Introduction
Phenylboronic acid or benzeneboronic acid, abbreviated as PhB(OH)2 where Ph is the phenyl group C6H5- and B(OH)2 is a boronic acid containing a phenyl substituent and two hydroxyl groups attached to boron. Phenylboronic acid is a white powder and is commonly used in organic synthesis. Boronic acids are mild Lewis acids which are generally stable and easy to handle, making them important to organic synthesis.
1. Properties
Phenylboronic acid is soluble in most polar organic solvents and is poorly soluble in hexanes and carbon tetrachloride. This planar compound has idealized C2V molecular symmetry. The boron atom is sp2-hybridized and contains an empty p-orbital. The orthorhombic crystals use hydrogen bonding to form units made up of two molecules.[3] These dimeric units are combined to give an extended hydrogen-bonded network. The molecule is planar with a minor bend around the C-B bond of 6.6° and 21.4° for the two PhB(OH)2 molecules.[4]
2. Synthesis
Numerous methods exist to synthesize phenylboronic acid. One of the most common synthesis uses phenylmagnesium bromide and trimethyl borate to form the ester PhB(OMe)2, which is then hydrolyzed to the product.[5]
PhMgBr + B(OMe)3 → PhB(OMe)2 + MeOMgBr
PhB(OMe)2 + H2O → PhB(OH)2 + MeOH
Other routes to phenylboronic acid involve electrophilic borates to trap phenylmetal intermediates from phenyl halides or from directed ortho-metalation.[4] Phenylsilanes and phenylstannanes transmetalate with BBr3, followed by hydrolysis form phenylboronic acid. Aryl halides or triflates can be coupled with diboronyl reagents using transition metal catalysts. Aromatic C-H functionalization can also be done using transition metal catalysts.
3. Reactions
The dehydration of boronic acids gives boroxines, the trimeric anhydrides of phenylboronic acid. The dehydration reaction is driven thermally, sometimes with a dehydration agent.[6]
Phenylboronic acid participates in numerous cross coupling reactions where it serves as a source of a phenyl group. One example is the Suzuki reaction where, in the presence of a Pd(0) catalyst and base, phenylboronic acid and vinyl halides are coupled to produce phenyl alkenes.[7]
This method was generalized to a route producing biaryls by coupling phenylboronic acid with aryl halides.
C-C bond forming processes commonly use phenylboronic acid as a reagent. Alpha-amino acids can be generated using the uncatalyzed reaction between alpha-ketoacids, amines, and phenylboronic acid.[8] Heck-type cross coupling of phenylboronic acid and alkenes and alkynes has been demonstrated.[9]
Aryl azides and nitroaromatics can also be generated from phenylboronic acid.[4] Phenylboronic acid can also be regioselectively halodeboronated using aqueous bromine, chlorine, or iodine:[10]
PhB(OH)2 + Br2 + H2O → PhBr + B(OH)3 + HBr
Boronic esters result from the condensation of boronic acids with alcohols. This transformation is simply the replacement of the hydroxyl group by alkoxy or aryloxy groups.[4] This reversible reaction is commonly driven to product by the use of Dean-Stark apparatus or a dehydration agent to remove water.
PhB(OH)2 + 2 ROH ⇌ PhB(OR)2 + 2 H2O
As an extension of this reactivity, PhB(OH)2 can be used as a protecting group for diols and diamines.
This reactivity is the basis of the use of phenylboronic acid’s use as a receptor and sensor for carbohydrates, antimicrobial agents, and enzyme inhibitors, neutron capture therapy for cancer, transmembrane transport, and bioconjugation and labeling of proteins and cell surface.[4]
1. Phenylboronic Acid-polymers for Biomedical Applications
Abstract
Background: Phenylboronic acid-polymers (PBA-polymers) have attracted tremendous attention as potential stimuli-responsive materials with applications in drug-delivery depots, scaffolds for tissue engineering, HIV barriers, and biomolecule-detecting/sensing platforms. The unique aspect of PBA-polymers is their interactions with diols, which result in reversible, covalent bond formation. This very nature of reversible bonding between boronic acids and diols has been fundamental to their applications in the biomedical area.
Methods: We have searched peer-reviewed articles including reviews from Scopus, PubMed, and Google Scholar with a focus on the 1) chemistry of PBA, 2) synthesis of PBA-polymers, and 3) their biomedical applications.
