2-Bromopropane

2-Bromopropane, also known as isopropyl bromide, is an organobromine compound with the molecular formula C₃H₇Br and the structural formula (CH₃)₂CHBr.^[1] It is a secondary alkyl halide that appears as a colorless to slightly yellow, volatile liquid with a sweet, ether-like odor.^[2][3]

Physical and Chemical Properties

2-Bromopropane has a molecular weight of 122.99 g/mol, a density of 1.31 g/mL at 25 °C, a boiling point of 59 °C, and a melting point of -89 °C.^[1][2][3] Its flash point is 19 °C, making it highly flammable, and it has low solubility in water (0.3 g/100 mL) but is miscible with many organic solvents.^[2][4] Chemically, it undergoes typical reactions of secondary alkyl bromides, including nucleophilic substitution (SN1 and SN2) and elimination to form propene.^[1]

Preparation

2-Bromopropane is commonly prepared by the reaction of isopropyl alcohol (isopropanol) with hydrobromic acid, often involving heating to facilitate the substitution.^[2] This method yields the compound through protonation of the alcohol followed by bromide ion attack.^[1]

Uses

In organic synthesis, 2-bromopropane serves primarily as an alkylating agent to introduce the isopropyl group into molecules, such as in the preparation of ligands or other intermediates.^[1][3] It is also employed as a solvent in industrial cleaning processes and as an intermediate in the production of amines and organometallic compounds.^[2] Historically, it has been used in electronics manufacturing for cleaning, though such applications have raised health concerns.^[5]

Safety and Toxicity

2-Bromopropane is classified as highly flammable (Hazard Class 3, UN 2344) and poses risks of skin, eye, and respiratory irritation upon exposure.^[2][6] It is a reproductive toxicant (Category 1B), capable of damaging fertility and the unborn child, and has been linked to hematopoietic disorders.^[2][1] The International Agency for Research on Cancer (IARC) classifies it as probably carcinogenic to humans (Group 2A), based on sufficient evidence of carcinogenicity in experimental animals.^[7] This classification stems from studies showing tumors in rodents and human epidemiological data.^[7] A notable 1995 incident in South Korea involved occupational exposure to high levels of 2-bromopropane in a cleaning facility, resulting in an outbreak of reproductive and hematopoietic disorders among workers, which heightened global awareness of its hazards.^[8] Exposure limits are recommended below 10 ppm (TWA) to minimize risks.^[5]

Structure and identification

Molecular structure

2-Bromopropane has the molecular formula C₃H₇Br and the condensed structural formula CH₃CHBrCH₃, in which a bromine atom is covalently bonded to the central carbon of a linear three-carbon chain flanked by two methyl groups.^[1] This arrangement positions the bromine on a secondary carbon atom, classifying the compound as a secondary alkyl bromide, where the halogen-bearing carbon is directly attached to two alkyl groups. The molecule is also known by its common name, isopropyl bromide.^[1] The central carbon atom in 2-bromopropane adopts a tetrahedral geometry due to sp³ hybridization, resulting in bond angles of approximately 109.5° around this atom. The C-Br bond length measures 1.957 Å, as determined by microwave spectroscopy.^[9] In the Simplified Molecular Input Line Entry System (SMILES) notation, the structure is represented as CC(C)Br, reflecting the branched propane backbone with bromine substitution.^[1] This compound exists as one of two isomers with the formula C₃H₇Br; the other is 1-bromopropane (CH₃CH₂CH₂Br), a primary alkyl bromide where bromine attaches to a terminal carbon, leading to distinct chemical behaviors despite sharing the same molecular formula.

Nomenclature

2-Bromopropane is the systematic name according to the International Union of Pure and Applied Chemistry (IUPAC) nomenclature for halogenated hydrocarbons, where the parent chain is propane and the bromine substituent is located at the second carbon atom. This naming convention prioritizes the longest carbon chain and assigns the lowest possible number to the halogen substituent. Commonly, it is referred to as isopropyl bromide or 2-propyl bromide, names derived from the isopropyl group attached to the bromine atom, a traditional approach in organic chemistry for simple alkyl halides.^[3] These alternative designations highlight its role as a secondary alkyl bromide and have been used historically in chemical literature to denote the branched structure corresponding to CH₃CHBrCH₃. Unique identifiers for 2-bromopropane include the CAS Registry Number 75-26-3, which uniquely catalogs the substance in chemical databases, and the European Community (EC) Number 200-855-1, assigned by the European Chemicals Agency for regulatory purposes.^[10] Additionally, its International Chemical Identifier (InChI) is InChI=1S/C3H7Br/c1-3(2)4/h3H,1-2H3, providing a standardized textual representation of its molecular structure for computational and database applications.^[1]

