Fluorinated Boronic Acid-Appended Bipyridinium Salts for Diol Recognition and Discrimination via 19F NMR Barcodes

Article abstract of DOI:10.1021/jacs.5b10934

Fluorinated boronic acid-appended benzyl bipyridinium salts, derived from 4,4′-, 3,4′-, and 3,3′-bipyridines, were synthesized and used to detect and differentiate diol-containing analytes at physiological conditions via ¹⁹F NMR spectroscopy. An array of three water-soluble boronic acid receptors in combination with ¹⁹F NMR spectroscopy discriminates nine diol-containing bioanalytescatechol, dopamine, fructose, glucose, glucose-1-phosphate, glucose-6-phosphate, galactose, lactose, and sucroseat low mM concentrations. Characteristic ¹⁹F NMR fingerprints are interpreted as two-dimensional barcodes without the need of multivariate analysis techniques.

Full text of DOI:10.1021/jacs.5b10934

Communication
pubs.acs.org/JACS
Fluorinated Boronic Acid-Appended Bipyridinium Salts for Diol
19
Recognition and Discrimination via F NMR Barcodes
Jorg Axthelm,† Helmar Gorls,† Ulrich S. Schubert,‡,§ and Alexander Schiller*,†,§
̈
̈
†Institute for Inorganic and Analytical Chemistry (IAAC), Friedrich Schiller University Jena, Humboldtstrasse 8, D-07743 Jena,
Germany
‡Institute for Organic Chemistry and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10,
D-07743 Jena, Germany
§Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, D-07743 Jena, Germany
S
* Supporting Information
reported receptor molecules are the following: direct signaling
of the binding event (chemical selectivity of the 19F NMR
ABSTRACT: Fluorinated boronic acid-appended benzyl
signals on conjugated sp2/sp3 boron); usually, the absence of a
background signal; the high sensitivity25 of non-invasive19F
NMR spectroscopy (100% natural abundance); the broad
chemical shift range of fluorine; and the robustness of
receptor−analyte signals against pH changes.26 Further, the
19F chemical shift is sensitive to minor structural changes in the
binding environment.20,21,24 These favorable characteristics of
19F as an NMR probe let us anticipate that the fluorine
substituent would provide a sensitive probe of boron
hybridization and structural binding environment of boronic
acid receptors for diol-containing analytes.25,27,28
We have previously used the fluorescent Singaram−
Wessling-type sugar probe13,29−31 as an allosteric indicator
displacement assay for cyanide.32 In addition, the two-
component probe can be described as the molecular logic
function “implication” on the few-molecule level of the
reporting dye.33 Concatenated molecular logic gates in large
circuits have been demonstrated with a “sugar computer” for
arithmetic calculation33,34 and playing tic-tac-toe.35
In this study, three fluorinated boronic acid-appended
bipyridinium salts serve as probes for diol-containing (bio)-
analyte recognition and discrimination with 19F NMR spec-
troscopy at physiological conditions. We chose fluorine-labeled
boronic acid-appended bipyridinium salts (BBVs) because of
their increased selectivity for monosaccharides and solubility in
water (up to 5 mM).13,29 A structural variable is the position of
nitrogens in the bipyridyl cores. F-4,4′-o-BBV (1), F-3,3′-o-BBV
(2), and F-3,4′-o-BBV (3) were synthesized by N-alkylation of
corresponding bipyridines via 2-bromomethyl-4-fluorophenyl-
boronic acid in dimethylformamide (Scheme 1).32 Isolation and
purification of the products was achieved by precipitation and
washing with acetone. X-ray structures of 4 and 5 could be
elucidated and are shown in Scheme 1.
bipyridinium salts, derived from 4,4′-, 3,4′-, and 3,3′-
bipyridines, were synthesized and used to detect and
differentiate diol-containing analytes at physiological
conditions via 19F NMR spectroscopy. An array of three
water-soluble boronic acid receptors in combination with
19F NMR spectroscopy discriminates nine diol-containing
bioanalytescatechol, dopamine, fructose, glucose, glu-
cose-1-phosphate, glucose-6-phosphate, galactose, lactose,
and sucroseat low mM concentrations. Characteristic
19F NMR fingerprints are interpreted as two-dimensional
barcodes without the need of multivariate analysis
techniques.
oronic acid-containing molecular probes1 have been
Bdeveloped as chemosensors for the recognition of diol-
containing analytes, such as sugars, nucleotides, catechols, and
hydroxyl carboxylic acids.2−5 Primarily, probes have been
generated with the aim to selectively detect glucose in vivo.6 To
increase glucose selectivity, the concept of bidentate binding7
via diboronic acids has been extensively utilized.8−10 In contrast
to the traditional “lock-and-key” approach in carbohydrate
detection, differential sensing with multivariate analytical
methods represents an attractive alternative.4,11−16 This
technique relies on multiple replicated experiments, and the
use of multivariate analysis can be seen as a “black box”
calculation with less control over possible false interpretations
by non-experts.15,17 An elegant alternative to reduce complexity
is the generation of barcodes without chemometrical methods.
