Boronic acid

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The general structure of a boronic acid, where R is a substituent.

A boronic acid is a compound related to boric acid in which one of the three hydroxyl groups is replaced by an alkyl or aryl group.[1] As a compound containing a carbon–boron bond, members of this class thus belong 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. Boronic acids are known to bind to active site serines and are part of inhibitors for porcine pancreatic lipase[2], subtilisin[3] and the protease Kex2[4]. Furthermore, boronic acid derivatives constitute a class of inhibitors for human acyl protein thioesterase 1 and 2, which are cancer drug targets within the Ras cycle.[5]

Structure and synthesis[edit]

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.[6][7][8] 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 anhydrides by loss of water molecules, typically to give cyclic trimers.

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

Synthesis[edit]

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.[9][10][11][12] For example, phenylboronic acid is produced from phenylmagnesium bromide and trimethyl borate followed by hydrolysis[13]

PhMgBr + B(OMe)3 → PhB(OMe)2 + MeOMgBr
PhB(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).[14][15]

Boronic esters (also named boronate esters)[edit]

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-acid-2D.png
Boronic ester RB(OR)2
Boronate-ester-2D.png

The compounds can be obtained from borate esters[16] by condensation with alcohols and diols. Phenylboronic acid can be selfcondensed to the cyclic trimer called triphenyl anhydride or triphenylboroxin.[17]

Examples of boronic esters
Boronic ester Diol Structural formula Molar mass CAS number Boiling point (°C)
Allylboronic acid pinacol ester pinacol Allylboronic acid pinacol ester or 2-Allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 168.04 72824-04-5 50–53 (5 mmHg)
Phenyl boronic acid trimethylene glycol ester trimethylene glycol Phenyl boronic acid glycol ester or 2-Phenyl-1,3,2-dioxaborinane 161.99 4406-77-3 106 (2 mm Hg)
Diisopropoxymethylborane isopropanol Diisopropoxymethylborane 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[edit]

Suzuki coupling reaction[edit]

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.

 

 

 

 

(1)

Chan–Lam coupling[edit]

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[18][19] forming a new carbon–nitrogen bond or carbon–oxygen bond for example in this reaction of 2-pyridone with trans-1-hexenylboronic acid:

Chan–Lam coupling

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[edit]

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

Conjugate addition[edit]

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:[20]

Boronic acids in 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:[21]

Gramine reaction with phenylboronic acid

Oxidation[edit]

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

Homologation[edit]

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[edit]

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[23][note 1]:

Double allylation reagent based on boronic ester

Hydrolysis[edit]

Hydrolysis of boronic esters back to the boronic acid and the alcohol can be accomplished in certain systems with thionyl chloride and pyridine.[24] Aryl boronic acids or esters may be hydrolyzed to the corresponding phenols by reaction with hydroxylamine at room temperature.[25]

C–H coupling reactions[edit]

The diboron compound bis(pinacolato)diboron[26] reacts with aromatic heterocycles[27] or simple arenes[28] 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:

Iridium CH activation Miyaura Hartwig 2003

In one modification the arene reacts 1 on 1 (instead of a large excess) with cheaper pinacolborane[29]

Iridium Arene Borylation Miyaura Hartwig 2005

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[30][note 2]:

Metahalogenation Aryl borylation Murphy 2007

Protonolysis[edit]

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:

A simple protodeboronation in acidic medium

Supramolecular chemistry[edit]

Saccharide recognition[edit]

An example of a fluorescent complex of a diboronic acid and tartaric acid[31]

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.[32] One of the key advantages with this dynamic covalent strategy[33] 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.[34]

Notes[edit]

  1. ^ 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
  2. ^ In situ second step reaction of boronate ester with copper(II) bromide

References[edit]

