Synthesis of Functional Fluorescent BODIPY-based Dyes through Electrophilic Aromatic Substitution: Straightforward Approach towards Customized Fluorescent Probes

Article abstract of DOI:10.1002/open.201600067

Fluorescent materials are widely used in biological and material applications as probes for imaging or sensing; however, their customization is usually complicated without the support of an organic chemistry laboratory. Here, we present a straightforward method for the customization of BODIPY cores, which are among the most commonly used fluorescent probes. The method is based on the formation of a new C?C bond through Friedel–Crafts electrophilic aromatic substitution carried out at room temperature. The method presented can be used to obtain completely customized fluorescent materials in one or two steps from commercially available compounds. Examples of the preparation of fluorescent materials for cell staining and functionalization of silica colloids are also presented.

Full text of DOI:10.1002/open.201600067

DOI: 10.1002/open.201600067
Synthesis of Functional Fluorescent BODIPY-based Dyes
through Electrophilic Aromatic Substitution:
Straightforward Approach towards Customized
Fluorescent Probes
ˇ [c]
ˇ
ˇ [a]
Giorgio Mirri,*[a, b] Daniꢀl C. Schoenmakers,[b] Paul H. J. Kouwer,*[b] Peter Veranic, Igor Musevic, and
Bogdan Stefane*
[d]
ˇ
Fluorescent materials are widely used in biological and materi-
al applications as probes for imaging or sensing; however,
their customization is usually complicated without the support
of an organic chemistry laboratory. Here, we present a straight-
forward method for the customization of BODIPY cores, which
are among the most commonly used fluorescent probes. The
method is based on the formation of a new CÀC bond through
Friedel–Crafts electrophilic aromatic substitution carried out at
room temperature. The method presented can be used to
obtain completely customized fluorescent materials in one or
two steps from commercially available compounds. Examples
of the preparation of fluorescent materials for cell staining and
functionalization of silica colloids are also presented.
extinction coefficients and fluorescence quantum yields. In ad-
dition, they are relatively stable and easily prepared and func-
tionalized.[1] Currently, BODIPYs are widely used as fluorescent
tags in biology,[1d] as sensors,[2] laser dyes,[3] and recently they
were proposed as dyes for non-linear optics,[4] as photosensitiz-
ers in solar cells[5] and for photodynamic therapy.[6]
For these reasons, a plethora of different synthetic strategies
have been developed to introduce modifications on the fluo-
rescent core to tune the spectroscopic properties, to increase
the dye’s solubility in polar sol-
vents, or for conjugation to silica,
proteins, or nucleosides.[1a,b] Func-
tionalization of the dye can be per-
formed in all of the positions indi-
cated with numbers in Figure 1,
1. Introduction
either before or after the prepara-
Figure 1. IUPAC numbering of
tion of the fluorescent core. In the
the BODIPY core.
Dyes based on 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene
(BODIPY) have been studied extensively throughout the last
three decades, owing to their excellent chemical and photo-
physical properties. They typically possess narrow absorption
peaks that can be tuned in the visible spectrum, rather high
majority of synthetic approaches,
these modifications are introduced
in before the assembly of the aro-
matic core.
