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

A boronic acid is an organic compound related to boric acid (B(OH)3) in which one of the three hydroxyl groups (−OH) is replaced by an alkyl or aryl group (represented by R in the general formula R−B(OH)2).[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

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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

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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 + 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).[14][15][16]

Boronic esters (also named boronate esters)

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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 borate esters[17] by condensation with alcohols and diols. Phenylboronic acid can be selfcondensed to the cyclic trimer called triphenyl anhydride or triphenylboroxin.[18]

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

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Suzuki coupling reaction

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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

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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[19][20] 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. In catalytic systems oxygen also regenerates the Cu(II) catalyst.

Liebeskind–Srogl coupling

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

Conjugate addition

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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:[21]

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:[22]

Gramine reaction with phenylboronic acid

Oxidation

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

Homologation

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  • Boronic ester homologization
    Boronic ester homologization
  • Homologization application
    Homologization application

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

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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[24][note 1]:

Double allylation reagent based on boronic ester

Hydrolysis

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Hydrolysis of boronic esters back to the boronic acid and the alcohol can be accomplished in certain systems with thionyl chloride and pyridine.[25] Aryl boronic acids or esters may be hydrolyzed to the corresponding phenols by reaction with hydroxylamine at room temperature.[26]

C–H coupling reactions

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The diboron compound bis(pinacolato)diboron[27] reacts with aromatic heterocycles[28] or simple arenes[29] 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 using only a stoichiometric equivalent rather than a large excess using the cheaper pinacolborane:[30]

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:[31][note 2]

Metahalogenation Aryl borylation Murphy 2007

Protonolysis

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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

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Saccharide recognition

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An example of a fluorescent complex of a diboronic acid and tartaric acid[32]

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.[33] One of the key advantages with this dynamic covalent strategy[34] 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.[35]

Safety

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Some commonly used boronic acids and their derivatives give 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.[36]


Notes

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Boronic acid

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Boronic acids are organoboron compounds defined by the general R–B(OH)₂, where R represents an organic such as an alkyl or , featuring a tricoordinate atom bonded to one carbon and two hydroxyl groups. These compounds exhibit sp² hybridization at the center, resulting in a trigonal planar with a vacant p-orbital that confers mild Lewis acidity and the ability to form reversible tetrahedral adducts with nucleophiles like diols or water. Structurally, they often exist as hydrogen-bonded dimers in the solid state and can dehydrate to form boroxine anhydrides or cyclic boronate esters, with pKa values typically ranging from 8 to 10 depending on the (e.g., 9.0 for phenylboronic acid). In , boronic acids are prized for their stability under air and low toxicity, degrading harmlessly to , which enables their widespread use as versatile synthetic intermediates. They serve as essential reagents in palladium-catalyzed cross-coupling reactions, most notably the –Miyaura reaction, which facilitates selective carbon-carbon bond formation between aryl or vinyl boronic acids and halides or pseudohalides under mild conditions, earning its developers a share of the 2010 . This methodology has enabled efficient synthesis of biaryls, conjugated polymers, and natural products, with derivatives like MIDA boronates and potassium organotrifluoroborates enhancing stability and selectivity in iterative couplings. Beyond synthesis, boronic acids play pivotal roles in and , acting as transition-state analogs for proteases by forming reversible covalent boronate esters with active-site nucleophiles such as serines or threonines. Notable examples include (Velcade®), approved in 2003, and , approved in 2015, both functioning as inhibitors for treatment. Their reversible binding to cis-diols also underpins applications in sensing, such as glucose monitors, and boron neutron capture therapy (BNCT) for cancer, where boron delivery agents like 4-boronophenylalanine (BPA) target tumors. Recent developments as of 2025 include boronic acid derivatives in fungicides and peptide-based tools for synthetic .

Introduction and Properties

Definition and Nomenclature

Boronic acids are a class of organoboron compounds characterized by the general RB(OH)2RB(OH)_2, where RR represents an organic substituent such as an alkyl or bonded directly to the atom. These compounds feature a trivalent center with two hydroxyl groups and one carbon- bond, rendering the electron-deficient due to its vacant p-orbital. In contrast to , B(OH)3B(OH)_3, which has three hydroxyl groups attached to , boronic acids incorporate an organic moiety that replaces one hydroxyl, distinguishing them as synthetic derivatives within the broader family of boron oxyacids. The nomenclature of boronic acids has evolved from early descriptions as derivatives of to standardized IUPAC conventions. Initially recognized in the as organoboron species related to —itself obtained by acidifying natural deposits—the naming reflected their structural similarity to inorganic compounds. The first boronic acid, ethylboronic acid, was isolated in 1860 through the reaction of diethylzinc with triethyl borate, marking the beginning of systematic . By the mid-20th century, with advancements in synthetic methods, IUPAC formalized the terminology, designating them as alkylboronic acid or arylboronic acid based on the nature of the RR group; for instance, alkenyl or alkynyl variants follow analogous patterns. The prefix "borono-" is used for the group −B(OH)2-B(OH)_2 in more complex molecules, such as 3-boronoacrolein. A representative example is phenylboronic acid, C6H5B(OH)2C_6H_5B(OH)_2, commonly referred to by its but systematically named as phenylboronic acid under IUPAC rules, highlighting the aryl . This compound exemplifies the class's utility in , where the parent chain or dictates the base name, followed by "boronic acid." Such naming ensures clarity in distinguishing boronic acids from related species like borinic acids (RB(OH)HRB(OH)H) or borates.

