22 in 43% yield along with a trace
amount of BODIPY 16 (Scheme 6). Finally, an ethoxyvinyl
group was introduced into the 5-position of BODIPY 22 by
reaction with tributyl(1-ethoxyvinyl)tin to provide the fully
asymmetric BODIPY 23 in 51% yield.
Spectroscopic Properties. The spectroscopic properties
of all BODIPYs synthesized, including UV/visible absorption
and steady-state fluorescence emission, were studied in
dichloromethane solution, and the results are summarized in
Table 1. Furthermore, as an example, Figure 6 shows the
normalized absorption and fluorescence spectra for BODIPYs
5, 9, 13, and 15 (others are presented in Supporting
Information). All BODIPYs show typical absorption and
emission spectra for this type of compound, with strong
absorption bands corresponding to the S0−S1 transition (log ε
= 4.1−5.1), a shoulder at shorter wavelength due to the 0−1
vibrational band of the same transition, and Stokes-shifted
emission bands. The Stokes shifts vary considerably for this
group of BODIPYs, from 186 to 1524 cm−1; BODIPYs 8, 16,
and 18, bearing 3,5-thienyl groups, have the largest Stokes shifts
(1427−1524 cm−1) followed by BODIPYs 21−23, bearing only
The synthesis of asymmetric BODIPYs was also accom-
plished using first 2 equiv of organotin reagent, followed by a
second organotin; this strategy produces asymmetrical
BODIPYs on account of the higher reactivity at the 8-position
and the molecular symmetry about the 3,5-positions. The
reaction of BODIPY 5 with 2 equiv of trimethyl-
[(tributylstannyl)ethynyl]silane produced the 3,8-disubstituted
BODIPY 20 as the major product in 53% yield, along with a
trace amount of the trisubstituted-BODIPY 10 (Scheme 5).
BODIPY 20 was then treated with 2-(tributylstannyl)thiophene
to yield BODIPY 21 in 63% yield. The structure of BODIPYs
20 and 21 were confirmed by their X-ray crystallography,
shown in Figure 5.
As with all previous structures, except for 5 and 7, the methyl
propanoate substituents of 20 and 21 are extended, with
torsion angle magnitudes about the CH2−CH2 bonds in the
range 175.0° to 179.0°. The conformation of the central rings
are fairly planar, similar to those of 11−13, with the B atom
0.11 Å out of the C3N2 plane for 20 and 0.15 Å for 21. The
BN2/BF2 dihedral angle is typical of these compounds, 89.6°
for 20 and 89.5° for 21. In 21, the BODIPY core forms a
dihedral angle of 43.1° with the thiophene plane.
Attempts to introduce three different groups at the 3-, 5-, and
8-positions of the BODIPY core were also investigated by
E
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Figure 4. X-ray structures of BODIPYs 15−19, with 50% ellipsoids.
Scheme 5. Consecutive Stille Coupling Reactions of BODIPY 5 To Give Differentially Functionalized BODIPYs 20 and 21
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the π-conjugation system and decreasing the HOMO−LUMO
gap.41 On the other hand, the aromatic substituents on 8 and 9,
particularly the 8-aryl groups, orient themselves nearly
perpendicular to the BODIPY core to minimize steric
interactions, inducing smaller red-shifts. In addition, the
electron-releasing effect of the thiophene group tends to
decrease the HOMO−LUMO gap,35 inducing larger red-shifts
compared with the phenyl-substituted analogues (see below).
Similarly, the 3,5,8-trisubstituted BODIPYs 14−19, 21, and 23
obtained by mixed Stille coupling reactions all show bath-
ochromic shifts (21−107 nm) compared with BODIPY 5; the
greatest red-shifts were observed for the trimethylsilylethynyl-
containing BODIPYs 15, 17−19, and 21, and the smallest for
the phenyl-containing BODIPYs 14 and 16.