Herein, we present a new method that allows for the instal-
lation of customized molecular moieties in one step directly on
the unsubstituted position 2 of a BODIPY core. To the best of
our knowledge, there are only two examples of functionaliza-
tion at position 2 of a fully formed BODIPY core through the
direct formation of a new CÀC bond; one is the introduction
of a formyl group by using a Vilsmeier–Haack reaction,[7] and
the second is the addition of electron-deficient alkenes
ˇ
ˇ
[a] Dr. G. Mirri, Prof. I. Musevic
ˇ
Condensed Matter Physics Department, Jozef Stefan Institute
Jamova 39, 1000 Ljubljana (Slovenia)
E-mail: giorgio.mirri@ijs.si
[b] Dr. G. Mirri, D. C. Schoenmakers, Dr. P. H. J. Kouwer
Institute for Molecules and Materials, Radboud University Nijmegen
Heyendaalseweg 135, 6525 AJ Nijmegen (The Netherlands)
E-mail: p.kouwer@science.ru.nl
through
a
Pd-catalyzed Heck-like reaction.[8] Alternatively,
ˇ
[c] Prof. Dr. P. Veranic
BODIPY core functionalization has been realized in a two-step
procedure comprised of a halogenation reaction, followed by
a Sonogashira, Heck, or Suzuki cross-coupling reaction.[9]
Institute of Cell Biology
Faculty of Medicine, University of Ljubljana
Vrazov trg 2, 1000 Ljubljana (Slovenia)
ˇ
Our strategy for BODIPY functionalization is based on acid-
catalyzed Friedel–Crafts electrophilic aromatic substitution
(SEAr) with acyl chlorides in the presence of trifluoroborate di-
ethyletherate (BF3·OEt2) as the Lewis acid (Scheme 1). Posi-
tions 2 and 6, owing to resonance, are the most nucleophilic
and are, therefore, favored for SEAr;[1b] on these positions, elec-
trophilic substitutions that introduce formyl,[7] nitro,[10] and sul-
fonic acid groups[11] as well as halides have been reported.[9a,b]
However, Lewis-acid-catalyzed acylations like Friedel–Crafts re-
actions have not been reported for the functionalization of
BODIPYs. This is most probably because of the lability of the
[d] Dr. B. Stefane
Organic Chemistry Department
Faculty of Chemistry and Chemical Technology, University of Ljubljana
Vecna pot 113, 1000 Ljubljana (Slovenia)
E-mail: bogdan.stefane@fkkt.uni-lj.si
ˇ
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under http://dx.doi.org/10.1002/
open.201600067.
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The yields of BODIPYs 2a–e after purification (15–60%) are
competitive with the traditional methodologies for functionali-
zation of BODIPY in position 2 (overall yields of two-step meth-
ods are in the 25–60% range). With this reaction, we are able
to introduce aliphatic (2a, 2c–2e) and aromatic (2b) substitu-
ents, including functional (2d, 2e) groups, which can be di-
rectly used for further conjugation through the increasingly
popular copper-catalyzed azide–alkyne click reaction (2e),[19] or
by using standard N-hydroxy succinimide (NHS) ester chemistry
(2d).[20]
Aliphatic acyl chlorides gave the highest yields. Double acy-
lation products (where also the 6-position is substituted) were
not observed in the analysis; in fact, even with a four-fold
excess of acyl chloride, no significant amounts of doubly sub-
stituted BODIPYs were found (see Figure S4 in the Supporting
Information for analysis of the crude reaction mixture). The
prevalence of mono-substitution is attributed to the relatively
low acidity of BF3 and the inductive effect of the formed
ketone, which withdraws electrons from the BODIPY, deactivat-
ing position 6.
When the aromatic biphenyl acyl chloride was used as the
electrophile (to form 2b), the yield was slightly lower. This ex-
ample shows, however, that although the acyl chloride used
carries competing acylation sites (the biphenyl), the reaction is
selective for the BODIPY core.
Scheme 1. Reaction scheme for the method proposed and products
prepared.
2.2. Spectroscopic Properties
The carbonyl group inserted with the proposed method is con-
jugated to the BODIPY core, as evidenced by the IR vibrations
of the C=O bond at relatively short wavenumbers (around v
ꢀ1650 cmÀ1). The conjugation of the carbonyl can allow us to
tune the fluorescent properties of the materials prepared. For
example, the ketone resulting from the acylation reaction can
be removed under mild conditions with NaBH3CN and ZnI.[21]
As an illustration, we reduced 2a to give the alkyl-substituted
BODIPY analogue 3 (Scheme 2). We notice that, although the
BF2 group under acidic conditions. For example, the archetypal
Lewis acid used for Friedel–Crafts SEAr (AlCl3) was used to sub-
stitute the fluorine atoms for alkoxy or carboxylate groups;[3,12]
whereas, Brønsted acids were used to remove the BF2
group.[13] There are only limited examples of the Friedel–Crafts
acylation of aromatic substrates from acyl chlorides using
BF3·OEt2,[14] which possess a lower relative acidity compared to
AlCl3.[15] It is reasonable to think that BF3·OEt2 will not majorly
affect the BODIPY core as it is commonly used to introduce
the boron difluoride group during the synthesis of the dye.[16]
Such an approach therefore allows for selective acylation of
position 2 without the need to protect the other positions,
which are disfavored by resonance.