Physical Properties

Boronic acids are typically white to off-white crystalline solids, particularly for aryl derivatives such as phenylboronic acid, and they are often hygroscopic, readily absorbing moisture from the air. The melting points of boronic acids vary depending on the substituents attached to the boron-bound carbon, but arylboronic acids generally exhibit high stability with melting points above 200 °C; for example, phenylboronic acid at 216–219 °C. Solubility profiles of boronic acids reflect their polar B(OH)₂ group, which enables moderate solubility in through —phenylboronic acid, for instance, has a solubility of 10 g/L in at 20 °C—while they dissolve more readily in organic solvents such as ethers and ketones (high ), chloroform (), and tetrahydrofuran or (generally favorable due to similar polarity). is notably low in nonpolar hydrocarbons, which can aid in purification processes. Spectroscopic characterization of boronic acids reveals distinctive features: in ¹¹B NMR, the trivalent boron nucleus typically resonates at 30–35 ppm for RB(OH)₂ compounds, shifting slightly upfield for aryl or vinyl substituents compared to alkyl analogs. Infrared spectroscopy shows strong B–O stretching bands around 1350–1310 cm⁻¹, diagnostic of the boronic acid moiety. The pKₐ values for the B–OH group in boronic acids are typically around 9, as exemplified by phenylboronic acid with a pKₐ of 8.83 at 25 °C, which governs their behavior in aqueous environments by allowing deprotonation to form boronate anions under mildly basic conditions.

Chemical Properties

Boronic acids feature a trivalent atom that adopts a trigonal planar owing to sp² hybridization, resulting in an empty p-orbital perpendicular to the plane that confers significant electrophilicity to the center. This electronic configuration renders the a mild Lewis acid, weaker than that of simple due to partial donation from the oxygen lone pairs into the empty orbital, yet sufficient to facilitate coordination with nucleophiles such as or amines. The Lewis acidity can be modulated by substituents on the -bound carbon, with electron-withdrawing groups enhancing it and steric bulk reducing it. In aqueous environments, boronic acids display a pronounced tendency for under basic conditions, undergoing reversible to form tetrahedral anions. This process is governed by the acid dissociation equilibrium: R-B(OH)2+H2O⇌R-B(OH)3−+H+\text{R-B(OH)}_2 + \text{H}_2\text{O} \rightleftharpoons \text{R-B(OH)}_3^- + \text{H}^+ with pKa values typically ranging from 8.6 to 9.0 for arylboronic acids like phenylboronic acid (pKa 8.83 at 25 °C), reflecting their weak Brønsted acidity compared to carboxylic acids. The equilibrium favors the neutral form at physiological but shifts toward the anionic in alkaline media, influencing and reactivity. Boronic acids exhibit variable stability depending on the and reaction conditions, with protodeboronation—a deboronation process yielding the corresponding —being a key degradation pathway in acidic media. The rate of protodeboronation is substituent-dependent, proceeding more rapidly for alkylboronic acids than for arylboronic acids, which benefit from greater conjugative stabilization of the boron-carbon bond. Aryl variants thus demonstrate superior stability under mildly acidic conditions, though highly electron-deficient arylboronic acids show even lower susceptibility. The chemistry of boronic acids involves facile oxidation of the C-B bond to hydroxyl groups, converting arylboronic acids to using mild oxidants such as . Additionally, under dehydrating conditions, boronic acids undergo self-condensation to form boroxines, cyclic trimers with the formula (RBO)3, via the elimination of : 3R-B(OH)2⇌(RBO)3+3H2O3 \text{R-B(OH)}_2 \rightleftharpoons (\text{RBO})_3 + 3 \text{H}_2\text{O} This equilibrium is reversible and pH-dependent, with boroxines predominating in non-aqueous or anhydrous environments.

