Effect of the electron donor/acceptor orientation on the fluorescence transduction efficiency of the d-pet effect of carbazole-based fluorescent boronic acid sensors

Article abstract of DOI:10.1021/jo100119y

We have synthesized three new carbazole-based fluorescent boronic acid sensors to investigate the fluorescence transduction efficiency of the novel d-PET effect, in which the fluorophore acts as the electron donor and the protonated amine/boronic acid group as the electron acceptor of the photoinduced electron transfer process (PET). Aryl ethynyl groups are attached at the 3,6-position of carbazole (aryl = 4-dimethylaminophenyl for sensor 1 or phenyl for sensor 2). Sensor 3 is without 3,6-substitutions. The phenylboronic acid moiety is attached at the 9-position (N-atom) of the carbazole in these sensors. We found that 1 and 3 are d-PET sensors (fluorophore as the electron donor, supported by DFT/TDDFT calculations), which show diminished emission at acidic pH but intensified emission at neutral/basic pH, which is in stark contrast to the normal a-PET (fluorophore as the electron acceptor) sensors, e.g., 2, which shows intensified emission at acidic pH but diminished emission at neutral pH. The fluorescence modulation efficiency of the d-PET effect of the new sensors, i.e., the emission intensity enhancement upon switching from acidic pH to neutral pH, is up to 10-fold, which is greatly improved compared to our previous d-PET sensors (ca. 3-fold). The efficient d-PET effect of the new sensors is attributed to the proper orientation of the electron donor/acceptor; i.e., the dipole moment and the transition moment (the direction of PET) of the new sensors are oriented in the same direction, and the dipole moment values of the new sensors along the vector direction of the PET are larger than that of the reported d-PET sensors. Selective recognition of α-hydroxyl carboxylic acids, such as tartaric acid, was achieved with the d-PET sensors, and a novel fluorescence transduction profile of enhancement/ diminishment for chemoselectivity was observed. Herein we propose that the orientation of the electron donor/acceptor may significantly affect the fluorescence modulation efficiency of the PET effect; this discovery will be important for the future design of PET sensors with improved fluorescence transduction efficiencies.

Full text of DOI:10.1021/jo100119y

Exploiting the Reversible Covalent Bonding
of Boronic Acids: Recognition, Sensing,
and Assembly
STEVEN D BULL,† MATTHEW G. DAVIDSON,†
JEAN M. H. VAN DEN ELSEN,‡ JOHN S. FOSSEY,§
A. TOBY A. JENKINS,† YUN-BAO JIANG,^ YUJI KUBO,
FRANK MARKEN,† KAZUO SAKURAI,# JIANZHANG ZHAO,3 AND
TONY D. JAMES*, †
†Department of Chemistry, University of Bath, Bath BA2 7AY UK,
‡Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY UK,
§School of Chemistry, University of Birmingham, Edgbaston, Birmingham,
West Midlands, B15 2TT, UK, Department of Applied Chemistry,
Graduate School of Urban Environmental Sciences, Tokyo Metropolitan
University, 1-1 Minami-ohsawa, Hachioji, Tokyo 192-0397, Japan,
^Department of Chemistry, College of Chemistry and Chemical Engineering and
the MOE Key Laboratory of Analytical Sciences, Xiamen University,
Xiamen 361005, China, #Faculty of Environmental Engineering,
The University of Kitakyushu, 1-1 Hibikino, Wakamatsu, Kitakyushu City,
Fukuoka, 808-0135 Japan, and 3State Key Laboratory of Fine Chemicals,
School of Chemical Engineering, 2 Ling-Gong Road, Dalian University of
Technology, Dalian 116024, China
RECEIVED ON MAY 15, 2012
C O N S P E C T U S
oronic acids can interact with Lewis bases to generate boronate anions,
B
and they can also bind with diol units to form cyclic boronate esters.
Boronic acid based receptor designs originated when Lorand and Edwards
used the pH drop observed upon the addition of saccharides to boronic acids to
determine their association constants. The inherent acidity of the boronic acid is
enhanced when 1,2-, 1,3-, or 1,4-diols react with boronic acids to form cyclic
boronic esters (5, 6, or 7 membered rings) in aqueous media, and these
interactions form the cornerstone of diol-based receptors used in the construc-
tion of sensors and separation systems.
In addition, the recognition of saccharides through boronic acid complex
(or boronic ester) formation often relies on an interaction between a Lewis
acidic boronic acid and a Lewis base (proximal tertiary amine or anion). These
properties of boronic acids have led to them being exploited in sensing and
separation systems for anions (Lewis bases) and saccharides (diols).
The fast and stable bond formation between boronic acids and diols to form boronate esters can serve as the basis for forming
reversible molecular assemblies. In spite of the stability of the boronate esters' covalent BꢀO bonds, their formation is reversible
under certain conditions or under the action of certain external stimuli.
The reversibility of boronate ester formation and Lewis acidꢀbase interactions has also resulted in the development and
use of boronic acids within multicomponent systems. The dynamic covalent functionality of boronic acids with structure-
directing potential has led researchers to develop a variety of self-organizing systems including macrocycles, cages, capsules,
and polymers.
This Account gives an overview of research published about boronic acids over the last 5 years. We hope that this Account will
inspire others to continue the work on boronic acids and reversible covalent chemistry.
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Reversible Covalent Bonding of Boronic Acids Bull et al.
1. Introduction
SCHEME 3. Some of the Key Interactions of Boron, With Respect to the
Self-Assembly
The origins of boronic acid based receptor design can be
traced back to the seminal work of Lorand and Edwards.1
They used the pH drop observed on addition of saccha-
rides to determine their association constants (Scheme 1).
