Fluoride indicator that functions in mixed aqueous media: Hydrogen bonding effects

Article abstract of DOI:10.1016/j.tetlet.2011.11.099

A urea-based fluoride anion indicator, 3, that functions in mixed aqueous media is reported. Under these conditions, indicator 3 and the two control systems 1 and 2 are colorless. Addition of fluoride anions produces an easy-to-visualize colorimetric resp

Full text of DOI:10.1016/j.tetlet.2011.11.099

Tetrahedron Letters 53 (2012) 575–578
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fluoride indicator that functions in mixed aqueous media: hydrogen
bonding effects
Ananta Kumar Atta a, In-Ho Ahn a, Ah-Young Hong a, Jungseok Heo b, Chan Kyung Kim a, Dong-Gyu Cho a,
⇑
a Department of Chemistry, Inha University, 253 Yonghyundong, Namgu, Incheon 402-751, Republic of Korea
b Department of Chemistry, Chungnam National University, 99 Daehak-ro, Yuseong-go, Daejeon 305-764, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A urea-based fluoride anion indicator, 3, that functions in mixed aqueous media is reported. Under these
conditions, indicator 3 and the two control systems 1 and 2 are colorless. Addition of fluoride anions pro-
duces an easy-to-visualize colorimetric response (colorless to yellow) in the case of 3, but not 1 or 2 as
the result of anion-induced Si–O bond cleavage. Most of the colorimetric response is believed to stem
Received 14 October 2011
Revised 17 November 2011
Accepted 18 November 2011
Available online 26 November 2011
from an alteration in the hydrogen bonding network, rather than changes to the
per se.
p-conjugation pathway
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Fluoride indicator
Colorimetric response
Hydrogen bond
Fluoride ions are ubiquitous in daily life. They are broadly
used as additives in toothpastes and water to prevent dental
caries1 and enamel demineralization resulting from wearing
orthodontic appliances. Additionally, for the treatment of osteo-
porosis,2 higher doses of fluoride are frequently administered.
On the other hand, accidental or unnecessary fluoride ingestion
can induce acute poisoning, which involves the combination of
fluoride anions with calcium ions in the blood to form insoluble
calcium fluoride; this results in hypocalcemia.3 The differential
response engendered by differing concentrations of fluoride anion
provides an incentive to develop fluoride selective sensors, par-
ticularly those that are effective for the use aqueous media.
While considerable effort has been devoted to the development
of fluoride anion sensors, the goal of achieving fast, reliable,
detection in water and low fluoride anion analyte concentrations
remains elusive.
In large measure the challenge of developing fluoride anion
sensors that function in aqueous media can be traced to the high
hydration enthalpy of fluoride ions in water. This hydration en-
ergy makes it difficult to generate non-covalent receptors that
produce a sensitive response when exposed to the fluoride anion
in the presence of high concentrations of water. Therefore, our
group and others have elected to focus on reaction-based recep-
tors (indicators),4 for use in aqueous or mixed aqueous environ-
ments. Reaction-based receptors stand in contrast to approaches
based on reversible receptors, many of which signal effectively
the presence of fluoride in noncompetitive media.5 Thus far,
two different types of fluoride selective reaction-based detection
strategies have been developed. The first of these, developed by
Gabaïi, takes advantage of an electron deficient boron and forma-
tion of a boron-fluoride bond.6 Swager and Kim meanwhile devel-
oped coumarin-based polymer receptors that rely on Si–O bond
cleavage to signal the presence of the fluoride anion in organic
solvents.7 Following this seminal report, it was found that similar
sensors could be used to detect fluoride in buffer or aqueous solu-
tions.8 Recently, a benzamide derivative protected with a TBDPS
group, which is thought to form micelles, has been put forward
as a means of detecting fluoride anions in water as the result of
anion-induced Si–O bond cleavage.9 However, none of these sen-
sor systems displays a detectable visible color change in the pres-
ence of fluoride in aqueous buffers or mixed aqueous media.
