A boronic acid is an alkyl or aryl substituted boric acid containing a carbon–boron bond belonging to the larger class of organoboranes. Boronic acids act as Lewis acids. Their unique feature is that they are capable of forming reversible covalent complexes with sugars, amino acids, hydroxamic acids, 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 pKa ~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 proteasomes are blocked that would otherwise degrade proteins.
- 1 Boronic acids
- 2 Boronic esters (also named boronate esters)
- 3 Boronic acids in organic chemistry
- 4 Boronic acids in supramolecular chemistry
- 5 Borinic acids and esters
- 6 Borate salts
- 7 Notes
- 8 See also
- 9 References
- 10 External links
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.
|Boronic acid||R||Structure||Molar mass||CAS number||Melting point °C|
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 + MeOMgBr
- PhB(OMe)2 + H2O → PhB(OH)2 + MeOH
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.
|Compound||General formula||General structure|
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.
|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)|
Compounds with 5-membered cyclic structures containing the C–O–B–O–C linkage are called dioxaborolanes and those with 6-membered rings dioxaborinanes.
Boronic acids in organic chemistry
Suzuki coupling reaction
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.
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.
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
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:
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[note 2]:
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:
Boronic acids in supramolecular chemistry
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.
|compound||general formula||general structure|
- In this sequence the boronic ester allyl shift is catalyzed by boron trifluoride. In the second step the hydroxyl group is activated as a leaving group by conversion to a triflate by triflic anhydride aided by 2,6-lutidine. The final product is a vinyl cyclopropane. Note: ee stands for enantiomeric excess
- In situ second step reaction of boronate ester with copper(II) bromide
- Boron bonded to three oxygen atoms: boric acid and borates
- Suzuki reaction
- Supramolecular chemistry
- Dynamic covalent chemistry
- Blood glucose monitoring
- Boronic Acids. Edited by Dennis G. Hall 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN 3-527-30991-8
- Example: Jesper Langgaard Kristensen, Morten Lysén, Per Vedsø, and Mikael Begtrup Günter Seidel and Alois Fürstner Published in Org. Synth. 2005, 81, 134 Org. Synth. 2009, Coll. Vol. 11, 1015 link Archived 22 March 2012 at the Wayback Machine.
- Example: Quinoline, 3-(3-pyridinyl)- Wenjie Li, Dorian P. Nelson, Mark S. Jensen, R. Scott Hoerrner, Dongwei Cai, and Robert D. Larsen, Scott E. Denmark, Geoff T. Halvorsen, and Jeffrey M. Kallemeyn Published in Org. Synth. 2005, 81, 89 Org. Synth. 2009, Coll. Vol. 11, 393 Link Archived 22 March 2012 at the Wayback Machine.
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