The acidity of the boronic acid is enhanced when 1,2-,
1,3-, or 1,4-diols react with boronic acids to form cyclic
boronic esters (5, 6, or 7 membered rings) in aqueous
media.2,3
The recognition of saccharides through boronic acid
complex (or boronic ester) formation often relies on an
interaction between a Lewis acidic boronic acid and a
proximal tertiary amine (Lewis base). The true nature of
the nitrogenꢀboron (NꢀB) interaction has been much
debated (especially in an aqueous environment), but it is
clear that an interaction of some kind exists which offers
two advantages.4 First, this interaction enhances binding
at neutral pH (by facilitating tetrahedral boronate forma-
tion), allowing the development of receptors with practi-
cal applicability. Second, saccharide binding enhances
the NꢀB interaction (due an increase in Lewis acidity of
the boron on saccharide binding) and modulates the
fluorescence of nearby fluorophores (fluorescent photo-
induced electron transfer (PET) from the nitrogen is con-
trolled by the strength of the NꢀB interaction), which is
extremely useful in the design and application of chemo-
sensors.2
bonds, their formation is reversible under certain con-
ditions or under the action of certain external stimuli
(Scheme 3).6,7
2. Boronic Acids as Sensors
The Lewis acidic nature of boron has also lead
to the development of anion receptors and sensors
(Scheme 2).2,5
2.1. Anion Sensors. The first fluorescent sensor for fluo-
ride was developed in 1998.8 Fluorescence quenching of
a series of simple aromatic boronic acids was observed in
buffered aqueous methanol solution at pH 5.5 upon
addition of KF. Tetrahedral boronate anions had already
been shown to quench the fluorescence of directly at-
tached fluorophores, and the same internal charge trans-
fer (ICT) mechanism was shown to operate upon fluoride
binding. The 11B NMR spectroscopic observations of 1
and 2, displayed shifts consistent with a change from an
sp2 to sp3 boron center as the concentration of fluoride
was increased.
The fast and stable bond formation between bo-
ronic acids and diols to form boronate esters can also
be utilized to build reversible molecular assemblies. In
spite of the stability of the boronate esters' covalent BꢀO
SCHEME 1. Rapid and Reversible Formation of a Cyclic Boronate Ester
SCHEME 2. Diagram Illustrating the Change in Geometry at the Boron
Centre on Interaction with a Nucleophile
The amine of 3 has a pKa of 5.5, and so under
the measurement conditions, the nitrogen is partially
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Reversible Covalent Bonding of Boronic Acids Bull et al.
protonated, allowing a hydrogen bonding interaction with a
bound fluoride (4). This family of chemosensors serves to
demonstrate the importance of tunability. Since different
environments require monitoring across varying concentra-
tion ranges, only simple modifications need to be made in
order to enhance binding without changing the mode of
action.
similar ion pairs such as potassium chloride and potas-
sium bromide.
In order to enhance fluoride binding, the use of a
rigid framework as a scaffold for boronic acid based
anion sensors was investigated. It was found that the
bis(bora)calix[4]arene 5 acts as a sensor for tetra-n-
butylammonium fluoride (Bu4NF) in chloroform. Sub-
sequently, in order to probe the factors affecting
fluoride binding, related boronates 8 and 9 were
prepared.9
The bidentate fluoride receptor 11 was designed and
synthesized (Scheme 4) that employs a boronic acid site
and an imidazolium group.10 The ortho derivative (shown)
was crucial, since only this isomer gave the desired selec-
tivity. The CꢀH hydrogen bond donor stabilizes the bind-
ing, allowing recognition to occur in competitive media
(Scheme 4).
SCHEME 4. Sensor 11 Combines
CHꢀAnion Interaction
a Boronic Acid Receptor with
2.2. Saccharide Sensors. The ICT sensor 12 reported by
Czarnik and Yoon in 1992 consisted of a boronic acid
fragment directly attached to anthracene.11 On addition
of saccharide, it was noted that the intensity of the
fluorescence emission for the 2-anthrylboronic acid 12
was reduced by ∼30%. This change in fluorescence emis-
sion intensity is ascribed to the change in electronic
properties that accompany rehybridization at boron. The
9-anthrylboronic isomer, 13, was also examined but dis-
played smaller changes in fluorescence emission, a fea-
ture attributed to the unfavorable peri-interactions that
would be expected at the 9-position from the ancillary
hydrogens.
While fluoride caused deboronation of compound
9 and dramatic color changes, Bu4NCl and Bu4NBr
produced no color change. However, Bu4NCl caused
fluorescence quenching of compound 9 but did not
quench 8, or alcohols 6 and 7. Bu4NBr did not cause
a significant change in the fluorescence spectra of
compounds 6ꢀ9. The fluorescence quenching by
chloride has been attributed to bidentate binding
through two BOH hydrogen bonds, with the conforma-
tional change in the fluorophore causing the fluores-
cence quenching.
Ditopic receptors 10a and 10b function as AND
logic gates; the boronic acid interacts strongly with a
fluoride anion while a potassium cation is held partly
by the crown ether and by an electrostatic interaction
with bound fluoride anion. This cooperative complexa-
tion allows the cationic and anionic guests to be bound
to the host as an ion pair, while allowing the host
to discriminate between potassium fluoride and other
These ICT sensors have one drawback for potential real
world sensor development, which is pH sensitivity. In the
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Reversible Covalent Bonding of Boronic Acids Bull et al.
case of PET sensors, the interaction between o-methylphe-
nylboronic acids (Lewis acids) and proximal tertiary amines
(Lewis bases) has been exploited.
excessive hydrophobicity, and steric crowding at the bind-
ing pocket.
