A Fluorinated Carbanionic Substituent for Improving Water Solubility and Lipophilicity of Fluorescent Dyes

Article abstract of DOI:10.1002/anie.202012764

Installation of a carbanionic substituent, that is strongly stabilized by two (trifluoromethyl)sulfonyl (Tf=SO₂CF₃) groups, into several fluorescence dyes including boron-dipyrromethenes (BODIPYs), fluoresceins, and aminocoumarins ha

Full text of DOI:10.1002/anie.202012764

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Accepted Article
Title: A Fluorinated Carbanionic Substituent for Improving Water-
solubility and Lipophilicity of Fluorescent Dyes
Authors: Hikaru Yanai, Shoki Hoshikawa, Yukiiko Moriiwa, Atsushi
Shoji, Akio Yanagida, and Takashi Matsumoto
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A Fluorinated Carbanionic Substituent for Improving Water-
solubility and Lipophilicity of Fluorescent Dyes
Hikaru Yanai,*[a] Shoki Hoshikawa,[a] Yukiko Moriiwa,[a] Atsushi Shoji,[a] Akio Yanagida,[a]
and Takashi Matsumoto*[a]
[a]
Dr. H. Yanai, S. Hoshikawa, Dr. Y. Moriiwa, Dr. A. Shoji, Prof. Dr. A. Yanagida, Prof. Dr. T. Matsumoto
School of Pharmacy
Tokyo University of Pharmacy and Life Sciences
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
E-mail: yanai@toyaku.ac.jp (HY), tmatsumo@toyaku.ac.jp (TM)
Supporting information for this article is given via a link at the end of the document.
Abstract: Installation of a carbanionic substituent, that is strongly
stabilised by two (trifluoromethyl)sulfonyl (Tf = SO2CF3) groups, into
several fluorescence dyes including boron-dipyrromethenes
(BODIPYs), fluoresceins, and aminocoumarins has been achieved
by the 2,2-bis(triflyl)ethylation reaction of the dye frameworks with
highly electrophilic Tf2C=CH2, followed by neutralisation with
NaHCO3. Despite the contradiction between water-solubility and
lipophilicity, the carbanion-decorated dyes thus obtained showed
significant enhancement of not only water-solubility but also
lipophilicity. This work clearly demonstrates that the fluorinated,
Although perfluoroalkyl groups usually make liposolubilitiy of the
compounds lower (cf. poor solubility of fluorous compounds in
organic solvents),[4] structural decoration by such substituents
enhances apparent lipophilicity of the compounds because
lowering the water-solubility is more appreciable (Figure 1C).
Such phenomenon implies that scientists still face with a
problem on water-solubilisation methodology with keeping or
enhancing lipophilicity.[5] One of traditional approaches against
this antinomy is the use of suitable hydrophobic linkers inserted
between the hydrophilic functionalities and the core structure
(Figure 1D).[6] The linkers not only provide a chance to moderate
the electronic and/or steric effects of the ionic groups on their
molecular functions, but also, they relieve their substituent
effects on the macroscopic properties of compounds. However,
tiresome trial and error is necessary to discover compounds with
the desired properties. Upon such background, we are
interested in the use of a fluorinated carbanion as a novel
substituent for water-solubilisation without impairing lipophilicity
(Figure 1E). This idea may be outlandish because carbanions
are, in most cases, reactive and strongly basic chemical species.
However, recent progress on highly stable and isolable
carbanion-containing salts motivated us.[7,8] Among them, inter-
or intramolecular salts bearing Tf2C‒ group(s), which is a
chemically inert carbanionic substituent, were reported one after
another.[9] Utilisation of this carbanionic group is attractive in the
context of controlling macroscopic properties because of its ionic
character and trivalency of the carbon centre permitting to place
a couple of triflyl groups and a linker to the functional moiety on
it. During investigating water-solubilisation involving the
carbanionic substituent, interesting observations were made
regarding solubility and lipophilicity. Herein, we report that this