Regioselective coupling at only the 8-position caused a slight
blue-shift in the case of 8-phenyl-BODIPY 12, and a slight red-
shift in the case of 8-thienyl-BODIPY 11, as previously
observed,30 indicating that the most pronounced effect on the
absorption and emission wavelengths of the BODIPYs arise
from 3,5-aryl (rather than 8-) substitution. The large dihedral
angle (ca. 87° from crystal structure) between the 8-phenyl
group and the BODIPY core in 12 as a result of 1,7-
disubstitution induces blue-shifted absorption and emission
spectra. On the other hand, an 8-trimethylsilylethynyl group, as
found in BODIPY 10, effectively extends the π-conjugation,
inducing a 46 nm bathochromic shift. In agreement with these
results, it has been previously observed that an 8-(2-
phenylethynyl) group induces ca. 40 nm red-shifts although
small Stokes shifts.41,42 Although the 8-thienyl group forms an
even larger dihedral angle with the BODIPY core in 11 (ca. 89°
from crystal structure), the electron-releasing effect of the
thienyl group decreases the HOMO−LUMO gap, therefore
increasing the absorbance and emission wavelengths relative to
BODIPY 12.35
The fluorescence quantum yields determined in dichloro-
methane were significantly higher for the phenyl-substituted
BODIPYs compared with the thienyl- and trimethylsilylethynyl-
substituted BODIPY analogues. For example, the 8-phenyl-
BODIPY 12 showed the highest quantum yield (Φf = 0.86) of
all BODIPYs in this series, whereas the 3,5,8-trimethylsilyle-
thynyl-BODIPYs 10 showed the lowest (Φf = 0.01). These
results are in agreement with our previous studies30,35 and
reflect the greater freedom of rotation of the smaller thienyl
group in comparison with phenyl, even in the presence of the
1,7-propanoate substituents, increasing the amount of energy
lost to nonradiative decay to the ground state. The aryl-ring
rotation has been demonstrated to be critical in determining
the excited-state dynamics of BODIPYs, and in particular their
fluorescence quantum yields.43,44 On the other hand, the
trimethylsilylethynyl groups increase the nonradiative molec-
ular relaxation which decreases the fluorescence quantum
yields. We have previously shown that upon deprotection of the
trimethylsilyl group, the resulting 8-ethynyl-BODIPY shows
increased fluorescence quantum yield.30
Figure 5. X-ray structures of BODIPYs 20 and 21, with 50% ellipsoids.
one thienyl group at the 5-position. In agreement with these
values, Stokes shifts of ca. 1500 cm−1 have been reported for
3,5-thienyl-substituted BODIPYs, and larger values were
achieved upon boron substitution with alkynylaryl groups via
intramolecular energy transfer.11,36 It has also been shown that
8-thienyl-substituted BODIPYs normally show small Stokes
shifts (ca. 350 cm−1) typical of BODIPY derivatives,2 and that
2,6-dithienyl-BODIPYs can show even larger Stokes shifts,
presumably due to increased geometry relaxation, i.e., the
geometry difference between the S0 and the S1 states, upon
photoexcitation.37,38
The introduction of chlorines at the 3,5-positions slightly
red-shifts the absorption and emission bands and increases the
molar extinction coefficients and fluorescence quantum yields,
as previously observed, due to the decrease in nonradiative
deactivation processes.24,39,40 As expected, the global Stille
coupling on BODIPY 5 caused pronounced red-shifts in the
absorption and emission bands, particularly for the 3,5,8-
trimethylsilylethynyl-BODIPY 10 which showed a 110 nm
bathochromic shift compared with 5 due to larger electronic
coupling with the BODIPY chromophore, therefore extending
CONCLUSIONS
■
A very useful method for transformation of dipyrroketones into
5-chlorodipyrromethene hydrochlorides by using phosgene is
inhibited by the presence of conjugated 2,9-ester substituents.
However, catalytic debenzylation followed by decarboxylative
iodination affords a 2,9-diiodopyrroketone which does undergo
the phosgene reaction to provide 2,5,9-trichlordipyrromethene
hydrochlorides after nucleophilic addition/elimination with
G
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Scheme 6. Stille Coupling Reactions of BODIPY 12 To Give 23 Featuring Three Different Groups on the 3,5,8-Positions
BODIPYs (Φf = 0.10−0.27), whereas the 8-ethynyl-BODIPYs
showed the lowest quantum yields (Φf = 0.01−0.21).
EXPERIMENTAL SECTION
■
1
General. H and 13C NMR spectra were measured on a 400 MHz
NMR spectrometer at room temperature. Chemical shifts (δ) are
given in ppm relative to TMS. High-resolution mass spectra were
obtained using the ESI-TOF mode. UV−visible absorption spectra and
fluorescence emission spectra were recorded on a commercial
spectrophotometer (190−900 nm scan range). The slit width was
set at 3.0 nm. Relative fluorescence quantum yields (Φf) were
calculated as follows: rhodamine 6G was used as the standard for
compounds 5−9 and for compounds 11 and 12; rhodamine B was
used as the standard for compounds 13, 14, 16, 17, 22, and 23;
methylene blue was used as the standard for compounds 10, 15, 18−
21. All commercial reagents were used without further purification.
Water- and air-sensitive reactions were performed under argon
protection and in dry solvents.
Dibenzyl 3,7-Bis(2-methoxycarbonylethyl)-2,8-dimethyldipyrro-
Figure 6. Normalized UV/visible absorption (solid line) and
fluorescence emission (dashed line) spectra of selected BODIPYs 5,
9, 13, and 15 (left to right) in dichloromethane solution.
