2-Bromo-5-Fluorotoluene: Properties, Synthesis & Applications

2-Bromo-5-fluorotoluene is a difunctionalized halogenated aromatic compound widely used as a versatile building block in pharmaceutical synthesis, agrochemical development, and transition-metal-catalyzed cross-coupling reactions.

CAS Number

1422-54-4

Molecular Formula

C7H6BrF

Molecular Weight

189.02 g/mol

Appearance

Colorless to pale yellow liquid

Key Functional Groups

Aryl bromide, aryl fluoride, methyl substituent

Primary Use

Synthetic building block in cross-coupling and nucleophilic aromatic substitution reactions

Storage

Store in a cool, dry, well-ventilated area away from light and moisture

Chemical Identity and Physical Properties

2-Bromo-5-fluorotoluene (CAS 1422-54-4) is a monosubstituted benzene derivative bearing a bromine atom at the 2-position, a fluorine atom at the 5-position, and a methyl group at the 1-position of the aromatic ring. Its molecular formula is C₇H₆BrF with a molecular weight of approximately 189.02 g/mol.

The compound is typically encountered as a colorless to pale yellow liquid at room temperature. The simultaneous presence of bromine and fluorine on the aromatic ring imparts distinct electronic properties: the fluorine atom is a strong inductive electron-withdrawing group and a weak π-donor, while the bromine serves as a leaving group amenable to oxidative addition into transition-metal catalysts. The methyl group provides a modest electron-donating effect through hyperconjugation and can serve as a handle for further functionalization.

The ortho relationship between the bromine and methyl groups introduces a degree of steric influence that can be exploited to direct regioselectivity in downstream transformations. These combined electronic and steric features make 2-bromo-5-fluorotoluene a predictable and reliable reagent for complex molecule synthesis.

Synthesis and Preparation Methods

2-Bromo-5-fluorotoluene is most commonly prepared via electrophilic aromatic bromination of 4-fluorotoluene. Using bromine (Br₂) in the presence of a Lewis acid catalyst such as FeBr₃ or AlBr₃, electrophilic substitution is directed ortho to the methyl group and ortho/para to the fluorine atom. The confluence of these directing effects favors formation of the 2-bromo-5-fluoro regioisomer as the predominant product, though careful control of reaction conditions is required to minimize formation of regioisomeric byproducts.

An alternative synthetic route involves the Balz-Schiemann reaction, where an appropriately substituted aniline precursor is diazotized and subsequently treated with fluoroboric acid to introduce the fluorine substituent. However, the direct bromination of 4-fluorotoluene remains the more operationally straightforward and scalable approach for laboratory and industrial-scale production.

Purification is typically achieved by fractional distillation under reduced pressure or by column chromatography on silica gel, yielding the target compound in high purity. Commercial suppliers, including Aladdin Scientific (SKU: B120723), provide this compound in research-grade purity suitable for direct use in synthetic applications.

Synthetic Utility and Key Reactions

The principal synthetic value of 2-bromo-5-fluorotoluene lies in its aryl C–Br bond, which undergoes facile oxidative addition to Pd(0), Ni(0), and other low-valent transition-metal complexes. This makes it an excellent electrophilic partner in a broad array of metal-catalyzed cross-coupling reactions, including:

• Suzuki–Miyaura coupling: Reaction with aryl- or heteroarylboronic acids in the presence of a Pd catalyst and base furnishes biaryl and aryl-heteroaryl products bearing the 4-fluoro-2-methylphenyl motif.
• Buchwald–Hartwig amination: Palladium-catalyzed C–N bond formation with primary or secondary amines enables access to fluorine-containing diarylamines and N-aryl heterocycles.
• Negishi and Kumada couplings: Transmetalation with organozinc or organomagnesium reagents provides efficient routes to alkyl- or aryl-substituted fluorotoluene derivatives.
• Lithium–halogen exchange: Treatment with n-BuLi at low temperature generates a stable aryllithium species that can be trapped with a wide range of electrophiles, enabling introduction of aldehyde, ketone, ester, boronate, and other functional groups at the former bromide position.

The fluorine substituent, while less reactive toward oxidative addition than bromine under standard cross-coupling conditions, can participate in nucleophilic aromatic substitution (SNAr) when activated by additional electron-withdrawing groups or under forcing conditions, or it can be retained as a bioactive fluorine motif in the final product.

Applications in Pharmaceutical and Agrochemical Research

Fluorinated aromatic compounds occupy a central position in modern medicinal chemistry. The strategic incorporation of fluorine into drug candidates is known to modulate metabolic stability, membrane permeability, binding affinity, and pKa of adjacent ionizable groups. 2-Bromo-5-fluorotoluene serves as a key precursor for introducing the 4-fluoro-2-methylphenyl pharmacophore into lead compounds.