Results: We have summarized approximately 179 papers in this review. Most of the applications described in this review are focused on the unique ability of PBA molecules to interact with diol molecules and the dynamic nature of the resulting boronate esters. The strong sensitivity of boronate ester groups towards the surrounding pH also makes these molecules stimuli-responsive. In addition, we also discuss how the re-arrangement of the dynamic boronate ester bonds renders PBA-based materials with other unique features such as self-healing and shear thinning.
Conclusion: The presence of PBA in the polymer chain can render it with diverse functions/ relativities without changing their intrinsic properties. In this review, we discuss the development of PBA polymers with diverse functions and their biomedical applications with a specific focus on the dynamic nature of boronate ester groups.
2. Exploring biomedical applications of phenylboronic acid—functionalized chitosan conjugates
Abstract
Chitosan (CS), a cationic polysaccharide has received increasing attention ever since its entry into the pharmaceutical domain due to excellent biocompatibility, biodegradability, and high chemical reactivity. Evidence from the literature reveals that chemical modification on the primary amine group or the hydroxyl group of CS can augment its application to achieve a specific biomedical application.
Phenylboronic acid (PBA) and its moieties are known to form covalent bonds with polyol compounds and have thus allured researchers owing to their enormous potential. The conjugation of these two moieties has shown to exhibit a plethora of properties that can be exploited for a variety of applications. In this review, an effort is made to compile different PBA derivatives conjugated to CS and showcase their potential. An important application of these conjugates is their ability to function as glucose sensitive polymer which enables self regulated insulin release in the treatment of diabetes besides functioning as a diagnostic agent. Also, the noteworthy use of these conjugates has been in wound healing and tumor targeting. This review gives an overview of research undertaken with CS-PBA highlighting their applications to make the reader aware of their enormous potential.
Introduction
been extensively explored for diverse pharmaceutical and biomedical application. CS is derived from chitin poly (N-acetyl glucosamine), which is isolated from the shells of the crustaceans, via alkaline deacetylation. CS contains glucosamine and N-acetyl glucosamine units connected together by (1–4) glycosidic links [1]. The structure of CS offers multiple options for chemical modification which can result in a wide range of derivatives possessing unique properties.
There are three reactive sites on the CS chain enabling chemical modification: one primary amine and two hydroxyl groups (primary or secondary) (Fig. 1). The primary amine groups present special properties that render CS suitable for pharmaceutical applications. The cationic character of CS contributes to the permeation enhancing, in situ gelling, mucoadhesive, antibacterial, and efflux pump inhibitory functions [1,2]. CS has also demonstrated potential for nucleic acid delivery, tissue engineering, wound healing, and cancer diagnosis.
In addition, the property of chitosan nanoparticles (CS NPs) to widen cellular junctions and surface modification has also been well documented. Due to these aforementioned properties, CS is of great interest to researchers in the pharmaceutical and biomedical fields [3,4]. Nevertheless, chemical modification of CS has been prepared and assessed for their different applications. CS conjugates have been developed and proven to be effective.
Recently, CS-phenyl boronic acid conjugates have been explored for their various functions. Boronic acid compounds have a variety of biomedical applications. The majority of the polymeric boronic acids reported in the literature have phenyl boronic acid moieties. Most phenyl boronic acids have pKa values higher than physiological pH. The addition of different substituents on the phenyl ring permits the pKa to be attuned favoring the use of boronic acid-holding polymers at a physiologically appropriate pH range [5].
Methodology
The literature search was done using the scientific databases Scopus, PubMed, and Science direct. The document search tool was employed using the combination of keywords “CS “and PBA. The inclusion criteria were to consider all research articles published from 2000 to 2022. The exclusion criteria was to exclude those articles that did not have biomedical application. The major focus was on the articles which had applications for drug delivery.
Results And Discussion
The database search using the combination of keywords “CS “and PBA resulted in 74 documents. The articles were screened and sectioned under the following sections pertaining to the type of PBA moiety involved in the conjugation with CS. This review discusses CPBA conjugated CS, formyl PBA conjugated CS, fluoro PBA conjugated CS, aminophenylboronic acid conjugated CS, and acrylamidophenylboronic acid (APBA)-conjugated CS.
PATENTS
Glucose-sensitive nanoparticle for cancer diagnosis and therapy. Application KR1020140078399A. This patent relates to a glucose-sensitive nanoparticle that comprises a PBA derivative and a biocompatible polymer and is formed via amphiphilic conjugation of the PBA derivative and the biocompatible polymer which are chemically bonded with each other.
Conclusion
The conjugation of CS with PBA has been shown to exhibit a plethora of properties that can be exploited for a variety of applications. In this review, an effort was made to compile different PBA derivatives conjugated to CS and showcase their potential.
