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,...