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Boron
Sensing, Synthesis and Supramolecular Self-Assembly
By Meng Li, John S. Fossey, Tony D. James The Royal Society of Chemistry
Copyright © 2016 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-674-9
CHAPTER 1
Supramolecular Chemistry of Boronic Acids
YASUMASA KANEKIYOA AND SEIJI SHINKAI
1.1 Boronic Acid-Based Organogels
1.1.1 Low Molecular Weight Gelators
Various organic solvents are gelatinized by low molecular weight gelators. These phenomena are interesting in that the fibrous aggregates formed by non-covalent interactions between gelators are responsible for the gelation. In particular, cholesterol-based gelators show excellent gelation ability towards various organic solvents at sufficiently low concentrations. The resulting gels display chirally oriented structures that are imparted from the cholesterol skeleton having chiral centers.
James et al. synthesized a new gelator by combining a boronic acid moiety with the cholesterol skeleton (cholesterylphenylboronic acid 1). It was found that saccharide complexes of 1 efficiently gelatinize several organic solvents. The gelation properties such as the sol–gel phase transition temperature, xerogel fiber structure, gel stability difference between the D-versus L-complexes, etc. are changeable by a slight difference in the saccharide structure (Figure 1.1).
Inoue et al. utilized the xerogel fibers prepared from 1 to host matrixes exhibiting binding ability towards saccharides. The process consists of three stages. In the initial stage, benzene is gelatinized by the 1 : 2 complex between xylose and 1, and then the gel is freeze-dried. In the next stage, the resulting xerogel is washed with aqueous acetic acid solution and a water/methanol mixture to remove xylose from the xerogel. In the final stage, the xylose-removed xerogel is dispersed in aqueous xylose solutions, and the amount of rebound xylose is determined after stirring for 40 h. Interestingly, the xerogel prepared with l-xylose as a template exhibits four-times higher re-binding ability for l-xylose than for D-xylose. This chiral discrimination ability indicates that the "memory" for the originally imprinted saccharide is retained in the xerogel.
Kimura et al. prepared another type of boronic acid-appended gelator 2 consisting of long alkyl chains and l-glutamate segment. Aqueous solutions containing 2 were gelatinized in the presence of various saccharides, and the aggregation structures of the gelator were observed by tem measurements. It was revealed that various types of higher-order structures are developed depending on the saccharide used.
A gel-based fluorocolorimetric sensor for polyols was reported by Ikeda et al. a boronic acid-appended receptor bearing 7-nitrobenzoxal[1,2,5]diazole (NBD) (3) is incorporated into self-assembled nanofibers consisting of gelator 4 and hydrophobic coumarin dye 5. In the absence of polyols, FRET (fluorescence resonance energy transfer) from the NBD moiety of 3 to the coumarin unit in 5 is observed. With increasing polyol concentration, the spectral change appeared due to cancellation of FRET. This is attributed to the migration of 3 from the hydrophobic nanofiber phase to the hydrophilic aqueous phase upon binding of polyols (scheme 1.1). The authors demonstrated that the gel-based sensor is capable of detecting polyols such as catechol, dopamine, and catechin under dry conditions by integrating the gel-based sensor into a filter paper.
Zhou et al. developed a new boronic acid-based gelator 6 that can gelate several organic solvents by self-assembling to form a nanofiber network. The driving force for the aggregation is attributed to the hydrogen bonding and the π–π stacking between the gelators. It was found that the addition of glucose induces a gel–sol transition, due to the formation of a gelator–glucose complex. This gel exhibits excellent sensitivity towards glucose among six saccharides (mannitol, galactose, lactose, maltose, sucrose, and fructose). The gelator is reusable by dissociating the complex with an acidic solution and then extracting with an organic solvent.
1.1.2 Polymeric Hydrogels
Stimuli-responsive polymer gels have attracted much attention due to their potential application for the design of self-regulated materials and systems. So far, many attempts have been made to design of glucose-regulated insulin delivery systems using stimuli-responsive hydrogels. Usually, two different types of approaches have been utilized for endowing hydrogels with glucose-responsiveness: (1) enzymatic reactions between glucose oxidase and glucose and (2) complementary binding of lectin (concanavalin a) to glucose. The boronic acid-based system is a third candidate.
