Pinacolborane

Pinacolborane, systematically named 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, is an organoboron compound with the molecular formula C₆H₁₃BO₂ and a structure featuring a five-membered 1,3,2-dioxaborolane ring bearing four methyl groups and a boron-hydrogen bond.^[1] It appears as a clear, colorless to light yellow liquid that is air- and moisture-sensitive, with a boiling point of 42–43 °C at 50 mm Hg and a density of 0.882 g/mL at 25 °C.^[2] This compound is widely utilized in organic synthesis as a monofunctional hydroborating agent, enabling the addition of boron-hydrogen across unsaturated bonds in alkenes and alkynes, often under catalytic conditions such as with transition metals like iridium or ruthenium.^[3] Pinacolborane serves as a stable, commercially available alternative to more reactive boranes like catecholborane, facilitating the preparation of pinacolboronate esters—key precursors for Suzuki-Miyaura cross-coupling reactions to form carbon-carbon bonds in the synthesis of pharmaceuticals, agrochemicals, and materials.^[4] Additionally, it participates in direct C-H borylation of arenes and the reduction of functional groups like nitriles and imines, expanding its utility in asymmetric synthesis and complex molecule assembly.^[5] Pinacolborane is typically synthesized by the reaction of pinacol with borane-methyl sulfide complex at 0 °C in dichloromethane, yielding the product as a solution that can be used directly or distilled under reduced pressure.^[5] Due to its high flammability (flash point 41 °F) and sensitivity to air and moisture, it requires storage under inert atmosphere at 2–8 °C and handling with appropriate safety precautions.^[2]

Introduction and Structure

Overview

Pinacolborane is an organoborane compound with the chemical formula HBpin or (CH₃)₄C₂O₂BH, where the "pin" abbreviation refers to the pinacolato ligand derived from pinacol, or 2,3-dimethylbutane-2,3-diol.^[6] This structure incorporates a boron hydride functional group within a five-membered ring, distinguishing it as a versatile hydroborating agent.^[6] First reported in 1992 by Tucker, Davidson, and Knochel, pinacolborane marked an advancement in boron reagent design, offering improved stability and selectivity compared to earlier boranes like catecholborane.^[6] Its introduction has since solidified its place in contemporary boron chemistry, supporting applications in selective hydroborations and related transformations.^[7] It appears as a colorless, monomeric liquid at room temperature, facilitating its handling in laboratory settings.^[2] The reactive B-H bond underpins its utility in these processes.^[6]

Molecular Structure

Pinacolborane has the molecular formula C₆H₁₃BO₂ and consists of a boron atom bonded to a hydride (B–H) and two oxygen atoms derived from the pinacol diolate ligand, which together form a five-membered B–O–C–C–O ring.^[6] The B–O bonds measure approximately 1.36 Å, while the B–H bond length is around 1.19 Å; the ring exhibits a puckered envelope conformation attributable to the steric demands of the four methyl substituents on the ethylene carbons.^[8] Structural features are corroborated by spectroscopy, including a ¹¹B NMR resonance at ~28 ppm and an IR absorption for the B–H stretch in the 2500–2600 cm⁻¹ region. In contrast to dialkylboranes that typically dimerize through bridging hydrides, pinacolborane remains monomeric due to the stabilizing chelation by the pinacolato moiety, which inhibits intermolecular associations.^[6]

Physical and Chemical Properties

Physical Properties

Pinacolborane (C₆H₁₃BO₂) has a molar mass of 127.98 g/mol.^[2] It appears as a clear, colorless to light yellow liquid at room temperature.^[2] The density is 0.882 g/cm³ at 25 °C.^[1] Its boiling point is 42–43 °C at 50 mmHg.^[1] The refractive index is 1.396 at 20 °C.^[2] Its vapor pressure is 29–119.9 hPa at 20–50 °C.^[2] Pinacolborane exhibits good solubility in common organic solvents, including dichloromethane and tetrahydrofuran, due to its nonpolar character, but it is insoluble in water, attributable to the hydrophobic methyl groups of the pinacol ligand.^[9][10] Spectroscopic characterization confirms its structure.

