Chlorocyclobutane: Properties, Synthesis & Lab Uses

Chlorocyclobutane is a strained cyclic alkyl chloride widely employed as a synthetic building block and alkylating agent in organic chemistry research.

Chemical Name

Chlorocyclobutane (Cyclobutyl chloride)

Molecular Formula

C₄H₇Cl

Molecular Weight

90.55 g/mol

CAS Number

2211-74-3

Compound Class

Cyclic alkyl halide (secondary alkyl chloride)

Key Reactivity

Undergoes SN1, SN2, and E2 reactions; ring strain enhances reactivity

Storage Condition

Store in a cool, dry, well-ventilated area away from ignition sources

Chemical Identity and Physical Properties

Chlorocyclobutane (CAS 2211-74-3), also known as cyclobutyl chloride, has the molecular formula C₄H₇Cl and a molecular weight of approximately 90.55 g/mol. It belongs to the class of secondary cyclic alkyl halides, distinguished from open-chain analogues by the four-membered carbocyclic ring. The ring confers an internal angle of approximately 90°, well below the tetrahedral ideal of 109.5°, resulting in significant angle strain (Baeyer strain) that influences both physical and chemical behaviour.

Chlorocyclobutane is a colourless, volatile liquid at room temperature with a characteristic ethereal odour. Its boiling point and density are consistent with a low-molecular-weight organochloride; exact values should be confirmed against the Aladdin Scientific certificate of analysis for lot-specific data. The compound is immiscible with water but miscible with common organic solvents such as diethyl ether, dichloromethane, THF, and acetone, facilitating its use in a broad range of reaction media.

Reactivity and Mechanistic Considerations

As a secondary alkyl chloride, chlorocyclobutane can participate in nucleophilic substitution (SN1 and SN2) and elimination (E1 and E2) reactions, with the dominant pathway depending on the nature of the nucleophile or base, solvent polarity, and temperature. The ring strain of the cyclobutane skeleton subtly modulates transition-state energetics compared with acyclic secondary chlorides.

Under strongly basic conditions (e.g., KOH/ethanol or LDA in THF), elimination is favoured, yielding methylenecyclobutane or other cyclobutene-derived products depending on reaction conditions. With soft nucleophiles under polar aprotic conditions (e.g., NaI in acetone via Finkelstein exchange, or thiolates in DMF), SN2 substitution is competitive. The cyclobutyl cation formed under SN1-promoting conditions is relatively stable due to hyperconjugation and partial relief of ring strain, though ring-opening rearrangements to homoallylic or allyl cations can occur and should be considered when designing synthetic routes.

Chlorocyclobutane can also serve as a precursor to cyclobutyl Grignard reagents (cyclobutylmagnesium chloride) by reaction with magnesium turnings in anhydrous THF or diethyl ether, enabling introduction of the cyclobutyl scaffold onto electrophilic partners.

Synthesis and Preparation Methods

The most straightforward laboratory route to chlorocyclobutane is the treatment of cyclobutanol with a chlorinating agent. Thionyl chloride (SOCl₂) in the presence of a base such as pyridine or triethylamine is a common choice, converting the hydroxyl group to the chloride with inversion or retention depending on the mechanism (typically proceeding via a chlorosulfite intermediate). Alternatively, hydrogen chloride gas can be passed through cyclobutanol under anhydrous conditions, though this approach tends to give more variable regioselectivity.

Halogen-exchange (Finkelstein) reactions starting from cyclobutyl iodide or bromide using chloride sources offer another pathway, though these are less commonly employed given the ready availability of chlorocyclobutane as a commercial reagent. Radical chlorination of cyclobutane using Cl₂ under UV irradiation is possible but gives a mixture of mono- and polychlorinated products and is not synthetically useful for pure material preparation.

Aladdin Scientific supplies chlorocyclobutane (SKU C115990) as a catalogue reagent, enabling researchers to bypass multi-step preparation and directly incorporate it into their workflows.

Research Applications

Chlorocyclobutane is valued in medicinal chemistry and drug discovery as a source of the cyclobutyl motif, a bioisostere of tert-butyl groups and gem-dimethyl groups that imparts improved metabolic stability, reduced lipophilicity, and constrained three-dimensional geometry to lead compounds. Incorporation of the cyclobutyl ring into pharmaceutical candidates has been extensively explored to modulate pharmacokinetic profiles.