Synthesis

Classical Methods

The first synthesis of a boronic acid was achieved by Edward Frankland in 1860 through the reaction of diethylzinc with triethylborate, followed by air oxidation to isolate ethylboronic acid. This landmark work laid the foundation for , though early methods were limited to simple alkyl derivatives due to the rudimentary understanding of boron reactivity at the time. One of the classical routes to boronic acids involves the , where an organomagnesium halide (RMgX) reacts with a trialkyl such as B(OR')₃ to form, after , the corresponding boronic RB(OR')₂, which is then converted to the free boronic acid RB(OH)₂. This method, developed in the early and refined through the mid-1900s, typically affords arylboronic acids in yields around 70%, though it requires low temperatures (e.g., -70°C) to minimize side reactions like multiple alkylations. For instance, with tri-n-butyl borate exemplifies the process, producing phenylboronic acid upon acidic workup. A related approach employs organolithium reagents (RLi), generated via halogen-metal exchange or direct lithiation, which are trapped with trimethyl borate B(OMe)₃ at -78°C to yield the boronic ester RB(OMe)₂ after quenching, followed by acidification to the boronic acid. This lithiation route, prominent since the 1950s, offers broader substrate scope for aryl and heteroaryl systems but demands strictly anhydrous conditions to prevent decomposition. It is particularly useful for functionalized aromatics, as demonstrated in the preparation of ortho-substituted phenylboronic acids from directed lithiation. Boronic acids can also be obtained by hydrolysis of boronic esters derived from diborane (B₂H₆) adducts or catecholborane (HBcat). In the case of diborane, of alkenes or alkynes generates organoboranes, which are converted to boronic esters via oxidation or steps before to the acids; this sequence, pioneered in the 1950s–1970s, is effective for alkyl and vinyl derivatives. Similarly, catecholborane terminal alkynes to vinylcatecholborane esters, which upon mild acidic yield vinylboronic acids, providing stereospecific access to unsaturated systems. These classical methods suffer from inherent limitations, including high sensitivity of the organometallic intermediates and boronic acids to air and moisture, necessitating inert atmospheres and rigorous purification. Additionally, low functional group tolerance—particularly toward esters, carbonyls, or halides—often leads to competing reactions or decomposition, restricting their use to simple substrates.

Modern Methods

Modern methods for the synthesis of boronic acids have emerged since the early 2000s, focusing on catalytic processes that enhance efficiency, reduce synthetic steps, and promote sustainability compared to classical organometallic approaches. These advancements leverage transition metal catalysis, direct C-H activation, and innovative reagent designs to access aryl, alkenyl, and alkyl boronic acids with high selectivity and minimal waste. Key strategies include palladium- and iridium-catalyzed borylations, homologation techniques, and emerging catalyst-free or electrochemical protocols, often employing stable borane reagents like pinacolborane (HBpin) to achieve yields exceeding 90% across diverse substrates. The Miyaura borylation represents a cornerstone Pd-catalyzed method, involving the reaction of aryl or vinyl halides (ArX) with HBpin or bis(pinacolato)diboron (B₂pin₂) to form boronic esters, which are subsequently hydrolyzed to boronic acids. This process proceeds under mild conditions with broad functional group tolerance, enabling the preparation of electron-rich and -poor arylboronic acids in high yields. A typical reaction is depicted as: \ceAr−Br+HBpin−>[Pdcat.]Ar−Bpin+HBr\ce{Ar-Br + HBpin ->[Pd cat.] Ar-Bpin + HBr} followed by ester hydrolysis using aqueous acid or base. Post-2000 improvements, such as ligand-optimized Pd systems, have expanded the scope to include heteroaryl halides and reduced catalyst loadings, achieving isolated yields of 85-95% for complex substrates. Iridium-catalyzed C-H borylation provides a direct route to boronic esters from unactivated arenes using B₂pin₂, bypassing the need for prefunctionalized halides and offering high regioselectivity. Developed in the early 2000s, this method employs Ir(I) precursors with bipyridine or phenanthroline ligands to activate aromatic C-H bonds, favoring sterically accessible meta positions in monosubstituted benzenes and achieving site-selectivities greater than 20:1 in many cases. Yields typically range from 70-95% for arylboronic pinacol esters, which are hydrolyzed to the corresponding boronic acids, making it ideal for late-stage functionalization of pharmaceuticals and materials. The reaction's atom economy and avoidance of stoichiometric metals align with green chemistry principles. For alkylboronic acids, the Matteson extends carbon chains from primary alkylboronic s through sequential chlorination with dichloromethyllithium and nucleophilic rearrangement, enabling stereocontrolled synthesis of secondary and tertiary boronic derivatives. This zinc-mediated process involves migration of the alkyl group from to carbon, followed by substitution with organometallic nucleophiles like Grignard reagents, preserving with up to 99% in modern variants. Recent applications post-2010 have demonstrated its utility in iterative homologations for fragments, with overall yields of 60-80% over multiple steps for functionalized alkylboronic acids after ester deprotection. Advancements up to 2025 include catalyst-free protocols and electrochemical borylations, particularly for alkylboronics. Catalyst-free of alkynes or with HBpin or silylboronates under mild heating or base mediation directly affords vinyl- or allenylboronic esters in 70-90% yields, avoiding metal residues and enabling solvent-free conditions for sustainable synthesis. Electrochemical methods, such as decarboxylative borylation of alkyl carboxylic acids or NHPI esters using B₂cat₂ at , provide scalable access to primary and secondary alkylboronic esters with moderate to excellent yields (50-90%), tolerant of sensitive groups like amines and heterocycles. These electroreductions operate at room temperature without sacrificial metals, highlighting their green potential for industrial applications. The widespread use of HBpin in these methods underscores benefits, as its stability prevents protodeboronation and allows air-tolerant handling, while broad substrate scopes—encompassing over 100 examples in Pd- and Ir-catalyzed systems—routinely deliver >90% yields with low E-factors due to recyclable catalysts and minimal byproducts.