Chemical Properties

Pinacolborane features a polar B-H bond, where the hydrogen exhibits hydridic character, facilitating nucleophilic hydride transfer in reactions, while the boron center enables nucleophilic addition in processes such as hydroboration.^[11] The compound is air-sensitive and decomposes upon prolonged exposure to oxygen, though it can be handled briefly in air without significant degradation.^[1] Under inert atmosphere, pinacolborane demonstrates thermal stability suitable for reactions conducted up to approximately 100 °C.^[12] Pinacolborane reacts rapidly with protic compounds such as water or alcohols, undergoing protodeboronation to yield the corresponding boronic acid and hydrogen gas; for instance, the reaction with water proceeds as HBpin + H₂O → pinB-OH + H₂.^[13] In terms of redox behavior, the boron atom in pinacolborane adopts the +3 oxidation state and can undergo oxidation to borate species under appropriate conditions, such as in the presence of peroxo complexes.^[14] Reduction of the B-H bond occurs in specific catalytic contexts, leading to further transformation of the boron center. Pinacolborane acts as a Lewis acid at the electron-deficient boron site, readily forming adducts with Lewis bases including amines, which stabilize the complex through dative bonding.^[15]

Synthesis and Preparation

Laboratory Synthesis

Pinacolborane (HBpin) is commonly prepared in the laboratory by reacting pinacol with the borane-methyl sulfide complex (BH₃·SMe₂) at 0 °C in dichloromethane, which generates HBpin and dimethyl sulfide as a byproduct.^[6][5] The reaction proceeds as follows: $$\text{pinacol} + \ce{BH3 \cdot SMe2} \rightarrow \ce{HBpin} + \ce{Me2S}$$pinacol+\ceBH3⋅SMe2→\ceHBpin+\ceMe2S This approach, originally developed by Knochel and coworkers, affords HBpin in 63% yield after workup.^[6] An alternative synthetic route involves the condensation of pinacol with dichloroborane (HBCl₂) in the presence of a base such as triethylamine, producing HBpin and eliminating HCl.^[16] Additionally, HBpin can be generated from amine-borane adducts, such as the borane-diethylaniline complex, by reaction with pinacol at low temperature; this variant facilitates one-pot borylation sequences in subsequent transformations.^[17] These methods typically deliver yields of 63–91%, with the amine-borane approach reaching around 75%.^[17][5] The product is purified by vacuum distillation under reduced pressure.^[18] All preparations must be conducted under an inert atmosphere of nitrogen or argon to prevent decomposition.^[5] The synthesis was refined in 2008 to enable more practical and scalable production, circumventing the use of hazardous HBCl₂ while leveraging stable amine-borane precursors.^[17]

Commercial Availability

Pinacolborane is commercially produced on an industrial scale primarily through the reaction of pinacol with borane complexes, such as borane-dimethyl sulfide or borane-diethylaniline, in scaled-up processes that mirror laboratory methods but incorporate efficient distillation and stabilization techniques to achieve high yields.^[17] An alternative route involves the reduction of bis(pinacolato)diboron (B₂pin₂) via catalytic hydrogenolysis with H₂ using group 10 metal catalysts (such as Ni, Pd, or Pt), enabling cost-effective generation for larger volumes.^[19] Major producers and suppliers include Sigma-Aldrich (now MilliporeSigma), Thermo Fisher Scientific (incorporating Alfa Aesar), TCI Chemicals, and Oakwood Chemical Systems, with manufacturing facilities predominantly located in the United States and Europe.^[1][20][21] It is available in purity grades of 97% or higher, typically supplied as a stabilized colorless liquid in glass bottles ranging from 5 g to 25 g for laboratory use, with larger quantities (up to 100 g) offered for research-scale applications.^[1][20] Pricing varies by quantity and supplier, generally ranging from $6 to $20 per gram for small-scale purchases; for example, 5 g is available for approximately $33 from Oakwood Chemical and $66 from Sigma-Aldrich, while bulk pricing can drop to around $0.30 per gram for kilogram quantities from select manufacturers.^[21][1][2] Global supply is stable, with production centered in North America and the European Union to meet demand from research institutions and pharmaceutical industries, where its role in borylation reactions has driven increased procurement since the early 2000s.^[22] The market for pinacolborane was valued at approximately USD 100 million in 2023 and is projected to reach USD 200 million by 2032, reflecting growing applications in drug synthesis without reported shortages.^[22][23] Under the CAS number 25015-63-8, pinacolborane is registered and compliant with the EU REACH regulation, ensuring safe handling and environmental standards for import and use across member states as of 2025.^[24]