To increase the sensitivity of reaction-based indicators, we felt
it could be beneficial to incorporate some of the design principles
that underlie the efficacy of many reversible anion sensors used
in organic media. In particular, we thought it may be possible to
exploit changes in hydrogen bonding patterns to enhance the effi-
cacy of indicators that rely on a Si–O bond cleavage reaction. In
principle, such bond scission can either alter or create new hydro-
gen bonds and the resulting changes in interactions could be used
to generate preferentially a colorimetric response. With such con-
siderations in mind, the urea containing indicator 3 was designed.
Here, analyte-induced structural modification would be ‘read out’
with the help of a simple nitrophenol chromophore. To obtain
mechanistic insights, the control systems 1 and 2 were also
prepared.
⇑
Corresponding author. Tel.: +82 32 860 7686; fax: +82 32 867 5604.
E-mail address: dgcho@inha.ac.kr (D.-G. Cho).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.099

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A. K. Atta et al. / Tetrahedron Letters 53 (2012) 575–578
unreacted phenol 11, which could be isolated with a recovery yield
NO2
of 34%. Additionally, intermediate 1014 was silylated to give 2 in a
77% yield.
NO2
NO2
The optical properties of compound 3 as a fluoride indicator
were monitored via UV–vis spectroscopy, as shown in Figure 1a.
In the absence of NaF, no absorption peak occurs in the visible
range. After the addition of 20 equiv of NaF, a new peak at
420 nm evolves and does so immediately on the time scale of the
experiment. Additionally, an isosbestic point at 339 nm is seen,
as would be expected for a conversion involving two compounds,
presumably compounds 3 and 11 (seen more clearly in Fig. 3a).
Encouraged by these results, an effort was made to increase the
level of the response by modifying the buffer conditions. Typically,
mixtures of 3 (3.20 Â 10À5 M) were turbid in PBS-buffered CH3CN/
water (9/1, v/v), (10 mM PBS buffer, pH = 7.0); however, it pro-
duced a clear solution in HEPES buffered CH3CN/water (9/1, v/v),
(10 mM HEPES buffer, pH = 7.0). When the water content was in-
creased to 20% in the HEPES buffer solution, the reaction was
slow (Fig. S1). In light of these findings, all subsequent sensing
experiments were conducted in HEPES-buffered CH3CN/water
(9/1, v/v), (10 mM HEPES buffer, pH = 7.0).
To evaluate the role of the urea moiety, solutions of these two
species (3 and 11) were made up as per the above and the absor-
bance of each solution at 420 nm was recorded every 8 min after
the addition of 2 equiv of NaF (Fig. 1b). Under these conditions, indi-
cator 3 produced a large increase in the intensity of the peak at
420 nm, which was nearly saturated 4 h after the addition. The ori-
gin of the 420 nm peak was assigned by comparing the UV–vis spec-
trum of 11 in the presence of NaF to that obtained after adding NaF
to the solution of compound 3. After several hours, the two spectra
could be reasonably coincident as recorded in the HEPES buffer
media used for the addition experiments involving 3 (Fig. S2). This
experiment and NMR studies (Fig. S3) provide support for the rea-
sonable supposition that the 420 nm peak reflects the production
of compound 11 via a Si–O bond cleavage reaction in the presence
of NaF. In other words, the absorbance at 420 nm is proportional
to the progress of the Si–O bond cleavage reaction. By contrast, indi-
cator 2 did not generate a significant color change as was seen with
compound 3 (Fig. 1b and c). It is also worth noting that a fourfold dif-
ference in absorbance intensity between 2 and 3 was observed 1 h
after the addition of 2 equiv of fluoride (absorbance of 3 = 0.43
and absorbance of 2 = 0.10 at 420 nm). Furthermore, in the case of
OTBDPS
NH
OTBDPS
OTBDPS
O
NH(CH2)5CH3
2
3
1
The target indicator 3 is based on the incorporation of a substi-
tuted urea functionality within a diphenylacetylene framework.
