Test-strip-based fluorometric detection of fluoride in aqueous media with a BODIPY-linked hydrogen-bonding receptor

Article abstract of DOI:10.1002/anie.201307848

The measurement of biologically relevant anions, such as fluoride, is an important task in analytical chemistry, in particular, for dental health and osteoporosis. Although a large number of fluoride probes are known, the applicability under relevant conditions is limited to a few examples. To improve this situation, BODIPY-amidothiourea dyes with varying hydrogen-bond donating strengths were developed, the most H-acidic of which (1 c) could detect F ^- from an inorganic source (NaF) in 50 % aqueous solution (DMSO/water 1:1, v/v) with 0.01ppm sensitivity through selective fluorescence quenching by a photoinduced electron-transfer (PET) process. Use of the probe and a reference dye with a test-strip assay and a portable and rapidly recording lateral-flow fluorescence reader made determination of F^- in neat aqueous solutions, such as spiked water samples and toothpaste extracts, possible in a self-referenced manner, achieving a detection limit of 0.2ppm. Dip and detect: BODIPY dyes with strong hydrogen-bond-donating amidothiourea receptors can detect fluoride in organic-aqueous media. The probe embedded in a nitrocellulose test strip enables a quantitative detection of fluoride in pure aqueous medium by using a simple lateral-flow fluorescence reader. Copyright

Full text of DOI:10.1002/anie.201307848

Angewandte
Chemie
DOI: 10.1002/anie.201307848
Fluoride Sensing
Hot Paper
Test-Strip-Based Fluorometric Detection of Fluoride in Aqueous
Media with a BODIPY-Linked Hydrogen-Bonding Receptor**
Pichandi Ashokkumar, Hardy Weißhoff, Werner Kraus, and Knut Rurack*
Abstract: The measurement of biologically relevant anions,
such as fluoride, is an important task in analytical chemistry, in
particular, for dental health and osteoporosis. Although a large
number of fluoride probes are known, the applicability under
relevant conditions is limited to a few examples. To improve
this situation, BODIPY-amidothiourea dyes with varying
hydrogen-bond donating strengths were developed, the most
H-acidic of which (1c) could detect FÀ from an inorganic
source (NaF) in 50% aqueous solution (DMSO/water 1:1, v/v)
with 0.01 ppm sensitivity through selective fluorescence
quenching by a photoinduced electron-transfer (PET) process.
Use of the probe and a reference dye with a test-strip assay and
a portable and rapidly recording lateral-flow fluorescence
reader made determination of FÀ in neat aqueous solutions,
such as spiked water samples and toothpaste extracts, possible
in a self-referenced manner, achieving a detection limit of
0.2 ppm.
binding site of the host in competitive solvents.[10] To achieve
anion detection in aqueous solution, several design strategies
have been proposed: Lewis acid[11] or metal–anion coordina-
tion,[12] cationic receptors,[13] anion–p interaction,[14] forma-
[15]
À
tion of Si F bonds,
the construction of hydrophobic
microenvironments around receptor moieties[16] and the use
of highly acidic donor units.[17] However, most of these
probes[11–14,16,17] accomplish only the detection of FÀ from
organic origin, that is, with tetrabutylammonium fluoride
(TBAF) as the source, and in mixed organic–aqueous solution
(typically with a content of 5–30% of an organic co-solvent
such as DMSO, CH3CN or EtOH).[18] Moreover, for charged
receptors not only do electrostatic forces govern and com-
promise directional binding but problems associated with the
additional introduction of counterions into the system have to
be faced. On the other hand, FÀ dosimeters based on
a desilylation reaction were reported to operate in aqueous
solution.[15] A drawback of this irreversible reaction, however,
is the rather slow response time from tens of minutes to even
hours, which limits real-time and on-site applicability. The
preferable binding units are thus neutral receptors with
a directional hydrogen-bonding motif. However, what still
remains to be overcome for these receptors is the competition
of water.