Bode et al. discriminated polyols with shape-shifting boronic
acids as self-contained sensor arrays.18 Boronic acid probes are
often combined with optical indicators (a fluorophore or
chromophore).3,5,19 However, the intrinsically unselective
signals can be exchanged by highly sensitive and discriminative
19F NMR detection.20−23 Moreover, sensing systems that
provide unique and characteristic fingerprints of specific
analytes and work at physiological conditions are highly
desirable.24 Herein, we report on an array of water-soluble
boronic acid receptors with fluorine probes for sugar
recognition and discrimination via two-dimensional (2D)
barcodes. The advantages of 19F NMR probes attached to the
Fluorinated boronic acid receptors 1−3 comprise two diol
binding sites (at boron) and two 19F nuclei as reporters for
increased sensitivity25,28 and selectivity.13,29 When a diol was
added to the receptors in a physiological medium, the boronic
acids were converted into boronate esters, inducing an upfield
Received: October 23, 2015
© XXXX American Chemical Society
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DOI: 10.1021/jacs.5b10934
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It is important to note that the receptors 1−3 serve as 19F
NMR probes mainly for 1,2-syn-diols at the boron atom1 over
five conjugated bonds within the arene unit. On the NMR time
scale, the equilibrium between the boronic acid and the
corresponding ester is slow. As a result, the 19F NMR signals of
unbound receptor and the formed complexes are well
separated. Both sp2- and sp3-hybridized boron moieties showed
relatively broad fluorine peaks in water because of the exchange
equilibrium of the boronic acid/ester with their corresponding
“ate” complexes compared to samples in DMSO-d6. Interest-
ingly, the 19F NMR signals of the formed receptor−analyte
complexes were not altered by non-interfering buffer media and
pH in the measured range of 7−9. Determination of pKa values
of the fluorinated boronic acids has been performed by titration
with base and monitored via potentiometry and 19F NMR.
Compounds 1−3 displayed lower pKa values with a drop of
0.2−1 pH unit compared to the non-fluorinated counterparts
4,4′-, 3,3′-, and 3,4′-o-BBV.29 That result can be explained by
the electron-withdrawing effect of fluorine on the boron
moiety,36,37 which enhances diol binding. 19F NMR titration
experiments have been performed to determine binding
constants of catechol, D-fructose, and D-glucose with 1. In
addition, binding constants have been further confirmed by
fluorescence experiments due to the fact that 1−3 as dicationic
viologen derivatives are quenchers of water-soluble fluorescent
dyes, such as anionic pyranine and perylene diimides (see the
Supporting Information).13,29,33
Scheme 1. Synthesis Route, Molecule Structures of
Receptors 1−3, and the X-ray Structures of 4 and 5
a
a
4 is the trimeric anhydride of the precursor a. 5 is the monomethyl
ester of the dication of 1. Solvent molecules, bromide anions, and
hydrogens are omitted for clarity; gray = carbon, green = fluorine, blue
= nitrogen, red = oxygen, pink = boron. For details, see the Supporting
Information).
Scheme 2. Illustration of Reversible Boronic Acid−Diol
a
Interaction Recorded with 19F NMR Spectroscopy
For 19F NMR sensing experiments, the receptors 1−3 were
used in an array to check their cross-reactive sensing potential.
Reversible boronic acid−diol interactions were probed in
buffered aqueous solution (50 mM HEPES or phosphate
buffer, 10% D2O, pH 7.4) at room temperature. Receptors 1−3
(single receptor solutions, 4 mM each) gave fluorine NMR
patterns in the presence of the following bioanalytes: catechol,
dopamine, D-fructose, D-glucose, D-glucose-1-phosphate, D-
glucose-6-phosphate, D-galactose, D-lactose, and sucrose (40
mM for receptor saturation and high signal-to-noise (S/N) in
19F NMR). However, the limit of detection (LOD) for catechol
sensed by F-4,4′-o-BBV (1) is <100 μM at 188 MHz and 1024
scans. The LOD for D-fructose and D-glucose is 200 μM (see
the Supporting Information).