Matsumoto et al. developed boronic acid-based hydrogels showing glucose responsiveness. They were synthesized by copolymerizing boronic acid monomer 7, N-isopropylmethacrylamide, and 2-carboxyisopropylacrylamide with a crosslinker (N,N'-methylene-bis-acrylamide). The hydrogels tend to shrink with increasing temperature due to the thermo-responsive nature of the main chain [poly (N-isopropylmethacrylamide)]. The gel prepared under the optimal monomer composition is shrunken in the absence of glucose, whereas the gel volume increases with increasing glucose concentration. The observed glucose responsiveness is derived from the formation of anionic boronate esters that make the polymer chain more hydrophilic. This totally-synthetic material is potentially applicable to insulin-delivery diabetes-devices that can tolerate long-term use and storage.
It is known that polycations and polyanions form charge-neutralized polyion complexes in aqueous solutions. By using polyion complex formation reactions, Kanekiyo et al. invented a novel molecular imprinting method for nucleotides as templates. Firstly, a polycation (8) was mixed with a boronic acid-containing polyanion (9) in the presence of AMP (adenosine monophos phate). Then, the obtained polyion complex containing AMP was washed with an acidic solution to remove the template AMP. Finally, the resultant "cleft" polyion complex was tested for the re-binding ability towards nucleotides. It was proven that the "cleft" polyion complex shows high affinity and selectivity towards AMP. This means that the memory for AMP is retained in the polyion complex matrix. Interestingly, the removal and re-binding processes for AMP coincide with the swelling and shrinking of the polyion complex (scheme 1.2): without AMP, it is swollen due to existence of excess cationic charges, which create electrostatic repulsion within the polyion complex matrix, whereas the re-binding of AMP neutralized the excess cationic charges resulting in the shrinkage of the polyion complex. This stimuliresponsive polyion complex was subsequently applied as a sensing element in a QCM (quartz crystal microbalance) system. For this purpose, the polyions were alternatingly adsorbed onto a QCM resonator surface in the presence of AMP (scheme 1.3). After removal of AMP from the surface polyion complex, a swollen gel layer with excess cationic charges resulted. It was confirmed that this QCM system selectively responds to AMP among various adenosine derivatives. The responsiveness is derived from the mass decrease induced by the shrinkage of the surface.
Kanekiyo et al. also developed nucleotide-responsive hydrogels by copolymerizing boronic acid monomer 10 and cation monomer 11 with a cross linker (N,N'-methylene-bis-acrylamide). The hydrogels efficiently bind nucleotides such as AMP and ATP (adenosine triphosphate) by a cooperative action of the boronate ester formation and the electrostatic interaction between the cationic units and the phosphate group. The binding process coincides with the swelling and shrinking behavior of these hydrogels. For the hydrogel with the specific monomer composition, a unique "charge inversion" is observable: with increasing nucleotide concentrations, the cation-rich hydrogel is gradually shrunken due to charge neutralization, then it is swelled again because of the introduction of excess anionic charges (scheme 1.4). These nucleotide-induced swelling and shrinking phenomena are applicable to nucleotide sensors by reproducing the gels on the surface of a QCM resonator.
1.2 Boronic Acid-Appended Porphyrins
1.2.1 Monomeric Porphyrins
Porphyrin is a useful scaffold for developing molecular recognition elements, since it shows highly sensitive UV-vis absorption and fluorescence emission. By combining porphyrin and boronic acid, one can construct supramolecular systems that exhibit unique guest-induced spectroscopic changes.
Imada et al. synthesized a porphyrin derivative bearing four boronic acid moieties (12). It was confirmed that 12 forms a one-dimensionally stacked aggregate in water/DMSO mixture at pH 6.9. After adding saccharides to the solution, CD (circular dichroism) spectra were measured. In the presence of saccharides (except fructose), the solutions of 12 become CD-active and the sign of the exciton-coupling band (ECB) changes depending on the added saccharides. These results demonstrate that the absolute configuration of saccharides is predictable by CD measurements. Subsequently, a further sophisticated procedure was reported by takeuchi et al. a porphyrin derivative bearing only one boronic acid moiety (13) was synthesized, and 1 : 2 sugar–boronic acid complexes were prepared. Then, the photochemical properties of the 1 : 2 complexes were studied by UV, fluorescence, and CD spectroscopy. It was confirmed that the extinction coefficients and fluorescence intensities are linearly correlated with the theoretically calculated dihedral angles between the two porphyrin moieties in the 1 : 2 complexes. In addition, the CD signs are explained by the absolute configurations of saccharides. These results establish that the dihedral angle between the two porphyrins plays a decisive role in electronic properties of the 1 : 2 complexes, and the saccharide structure can be conveniently determined by CD measurements.