The first fluorescent PET sensor 14 for saccharides
was developed in 1994, and it employs an N-methyl-
o-(aminomethyl)phenylboronic acid receptor unit. The
amino baseꢀboronic acid (NꢀB) interaction found in
sensor 14 allows the system to function as an “offꢀon”
sensor, producing a large fluorescence enhancement on
addition of saccharides, and functions over a broad pH
range.
A modular PET sensor 17 was prepared, containing two
phenylboronic acid groups, a pyrene fluorophore and a
variable linker. The linker was varied from n-propylene
(n = 3) to n-octylene (n = 8). In most cases, the observed
stability constants (Kobs) with diboronic acid sensor 17 are
higher than those for monoboronic acid sensor 18. D-Glucose
and D-galactose bind to diboronic acids readily using two sets
of diols, thus forming stable, cyclic 1:1 complexes. The six
carbon linker provided the optimal selectivity for glucose over
other monosaccharides. However, there is an inversion in this
selectivity on increasing the linker length to n-heptylene (n = 7)
and n-octylene (n = 8) with the larger spacing between the two
boronic acid groups producing a galactose selective system.
The simple fructose selective monoboronic acid based
sensor 14 was improved in 1995 with the introduction of
a second boronic acid group to form the diboronic acid
sensor 15.12 This ReceptorꢀSpacerꢀFluorophoreꢀSpacerꢀ
Receptor system retained the advantage of utilizing PET to
modulate an “offꢀon” response to saccharides while intro-
ducing an advanced recognition site. The modification
proved successful, and, fortuitously, the spacing of the two
boronic acid groups provided an effective binding pocket for
glucose.
Molecular tweezer 19 was developed that selectively
opens for certain saccharides.13 The fluorescence intensity
at 377 nm of tweezer 19 increases with increasing concen-
tration of D-glucose, D-fructose, D-galactose, and D-mannose,
and fluorescence intensity changes at 470 nm differ among
the four carbohydrates. The 470 nm band decreases with
increasing D-glucose and D-mannose concentration. The
intensity of the 470 nm band is invariant with added
D-fructose. Finally, D-galactose shows an initial quenching
of the 470 nm band at low concentrations followed by
fluorescence recovery as the concentration increases. In
the case of D-glucose, D-galactose, and D-mannose, the
complex formed is a cyclic 1:1 structure (Scheme 5). This
explains the quenching of the intramolecular excimer
2.3. Modular Fluorescent Sensors. While retaining the
same dual boronic acid recognition units throughout,
modular systems, in which the linker and fluorophore
units of these sensors could be modified independently,
have been developed. The design 16 includes two boronic
acid groups required for selectivity but allows the separa-
tion between them to be varied by altering the linker. It
also permits the fluorophore to be varied independently
and by using only one fluorophore overcomes the prob-
lems that may arise from excimer emission, insolubility,
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Reversible Covalent Bonding of Boronic Acids Bull et al.
SCHEME 5. Two Possible Binding Modes for the Molecular Tweezer 19
emission at 470 nm, since the binding of the saccharide
separates the pyrene units. The more complex behavior of
the sensor in the presence of D-galactose indicates initial
formation of a 1:1 complex at low concentration and
subsequent formation of a 1:2 complex at higher concen-
tration. For molecular tweezer 19 with D-fructose, only the
noncyclic 1:2 complex forms even at low saccharide
concentration. (Scheme 5)
SCHEME 6. Fluorescence Dosimeter for Saccharides and Mercury
A convenient syntheses of fluorescent boronic acids
using a Huisgen [3 þ 2] cycloaddition to generate a “click
fluor” 20 was developed,14 an approach well suited to
modular syntheses. The so-called “click reaction” was used
to form a 1,2,3-triazole from an azide and a terminal alkyne,
this created a fluorescent sensor from nonfluorescent con-
stituent units. The phrase “click-fluor” describes the generation
of a fluorophore from nonfluorescent units via the so-called
“click reaction”. Two of the most attractive features of “click-
fluor” are that a fluorophore is generated when the triazole is
formed and the wide availability of acetylene units facilitating
potential diversity. Therefore, we believe that “click-fluor”will be
particularly amenable to sensor array development.15
fluorescent output at 478 nm was significantly enhanced
(>5-fold) in the presence of both Hg2þ and D-fructose in pH
8.21 buffer. While a less intense enhancement (∼3-fold) was
obtained on the addition of only Hg2þ, an even lower en-
hancement (<2-fold) was observed for the addition of
D-fructose alone. The system can be construed as a dosim-
eter with AND logic functionality, in that it reports a HIGH
output when two inputs are simultaneously applied.
2.4. Chiral Sensors. Chiral fluorescent boronic acid sen-
sors have attracted much interest for a number of years.17ꢀ22
The first fluorescent chiral boronic acid sensor for glucose
was prepared in 1995 (sensor 21). With sensor 21, the BINOL
moiety performs the roles of fluorophore, scaffold, and the
stereogenic center. More recently, the same BINOL-based
chiral boronic acid sensors were used for enantioselective
recognition of tartaric acids. However, the BINOL fluoro-
phore emits UV light, whereas emission in the visible region
is desired for routine applications. Furthermore, the fluoro-
phore and the stereogenic centers of the BINOL-based chiral
sensors are one and the same (the same is true for the chiral
sensors 21ꢀ23), making it difficult to vary the fluorophores
More recently a ditopic fluorescence sensor for saccha-
rides and mercury has been developed based on a boronic
acid receptor and desulfurisation reaction (Scheme 6).16 The
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Reversible Covalent Bonding of Boronic Acids Bull et al.
