4-Bromo-1,1-difluorocyclohexane: Handling & Application Guide

4-bromo-1,1-difluorocyclohexane is a versatile gem-difluorocyclohexane building block widely employed in medicinal chemistry and drug discovery for the introduction of metabolically stable difluoromethylene-containing ring systems into candidate molecules.

CAS Number

Not confirmed in source material — see review flags

Molecular Formula

C6H9BrF2

Molecular Weight

203.04 g/mol (calculated)

Key Functional Groups

gem-Difluoro (1,1-CF2) and alkyl bromide (C-4)

Primary Application

Pharmaceutical intermediate and synthetic building block in C–C and C–heteroatom bond-forming reactions

Storage Recommendation

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

Physicochemical Properties and Structure

4-Bromo-1,1-difluorocyclohexane (B172480) is a saturated six-membered carbocyclic compound bearing a gem-difluoro substitution at the 1-position and a bromine atom at the 4-position. The molecular formula is C₆H₉BrF₂ with a calculated molecular weight of approximately 203.04 g/mol.

The gem-difluoro motif (–CF₂–) confers distinctive electronic and conformational properties compared to the parent cyclohexane. Fluorine's strong inductive withdrawal significantly reduces electron density at the ring carbon, while the two C–F bond dipoles influence the preferred chair conformation of the ring. These characteristics translate directly into altered lipophilicity (LogP) and metabolic stability of derivatives compared to their non-fluorinated analogues.

The C–Br bond at the 4-position (equatorial preference in the chair conformation relative to the 1,1-CF₂ group) provides a versatile handle for nucleophilic substitution (S_N2), elimination, metal-halogen exchange, and transition-metal-catalyzed cross-coupling reactions. The compound is expected to be a colorless to pale yellow liquid or low-melting solid; precise physical constants (melting point, boiling point, density) should be confirmed from the certificate of analysis supplied with lot B172480.

Synthetic Applications in Medicinal and Organic Chemistry

Role as a Bioisostere Precursor: The 4-substituted-1,1-difluorocyclohexane scaffold is increasingly exploited as a bioisostere for gem-dimethyl, tert-butyl, or spirocyclic moieties. Incorporation of the –CF₂– group can improve aqueous solubility and metabolic stability while maintaining or enhancing target binding, making B172480 a valuable entry point to drug candidates in CNS, oncology, and anti-infective programs.

Nucleophilic Substitution (S_N2): The primary alkyl bromide character of the C4–Br bond makes it reactive toward carbon, oxygen, nitrogen, and sulfur nucleophiles. Reaction with amines, alcohols, thiols, or organocuprates under standard conditions affords 4-substituted-1,1-difluorocyclohexane derivatives with good yields.

Cross-Coupling Reactions: Via lithium-halogen exchange at low temperature (e.g., n-BuLi, –78 °C in THF) or Grignard formation (Mg, THF), the bromide can be converted to a reactive organometallic species for addition to carbonyl compounds or participation in Kumada, Negishi, or Suzuki-Miyaura protocols after transmetalation.

Elimination to Difluorocyclohexene: Treatment with strong base (e.g., KOtBu, DBU) can promote E2 elimination to generate 1,1-difluoro-4-cyclohexene derivatives, useful as strained or unsaturated fluorinated intermediates for further functionalization.

Radical Reactions: Under radical initiation conditions, the C–Br bond can participate in atom-transfer radical addition (ATRA) or other radical chain processes to deliver branched fluorinated products.

Safe Handling, Storage, and Disposal

General Hazard Profile: 4-Bromo-1,1-difluorocyclohexane contains both an alkyl bromide and organofluorine functionalities. Alkyl bromides are generally considered irritants to skin, eyes, and the respiratory tract and may be harmful if inhaled or absorbed through skin. Specific GHS classification and hazard statements for B172480 should be verified from the current Safety Data Sheet (SDS) available on the Aladdin Scientific product page.

Personal Protective Equipment (PPE): Use chemical-resistant gloves (nitrile or neoprene), safety spectacles or goggles, and a laboratory coat as a minimum. Work in a well-ventilated fume hood when handling neat material or concentrated solutions.

Storage: Store tightly sealed in a cool (2–8 °C recommended for extended stability), dry location, away from strong bases, oxidizers, and ignition sources. Keep in original packaging under inert atmosphere (nitrogen or argon) if prolonged storage is anticipated to prevent moisture ingress and decomposition.

