Synthesis of anionic chemodosimeters based on silylated pyridinium N-phenolate betaine dyes

Article abstract of DOI:10.1016/j.tetlet.2015.06.037

Three novel silylated pyridinium N-phenolate betaine dyes were synthesized and characterized. These compounds were used in acetonitrile as anionic chemodosimeters for the colorimetric detection of F^- and CN^-. In addition, the system was made highly selective to CN^- in relation to other anions in acetonitrile/water mixtures. The nucleophilic attack of the anion on the silicon center of the chemodosimeters, through a nucleophilic substitution at silicon (S_N2@Si), immediately breaks the Si-O bond, with the formation of their corresponding colored pyridinium N-phenolate betaine dyes as the leaving groups. Thus, this process is effective for the detection of F^- and CN^-, which are strongly nucleophilic analytes in anhydrous acetonitrile. Fluoride is strongly hydrated when water is present in the medium, this being the reason for the pronounced reduction in the selectivity of this anion in comparison with CN^-.

Full text of DOI:10.1016/j.tetlet.2015.06.037

Tetrahedron Letters 56 (2015) 4733–4736
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of anionic chemodosimeters based on silylated pyridinium
N-phenolate betaine dyes
João P. T. A. Guerra, Alexandra Lindner, Celso R. Nicoleti, Vanderléia G. Marini, Marcelo Silva,
⇑
Vanderlei G. Machado
Departamento de Química, Universidade Federal de Santa Catarina, UFSC, CP 476, Florianópolis, Santa Catarina 88040-900, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Three novel silylated pyridinium N-phenolate betaine dyes were synthesized and characterized. These
compounds were used in acetonitrile as anionic chemodosimeters for the colorimetric detection of FÀ
and CNÀ. In addition, the system was made highly selective to CNÀ in relation to other anions in acetoni-
trile/water mixtures. The nucleophilic attack of the anion on the silicon center of the chemodosimeters,
through a nucleophilic substitution at silicon (SN2@Si), immediately breaks the Si–O bond, with the for-
mation of their corresponding colored pyridinium N-phenolate betaine dyes as the leaving groups. Thus,
this process is effective for the detection of FÀ and CNÀ, which are strongly nucleophilic analytes in anhy-
drous acetonitrile. Fluoride is strongly hydrated when water is present in the medium, this being the rea-
son for the pronounced reduction in the selectivity of this anion in comparison with CNÀ.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 23 April 2015
Revised 2 June 2015
Accepted 10 June 2015
Available online 17 June 2015
Keywords:
Chemodosimeters
Anion sensing
Naked-eye detection
Pyridinium N-phenolates
Fluoride
Cyanide
Pyridinium N-phenolate betaine dyes comprise a family of zwit-
terionic compounds recognized for their solvatochromic proper-
ties, the most important and interesting example of which is
compound 1, 2,6-diphenyl-4-(2,4,6-triphenylpyridinium-1-yl)phe-
nolate.1–4 The solvatochromic visible charge-transfer (CT) band of
dye 1 is hypsochromically shifted from kmax = 810 nm in diphenyl
ether to kmax = 453 nm in water, corresponding to a solvent-in-
reported17,18,28–35 due to the fact that this anion is present in sev-
eral industrial processes, such as metallurgy, mining, and the fab-
rication of polymers.36 CNÀ is also delivered through hydrolysis
from warfare neurotoxic agents37 and from some fruit seeds and
roots.38–40 The lethality of this anion in very low concentrations
is due to its strong binding to the active site of cytochrome-oxi-
dase, which causes a decrease in the oxidative metabolism.41
Fluoride, another anion of interest in terms of detection, plays an
important role in environmental pollution, in industry, and in
many diseases.42–44
duced band shift of
D
kmax = À357 nm (
D
ET = 117 kJ molÀ1).3,4 This
enables dye 1 and related compounds to be applied in the study
of the polarity of pure solvents, ionic liquids, electrolyte solutions,
and solvent mixtures.4 The very popular Reichardt ET(30) solvent
polarity scale is based on the position of the visible CT absorption
band of 1.1,4 These dyes exhibit also thermosolvatochromic,
chiro-solvatochromic, and piezo-solvatochromic properties.1,4
Pyridinium N-phenolate dyes are also commonly applied in sys-
tems other than liquid solvents as probes to measure the polarity
of solid surfaces, micelles, vesicles, polymers, glasses, and gels,
and their more general use means that they are considered as peri-
chromic dyes.4 These dyes have been used as signalizing units in
the construction of various optical devices, especially for the detec-
tion of neutral,4–12 cationic,4,13–15 and anionic4,16–18 species. The
recognition and detection of anions represent a field of great inter-
est.19–28 Many strategies for the optical detection of CNÀ have been
R2
x
N
O
N
O
R1
R1
R3
The chemodosimeter approach is a very attractive optical tech-
nique among the various strategies which have been developed in
recent years for the detection of anionic species.19,21,26 This is based
⇑
Corresponding author. Tel.: +55 48 3721 4542; fax: +55 48 3721 6850.
E-mail address: vanderlei.machado@ufsc.br (V.G. Machado).
http://dx.doi.org/10.1016/j.tetlet.2015.06.037
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

