Boronic acid

A boronic acid is an

Boronic acids act as

Boronic acids are used extensively in

The compound

The boronic acid functional group is reputed to have low inherent toxicity. This is one of the reasons for the popularity of the Suzuki coupling in the development and synthesis of pharmaceutical agents. However, a significant fraction of commonly used boronic acids and their derivatives were recently found to gives a positive Ames test and act as chemical mutagens. The mechanism of mutagenicity is thought to involve the generation of organic radicals via oxidation of the boronic acid by atmospheric oxygen.^[6]

Structure and synthesis

In 1860, Edward Frankland was the first to report the preparation and isolation of a boronic acid. Ethylboronic acid was synthesized by a two-stage process. First, diethylzinc and triethyl borate reacted to produce triethylborane. This compound then oxidized in air to form ethylboronic acid.^[7][8][9] Several synthetic routes are now in common use, and many air-stable boronic acids are commercially available.

Boronic acids typically have high melting points. They are prone to forming

.

Examples of boronic acids

Boronic acid	R	Structure	Molar mass	CAS number	Melting point °C
Phenylboronic acid	Phenyl		121.93	98-80-6	216–219
2-Thienylboronic acid	Thiophen		127.96	6165-68-0	138–140
Methylboronic acid	Methyl		59.86	13061-96-6	91–94
cis-Propenylboronic acid	propene		85.90	7547-96-8	65–70
trans-Propenylboronic acid	propene		85.90	7547-97-9	123–127

Synthesis

Boronic acids can be obtained via several methods. The most common way is reaction of organometallic compounds based on lithium or magnesium (

A third method is by palladium catalysed reaction of aryl halides and triflates with diboronyl esters in a coupling reaction known as the Miyaura borylation reaction. An alternative to esters in this method is the use of diboronic acid or tetrahydroxydiboron ([B(OH₂)]₂).^[15][16][17]

Boronic esters (also named boronate esters)

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

Comparison between boronic acids and boronic esters

Compound	General formula	General structure
Boronic acid	RB(OH)2
Boronic ester	RB(OR)2

The compounds can be obtained from

Examples of boronic esters

Boronic ester	Diol	Structural formula	Molar mass	CAS number	Boiling point (°C)
Allylboronic acid pinacol ester	pinacol		168.04	72824-04-5	50–53 (5 mmHg)
Phenyl boronic acid trimethylene glycol ester	trimethylene glycol		161.99	4406-77-3	106 (2 mm Hg)
Diisopropoxymethylborane	isopropanol		144.02	86595-27-9	105 -107

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

Organic chemistry applications

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.

${\displaystyle {\begin{matrix}{}\\{\ce {{R1-BY2}+R2-X->[{\underset {\text{catalyst}}{\text{Pd}}}][{\text{Base}}]R1-R2}}\\{}\end{matrix}}}$

(1)

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

The

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:^[23]

Oxidation

Boronic esters are

• In boronic ester
  homologization an alkyl group shifts from boron in a boronate to carbon:^[24]

• 
  Boronic ester homologization
• 
  Homologization application

In this reaction

Hydrolysis

Hydrolysis of boronic esters back to the boronic acid and the alcohol can be accomplished in certain systems with thionyl chloride and pyridine.^[26] Aryl boronic acids or esters may be hydrolyzed to the corresponding phenols by reaction with hydroxylamine at room temperature.^[27]

C–H coupling reactions

The diboron compound

In one modification the arene reacts using only a

Unlike in ordinary

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:

Supramolecular chemistry

Saccharide recognition

The covalent pair-wise interaction between boronic acids and hydroxy groups as found in alcohols and acids is rapid and reversible in aqueous solutions. 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.^[34] One of the key advantages with this dynamic covalent strategy^[35] 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 blood glucose monitoring systems to help manage diabetes mellitus. 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 that contains a boronic acid based sensor molecule to detect glucose levels within ocular fluids.^[36]

Notes