O
ver the past decade, the field of anion detection has grown
exponentially because of the significant role of anions in
biological systems and the environment.[1] Among the small
inorganic anions, FÀ is of paramount importance because of
its duplicitous nature.[2] Water fluoridation or addition of
fluoride to toothpaste has become a widespread practice in
many countries owing to the beneficial effects for dental
health and the treatment of osteoporosis.[3] High doses of FÀ
are, however, dangerous and can lead to dental or skeletal
fluorosis;[4] they are also associated with kidney failure[5] and
nephrolithiasis.[6] Only in 2011, the US Environmental
Protection Agency (EPA) followed various other countries[7]
and reduced the recommended FÀ level in drinking water
from 1 to 0.7 ppm.[8] Although considerable attention has
been devoted to the development of molecular probes for FÀ
potentially suitable for rapid at-site analyses, the applicability
of the probes as such under environmentally relevant
conditions is limited to a very few examples.[9] This problem
has been ascribed to the strong solvation of both, anion and
Several analytical techniques have been demonstrated for
quantitative fluoride determination,[19] mostly requiring costly
instrumentation, experienced operators, and tedious proce-
dures. Thus, the development of a simple and inexpensive
method for FÀ detection is still urgently needed. Herein, we
report how newly designed boron dipyrromethene-
(BODIPY-) amidothiourea probes (1a–c) can be used for
the detection of FÀ ions in aqueous media in a test-strip-based
assay with a portable, handheld, and rapidly recording lateral-
flow fluorescence reader. Several recent reports on such
simple dipstick-based tests for metal ions[20] and small
molecules[21] have demonstrated the enormous potential
that lies with such assays. However, the application of such
a system for the quantitative detection of anions has not been
reported to date.
BODIPY–amidothiourea dyes (1a–c) were synthesized as
shown in Scheme 1 and all the compounds have been
characterized by standard analytical procedures. The hydro-
gen-bond donating ability of the thiourea group has been
tuned by the incorporation of electron releasing (OCH3) and
withdrawing (NO2) groups on the thiouredio phenyl group.
As expected, the presence of the -NO2 group increases the
acidity of the thiourea protons, which is evident from
a downfield shift (d = 0.1 and 0.3 ppm) of the 1H NMR signals
of the NH protons.
[*] Dr. P. Ashokkumar, Dr. W. Kraus, Dr. K. Rurack
BAM Bundesanstalt fꢀr Materialforschung und -prꢀfung
Richard-Willstꢁtter-Strasse 11, 12489 Berlin (Germany)
E-mail: knut.rurack@bam.de
Dr. H. Weißhoff
Institut fꢀr Chemie, Humboldt Universitꢁt zu Berlin
Brook-Taylor-Strasse 2, 12489 Berlin (Germany)
[**] Financial support by the Alexander von Humboldt Foundation is
gratefully acknowledged. We are indebted to J. Pautz and S.
Recknagel of BAM for ISE control measurements. BODIPY=boron
dipyrromethene.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307848.
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Scheme 1. Synthetic route to probes 1a–c.
Figure 1. Fluorescence quenching of 1c (2.0 mm) upon addition of FÀ
ions (0–0.8 ppm) in DMSO/water (1:1, v/v; 9 mm MES buffer, pH 6.8),
lexc =482 nm. Inset: changes in the fluorescence intensity at 513 nm
and the calculated 1:1 binding isotherm.
Single crystals suitable for X-ray diffraction were
obtained by slow evaporation of solutions of 1b and 1c in
CH2Cl2. Crystallographic data and refinement parameters are
given in Table S1 of the Supporting Information. Compounds
1b and 1c crystallize with four and two molecules in the unit
cell, respectively (Figures S1–S4). The BODIPY core is
virtually planar with a root-mean-square (rms) deviation of
0.0192 ꢀ (C1, C9, N1, N2) in 1b and 0.0532 ꢀ in 1c, that is, it
shows a higher distortion in 1c than in 1b. In both compounds,
the thiourea NHs are in syn conformation; the amide NH is
positioned anti to it.
Compounds 1a–c show absorption and emission bands
centered at 500 and 510 nm, respectively, which is character-
istic for the parent BODIPY dyes.[22] Table S2 shows the
photophysical features of 1a–c in MeCN, DMSO, and DMSO/
water mixtures. All the three dyes show an increased
fluorescence quantum yield and lifetime in DMSO/water
mixtures, when compared to the neat organic solvent, which is
an advantage for highly efficient sensing systems based on
fluorescence quenching.
titrations were carried out in aqueous DMSO with varying
percentages of water using sodium fluoride (NaF) as the FÀ
source. Among the three dyes, 1c showed the best response
towards FÀ in DMSO/water mixtures. Even at 50% water
content (DMSO/water 1:1, v/v), 1c showed significant fluo-
rescence quenching (Figure 1) with a binding constant (1:1
model) of (5.34 Æ 0.55) ꢁ 104 mÀ1. In contrast, dyes 1a and 1b
show only a weak response towards FÀ at ratios up to 30%
water (detailed binding data in Table S3); beyond that, any
response is significantly diminished. This clearly indicates that
the presence of the electron withdrawing -NO2 group is
essential for increasing the acidity of the thiourea NH groups
to successfully compete with water molecules for FÀ binding
in organic–aqueous media with a high water content. In fact,
computational analysis of the ground-state charge distribu-
tion in 1a–c and various receptor analogues from the
literature revealed the importance of pushing the electron
deficiency in the thiourea moiety to an extreme to enable H-
bonding complexation in the presence of competitive media
(Table S4). For 1c, the limit of detection for FÀ from an
inorganic source in 1:1 DMSO/water was determined to
0.01 ppm, which is significantly lower than for most reported
FÀ indicators.[11–17] To explore the selectivity of the probe, we
carried out titrations with all the other anions as shown in
Initial anion-interaction studies were carried out in polar
aprotic solvents, such as MeCN and DMSO. Addition of
a source of FÀ ions to 1a in MeCN results in a blue shift of the
absorption maximum of 2 nm (Figure S5) indicating an
increase in electron density at the meso-phenyl group due
to anion-receptor interaction. The corresponding emission
shows a 7.1-fold decrease without any spectral shift (Fig-
ure S6). Fluorescence quenching was found to saturate with
the addition of two equivalents of FÀ, revealing a strong
interaction between receptor and FÀ. The fluorescence
quenching data cannot be fitted to a 1:1 binding model
which indicates that more than one interaction mode is
present. Based on earlier observations for related recep-
tors,[23] we tentatively ascribe deprotonation to the second
competitive process besides H-bonding complexation.