The sugar sensing utilizing aggregation properties of boronic acid-appended porphyrin 14 were investigated by Murakami et al. in the absence of saccharides, 14 forms aggregates that are non-fluorescent. The aggregates are dissociated by the addition of saccharides, resulting in strong fluorescence. Among four monosaccharides tested, the spectral change occurs in the order D-fructose > D-arabinose > D-mannose > D-glucose. Sugar-controlled aggregate formation of 15 was studied by arimori et al. it was demonstrated that the morphology of oriented aggregates in aqueous media can be controlled by adding saccharides. Well-developed fibrous aggregates were obtained in the presence of D-fructose and D-glucose, whereas less-developed coagulated fibrous aggregates were obtained in the presence of D-ribose and D-fucose.
Arimori et al. succeeded in controlling photo-induced electron transfer process of porphyrins by saccharides. For this purpose, positively-charged porphyrins bearing boronic acids (16) were synthesized. When anionic fluorophores such as naphthalenedisulfonate and anthraquinonedisulfonate are mixed with 16 in aqueous solutions, fluorescence emission from these fluorophores is largely quenched. This change is attributed to the formation of electrostatically associated complexes between cationic 16 and the anionic fluorophores in which photo-induced electron transfer between the two components can efficiently take place. Addition of fructose dissociates the complexes because the positive charges on 16 are neutralized by the anionic charges on the boronate groups. As a result, the fluorescence intensity increases with fructose concentration since the quenching efficiency is sufficiently lowered by the dissociation of the complexes. An interaction between 16 and DNA was investigated by suenaga et al. at pH 8.01, 16 is strongly bound to DNA. Comparison of the absorption spectra and the CD spectra established that poly (dGdC)·poly(dGdC) double strand intercalates 16, whereas poly(dAdt)·poly (dAdt) double strand binds 16 to the outside of the main chain. When D-fructose is added, 16 is dissociated from DNA through complexation with D-fructose. These results show that one can conveniently control the association–dissociation equilibrium between 16 and DNA by saccharides.
The cooperative action of two boronic acids is indispensable to the selective binding of saccharides in aqueous solution. However, it is not so easy to synthesize porphyrin derivatives bearing two appropriately arranged boronic acid groups within a molecule. To overcome this difficulty, takeuchi et al. designed a boronic acid-based porphyrin receptor utilizing the metal coordination property in a metalloporphyrin with an axial ligand. For example, A boronic acid-appended Zn(ii) porphyrin (17) was synthesized and mixed with 3-pyridyl boronic acid to create a self-organized diboronic acid system. When saccharides are added to this system, characteristic CD patterns inherent to the absolute configurations of saccharides are observed. Imada et al. utilized 17 for selective binding of glucose-6-phosphate and 3,4-dihydroxyphenylalanine (DOPA). It was shown that 17 can bind these guest molecules in a two-point interaction manner: one between the diol and the boronic acid and the other between the phosphate or amino group and Zn(ii) in the metalloporphyrin moiety.
Hirata et al. designed porphyrin derivatives bearing a pair of boronic acid groups (18, 18-Zn, and 18-Cu). These compounds have a diethynyl porphyrin axis, which act as a saccharide-binding modulator. Saccharide binding studies were conducted in water–methanol (1 : 1, v/v) mixed solvent by UV-vis, fluorescence, and CD spectroscopies. It was found that 18-Zn can bind mono- and oligo-saccharides to produce 1 : 1 host–saccharide complexes with association constants (log K) of 2–3. The CD spectra indicate that the two boronic acid groups of 18-Zn are cooperatively used to bind one saccharide. The porphyrin unit efficiently works as a read-out functional moiety for the saccharide-binding information to give sharp spectral changes (Figure 1.2). The binding signal can be finely turned by metalation of the porphyrin unit. Following this study, hirata et al. designed porphyrin derivatives bearing two pairs of boronic acid groups 19 to construct an allosteric saccharide-sensing system. the conditions utilized for saccharide-binding studies are identical to those used for 18. The stepwise binding constants (log K1 and log K2) were, respectively, evaluated to be 3.58 and 3.48 for L-fucose and 3.95 and 3.69 for D-xylose. These K2 values are significantly larger than those that are statistically expected (K1 = 4K2). Therefore, the obtained data imply that once a pair of boronic acids in 19 binds the first guest saccharide, another pair of boronic acids enhances its affinity toward the second guest saccharide. Binding of the first guest saccharide is entropically disfavored since the host molecule has to lose its rotational freedom, whereas the second guest binding is entropically favored due to preorganization and alignment of the second binding site (Scheme 1.5). Thus, 19 can behave as a saccharide receptor exhibiting a positive allosteric effect.
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Excerpted from Boron by Meng Li, John S. Fossey, Tony D. James. Copyright © 2016 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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