methane-1,9-dicarboxylate 1. Benzyl 4-(2-methoxycarbonylethyl)-
3,5-dimethylpyrrole-2-carboxylate (15.7 g, 0.05 mol) was dissolved in
anhydrous diethyl ether (500 mL), and bromine (2.56 mL, 0.05 mol)
was added dropwise. The solution turned brown during addition, and
the mixture was further stirred at room temperature overnight,
whereupon a thick precipitate was apparent. Then the diethyl ether
was removed under vacuum to give a pink solid that was dissolved in
methanol (100 mL) and refluxed overnight. When the solution was
cooled to room temperature, a precipitate appeared, which was filtered
chloride to replace the two iodo groups. Treatment of these
3,5,8-trichlorodipyrromethene salts with BF3·Et2O gives a 3,5,8-
trichloroBODIPY that readily undergoes regioselective Stille
coupling at the 8-position, or a combination of differential 3,8-
disubstitution or 3,5- and 8-trisubstitution. X-ray structures of
and washed with cold methanol to give a white solid (10.70 g, 70%) of
dipyrromethane 1. Mp 102−104 °C, (lit.45 mp 102−103 °C). 1H
14 new BODIPYs are reported and analyzed. Global Stille
coupling at the 3,5,8-positions of BODIPY 5 caused up to 110
nm bathochromic shifts (in the case of the 3,5,8-trimethylsi-
lylethynyl-BODIPY 10) in the absorption and emission bands
of the BODIPYs. Regioselective and consecutive Stille coupling
reactions produced a variety of asymmetric BODIPYs; the 3,5-
aryl and 3(5)- and/or 8-ethynyl substitution induced the largest
bathochromic shifts whereas the presence of a 3(5)-thienyl
substituent caused the largest Stokes shifts (up to 1524 cm−1).
The 8-phenyl-BODIPYs showed the highest fluorescence
quantum yields (Φf = 0.34−0.86), followed by the 8-thienyl-
NMR (400 MHz; CDCl3): δ 9.00 (s, 2H), 7.38−7.31 (m, 10H), 5.25
(s, 4H), 3.97 (s, 2H), 3,56 (s, 6H), 2.75 (t, 4H), 2.51 (t, 4H), 2.28 (s,
6H); 13C NMR (100 MHz; CDCl3): 173.9, 161.4, 136.5, 130.9, 128.5,
128.0, 127.9, 127.2, 120.2, 118.0, 65.5, 51.8, 34.5, 22.4, 19.2, 10.4;
HRMS (ESI-TOF) calcd for C35H39N2O8 [M + H]+ 615.6928, found
615.6908.
Dibenzyl 3,7-Bis(2-methoxycarbonylethyl)-2,8-dimethyldipyrro-
ketone-1,9-dicarboxylate 2. A solution of dipyrromethane 1 (2.0 g,
3.25 mmol) in acetic acid (80 mL) was treated with Pb(OAc)4 (3.12 g,
7.0 mmol) and stirred at room temperature for 4 d under argon. Then
PbO2 (2.4 g, 9.3 mmol) was added, and the solution was stirred for
another 2 d. The solution was centrifuged, and the supernatant was
H
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poured into ice−water. The precipitate was collected and dissolved in
diethyl ether before being washed with water, 5% aqueous NaHCO3,
and brine and then dried over anhydrous Na2SO4. Then the solution
was concentrated to a minimum volume and crystallized in a
refrigerator to give product as a yellowish white solid (1.2 g, 60%),
mp 170−171 °C (lit.46 mp 173−174 °C). 1H NMR (400 MHz;
CDCl3) δ 7.38−7.31 (m, 10H), 5.00 (s, 4H), 3,67 (s, 6H), 3.01
(broad, 4H), 2.71 (broad, 4H), 2.27 (s, 6H); 13C NMR (100 MHz;
CDCl3) δ 176.7, 173.6, 161.7, 135.0, 132.2, 130.2, 128.7, 128.4, 127.7,
127.0, 121.7, 66.8, 51.6, 35.2, 20.3, 10.4; HRMS (ESI-TOF) calcd for
C35H36N2O9 [M + H]+: 629.2499, found 629.2497.
[M − F]+ 441.0955, found 441.0935, UV/vis (CH2Cl2): λmax (ε) =
534 nm (60 300). BODIPY 7: mp 148−149 °C; 1H NMR (400 MHz;
CDCl3) δ 7.58 (s, 2H), 3.73 (s, 3H), 3.21 (t, J = 8.1 Hz, 4H), 2.59 (t, J
= 8.1 Hz, 4H), 2.08 (s, 3H); 13C NMR (100 MHz; CDCl3) δ 172.8,
143.1, 142.5, 138.7, 130.4, 128.8, 51.9, 34.0, 22.2, 9.8; HRMS (ESI-
TOF) calcd for C19H22BClFN2O4 [M − F]+ 407.1345, found
407.1342. UV/vis (CH2Cl2): λmax (ε) = 528 nm (38 000).
General Procedure for Stille Coupling Reactions. Global Coupling
Reactions. BODIPY 5 (15 mg, 0.03 mmol) and Pd(PPh3)4 (2.0 mg,
5%) were added to a round-bottomed flask. The flask was flushed with
argon, and then anhydrous toluene (15 mL) was injected, followed by
injection of the organotin reagent (0.14 mmol, 4.5 equiv). The
solution was refluxed for 12 h until the starting material disappeared
from TLC and the UV/vis spectrum showed a sharp peak around 600
nm. Then the toluene was removed, and the residue was taken up in
CH2Cl2, washed with water and brine, and then dried over anhydrous
Na2SO4. The crude product was purified by chromatography to give
the fully (tri-) substituted products.