Spill Management: Absorb small spills with inert material (vermiculite, dry sand). Avoid generating dusts or vapors. Collect waste in appropriately labeled containers and dispose of in accordance with local environmental regulations governing halogenated organic waste.

First Aid: In the event of skin or eye contact, flush thoroughly with water for at least 15 minutes. If inhaled, move to fresh air immediately and seek medical attention if symptoms persist. Consult the product SDS for full emergency procedures.

Quality, Purity, and Analytical Characterization

Purity Standards: Aladdin Scientific's B172480 is supplied with a defined purity specification; consult the product page or certificate of analysis (CoA) for the current lot-specific purity value. For most synthetic applications in medicinal chemistry, purities of ≥95% (GC or HPLC) are desirable to minimize side reactions from halide impurities or isomeric byproducts.

Identity Confirmation: The compound is conveniently characterized by ¹H NMR, ¹³C NMR, and ¹⁹F NMR. Key NMR signatures include:

• ¹⁹F NMR: a characteristic singlet or multiplet in the –90 to –100 ppm region (relative to CFCl₃) for the gem-CF₂ group.
• ¹H NMR: multiplets for the axial and equatorial CH₂ protons flanking both the CF₂ and CHBr centers; a multiplet for the CH at C-4 (the methine bearing Br).
• GC-MS: molecular ion cluster at m/z 202/204/206 (isotope pattern consistent with one Br and two F atoms).

Moisture Sensitivity: Although not as moisture-sensitive as Grignard reagents, the compound should be handled under standard benchtop conditions with attention to minimizing prolonged exposure to humid air, which could promote slow hydrolysis at the C–Br bond.

Frequently asked questions

What reactions is 4-bromo-1,1-difluorocyclohexane most commonly used for?

The compound serves primarily as an alkylating agent in SN2 reactions with various nucleophiles (amines, thiols, alkoxides) and as a precursor to organolithium or Grignard reagents for addition and cross-coupling reactions. Its gem-difluoro cyclohexane core is also valuable as a bioisosteric replacement in medicinal chemistry programs.

How should 4-bromo-1,1-difluorocyclohexane (B172480) be stored to maintain stability?

Store the compound in a tightly sealed container at 2–8 °C in a cool, dry, well-ventilated area, protected from moisture, strong bases, and oxidizers. For extended storage, maintaining an inert atmosphere (N2 or Ar) inside the container is recommended to prevent hydrolysis of the C–Br bond and oxidative degradation.

Why is the gem-difluoro (1,1-CF2) cyclohexane motif important in drug discovery?

The gem-CF2 group is metabolically stable because strong C–F bonds resist cytochrome P450-mediated oxidation that commonly occurs at sp3 carbon centers. It also modulates the lipophilicity and pKa of adjacent groups, and can act as a bioisostere for gem-dimethyl, ketal, or carbonyl functionalities, offering medicinal chemists a tool to improve pharmacokinetic profiles without dramatically altering molecular shape.

Is 4-bromo-1,1-difluorocyclohexane compatible with aqueous reaction conditions?

The compound is generally more suitable for anhydrous organic solvent systems (THF, DMF, DCM, acetonitrile). Under strongly aqueous or basic aqueous conditions, the alkyl bromide is susceptible to hydrolysis or elimination. For reactions requiring aqueous co-solvents, keep reaction times short and monitor for decomposition.

How can I confirm the identity and purity of received lot B172480?

Review the Certificate of Analysis (CoA) provided with your shipment for lot-specific purity data (typically GC purity). Confirm identity via 1H, 13C, and 19F NMR spectroscopy and GC-MS (expected molecular ion cluster at m/z ~202/204/206). If discrepancies are found, contact Aladdin Scientific customer service for technical support or replacement.

References

1. Gouverneur, V.; Müller, K. (Eds.) Fluorine in Pharmaceutical and Medicinal Chemistry. Imperial College Press, 2012. (General reference on fluorinated building blocks in drug discovery.)
2. Meanwell, N. A. Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. J. Med. Chem. 2018, 61, 5822–5880. doi:10.1021/acs.jmedchem.7b01788
3. Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315–8359. doi:10.1021/acs.jmedchem.5b00756
4. Aladdin Scientific Product Page: 4-Bromo-1,1-difluorocyclohexane, SKU B172480. (For lot-specific CoA, SDS, and purity data.)

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