Functionalisation of fluorescent BODIPY dyes by nucleophilic
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
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
BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) derivatives
11have been known for almost 40 years2but 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,3as probes in biochemical experiments4and in
supramolecular photochemistry.5There 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
Electronic conjugation between the meso-aryl group and the
chromophore is weak, due to the two moieties being almost
perpendicular to each other.6A more effective way to modulate
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.7However, 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
Firstly, we prepared the novel 3,5-dichloro-BODIPY derivative
4 in a few simple steps adapting literature procedures,8starting
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.
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
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266 | Chem. Commun., 2006, 266–268This journal is ? The Royal Society of Chemistry 2006
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
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
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:9i.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
the typical emission features of BODIPY:9i.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),
and the Stokes shifts (Dn ¯ 5 n ¯abs2 n ¯em)] of several new BODIPY
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.
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
centred nucleophiles. The solvent was acetonitrile, except for the
reactions with NaOMe where methanol was used
Nucleophilic substitution of 4 (or 7a ) with O, N, S, and C
Nucleophile (equiv.) Temp.
HOCH2CH2OH (2), NaH (1)
EtOOCCH2SH (2), Et3N (2)
EtOOCCH2SH (4), Et3N (2)
Diethyl malonate (2.2), NaH (1)
Diethyl malonate (4), NaH (2)
N-Methyl aniline (2.2), NaH (1)
astarting from 7a
(black), 8a (green) and 8e (red) in methanol.
Normalized absorption and fluorescence emission spectra of 7a
This journal is ? The Royal Society of Chemistry 2006Chem. Commun., 2006, 266–268 | 267
photophysics of the BODIPY fluorophore, causing shifts in Download full-text
the absorption and/or emission spectra (see Fig. 1), and affecting
the fluorescence quantum yields.
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.
The authors thank the University Research Fund of the
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.
Notes and references
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Labeling Technologies, 10th edn, Molecular Probes Inc., Eugene, Oregon,
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compounds 4, 7a–f, 8a, 8c–f in methanol and cyclohexane
Absorption and fluorescence emission spectral data of
268 | Chem. Commun., 2006, 266–268This journal is ? The Royal Society of Chemistry 2006