Boronic Esters

Preparation

Boronic esters are typically prepared from boronic acids through esterification reactions involving s, which serve to protect the and enhance stability. The general process involves the condensation of a boronic acid, R-B(OH)_2, with a vicinal , such as pinacol (2,3-dimethylbutane-2,3-diol), to form the corresponding boronic , R-B(OR')_2, and as a . This reaction is often facilitated by azeotropic removal of using a Dean-Stark apparatus in refluxing or , or by employing dehydrating agents like molecular sieves or anhydrous . For instance, arylboronic acids react with pinacol in warm or even aqueous media, where the precipitates upon cooling, providing a simple isolation method. Yields for these esterifications are generally high, exceeding 95% for aryl pinacol esters under optimized conditions, due to the favorable equilibrium driven by removal. Microwave-assisted heating has been employed to accelerate the process, reducing reaction times from hours to minutes while maintaining high efficiency. from other borate precursors, such as dialkyl borates, can also be used by distilling off the volatile alcohol, though direct diol esterification remains the most straightforward route. Direct synthesis of boronic bypasses free boronic acids by incorporating the ester formation during of alkenes or alkynes. A key method uses catecholborane (HBcat) as the hydroborating agent, which adds across the unsaturated bond to yield catecholborane esters (R-Bcat) regioselectively and stereospecifically; subsequent with a like pinacol in the presence of a catalyst or under heating affords the desired ester. This approach, pioneered in the , provides - or alkenylboronic esters in good yields (typically 70–90%) and avoids the handling issues of unstable boronic acids. Among common diols for ester formation, pinacol is the most widely adopted , forming the stable "Bpin" ester that resists protodeboronation and facilitates purification. Neopentyl glycol (2,2-dimethylpropane-1,3-diol) is another popular choice, yielding six-membered ring esters with similar stability advantages, particularly for alkylboronic derivatives. These are selected for their ability to form crystalline, easily handled solids that maintain the functionality for downstream applications. Purification of boronic esters commonly involves , often with the stationary phase impregnated with (5–10 wt%) to suppress during elution with non-polar solvents like hexane- mixtures. Recrystallization from solvents such as , , or is effective for crystalline esters, yielding analytically pure materials while avoiding protic conditions that could lead to reversion to the boronic acid. These methods ensure high purity without significant .

Properties and Applications

Boronic esters exhibit enhanced stability relative to their corresponding boronic acids, particularly with respect to oxidation by atmospheric oxygen, allowing them to be isolated and stored as air-stable solids without rapid decomposition. This stability arises from the protective esterification, which shields the center and reduces susceptibility to oxidative degradation, making boronic esters preferable for long-term storage and handling in synthetic workflows. Unlike boronic acids, which can form insoluble anhydrides or undergo slow oxidation over time, boronic esters such as pinacolboranes (Bpin) maintain integrity under ambient conditions, facilitating their use in large-scale preparations. Electronically, boronic esters display slightly reduced Lewis acidity compared to boronic acids due to the electron-donating effect of the alkoxy groups, which increase at the atom and alter its coordination behavior. This modulation is evident in their ¹¹B NMR chemical shifts, typically observed around 27-30 ppm in the solid state, reflecting a trigonal planar environment with diminished electrophilicity. The lower Lewis acidity influences reactivity, often requiring milder conditions for coordination with Lewis bases and contributing to their role in selective transformations. A key distinction from boronic acids is the slower rate of of boronic esters under neutral or basic aqueous conditions, which enables orthogonal protection strategies in polyfunctional molecules where multiple groups must be differentially activated or deprotected. In organic synthesis, boronic esters serve as effective transmetalation agents in palladium-catalyzed cross-coupling reactions, transferring the organic substituent to the metal center while forming a stable boronate byproduct. This process can occur directly without prior hydrolysis, as illustrated in the simplified transmetalation step: \ceR−Bpin+[Pd]−>R−[Pd]+Bpin−O−[Pd]\ce{R-Bpin + [Pd] -> R-[Pd] + Bpin-O-[Pd]} where Bpin denotes the pinacolboryl group, highlighting their utility in efficient, anhydrous conditions. Beyond synthesis, boronic esters are incorporated into polymeric materials to enable self-healing properties through dynamic covalent exchange reactions, where boronate linkages reversibly break and reform in response to stimuli like heat or solvents, restoring structural integrity without external intervention. These dynamic networks, often formed via thiol-ene click chemistry with diol-functionalized monomers, demonstrate room-temperature healability and recyclability, expanding applications in durable coatings and adhesives.