4734
J. P. T. A. Guerra et al. / Tetrahedron Letters 56 (2015) 4733–4736
on the use of the target analyte, for instance a nucleophile, in an
irreversible process, in order to generate a chromophore and/or flu-
orophore species. When these signalizing units are released into a
solution, the quantitative naked-eye detection of the species can
be performed. One possible design for a chemodosimeter is the
reaction of the electron-donor group in a dye with a protective
group, leading to the product being colorless in solution. The addi-
tion of a nucleophilic species to the medium leads to the dye
release, which signals the presence of these species. Many chemo-
dosimeters have been assessed using classical reactions involving
protection of the hydroxylic group in phenols with, for instance, tri-
isopropylsilyl chloride (TIPS-Cl) to form O-silyl ethers,26,44–46 which
are colorless in solution. The addition of FÀ to the solutions of these
ethers in organic solvents displaces the dye as the leaving group,
leading to the detection of the anion.26,44 Recently, we demon-
strated that adequately designed leaving group dyes can be used
to synthesize O-silyl chemodosimeters highly selective toward
CNÀ,47 the anion selectivity being determined by the presence of
water in the medium, which acts by strongly solvating FÀ and hin-
dering the nucleophilic attack of the anion on the silicon center.
Herein, we report the synthesis and characterization of three
novel silylated pyridinium N-phenolate betaine dyes (2–4). These
compounds were used in acetonitrile as anionic chemodosimeters
for the colorimetric detection of nucleophilic anions, such as FÀ
and CNÀ. In addition, we also demonstrate that the system is made
highly selective for CNÀ in relation to other anions in acetoni-
trile/water mixtures. In order to verify the products of the reaction
of 2–4 with the anions, compounds 5a–7a were also prepared,
which could be deprotonated in solution to generate the corre-
sponding pyridinium N-phenolate betaine dyes 5b–7b.
TIPS-Cl in DMF using imidazole as a base. Amine 12 was synthe-
sized through the catalytic reduction of compound 11 in the pres-
ence of Pd and H2, using THF as the solvent. Novel compounds 2–4,
as well as compounds 5a–7a, were characterized by means of IR,
1H NMR, 13C NMR, and HRMS spectrometric techniques. All com-
pounds were sufficiently pure to be used in the further assays.
Figure 1 shows the behavior of solutions of compounds 2–4 in
acetonitrile in the absence and presence of various anions. The
solutions of these compounds are colorless, but when several
anions (HSOÀ4 , H2PO4À, NO3À, CNÀ, CH3COOÀ, FÀ, ClÀ, BrÀ, and IÀ)
are added individually, only FÀ and CNÀ are responsible for the
appearance of vivid colors in the solutions, dark red for compound
2 and dark blue for compounds 3 and 4. The colors of the solutions
correspond to the color of the corresponding pyridinium N-pheno-
late betaine dyes 5b–7b, which were generated from the deproto-
nation of 5a–7a. This suggests that the reaction of compounds 2–4
with FÀ and CNÀ leads to the formation of 5b–7b. Figure 1 also
shows that CH3COOÀ and, to a lesser extent, H2POÀ4 change the
color of the solutions of the compounds to pale yellow, suggesting
a weak interaction between these anions and the compounds.
Figure 1 also shows that the addition of water volumes to the
solutions of 2–4 changes the ability of the anions to color the solu-
tions: with the addition of 10% of water only CNÀ causes a change
in the color of the solutions of the compounds, to orange for com-
pounds 2 and 4 and dark red for compound 3. The selectivity of