fluorinated carbanionic substituent could serve as a new option
for enhancing both water-solubility and lipophilicity.
highly stabilised carbanionic substituent is
a new option for
controlling the macroscopic property of chemical materials.
Water-solubility (and aqueous solubility) is a key macroscopic
property for chemical materials directed towards bio-relevant
applications.[1] The most common way to improve the water-
solubility of less soluble compounds is introduction of ionic
groups such as the sulfonato group into the molecular structure
(Figure 1A). However, such ionic functionalities generally impair
the lipophilicity of the compounds. Indeed, a strong correlation of
water-solubility with lipophilicity parameters including log Po/w (an
octan-1-ol/water-biphasic partition coefficient; where Po/w is a
quotient of the concentrations of solute in each phase) has been
demonstrated in a large set of compounds.[2,3] In contrast, simple
alkyl groups increase lipophilicity through reducing water-
solubility and increasing liposolubility (Figure 1B).
Boron-dipyrromethene (BODIPY) constitutes an emerging
class of heterocyclic scaffolds utilised for various applications
including fluorescence bio-probes, which show sharp
fluorescence emission spectra in several media, and
photosensitisers for medical purposes.[10] However, simple
BODIPYs are insoluble in common aqueous solvents. Water-
solubilisations of BODIPYs through the introduction of sulfonato
group(s)[11] or conjugation with water-soluble peptides,
saccharides, and poly(oxyalkylene)s[12] were examined. To
investigate the effects of the fluorinated carbanionic substituent
to the macroscopic properties of fluorescence dyes, we
examined the reaction of BODIPY 2a using 2-fluoropyridinium
ethanide 1,[13,14] an effective reagent for in-situ generation of
Figure 1. Substituent-based Control of Water-solubility and Lipophilicity.
1
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Scheme 1. Two-step synthesis of carbanion-decorated BODIPYs.
Scheme 3. 2,2-Bis(triflyl)ethylation reaction of BODIPYs.
Scheme 4. 2,2-Bis(triflyl)ethylation reaction of BODIPY dimer 9.
Scheme 2. Two-step decoration of fluorescein and aminocoumarin.
substituted BODIPYs selectively occurred at the 2,6-positions
(3g‒j). Moreover, several functionalities including ester (3e),
carboxylic acid (3f), aldehyde (8b), and bromine atom (8c) were
well tolerated during the reaction. Likewise, tri-acid 10 was
obtained by the reaction of BODIPY dimer 9 with 3 equiv of 1
(Scheme 4).
Tf2C=CH2 (Scheme 1).[15] Fortunately, the reaction of 2a with 2.1
equiv of 1 was quickly completed (<15 min) in acetonitrile at
room temperature to give 2,6-dialkylated product 3a-H. Through
neutralisation using NaHCO3, acid 3a-H was converted to
sodium salt 3a-Na in 99% yield. Although the 1:1 reaction of 2a
with 1 yielded a mixture of mono- and di-alkylated products, we
failed to separate them despite various efforts including
chromatographic methods. Similarly, more lipophilic 3,5-
dialkenyl-8-phenyl BODIPY 2b was converted to sodium salt 3b-
Na in 95% overall yield. In contrast, all our efforts for the
sulfonylation reaction of 2b resulted in failure.[11a,b] This two-step
protocol to incorporate the carbanionic group was successfully
applied to other classes of fluorescence dyes (Scheme 2). For
example, fluorescein 4 was converted to sodium salt 5-Na in
89% yield. Likewise, blue fluorescent aminocoumarin 6 gave
sodium salt 7-Na in 91% yield. The carbanion-decorated dyes
3a-Na, 3b-Na, 5-Na, and 7-Na, thus obtained, were easy-to-
handle (non-fuming and non-hygroscopic) and could be stored
for at least a few months in light-shielding vials without
detectable decomposition.
Next, the photochemical and macroscopic properties were
evaluated (Table 1 and Figure 2). BODIPY sodium salt 3a-Na
showed the wavelength maxima of UV-Vis absorption and
PLE
photoluminescence emission (PLE) bands (absmax and