Applications in Organic Synthesis

Cross-Coupling Reactions

Boronic acids and their esters are widely employed as organoborane nucleophiles in transition-metal-catalyzed cross-coupling reactions, enabling the formation of carbon-carbon bonds between sp²- or sp³-hybridized carbons under mild conditions. These reactions typically involve or catalysts and proceed via a three-stage : of an organic to the low-valent metal center, of the organic residue from to the metal, and to yield the coupled product while regenerating the catalyst. The Suzuki-Miyaura coupling represents a prominent example of this class, particularly for biaryl synthesis. The step is pivotal, involving the transfer of the organic group (R) from the atom in R-B(OR')₂ to the metal (typically Pd or Cu), forming an organometallic intermediate. A base, such as aqueous Na₂CO₃ or K₃PO₄, plays a critical role by deprotonating the boronic acid or displacing the alkoxy group to generate a more nucleophilic boronate anion [R-B(OR')O⁻], which accelerates the rate of group transfer and suppresses protodeboronation side reactions. then rapidly forms the C-C bond. The rate-determining step is often or , depending on the substrates and conditions. The scope of these couplings encompasses aryl, alkenyl, and alkyl boronic acids or esters reacting with electrophiles like aryl or vinyl halides (I, Br, Cl) and triflates. Alkenylboronic acids couple with complete retention of , preserving (E) or (Z) configurations in the product. Alkylboronics extend the utility to sp³-sp³ couplings, though they require careful catalyst selection to avoid β-hydride elimination. Compared to other organometallic like Grignard or organozinc , boronic derivatives exhibit exceptional air and moisture stability, along with high tolerance for sensitive functional groups such as esters, ketones, and nitro moieties, enabling their use in complex molecule synthesis. In the 2020s, nickel-catalyzed variants have gained prominence as earth-abundant alternatives to systems, particularly for alkyl-alkyl cross-couplings that were historically challenging due to competing side reactions. These Ni processes often employ bidentate ligands and operate under mild conditions, achieving broad substrate compatibility with aryl, heteroaryl, and alkyl boronics paired with alkyl halides. For instance, migratory Ni-catalyzed Suzuki-Miyaura reactions demonstrate high for benzylic or allylic positions in alkyl chains, facilitating the construction of complex carbon frameworks with yields often exceeding 80%. Mechanistically, these proceed via reduction of Ni(II) to Ni(0), mirroring the Pd cycle but with enhanced reactivity toward unactivated alkyl electrophiles.

Addition and Functionalization Reactions

Boronic acids serve as versatile nucleophilic partners in conjugate reactions, particularly with α,β-unsaturated carbonyl compounds under . In this process, the aryl or alkenyl group from the boronic acid adds to the β-position of the enone, yielding β-substituted carbonyl products after . The mechanism involves transmetalation of the boronic acid with a rhodium(I) complex, followed by coordination and insertion of the alkenyl species into the C=C bond of the substrate. A representative example is the of phenylboronic acid to , affording 4-phenylbutan-2-one in high yield. This reaction typically proceeds in aqueous media with yields ranging from 80% to 95%, enabling efficient construction of complex carbon frameworks in synthesis. Electrophilic allyl shifts in allylboronate derivatives, often derived from boronic acids, facilitate the synthesis of homoallylic alcohols via Lewis acid activation. Under coordination with a Lewis acid such as BPh₃ or Sc(OTf)₃, the allylboronate undergoes a migratory insertion where the shifts to an electrophilic center, typically a carbonyl, forming a new C-C bond with anti-diastereoselectivity. This migration exploits the closed of the boronate complex, minimizing side reactions and providing access to chiral homoallylic alcohols with high enantiomeric excess when chiral ligands are employed. Yields for these transformations commonly exceed 85%, making them valuable for assembling polyfunctionalized molecules in . Homologation reactions based on Matteson-type chemistry allow for precise carbon insertion into boronic acid-derived esters, extending the carbon chain by one unit. The process begins with of a chloromethylboronate (prepared from the boronic acid), generating a carbenoid that inserts into the C-B bond, followed by trapping with a or to set . This iterative method achieves excellent stereocontrol (>95% ee in many cases) and is particularly useful for constructing stereodefined acyclic chains in target-oriented synthesis. Overall efficiencies reach 80-90% over multiple steps, highlighting its role in assembling complex architectures without . C-H activation couplings involving directed borylation with boronic acid equivalents, followed by arylation, enable site-selective functionalization without pre-installed halides. Initial directed C-H borylation installs a boronate group ortho to a directing moiety (e.g., or ), which then participates in a migratory arylation step under , forming new C-C bonds. This sequence avoids traditional cross-coupling prerequisites and delivers arylated products in 80-95% yields, facilitating late-stage diversification of pharmaceuticals and materials. The approach is especially impactful for electron-deficient heterocycles, streamlining synthetic routes to bioactive compounds.