1,9-Diiodo-3,7-bis(2-methoxycarbonylethyl)-2,8-dimethyldipyr-
roketone 3. Dipyrroketone 2 (6.14 g, 0.01 mol) was dissolved in 300
mL of THF, and then 5% Pd/C (350 mg) catalyst was added. The
suspension was stirred under a H2 atmosphere overnight. After TLC
showed that reaction was complete, it was stopped and the reaction
solution was passed through a Celite cake to remove the catalyst. The
sticky solid on the top of the Celite cake was redissolved and
neutralized in water with aqueous ammonia, and the solution was
passed through the Celite cake once again. The filtrate was acidified
with acetic acid which caused a precipitate to appear from the aqueous
solution. The solid was collected by filtration. The THF filtrate was
evaporated and combined with the solid to give a total of 4.0 g (92%)
of the 1,9-dicarboxylic acid product. This dicarboxylic acid was
suspended in a solution of H2O (250 mL)/MeOH (100 mL), and
NaHCO3 (4.48 g, 51.2 mmol) was added to the solution, which was
sonicated to form a slurry and then a clear solution. Then a solution of
I2 (3.84 g, 14.72 mmol) in methanol (60 mL) was added to the
mixture dropwise at room temperature with vigorous stirring, and
some brown solid was formed during the addition. When the addition
of iodine was complete, the stirring was continued for another 2 h and
the precipitate was filtered and washed with water, saturated aqueous
NaHCO3, and water again, followed by hexane to remove any excess
I2, to yield a yellowish solid. The product was left to air-dry or
dissolved in CH2Cl2 and dried over anhydrous Na2SO4 before removal
of the solvent to give diiodopyrroketone 3 (4.2 g, 75%), mp 162 °C.
1H NMR (400 MHz; CDCl3) δ 9.47 (s, 2H), 3.65 (s, 6H), 2.70 (t, J =
1
BODIPY 8. (16.0 mg, 83%), mp 198 °C; H NMR (400 MHz;
CDCl3) δ 7.56−7.49 (m, 5H), 7.20−7.09 (m, 4H), 3.63 (s, 6H),
2.33−2.22 (m, 6H), 2.00 (s, 6H), 1.94−1.86 (m, 2H); 13C NMR (100
MHz; CDCl3) δ 172.5, 149.7, 142.4, 134.4, 133.2, 133.0, 131.7, 129.7,
128.8, 128.0, 127.4, 127.2, 51.6, 35.1, 21.4, 10.6; HRMS (ESI-TOF)
calcd for C31H30BF2N2O4S3 [M + H]+ 639.1429, found 639.1429. UV/
vis (CH2Cl2): λmax (ε) = 594 nm (43 700).
1
BODIPY 9. (8.2 mg, 42%), mp 165−166 °C; H NMR (400 MHz;
CDCl3) δ 7.53−7.38 (m, 15H), 3.60 (s, 6H), 2.12 (m, 4H), 2.00 (m,
4H), 1.80 (s, 6H); 13C NMR (100 MHz; CDCl3) δ 172.4, 156.6,
142.23, 134.6, 132.0, 131.3, 129.7, 129.4, 128.8, 128.7, 128.4, 128.3,
127.8, 51.5, 34.5, 21.7, 9.7; HRMS (ESI-TOF) calcd for
C37H35BFN2O4 [MW − F]+ 601.2674, found 601.2656. UV/vis
(CH2Cl2): λmax (ε) = 546 nm (29 500).
1
BODIPY 10. (12.6 mg, 61%), mp 171 °C; H NMR (400 MHz;
CDCl3) δ 3.69 (s, 6H), 3.25 (t, J = 8.0 Hz, 4H), 2.25 (t, J = 8.0 Hz,
4H), 2.08 (s, 6H). 0.32 (s, 9H), 0.28 (s, 9H); 13C NMR (100 MHz;
CDCl3) δ 172.8, 140.5, 136.0, 134.7, 132.8, 118.3, 114.0, 113.3, 99.2,
96.4, 51.7, 34.2, 21.4, 14.1, 9.5; HRMS (ESI-TOF) calcd for
C34H48BF2N2O4Si3 [M + H]+ 680.3014, found 680.3001. UV/vis
(CH2Cl2): λmax (ε) = 648 nm (88 000).
Regioselective Stille Coupling Reactions. The selective coupling
reactions followed the procedure used for the global coupling
reactions. The only difference was that 1 equiv of organotin reagent
was used instead of excess organotin reagents.