In synthetic methodology research, chlorocyclobutane serves as a model substrate for studying ring-strain-assisted reactions, including transition-metal-catalysed cross-coupling (e.g., nickel- or palladium-catalysed Kumada or Negishi couplings of the derived organometallic species), radical reactions, and strain-release cycloadditions. It is also used in polymer chemistry as a monomer precursor for cyclobutane-containing polyethers and related materials.

Physical organic chemists employ chlorocyclobutane as a benchmark compound for investigating solvolysis kinetics, isotope effects, and computational modelling of ring-strain effects on reactivity, given the well-characterised nature of the cyclobutyl system.

Safety, Handling and Storage

Chlorocyclobutane is a flammable volatile liquid and should be handled with appropriate precautions. Work should be performed in a well-ventilated fume hood away from open flames and ignition sources. Personnel should wear nitrile or neoprene gloves, safety spectacles, and a lab coat as standard personal protective equipment. Prolonged or repeated inhalation of vapours and skin contact should be avoided.

Store chlorocyclobutane in a tightly sealed container in a cool, dry location segregated from oxidising agents and strong bases. Containers should be kept away from heat sources and direct sunlight. Consult the Safety Data Sheet (SDS) provided by Aladdin Scientific (SKU C115990) for complete hazard classifications, first-aid measures, spill procedures, and disposal guidance in compliance with local regulations.

Waste disposal must comply with applicable national and local environmental regulations for halogenated organic solvent waste. Do not pour down the drain; use licensed waste disposal services.

Frequently asked questions

What is the CAS number for chlorocyclobutane?

The CAS Registry Number for chlorocyclobutane (cyclobutyl chloride) is 2211-74-3. Aladdin Scientific stocks this compound under SKU C115990.

How does ring strain affect the reactivity of chlorocyclobutane compared with secondary acyclic alkyl chlorides?

The approximately 90° C–C–C bond angles in the cyclobutane ring introduce significant angle (Baeyer) strain relative to the ideal tetrahedral geometry. This strain raises the ground-state energy of chlorocyclobutane and can lower activation barriers for certain reactions, including SN1 solvolysis and ring-opening pathways, compared with open-chain secondary chlorides. However, the magnitude of the effect depends strongly on the reaction mechanism and conditions, and should be evaluated experimentally for each transformation.

Can chlorocyclobutane be used to prepare cyclobutyl Grignard reagents?

Yes. Chlorocyclobutane reacts with magnesium turnings in anhydrous THF or diethyl ether under inert atmosphere to generate cyclobutylmagnesium chloride. Standard Grignard initiation techniques (e.g., activation of magnesium with iodine or a small amount of 1,2-dibromoethane) are typically employed. The resulting reagent can be used in additions to aldehydes, ketones, esters, and other electrophiles to install the cyclobutyl group.

What solvents are compatible with chlorocyclobutane for organic synthesis?

Chlorocyclobutane is miscible with common organic solvents including diethyl ether, THF, dichloromethane, acetone, DMF, and DMSO. It is immiscible with water. For reactions requiring polar aprotic conditions (SN2 favoured), DMF or DMSO are appropriate; for Grignard formation, anhydrous THF or diethyl ether are standard choices.

How should chlorocyclobutane be stored to maintain stability?

Store chlorocyclobutane in a tightly sealed container in a cool, dry, well-ventilated area away from heat, open flames, and oxidising agents. Refrigerated storage (2–8 °C) is typically recommended for long-term stability. Always refer to the Aladdin Scientific SDS and CoA for lot-specific storage recommendations.

References

1. March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. 4th ed. Wiley-Interscience, 1992.
2. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry. 2nd ed. Oxford University Press, 2012.
3. Aladdin Scientific. Product Page: Chlorocyclobutane, SKU C115990. https://www.aladdin-e.com
4. Wiberg, K. B. The concept of strain in organic chemistry. Angew. Chem. Int. Ed. Engl. 1986, 25, 312–322. doi:10.1002/anie.198603121

Products are supplied for research and development use only. Not for use in humans, animals, diagnosis, or therapy.