Oxidation and Reduction Reactions

One of the fundamental transformations of boronic acids involves their oxidation to , a process that is particularly selective for arylboronic acids due to the stability of the ipso-substituted intermediate. This reaction typically utilizes (H₂O₂) as the oxidant, leading to the replacement of the boronic acid group with a hydroxyl functionality while generating as a . The general reaction can be represented as: \ceR−B(OH)2+H2O2−>R−OH+B(OH)3\ce{R-B(OH)2 + H2O2 -> R-OH + B(OH)3} This catalyst-free protocol operates under mild aqueous conditions, often achieving high yields in short reaction times, and H₂O₂ can serve dual roles as both oxidant and solvent. Alternative oxidants, such as sodium perborate, have also been employed for efficient ipso-hydroxylation in water, further enhancing the practicality for diverse aryl substrates. Recent advancements in this oxidation have focused on greener methodologies, including the use of molecular oxygen (O₂) under catalytic conditions to minimize waste and avoid stoichiometric peroxides. For instance, magnetic CuFe₂O₄ nanoparticles catalyze the oxidative of arylboronic acids with O₂ at ambient temperature, enabling easy catalyst recovery via and broad substrate compatibility. A review highlights ongoing innovations, such as photocatalyst-free aerobic processes and non-metal-catalyzed variants, which expand accessibility while maintaining high selectivity and sustainability. However, under conditions, boronic acids may dehydrate to form boroxines (cyclic trimers, [RBO]₃), potentially leading to side products that complicate oxidation efficiency by altering reactivity. Oxidative couplings, such as the Chan-Lam reaction, further exemplify redox processes involving boronic acids, where catalysis facilitates C-N or C-O bond formation with or alcohols under aerobic conditions. In the C-N variant, an arylboronic acid reacts with a secondary to yield the corresponding arylamine, with the oxidant (typically air or a ) regenerating the active species: \ceAr−B(OH)2+HNR2−>Ar−NR2+B(OH)3\ce{Ar-B(OH)2 + HNR2 -> Ar-NR2 + B(OH)3} This method is versatile for constructing diarylamines and aryl ethers, proceeding at with high tolerance. Detailed discussions of related cross-coupling oxidations appear in the Cross-Coupling Reactions section. Reduction reactions of boronic acids primarily involve protodeboronation, which cleaves the C-B bond to install a or atom at the ipso position. This process is particularly useful for late-stage deuteration in , where arylboronic acids undergo selective replacement of the B(OH)₂ group with D using D₂O as the deuterium source. A synergistic photoredox/thiol-ligand system enables mild, metal-free conditions for this transformation, achieving high deuterium incorporation (>95%) across electron-rich and electron-poor aryl substrates without protodeboronation side reactions under protic conditions. While direct reduction to (R-BH₂) is uncommon and typically requires strong reductants like LiAlH₄, emerging catalytic approaches using silanes have been explored for deoxygenative transformations in related organoboron systems, though not yet standard for boronic acids.

Applications in Medicinal Chemistry

Drug Design and Protease Inhibitors

Boronic acids serve as electrophilic warheads in the design of covalent inhibitors, forming reversible tetrahedral adducts with the nucleophilic hydroxyl groups of active-site serine or residues. This binding mimics the of , enabling selective inhibition of enzymes such as serine proteases and threonine-based proteasomes. The resulting boronate linkage provides slow dissociation kinetics, enhancing potency while allowing reversibility to minimize off-target effects. A landmark example is (Velcade), the first boronic acid-based drug approved by the FDA in 2003 for relapsed . features a dipeptidyl structure where the boronic acid is appended to a mimic at the , targeting the chymotrypsin-like activity of the 20S 's residue. Another prominent analog is (Ninlaro), approved in 2015 as the first oral , incorporating a boronic acid with enhanced through a cyclohexenyl modification. Both drugs selectively inhibit the , disrupting protein degradation and inducing in cancer cells. Boronic acids are also utilized in antibacterial agents, such as vaborbactam, a cyclic boronic acid derivative approved by the FDA in 2017 in combination with (Vabomere) for treating complicated urinary tract infections caused by multidrug-resistant . Vaborbactam acts as a reversible covalent inhibitor of serine beta-lactamases, restoring the efficacy of the beta-lactam by protecting it from enzymatic degradation. Design principles for these inhibitors emphasize optimization of the P1-P3 subsites to match the target's S1-S3 pockets, ensuring specificity and affinity. The boronic acid typically occupies the P1 position, with hydrophobic residues like leucine or phenylalanine at P1 for S1 pocket fitting, while P2 (e.g., leucinyl in bortezomib) and P3 (e.g., pyrazinylcarbonyl) provide additional interactions for selectivity. Stability enhancements, such as stereochemical control at the α-carbon (favoring L-isomers) and lipophilic modifications, improve cellular permeability and reduce hydrolysis in vivo, as demonstrated in structure-activity relationship studies of α-amino boronic acids. These inhibitors have profoundly influenced , with establishing proteasome targeting as a viable therapeutic strategy and treating hundreds of thousands of patients globally by the mid-2020s. Ixazomib's oral formulation has further , particularly for maintenance therapy. Ongoing clinical trials explore their applications in solid tumors, lymphomas, and even antiviral contexts by modulating host protein degradation pathways.