Diphenylacetylene motifs have been broadly employed as struc-
tural elements because unmodified diphenylacetylenes are known
to rotate along the acetylene axis, whereas the rotations are re-
stricted when the diphenyl groups participate in hydrogen bond-
ing. This feature has been applied to good effect to create a
robust peptide mimic,10 to prepare a conformational lock11 to as-
sist structure folding and rigidification of phenylacetylene-based
oligomers, to produce a cyanide anion sensor.12 In light of this prior
art, we considered that the urea NH protons present in 3 would not
form additional hydrogen bonds readily due to the bulkiness of the
TBDPS group and longer distance from the oxygen atom of the
TBDPS ether. However, fluoride anion-induced Si–O bond cleavage
would lead to exposure of the phenolic OH group. This exposed
moiety would be expected to form hydrogen bonds with the urea
NH protons or carbonyl group, owing to the free rotation along
the acetylene axis. The hydrogen bonds that are expected to form
in this way are, in turn, expected to be manifest in terms of a sig-
nificant color change.
Compound 3 and the control system 2 were synthesized accord-
ing to Scheme 1. This synthetic procedure begins with 2-iodoani-
line 4, which was reacted with hexylisocyanate to produce 5 in a
78% yield. Urea 5 was then subjected to Sonogashira coupling with
trimethylsilylacetylene to generate 6 in a 73% yield. Subsequent
deprotection of the trimethylsilyl group provided 7 in a 79% yield.
Sonogashira coupling of intermediate 7 with 2-iodo-4-nitrophenyl
acetate (8)13 by coupling then provided 9 in a moderate yield
(59%). Deprotection of the acetate group on the phenol moiety
was accomplished by treating with hydrazine. This gave 11, which
was silylated with TBDPSCl to afford 3 in a 46% yield along with
Pd(PPh3)4, CuI
trimethylsilylacetylene
I
CH3(CH2)5NCO
DCM, rt, 12 h, 78%
I
O
THF, TEA, 50 oC, 73%
N
H
NH(CH2)5CH3
NH2
5
4
NO2
I
R1
AcO
Pd(PPh3)4, CuI
THF, TEA, rt, 4 h
O
+
NO2
OAc
N
H
NH(CH2)5CH3
8
R2
6
(R1 = TMS)
9
R2 = NHCONH(CH2)5CH3, 59%
NO2
TBAF, rt,
1 h, 79%
7 (R1 = H)
NO2
OH
TBDPSCl, DCM/THF
TEA, rt, 1 h
NH2NH2 H2O
MeOH, rt, 30 min.
OTBDPS
R2
R2
2 = H)
2 = NHCONH(CH2)5CH3, 58%
(10
11
R
R
(2
3
R
2 = H, 77%)
R2 = NHCONH(CH2)5CH3, 46%
Scheme 1. Syntheses of 2 and 3.

A. K. Atta et al. / Tetrahedron Letters 53 (2012) 575–578
577
0.6
0.4
0.2
0.0
a
a
1.0
0.8
0.6
0.4
0.2
0.0
1.2
3 + 20 equiv.of NaF
3
1.0
0.8
0.6
0.4
0.2
0.0
0
2
4
Equiv. of NaF
250
300
350
400
450
500
Wavelength (nm)
b
c
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
250
300
350
400
450
500
Wavelength (nm)
b
c
3
2
1
Figure 3. (a) Changes in the UV–vis absorption spectrum of 3 (3.20 Â 10À5 M) as
monitored 1 h after reaction with various concentrations of a stock solution of NaF
(6.60 Â 10À3 M) in CH3CN/water (9:1, v/v) (10 mM HEPES buffer, pH = 7.0) at 25 °C.
