6-Bromo-2,3-difluorobenzaldehyde

    6-Bromo-2,3-difluorobenzaldehyde is an important organohalogen compound widely utilized in organic synthesis, pharmaceutical development, and materials science. With the molecular formula C₇H₃BrF₂O and a molecular weight of 221.00 g/mol, this compound features a benzaldehyde core substituted with bromine at the 6-position and fluorine atoms at the 2- and 3-positions of the aromatic ring. Its unique substitution pattern imparts distinctive chemical reactivity and electronic properties that make it a valuable building block for constructing complex molecular architectures.

    The compound typically appears as a white to pale yellow crystalline solid with a melting point range of 39-43°C. It has a boiling point of approximately 225.7°C at 760 mmHg and a density of 1.758 g/cm³. The XLogP3 value of 2.3 indicates moderate lipophilicity, which influences its solubility behavior. The molecule contains three hydrogen bond acceptors, zero hydrogen bond donors, and one rotatable bond, with a topological polar surface area of 17.1 Ų.

    The computed InChI Key for this compound is LAVPYRPTHABUAD-UHFFFAOYSA-N, and its canonical SMILES representation is C1=CC(=C(C(=C1F)F)C=O)Br. The exact mass of the compound is 219.93353 Da.

    The compound can be synthesized through several routes. One common method involves the bromination of 2,3-difluorobenzaldehyde using bromine or N-bromosuccinimide (NBS) in the presence of catalysts such as iron or aluminum chloride. The reaction requires controlled conditions to ensure selective bromination at the desired position.

    A well-documented synthetic procedure involves the lithiation of 1-bromo-3,4-difluorobenzene at -75°C using n-butyllithium and 2,2,6,6-tetramethylpiperidine in dry tetrahydrofuran. After maintaining the temperature for four hours, dimethylformamide is added dropwise, followed by hydrolysis, acidification, and extraction. Purification by silica gel chromatography and recrystallization from n-heptane yields the product with approximately 56% efficiency.

    6-Bromo-2,3-difluorobenzaldehyde undergoes several important chemical transformations due to its reactive functional groups:

Substitution Reactions: The bromine atom can be substituted with various nucleophiles including amines, thiols, and alkoxides. These reactions typically employ palladium or copper catalysts in solvents such as dimethylformamide or tetrahydrofuran.

    Oxidation Reactions: The aldehyde group can be oxidized to form 6-bromo-2,3-difluorobenzoic acid using oxidizing agents like potassium permanganate or chromium trioxide.

    Reduction Reactions: The aldehyde can be reduced to 6-bromo-2,3-difluorobenzyl alcohol using reducing agents such as sodium borohydride or lithium aluminum hydride. The compound serves as a crucial intermediate in the synthesis of various biologically active molecules. Patent literature indicates its utility in the development of KRAS G12C inhibitors, which are promising anticancer agents targeting specific mutations in lung and colorectal cancers. The presence of both bromine and fluorine atoms allows medicinal chemists to fine-tune pharmacokinetic properties including metabolic stability and membrane permeability.

    As a versatile building block, 6-bromo-2,3-difluorobenzaldehyde is employed in the synthesis of halogenated benzimidazoles and other heterocyclic compounds known for their diverse biological activities. It can participate in Buchwald coupling reactions to prepare N,N-disubstituted amine benzaldehyde derivatives and can form Schiff bases with aminoindole compounds, some of which demonstrate anti-proliferative activity against various tumor cell lines. The compound finds applications in the production of specialty chemicals and functionalized polymers. Incorporating this compound into polymer structures can enhance material properties such as thermal stability and solubility.

    According to the Globally Harmonized System (GHS) classification, 6-bromo-2,3-difluorobenzaldehyde is categorized as an irritant. Hazard statements include H315 (causes skin irritation), H319 (causes serious eye irritation), and H335 (may cause respiratory irritation). The compound has a warning signal word designation. It should be stored long-term at 2-8°C and handled with appropriate personal protective equipment. The compound is considered air-sensitive and should be stored under inert atmosphere such as nitrogen or argon to prevent degradation.

    6-Bromo-2,3-difluorobenzaldehyde represents a valuable synthetic intermediate in modern organic chemistry. Its unique combination of halogen substituents and an aldehyde functional group provides versatile reactivity that enables access to diverse chemical space. From pharmaceutical intermediates to materials science applications, this compound continues to play an important role in research and development across multiple scientific disciplines.