and binding sites to other units in order to optimize the
molecular sensing performance of the sensors. To tackle the
limitations of the BINOL system, anthracene based chiral
boronic acid sensors, which produced visible emission and
good chiral selectivity toward tartaric acid and sugar acids or
sugar alcohols (sensor 22), were developed. More recently,
the carbazole based boronic acids were devised 23ꢀ26 with
the fluorophore as the electron donor of the photoinduced
electron transfer (d-PET) and protonated amine/boronic acid
moiety as the acceptor of the PET; the background emission
for the sensor at acidic pH was much lower than that with
normal PET sensors where the fluorophore is the acceptor
(a-PET).17,23 However, the integrated carbazole fluorophores
used in these sensors also restrict variation of the molecular
scaffold.
fluorophore are avoided. Phenothiazine was selected as
the fluorophore for d-PET because the chromophore is a
strong electron donor. The contrast ratio obtained with
the new sensors of 8.0 is significantly better than the
carbazole-based d-PET fluorescent sensors.17ꢀ19 Enantio-
selective discrimination of D- and L-tartaric acid was
achieved with these sensors, and the recognition of the
analytes is dependent on the size of the binding poc-
ket of the boronic acid sensors. The sensors were also
used for the chemoselective discrimination of disaccha-
rides (sucrose, lactose, and maltose) and glycosylated
steroids (ginsenosides).
The drawbacks of the BINOL, anthracene, and carbazole
systems are that the fluorophore, the scaffold, and the
chirogenic centers are integrated (sensors 21ꢀ23). There-
fore, the selection of the fluorophore for chiral sensors is
limited. Also, the PET efficiency of the d-PET boronic acid
sensors using carbazole as the fluorophore is low; the
emission enhancement (or the contrast ratio) is about 2.0-
fold on switching the pH from acidic pH to neutral pH, while
the a-PET sensor 22 has a much larger contrast ratio of
around 10-fold.
2.5. Dye Displacement Assay. Boronic acids in combi-
nation with (1,2-diol containing) alizarin red-S (ARS) have
been used in competitive binding assays. Of particular
note is the anion mediated enhancement of alizarin red
binding to boronic acids used to determine the presence
and amount of analyte anions in a given system.24 For ex-
ample, when a boronic acid and a zinc complex are com-
bined in one molecule to create a pyrophosphate sensor
that binds the fluorescent molecule ARS in the absence
of phosphate (and displays reduced fluorescence as a
result). Upon exposure to PPi, ARS becomes part of a now
highly fluorogenic unit, and the fluorescence increases
(Scheme 7).24
Therefore, sensors 27 and 28 were devised, in which the
fluorophore (phenothiazine) and the chirogenic centers (R- or
S-R-benzylamine) are joined to a scaffold of 2-iodo-1,4-
benzenedicarboxaldehyde.21 The rigid linker between the
fluorophore and the boronic acid binding sites ensures that
unwanted interactions between the binding sites and the
Hydrogel spheres, 5 mm in diameter, incorporating phe-
nylboronic acid functionality were exposed to ARS dye, and
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Reversible Covalent Bonding of Boronic Acids Bull et al.
FIGURE 1. Gel slabs: Borogel (left), blank gel plus alizarin red-S (middle), and borogel plus alizarin red-S (right).
the corresponding boronic ester was formed. Once excess
dye had been removed by washing, the spheres were expo-
sed to an analyte diol (fructose, for example), releasing
the dye into solution (as represented in Scheme 8). To
demonstrate the hydrogel displacement assay, the relative
amounts of boron binding species (saccharides) in samples of
fruit juices were determined.25
phenyl alkyl pyridinium boronic acid showed characteristic
cationꢀπ stacking exciplex fluorescence.31 Of the anions
investigated, the most intense fluorescence response came
from the boronic acid ion pair with the most diffuse negative
charge (e.g., boronic acid, Scheme 9, Xꢀ = PF6). The relative
ꢀ
fluorescence intensity (PF6 > Brꢀ > Clꢀ > Fꢀ) may be inter-
preted as the tighter the ion pair the weaker the fluorescence,
so for a “turn on” sensor it is better to start with a low
fluorescence (tight pair) situation that has the potential to
undergo fluorescence enhancement upon interaction with a
diol analyte.
A hypsochromic shift is indicative of ARS binding to
boron; ARS develops an orange color on binding to boron.
Comparing 10 ꢁ 10 ꢁ 1.5 mm3 gel slabs with and without
boron, Figure 1 right and center, respectively (a boron
containing gel prior to exposure to ARS is shown for com-
parison, left), it is possible to observe the color difference.
The dye displacement assay has also been used to
evaluate biocompatible polymers as potential drug delivery
conjugates.26 Boronic acid terminated PLA (BA-PLA) was
prepared and the reversible formation of a well-defined
fluorescent ARS-PLA conjugate was used to follow the
binding of a range of hydroxyl-containing species to the
BA-PLA polymer. Displacement of the ARS and selectivity
for diols over simple alcohols was observed. The potential
for formation of strong complexes between BA-PLA and
hydroxyl-containing therapeutic agents suggests a versa-
tile and highly specific route to quantitative polymerꢀdrug
conjugates and nanoconjugates, which have become a key
target as drug delivery vehicles.
Indeed, for the sensing regime depicted in Scheme 9
when X = PF6, no fluorescence change was observed;
essentially, the starting position was already at maximum
fluorescence. The best “fluorescence on” response for pina-
col was observed when chloride was used as the counter-
anion (X = Cl).
2.7. Electrochemical Methods. Boronic acid functionality
has been employed in electrochemical sensing systems
predominantly based on direct effects of analyte binding
on current and/or potential responses in voltammetric ex-
periments. In a recent review, the role of phenylboronic
acids, in particular, for electrochemical sugar sensing, was
highlighted.32 Broadly, electrochemical assays employing
boronic acids can be divided into solution phase processes and
surface immobilized processes.
