Phenylboronic acid-functionalized TTFAQ: modular synthesis and electrochemical recognition for saccharides

Article abstract of DOI:10.1016/j.tetlet.2010.02.171

A phenylboronic acid-functionalized π-extended tetrathiafulvalene (TTFAQ) derivative was prepared through an efficient Cu-catalyzed alkyne-azide [3+2] cycloaddition reaction (click reaction). This boronic acid-TTFAQ hybrid system shows different electrochemical redox behavior upon titration with various saccharides in DMSO/H₂O at pH 8.75, suggesting potential use in saccharide sensing and recognition.

Full text of DOI:10.1016/j.tetlet.2010.02.171

Tetrahedron Letters 51 (2010) 2508–2511
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Phenylboronic acid-functionalized TTFAQ: modular synthesis
and electrochemical recognition for saccharides
*
Min Shao, Yuming Zhao
Department of Chemistry, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada A1B 3X7
a r t i c l e i n f o
a b s t r a c t
Article history:
A phenylboronic acid-functionalized
p-extended tetrathiafulvalene (TTFAQ) derivative was prepared
Received 17 February 2010
Revised 25 February 2010
Accepted 26 February 2010
Available online 3 March 2010
through an efficient Cu-catalyzed alkyne-azide [3+2] cycloaddition reaction (click reaction). This boronic
acid-TTFAQ hybrid system shows different electrochemical redox behavior upon titration with various
saccharides in DMSO/H2O at pH 8.75, suggesting potential use in saccharide sensing and recognition.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Boronic acid
Tetrathiafulvalene
Click reaction
Saccharide sensor
Electrochemistry
The development of biosensors to detect saccharides has been a
topical research in the past decade, driven by the growing need for
understanding the crucial roles that various saccharide species
play in numerous biologically important events ranging from pro-
tein targeting, cell recognition, and production of metabolic energy
to disease diagnosis and management.1,2 A general design architec-
ture for a saccharide biosensor contains three essential compo-
nents: receptor, reporter (i.e., read-out unit), and linkage group.
Phenylboronic acid, ever since the discovery of its ability to rapidly
form cyclic ester with cis 1,2- or 1,3-diols in aqueous media, has
been extensively explored as saccharide receptors.2–5 A major
advantage of using phenylboronic acid for saccharide sensing lies
in the possibility to achieve selectivity for a range of saccharides.
Organic chromophores, fluorophores, and electrophores are com-
monly employed read-out units to be associated with phenylbo-
ronic acid in the design of saccharide sensors, which lead to
various types of colorimetric,6–8 fluorimetric,9–14 and electrochem-
ical saccharide sensors.15–18
ties of forming charge-transfer complexes to show metallic con-
ductance.21,22 In the field of sensor design, the application of TTF
components in constructing chemosensors for anion detection
has made a significant progress in the past few years. Little atten-
tion, on the other hand, has been given to TTF-based saccharide
sensors bearing boronic acid functionality. Recently, the Zhu group
devised a TTF-anthracene-boronic acid triad system, in which the
TTF unit was enlisted to modulate photoinduced electron transfer
(PeT) to attain fluorescence-sensing function toward saccha-
rides.23,24 Nonetheless, boronic acid-based electrochemical sensors
for saccharides using TTF as the electrochemical reporter still re-
main an uncharted territory awaiting further exploration.
To shed light on this issue, a molecular array involving diph-
enylboronic acids and a central exTTF unit was designed and tested
by us as a prototypical sensor system for electrochemical recogni-
tion of saccharides. A proposed working principle for this type of
electrochemical sensors is depicted in Scheme 1. Basically, the
binding of boronic acid groups with the diols of saccharides under
aqueous conditions is expected to alter the oxidation potential of
the central exTTF donor unit. As such, it may render recognition
of saccharides via certain electrochemical (e.g., potentiometric or
voltammetric) means. Moreover, the incorporation of two boronic
acid groups was anticipated to deliver a twofold benefit: (1) to in-
crease the affinity for saccharides and (2) to afford enhanced selec-
tivity to particular saccharides through chelate complexation.
We chose an anthraquinodimethane-type exTTF (TTFAQ) as the
electrochemical reporter, in view of the strong electron-donating
ability and redox activity of this type of molecules.22 The synthetic
step linking boronic acid groups to TTFAQ was planned to proceed
In recent years, boronic acid-based electrochemical sensors
have emerged as an appealing alternative to the conventionally
used enzymatic electrochemical sensors for saccharides.19,20
Molecular components with excellent redox reversibility and sta-
bility, such as ferrocene15,17 and polyanilines,16,18 have been
exploited within this context. Tetrathiafulvalene (TTF) and
p-ex-
tended TTF analogues (exTTFs) are well-known organic electronic
materials for their remarkable redox activities and unique proper-
* Corresponding author. Tel.: +1 709 737 8747; fax: +1 709 737 3702.
E-mail address: yuming@mun.ca (Y. Zhao).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.171