Physical and thermodynamic properties

Appearance and phase behavior

2-Bromopropane is a colorless to slightly yellow liquid at room temperature.^[1] Its molar mass is 122.993 g/mol.^[1] The compound has a density of 1.31 g/mL at 20 °C.^[4] It exhibits a low melting point of -89.0 °C, indicating it remains in the liquid phase under typical ambient conditions, and a boiling point ranging from 59 to 61 °C at standard pressure.^[3] These phase transition temperatures highlight its volatility as a small alkyl halide. The flash point of 2-bromopropane is 19 °C, underscoring its flammability.^[6] Its vapor pressure is 31.5 kPa at 25 °C, further contributing to its ease of evaporation and potential for vapor-phase hazards.^[11]

Solubility and other properties

2-Bromopropane exhibits limited solubility in water, with a reported value of approximately 3.18 g/L at 20°C, reflecting its hydrophobic character due to the nonpolar alkyl chain and bromine substituent.^[2] It is miscible with common organic solvents such as ethanol, diethyl ether, chloroform, acetone, and benzene, facilitating its use in non-aqueous reaction media.^[12] This solubility profile underscores its preference for lipophilic environments over aqueous ones.^[1] The octanol-water partition coefficient (log P) of 2-bromopropane is 2.14, indicating moderate lipophilicity that influences its distribution between organic and aqueous phases in biological and environmental contexts.^[13] Key optical and transport properties include a refractive index of 1.4251 at 20°C, as measured for the sodium D line, which is consistent with its molecular structure.^[1] The dynamic viscosity is 0.49 mPa·s at 20°C, contributing to its flow behavior as a low-viscosity liquid suitable for synthetic applications.^[13] Additionally, the dielectric constant is approximately 9.46 at 25°C, highlighting its moderate polarity as a solvent.^[2]

Chemical properties

Reactivity and reactions

2-Bromopropane, as a secondary alkyl halide, exhibits reactivity characteristic of this class, undergoing nucleophilic substitution via SN1 and SN2 mechanisms or elimination via E1 and E2 pathways, with the dominant process depending on factors such as the nucleophile/base strength, solvent polarity, and temperature.^[14] The bromine atom serves as an effective leaving group due to its weak C-Br bond and ability to stabilize the transition state or carbocation intermediate.^[15] In polar protic solvents, the secondary nature of the central carbon facilitates SN1 and E1 reactions through carbocation formation, where the planar intermediate allows nucleophilic attack from either side, often leading to racemization.^[16] A representative substitution reaction occurs with sodium methylthiolate (NaSCH₃) in a polar aprotic solvent, proceeding via an SN2 mechanism to yield isopropyl methyl sulfide, $\ce{(CH3)2CHSCH3}$\ce(CH3)2CHSCH3, with inversion of configuration at the chiral center.^[15] This backside attack by the strong nucleophilic thiolate ion displaces bromide in a concerted, bimolecular process, favored for secondary halides under these conditions.^[14] In contrast, treatment with sodium methoxide (NaOMe) in methanol typically favors elimination, predominantly forming propene ($\ce{CH3CH=CH2}$\ceCH3CH=CH2) and HBr through an E2 mechanism, where the strong base abstracts a β-proton anti-periplanar to the leaving group in a single step.^[17] This bimolecular elimination is enhanced by the basic conditions and elevated temperatures, outcompeting substitution.^[15]

Stability

2-Bromopropane is chemically stable under normal storage and handling conditions at room temperature and atmospheric pressure.^[2] It is generally stable to light and air under normal conditions, though prolonged exposure to heat should be avoided.^[1] It undergoes slow hydrolysis in aqueous solution, with a half-life of approximately 2.1 days at 25 °C and pH 7.^[1] In the presence of strong bases such as sodium hydroxide or potassium hydroxide, particularly when heated, 2-bromopropane decomposes via dehydrohalogenation, yielding propene and hydrogen bromide gases.^[18] This exothermic elimination reaction generates gaseous products that can cause significant pressure buildup in closed vessels, potentially leading to rupture if not properly vented.^[19] To reduce the risk of such decomposition during base-catalyzed substitution reactions, milder bases like potassium carbonate are recommended over sodium hydroxide or potassium hydroxide, as they promote nucleophilic substitution while minimizing elimination pathways.^[20] Regarding thermal stability, 2-bromopropane remains intact below its boiling point of 59–61 °C but decomposes at elevated temperatures, releasing toxic hydrogen bromide fumes.^[1] Decomposition occurs at 251 °C, consistent with unimolecular elimination processes observed in alkyl bromides.^[19]