2.6. Cationꢀπ Interactions. Recently, it has been demon-
strated that pyridium cationꢀπ interactions can be evalu-
ated using fluorescence spectroscopy.27ꢀ29 Since pyridinium
boronic acids have already been used to prepare a saccharide
sensor,30 the next logical step was to combine cationꢀπ
interactions and pyridinum boronic acids into one construct
for diol detection. A simple propylene (Leonard Linker) linked
2.7.1. Solution Processes. Most widely studied are solu-
ble ferrocenylboronic acid redox probes which were first
synthesized by Nesmayanov and have been shown to allow
direct electrochemical saccharide sensing in aqueous media.
A typical differential pulse voltammetry solution essay for
sorbitol binding is shown in Figure 2. Ferrocenylboronic
acids suitable for sensing glucose have been prepared, and
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Reversible Covalent Bonding of Boronic Acids Bull et al.
SCHEME 7. Pyrophosphate-Induced Reorganization of a Reporterꢀ
SCHEME 8. Binding and Analyte-Mediated Release of Alizarin Red-S
with Hydrogel-Bound Boronic Acid (Reproduced with permission from
ref 25. Copyright 2009 The Royal Society of Chemistry)
Receptor Assembly
SCHEME 9. Phenyl Propylpyridium Boronic Acid Receptor for Diols
chiral ferrocenylboronic acids have been reported for chiral
electroanalysis.33
2.7.2. Surface Immobilized Processes. Due to electro-
chemical processes fundamentally being heterogeneous in
nature, much more sensitive and probably more selective
sensing processes can occur directly at the electrode/solu-
tion interface. Amphiphilic N-hexadecyl-pyridinium-4-boro-
nic acid cations have been self-assembled into a monolayer
at graphite electrodes.34 Figure 3 shows the effect of binding
ortho-quinols to the modified graphite surface. The area
under process P2 is consistent with the amount of immo-
bilized boronic acid, and typical binding constants for a
range of ortho-quinols suggest selectivity for the hydro-
phobic alizarin red-S. The self-assembly of boronic acid
dendrimers with nanocellulose whiskers has also been
investigated.35
Finally, in recent studies on biphasic redox systems, micro-
droplet deposits of water-insoluble organic liquids at electrode
surfaces have been employed with dissolved boronic acids. In
this liquidꢀliquid system, highly hydrophobic naphtalenyl and
anthracenyl derivatives of boronic acids are dissolved in micro-
droplets of 4-(3-phenylpropyl)-pyridine solvent (see Figure 4).
An additional redox system such as tetraphenylpor-
phyrinatomanganese(II/III) then allows anions to be ac-
tively transferred from aqueous to organic phase with
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Reversible Covalent Bonding of Boronic Acids Bull et al.
selectivity for anions with affinity for boronic acids. The
transfer of carbonate and bicarbonate36 as well as the
transfer of R-hydroxycarboxylates have been repor-
ted.30 Here, the selectivity of the boronic acid is com-
bined with the selectivity effect introduced by the Gibbs
energy of anion transfer from the aqueous into the
organic phase. In future, these biphasic redox systems
with boronic acids could potentially be incorporated into
hydrophobic membranes for analytical and also for se-
paration purposes.
2.8. Fluorophore Quencher Interactions. A new signal-
ing regime was conceived whereby a fluorescent boronic
acid, that when exposed to an analyte diol, appended with a
quencher, would reduce the fluorescence output of the
system due to the formation of a static fluorphoreꢀquencher
pair. Thus, signaling the presence of the diol appended
quencher (Figure 5).
A fluorescein boronic acid derivative was simply pre-
pared from commercially available materials in order to
function as the fluorescent partner, and a series of methyl
red inspired diols were synthesized as potential boronate
FIGURE 2. Binding of a diol to ferrocene boronic acid and differential
pulse voltammetry data set for sorbitol binding associated with a shift in
reversible potential.
FIGURE 3. Voltammetric responses (scan rate 0.1 V sꢀ1) for the oxidation of dopamine at a 4.9 mm diameter graphite electrode with a 1 nmol N-
hexadecyl-pyridinium-4-boronic acid hexafluorophosphate deposit immersed in aqueous 0.1 M phosphate buffer containing (i) 1 ꢁ 10ꢀ5, (ii) 2 ꢁ
10ꢀ5, (iii) 5 ꢁ 10ꢀ5, (iv) 1 ꢁ 10ꢀ4, (v) 2 ꢁ 10ꢀ4, (vi) 5 ꢁ 10ꢀ4, and (vii) 1 ꢁ 10ꢀ3 mol dmꢀ3 dopamine. The schematic drawing shows the binding of
alizarin red-S, and the table summarizes binding constants.
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FIGURE 4. (A) Schematic drawing of the electrochemically driven
anion transfer at an oil microdroplet/aqueous electrolyte interface.
(B) Schematic drawing of the process with boronic acid B present
(see equation). (C) Typical cyclic voltammograms (scan rate 10 mV
sꢀ1) for the oxidation and re-reduction of 75 mM MnTPP dissolved in
4-(3-phenylpropyl)-pyridine (75 nL) and immobilized onto a 4.9 mm
diameter graphite electrode immersed in aqueous 0.1 M sodium
lactate pH 7.34. The presence of (i) 0 mM, (ii) 114 mM, and (iii) 973 mM
naphtalene-2-boronic acid is shown to cause a shift in the voltam-
metric response.
FIGURE 6. Fluorescein boronic acid derivative, three diol-appended
quenchers, and a representation of the FRET quenching interaction.