The individual spectra were recorded in the presence of 0 to 5 equiv of NaF. The
inset is a plot of the absorbance change of 3 (3.20 Â 10À5 M) at 420 nm as a function
of fluoride concentration (equiv) in CH3CN/water (9:1, v/v) (10 mM HEPES buffer,
pH = 7.0) at 25 °C. (b) Color changes observed upon the addition of varying
quantities of NaF to a solution of indicator 3 (3.20 Â 10À5 M) in CH3CN/water (9:1,
v/v) (10 mM HEPES buffer, pH = 7.0) at 25 °C. From left to right: 0, 8, 16, 32, and
0
50
100
150
200
250
Time (minute)
Figure 1. (a) UV–vis spectra of indicator 3 (3.20 Â 10À5 M in CH3CN/ water (9/1, v/
v)) recorded before and immediately after the addition of NaF (20 equiv,
6.60 Â 10À3 M in water) at 25 °C. (b) Plots of absorbance change of indicators
(3.20 Â 10À5 M) at 420 nm as a function of time with 2 equiv of NaF in CH3CN/water
(9:1, v/v) (10 mM HEPES buffer, pH = 7.0) at 25 °C. (c) Observed color changes of
putative indicators (3.20 Â 10À5 M) in CH3CN/water (9:1, v/v) (10 mM HEPES
buffer, pH = 7.0) 1 h after the addition of NaF (2 equiv, 6.60 Â 10À4 M in water) at
25 °C. From left to right: 1 + FÀ, 2 + FÀ, and 3 + FÀ.
64 lM of NaF. (c) Color changes observed 1 h after the addition of 2 equiv of various
anions to a solution of 3 (3.2 Â 10À5 M) in CH3CN/water (9:1, v/v) (10 mM HEPES
buffer, pH = 7.0) at 25 °C. All anions are used as TBA salts except fluoride, which was
used in the form of NaF. From left to right: IÀ, BrÀ, ClÀ, HSOÀ4 , H2PO4À, FÀ, BzOÀ, AcOÀ,
NÀ3 , and CNÀ.
indicator 1, no peak was detected at 420 nm. Usually, a nitrophenol
solution has a yellow color in basic conditions due to nitrophenox-
ide ions. However, in our buffered condition, a nitrophenol solution
does not display any color even in the presence of 2 equiv of FÀ.
Taken in concert, these results support the contention that the
majority of the color change seen in the case of 3 + FÀ when tested
in neutral buffer media involves in the urea motif, as opposed to
In polar media, including the mixed aqueous solution used in
the present study, these intermolecular hydrogen bonds are ex-
pected to be attenuated, particularly under conditions of moderate
to high dilution, both by competition with the solvent and intra-
molecular hydrogen bonding interactions between phenolic OH
and urea carbonyl group. Consistent with this supposition were
the results of dilution studies involving control system 11. These
studies were conducted in DMSO-d6/CD3CN (1/9, v/v) due to the
limited solubility of 11 in CD3CN and the fact that in this latter sol-
vent, the phenolic OH proton in compound 11 could not observed
in the 1H NMR spectrum. On the other hand, this key resonance
appeared at 11.5 ppm in DMSO-d6/CD3CN (3/5, v/v) (Fig. S4). By
monitoring this and other signals, it was determined that at ca.
0.3 mM (concentration of 11), a clear transition in the nature of
simple elongation of the p-conjugation pathway.
X-ray crystallographic analysis of compound 11 reveals that the
phenolic OH is hydrogen-bonded to two urea NH protons, as well
as the urea carbonyl group (Fig. 2a).15 In the solid state, these inter-
actions occur in an intermolecular fashion. The result is an infinite
hydrogen bonding network. The shortest hydrogen bond distance
between two heteroatoms is 2.63 Å (O–H–O@C), a finding that is
consistent with the presence of a strong hydrogen bond.
Figure 2. (a) X-ray structure of 11 showing intermolecular hydrogen bonds. Thermal ellipsoids are scaled to the 50% probability level. (b) A proposed hydrogen bonding mode
of 11 based on density functional theory (PCM-B3LYP/6-311+G⁄⁄) in acetonitrile.

578
A. K. Atta et al. / Tetrahedron Letters 53 (2012) 575–578
the spectrum is seen. This is ascribed to a change from an inter- to
intramolecular hydrogen bonding pattern (Fig. S5).