Synthesis

Laboratory methods

2-Bromopropane is commonly prepared in laboratory settings through the nucleophilic substitution reaction of isopropanol with hydrobromic acid, a standard method for converting secondary alcohols to alkyl bromides. The reaction proceeds as follows: $$(\ce{CH3})_2\ce{CHOH} + \ce{HBr} \rightarrow (\ce{CH3})_2\ce{CHBr} + \ce{H2O}$$(\ceCH3)2​\ceCHOH+\ceHBr→(\ceCH3)2​\ceCHBr+\ceH2O In a typical procedure, 40 g (51 mL) of isopropanol is mixed with 460 g (310 mL) of 48% hydrobromic acid in a 500 mL distilling flask equipped with a reflux condenser. The mixture is gently heated and distilled slowly at a rate of 1-2 drops per second until approximately half the volume has passed over, which takes about 1 hour at around 100°C. The lower organic layer is separated, and the aqueous layer is redistilled to recover additional product. The combined organic layers are washed successively with concentrated hydrochloric acid, water, 5% sodium bicarbonate solution, and water to remove impurities, then dried over anhydrous calcium chloride. The product is purified by distillation, collecting the fraction boiling at 59°C under atmospheric pressure, although reduced pressure (e.g., 100-200 mmHg) is often employed to minimize potential decomposition via elimination of HBr at higher temperatures. This method typically affords yields of 70-80%, with 66 g of pure 2-bromopropane obtained from the starting 40 g of isopropanol.^[21] An alternative laboratory route utilizes phosphorus tribromide (PBr₃) as the brominating agent, which reacts with isopropanol to form 2-bromopropane while avoiding the need for pre-formed hydrobromic acid. The balanced equation is: $$3 (\ce{CH3})_2\ce{CHOH} + \ce{PBr3} \rightarrow 3 (\ce{CH3})_2\ce{CHBr} + \ce{H3PO3}$$3(\ceCH3)2​\ceCHOH+\cePBr3→3(\ceCH3)2​\ceCHBr+\ceH3PO3 The reaction is conducted by adding isopropanol dropwise to PBr₃ at low temperature (0-5°C) to control the exothermic process, followed by warming to room temperature or gentle reflux (around 100-110°C) for 1-2 hours. The mixture is then poured into ice water, and the organic layer is separated, washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to yield the product. This approach is preferred for smaller scales or when high purity is required, as it proceeds via an SN2 mechanism with inversion at the chiral center if applicable, and typically provides yields of 80-90%.^[21] Another established method involves the in situ generation of PBr₃ from red phosphorus and bromine in the presence of isopropanol, an older but effective technique for bench-scale preparation. Red phosphorus (approximately 1/3 the weight of the alcohol) is added to isopropanol, followed by the slow addition of bromine (3 equivalents) with cooling to maintain temperatures below 50°C initially, then refluxed at 100-120°C for 2-3 hours. The reaction mixture is worked up similarly by dilution with water, extraction of the organic phase, washing, drying, and distillation under reduced pressure to isolate 2-bromopropane, achieving yields in the 70-85% range. This route is particularly useful in laboratories where PBr₃ is not readily available.^[21] 2-Bromopropane is commercially available from chemical suppliers, allowing researchers to bypass synthesis when small quantities are needed.^[1]

Industrial production

2-Bromopropane is commercially produced on an industrial scale primarily through the nucleophilic substitution reaction of isopropanol (2-propanol) with hydrogen bromide (HBr), typically conducted by heating the mixture to facilitate the conversion. This process yields 2-bromopropane as a distillable product, with the reaction often optimized for selectivity toward the secondary bromide over potential n-propyl isomers. In many manufacturing setups, HBr is generated in situ from sodium bromide (NaBr) and concentrated sulfuric acid to avoid handling and storage challenges associated with anhydrous HBr gas.^[2] The reaction mixture is heated to 140–150°C, allowing 2-bromopropane to be isolated via distillation, achieving high yields suitable for large-scale operations.^[22] To enhance efficiency and scalability, industrial processes have incorporated continuous flow reactors and catalytic systems, such as supported acid catalysts like sulfated zirconia on alumina, which promote the bromination while minimizing side reactions and energy use.^[23] These advancements address scale-up challenges, including heat management and byproduct formation (e.g., water and salts), enabling consistent production rates. Global manufacturing is concentrated in Asia, with at least 13 producers in China; one facility reported an output of 2,000 tonnes in 2015. In the United States, annual production volumes were below 450 tonnes from 2016 to 2019, primarily for use as a chemical intermediate. Japan recorded 1–1,000 tonnes per year from 2012 to 2020, peaking at 1,000–2,000 tonnes in 2014. Overall, worldwide output reaches several thousand tonnes annually (data as of 2020), supplied by companies such as Great Lakes Chemical and various Chinese firms.^[24] The cost-effectiveness of production stems from the availability of inexpensive feedstocks: isopropanol derived from propylene hydration and bromide sources like NaBr from industrial brines.^[2] Historically, production expanded in the 1990s, particularly in Asia, as 2-bromopropane served as a substitute for ozone-depleting chlorofluorocarbons (CFCs) and 1,1,1-trichloroethane in solvent applications, driven by the Montreal Protocol.^[25] This shift increased demand and prompted process refinements for broader industrial adoption.