Imaging and Sensing Agents

Boronic acids and their derivatives have emerged as valuable components in (PET) imaging agents, particularly for visualizing tumor tissues. Arylboronic acid-based tracers, such as ¹⁸F-labeled boramino acids like [¹⁸F]4-borono-2-[¹⁸F]fluoro-L-phenylalanine ([¹⁸F]FBPA), enable the assessment of boron distribution in tumors, which is crucial for planning boron neutron capture therapy (BNCT) and providing insights into tumor transport. These agents exhibit favorable , with rapid uptake in glioma cells via the L-type transporter 1 (LAT1), allowing for high-contrast PET imaging of brain tumors as demonstrated in first-in-human studies. Although primarily used for general tumor delineation, adaptations incorporating hypoxia-sensitive motifs, such as conjugates with boronic acid scaffolds, have been explored to target low-oxygen regions in solid tumors, akin to [¹⁸F]FAZA mechanisms but leveraging boronic stability for improved retention. In biosensing applications, boronic acids play a pivotal role in glucose monitoring devices due to their reversible binding affinity for cis-diols in glucose molecules. This interaction modulates intensity in boronic acid-functionalized probes, enabling continuous, non-invasive detection of glucose levels in interstitial fluid for . For instance, diboronic acid derivatives integrated into microneedle arrays or sensors provide stable, real-time signals with sensitivities in the physiological range (4-8 mM), outperforming traditional enzymatic methods by avoiding and offering long-term implantation viability up to 14 days . These sensors exploit the pH-dependent equilibrium of boronate ester formation, where glucose binding shifts the emission , facilitating ratiometric readout for accurate quantification without frequent . Recent advancements since 2021 have focused on enhancing the of boronic acids to improve their performance in imaging and sensing. Traditional phenylboronic acids are prone to rapid oxidation by at physiological , leading to high background signals and reduced specificity. However, stereoelectronically tuned , such as those with constrained ortho-substituents, exhibit over 10,000-fold greater resistance to H₂O₂-mediated degradation, enabling prolonged circulation and clearer signal-to-noise ratios in biological environments. This stability has been applied in fluorescence-based probes for real-time monitoring of in hypoxic tumors, minimizing false positives from unintended . Boronic acid conjugates also serve as pH-responsive components in targeted delivery systems that integrate sensing with therapeutic release. These systems exploit the acidity of tumor microenvironments ( ~6.5) to trigger boronate ester disassembly, releasing imaging agents or payloads selectively at disease sites. Phenylboronic acid-grafted nanoparticles, for example, form dynamic esters with polyols that hydrolyze under acidic conditions, achieving over 65% cargo release within 48 hours while maintaining stability at neutral , thus enhancing tumor-specific accumulation and reducing off-target effects in fluorescence or PET-guided diagnostics. Boronolectins, multivalent boronic acid constructs mimicking lectin-carbohydrate interactions, have been developed for cellular imaging of carbohydrates. These agents bind sialylated glycans on cell surfaces with high , enabling labeling of glycan patterns in live cells for studying cancer or . Representative examples include anthracene-based boronolectins that display turn-on upon binding, allowing visualization of distribution in tumor cells with minimal and sub-micromolar affinity.

Supramolecular and Analytical Applications

Saccharide Recognition

Boronic acids recognize saccharides through reversible covalent binding, where the boron atom coordinates with vicinal groups on the , transitioning from a trigonal planar sp²-hybridized structure to a tetrahedral sp³-boronate anion, typically forming five- or six-membered cyclic esters. This interaction is pH-dependent, with the anionic boronate form predominant at physiological , facilitating rapid exchange and higher affinity in aqueous media; dissociation constants (K_d) for glucose binding to simple monoboronic acids range from approximately 10 to 100 mM under neutral conditions. The foundational studies on this binding date to 1959, when Lorand and Edwards reported the first quantitative measurements of phenylboronic acid interactions with polyols, including saccharides, establishing the basis for boronic acids as synthetic mimics of in molecular recognition. Subsequent developments in the 1990s built on this by integrating boronic acids into artificial receptor systems for selective saccharide detection. Selectivity arises from the structural features of saccharides, particularly the presence and accessibility of cis-1,2-diols; for instance, exhibits higher affinity than glucose due to the greater proportion of its form (about 25% β-D-fructofuranose) featuring a favorable cis-diol configuration, compared to glucose's predominantly forms with trans-diols. This preference is reflected in binding constants, where phenylboronic acid shows roughly 10- to 100-fold stronger association with (K_a ≈ 1000 M⁻¹) over glucose (K_a ≈ 10-100 M⁻¹) at 7.4. The equilibrium can be represented as: \ceR−B(OH)2+sugar−diol⇌R−B(sugar)+H2O\ce{R-B(OH)2 + sugar-diol ⇌ R-B(sugar) + H2O} where R denotes the aryl or alkyl substituent on the boronic acid. In applications, boronic acids enable saccharide detection through changes in ; for example, conjugates like ortho-aminomethylphenylboronic acid linked to exhibit enhancement upon glucose binding due to disruption of , allowing sensitive monitoring in aqueous solutions. Colorimetric variants, such as those using dyes displaced by saccharide coordination, produce visible color shifts for qualitative or quantitative assays. To overcome the moderate affinity of monoboronic acids in aqueous environments, multivalent designs—such as diboronic acid scaffolds—leverage effects, achieving up to 100-fold higher association constants (e.g., K_a ≈ 4000 M⁻¹ for glucose) through and reduced loss, thus enabling effective recognition under physiological conditions.