BODIPY 11. Starting with BODIPY 5 (29.2 mg, 0.059 mmol), 23.07
mg (72%) of the monosubstituted BODIPY was obtained, mp 212 °C;
1H NMR (400 MHz; CDCl3) δ 7.56 (dd, J = 5.0, 1.3 Hz, 1H), 7.15 (d,
J = 1.8 Hz, 1H), 7.09 (d, J = 1.6, 1H), 3.62 (s, 6H), 2.28−2.02 (m,
6H), 1.96 (s, 6H), 1.89−1.83 (m, 2H); 13C NMR (100 MHz; CDCl3)
δ 172.1, 145.0, 143.3, 133.5, 132.8, 131.0, 129.1, 128.5, 127.4, 126.9,
51.7, 34.8, 21.5, 8.8; HRMS (ESI-TOF) calcd for C23H23BCl2FN2O4S
[MW − F]+ 523.0833, found 523.0836. UV/vis (CH2Cl2): λmax (ε) =
548 nm (77 600).
BODIPY 12. A 1:1 ratio of BODIPY 5 (30.4 mg, 0.061 mmol) and
tributylphenyltin (20.0 μL, 0.061 mmol) was used to give the product
12 (7.0 mg, 21%); a 1:2 ratio of BODIPY 5 (32.6 mg, 0.066 mmol)
and tributylphenyltin (40.0 μL, 0.122 mmol) was used to give the
product 12 (19.45 mg, 57%), mp 172 °C; 1H NMR (400 MHz;
CDCl3) δ 7.56−7.38 (m, 5H), 3.58 (s, 6H), 2.04 (m, 4H), 1.95 (m,
10H); 13C NMR (100 MHz; CDCl3) δ 171.9, 144.4, 143.2, 141.1,
133.3, 130.1, 129.9, 129.0, 128.1, 126.5, 51.6, 34.3, 21.4, 8.7; HRMS
(ESI-TOF) calcd for C25H25BCl2FN2O4 [M − F]+: 517.1268, found:
517.1278. UV/vis (CH2Cl2): λmax (ε) = 534 nm (69 200).
7.6 Hz, 4H), 2.61 (t, J = 7.6 Hz, 4H), 2.04 (s, 6H); 13C NMR (100
MHz; CDCl3) δ 173.8, 173.5, 132.7, 128.5, 126.4, 51.8, 33.9, 20.9,
12.2; HRMS (ESI-TOF) calcd for C19H23I2N2O5 [M + H]+: 612.9691,
found: 612.9697.
BODIPYs 5−7. Diiodopyrroketone 3 (1.0 g, 1.63 mmol) was
dissolved in CHCl3 (150 mL), and excess phosgene in toluene
solution was added to the solution, which turned deep red with time;
the reaction was monitored by UV/vis spectrophotometry, and the
reaction was stopped when a sharp absorption peak appeared at about
480 nm. Then N2 gas was passed through the solution to purge it of
excess phosgene into an aqueous NaHCO3 solution trap. Solvent was
removed in vacuo to give a reddish solid, which was dissolved in 150
mL of CHCl3, followed by addition of DIEA (2 mL, 7.0 equiv). The
solution was stirred for 30 min, BF3·OEt2 (2.1 mL, 10 equiv) was
added, and the solution turned bright red with a yellow fluorescence
under long wavelength UV light. The reaction was monitored by UV/
vis spectroscopy, which showed a sharp peak at 538 nm. The mixture
was stirred for 24 h before being washed with water, saturated aqueous
NaHCO3, and brine and then dried over anhydrous Na2SO4 to give a
red solid. The product was purified by silica gel column
chromatography, eluting with ethyl acetate/hexane (1:4) to give the
product 5 (430 mg, 55%) as the major fraction and 6 (88.5 mg, 11%)
and 7 (40.2 mg, 5%) as minor products. BODIPY 5: mp 156−157 °C;
1H NMR (400 MHz; CDCl3) δ 3.72 (s, 6H), 3.20 (t, J = 8.0 Hz, 4H),
2.57 (t, J = 8.0 Hz, 4H), 2.05 (s, 6H); 13C NMR (100 MHz; CDCl3) δ
172.5, 144.0, 142.3, 134.9, 128.5, 127.3 52.0, 33.8, 22.8, 8.9; HRMS
(ESI-TOF) calcd for C19H20 BCl3FN2O4 [M − F]+: 475.0566, found:
475.0562; UV/vis (CH2Cl2): λmax (ε) = 538 nm (112 200). BODIPY
6: mp 116−118 °C; 1H NMR (400 MHz; CDCl3) δ 7.57 (s, 1H), 3.71
(s, 3H), 3.71 (s, 3H), 3.20 (m, 4H), 2.58 (m, 4H), 2.07 (s, 3H), 2.04
(s, 3H); 13C NMR (100 MHz; CDCl3) δ 172.5, 172.5, 143.5, 142.6,
142.4, 136.8, 130.1, 129.1, 128.7, 127.3, 126.8, 52.0, 51.9, 33.9, 33.9,
22.8, 22.2, 9.9, 8.9; HRMS (ESI-TOF) calcd for C19H21BCl2FN2O4
BODIPY 13. Starting with BODIPY 5 (20.0 mg, 0.04 mmol), 15.2
1
mg (65%) of 13 was isolated, mp 121 °C; H NMR (400 MHz;
CDCl3) δ 3.71 (s, 6H), 3.30 (t, J = 8.8 Hz, 4H), 2.59 (t, J = 8.8 Hz,
4H), 2.04 (s, 6H), 0.30 (s, 9H); 13C NMR (100 MHz; CDCl3) δ
172.6, 143.0, 142.1, 131.7, 126.4, 119.3, 114.8, 98.4, 51.8, 34.2, 21.7,
8.8; HRMS (ESI-TOF) calcd for C24H29BCl2FN2O4Si [M − F]+
537.1321, found 537.1340. UV/vis (CH2Cl2): λmax (ε) = 584 nm (67
600).
