Cyclobutyl Bromide: Properties, Synthesis & Lab Uses

Cyclobutyl Bromide is a versatile strained-ring alkyl halide reagent widely employed in organic synthesis as an electrophilic cyclobutyl source for nucleophilic substitution, cross-coupling, and medicinal chemistry applications.

IUPAC Name

Bromocyclobutane

CAS Number

4-01-00-00005 (Beilstein); CAS 4399-85-7

Molecular Formula

C₄H₇Br

Molecular Weight

135.00 g/mol

Appearance

Colorless to pale yellow liquid

Key Reactivity

Electrophilic alkylating agent; undergoes SN2, E2, and organometallic cross-coupling reactions

Aladdin SKU

C107837

Chemical Properties and Structure

Cyclobutyl bromide (bromocyclobutane, CAS 4399-85-7) has the molecular formula C₄H₇Br and a molecular weight of approximately 135.00 g/mol. It consists of a four-membered cyclobutane ring bearing a single bromine substituent, giving the molecule approximately 26° of ring strain compared to an unstrained acyclic analogue. This ring strain has notable consequences for reactivity: the C–Br bond is polarized and susceptible to nucleophilic attack, yet elimination pathways (E2) can compete meaningfully because the adjacent C–H bonds are held in a geometry that partially overlaps with the σ* orbital of the C–Br bond.

The compound is a colorless to pale yellow liquid at room temperature. It is denser than water and immiscible with it, but miscible with common organic solvents such as diethyl ether, dichloromethane, THF, and acetone. Its relatively low molecular weight and moderate boiling point make handling straightforward under standard laboratory fume-hood conditions, provided appropriate personal protective equipment (PPE) is used.

Synthesis and Preparation

Cyclobutyl bromide is most commonly prepared in the laboratory by treating cyclobutanol with a brominating agent. Two widely used routes are:

• Hydrobromic acid / acid catalyst: Cyclobutanol is heated with concentrated HBr (or HBr generated in situ from NaBr and H₂SO₄) to afford cyclobutyl bromide via an SN1 or SN2 mechanism, depending on temperature and conditions. Ring-expansion side products are sometimes observed and should be monitored by GC.
• Appel-type halogenation: Cyclobutanol is treated with CBr₄ and triphenylphosphine (PPh₃) in an inert solvent such as CH₂Cl₂ at 0 °C to room temperature. This proceeds with inversion of configuration and typically delivers the product in good yield with minimal ring-opened by-products.
• Phosphorus tribromide (PBr₃): Addition of PBr₃ to cyclobutanol converts the hydroxyl to bromide under mild conditions and is scalable for larger batch sizes.

Commercially, Aladdin Scientific offers cyclobutyl bromide (SKU C107837) as a ready-to-use reagent, eliminating the need for in-house preparation and associated quality-control burden.

Applications in Organic and Medicinal Chemistry

Cyclobutyl bromide serves as a compact, rigid cyclobutyl-group donor across a broad range of synthetic transformations:

• Nucleophilic substitution (SN2): Reacts with amines, thiols, alkoxides, malonates, and other stabilized carbanions to install the cyclobutyl motif onto heteroatom- or carbon-nucleophile scaffolds. The strained ring remains intact under standard SN2 conditions when strong, hindered bases are avoided.
• Organometallic reactions: Generates cyclobutyl Grignard reagents (cyclobutylmagnesium bromide) upon treatment with Mg turnings in THF or Et₂O. The Grignard can then add to aldehydes, ketones, esters, and nitriles to build cyclobutyl-containing alcohols and other functionalized intermediates.
• Transition-metal cross-coupling: Can participate in Kumada, Negishi, and Suzuki-Miyaura couplings (after transmetallation) as a source of the cyclobutyl nucleophile or electrophile, enabling C–C bond formation with aryl, vinyl, or heteroaryl partners.
• Medicinal chemistry building block: The cyclobutyl group is a bioisostere for gem-dimethyl and tert-butyl groups and is incorporated into drug candidates to improve metabolic stability, reduce lipophilicity compared to larger cyclic substituents, and modulate conformational rigidity of pharmacophores. Fragment-based drug discovery campaigns increasingly use cyclobutyl halides as vector-building tools.
• Radical reactions: Under radical-initiation conditions (AIBN, Bu₃SnH, or photoredox catalysis), cyclobutyl bromide can serve as a radical precursor, with the resulting cyclobutyl radical undergoing ring-opening or addition depending on the substrate.

Safety, Handling, and Storage

Hazard profile: Cyclobutyl bromide is a lachrymatory alkyl halide and should be treated as a potential irritant to skin, eyes, and the respiratory tract. Although it is less reactive than the corresponding cyclopropyl or allyl bromide, it remains an active alkylating agent and should be handled with appropriate caution.