Applications in Organic Synthesis

Hydroboration Reactions

Pinacolborane (HBpin) serves as a key reagent in the catalytic hydroboration of alkenes and alkynes, enabling the syn, anti-Markovnikov addition of the B-H bond across unsaturated C-C bonds to produce alkylboronates or vinylboronates, respectively.^[25] For terminal alkenes, the reaction proceeds as R-CH=CH₂ + HBpin → R-CH₂-CH₂-Bpin, with the boron attaching selectively to the less substituted carbon.^[26] This process is typically catalyzed by late transition metal complexes, such as iridium or copper species, under mild conditions, offering a versatile route to organoboranes that can undergo subsequent transformations like Suzuki-Miyaura cross-coupling.^[25] Iridium-based catalysts, particularly [Ir(cod)OMe]₂ combined with bipyridine ligands like 4,4'-di-tert-butyl-2,2'-bipyridine, facilitate hydroboration of alkenes at room temperature using 1.2 equivalents of HBpin, achieving yields greater than 90% for a range of terminal alkenes with excellent regioselectivity (>95:5 in favor of the linear anti-Markovnikov product).^[26] These systems exhibit high functional group tolerance, including esters, ketones, and halides, without requiring protection, and extend effectively to internal alkenes and 1,3-dienes, where regioselectivity remains high for addition to the less hindered position.^[25] Copper catalysts, often phosphine-ligated Cu(I) complexes, provide complementary selectivity, particularly for enantioselective hydroboration of 1,1-disubstituted or aryl-substituted alkenes, delivering chiral alkylboronates with enantiomeric ratios up to 99:1. The mechanism for iridium-catalyzed hydroboration begins with oxidative addition of the B-H bond to the Ir(I) center, forming an Ir(III) hydride-boryl intermediate, followed by coordination and migratory insertion of the alkene into the Ir-H bond to generate an alkyliridium species, and concluding with reductive elimination to release the alkylboronate and regenerate the catalyst.^[25] In copper-catalyzed variants, the cycle typically involves formation of a Cu-H species, syn insertion of the alkene to yield an alkylcopper intermediate, and σ-bond metathesis with HBpin to transfer the boryl group and reform Cu-H, with the transmetalation step often rate-limiting.^[27] For alkynes, HBpin enables syn hydroboration to afford (Z)-vinylboronates from terminal substrates, catalyzed by iridium or copper complexes with high regioselectivity (boron addition to the terminal carbon) and yields exceeding 95%.^[25] These reactions are broadly applicable to aryl- and alkyl-substituted alkynes, providing intermediates for stereocontrolled synthesis of alkenes via protonolysis or oxidation.^[28] Overall, pinacolborane's hydroboration stands out for its efficiency in constructing C-B bonds with precise control, underpinning its utility in complex molecule assembly.^[25]