In order to assemble a sensor construct at a goldꢀ
strepatividin surface, the molecule FLAB (Fluorophore Linker
boronic Acid Biotin) was prepared. The design incorporated
a terminal biotin for attachment to surface bound streptavi-
din, a boronic acid receptor and a fluorophore (Alexa Fluor
647, Invitrogen, exmax 647 nm). The quencherꢀdiol con-
jugate was prepared utilizing a quencher for Alexa Fluor 647,
BHQ-3 (Biosearch Tech).38 Attachment of FLAB to a strepta-
vidin-appended gold surface was confirmed by both SPR
and concomitant fluorescence (f-SPR). Exposure of the
surface prepared to BHQ-diol gave rise to both fluores-
cence quenching and an SPR response, demonstrating the
potential for the dual techniques of SPR and fluorecence to
work in unison in a sensor regime under the guise of f-SPR.
FIGURE 5. Fluorophore appended boronic acid interacting with a diol-
appended quencher.
ester forming quencher partners to probe a FRET quenching/
sensing regime based on boronate ester formation (see
Figure 6).37
A detailed study of the combination of fluorescein boro-
nic acid with diol appended quenchers 29aꢀc and compar-
ison with the fluorescence outputs of nonboron or nondiol
containing systems (i.e., fluorescein or methyl red were
employed directly) revealed boronate ester formation does
indeed result in a quenching enhancement in each case, and
that compound 29c was the best overall quencher based on
the ratiomentric quenching enhancement between the non-
binding dynamic systems versus the boronate forming static
systems.37 Utilizing a boronic acid receptor to catch quench-
er analytes is a generic sensing format, schematically illu-
strated in Figure 7.
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Reversible Covalent Bonding of Boronic Acids Bull et al.
the separation of carbohydrates called FACE (Fluorophore
Assisted Carbohydrate Electrophoresis). However, the
FACE technique requires the labeling of analytes with a
fluorophore, does not separate saccharides of similar size
and charge particularly well, and is limited to reducing
sugars.
In order to address the need to provide a separation tool
for similar mass saccharides, Boron Affinity Saccharide Elec-
trophoresis (BASE) was developed.40 Hydrogels could be
prepared that contained ortho, meta, and para boronic acids
although solubility allowed up to about 3% reliable incor-
poration, but this was more than enough to obtain excellent
results in electrophoresis. For the majority of investigations,
the meta derivative was preferred due to its overall higher
synthetic yield. In comparison to the para derivative, no
differences were observed in terms of electrophoresis appli-
cations; however, the ortho derivative gave less effective
separation (analyte mobility was more facile) and was prone
to degradation.
FIGURE 7. Surface appended FLAB (Fluorophore Linker boronic Acid
Biotin) for use in a fluorescence surface plasmon resonance (f-SPR).
While FACE performs poorly in separating a series of
2-AMAC labeled saccharides, the BASE system induces
dramatic mobility differences among the saccharides in-
vestigated. In the BASE gel, previously inseparable sac-
charides are now clearly resolved, even though in some
cases resolution is not perfect the modulated mobility
achieved as a function of reversible boron diol interac-
tions within a hydrogel domain opened the door to a
range of new applications, not only in electrophoresis,41
but also for applications such as hydrogel sensors men-
tioned earlier.25
BASE was next employed in the detection of a gluco-
nolactone modification of a protein that had been shown
by van den Elsen to inhibit the innate immune system
and is under development as a therapy for comple-
ment mediated acute inflammatory diseases. Purified
protein was exposed to gluconolactone, and its electro-
phoretic analysis was performed at various time intervals
by standard polyacrylamide gel electrophoresis (PAGE)
and protein BASE (coined Pro-BASE or mP-AGE); see
Figure 9. For protein incubation with gluconolactone,
Pro-BASE reveals a new band which was almost indis-
tinguishable from the main band by a normal electro-
phoresis experiment.
FIGURE 8. Upper: Schematic of SuperAvidin microsphere functionali-
zation with fluorescein-FLAB. Lower: Overlaid fluorescence and bright
field images of FLAB functionalized microspheres.
Taking advantage of biotin appended sensors in other
scenarios directly led to another model system, using micro-
scale avidin appended polystyrene microspheres (Bang
Laboratories) (Figure 8). These microspheres could be func-
tionalized with FLAB fluorescein, as demonstrated by fluo-
rescence microscopy.39
3. Electrophoresis
4. Boronic Acids as Building Blocks for Self
Assembly
Polyacrylamide gel electrophoresis exploits hydrogel poly-
mers to separate molecules on a size and charge basis.
Among the useful separations of biomolecules that elec-
trophoresis is commonly employed for is a technique for
Despite the stability of boronate ester covalent BꢀO bonds,
their formation is reversible under certain conditions or
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under the action of certain external chemical stimuli. The
reversible nature of boronate formation enables reversible
molecular assembly. The reaction of 2-formyl-aryl-boronic
acids with 1,2-amino alcohols results in dynamic covalent
self-assembly to quantitatively afford macrocyclic Schiff
base boracycles containing bridging boronꢀoxygenꢀboron
functionality (Scheme 10).42
either chiral amines or chiral diols by NMR spectroscopy,
electrochemical, and circular dichroism (CD) methods
(Scheme 11).33,43ꢀ45
Boronate esterification can also be utilized in the con-
struction of capsule structures which display three-dimen-
sional cavities, such as the recently reported ion-pair-driven
heterodimeric capsule formation.46,47 The system consists
of cyclotricatechylene and a boronic-acid-appended hexa-
homotrioxacalix[3]arene. The two components do not inter-
act with each other until Et4NOAc is added to the solution.