Phenyl boronic acid-conjugated CS were formulated as nanoparticles, micelles, and hydrogel functioning as drug carriers for diverse therapeutic applications. Many studies have reported enhanced tumor targeting with phenylboronic acid-conjugated CS. Another important application of these conjugates is their ability to function as glucose sensitive polymer which enables self-regulated insulin release in the treatment of diabetes besides functioning as a diagnostic agent.
Though considerable research has been done with CSPBA conjugates demonstrating potential in various biomedical applications, there aren’t clinical studies reported to facilitate transition into clinics. We hope that this review will provide insight into the novel applications of CS-PBA conjugates to researchers to further explore their potential.
3. Phenylboronic Acid (Pba) Solid Phase Extraction Mechanisms And Applications
1. Introduction
Bond Elut PBA is a unique silica SPE sorbent containing a phenylboronic acid functionality that can retain analytes via a reversible covalent bond. This very strong covalent retention mechanism enables high specificity and cleanliness. The boronate group has a strong affinity for cis-diol containing compounds such as catechols, nucleic acids, some proteins, carbohydrates and PEG compounds. Aminoalcohols, alpha-hydroxy amides, keto compounds, and others can also be retained.
2. PBA SPE Mechanism
Most solid phase extraction methodologies are based on nonpolar, polar or ionic interactions. Phenylboronic acid (PBA) solid phase extraction media is unique in that it employs a reversible covalent interaction between the PBA and sample molecule(s). Covalent chromatography involves an interaction of considerably greater energy than other extraction mechanisms (Figure 1). This strong interaction allows for the development of extraction methods of much greater specificity. The mechanism of boronate binding is illustrated in Figure 2.
The immobilized phenylboronic acid is first equilibrated with an alkaline solution to obtain the reactive boronate form RB(OH)3 -. The diol-containing compound is next applied and is covalently bound with the concomitant release of water. Once the compound of interest is retained, contaminants may be selectively washed from the bonded phase provided that an alkaline pH is maintained. Finally, the compound of interest is eluted by acidification of the boronate complex, which releases the diol-containing compound and renders the immobilized phenylboronic acid neutral (RB(OH)2 ).
3. Applicable Analytes
A variety of diol-containing and other compounds are retained by immobilized phenylboronic acid, including vicinal diols, 1,3-diols and 1,3,5-triols. Retention of vicinal diols requires that the diol maintains a coplanar or cis conformation. Intramolecular hydrogen bonding often renders 1,3-diols coplanar and they are retained. Carbohydrate rings that exhibit pseudorotation may be retained depending on other ring substitutions. Theoretically, any two or three hydroxyls spaced so as to fill the tetrahedral sites surrounding the trihydroxyboronyl functionality may be retained. A variety of functional groups other than diols will be retained by immobilized phenylboronic acid through the combination of chargetransfer and covalent interactions. Compounds not yet mentioned include aromatic o-hydroxy acids and amides, α-hydroxy acids, 1,3-dihydroxy-, diketo-, triketo- and aminoalcohol-containing compounds.
4. Extraction Procedure
Cartridge conditioning
It is necessary to properly equilibrate the PBA bonded phase with an alkaline solution to obtain the active boronate form RB(OH)3 -. The pKa of the immobilized phenylboronic acid is approximately 9.2. Recall that at pH 9.2 only half the immobilized groups will be reactive (ionized). A sample preparation column can be briefly equilibrated at pH 10 or 12 without damage to the silica substrate. For example, equilibrate PBA with 50-100 mM phosphate buffer, pH 10. If samples are base-sensitive, it can be effective to condition the extraction column with 0.05-1.5 M alkaline buffer, pH 10-12, followed by 0.01-0.50 M buffer at pH 8-8.5.
Secondary interactions
The secondary interactions anticipated for an immobilized phenylboronic acid are illustrated in Figure 3. Below pH 7 these secondary interaction will generally predominate. Both the neutral and anionic forms of the immobilized functionality contain hydroxylated boron which functions as a hydrogen bond donor under appropriate conditions. Consequently, polar compounds including diols may be retained by normal phase mechanisms, if extracted from organic solvents.
The propyl linkage and phenyl ring through which the boron functionality is immobilized may provide sites of nonspecific retention owing to Van der Waals and pi-pi interactions if compounds of hydrophobic character are present. Ionic repulsion may occur between the boronate anion and anions on the compound of interest.