M. Shao, Y. Zhao / Tetrahedron Letters 51 (2010) 2508–2511
2509
Scheme 1. Proposed working principle for saccharide sensing by a TTFAQ-diboronic acid triad.
in a modular manner by using a well-documented click reaction,
namely Cu-catalyzed alkyne-azide cycloaddition (CAAC) reac-
tion.25–28 The detailed synthetic route is shown in Scheme 2. A
2,6-dialkynylated TTFAQ building block 1, which was previously
developed by our group,29,30 was expected to react with azido-ap-
pended pinacol boronate 231 under the catalysis of CuI in THF to af-
ford diboronate ester-functionalized TTFAQ 3. Our initial attempts
at this reaction under room temperature conditions were not suc-
cessful, due to very slow reaction rate. Increasing the reaction tem-
perature to 65 °C and the amount of CuI (0.89 M equiv relative to 1)
greatly sped up the reaction, giving compound 3 in 55% yield.32
Boronate ester 3 was then subjected to an ester exchange reac-
tion with excess o-tolueneboronic acid (6 equiv) in dioxane at
100 °C to yield the desired product, TTFAQ-diboronic acid 5, in
79% yield, while the byproduct pinacol o-tolueneboronic ester
was recovered as a precursor to the starting material 2. TTFAQ-
diboronic acid 5 appears as a dark brown solid, showing good sol-
ubility in DMSO. The structure and purity of compound 5 were ver-
ified by 1H NMR, IR, and MS analyses.33
To test the sensing function of 5 toward saccharides, four differ-
ent saccharide species—glucose, fructose, ribose, and rinose—were
titrated, respectively, into a solution of 5 in DMSO/H2O (3:2, v/v). A
buffer system (KCl 2.08 M, KH2PO4 0.022 M, Na2HPO4 0.022 M)
was added to the solution of 5 to keep the pH at ca. 8.75 as well
as to function as the electrolytes for voltammetric experiments.
The binding of saccharide molecules with 5 was monitored by dif-
ferential pulse (DP) voltammetry, and the detailed titration vol-
tammograms are given in Figure 1.
The employment of DMSO/H2O (3:2, v/v) as the medium for the
titration experiments was due to the poor solubility of compound 5
in H2O. With the assistance of DMSO, compound 5 could be coaxed
into aqueous solvents with a sufficient concentration (2.56 mM)
for electrochemical analysis. The DP voltammogram of 5 (see
Fig. 1A) before titration with saccharides showed rather weak cur-
rent signals, likely as a result of significant viscosity and diminu-
tive diffusion coefficient. Nonetheless,
a noticeable oxidation
peak is discernible at +0.62 V, which coincides with a two-electron
quasi-reversible process as revealed by cyclic voltammetric
analysis.34
Upon titration of 5 with fructose, the solution appeared to be
less viscous and the current intensity increased steadily with
increasing addition of fructose. Of significance in the voltammo-
gram of 5 is the observation of a new oxidation peak that emerged
at ca. +0.36 V besides the original peak at +0.62 V upon titration of
Scheme 2. Synthesis of diboronic acid-TTFAQ 5 via click chemistry.