  1. ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "Boronic Acids".
  2. ^ Garner, C. W. (1980-06-10). "Boronic acid inhibitors of porcine pancreatic lipase". The Journal of Biological Chemistry. 255 (11): 5064–5068. ISSN 0021-9258. PMID 7372625. 
  3. ^ Lindquist, R. N.; Terry, C. (January 1974). "Inhibition of subtilisin by boronic acids, potential analogs of tetrahedral reaction intermediates". Archives of Biochemistry and Biophysics. 160 (1): 135–144. ISSN 0003-9861. PMID 4364061. 
  4. ^ Holyoak, Todd; Wilson, Mark A.; Fenn, Timothy D.; Kettner, Charles A.; Petsko, Gregory A.; Fuller, Robert S.; Ringe, Dagmar (2003-06-10). "2.4 A resolution crystal structure of the prototypical hormone-processing protease Kex2 in complex with an Ala-Lys-Arg boronic acid inhibitor". Biochemistry. 42 (22): 6709–6718. doi:10.1021/bi034434t. ISSN 0006-2960. PMID 12779325. 
  5. ^ Zimmermann, Tobias J.; Bürger, Marco; Tashiro, Etsu; Kondoh, Yasumitsu; Martinez, Nancy E.; Görmer, Kristina; Rosin-Steiner, Sigrid; Shimizu, Takeshi; Ozaki, Shoichiro (2013-01-02). "Boron-based inhibitors of acyl protein thioesterases 1 and 2". Chembiochem: A European Journal of Chemical Biology. 14 (1): 115–122. doi:10.1002/cbic.201200571. ISSN 1439-7633. PMID 23239555. 
  6. ^ Frankland, E.; Duppa, B. F. (1860). "Vorläufige Notiz über Boräthyl". Justus Liebigs Ann. Chem. 115 (3): 319. doi:10.1002/jlac.18601150324. 
  7. ^ Frankland, E.; Duppa, B. (1860). "On Boric Ethide". Proceedings of the Royal Society. 10: 568. doi:10.1098/rspl.1859.0112. 
  8. ^ Frankland, E. (1862). "On a new series of organic compounds containing boron". J. Chem. Soc. 15: 363. doi:10.1039/JS8621500363. 
  9. ^ Dennis G. Hall, ed. (2005). Boronic Acids. Wiley. ISBN 3-527-30991-8. 
  10. ^ Example: Kristensen, Jesper Langgaard; Lysén, Morten; Vedsø, Per; Begtrup, Mikael (2005). "Synthesis of Ortho Substituted Arylboronic Esters by in situ Traping of Unstable Lithio Intermediates: 2-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)benzoic acid ethyl ester". Organic Syntheses. 81: 134. ; Collective Volume, 11, pp. 1015 prep= v81p0134 
  11. ^ Example: Li, Wenjie; Nelson, Dorian P.; Jensen, Mark S.; Scott Hoerrner, R.; Cai, Dongwei; Larsen, Robert D. (2005). "Synthesis of 3-Pyridylboronic Acid and its Pinacol Ester. Application of 3-Pyridylboronic acid in Suzuki Coupling to Prepare 3-Pyridin-3-ylquinoline". Organic Syntheses. 81: 89. ; Collective Volume, 11, p. 393 
  12. ^ Charette, André B.; Lebel, Hélène (1999). "(2S,3S)-(+)-(3-Phenylcyclopropyl)methanol". Organic Syntheses. 76: 86. ; Collective Volume, 10, p. 613 
  13. ^ Washburn, Robert M.; Levens, Ernest; Albright, Charles F.; Billig, Franklin A. (1959). "Benzeneboronic anhydride". Organic Syntheses. 39: 3. ; Collective Volume, 4, p. 68 
  14. ^ Pilarski, Lukasz T.; Szabó, Kálmán J. (2011). "Palladium-Catalyzed Direct Synthesis of Organoboronic Acids". Angewandte Chemie International Edition. 50: 8230–8232. doi:10.1002/anie.201102384. 
  15. ^ Molander, Gary A.; Trice, Sarah L. J.; Dreher, Spencer D. (2010). "Palladium-Catalyzed, Direct Boronic Acid Synthesis from Aryl Chlorides: A Simplified Route to Diverse Boronate Ester Derivatives". Journal of the American Chemical Society. 132 (50): 17701–17703. doi:10.1021/ja1089759. 
  16. ^ Kidwell, R. L.; Murphy, M.; Darling, S. D. (1969). "Phenols: 6-Methoxy-2-Naphthol". Organic Syntheses. 49: 90. ; Collective Volume, 5, p. 918 
  17. ^ Washburn, Robert M.; Levens, Ernest; Albright, Charles F.; Billig, Franklin A. (1959). "Benzeneboronic anhydride". Organic Syntheses. 39: 3. ; Collective Volume, 4, p. 68 