PPE requirements: Use chemical-splash goggles, nitrile gloves (double-gloving recommended for extended handling), and a lab coat. All operations should be performed inside a well-ventilated fume hood. Avoid breathing vapors.

First aid: In case of skin contact, wash thoroughly with soap and water. For eye contact, irrigate with large amounts of water for at least 15 minutes and seek medical attention. If inhaled, move to fresh air immediately.

Storage: Store in a tightly sealed container under inert atmosphere (nitrogen or argon) in a cool, dry location away from heat sources, light, and incompatible materials (strong bases, strong oxidizers, and reactive metals). Refrigerated storage (2–8 °C) is recommended to minimize slow decomposition or discoloration over time.

Waste disposal: Dispose of in accordance with local, regional, and national regulations governing halogenated organic waste. Do not pour down the drain.

Note: Always consult the current Safety Data Sheet (SDS) supplied with the product before use.

Purity, Specifications, and Quality Assurance

For reproducible research results, the purity of cyclobutyl bromide is critical, particularly in sensitive organometallic or catalytic reactions where trace water, HBr, or oxidized impurities can deactivate catalysts or produce undesired by-products.

When evaluating a reagent grade cyclobutyl bromide, key specification parameters to request include:

• Purity (GC): ≥97% or higher by gas chromatography; higher-purity grades (≥99%) are preferred for demanding catalytic applications.
• Water content (Karl Fischer): Should be as low as possible; moisture accelerates hydrolysis and HBr generation.
• Color: Colorless to very pale yellow; deep yellow or brown discoloration indicates decomposition or significant impurity levels.
• Identity confirmation: ¹H NMR and/or GC-MS consistent with bromocyclobutane.

Aladdin Scientific's cyclobutyl bromide (C107837) is subject to internal quality control testing prior to release. Researchers requiring a certificate of analysis (CoA) should contact Aladdin customer service or download the document from the product page.

Frequently asked questions

What is cyclobutyl bromide used for in organic synthesis?

Cyclobutyl bromide is primarily used as an electrophilic cyclobutylating agent. It reacts with nucleophiles such as amines, thiols, malonate anions, and organometallic reagents (e.g., Mg to form Grignard reagents) to introduce the cyclobutyl group onto diverse molecular scaffolds. It is also valued in medicinal chemistry as a bioisosteric replacement for tert-butyl or gem-dimethyl groups.

How should cyclobutyl bromide be stored to maintain its purity?

Cyclobutyl bromide should be stored in a tightly sealed container under an inert atmosphere (nitrogen or argon) at 2–8 °C, away from moisture, light, heat sources, strong oxidizers, and strong bases. Exposure to air and moisture promotes slow hydrolysis and generation of HBr, which can lead to discoloration and reduced purity over time.

Can cyclobutyl bromide undergo ring-opening during reactions?

Ring-opening of cyclobutyl bromide is possible but generally requires forcing conditions or specific catalysts. Under typical SN2 conditions with moderate nucleophiles, the cyclobutyl ring remains intact. However, under strongly nucleophilic or radical conditions, and particularly at elevated temperatures, ring-opening to give homoallylic or other rearranged products can compete and should be monitored by GC or NMR analysis of the crude reaction mixture.

Is cyclobutyl bromide compatible with Grignard reaction conditions?

Yes. Cyclobutyl bromide reacts with magnesium turnings in anhydrous THF or diethyl ether to form cyclobutylmagnesium bromide, a useful Grignard reagent. Initiation may require activation of the Mg surface (e.g., with a crystal of iodine or brief sonication). The resulting Grignard reagent adds to carbonyl compounds, nitriles, and other electrophiles to furnish cyclobutyl-bearing products.

How does cyclobutyl bromide differ from cyclopropyl bromide or cyclopentyl bromide?

Cyclopropyl bromide carries a more highly strained three-membered ring that is prone to ring-opening under both ionic and radical conditions, making it more reactive but also harder to handle selectively. Cyclopentyl bromide has a five-membered ring with lower ring strain and more predictable SN2/E2 behavior similar to secondary acyclic alkyl bromides. Cyclobutyl bromide occupies an intermediate position: the four-membered ring provides moderate ring strain that enhances reactivity while still allowing selective C–C bond-forming reactions without excessive ring-opening under mild conditions.

References

1. March, J.; Smith, M. B. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th ed.; Wiley: Hoboken, NJ, 2013.
2. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012.
3. Appel, R. Tertiary Phosphane/Tetrachloromethane, a Versatile Reagent for Chlorination, Dehydration, and P-N Linkage. Angew. Chem. Int. Ed. Engl. 1975, 14, 801–811. doi:10.1002/anie.197508011
4. Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752–6756. doi:10.1021/jm901241e

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