Functionalisation of fluorescent BODIPY dyes by nucleophilic substitution

Article abstract of DOI:10.1039/b512756d

The BODIPY chromophore can be easily modified by nucleophilic mono- or disubstitution of 3,5-dichloroBODIPY with O-, N-, S- and C-nucleophiles. Absorption and fluorescence spectral data of the new BODIPY derivatives are also reported. The Royal Society of

Full text of DOI:10.1039/b512756d

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Functionalisation of fluorescent BODIPY dyes by nucleophilic
substitution
Taoufik Rohand, Mukulesh Baruah, Wenwu Qin, Noe¨l Boens and Wim Dehaen*
Received (in Cambridge, UK) 13th September 2005, Accepted 18th October 2005
First published as an Advance Article on the web 22nd November 2005
DOI: 10.1039/b512756d
the properties of the BODIPY chromophore 1 is to work with
differently substituted aryl groups at the pyrrole rings, e.g. the 3,5-
positions.7 However, this will involve a preceding, not always
straightforward synthesis of the arylpyrrole building blocks.
Direct introduction of electron donating groups, without aryl
spacer, at the 3,5-positions would also have a significant effect, but
the corresponding pyrroles are not readily available for condensa-
tion reactions. Therefore, we wanted to investigate whether it
would be possible to introduce these substituents on a ready-made
BODIPY chromophore by nucleophilic substitution at the
3,5-positions.
The BODIPY chromophore can be easily modified by
nucleophilic mono- or disubstitution of 3,5-dichloroBODIPY
with O-, N-, S- and C-nucleophiles. Absorption and fluores-
cence spectral data of the new BODIPY derivatives are also
reported.
BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) derivatives
11 have been known for almost 40 years2 but in the last decade the
number of papers on these interesting fluorescent dyes has
increased exponentially. This is due to a combination of valuable
properties such as elevated chemical and photostability, relatively
high absorption coefficients and fluorescence quantum yields,
combined with a rather short synthesis for the simpler derivatives.
Furthermore, BODIPY dyes can be optically excited with visible
light, show narrow absorption and emission bands with high peak
intensities, and are amenable to structural modification so that
spectral shifts in the absorption and emission bands can be
generated by introducing the appropriate substituent pattern. In
fact, a number of BODIPY dyes are commercially available,
allowing their widespread use. We will restrict ourselves to
mentioning recent applications of BODIPY derivatives as fluoro-
ionophores,3 as probes in biochemical experiments4 and in
supramolecular photochemistry.5 There are several positions on
the chromophore where functionalisation can be carried out. Most
commonly in the literature, the pyrroles are substituted with
phenyl or alkyl groups, and functional groups such as ligands or
biomolecules are introduced via the 8-aryl group. This functional
group may be introduced before or after the BODIPY formation
from pyrrole 2 and substituted benzaldehyde or benzoyl chloride 3
(Scheme 1).
Firstly, we prepared the novel 3,5-dichloro-BODIPY derivative
4 in a few simple steps adapting literature procedures,8 starting
from 4-methylbenzaldehyde 5 that was converted to the dipyrro-
methane 6a (R 5 H) with an excess of pyrrole and trifluoroacetic
acid (TFA) as a catalyst (Scheme 2). Chlorination of 6a (R 5 H)
with N-chlorosuccinimide (NCS), followed by oxidation of 6b
(R 5 Cl) with p-chloranil and complexation with BF3?Et2O gave
our starting material 4 in a 20% overall yield for the four steps.
Electronic conjugation between the meso-aryl group and the
chromophore is weak, due to the two moieties being almost
perpendicular to each other.6 A more effective way to modulate
Scheme 1
Department of Chemistry, Katholieke Universiteit Leuven,
Celestijnenlaan 200F, 3001 Leuven, Belgium.
E-mail: Wim.Dehaen@chem.kuleuven.be; Fax: +32 16 327990;
Tel: +32 16 327390
Scheme 2
266 | Chem. Commun., 2006, 266–268
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As a first oxygen-centred nucleophile, we tried methoxide
(2 equivalents in methanol as solvent) at room temperature. This
reaction gave the monosubstituted product 7a in good yield.
Under more forcing conditions, namely four equivalents of
methoxide at reflux temperature (again in methanol), we obtained
the disubstituted derivative 8a. Ethylene glycol with sodium
hydride in acetonitrile at room temperature reacted with 4 to
afford the monosubstituted 7b, while reaction with excess ethylene
glycol/sodium hydride at reflux temperature did not give the
disubstituted derivative 8b but led to the decomposition of the
chromophore.
Next, several nitrogen-centred nucleophiles were tried. Without
the addition of additional base, the secondary amine piperidine
caused monosubstitution of 4 at room temperature yielding 7c.
Again, heating at reflux temperature (in acetonitrile) with excess
nucleophile led to the disubstituted BODIPY derivative 8c.
Analogous mono- and disubstitution reactions occurred with
aniline, affording respectively 7d and 8d. The 1,10-diaza-18-crown-
6 9 at room temperature reacted with 4 (2 equivalents) to give the
disubstituted bis(BODIPY)diazacrown ether 10.
We then used ethyl 2-thioacetate with triethylamine as base to
demonstrate the reactivity of sulfur-based nucleophiles. Again,
reaction at room temperature yielded the monosubstituted
derivative 7e, while disubstitution was possible at reflux tempera-
ture, yielding 8e.
Finally, diethyl malonate together with sodium hydride as base
was used as a carbon nucleophile to afford either the mono or
disubstituted BODIPY derivatives 7f and 8f, respectively.
Two different nucleophiles can be introduced after each other
using similar conditions. Thus, monosubstituted 7a could be
substituted with N-methylaniline and sodium hydride base to
afford 11. Reaction conditions and yields are summarized in
Table 1
As an example, Fig. 1 shows the absorption and steady-state
fluorescence emission spectra of 7a, 8a and 8e dissolved in
methanol. The absorption spectra of 7a and 8a are of similar shape
as those of previously described boron dipyrromethene dyes:9 i.e.,
a narrow absorption band with a maximum around 500 nm, and
in addition, a considerably weaker, broad absorption band with a
maximum around 350 nm. Compounds 7a, 8a and 8e also show
Fig. 1 Normalized absorption and fluorescence emission spectra of 7a
(black), 8a (green) and 8e (red) in methanol.
the typical emission features of BODIPY:9 i.e., a narrow, slightly
Stokes-shifted fluorescence emission band of mirror image shape.
Table 2 summarizes the photophysical data [the position of the
spectral maxima (labs, lem), the fluorescence quantum yields (wf),
Table 1 Nucleophilic substitution of 4 (or 7a ) with O, N, S, and C
centred nucleophiles. The solvent was acetonitrile, except for the
reactions with NaOMe where methanol was used
and the Stokes shifts (Dn 5 n 2 nem)] of several new BODIPY
¯
¯
¯
abs
compounds in methanol and cyclohexane. The excitation maxima
coincide exactly with the absorption maxima. The absorption,
excitation and emission spectra can be shifted considerably by the
appropriate substitution pattern at positions 3 and 5.
Reaction
Temp. time
Yield
Product (%)
Nucleophile (equiv.)
NaOMe (2)
NaOMe (4)
HOCH2CH2OH (2), NaH (1)
Piperidine (2)
Piperidine (4)
Aniline (2)
Aniline (4)
EtOOCCH2SH (2), Et3N (2)
EtOOCCH2SH (4), Et3N (2)
1,10-Diaza-18-crown-6 (0.5)
rt
reflux
rt
rt
reflux
rt
reflux
rt
reflux
rt
30 min
3 h
2 h
15 min
2 h
30 min
8 h
3 h
8 h
30 min 10
2 h
5 h
4 h
7a
8a
7b
7c
8c
7d
8d
7e
8e
65
66
68
74
78
69
64
65
70
61
67
71
60
The photophysical properties of the new BODIPY derivatives
will be described in detail elsewhere.
The easily obtained 3,5-dichloroBODIPY can be substituted
with a wide range of oxygen, nitrogen, sulfur, and carbon centred
nucleophiles and the reaction conditions can be adjusted to have
either mono- or disubstitution. These nucleophilic addition–
elimination substitution reactions of the 3,5-dichloroBODIPY
core happen to be a very successful approach for preparing a
variety of symmetric and asymmetric BODIPY compounds with
substitution patterns that are difficult to realize otherwise. The
substituents at the 3 and 5 positions have a significant effect on the
Diethyl malonate (2.2), NaH (1) rt
Diethyl malonate (4), NaH (2) reflux
N-Methyl aniline (2.2), NaH (1) reflux
7f
8f
11a
a
starting from 7a
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Chem. Commun., 2006, 266–268 | 267