On addition of Et4NOAc, quantitative capsule formation by
boronate esterification is observed. The self-assembly pro-
cess is a direct result of anion directed boronate ester
formation and the presence of the Et4Nþ template. A similar
capsule was also formed when Et3N was added to a
methanolic solution containing cyclotricatechylene and
the boronic acid-appended hexahomotrioxacalix[3]arene.
The reaction involves the initial formation of a capsule
consisting of cyclotricatechylene, the boronic acid and
three amines; subsequent solvolysis results in encapsula-
tion of Et3NHþ within the capsule. When the larger Bu3N
was used to trigger capsule formation, solvolysis in the
presence of guests such as Et4Nþ, Me4Nþ, Me4Pþ, and Csþ
results in encapsulation of these guests rather than the
bulky Bu3NHþ (Scheme 12).
A similar self-assembly protocol with chiral consti-
tuents provided a robust probe for enantiomeric excess of
FIGURE 9. Separation by protein-Boron Assisted Saccharide Electro-
phoresis (pro-BASE or mP-AGE) of a glyconoylated protein utilizing
stationary phases that do not (left) and do (right) contain boronic acid.
SCHEME 10. Synthesis of Macrocyclic Schiff Base Boracycles Containing Bridging BoronꢀOxygenꢀBoron Bond from [2 þ 2]-type Condensation of
2-Formyl-aryl-boronic Acids and 1,2-Amino Alcohols
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Reversible Covalent Bonding of Boronic Acids Bull et al.
SCHEME 11. Three Component Reaction for Boron Mediated Enantiomeric Excess Determination
SCHEME 12. Amine-Triggered Molecular Capsules via Dynamic Boronate Esterification
5. Conclusions
supported by many funding sources, but the EPSRC, The Royal
Society (including International Joint Projects with Y.K., K.S., and
J.Z.), The Leverhulme Trust, The Japan Society for the Promotion of
Science (JSPS), the GB Sasakawa Foundation, the Daiwa Founda-
tion, the University of Birmingham and the University of Bath are all
thanked for providing funding and support. The core of the research
presented has been enhanced by collaboration both within the
University of Bath, the U.K., and Internationally. S.D.B., J.S.F., Y.-B.J.,
J.Z., and T.D.J. would also like to thank The Catalysis and Sensing for
our Environment (CASE) network for networking opportunities.
This is a personal perspective on the use of boronic acid
based receptors and focuses on papers and reviews pub-
lished over the last 5 years. While assembling this Account, it
was pleasing to note that while some areas of research have
faded, many new and exciting areas have developed. More
importantly, from a personal perspective, the science of
boronic acid receptors is as exciting now as it has ever been.
It is hoped that this Account will inspire others to explore some
of the yet uncharted regions of reversible covalent chemistry of
boronic acids to even more exciting discoveries.
BIOGRAPHICAL INFORMATION
While this is a personal account of research into Boronic Based
Receptors, the 10 coauthors have contributed to the construction
of this Account and the research that underpins it and are the
people without whose friendship and collaboration the research
concepts contained in this Account would not be possible. The
contribution of Postdoctoral Researchers, Ph.D. Students, and
Undergraduate Students is also acknowledged, since it was their
work that provides the results discussed in this Account (see
references). The research presented in this Account has been
Steven D. Bull is a Reader at the University of Bath. His research
interests include Asymmetric Synthesis, Combinatorial Chemistry,
and Biocatalysis.
Matthew G. Davidson is a Professor at the University of Bath.
His research interests include Structure and Bonding and Catalysts
for Organic Transformations.
Jean M. H. van den Elsen is a Reader in Molecular Structure
and Function in the Department of Biology and Biochemistry at the
University of Bath. His research interests include carbohydrate
modifications in proteins and the development of proteomics tools.
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Reversible Covalent Bonding of Boronic Acids Bull et al.
John S. Fossey is a lecturer and Royal Society Industry Fellow at
the University of Birmingham and is working on projects that
exploit molecular recognition in catalysis and sensing.
9
Galbraith, E.; Fyles, T. M.; Marken, F.; Davidson, M. G.; James, T. D. Fluorescent boron
bis(phenolate) with association response to chloride and dissociation response to fluoride.
Inorg. Chem. 2008, 47, 6236–6244.
10 Xu, Z. C.; Kim, S. K.; Han, S. J.; Lee, C.; Kociok-Kohn, G. I.; James, T. D.; Yoon, J.
Ratiometric Fluorescence Sensing of Fluoride Ions by an Assymetric Bidentate Receptor
Containing a Boronic Acid and Imidazolium Group. Eur. J. Org. Chem. 2009, 18, 3058–3065.
11 Yoon, J.; Czarnik, A. W. Fluorescent chemosensors of carbohydratesꢀa means of
chemically communicating the binding of polyols in water based on chelation- enhanced
quenching. J. Am. Chem. Soc. 1992, 114, 5874–5875.
12 James, T. D.; Sandanayake, K. R. A. S.; Iguchi, R.; Shinkai, S. Novel saccharide-
photoinduced electron-transfer sensors basedon the interactionof boronicacid and amine.
J. Am. Chem. Soc. 1995, 117, 8982–8987.
A. Toby A. Jenkins is Reader in Biophysical Chemistry at the
University of Bath. His research interests include electrochemical
and optical sensing for clinical microbiology and studies of the
abioticꢀbiotic interface.
Yun-Bao Jiang is a Professor at the Department of Chemistry in
Xiamen University. His research focuses on photophysics of elec-
tron/proton transfer and supramolecular chemical sensing and
molecular recognition.
13 Phillips, M. D.; Fyles, T. M.; Barwell, N. P.; James, T. D. Carbohydrate sensing using a
fluorescent molecular tweezer. Chem. Commun. 2009, 6557–6559.