Scheme 2. Reduction of compound 2a.
2. Results and Discussion
absorption maxima of acylated products 2a–e remain the
same as starting material 1, the Stokes shifts and the extinction
coefficient increased, as described in Table 1. Moreover, in 3,
where the ketone is reduced, the Stokes shift is again reduced
and the absorption maximum increases to lmax =521 nm
(Figure 2).
2.1. Synthesis of the Materials
We prepared the substrate tetramethyl-BODIPY 1 from 3,5-di-
methyl-1H-pyrrole-2-carbaldehyde following a previously re-
ported one-step process;[17] however, this compound is com-
mercially available, giving us the possibility to reduce the pro-
posed method to only a single step. The Friedel–Crafts reac-
tion was then carried out in the presence of BF3·OEt2 as a reac-
tant (1–3 equiv) and an acyl chloride (1.3 equiv), which can be
commercially available or can be prepared following usual lab
procedures.[18] After stirring for several hours (4–24 h) at room
temperature, the excess BF3·OEt2 was quenched with water.
2.3. Direct Applications of the Materials
To demonstrate direct application of the materials prepared
with our method, we used compound 2d, prepared in one
step from tetramethyl-BODIPY 1 and adipoyl chloride (both
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posed fluorescence and bright-field microscope images of one
silica colloid are shown in Figure 3b.
Table 1. Spectroscopic properties of the products. Measurements were
carried out in dichloromethane. The absorption maximum and emission
maximum excitation wavelengths were 400 nm and a slit of 5 nm was
used. The Stokes shift (Dl), extinction molar coefficient (e), and quantum
yield (f) were calculated by using Rhodamine B in absolute ethanol as
the reference (f=0.5 at 228C).
3. Conclusions
We have presented a novel approach for the selective func-
tionalization of a BODIPY core at position 2 through an electro-
philic aromatic substitution carried out by using trifluoroborate
diethyletherate (BF3·OEt2) as the Lewis acid and acyl chlorides
as electrophiles. The method presented is specific for posi-
tion 2 and allows functionalization without the need for further
protection of other free positions on the BODIPY core. The
products were obtained in reasonably good yields and the re-
action also allows the connection of functional groups to the
fluorescent cores. Besides, we have demonstrated some direct
biological applications of one dye that could be obtained in
one step at room temperature from commercially available
starting materials, in addition to further manipulation of the
same dye to obtain a fluorescent trimethoxysilyl material for
silica functionalization. This approach presents a good alterna-
tive to multistep and metal-catalyzed functionalization strat-
egies for BODIPY dyes and can be used to create customized
fluorescent probes as alternatives to commercially available flu-
orescent compounds. The fact that the process consists of only
one step, in which the reagents are all commercially available,
allows for a fast preparation of customized fluorescent mole-
cules with tailor-made characteristics. However, there is still
room for improvement, and the approach presented could, in
principle, be applied to different electrophiles[26] and
substrates.
Product
Absorption
[nm]
Emission
[nm]
Dl
e
f
[nm]
[mÀ1 cmÀ1
]
1
506
505
509
506
499[a]
503
521
512
515
519
516
508[a]
513
528[b]
6
10
10
10
9[a]
10
7
98500
163500
151000
121000
23500[a]
147500
82500
0.95
0.80
0.82
0.79
0.62[a]
0.85
0.75[b]
2a
2b
2c
2d
2e
3
[a] Measurement carried out in acetonitrile. [b] Excitation wavelength
450 nm.
the substrates are commercially available), to stain Madin
Darby Canine Kidney (MDCK) cells. The endosomes of com-
pound 2d present in the cytosol, as shown in the fluorescent
confocal microscopy image (3D reconstruction of optical sec-
tions) of the dye in MDCK confluent cells (Figure 3a), demon-
strate that amphiphilic 2d was adsorbed on the cellular mem-
brane and then internalized by endocytosis. The cell nuclei of
the cells were stained with DAPI (blue in Figure 3a).