Carbonyl Reductions and Other Uses

Pinacolborane (HBpin) facilitates the hydroboration of carbonyl compounds, converting aldehydes and ketones to the corresponding alkoxypinacolboranes, which upon hydrolysis yield primary and secondary alcohols, respectively. For aldehydes, the reaction proceeds catalyst-free or with minimal catalysis under mild conditions, such as room temperature in tetrahydrofuran (THF), achieving yields of 82–99% for substrates like benzaldehyde and 4-nitrobenzaldehyde. In contrast, ketones often require a catalyst like potassium carbonate (K₂CO₃, 0.5–5 mol%) to attain high efficiency, with reactions at ambient temperature in THF yielding 86–99% for acetophenone and similar aryl alkyl ketones after 12 hours. The general transformation is represented as: $$\mathrm{R_2C=O + HBpin \rightarrow R_2CH-OBpin}$$R2​C=O+HBpin→R2​CH−OBpin followed by aqueous workup to alcohols, offering a metal-free alternative with broad substrate scope. The reduction of carboxylic acids to primary alcohols using HBpin proceeds through bis(boryl) intermediates and is notably chemoselective. Under catalyst-free conditions or with promoters like potassium tert-butoxide (KO^tBu, 1 mol%) in THF at room temperature, various aliphatic and aromatic carboxylic acids are converted to alcohols in excellent yields (75–92%), including complex molecules like naproxen (57% isolated on 1 g scale). The process involves in situ generation of borane species that selectively hydroborate the carboxylic acid carbonyl over other functional groups, with 6–7 equivalents of HBpin typically employed. This method avoids over-reduction and tolerates ketones, esters, and olefins. Pinacolborane also enables the hydroboration of nitriles and imines, converting them to N-boryl amines, which upon hydrolysis yield primary amines. These reactions proceed under mild conditions with various catalysts, including ruthenium complexes, achieving high yields (up to 99%) and good functional group tolerance for aryl, alkyl, and heteroaryl substrates.^[29] This provides a selective route to amines, useful in the synthesis of pharmaceuticals and fine chemicals. Iridium-catalyzed C-H borylation with HBpin enables the direct activation of aromatic C-H bonds, forming aryl pinacolboronate esters (Ar-Bpin) and H₂ under mild conditions. Using Ir(I) precursors with bipyridine ligands, such as [Ir(COD)OMe]₂ and 4,4'-di-tert-butylbipyridine, arenes undergo borylation at room temperature or 100 °C with high turnover numbers (>1000) and yields up to 90% for benzene and substituted arenes. The reaction favors less hindered, electron-rich positions and is particularly useful for installing directing groups in synthesis, with scope including electron-withdrawing and -donating substituents. Beyond reductions, HBpin reacts with Grignard reagents to form alkyl, aryl, vinyl, and allyl pinacolboronates in good yields under ambient conditions in THF, providing a mild, one-pot route without side products like Wurtz coupling. In polymer chemistry, Ir-catalyzed C-H borylation of aromatic main-chain polymers with HBpin introduces pinacolboronate groups that are converted to boronic acids for iterative Suzuki–Miyaura cross-couplings, enabling regioselective functionalization at meta positions relative to directing groups like sulfones. Compared to borane (BH₃), HBpin offers advantages in mild reaction conditions, enhanced functional group tolerance (e.g., selectivity for carboxylic acids over ketones), and stability, reducing over-reduction risks in complex syntheses.

Related Compounds

Diboron Analogues

Bis(pinacolato)diboron (B₂pin₂) is the primary diboron analogue of pinacolborane (HBpin), formed through the dehydrogenative dimerization of HBpin according to the reaction 2 HBpin → B₂pin₂ + H₂.^[30] This process is typically facilitated by transition metal catalysts such as rhodium or platinum complexes, enabling efficient coupling under mild conditions.^[30] B₂pin₂ serves as a convenient, storable equivalent of the "pinB" moiety, offering greater stability compared to HBpin. B₂pin₂ is a white solid with a melting point of 138 °C, exhibiting good air and moisture stability that allows for straightforward handling and long-term storage.^[31] Its synthesis from HBpin can also proceed via thermal or base-promoted methods, though catalytic approaches predominate due to higher yields and selectivity; B₂pin₂ is commercially available and preferred over HBpin in many borylation protocols because of its reduced tendency to liberate hydrogen gas during reactions.^[30][31] In organic synthesis, B₂pin₂ acts as a boron nucleophile for transferring the pinacolboryl (pinB) group, particularly in palladium-catalyzed cross-coupling reactions such as the Suzuki-Miyaura coupling, where it enables the formation of C-C bonds from aryl or vinyl halides.^[32] Compared to HBpin, B₂pin₂ is less reactive but circumvents issues associated with H₂ evolution, making it suitable for large-scale applications and one-pot borylations.^[30] Other variants include mixed diboron compounds like pinB-Bdan (where dan = naphthalene-1,8-diaminato), which feature boron atoms bound to different ligands for differential reactivity. These unsymmetrical diborons enable sequential functionalizations, such as selective transfer of one boryl group in diboration reactions, facilitating stereoselective synthesis of vicinal diboronates.