max
)
in EtOH at 519 and 541 nm, respectively (entry 1). These values
were close to those of acid 3a-H (entry 2). Compared with 2,6-
unsubstituted BODIPY 2a (entry 3), both the UV-Vis absorption
and PLE bands of 3a-Na were slightly red-shifted. In addition, in
phosphate buffers, the PLE profile of 3a-Na was less sensitive to
pH changes (Figure 2A and Supporting Information).[16] These
data suggest that protonated species of 3a-Na are negligibly
minor components in slightly acidic buffers as well as EtOH. The
electron-donating ability of the anionic CH2C‒Tf2 group on the
fluorophore was estimated to be similar in magnitude to that of
the ethyl group in 11 (entry 1 vs. entry 4; also see, Figure 2B).
The structural decoration of the BODIPYs by this substituent did
not impair the fluorescence quantum yields PLE (entry 1 vs.
entries 3 and 4) as well. These facts evidence that the benzylic
methylene moiety separating the  system from a lone electron
pair on the anionic carbon atom mitigated the electronic effects
on the photophysical properties.
Scheme 3 shows the scope of the BODIPY modification.
High-yield incorporation of the carbon acid moiety at two
positions (3c‒j) and one position (8a‒c) was attained by
employing 2 equiv or 1 equiv of 2-fluoropyridinium salt 1,
respectively. It is noteworthy that the reactions of the 3,5,8-tri-
2
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Table 1. Photophysical Data, Water-solubility, and log D of PLE Dyes.[a]
[b]
Entry
1
absmax (nm)
519
 (M–1 cm–1
74,400
84,400
89,400
81,000
98,400
63,000
87,800
87,800
88,800
20,600
23,000
)
PLEmax (nm)
541
Stokes shift (cm–1
)
PLE
Water-solubility (mg L–1
)
log D [c]
6.8
3a-Na
3a-H
2a
784
787
0.77
0.76
0.76
0.77
0.71
0.80
0.76
0.47
0.93
0.70
0.71
>10,000
300
2
518
540
7.6
3
494
506
480
<1
4.1
4
11
517
536
686
<1
4.6
5 [d]
6 [e]
7 [e]
8 [f]
9 [f]
10
11
12
497
525
1,070
808
>10,000
–0.9
3a-Na
12
511
533
491
519
1,100
821
5-Na
4
518
541
>10,000
110
6.6
–1.2
6.5
502
524
836
7-Na
6
359
443
5,280
4,950
3,600
<1
366
447
2.5
[a] Measurements were conducted by using 5.0 x 10–6 mol L–1 solutions for UV-Vis and 1.0 x 10–6 mol L–1 solutions for fluorescence in EtOH, respectively. [b] PLE
values were obtained by using a solution of rhodamine 6G in EtOH as a reference (PLE = 0.95). [c] Calculated by distribution coefficient in a biphasic system
prepared by MeCN / pH 7.4 phosphate buffer / octan-1-ol (25:25:4 v/v/v). See, ref. 17. [d] In MeOH. [e] In H2O. [f] In 0.1 M NaOH (aq.).
(A)
(C)
(B)
Figure 2. (A) UV-Vis absorption and PLE spectra of 3a-Na in pH 6.0-8.0 phosphate buffers. (B) PLE spectra of BODIPY derivatives in EtOH (1.0 x 10‒6 mol L‒1
solutions) in EtOH. Due to poor solubility, the spectrum of 12 was measured in MeOH instead of EtOH. (C) PLE spectra of sodium salts 3a-Na, 3b-Na, 5-Na, and
7-Na in aqueous solvents.
Notably, the water-solubility (>10,000 mg L‒1) of carbanion-
decorated BODIPY 3a-Na was over 10,000 times greater than
that of simple BODIPYs 2a and 11 (<1 mg L‒1). Also, we found
that the log D (distribution coefficient in an octan-1-ol/pH 7.4
phosphate buffer biphasic system) of 3a-Na was 6.8 by applying
Yanagida’s protocol[17] using a biphasic system containing
acetonitrile, 0.1 M phosphate buffer, and octan-1-ol in a ratio of
25:25:4 v/v/v (see, SI). In contrast, a known water-soluble
BODIPY 12[10a] bearing two sulfonato groups showed
remarkable hydrophilic character with ‒0.9 of log D (entry 5). As
shown in Figure 3, such a notable difference in the distribution
properties in the biphasic system containing acetonitrile was
visible as a macroscopic phenomenon. Even in water, 3a-Na
showed a PLE band maximum of 533 nm with 0.80 of PLE
(entries 6 and 7). Similar substituent effects by the carbanionic
substituent towards water-solubility and log D were observed not
only in the series of BODIPYs but also in fluorescein and
aminocoumarin dyes (entries 8‒11). That is, 5-Na and 7-Na
showed significant enhancement of lipophilicity as well as water-
solubility. These results evidence a wide range of generality in
the present water-solubilisation with enhancement of lipophilicity
by the highly fluorinated carbanionic substituent. As a result, we
3
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levels increased by raising negative charge, the energy gaps
between HOMO and LUMO of them were in a narrow range
from 2.92 eV to 3.07 eV. Likewise, the HOMO/LUMO gap of 2a
was 3.07 eV. These results were consistent with the observed
experimental photochemical signatures of BODIPY derivatives.
In conclusion, we developed a unique water-solubilisation
method for hydrophobic BODIPY derivatives through
incorporating the fluorinated carbanionic group. This protocol
was successfully applied to other fluorescence dyes including
fluorescein and aminocoumarin derivatives. Although this
substituent did not impair the photophysical properties of the
parent fluorophores, the macroscopic properties of the
compounds were dramatically affected. That is, the
enhancement of both their water-solubility and lipophilicity was
observed. As the incorporation of conventional ionic substituents
reduced the lipophilicity, the present group may be regarded as
a new candidate to tune the macroscopic properties.
(A)
(C)
(B)
Acknowledgements
(D)
This work was financially supported by a Grant-in-Aid for
Scientific Research (17K08224 and 20K06947), the Hoansha
Foundation, Mitsubishi Gas Chemical Co., Inc..
(E)
Figure 3. Distribution of BODIPY Derivatives in a Biphasic System Containing
Acetonitrile, pH 7.4 Phosphate Buffer, and Octan-1-ol (25:25:4 v/v/v). Upper
layers are organic phases and lower layers are aqueous phases. (A)
Carbanion-decorated BODIPY 3a-Na, (B) 2,6-unsubstituted BODIPY 2a, (C)
2,6-disulfonato-BODIPY 12, (D) Solubility of 3a-Na in pH 7.4 phosphate buffer,
(E) Insolubility of 2a in pH 7.4 phosphate buffer. Red crystals of 2a float on the
aqueous phase.
Keywords: Carbanions • Fluorine • Ion pairs • Lipophilicity •
Luminescence
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10.1002/anie.202012764
Angewandte Chemie International Edition
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Fluorinated carbanionic substituent enhanced both water-solubility and lipophilicity of organic fluorescence dyes, including BODIPYs,
fluorescein, and aminocoumarin, without impairing the photophysical properties of the parent fluorophores. Considering that
incorporation of conventional ionic substituents reduces the lipophilicity, the present carbanion structure is a new and promising
candidate to tune such macroscopic properties.
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