In DMSO-d6, compounds 1 and 2 showed one single peak at
δF −110.45 and −110.42 ppm, respectively. In contrast,
receptor 3 displayed two signals at δF −110.49 and −110.54
ppm due to its asymmetry. In buffered aqueous solution,
receptor 1 still showed one broad signal at δF −111.76 ppm
(Figure 1a). In contrast, 2 (δF −112.21 ppm) and 3 (δF
−112.24 and −112.33 ppm) possess signals with smaller
intensity at δF −111.86 and −111.89 ppm, respectively. This
downfield-shifted minor set of signals for 2 and 3 can be
tentatively assigned to the free boronic acid form. Broadening
of the fluorine peaks in buffered aqueous solution can be
explained by the boronic acid−boronate equilibrium (Scheme
2).1 19F NMR spectra obtained by screening receptor−diol
solutions of 1−3 will be discussed below (Figure 1). With the
addition of catechol (Figure 1b) as an aromatic 1,2-diol, all
peaks of unbound 1 disappeared, and only one sharp signal at
δF −116.05 ppm was visible, indicating strong 1:1 boronic
acid−catechol esters.1 The symmetric isomer 2 displayed one
a
Top, equilibrium of F-4,4′-o-BBV (1) and diol-containing analyte.
Bottom, 19F NMR spectra of 1 (4 mM) and with addition of D-glucose
(40 mM) in 50 mM phosphate buffer (10% D2O, pH 7.4), 188 MHz,
and 256 scans. Newly appearing and characteristic shifts at δF −115.72
and −117.04 ppm belong to the receptor−glucose complex, whereas
δF −111.76 ppm describes unbound 1.
chemical shift in the 19F NMR spectrum (Scheme 2). For
instance, the simple 19F NMR spectrum of 1 (δF −111.76 ppm)
changes rapidly when D-glucose binds to boron, leading to two
new signals at δF −115.72 and −117.04 ppm (50 mM
phosphate buffer, 10% D2O, pH 7.4). Multiple possible binding
modes were indicated by several peaks (Scheme 2). In the case
of reducing sugars, such as D-glucose, that could be explained
by the equilibrium of open-ring, α/β-pyranose, and α/β-
furanose forms. Binding to 1,2-syn-periplanar OH groups
seems to be favored.9 The intensity and line width of the new
signals depended on the binding affinity of the analyte. In
general, upfield shifts of approximately δF 4−5 ppm with an
error of 0.01 ppm were observed for all analytes.
sharp signal at δF −115.81 ppm, whereas 3 with two diverse 19
F
nuclei produced two sharp signals at δF −115.92 and −116.09
ppm. Interestingly, the similar neurotransmitter dopamine
(Figure 1c) can be discriminated from catechol with the shift
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shifted 19F peaks with 1 (δF −115.93 ppm), 2 (δF −115.60
ppm), and 3 (δF −115.76 and −115.95 ppm). The complexity
of 19F NMR signals of 1−3 was further demonstrated with a
selection of mono- and disaccharides: D-fructose (Figure 1d),
which is known for its strong affinity to boronic acids,1,2 yields
one sharp receptor−analyte peak at δF −116.10 ppm with 1 and
−115.97 ppm with 2 (δF −116.00 and −116.11 ppm for 3). In
contrast, D-glucose (Figure 1e), typically difficult to discrim-
inate from D-fructose, generated two peaks with 1 at δF
−115.72 and −117.04 ppm. Two binding peaks were also
observed for 2 (δF −116.04 and −116.65 ppm) and 3 (δF
−116.68 and −117.07 ppm). However, the smaller affinity of D-
glucose was displayed by the presence of unbound receptor
species. In addition, binding constants have been determined
via 19F NMR and fluorescence quenching.29 For D-fructose and
D-glucose, the apparent Kb values from the two techniques are
similar, within the same order of magnitude. However, Kb
values for all analytes have been compared from the
fluorescence quenching (Table S3 in the Supporting
Information). Receptor 1 and 4,4′-o-BBV29 show very similar
binding constants, ranging over two orders of magnitude (D-
fructose with 1, 1692 M−1; 2, 210 M−1; and 3, 142 M−1). Also
the Kb values for D-glucose (1, 45 M−1; 2, 16 M−1; 3, not
determinable) follow the trend of decreasing affinity. However,
receptor 2 displays higher affinities for D-glucose-6-phosphate
and galactose (Table S3). D-galactose (Figure 1h), with one
strong 19F signal at δF −115.90 ppm with 1, shows good affinity
compared to 2 (δF −115.74, −116.48, and −116.65 ppm) and
3 (δF −115.77 and −115.91 ppm). D-Lactose (Figure 1i)
displays only a broad signal with 1 at δF −117.07 ppm. Overall,
the strongest affinity for all analytes within the 19F NMR assay
was monitored with the 4,4′-isomer 1. Very weak to no
affinities to all receptors were measured with the control
substrates D-glucose-1-phosphate (Figure 1f) and the di-
saccharide sucrose (Figure 1j). Non-reducing sugars rarely
bind to boronic acids.13,38 All 19F NMR sensing experiments
and data of 1−3 are given in the Supporting Information.
