Boronic acid

Boronic acids

Many air-stable boronic acids are commercially available. They are characterised by high melting points. Since boronic acids easily lose water to form the cyclic trimeric anhydride, commercial material often contains substantial quantities of this anhydride. This does not affect reactivity.

Synthesis

Boronic acids can be obtained via several methods. The most common way is reaction of organometallic compounds based on lithium or magnesium (Grignards) with borate esters. For example, phenylboronic acid is produced from phenylmagnesium bromide and trimethyl borate followed by hydrolysis

PhMgBr + B(OMe)₃ → PhB(OMe)₂ + MeOMgBrPhB(OMe)₂ + H₂O → PhB(OH)₂ + MeOH

Another method is reaction of an arylsilane (RSiR₃) with boron tribromide (BBr₃) in a transmetallation to RBBr₂ followed by acidic hydrolysis.

A third method is by palladium catalysed reaction of aryl halides and triflates with diboronyl esters in a coupling reaction. An alternative to esters in this method is the use of diboronic acid or tetrahydroxydiboron ([B(OH₂)]₂).

Boronic esters (also named boronate esters)

Boronic esters are esters formed between a boronic acid and an alcohol.

The compounds can be obtained from borate esters by condensation with alcohols and diols. Phenylboronic acid can be selfcondensed to the cyclic trimer called triphenyl anhydride or triphenylboroxin.

Compounds with 5-membered cyclic structures containing the C–O–B–O–C linkage are called dioxaborolanes and those with 6-membered rings dioxaborinanes.

Suzuki coupling reaction

Boronic acids are used in organic chemistry in the Suzuki reaction. In this reaction the boron atom exchanges its aryl group with an alkoxy group from palladium.

Chan–Lam coupling

In the Chan–Lam coupling the alkyl, alkenyl or aryl boronic acid reacts with a N–H or O–H containing compound with Cu(II) such as copper(II) acetate and oxygen and a base such as pyridine forming a new carbon–nitrogen bond or carbon–oxygen bond for example in this reaction of 2-pyridone with trans-1-hexenylboronic acid:

The reaction mechanism sequence is deprotonation of the amine, coordination of the amine to the copper(II), transmetallation (transferring the alkyl boron group to copper and the copper acetate group to boron), oxidation of Cu(II) to Cu(III) by oxygen and finally reductive elimination of Cu(III) to Cu(I) with formation of the product. Direct reductive elimination of Cu(II) to Cu(0) also takes place but is very slow. In catalytic systems oxygen also regenerates the Cu(II) catalyst.

Liebeskind–Srogl coupling

In the Liebeskind–Srogl coupling a thiol ester is coupled with a boronic acid to produce a ketone.

Conjugate addition

The boronic acid organic residue is a nucleophile in conjugate addition also in conjunction with a metal. In one study the pinacol ester of allylboronic acid is reacted with dibenzylidene acetone in such a conjugate addition:

The catalyst system in this reaction is tris(dibenzylideneacetone)dipalladium(0) / tricyclohexylphosphine.

Another conjugate addition is that of gramine with phenylboronic acid catalyzed by cyclooctadiene rhodium chloride dimer:

Oxidation

Boronic esters are oxidized to the corresponding alcohols with base and hydrogen peroxide (for an example see: carbenoid)

Homologation

In boronic ester homologization an alkyl group shifts from boron in a boronate to carbon:

In this reaction dichloromethyllithium converts the boronic ester into a boronate. A Lewis acid then induces a rearrangement of the alkyl group with displacement of the chlorine group. Finally an organometallic reagent such as a Grignard reagent displaces the second chlorine atom effectively leading to insertion of an RCH₂ group into the C-B bond. Another reaction featuring a boronate alkyl migration is the Petasis reaction.

Electrophilic allyl shifts

Allyl boronic esters engage in electrophilic allyl shifts very much like silicon pendant in the Sakurai reaction. In one study a diallylation reagent combines both:

Hydrolysis

Hydrolysis of boronic esters back to the boronic acid and the alcohol can be accomplished in certain systems with thionyl chloride and pyridine. Aryl boronic acids or esters may be hydrolyzed to the corresponding phenols by reaction with hydroxylamine at room temperature.

C–H coupling reactions

The diboron compound bis(pinacolato)diboron reacts with aromatic heterocycles or simple arenes to an arylboronate ester with iridium catalyst [IrCl(COD)]₂ (a modification of Crabtree's catalyst) and base 4,4′-di-tert-butyl-2,2′-bipyridine in a C-H coupling reaction for example with benzene:

In one modification the arene reacts 1 on 1 (instead of a large excess) with cheaper pinacolborane

Unlike in ordinary electrophilic aromatic substitution (EAS) where electronic effects dominate, the regioselectivity in this reaction type is solely determined by the steric bulk of the iridium complex. This is exploited in a meta-bromination of m-xylene which by standard AES would give the ortho product:

Protonolysis

Protodeboronation is a chemical reaction involving the protonolysis of a boronic acid (or other organoborane compound) in which a carbon-boron bond is broken and replaced with a carbon-hydrogen bond. Protodeboronation is a well-known undesired side reaction, and frequently associated with metal-catalysed coupling reactions that utilise boronic acids (see Suzuki reaction). For a given boronic acid, the propensity to undergo protodeboronation is highly variable and dependent on various factors, such as the reaction conditions employed and the organic substituent of the boronic acid:

Saccharide recognition

The covalent pair-wise interaction between boronic acids and 1,2- or 1,3-diols in aqueous systems is rapid and reversible. As such the equilibrium established between boronic acids and the hydroxyl groups present on saccharides has been successfully employed to develop a range of sensors for saccharides. One of the key advantages with this dynamic covalent strategy lies in the ability of boronic acids to overcome the challenge of binding neutral species in aqueous media. If arranged correctly, the introduction of a tertiary amine within these supramolecular systems will permit binding to occur at physiological pH and allow signalling mechanisms such as photoinduced electron transfer mediated fluorescence emission to report the binding event.

Potential applications for this research include systems to monitor diabetic blood glucose levels. As the sensors employ an optical response, monitoring could be achieved using minimally invasive methods, one such example is the investigation of a contact lens doped with boronic acid based sensors to monitor glucose levels within ocular fluid.

Borinic acids and esters

Borinic acids and borinate esters have the general structure R₂BOR.

Borate salts

Borate salts are ate complexes and have the general structure R₄B⁻M⁺ for example potassium tetraphenylborate (IUPAC name: potassium tetraphenylboranuide).