I
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Consecutive Stille Coupling Reactions. BODIPY 11 (16.5 mg,
0.030 mmol) and Pd(PPh3)4 (3.4 mg, 5%) were added to a round-
bottomed flask and flushed with argon several times. Anhydrous
toluene (10 mL) was added, followed by injection of tributylphenyltin
(28.0 μL, 3.0 equiv); the solution was refluxed for 12 h until a sharp
peak appeared in the UV/vis spectrum at 562 nm in CH2Cl2. The
reaction was stopped, and the toluene was removed; the residue was
taken up in CH2Cl2, which was washed with water and brine and then
dried over anhydrous Na2SO4. The crude product was purified by silica
gel column chromatography, eluting with ethyl acetate/hexane (1:4)
to give the product as a purple-red solid. All the other Stille cross-
coupling reactions followed this procedure.
chromatography to give the disubstituted product 20 (10.0 mg, 53%),
mp 122 °C. 1H NMR (400 MHz; CDCl3) δ 3.68 (s, 3H), 3.68 (s, 3H),
3.25 (m, 4H), 2.56 (m, 4H), 2.07 (s, 3H), 2.02 (s, 3H), 0.30 (s, 9H),
0.27 (s, 9H); 13C NMR (100 MHz; CDCl3) δ 172.8, 172.7, 144.0,
142.1, 140.5, 135.2, 133.3, 132.9, 126.6, 118.9, 114.4, 113.1, 98.7, 96.0,
51.8, 51.7, 34.2, 34.1, 21.7, 21.4, 9.5, 8.2, 0.3, 1.2; HRMS (ESI-TOF)
calcd for C29H39BClF2N2O4Si2 [M + H]+ 619.2198, found 619.2185.
UV/vis (CH2Cl2): λmax (ε) = 616 nm (46,800).
BODIPY 21. BODIPY 20 (10 mg, 0.016 mmol) and Pd(PPh3)4 (2.0
mg, 5%) were added to a round-bottomed flask. The flask was flushed
with argon, and then anhydrous toluene (15 mL) was injected,
followed by injection of the organotin reagent 2-(tributylstannyl)-
thiophene (8.0 μL, 1.5 equiv); the mixture was then refluxed for 5 h.
The toluene was removed, and the residue was taken up in CH2Cl2,
washed with water and brine, and then dried over anhydrous Na2SO4.
The crude product was purified by silica gel column chromatography
to give the fully substituted product 21 (6.8 mg, 63%), mp 151 °C. 1H
NMR (400 MHz; CDCl3) δ 7.75 (d, J = 3.44 Hz, 1H), 7.58 (d, J =
4.92 Hz, 1H), 7.20 (t, J = 4.24 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H),
3.37 (t, J = 7.88 Hz, 2H), 3.28 (t, J = 7.36 Hz, 3H), 2.64 (t, J = 7.88
Hz, 3H), 2.57 (t, J = 7.36 Hz, 3H), 2.15 (s, 3H), 2.09 (s, 3H). 0.30 (s,
9H), 0.28 (s, 9H); 13C NMR (100 MHz; CDCl3) δ 172.9, 151.9,
150.2, 142.5, 139.2, 133.6, 132.9, 132.6, 131.7, 129.7, 129.5, 127.5,
118.5, 113.6, 112.0, 99.3, 96.6, 51.7, 51.6, 34.4, 34.2, 21.6, 21.4, 10.9,
9.6. 1.0; HRMS (ESI-TOF) calcd for C33H42BF2N2O4SSi2 [M + H]+
667.2465, found 667.2478. UV/vis (CH2Cl2): λmax (ε) = 645 nm (29
500).
1
BODIPY 14. (10.6 mg, 56%), mp >260 °C. H NMR (400 MHz;
CDCl3) δ 7.59−7.14 (m, 13H), 3.65 (s, 6H), 2.29−2.27 (m, 6H),
2.07−1.96 (m, 2H), 1.86 (s, 6H); 13C NMR (100 MHz; CDCl3) δ
172.6, 157.2, 142.5, 134.5, 132.3, 131.9, 129.6, 128.9, 128.7, 128.3,
127.9, 127.8, 127.2, 51.6, 35.1, 21.5, 9.8; HRMS (ESI-TOF) calcd for
C35H33BFN2O4S [M − F]+ 607.2238, found 607.2234. UV/vis
(CH2Cl2): λmax (ε) = 560 nm (17 800).