Among the other anions, addition of 10 equivalents of
Figure S9. Addition of AcOÀ and H2PO4 (only at very high
À
concentration) also shows quenching, however, these changes
are smaller in magnitude (ca. 50% and 20%, respectively)
when compared to FÀ. In the presence of the other anions no
changes in fluorescence were observed. It is known that
unidirectional H-bonding anion receptors cannot discrimi-
nate entirely between FÀ and AcOÀ. However, most of the
FÀ-contaminated water samples and dental products lack
AcOÀ. The probe can hence be effectively used for the
detection of FÀ in organic–aqueous mixtures down to
0.01 ppm sensitivity.
The mechanism responsible for fluorescence quenching
was assessed with fluorescence-lifetime measurements. Probe
1c exhibits a bi-exponential decay with lifetimes of 0.04
(19%) and 2.62 ns (81%) in a DMSO/water (1:1, v/v)
mixture. Upon addition of an FÀ ion source, the shorter
lifetime further decreases to 0.02 ns with a concomitant
increase in amplitude to 64% (temporal resolution of the
instrument is Æ 3 ps); the lifetime of the other component
À
AcOÀ and H2PO4 show a 4.8- and 1.4-fold reduction in
fluorescence (Figure S6, S7), reflecting the order of basicity of
the anions. In addition, the interactions between 1a and AcOÀ
À
and H2PO4 obey to a stoichiometric model and fits of the
fluorescence titration data yielded binding constants of
(1.05 Æ 0.41) ꢁ 106 and (5.83 Æ 0.34) ꢁ 105 mÀ1, respectively.
For applicability in more realistic scenarios, the sensing
performance of 1a–c was investigated in various organic–
aqueous mixtures, of which DMSO/water[24] yielded the best
response and was used for further studies. Fluorescence
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Figure 3. Plot of the fluorescence intensity ratio of 1c (10.0 mm) versus
a) concentration of FÀ ions and b) logarithm of FÀ ion concentration.
Figure 2. 1H NMR titration spectra of 1c (2 mm) with 0, 1, 2, and
4 equivalents of FÀ ions in [D6]DMSO/H2O (95:5, v/v); proton labels
are shown in Scheme 1.
in water while ensuring that the full molecular PET response
can unfold. The test strip was then immersed for 10 s in
aqueous NaF solution of varying concentrations, dried (40 s
with and 5 min without hair dryer in cold-air-blow mode at
room temperature), and the fluorescence assessed with the
reader. Figure 3 shows the fluorescence-intensity changes and
the calibration curve of the test-strip assay with increasing
concentration of FÀ ions.
remains unchanged but shows a decrease in amplitude to
36%. The formation of a new, faster decaying component
with an increased amplitude indicates the formation of an
actual new species, the H-bound complex, involving a photo-
induced electron transfer (PET) process[25] from the FÀ-bound
receptor to the BODIPY fluorophore.
The test strip shows a detection limit of 0.2 ppm, which is
significantly less than the recommended FÀ levels mentioned
above.[7] Moreover, the intensity change is proportional to the
logarithm of FÀ concentration enabling straightforward
quantitative detection in aqueous media. To validate the
applicability, we measured the content of FÀ from two
commercially available toothpastes. An aqueous extract was
prepared with the necessary dilution and analyzed. By
knowing the extent of fluorescence quenching for the test
solutions and by extrapolating it to a calibration curve
generated from standard NaF solutions, the amount of FÀ in
toothpastes A and B was determined to 1679 Æ 72 and 1167 Æ
56 ppm, respectively, which is in reasonable agreement with
the value given by the manufacturer (A = 1450 and B =
1000 ppm). The observed positive error of approximately
16% is presumably due to the presence of an excess of
To understand the nature of the interaction between FÀ
ions and the receptor, we carried out 1H NMR titration
studies in a [D6]DMSO/H2O (95:5, v/v) mixture[26] (Figure 2).