Documented areas of application include:

• Kinase inhibitor synthesis: The fluorotoluene scaffold is frequently encountered in the construction of ATP-competitive kinase inhibitors, where the fluorine atom contributes to optimized binding within the hinge region of the kinase active site.
• GPCR ligand development: Fluorinated aryl groups are incorporated into G-protein-coupled receptor ligands to fine-tune lipophilicity and metabolic resistance.
• Agrochemical active ingredients: Fluorinated toluene-derived intermediates appear in the synthesis of modern fungicides and herbicides, where fluorine enhances bioactivity and environmental persistence profiles.
• Materials science: Functionalized fluorinated aromatics derived from 2-bromo-5-fluorotoluene have been explored as components of liquid crystals and organic electronic materials, where the fluorine atom influences molecular packing and charge transport.

In all these contexts, the ready commercial availability of 2-bromo-5-fluorotoluene (Aladdin Scientific SKU: B120723) in research-grade purity facilitates rapid access to complex molecular targets without the need for multistep preparation of the aryl halide starting material.

Handling, Safety, and Storage Guidelines

As with all halogenated aromatic reagents, appropriate precautions should be observed when handling 2-bromo-5-fluorotoluene. Researchers should consult the current Safety Data Sheet (SDS) prior to use. General guidance includes:

• Personal protective equipment (PPE): Wear chemically resistant gloves (nitrile or neoprene), safety goggles, and a laboratory coat. Work in a fume hood to avoid inhalation of vapors.
• Storage: Store in a tightly closed container in a cool (typically 2–25 °C), dry, well-ventilated area, away from direct light, heat sources, and incompatible materials such as strong oxidizers and strong bases.
• Waste disposal: Dispose of waste material in accordance with local, regional, and national regulations governing halogenated organic solvents and reagents.
• Spill management: Absorb spills with inert material (e.g., vermiculite or dry sand), collect into sealed containers, and handle as chemical waste.

2-Bromo-5-fluorotoluene should be regarded as a potential skin and eye irritant. Prolonged or repeated exposure should be avoided. In the event of skin or eye contact, flush immediately with copious water and seek medical advice. No specific antidote is known; treatment is supportive and symptomatic.

The compound is stable under recommended storage conditions and does not require special stabilizers. However, exposure to moisture over extended periods should be minimized to prevent potential hydrolysis of labile intermediates generated in downstream reactions.

Frequently asked questions

What is the CAS number of 2-bromo-5-fluorotoluene?

The CAS registry number for 2-bromo-5-fluorotoluene is 1422-54-4. This number uniquely identifies the compound across chemical databases and supplier catalogues. Aladdin Scientific lists this compound under SKU B120723.

Which cross-coupling reactions are most commonly used with 2-bromo-5-fluorotoluene?

2-Bromo-5-fluorotoluene is most frequently employed in Suzuki–Miyaura (Pd-catalyzed coupling with boronic acids), Buchwald–Hartwig amination (C–N bond formation), Negishi coupling (with organozinc reagents), and Kumada coupling (with Grignard reagents). It can also undergo lithium–halogen exchange with n-BuLi to generate an aryllithium nucleophile for reaction with a broad range of electrophiles.

Can the fluorine atom in 2-bromo-5-fluorotoluene participate in nucleophilic aromatic substitution?

Under standard cross-coupling conditions, the C–F bond is significantly less reactive than the C–Br bond toward oxidative addition to transition metals. However, the fluorine substituent can participate in nucleophilic aromatic substitution (SNAr) when the ring is sufficiently activated by additional electron-withdrawing groups or under harsh forcing conditions. In many synthetic applications, the fluorine is intentionally retained in the final product as a bioactive or physicochemical modulating element.

How should 2-bromo-5-fluorotoluene be stored to maintain its stability?

2-Bromo-5-fluorotoluene should be stored in a tightly sealed container at cool temperatures (typically 2–25 °C), in a dry, well-ventilated area protected from light and moisture. No special stabilizers are required. Under these conditions the compound is chemically stable for extended periods. Always consult the current SDS from the supplier for the most up-to-date storage recommendations.

What is the molecular weight of 2-bromo-5-fluorotoluene?

The molecular weight of 2-bromo-5-fluorotoluene (C7H6BrF) is approximately 189.02 g/mol. This value is used for stoichiometric calculations when preparing reaction mixtures and solutions in the laboratory.

References

1. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012. (General reference for electrophilic aromatic substitution and cross-coupling reactions.)
2. Beletskaya, I. P.; Cheprakov, A. V. The Heck reaction as a sharpening stone of palladium catalysis. Chem. Rev. 2000, 100 (8), 3009–3066. doi:10.1021/cr9903048
3. Müller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 2007, 317 (5846), 1881–1886. doi:10.1126/science.1131943
4. Hartwig, J. F. Evolution of a fourth generation catalyst for the amination and thioetherification of aryl halides. Acc. Chem. Res. 2008, 41 (11), 1534–1544. doi:10.1021/ar800098p

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