In addition, compound 2d can be easily converted in
a single step to the corresponding NHS ester 4; this is a versa-
tile intermediate for the connection of molecular moieties, be-
cause it quickly and quantitatively reacts with amines to give
amides. Such functional dyes are of particular interest to bio-
medical science for protein tagging.[22,23] We coupled 4 to (3-
aminopropyl)-trimethoxysilane to obtain 5 (Figure 3); this tri-
methylsilyl-containing dye can be used for the formation of
fluorescent monolayers on glass, silica, and indium tin oxide
(ITO).[24] As a proof-of-principle, we also functionalized silica
colloids (7.3 mm). Such labelled colloids can be used to create
colloidal assemblies in liquid-crystalline media.[25] The superim-
Experimental Section
General Procedure
A) Electrophilic Aromatic Substitution on BODIPY Cores
Tetramethyl BODIPY 1 (1 equiv) was placed in a round-bottom
flask and dissolved in dichloromethane in an argon atmosphere
Figure 2. Normalized UV/Vis absorption (left) and fluorescence emission (right) of 1 (red), 2a (blue), and 3 (black).
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Figure 3. Reaction scheme for the preparation of a trimethoxysilane bearing BODIPY 5. a) MDCK confluent cell culture treated with 2d (green). The nuclei
were stained with DAPI (blue) and live cells were labelled with 0.5 mm 2d (stock solution 5 mm in DMSO and then diluted 1:10 in ADMEM medium); the cells
were then fixed in 4% formaldehyde. b) Superimposition of fluorescence and bright-field images of a 7.3 mm silica colloid treated with 5 and dispersed in
a low birefringent liquid crystal mixture CCN47-55. Fluorescence was imaged with excitation at 470 nm and emission was detected in the range of 495–
574 nm (in this case the red color merely indicates high emission and does not reflect the real color of the light emitted).
(concentration of 1 ca. 0.07m). The mixture was cooled to 08C and
BF3·OEt2 (3 equiv) was added immediately. The mixture was stirred
for 10 min, and then the acyl chloride (1.3 equiv) was added. The
mixture was stirred for another 10 min at 08C and then for 4–24 h
at room temperature. The reaction process was assessed by using
thin-layer chromatography (TLC). The reaction was then quenched
by adding water and the biphasic mixture was stirred for between
10 min and 2 h. The mixture was then separated and the aqueous
layer extracted with fresh dichloromethane. The combined organic
layers were dried over Na2SO4 and the solvent was evaporated.
Products 2a–e were obtained after chromatographic purification
as orange solids.
7th European Community Framework Program. The APC fee for
this article has been funded by the EC FP7 Post-Grant Open
Access Pilot. The authors acknowledge the Centre for Mass Spec-
ˇ
troscopy at the Jozef Stefan Institute who carried out mass char-
acterization of the compounds prepared. G.M. acknowledges Dr.
ˇ
Franc Pozgan for allowing him to use his lab and for fruitful dis-
cussions and Gregor Posnjak for his help with the fluorescence
microscope.
Keywords: BODIPY
·
cell staining
·
dyes/pigments
·
electrophilic aromatic substitution · fluorescent colloids
B) Acyl Chlorides from Carboxylic Acids
A commercial carboxylic acid was placed in a round-bottom flask
and dissolved in dichloromethane. The mixture was cooled to 08C
and oxalyl chloride (1–3 equiv) was added immediately.[18] The mix-
ture was stirred for 10 min at 08C, and then allowed to warm to
room temperature. The mixture was stirred for another 1 h and fi-
nally refluxed for 2 h. The solvent was then gently evaporated
under vacuum at room temperature.
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Received: June 23, 2016
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COMMUNICATIONS
G. Mirri,* D. C. Schoenmakers,
One step for man… A simple and
straightforward method for the specific
functionalization of position 2 of
BODIPY cores based on electrophilic ar-
omatic substitution is presented. The
method allows the one-step preparation
of customized functional fluorescent
dyes directly from commercially avail-
able materials.
ˇ
ˇ
ˇ
P. H. J. Kouwer,* P. Veranic, I. Musevic,
ˇ
B. Stefane*
&& – &&
Synthesis of Functional Fluorescent
BODIPY-based Dyes through
Electrophilic Aromatic Substitution:
Straightforward Approach towards
Customized Fluorescent Probes
&
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ꢁ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!