Addition of 1 equivalent of FÀ ions results in the broadening
and downfield shift of the thiourea proton peaks “a” (Dd =
0.24 ppm) and “b” (Dd = 0.21 ppm), which indicated hydro-
gen-bonding interactions between the NH groups of 1c with
FÀ ions. At higher concentration of FÀ ions, peak “b”
disappears, indicating deprotonation. This two-step process
is in accordance with earlier reports.[27] However, in buffered
solution with 50% water as used for the spectroscopic studies,
FÀ does not induce deprotonation and only H-bonding
between the anion and receptor is detected, control experi-
ments with OHÀ support these findings (Figure S10). In
contrast, in neat [D6]DMSO (Figure S11), 1 equivalent of FÀ
results in the disappearance of peak “b”, and at higher
concentrations a new triplet at d = 16.1 ppm appears as
expected for deprotonation of this kind of receptor.[27c]
Fluorescent probes for FÀ ion detection are commonly
used in cuvette-based tests employing conventional fluorom-
eters. This approach is inconvenient and cannot be used for
in situ/on-site detection. Thus, a test-strip-based assay was
developed to achieve the detection of FÀ ions in neat aqueous
solution and enable the recording of the fluorescence
intensity changes with a portable, handheld, lateral-flow
reader. To date, dipstick-type FÀ tests have only been
reported and used for the qualitative detection of FÀ at
rather high concentrations.[15a,28] Hence, our goal was to
develop a simple dip-and-detect method for the quantitative
determination of FÀ at lower ppm concentrations. The
method that allowed us to achieve our goal is as follows. A
drop of an ethanolic solution of 1c was placed on the test strip
(pipette or dispenser), dried, and the fluorescence intensity
was measured using a lateral-flow reader. We used nitro-
cellulose strips in this case because this matrix ensures that,
although only sterically embedded(i.e. “physisorbed” no
leaching of the rather hydrophobic probe molecules occurs
À
H2PO4 in the toothpaste formulation, leading to a false
positive signal at such high phosphate concentrations.
The test-strip method was then tested for analyzing
various water samples, spiked with known concentrations of
FÀ in a range relevant for water fluoridation. Three water
samples were tested: distilled water, tap water (Berlin,
Germany) and simulated sea water.[29] The concentration of
FÀ was calculated from the calibration curve as discussed
above and the results obtained from the test-strip method
were compared to those assessed with an independent
method employing an ion-selective electrode (ISE, Table 1).
Both methods show a good agreement and the performance
of the test strip is unaffected by any other ions present in tap
Table 1: Measurement of FÀ ions in spiked water samples by ISE and
test-strip methods
Water sample
Amount of
FÀ spiked
[ppm]
FÀ [ppm]/
ISE
FÀ [ppm]/test-strip
assay
Distilled water
Tap water
Simulated sea
water
0.58
0.58
0.77
0.57Æ0.02
0.60Æ0.02
0.80Æ0.02
0.60Æ0.03
0.62Æ0.04
0.84Æ0.05
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or saline water. To further simplify the method, a two-point
referencing system was implemented on the strip by spotting
two defined concentrations of 1,3,5,7-tetramethyl-8-phenyl
BODIPY (4),[22] a dye that has almost the same spectroscopic
properties as 1c but does not respond to FÀ under assay
conditions. The concentrations of 4 were chosen to match
100% (4100) and 30% (430) signal intensity of the initial spot of
1c. Since the fluorescence of the reference spots does not
change in the presence of FÀ, a simple comparison of the
intensity change at spot 1c with spots 4100 and 430 and the
known FÀ quenching data enables the determination of FÀ
content in a single-dip measurement (Figure 4, and Fig-
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In summary, we have demonstrated the potent binding of
FÀ ions from an entirely inorganic fluoride source to an
amidothiourea receptor in aqueous DMSO solution, with as
much as 50% water, which is unprecedented for neutral
hydrogen-bond-based probes and shows the importance of
tuning the electronic properties of such binding sites to
extreme electron deficiency. Quantitative detection of inor-
ganic FÀ ions in 100% aqueous solution with a remarkable
detection limit of 0.2 ppm was possible by using the probe in
a straightforward manner with an internally referenced test-
strip assay and a lateral-flow reader. This simple and cost-
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content of drinking water. Further work is directed toward
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FÀ analysis in concerned households.
Received: September 6, 2013
Revised: October 21, 2013
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Published online: January 23, 2014
Keywords: amidothiourea · fluorescent probes · fluoride ·
.
hydrogen bonds · photoinduced electron transfer
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aggregation of the probe at more than 60% water content.
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