For example, because of the ionic repulsion between the boronate and phosphate groups of nucleic acids, it is necessary to add a divalent cation to the mobile phase in order to get good binding. Finally, cations may be retained by the anionic boronate functionality. If not removed in the wash step, these ions will coelute with the compound of interest when the bonded phase is acidified, and may subsequently interfere with detection, although most ionic species elute in the void volume of the analytical column. Ionic secondary interactions may also beavoided by using buffers of higher ionic strength, between 50 and 500 mM, in the equilibration, sample application and/or wash steps.
5. Buffer selection
An additional secondary interaction of considerable importance in understanding immobilized phenylboronic acid is the potential of boron to form a charge-transfer complex with 1’, 2’, 3’ amines. Unprotonated amines readily form such complexes. Although complex formation is believed to involve only the neutral phenylboronic acid form, equilibrium considerations allow for complex formation under alkaline conditions. In the charge-transfer complex the amine obtains a positive charge and the boron a negative charge rendering the complex neutral (Figure 4). Charge-transfer complex formation with an immobilized phenylboronic acid can have both favorable and deleterious impact on a bonded-phase extraction.
6. Removing interferences
It should be assumed that once the sample has been applied to a properly conditioned column, compounds are retained by both covalent and nonspecific mechanisms. It is at this stage of the extraction process that the advantages of covalent chromatography become apparent. The energetics of the covalent retention mechanism are high as compared to those of reverse phase mechanisms.
Consequently, compounds retained by nonspecific mechanisms may now be eluted while the compound of interest remains bound. Most contaminating species, including many ionic species, can be removed by washing the bonded phase with 50% methanol or acetonitrile. As long as the pH of the aqueous component of the wash solvent remains alkaline, the covalent complex will remain intact.
7. Elution
A variety of acids can be employed as elution solvents. In most cases, reduction to pH 5 is sufficient to effect elution and significant buffer capacity is not required. Acetic, formic, hydrochloric, phosphoric and trifluoroacetic acids (TFA) have been used. In many cases, HPLC mobile phase for reverse phase chromatography is an effective elution solvent. The addition of up to 90% organic modifier is permissible and ensures that the compound of interest is not retained by secondary interactions.
Charge transfer complexes involving amines require reduction to pH 3 to ensure complete elution. Competitive elution with a borate ion, competing diol such as sorbitol or mannitol, or an α-hydroxyl such as tris provide an alternative to acidification when extraction of proteins or acid labile compounds is required.
Question
1. What is the use of Phenylboronic acid?
Background: Phenylboronic acid-polymers (PBA-polymers) have attracted tremendous attention as potential stimuli-responsive materials with applications in drug-delivery depots, scaffolds for tissue engineering, HIV barriers, and biomolecule-detecting/sensing platforms.
2. What is another name for Phenylboronic acid?
Synonym(s): Benzeneboronic acid, Dihydroxyphenylborane, NSC 66487, Phenyl-boric acid, Phenylboric acid, Phenyldihydroxyborane
3. How to make phenylboronic acid?
In order to obtain phenylboronic acids, the compound of the formula (III) is reacted, preferably without interim isolation, with the borate of the formula B(OR′) 3, in particular with B(OCH 3) 3, B(OEt) 3 or B(OiPr) 3, and subsequently hydrolyzed under aqueous conditions to give a compound of the formula (IV).
4. What are the phenylboronic acid groups?
Phenylboronic acid groups covalently attached to silica or porous polymer supports are used for the selective isolation of compounds containing vicinal diol groups (e.g., nucleosides, catecholamines, steroids, drugs), α-hydroxy acids, 1,2-aminoalcohols, 1,2-diketones, 1,3-diols, etc., by formation of 5- or 6-membered …
5. What is the color of Phenylboronic acid?
Phenylboronic acid or benzeneboronic acid, abbreviated as PhB(OH)2 where Ph is the phenyl group C6H5- and B(OH)2 is a boronic acid containing a phenyl substituent and two hydroxyl groups attached to boron. Phenylboronic acid is a white powder and is commonly used in organic synthesis.
6. How do you make phenylacetic acid?
The standard method for the preparation of phenylacetic acid is the hydrolysis of benzyl cyanide with either alkali1 or acid. The acid hydrolysis runs by far the more smoothly and so was the only one studied.
7. What is the pKa of phenylboronic acid?
One of the most commonly used boronic acid compounds is phenylboronic acid (pKa 8.8), and its analogs, such as 3-acetamido phenylboronic acid (pKa 8.5), 2-formylphenyl boronic acid (pKa 7.5), and 3-pyridylboronic acid (pKa 4.0)