Applications

In organic synthesis

2-Bromopropane serves as a versatile alkylating agent in organic synthesis, primarily for introducing the isopropyl group into molecules through nucleophilic substitution reactions, enabling the formation of carbon-carbon (C-C) and carbon-nitrogen (C-N) bonds. It reacts with nucleophiles such as carbanions or amines to produce isopropyl-substituted derivatives, including isopropyl amines via SN2 displacement. For instance, treatment with primary amines under basic conditions yields N-isopropylated products, which are valuable intermediates in alkaloid synthesis. Similarly, in ether synthesis, 2-bromopropane undergoes Williamson etherification with phenoxides to form isopropyl aryl ethers, as demonstrated in the preparation of isopropyl (2-isopropylphenyl) ether from 2-isopropylphenol and the bromide in the presence of a base.^[24][22][26] A key application involves its conversion to Grignard reagents, which extend its utility in C-C bond formation. The reaction of 2-bromopropane with magnesium in anhydrous ether produces isopropylmagnesium bromide, a nucleophilic organometallic species used to alkylate carbonyl compounds like aldehydes and ketones to yield tertiary alcohols with isopropyl substitution. This Grignard reagent is prepared under standard conditions, typically refluxing the halide with magnesium turnings in diethyl ether or tetrahydrofuran, and finds broad use in laboratory-scale syntheses of complex organics. The equation for the formation is: $$(CH_3)_2CHBr + Mg \rightarrow (CH_3)_2CHMgBr$$(CH3​)2​CHBr+Mg→(CH3​)2​CHMgBr As a secondary alkyl halide, 2-bromopropane exhibits slower reaction rates in SN2 processes compared to primary halides due to steric hindrance at the carbon bearing the bromine, with relative rates approximately 1500 times slower than methyl halides and 50 times slower than primary analogs. This reduced reactivity can be advantageous for selective substitutions in multifunctional molecules, where primary sites react preferentially, allowing controlled isopropylation at secondary positions under optimized conditions like polar aprotic solvents.^[27][28][29] In pharmaceutical synthesis, 2-bromopropane acts as an intermediate for drugs like boceprevir and paxlovid, where it alkylates diphenyl sulfide to form key precursors via SN2 reaction, followed by further transformations to the active antiviral agents. For agrochemicals, it is employed in the production of herbicides such as napropamide, where the isopropyl group is introduced to the amide scaffold to enhance herbicidal activity against weeds in crops. These applications highlight its role in constructing branched structures essential for biological activity in both sectors.^[30][31]

Industrial uses

2-Bromopropane serves as a solvent in dry cleaning operations, where it facilitates the removal of soils from fabrics without damaging materials.^[32] It is also employed in adhesive production and application, aiding in the formulation and deployment of spray adhesives for industrial bonding processes.^[32] In the manufacturing of 1-bromopropane, a common degreaser, 2-bromopropane appears as an impurity or byproduct, typically present in small amounts that can influence the overall performance of the degreasing solvent in metal and plastics cleaning.^[33][32] As an intermediate, 2-bromopropane plays a key role in the production of pharmaceuticals, agrochemicals such as pesticides, dyes, and fragrances, where it introduces the isopropyl group into molecular structures during synthesis.^[32] It functions as a raw material for various specialty chemicals.^[22] Additionally, 2-bromopropane acts as a substitute for ozone-depleting solvents like chlorofluorocarbons in cleaning applications.^[1] Its use is significant in electronics cleaning, where it removes fluxes and contaminants from circuit boards, and in polymer processing, supporting the synthesis of additives and plasticizers.^[34][22] As a high-production-volume chemical, these applications reflect its substantial industrial scale.^[35]