BODIPY 15. Starting with BODIPY 11 (14.3 mg, 0.026 mmol)
1
afforded the product 15 (11.1 mg, 64%), mp 187 °C. H NMR (400
MHz; CDCl3) δ 7.54 (m, 1H), 7.14 (m, 1H), 7.08 (m, 1H), 3.63 (s,
6H), 2.19 (m, 6H), 2.02 (s, 6H), 1.90 (m, 2H), 0.33 (s, 18H); 13C
NMR (100 MHz; CDCl3) δ 172.4, 141.7, 137.8, 134.0, 133.6, 133.2,
129.0, 128.1, 127.2, 113.7, 96.2, 51.6, 34.9, 21.2, 9.5, 0.3; HRMS (ESI-
TOF) calcd for C33H42BF2N2O4SSi2 667.2465, found 667.2473. UV/
vis (CH2Cl2): λmax (ε) = 609 nm (89 100).
BODIPY 22. BODIPY 12 (21.6 mg, 0.042 mmol) and Pd(PPh3)4
(5.3 mg, 5%) were added to a round-bottomed flask. The flask was
flushed with argon, and then anhydrous toluene (15 mL) was injected,
followed by injection of the organotin reagent 2-(tributylstannyl)-
thiophene (14.0 μL, 1.0 equiv); the mixture was then refluxed for 5 h.
The toluene was removed, and the residue was taken up in CH2Cl2,
washed with water and brine, and then dried over anhydrous Na2SO4.
The crude product was purified by silica gel column chromatography
hexane/ethyl acetate (4:1) to give product 22 (10.5 mg, 43%), mp 164
°C. 1H NMR (400 MHz; CDCl3) δ 7.58−7.18 (m, 8H), 3.58 (s, 6H),
2.11−1.91 (m, 14H); 13C NMR (100 MHz; CDCl3) δ 172.2, 172.1,
150.4, 143.2, 143.1, 142.2, 141.1, 133.9, 132.0, 131.6, 130.4, 130.1,
129.7, 129.0, 129.0, 128.9, 128.2, 127.4, 126.1, 51.6, 34.4, 26.9, 21.9,
10.5, 7.5; HRMS (ESI-TOF) calcd for C29H28BClF2N2NaO4S [M +
Na]+ 607.1417, found 607.1391. UV/vis (CH2Cl2): λmax (ε) = 555 nm
(33 300).
BODIPY 16. Starting with BODIPY 12 (15.1 mg, 0.029 mmol)
afforded the product 16 (14.4 mg, 78%), mp 166 °C. H NMR (400
1
MHz; CDCl3) δ 7.59−7.47 (m, 9H), 7.14 (dd, J = 5.1, 3.6 Hz, 2H),
3.60 (s, 6H), 2.14−2.09 (m, 4H), 1.99−1.96 (m, 10H); 13C NMR
(100 MHz; CDCl3) δ 172.3, 149.3, 142.2, 141.2, 134.5, 132.0, 131.8,
131.5, 129.5, 129.3, 128.9, 128.5, 128.4, 127.3, 51.5, 34.5, 21.3, 10.5;
HRMS (ESI-TOF) calcd for C33H31BFN2O4S2 [M − F]+ 613.1802,
found 613.1803. UV/vis (CH2Cl2): λmax (ε) = 574 nm (38 900).
BODIPY 17. Starting with BODIPY 12 (17.3 mg, 0.033 mmol) gave
17 (15.7 mg, 71%), mp 182 °C. 1H NMR (400 MHz; CDCl3) δ 7.52−
7.45 (m, 3H), 7.37−7.28 (m, 2H), 3,57 (s, 6H), 2.06−2.00 (m, 10H),
1.94−1.89 (m, 4H), 0.33 (s, 18H); 13C NMR (100 MHz; CDCl3) δ
172.2, 149.3, 141.5, 140.5, 137.3, 133.8, 132.9, 129.6, 128.8, 128.3,
112.8, 96.2, 51.5, 34.3, 21.1, 9.5, 1.0; HRMS (ESI-TOF) calcd for
C35H43BF2N2NaO4Si2 [M + Na]+ 683.2720, found 683.2723. UV/vis
(CH2Cl2): λmax (ε) = 594 nm (47 900).