Other Borane Reagents

Catecholborane (HBcat) shares similar B-H insertion reactivity with pinacolborane (HBpin) in hydroboration processes but is notably more volatile, possessing a boiling point of 50 °C at 50 mmHg, which facilitates its distillation but requires careful handling to prevent evaporation losses.^[33] Unlike the more sterically encumbered HBpin, HBcat experiences less hindrance around the boron center, enabling faster hydroboration rates with alkenes and alkynes; however, this also renders it susceptible to protodeboronation under protic conditions, leading to deborylation side reactions that reduce yields in sensitive transformations.^[34] In practice, HBcat is often employed for rapid, transition-metal-catalyzed hydroborations where stability is secondary to speed, contrasting with HBpin's preference for applications demanding robust boronate ester products.^[25] 9-Borabicyclo[3.3.1]nonane (9-BBN), a dialkylborane reagent, demonstrates exceptional regioselectivity in hydroborations, particularly favoring terminal alkenes with up to 99% anti-Markovnikov addition due to its bulky bicyclic structure.^[35] In contrast to the monomeric HBpin, 9-BBN exists primarily as a dimer under ambient conditions, which limits its solubility in non-polar solvents like hexane (0.25 M at 25 °C) and necessitates dissolution in ethereal media such as THF for practical use.^[36] This dimerization enhances thermal stability but can complicate handling and slow reaction initiation compared to the freely soluble, monomeric HBpin, making 9-BBN ideal for selective mono-hydroborations of dienes or polyenes where steric control is paramount.^[37] Disiamylborane (Sia₂BH), another sterically demanding dialkylborane, excels in regioselective hydroborations of less hindered alkenes and alkynes, delivering high anti-Markovnikov selectivity similar to 9-BBN but with even greater bulk from its siamyl groups.^[38] Its reactivity toward carbonyl compounds is limited, often requiring elevated temperatures or specific conditions for reductions, rendering it less versatile than HBpin for multifunctional substrates involving both unsaturated bonds and carbonyls.^[39] Consequently, disiamylborane is typically reserved for precise alkene functionalizations where over-reduction of other groups must be avoided, whereas HBpin's chelated structure supports broader applicability in mixed transformations.^[40] The borane-tetrahydrofuran complex (BH₃·THF) serves as an unchelated, highly reactive hydroborating agent that readily adds to alkenes, alkynes, and carbonyls under mild conditions, often outperforming HBpin in terms of initial rate due to its lack of stabilizing ligands.^[41] However, its thermal instability—decomposing above 0 °C without stabilizers—contrasts sharply with HBpin's chelate-enhanced air and moisture tolerance, making BH₃·THF less suitable for prolonged or air-exposed reactions. HBpin is thus favored in modern protocols for its balance of reactivity and stability during air-sensitive manipulations.^[25] Overall, the pinacolato ligand in HBpin provides a key protective chelation that imparts advantages over dichloroborane (HBCl₂), including milder reaction conditions (often room temperature versus HBCl₂'s requirement for low temperatures to control exothermicity) and simpler handling without the corrosive HCl byproduct generation.^[42] This ligand shielding reduces boron's electrophilicity, enabling HBpin's widespread adoption in selective syntheses where HBCl₂'s high reactivity leads to over-addition or decomposition issues.^[43]