Acknowledgments
Support for the proposed role of hydrogen bonding interactions
came from DFT calculations. Here, the optimized structure of 11
was calculated at the PCM-B3LYP/6-311+G⁄⁄ level in acetonitrile
using Gaussian 03 (Fig. 2b).16 In the structure, the distance between
the oxygen atoms in the O–H–O@C contact (2.73 Å) falls within the
range expected for hydrogen bonds. The calculated structure thus
provides further support for the conclusion that the observed color
change produced when fluoride is added to compound 3 originates
from the nitrophenol chromophore that is liberated in the presence
of the fluoride anion. The presence of the hydrogen bonding subunit
This research was supported by Inha University Research Grant
and the Basic Science Research Program through the National
Research Foundation of Korea (NRF) funded by the Ministry of
Education, Science and Technology (Grant No. 2010-0004206). We
would also like to thank Dr. Kun Cho from the mass spectrometry
lab of the Korea Basic Science Institute for MS analysis.
Supplementary data
Supplementary data (experimental procedure for the synthesis
of all new compounds, spectroscopic data, and X-ray structural
data for 11) associated with this Letter can be found, in the online
version, at doi:10.1016/j.tetlet.2011.11.099.
coupled to the intrinsic p-conjugation pathway present in the com-
pounds of this study gives rise to the observed yellow color. The
fluoride specificity then comes from the intrinsically selective
nature of the Si–O bond cleavage reaction.
As part of our effort to test the linearity of the absorbance-based
response of 3 to various fluoride anion concentrations and to ascer-
tain the detection limit for the fluoride anion, the stability of 3 was
tested under various conditions. It was found that 3 undergoes
slow desilylation even in the absence of NaF both in HEPES buffer
and water. Fortunately, however, this background desilylation pro-
cess was relatively slow and essentially negligible in the absence of
NaF over a short time periods in both media (Fig. S7).
Roughly 4 h after the addition of NaF (2 equiv) the change in the
absorbance of 3 was nearly saturated (Fig. 1b). However, 1 h of
incubation was sufficient to observe a color change. Thus, this lat-
ter time was used for the subsequent sensing experiments. Further
studies under standard conditions (1 h incubation, in CH3CN/water
(9:1, v/v) (10 mM HEPES buffer, pH = 7.0) at 25 °C) revealed the lin-
earity of the absorbance of 3 relative to fluoride concentrations at
References and notes
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observed linearity between 1 and 8
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conducted largely in organic solvents, which were then diluted
with water or a buffer.8d
To evaluate the selectivity of 3,ÀvariousÀpotentially competing
anions, including IÀ, BrÀ, ClÀ, HSO4 , H2PO4 , FÀ, BzOÀ, AcOÀ, NÀ3 ,
and CNÀ as TBA salts (2 equiv of each anion) were added to solu-
tions of compound 3 (3.30 Â 10À5 in CH3CN/water (9:1, v/v)
(10 mM HEPES buffer, pH = 7.0) at 25 °C). No change in color was
observed in any of the cases. By contrast, NaF induced a color
change (Fig. 3c) and its counter cation effect of other anion sources
such as TBAF and CsF were negligible (Fig. S9).
15. Crystallographic data (excluding structure factors) for the structures in this
Letter have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication Nos. CCDC 847323. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
16. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A.; Vreven, T., Jr.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
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Gaussian 03, Revision D.02 ed.; Gaussian, Inc.: Wallingford, CT, 2004.
Using indicator 3, the presence of fluoride can be readily de-
tected in buffer media via the naked eye. A colorimetric response
is generally not observed even in fluoride-selective reaction-based
indicators in neutral buffer media. The observed colorimetric re-
sponse was modulated significantly by installing the urea group
introducing hydrogen bonds. The existence of hydrogen bonds
after the Si–O bond cleavage reaction was supported by the X-
ray structure and DFT calculation of 11. However, indicator 3 is
only a prototype of a hydrogen bonding-assisted reaction-based
indicator. Needless to say, it is necessary to improve the stability
of 3 to detect fluoride in living cells and real samples. However,
the convenience of this method and the possibility of further appli-
cations of the hydrogen bonding-assisted reaction-based indicator
could prove important for the detection of other analytes. Explora-
tions of these possibilities are currently underway in our
laboratory.