2510
M. Shao, Y. Zhao / Tetrahedron Letters 51 (2010) 2508–2511
Figure 1. Differential pulse voltammograms of 5 (2.56 mM) obtained during titration with various saccharides at pH 8.75 in DMSO/H2O (3:2, v/v). Electrolytes: KCl (2.08 M),
KH2PO4 (0.022 M), Na2HPO4 (0.022 M); Working electrode: glassy carbon; Counter: Pt wire; Reference: Ag/AgCl; Scan rate: 20 mV/s; Pulse width: 50 mV; Step: 4 mV; Pulse
period: 200 ms.
Figure 2. (A) Baseline-corrected differential pulse voltammograms of 5 upon titration with fructose. (B) Correlation of ip1/ip2 with [G]0/[H]0 upon titration with fructose. (C)
Baseline-corrected differential pulse voltammograms of 5 upon titration with ribose. (D) Correlation of ip1/ip2 with [G]0/[H]0 upon titration with ribose. Baseline corrections in
(A) and (C) were done using a non-linear curve-fitting program Fityk 0.90, and the data in (B) and (D) were fitted using a biexponential function.

M. Shao, Y. Zhao / Tetrahedron Letters 51 (2010) 2508–2511
2511
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13. Cao, H.; Heagy, M. D. J. Fluoresc. 2004, 14, 569–584.
fructose. This oxidation peak presumably arises from the complex
of compound 5 with sugar. Obviously, the binding of boronic acid
with sugar enhanced the electron-donating ability of the central
TTFAQ core, causing an anodic shift of its oxidation potential. In
a previous report by James and co-workers, a similar anodic shift
was observed when a ferrocene-boronic acid sensor was com-
plexed with sugars.17 As the titration proceeded, the two oxidation
peaks were observed to slightly drift from +0.62 to +0.68 V and
from +0.36 to +0.42 V, respectively. To clearly visualize the changes
of the two current peaks, the voltammograms were subjected to
baseline correction, and the results are shown in Figure 2.
Of note in this figure is that, in titration of fructose from 0.5 to
20 M equiv, the ratio of the intensities of two oxidation current
peaks (ip1/ip2) varied considerably in relation to the ratio of [G]0/
[H]0, where [G]0 refers to the initial concentration of sugar (guest)
and [H]0 to the initial concentration of 5 (host). When the ratio
[G]0/[H]0 was further increased, the current peak ratio ip1/ip2 re-
mained virtually constant (ca. 0.52), indicating that the titration
reached saturation.
14. Tan, W.; Zhang, D.; Wang, Z.; Liu, C.; Zhu, D. J. Mater. Chem. 2007, 17, 1964–1968.
15. Ori, A.; Shinkai, S. J. Chem. Soc., Chem. Commun. 1995, 1771–1772.
16. Shoji, E.; Freund, M. S. J. Am. Chem. Soc. 2002, 124, 12486–12493.
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2002, 2368–2369.
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660–664.
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20. Tucker, J. H. R.; Collinson, S. R. Chem. Soc. Rev. 2002, 31, 147–156.
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3928–3932.
The titration experiment of 5 with ribose gives a similar pattern
of DP voltammograms (see Fig. 1B); however, the degree of current
variation in response to ribose titration appears to be less signifi-
cant in comparison with the result of fructose (see Fig. 2C and
D). This observation suggests that compound 5 has a relatively
weaker affinity for ribose than fructose. The voltammograms of 5
upon titration with rinose and glucose under the same conditions
showed rather insignificant changes (see Fig. 1C and D), indicating
low binding affinities between compound 5 and these two saccha-
ride species.
27. Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51–68.
28. Wu, P.; Fokin, V. Aldrichim. Acta 2007, 40, 7–17.
29. Chen, G.; Zhao, Y. Tetrahedron Lett. 2006, 5069–5073.
30. Chen, G.; Shao, M.; Zhao, Y. Asian Chem. Lett. 2007, 11, 185–196.