At this point one discrete fluorinated boronic acid of the
collection 1−3 would be able to discriminate only some few
sugars. Thus, we collected the information for all three
receptors in an array. We refrained from using multivariate
analysis because we wanted to establish an easier and more
intuitive way to read out the data. Thus, the 19F NMR spectra
of 1−3 with the set of diol-containing bioanalytes were
transferred into a 2D barcode (Figure 1). For this purpose,
chemical shifts and intensities were extracted from all spectra.
The barcode uses NMR shifts in ppm units. Thresholds at 25,
50, and 75% of relative intensity of the peaks produce barcode
squares, such as quick response (QR) codes, at corresponding
shift values. The peak intensity is reflected by the
corresponding size of the colored squares. Originally, the
two-dimensional QR Code system was invented by the
automotive industry (Toyota, Denso-Wave, http://www.
qrcode.com/en/) to take advantage of its fast readability and
greater storage capacity compared to standard barcodes. Today,
QR Codes are applied in product tracking, item identification,
time tracking, and document management. Our 2D barcodes
can be used to visualize and conveniently compare the
interaction of an array of boronic acid receptors with a set of
diol-containing analytes. The square patterns resulted from 19F
NMR signals of bound and unbound receptors. Further
variance is given by the different sizes of the colored squares.
In this combination, the patterns of D-fructose (Figure 1d), D-
Figure 1. 19F NMR spectra of 1 with diol and 2D barcodes of the array
1−3. 2D barcodes underneath each spectrum relate to the receptors 1,
2, and 3 (blue, red, and green) and diol, respectively. Conditions: 1−3
(4 mM), diol (40 mM) in 50 mM phosphate buffer (10% D2O, pH
7.4), room temperature, 188 MHz, and 256 scans.
change significantly above the experimental error. The presence
of an ethylamine group on dopamine induced significantly
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glucose (Figure 1e), D-glucose-6-phosphate (Figure 1g), D-
galactose (Figure 1h), and D-lactose (Figure 1i) can be easily
differentiated by the naked eye. In contrast, only receptor 1
alone and its corresponding blue patterns with catechol (Figure
1b), dopamine (Figure 1c), D-fructose (Figure 1d), and D-
galactose (Figure 1h) hamper discrimination among the
mentioned analytes. This demonstrates the importance of
combining several boronic acid receptors in an array to provide
successful differentiation. In addition, magnetically diverse 19F
nuclei in receptor 3 add a more complex and better
discriminable sub-pattern to the array (e.g., with D-glucose
(Figure 1e), D-glucose-6-phosphate (Figure 1g), and D-
galactose (Figure 1h)). However, symmetric 19F probes, such
as receptors 1 and 2, are necessary for their increased binding
affinity. It is also important to demonstrate the limits of the 2D
barcodes. D-Glucose-1-phosphate and sucrose, which are not
binding to our receptors under the present conditions, display
patterns very similar to those of the unbound receptors (Figure
1a,f,j). Visual discrimination of catechol (Figure 1b) and
dopamine (Figure 1c) is also difficult; however, the 19F NMR
shifts are clearly separated. Further parameters from the 19F
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In summary, we present a new approach using three
fluorinated boronic acid-appended bipyridinium salts and 19F
NMR spectroscopy for the detection and discrimination of diol-
containing analytes in aqueous buffer solution via 2D barcodes.
The concept can be widened by screening other analyte classes,
monitoring enzyme reactions,39 and applying this technique in
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b10934.
■
S
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Experimental procedures and characterization data for all
new compounds (PDF)
X-ray crystallographic data for 4 and 5 (CIF)
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Tisne, C.; Micouin, L. Org. Biomol. Chem. 2015, 13, 8817.
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AUTHOR INFORMATION
Corresponding Author
*alexander.schiller@uni-jena.de
Notes
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The authors declare no competing financial interest.
(32) Jose, D. A.; Elstner, M.; Schiller, A. Chem. - Eur. J. 2013, 19,
14451.
ACKNOWLEDGMENTS
(33) Elstner, M.; Weisshart, K.; Mullen, K.; Schiller, A. J. Am. Chem.
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Soc. 2012, 134, 8098.
This work was supported by the German Science Foundation
(DFG) via grant SCHI 1175/5-1 and the Heisenberg program
SCHI 1175/4-1. A.S. is grateful to the Carl Zeiss foundation for
a Junior Professor fellowship and the EC for financial support
through the FP7 project “Novosides” (grant agreement no.
KBBE-4-265854). We thank also Tobias Otto, Martin Elstner,
and Esra Altuntas for their help in synthesis and character-
ization. Special thanks go to the NMR platform of the IAAC/
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