Dynamic Covalent Chemistry

Boronic acids participate in dynamic covalent chemistry through reversible bond formations, enabling adaptive materials and responsive systems. These interactions, such as B-N and B-O dative bonds, allow for equilibrium-driven assembly and disassembly under mild conditions, distinguishing them from irreversible reactions in synthesis. Key motifs include iminoboronates and salicylhydroxamic boronates, which exhibit tunable kinetics responsive to environmental stimuli like . Iminoboronates form via condensation of ortho-substituted boronic acids, such as 2-aminophenylboronic acid (2-APBA) or 2-formylphenylboronic acid, with or amines, yielding dynamic B-N bonds. The reaction proceeds rapidly at neutral pH, with association constants around 0.6 mM for , stabilized by intramolecular coordination (~10 kcal mol⁻¹). Exchange rates are pH-dependent, accelerating under acidic conditions due to of the , facilitating and exchange. This reversibility has been leveraged in and stimuli-responsive materials. Salicylhydroxamic-boronate (SHAB) linkages arise from boronic acids reacting with salicylhydroxamic acid (SHA), forming stable yet reversible esters with association constants of 10⁴ M⁻¹ at 7.4. These bonds hydrolyze rapidly below 5, enabling pH-triggered responses. In self-healing hydrogels, SHAB cross-links between phenylboronic acid-modified polymers and SHA-functionalized counterparts promote rapid reformation after damage, with release rates such as 5.93 × 10⁻⁵ μmol s⁻¹ for at 4.8, supporting applications in and controlled delivery. Applications extend to dynamic polymers and glucose-responsive drug delivery. Boronic acid-catechol networks form adaptive polymers that self-assemble into capsules or gels, disassembling upon glucose binding to release insulin; for instance, nanogels achieve >50% release within 2 hours at 16.6 mM glucose, stabilizing normoglycemia for up to 15 hours in diabetic models. These systems exploit competitive diol coordination for on-demand disassembly. Recent advances from 2020–2025 include dynamic covalent libraries for click chemistry, such as boronate-activated polyplexes that screen gene delivery vectors in situ, achieving transfection efficiencies rivaling Lipofectamine 2000 across cell lines. Additionally, hydrogen-bond-assisted photoredox activation of alkylboronic acids generates alkyl radicals under mild aqueous conditions, enabling alkylation and allylation with broad substrate scope, though primarily irreversible. These developments expand boronic acids into adaptive gene therapy and radical-based polymerizations. Kinetics of these bonds feature half-lives tunable from seconds to hours, dictated by pH and substituents; for example, iminoboronate exchange exceeds 10³ M⁻¹ s⁻¹ at neutral pH, while SHAB hydrolysis accelerates below pH 5, allowing adaptive responses in materials like hydrogels that reform in minutes. This range supports equilibrium-driven adaptability without external energy.

Safety and Handling

Toxicity and Health Effects

Boronic acids display moderate acute oral toxicity, with the LD50 for phenylboronic acid in rats estimated at 740 mg/kg. Broader studies on various boronic acids report LD50 values ranging from 460 to 2150 mg/kg in mice, indicating relatively low lethality at typical exposure levels. These compounds are primarily irritants, causing skin redness and eye damage upon direct contact, as evidenced by their classification under EU hazard codes H315 (causes skin irritation) and H319 (causes serious eye irritation). Chronic exposure to boronic acids poses risks of due to accumulation in tissues, mirroring effects seen with , which disrupts and fetal development in animal models. , a related species, is classified as toxic to (Category 1B, H360FD) under regulations, with no observed adverse effects levels around 2.5 mg /kg/day in rats. The primary toxicological mechanism of boronic acids involves interference with enzyme active sites, where the boron atom forms reversible tetrahedral adducts with nucleophilic residues such as serine or in proteases and other proteins. This binding can inhibit critical biological processes, though low systemic absorption—particularly through intact skin—limits broader distribution and exacerbates primarily local effects. Boronic acids are not classified as carcinogenic by the International Agency for Research on Cancer (IARC), which has found inadequate evidence of carcinogenicity for boron compounds in humans. Documented exposures to boronic acids and related boron compounds have caused , characterized by erythematous rashes and from prolonged skin contact. Systemic boronosis, involving widespread boron accumulation leading to alopecia and neurological symptoms, is rare and typically linked to high-dose chronic ingestions rather than routine lab handling.

Storage and Laboratory Practices

Boronic acids and their derivatives require careful storage to maintain stability, as they are susceptible to oxidation and . They should be kept in tightly sealed containers under an inert atmosphere, such as or , within a to minimize exposure to air and . Recommended storage temperatures range from -20°C to -70°C, depending on the specific compound, to extend shelf life, which typically ranges from 1 to 2 years under these conditions. In the , boronic acids must be handled in a well-ventilated to prevent of dust or vapors. Personnel should avoid contact with strong acids or bases, which can cause of the boron-carbon bond. Their inherent instability to air and moisture, as discussed in chemical properties, underscores the need for conditions during manipulation. Appropriate personal protective equipment (PPE) includes safety goggles or glasses compliant with NIOSH or EN 166 standards, gloves (with breakthrough times of at least 480 minutes), and protective clothing to shield against skin contact. Respiratory protection, such as a P2 or P3 filter mask, is advised when dust generation is possible. This PPE selection accounts for the mild irritant potential and reactivity of boronic acids. For spill response, immediately ensure adequate ventilation and avoid generating by using non-sparking tools to the material. Small spills can be absorbed with inert materials like , while larger ones may require neutralization with solution before collection; do not allow the substance to enter drains or waterways. Waste disposal of boronic acids and contaminated materials should follow local, national, and international regulations for hazardous boron-containing compounds, typically involving in approved containers and treatment at licensed facilities to prevent environmental release. Do not mix with other wastes, and may be suitable after compatibility checks.

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