A boronic acid is an organic compound related to boric acid () in which one of the three () is replaced by an alkyl or aryl group (represented by R in the general formula ).
Boronic acids act as . Their unique feature is that they are capable of forming reversible covalent complexes with , , , etc. (molecules with vicinal, (1,2) or occasionally (1,3) substituted Lewis base donors (alcohol, amine, carboxylate)). The pKa of a boronic acid is ~9, but they can form tetrahedral boronate complexes with p Ka ~7. They are occasionally used in the area of molecular recognition to bind to saccharides for fluorescent detection or selective transport of saccharides across membranes.
Boronic acids are used extensively in organic chemistry as chemical building blocks and intermediates predominantly in the Suzuki coupling. A key concept in its chemistry is transmetallation of its organic residue to a transition metal.
The compound bortezomib with a boronic acid group is a drug used in chemotherapy. The boron atom in this molecule is a key substructure because through it certain are blocked that would otherwise degrade proteins. Boronic acids are known to bind to active site serines and are part of inhibitors for porcine pancreatic lipase,
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
redox in air to form ethylboronic acid.
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 by loss of water molecules, typically to give cyclic trimers.
| + Examples of boronic acids |
|
| 216–219 |
| 138–140 |
| 91–94 |
| 65–70 |
| 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 (
Grignard reagent) with
.
[Example: ][Example: ] For example, phenylboronic acid is produced from phenylmagnesium bromide and
trimethyl borate followed by hydrolysis
- PhMgBr + B(OMe)3 → PhB(OMe)2 + MeOMgBr
- PhB(OMe)2 + 2 H2O → PhB(OH)2 + 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 known as the Miyaura borylation 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
formed between a boronic acid and an alcohol.
| + Comparison between boronic acids and boronic esters |
|
| |
| |
The compounds can be obtained from
| + Examples of boronic esters |
|
| 50–53 (5 mmHg) |
| 106 (2 mm Hg) |
| 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.
]\text{Base} R1-R2}\\
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. In catalytic cycle 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:
File:BoronicesterhomologizationMechanism.png|Boronic ester homologization
File:Boronicesterhomologization.png|Homologization application
In this reaction organolithium 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
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 using only a stoichiometric equivalent rather than a large excess using the 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:
Supramolecular chemistry
Saccharide recognition
The covalent pair-wise interaction between boronic acids and
as found in alcohols and
is rapid and reversible in
. 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 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 Aqueous humour.
Safety
Some commonly used boronic acids and their derivatives give a positive Ames test and act as chemical
. The mechanism of mutagenicity is thought to involve the generation of organic radicals via oxidation of the boronic acid by atmospheric oxygen.
Notes
External links