chromogenic chemosensors in solution toward CNÀ in the presence
of other anions, obtained applying different acid–base strategies, in
which the anion acts as a base generating the dye in solution, has
been reported in other papers with the addition of small
amounts of water to organic solvents.17,18,30,33,50–52 This is
commonly explained as being due to the high hydration
energies of FÀ (À465 kJ molÀ1), CH3COOÀ (À365 kJ molÀ1), and
H2POÀ4 (À465 kJ molÀ1) in comparison with that obtained for
CNÀ (À295 kJ molÀ1).53 In our study, the strong hydration of the
anions makes them less able to act as nucleophilic species. Since
CNÀ is less hydrated after the addition of water, this more nucle-
ophilic species (in comparison with the others) is consequently
more able to nucleophilically attack the silicon center in each com-
pound, generating 5b–7b.
Scheme 1 shows the route used for the synthesis of the com-
pounds. Silylated compounds 2–4 and their corresponding phenols
5a–7a were synthesized by means of the classical methodology
available in the literature,11,48,49 which involves the reaction of
the pyrylium salts 13 and 14 with the corresponding 4-aminophe-
nols (8 and 15) or their silylated derivatives 9 and 12. The reactions
were carried out by refluxing the reactants in ethanol in the pres-
ence of acetic acid (one drop) at 70 °C and in argon atmosphere.
Silylated compounds 9 and 11 were prepared through the reaction
of 4-aminophenol (8) or 2,6-dimethyl-4-nitrophenol (10) with
Additional evidence concerning the products of the reaction of
the chemodosimeters with the anions was obtained through mass
spectrometry. The mass spectrum for compound 2 exhibits a peak
corresponding to [M]+ at 556.3029 while the mass spectrum for
compound 5a shows [M]+ at 400.1696 (see Supporting
Information). The addition of FÀ and CNÀ to solutions of compound
2 causes a change in the spectrum, with the appearance of a peak
at 400.13, which coincides with the peak corresponding to com-
pound 5a. Therefore, the ensemble of data, as summarized in
Scheme 2, indicates that the anions FÀ and CNÀ nucleophilically
attack the silicon center at chemodosimeters 2–4, through a
SN2@Si mechanism,54 releasing pyridinium N-phenolate betaines
5b–7b as leaving groups.
(a)
H2N
OH
(a)
H2N
OTIPS
8
9
NO2
NO2
NH2
(b)
OH
OTIPS
OTIPS
11
12
10
Figure 2A shows the UV–vis spectra for 2 in acetonitrile in the
absence and in the presence of added anions. Only FÀ and CNÀ
cause significant spectral changes, with the appearance of a band
with a maximum at 542 nm. This band occurs at the same position
as that observed for 5b under the same experimental conditions,
providing further evidence for the fact that these anions react with
compound 2 at the silicon atom, releasing 5b as a product.
Figure 2B shows the UV–vis spectra for 2 with anions added in ace-
tonitrile in the presence of 10% (v/v) of water. Under this condition,
only CNÀ causes the appearance of a band in the visible region,
with a maximum at 455 nm. Again, this band occurs at the same
position as that observed for 5b under the same experimental con-
ditions and the fact that it shows a hypsochromic shift is because
5b is a solvatochromic dye.1–4
R2
NH2
2-4
(c)
+
and
5a 7a
- H2O
R1
R1
-
+
O
_
X
O
R3
8
9
: R1 = H; R3 = H
: R1 = H; R3 = TIPS
-
-
12: R1 = CH3; R3 = TIPS
15: R1 = CH3; R3 = H
13: R2 = H; X = ClO4
14: R2 = CN; X- = BF4
-
Scheme 1. Synthetic route for the synthesis of compounds 2–4 and 5a–7a.
Reagents and conditions: (a) TIPS-Cl, imidazole, DMF; (b) Pd, H2, THF; (c) acetic
acid (one drop), EtOH, argon, 70 °C.