  18. ^ Copper promoted C-N and C-O bond cross-coupling with phenyl and pyridylboronatesTetrahedron Letters, Volume 44, Issue 19, 5 May 2003, Pages 3863–3865 Dominic M. T. Chan, Kevin L. Monaco, Renhua Li, Damien Bonne, Charles G. Clark and Patrick Y. S. Lam doi:10.1016/S0040-4039(03)00739-1
  19. ^ Copper-promoted/catalyzed C-N and C-O bond cross-coupling with vinylboronic acid and its utilities Tetrahedron Letters, Volume 44, Issue 26, 23 June 2003, Pages 4927–4931 Patrick Y. S. Lam, Guillaume Vincent, Damien Bonne and Charles G. Clark doi:10.1016/S0040-4039(03)01037-2
  20. ^ Catalytic Conjugate Addition of Allyl Groups to Styryl-Activated Enones Joshua D. Sieber, Shubin Liu, and James P. Morken J. Am. Chem. Soc.; 2007; 129(8) pp 2214–2215; (Communication) doi:10.1021/ja067878w
  21. ^ Benzylic Substitution of Gramines with Boronic Acids and Rhodium or Iridium Catalysts Gabriela de la Herrán, Amaya Segura, and Aurelio G. Csák Org. Lett.; 2007; 9(6) pp 961 – 964; (Letter) doi:10.1021/ol063042m
  22. ^ 99% Chirally selective synthesis via pinanediol boronic esters: insect pheromones, diols, and an amino alcohol Donald S. Matteson, Kizhakethil Mathew Sadhu, and Mark L. Peterson J. Am. Chem. Soc.; 1986; 108(4); pp 810 – 819; doi:10.1021/ja00264a039
  23. ^ Simple, Stable, and Versatile Double-Allylation Reagents for the Stereoselective Preparation of Skeletally Diverse Compounds Feng Peng and Dennis G. Hall J. Am. Chem. Soc.; 2007; 129(11) pp 3070 – 3071; (Communication) doi:10.1021/ja068985t
  24. ^ New asymmetric syntheses with boronic esters and fluoroboranes Donald S. Matteson Pure Appl. Chem., Vol. 75, No. 9, pp. 1249–1253, 2003 Link.
  25. ^ A mild conversion of arylboronic acids and their pinacolyl boronate esters into phenols using hydroxylamine Ebrahim Kianmehr , Tetrahedron Letters ,vol. 48 , Issue 15 , 9 April 2007 [1]
  26. ^ Ishiyama, Tatsuo; Murata, Miki; Ahiko, Taka-aki; Miyaura, Norio (2000). "Bis(pinacolato)diboron". Organic Syntheses. 77: 176. ; Collective Volume, 10, p. 115 
  27. ^ Iridium-catalyzed C–H coupling reaction of heteroaromatic compounds with bis(pinacolato)diboron: regioselective synthesis of heteroarylboronates Tetrahedron Letters, Volume 43, Issue 32, 5 August 2002, Pages 5649–5651 Jun Takagi, Kazuaki Sato, John F. Hartwig, Tatsuo Ishiyama and Norio Miyaura doi:10.1016/S0040-4039(02)01135-8
  28. ^ Mild Iridium-Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions, and Isolation of a Potential Intermediate Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. (Communication); 2002; 124(3); 390–391. doi:10.1021/ja0173019
  29. ^ Room temperature borylation of arenes and heteroarenes using stoichiometric amounts of pinacolborane catalyzed by iridium complexes in an inert solvent Tatsuo Ishiyama, Yusuke Nobuta, John F. Hartwig and Norio Miyaura Chem. Commun. 2003, 2924–2925, doi:10.1039/b311103b
  30. ^ Meta Halogenation of 1,3-Disubstituted Arenes via Iridium-Catalyzed Arene Borylation Jaclyn M. Murphy, Xuebin Liao, and John F. Hartwig J. AM. CHEM. SOC. 2007, 129, 15434-15435 doi:10.1021/ja076498n
  31. ^ Zhao, Jianzhang; Davidson, Matthew G.; Mahon, Mary F.; Kociok-Köhn, Gabriele; James, Tony D. (2004). "An Enantioselective Fluorescent Sensor for Sugar Acids". J. Am. Chem. Soc. 126 (49): 16179–16186. doi:10.1021/ja046289s. 
  32. ^ Boronic Acids in Saccharide Recognition, Tony D. James, Marcus D. Phillips and Seiji Shinkai, Royal Society of Chemistry (2006) ISBN 978-0-85404-537-2 doi:10.1039/9781847557612
  33. ^ Stuart J. Rowan, Stuart J. Cantrill, Graham R. L. Cousins, Jeremy K. M. Sanders, J. Fraser Stoddart (2002). "Dynamic Covalent Chemistry". Angewandte Chemie International Edition 41 (6): 898–952 doi:10.1002/1521-3773(20020315)41:6<898::AID-ANIE898>3.0.CO;2-E PMID 12491278
  34. ^ US 6850786, Wayne Front March, "Ocular analyte sensor", issued 2005-02-01 

External links[edit]