Safety and toxicology

Health hazards

2-Bromopropane poses significant health risks to humans, primarily through inhalation as the main exposure route, though dermal contact and ingestion also contribute to toxicity. Acute exposure can lead to symptoms such as dizziness, nausea, vomiting, respiratory irritation, and skin dryness or cracking, with potential central nervous system depression at higher concentrations.^[1][6] Under the Globally Harmonized System (GHS), 2-bromopropane is classified as a highly flammable liquid (H225), a reproductive toxicant (H360: may damage fertility or the unborn child), and a specific target organ toxicant for repeated exposure (H373: may cause damage to organs through prolonged or repeated exposure, particularly the central nervous system, liver, and heart). The oral LD50 in rats is 3,600 mg/kg, indicating moderate acute toxicity.^[36][6] Reproductive toxicity is a primary concern, with 2-bromopropane causing ovarian and testicular damage, reduced sperm counts, impaired fertility, and menstrual irregularities in exposed individuals and animal models. It is listed under California Proposition 65 as known to cause reproductive toxicity (listed May 31, 2005), particularly for females, and cancer (listed August 11, 2023), based on evidence of infertility, ovarian failure, and IARC classification. The National Toxicology Program's Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) concludes there is some concern for adverse reproductive effects at high-end occupational exposure levels.^[37][38][39] Regarding carcinogenicity, the International Agency for Research on Cancer (IARC) classifies 2-bromopropane as probably carcinogenic to humans (Group 2A; as of July 2024), supported by sufficient evidence of tumor induction in experimental animals, including lung, skin, and intestinal tumors in rasH2 transgenic mice.^[7] Additional toxic effects include hematopoietic toxicity manifesting as anemia and leukopenia, developmental toxicity such as increased fetal death, reduced litter size, and lower fetal weight in rodent studies following inhalation exposure, and organ-specific damage to the central nervous system (e.g., neurotoxicity with behavioral changes), liver, and heart.^[40][41][42] Occupational case studies from the 1990s in South Korea highlight these risks, where workers in an electronics factory exposed to 2-bromopropane-containing solvents experienced outbreaks of hematopoietic disorders (e.g., anemia) and severe reproductive issues, including amenorrhea in females and oligospermia in males, with poor prognosis for fertility recovery.^[43][44]

Environmental considerations

2-Bromopropane is a volatile organic compound with a high vapor pressure of 216 mm Hg at 25°C, facilitating rapid volatilization from soil and water surfaces.^[1] Its estimated Henry's Law constant of 0.011 atm·m³/mol supports significant partitioning to air, promoting evasion from aquatic and moist soil environments.^[1] In soil, an estimated Koc value of 350 indicates moderate mobility, allowing potential leaching into groundwater.^[1] Atmospheric degradation occurs primarily via reaction with hydroxyl radicals, with an estimated half-life of 25 days; direct photolysis is negligible due to the absence of chromophores absorbing sunlight.^[1] Hydrolysis in neutral water proceeds with a half-life of approximately 2.1 days at 25°C and pH 7, contributing to its limited persistence in aqueous media.^[1] Bioaccumulation potential is low, with an estimated bioconcentration factor (BCF) of 9–15 in aquatic organisms, derived from its measured log Kow of 2.14.^[1] This suggests minimal uptake and retention in biota, though its moderate hydrophobicity may enable some partitioning into fatty tissues.^[1] Ecotoxicity assessments indicate harm to aquatic life, with an LC50 of 150 mg/L for goldfish (Carassius auratus) over 24 hours, classifying it as acutely toxic at higher concentrations.^[45] Although evaluated as a potential substitute for ozone-depleting chlorofluorocarbons due to its short atmospheric lifetime, 2-bromopropane releases bromine atoms upon degradation, which can participate in catalytic ozone depletion cycles in the stratosphere.^[46] Model calculations suggest it has a low ozone depletion potential (ODP) relative to CFC-11, similar to other short-lived brominated hydrocarbons.^[47] Under the European Union's REACH regulation, 2-bromopropane is classified as toxic to reproduction (category 1B) based on evidence of fertility impairment and developmental toxicity, subjecting it to authorization and restriction requirements for uses posing risks.^[48] In the United States, it is not designated as a hazardous air pollutant (HAP) by the EPA, unlike its isomer 1-bromopropane, though it is monitored in industrial contexts due to co-occurrence as a manufacturing impurity.^[49] Emissions primarily arise from its use in organic synthesis and solvent applications within industrial processes, with volatilization being the dominant release pathway.^[1] Biodegradation is feasible under aerobic conditions, as demonstrated by microbial degradation using marine yeast isolates, but data on anaerobic environments are limited, suggesting slower or incomplete breakdown in oxygen-poor settings like sediments.^[24]