J. P. T. A. Guerra et al. / Tetrahedron Letters 56 (2015) 4733–4736
4735
Figure 1. Solutions of compounds 2–4 in: acetonitrile (A) and acetonitrile with (B) 1%, (C) 3%, (D) 5%, and (E) 10% (v/v) of water, without anion added (a) and after the addition
of HSOÀ4 (b), H2PO4À (c), NOÀ3 (d), CNÀ (e), CH3COOÀ (f), FÀ (g), ClÀ (h), BrÀ (i), and IÀ (j) as tetra-n-butylammonium salts. The concentration of compounds 2–4 was
4.0 Â 10À4 mol LÀ1 and values for the anions were 1.0 Â 10À3 mol LÀ1
.
R2
R2
of 6b, as demonstrated by the appearance of a band with a maxi-
mum at 508 nm. For compound 4, the reaction with FÀ and CNÀ
in acetonitrile leads to the appearance of a band with a maximum
at 587 nm, which coincides with the position of the band verified
for dye 7b. The spectrum for 7b in acetonitrile with water (10%,
v/v) shows that its solvatochromic band is hypsochromically
shifted to kmax = 476 nm, which corresponds to the same band
obtained when 4 is mixed with CNÀ, under the same experimental
conditions.
Figure 3 shows the relative absorbances for the reaction of com-
pounds 2–4 with the anions in acetonitrile. The data show that on
using the same concentration of anions, 100% of the compounds
react with FÀ while with CNÀ only 68% and 86% of product was
obtained for 2 and 3, respectively. In the case of compound 4, only
50% of product was obtained. The data suggested that the electron-
withdrawing cyano group in the molecular structure of 4 influ-
ences the reactivity of the compound. Thus, an experiment was
carried out, adding CNÀ to the products of the reaction of 2–4 with
FÀ. The results for the compounds generated are summarized in
Figure 4 and they show that while CNÀ has practically no effect
_
X
+
+
_
N
N
+
Si Nu
+
X
R1
R1
R1
R1
O
_
Nu
O
_
_
Nu
Si
= CN- or F-
5b-7b
2-4
Scheme 2. Reaction of compounds 2–4 with CNÀ or FÀ to generate dyes 5b–7b.
Compounds 3 and 4 exhibited a similar behavior in pure ace-
tonitrile (Figs. S33A and S34b) and with water added (Figs. 33B
and S34B). Compound 3 reacts with FÀ and CNÀ in acetonitrile,
leading to the appearance of a band with a maximum at 624 nm,
which corresponds to the same band observed for 6b. Only CNÀ
reacts with 3 in the acetonitrile/water mixture, with the formation
Figure 3. Relative absorbance values for the reaction of compounds 2–4 with FÀ
), CNÀ
(
), CH3COOÀ
(
) and other anions (
) in acetonitrile. The
and the
Figure 2. UV–vis spectra for solutions of 2 (a) and 2 in the presence of HSOÀ4 (b),
H2POÀ4 (c), NO3À (d), CNÀ (e), CH3COOÀ (f), FÀ (g), ClÀ (h), BrÀ (i), and IÀ (j), as tetra-n-
butylammonium salts in (A) pure acetonitrile and (B) acetonitrile with 10% (v/v) of
water. For concentrations of 2 and the anions see Figure 1.
(
concentrations of 2–4 and of the anions are described in Figure
1
absorbance values were obtained at 542 nm for 2, and at 624 and 587 nm for 3 and
4, respectively.

4736
J. P. T. A. Guerra et al. / Tetrahedron Letters 56 (2015) 4733–4736
this article can be found, in the online version, at http://dx.doi.
org/10.1016/j.tetlet.2015.06.037.
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The financial support of the Brazilian governmental agencies
Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior (CAPES) and Fundação de Amparo à Pesquisa e Inovação
do Estado de Santa Catarina (FAPESC), as well as the Laboratório
Central de Biologia Molecular (CEBIME/UFSC) and UFSC is grate-
fully acknowledged.
Supplementary data
Supplementary data (materials and methods, UV–vis spectra,
synthetic procedures, and characterization data) associated with