31. Scrafton, D. K.; Taylor, J. E.; Mahon, M. F.; Fossey, J. S.; James, T. D. J. Org. Chem.
2008, 73, 2871–2874.
In summary, we have developed the modular synthesis of a
boronic acid-functionalized TTFAQ derivative 5 using the Cu-cata-
lyzed alkyne-azide cycloaddition (click) reaction as the key ligation
step. Compound 5 was found to show pronounced electrochemical
responses selectively toward fructose and ribose. To the best of our
knowledge, this is the first example demonstrating selective sac-
charide-sensing function for a TTFAQ-boronic acid hybrid. Deter-
mination of the stoichiometry and exact binding constants for
the complexation of 5 with various saccharides is not attainable
at this stage, due to the limited solubility of 5 in aqueous media
and viscosity effects. Efforts to modify the structure of 5 with
water-soluble functionalities are currently under way, and it is
anticipated that with improved water solubility the TTFAQ-boronic
acid system may find applicability in the field of saccharide recog-
nition and quantification.
32. Synthesis and characterization of compound 3: To a 100 mL round-bottomed
flask were charged compound 1 (0.18 g, 0.29 mM), 2 (0.23 g, 0.88 mM), CuI
(0.05 g, 0.26 mM), and THF (60 mL). The mixture was heated to 65 °C for 24 h,
and then cooled to room temperature. The solvent was removed in vacuo, and
the residue was redissolved in CH2Cl2, washed by saturated brine, and dried
over MgSO4. After the solvent was removed in vacuo, the crude product was
purified through flash column chromatography (EtOAc/hexanes, 1:4) to give
compound 3 (0.18 g, 0.16 mM, 55%) as an orange solid. Mp 138–140 °C; IR
(neat) 2976, 2921, 1601, 1532, 1495, 1455, 1382, 1348, 1144, 1069, 1045 cmÀ1
.
1H NMR (500 MHz, CDCl3) d 7.92 (d, J = 8.34 Hz, 2H), 7.81 (s, 2H, triazole-H),
7.76 (dd, J = 8.02, 1.60 Hz, 2H), 7.57 (d, J = 8.34 Hz, 2H), 7.45 (t, J = 7.69 Hz, 2H),
7.36 (t, J = 7.05 Hz, 2H), 7.29 (d, J = 7.69 Hz, 2H), 5.92 (s, 4H, CH2), 2.38 (s, 6H,
SCH3), 2.34 (s, 6H, SCH3), 1.39 (s, 24H, pinacol ester CH3); 13C NMR (125 MHz,
CDCl3) d 140.9, 136.7, 135.0, 134.1, 131.9, 131.6, 129.3, 129.0, 127.9, 126.5,
125.9, 125.4, 123.5, 123.3, 122.5, 120.0 (two sp2 carbon signals not observed
due to coincidental overlap), 84.3, 53.5, 25.0, 19.2, 19.1; HR-MALDI-TOF MS
(dithranol) m/z calcd for C54H56B2N6O4S8 1130.2315, found 1130.2339.
33. Synthesis and characterization of compound 5: To a 100 mL round-bottomed
flask were charged compound
3 (0.27 g, 0.24 mM), phenylboronic acid 4
Acknowledgments
(0.20 g, 1.44 mM), dioxane (12 mL), and aq HCl (5 M, 4 mL). The mixture was
heated at 100 °C for 24 h. After cooling to room temperature, the solvent was
removed in vacuo. The residual solid was sequentially washed with EtOAc,
acetonitrile, and then Et2O, affording compound 5 (0.18 g, 0.19 mM, 79%) as a
brown solid. Mp 230–232 °C; IR (neat) 3386 (OH), 2919, 1560, 1530, 1492,
1445, 1367, 1076; 1H NMR (500 MHz, DMSO-d6) d 8.59 (s, 2H), 8.05 (s, 2H),
7.83 (d, J = 9.62 Hz, 2H), 7.66 (d, J = 6.41 Hz, 2H), 7.63 (d, J = 8.34 Hz, 2H), 7.37
(t, J = 7.37 Hz, 2H), 7.31 (t, J = 7.05 Hz, 2H), 7.11 (d, J = 7.69 Hz, 2H), 5.87 (s, 4H,
CH2), 2.42 (s, 6H, SCH3), 2.37 (s, 6H, SCH3) (B(OH)2 signal not observed due to
rapid proton exchange); HR-MALDI-TOF MS (dithranol) m/z calcd for
C42H36B2N6O4S8 966.0750, found 966.0751.
The authors thank NSERC, CFI, and Memorial University of
Newfoundland for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.171.
34. A quasi-reversible redox wave pair was observed at E1/2 = +0.62 V in the cyclic
voltammogram of 5 measured in DMSO. For details, see the Supplementary data.
References and notes
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