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The authors thank the University Research Fund of the
Table 2 Absorption and fluorescence emission spectral data of
compounds 4, 7a–f, 8a, 8c–f in methanol and cyclohexane
K.U.Leuven for grant IDO/00/001 and for postdoctoral fellow-
ships to M.B. and W.Q. The Fonds voor Wetenschappelijk
Onderzoek – Vlaanderen (FWO) and the IAP-V-03 programme
are thanked for continuing support.
labs
lem
Dn
¯
BODIPY Solvent
(max/nm) (max/nm) (cm21
)
wf
4
MeOH
Cyclohexane 514
MeOH 499
Cyclohexane 508
MeOH 510
Cyclohexane 513
MeOH 500
Cyclohexane 509
MeOH 479
Cyclohexane 517
MeOH 572
Cyclohexane 584
MeOH 498
Cyclohexane 529
MeOH 588
Cyclohexane 594
MeOH 536
Cyclohexane 542
MeOH 564
Cyclohexane 568
MeOH 508
Cyclohexane 514
MeOH 509
Cyclohexane 515
508
519
525
515
520
523
525
515
520
562
565
612
611
566
567
613
616
550
553
579
583
522
526
522
527
417
645
623
738
487
446
583
416
3083
1643
1143
757
2412
1267
694
601
475
367
459
453
528
444
489
442
0.27
0.33
0.062
0.085
0.20
0.13
0.083
0.17
0.002
0.004
0.011
0.032
0.003
0.28
0.45
0.86
0.26
0.24
0.50
0.49
0.28
0.46
0.35
0.62
7a
8a
7b
7c
8c
7d
8d
7e
8e
7f
8f
Notes and references
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Labeling Technologies, 10th edn, Molecular Probes Inc., Eugene, Oregon,
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Eugene, Oregon, USA.
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the absorption and/or emission spectra (see Fig. 1), and affecting
the fluorescence quantum yields.
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Asymmetrically substituted BODIPY derivatives such as 7a–f,
10 and 11 are not readily available by any reported synthetic
method. For such compounds a multistep procedure would
normally be needed, starting from pyrroles substituted with
electron rich substituents that are unstable or difficult to obtain.
This new synthetic method allows for the easy linking of the
BODIPY unit to biomolecules or other groups of interest, as
demonstrated by the substitution of a diazacrown ether.
268 | Chem. Commun., 2006, 266–268
This journal is ß The Royal Society of Chemistry 2006