BODIPY 23. BODIPY 22 (9.4 mg, 0.016 mmol) and Pd(PPh3)4 (2.1
mg, 5%) were added to a round-bottomed flask. The flask was flushed
with argon, and then anhydrous toluene (15 mL) was injected,
followed by injection of the organotin reagent tributyl(1-ethoxyvinyl)
(11.0 μL, 1.5 equiv); the mixture was refluxed for 5 h. The toluene was
removed, and the residue was taken up in CH2Cl2, washed with water
and brine, and then dried over anhydrous Na2SO4. The crude product
was purified by silica gel column chromatography hexane/ethyl acetate
(4:1) to give the fully substituted BODIPY 23 (5.6 mg, 51%), mp,
>260 °C. 1H NMR (400 MHz; CDCl3) δ 7.59−7.15 (m, 8H), 4.62 (s,
2H), 3.90 (q, J = 7.1, 2H), 3.57 (s, 6H), 2.11−1.91(m, 14H), 1.35(t, J
= 7.1, 3H); 13C NMR (100 MHz; CDCl3) δ 172.4, 172.3, 152.3, 151.5,
142.6, 142.30 142.0, 141.9, 135.4, 134.4, 133.4, 131.5, 129.5, 129.3,
129.3, 128.8, 128.6, 128.4, 128.4, 128.2, 127.2,91.1, 63.7, 53.4, 51.5,
34.5, 21.4, 21.1, 14.3, 10.5, 9.3; HRMS (ESI-TOF) calcd for
C33H36BF2N2O5S [M + H]+ 621.2406, found 621.2406. UV/vis
(CH2Cl2): λmax (ε) = 559 nm (13 000).
BODIPY 18. Starting with BODIPY 13 (12.6 mg, 0.023 mmol) gave
18 (11.3 mg, 76%), mp 179 °C. 1H NMR (400 MHz; CDCl3) δ 7.54−
7.49 (m, 4H), 7.11 (ddd, J = 5.2, 3.8, 1.6 Hz, 2H), 3.72 (s, 6H), 3.39
(t, J = 8.2 Hz, 4H), 2.64 (t, J = 8.2 Hz, 4H), 2.09 (s, 6H), 0.32 (s,
18H); 13C NMR (100 MHz; CDCl3) δ 173.0, 147.9, 141.2, 133.8,
131.9, 131.7, 129.1, 128.7, 127.3, 119.2, 113.6, 99.4, 51.7, 34.4, 31.6,
21.6, 10.6, 1.1; HRMS (ESI-TOF) calcd for C32H35BFN2O4S2Si [MW
− F]+ 633.1885, found 633.1883. UV/vis (CH2Cl2): λmax (ε) = 636
nm (29 500).
BODIPY 19. Starting with BODIPY 13 (11.0 mg, 0.02 mmol) gave
product 19 (6.5 mg, 51%), mp 195 °C. 1H NMR (400 MHz; CDCl3)
δ 7.45−7.36 (m, 10H), 3.72 (s, 6H), 3.39 (t, J = 7.8 Hz, 4H), 2.67 (t, J
= 7.8 Hz, 4H), 1.89 (s, 6H), 0.33 (s, 9H); 13C NMR (100 MHz;
CDCl3) δ 173.0, 155.5, 141.3, 133.1, 131.9, 129.7, 128.8, 128.1, 127.7,
113.3, 99.3, 51.6, 34.4, 21.0, 9.7, 1.1; HRMS (ESI-TOF) calcd for
C36H39BFN2O4Si [M − F]+ 621.2756, found 621.2757. UV/vis
(CH2Cl2): λmax (ε) = 601 nm (38 900).
BODIPY 20. BODIPY 5 (15.0 mg, 0.03 mmol) and Pd(PPh3)4 (3.4
mg, 5%) were added to a round-bottomed flask. The flask was flushed
with argon and then anhydrous toluene (15 mL) was injected,
followed by injection of the organotin reagent trimethyl-
[(tributylstannyl)ethynyl]silane (22.3 μL, 0.06 mmol). The mixture
was refluxed until the starting material disappeared as observed by
TLC and the UV/vis spectrum showed a sharp peak around 615 nm.
Then the toluene was removed and the residue was taken up in
CH2Cl2 and washed with water, brine and then dried over anhydrous
Na2SO4. The crude product was purified by silica gel column
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra and of the normalized
absorption and fluorescence spectra of all new BODIPYs,
thermal ellipsoid plots and tables of fractional atomic
coordinates and displacement parameters for all X-ray
structures, and all 14 X-ray CIFs. This material is available
free of charge via the Internet at http://pubs.acs.org.
J
dx.doi.org/10.1021/jo501969z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(26) Gai, L.; Mack, J.; Lu, H.; Yamada, H.; Kuzuhara, D.; Lai, G.; Li,
Z.; Shen, Z. Chem.Eur. J. 2014, 20, 1091−1102.
(27) Fischer, H.; Orth, H. Justus Liebigs Ann. Chem. 1933, 502, 237−
264.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kmsmith@lsu.edu. Fax: (+) 225-578-3458.
(28) Leen, V.; Yuan, P.; Wang, L.; Boens, N.; Dehaen, W. Org. Lett.
2012, 14, 6150−6153.
Notes
The authors declare no competing financial interest.
(29) Misra, R.; Dhokale, B.; Jadhav, T.; Mobin, S. M. Dalton Trans.
2013, 42, 13658−13666.
(30) Wang, H.; Vicente, M. G. H.; Fronczek, F. R.; Smith, K. M.
Chem.Eur. J. 2014, 20, 5064−5074.
ACKNOWLEDGMENTS
■
This work was supported by the National Institutes of Health
(CA 132861, K.M.S.) and the National Science Foundation
(CHE-1362641, M.G.H.V.).
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