14 Scrafton, D. K.; Taylor, J. E.; Mahon, M. F.; Fossey, J. S.; James, T. D. 00Click-fluors00:
Modular fluorescent saccharide sensors based on a 1,2,3-triazole ring. J. Org. Chem.
2008, 73, 2871–2874.
Yuji Kubo is a Professor of Tokyo Metropolitan University. His
research interests focus on molecular systems based on self-
organization as well as materials for applications in organic
electronics.
15 Vendrell, M.; Zhai, D.; Er, J. C.; Chang, Y.-T. Combinatorial Strategies in Fluorescent Probe
Development. Chem. Rev. 2012, 112, 4391–4420.
16 Xing, Z. T.; Wang, H. C.; Cheng, Y. X.; James, T. D.; Zhu, C. J. A Ditopic Fluorescence
Sensor for Saccharides andMercury Basedon a Boronic-Acid Receptor and Desulfurisation
Reaction. Chem.;Asian. J. 2011, 6, 3054–3058.
17 Han, F.; Chi, L. N.; Liang, X. F.; Ji, S. M.; Liu, S. S.; Zhou, F. K.; Wu, Y. B.; Han, K. L.; Zhao,
J. Z.; James, T. D. 3,6-Disubstituted Carbazole-Based Bisboronic Acids with Unusual
Fluorescence Transduction as Enantioselective Fluorescent Chemosensors for Tartaric
Acid. J. Org. Chem. 2009, 74, 1333–1336.
18 Zhang, X.; Chi, L. N.; Ji, S. M.; Wu, Y. B.; Song, P.; Han, K. L.; Guo, H. M.; James,
T. D.; Zhao, J. Z. Rational Design of d-PeT Phenylethynylated-Carbazole Mono-
boronic Acid Fluorescent Sensors for the Selective Detection of alpha-Hydroxyl
Carboxylic Acids and Monosaccharides. J. Am. Chem. Soc. 2009, 131, 17452–17463.
19 Zhang, X.; Wu, Y. B.; Ji, S. M.; Guo, H. M.; Song, P.; Han, K. L.; Wu, W. T.; Wu, W. H.;
James, T. D.; Zhao, J. Z. Effect of the Electron Donor/Acceptor Orientation on the
Fluorescence Transduction Efficiency of the d-PET Effect of Carbazole-Based Fluorescent
Boronic Acid Sensors. J. Org. Chem. 2010, 75, 2578–2588.
20 Wu, Y. B.; Guo, H. M.; James, T. D.; Zhao, J. Z. Enantioselective Recognition of Mandelic
Acid by a 3,6-Dithiophen-2-yl-9H-carbazole-Based Chiral Fluorescent Bisboronic Acid
Sensor. J. Org. Chem. 2011, 76, 5685–5695.
21 Wu, Y. B.; Guo, H. M.; Zhang, X.; James, T. D.; Zhao, J. Z. Chiral Donor Photoinduced-
Electron-Transfer (d-PET) Boronic Acid Chemosensors for the Selective Recognition of
Tartaric Acids, Disaccharides, and Ginsenosides. Chem.;Eur. J. 2011, 17, 7632–7644.
22 Xing, Z.; Wang, H.-C.; Cheng, Y.; Zhu, C.; James, T. D.; Zhao, J. Selective Saccharide
Recognition Using Modular Diboronic Acid Fluorescent Sensors. Eur. J. Org. Chem. 2012,
2012, 1223–1229.
Frank Marken is a Professor at the Department of Chemistry,
University of Bath. Research interests are both fundamental and
applied, looking at mechanistic understanding of interfacial pro-
cesses and the development of novel electrochemical
technologies.
Kazuo Sakurai is a Professor at the Department of Chemistry
and Biochemistry in University of Kitakyushu. His research inter-
ests include the characterisation of Polysaccharide/DNA com-
plexes and their application to gene delivery.
Jianzhang Zhao is a Professor at the Department of Fine
Chemicals, School of Chemical Engineering in Dalian University
of Technology. His research interests include the preparation of
visible light-harvesting transition metal complexes that show long-
lived triplet excited states.
Tony D. James is a Professor at the University of Bath. His
research interests include Molecular Recognition, Molecular As-
semblies, and Sensor Design.
23 Chi, L.; Zhao, J. Z.; James, T. D. Chiral mono boronic acid as fluorescent
enantioselective sensor for mono alpha-hydroxyl carboxylic acids. J. Org. Chem.
2008, 73, 4684–4687.
FOOTNOTES
*To whom correspondence should be addressed.
The authors declare no competing financial interest.
This Account is dedicated to J. Grant Buchanan, a Great Scholar, Educator, and above all
Friend. Your endless enthusiasm and quest for knowledge will be sadly missed.
24 Nonaka, A.; Horie, S.; James, T. D.; Kubo, Y. Pyrophosphate-induced reorganization of a
reporter-receptor assembly via boronate esterification; a new strategy for the turn-on
fluorescent detection of multi-phosphates in aqueous solution. Org. Biomol. Chem. 2008,
6, 3621–3625.
25 Ma, W. M. J.; Pereira Morais, M. P.; D'Hooge, F.; van den Elsen, J. M. H.; Cox, J. P. L.;
James, T. D.; Fossey, J. S. Dye displacement assay for saccharide detection with boronate
hydrogels. Chem. Commun. 2009, 532–534.
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ꢀ
43 Kelly, A. M.; Perez-Fuertes, Y.; Fossey, J. S.; Yeste, S. L.; Bull, S. D.; James, T. D. Simple
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ꢀ
44 Perez-Fuertes, Y.; Kelly, A. M.; Fossey, J. S.; Powell, M. E.; Bull, S. D.; James, T. D. Simple
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