Safety and Handling

Hazards

Pinacolborane is a highly flammable liquid with a flash point of 5 °C (41 °F), capable of forming explosive mixtures with air over a wide range, and its vapors may travel to sources of ignition and flash back (GHS H225).^[44][45] This property underscores its potential to ignite spontaneously under ambient conditions, particularly when aerosolized or exposed to open flames, hot surfaces, or sparks. The compound presents notable reactivity hazards, reacting with moist air to release flammable hydrogen gas, which may self-ignite (GHS H260 or H261 depending on source), and reacting violently with water to liberate flammable hydrogen gas.^[46][9] Additionally, its water-reactive nature renders it corrosive to metals, potentially leading to structural degradation or hydrogen buildup in confined spaces.^[47] Health effects from exposure to pinacolborane include skin irritation (GHS H315) and serious eye damage or irritation (GHS H319), with inhalation potentially causing respiratory tract irritation.^[45][48] Some safety data sheets, such as from Thermo Fisher (revision September 2025), classify it with reproductive toxicity (GHS H360, may damage fertility or the unborn child) based on data for analogous boron compounds; others, like Sigma-Aldrich (November 2025), do not include this classification.^[45][44] No specific OSHA permissible exposure limit (PEL) exists for pinacolborane, requiring handling under inert atmospheres to prevent exposure; toxicological data remains limited, though oral LD50 values for similar boranes are approximately 500 mg/kg in rats.^[48][49] Note that GHS classifications for hazards like water reactivity (H260 vs. H261) and reproductive toxicity vary across manufacturers' 2025 safety data sheets.^[44][45]

Storage and Disposal

Pinacolborane must be stored in tightly closed containers under an inert atmosphere, such as nitrogen, at refrigerated temperatures of 2–8 °C in a cool, dry, and well-ventilated area to prevent degradation and reaction with moisture.^[44] It should be kept away from incompatible materials including water, strong oxidizers, heat sources, sparks, and open flames to avoid violent reactions or fire hazards.^[24] Suitable containers include glass bottles, often amber-tinted for light protection, though standard laboratory glassware suffices under inert conditions.^[50] For transportation, pinacolborane is classified as an organometallic substance, liquid, water-reactive, and flammable under UN 3399, with a primary hazard class of 4.3 (substances that emit flammable gases upon contact with water) and a subsidiary risk of class 3 (flammable liquids), packing group II.^[44] Shipments must comply with regulations from bodies like the U.S. Department of Transportation (DOT), International Air Transport Association (IATA), or International Maritime Dangerous Goods (IMDG) code, which limit quantities—for instance, up to 1 L may be transported without additional placarding in non-bulk packaging under certain exemptions.^[24] Disposal of pinacolborane requires treatment as hazardous waste due to its reactivity and flammability; small laboratory quantities can be safely neutralized by slow addition to a large volume of ice-cold dilute aqueous sodium hydroxide solution under inert atmosphere and controlled ventilation to generate borate salts and hydrogen gas, followed by dilution with water and disposal in accordance with local environmental regulations such as U.S. EPA Resource Conservation and Recovery Act (RCRA) guidelines, which may deem the treated effluent non-hazardous after verification. Larger amounts or untreated material should be collected in sealed containers and sent to a licensed chemical waste disposal facility for incineration with flue gas scrubbing to prevent boron release.^[46] Contaminated packaging must be treated similarly to the product itself.^[50] In case of spills, evacuate the area immediately, eliminate ignition sources, and ensure adequate ventilation while wearing appropriate personal protective equipment including chemical-resistant gloves, safety goggles, and fire-resistant clothing.^[44] Contain the spill using inert absorbents such as vermiculite or sand, avoiding water-based materials, then transfer to a spark-proof container for disposal; do not flush to sewers.^[24] As of 2025, under the European Union's Classification, Labelling and Packaging (CLP) Regulation, pinacolborane requires GHS pictograms for flammability (flame) and exclamation mark (for skin and eye irritation), with no specific updates altering its water-reactive classification.^[50] It is considered a persistent substance with no known biodegradation pathways, necessitating treatment as non-biodegradable waste.^[44]