2,6-Difluorophenol
[CAS# 28177-48-2]

Identification

• Classification: Organic raw materials >> Organic fluorine compound >> Fluorophenol series
• Name: 2,6-Difluorophenol
• Molecular Formula: C₆H₄F₂O
• Molecular Weight: 130.09
• CAS Registry Number: 28177-48-2
• EC Number: 248-884-9
• SMILES: C1=CC(=C(C(=C1)F)O)F

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*, 1.27 g/mL (Expl.)
• Melting point: 38 - 41 °C (Expl.)
• Boiling point: 157.7 °C 760 mmHg (Calc.)^*, 179 - 181.7 °C (Expl.)
• Flash point: 58.9 °C (Calc.)^*, 58 °C (Expl.)
• Index of refraction: 1.496 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS02;GHS05;GHS07 Danger
• Risk Statements: H228-H302-H312-H314-H315-H319-H335
• Safety Statements: P210-P240-P241-P260-P261-P264-P264+P265-P270-P271-P280-P301+P317-P301+P330+P331-P302+P352-P302+P361+P354-P304+P340-P305+P351+P338-P305+P354+P338-P316-P317-P319-P321-P330-P332+P317-P337+P317-P362+P364-P363-P370+P378-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335
Flammable solids	Flam. Sol.	1	H228
Acute toxicity	Acute Tox.	4	H302
Acute toxicity	Acute Tox.	4	H332
Acute toxicity	Acute Tox.	4	H312
Flammable solids	Flam. Sol.	2	H228
Serious eye damage	Eye Dam.	1	H318
Skin corrosion	Skin Corr.	1B	H314

• Transport Information: UN 1325

Discovery and Applications

2,6-Difluorophenol is an aromatic compound in which a phenol ring is substituted with fluorine atoms at the 2 and 6 positions relative to the hydroxyl group. Its molecular formula is C₆H₄F₂O, with a molecular weight of approximately 126.10 g/mol. The presence of electronegative fluorine atoms at the ortho positions to the hydroxyl group significantly influences the acidity, electronic distribution, and reactivity of the molecule. The hydroxyl group enables hydrogen bonding, contributing to solubility in polar solvents and providing a reactive site for esterification, etherification, or metal coordination.

Synthesis of 2,6-difluorophenol typically involves selective fluorination of phenol derivatives using electrophilic or nucleophilic fluorination strategies. One approach is the direct fluorination of phenol under controlled conditions to favor substitution at the 2 and 6 positions. Alternatively, the compound can be obtained via the hydrolysis of 2,6-difluorophenyl derivatives, such as 2,6-difluorophenyl halides or nitro compounds, under appropriate reaction conditions. Regioselectivity is controlled by the directing effects of the hydroxyl group and by steric hindrance from existing substituents.

Chemically, 2,6-difluorophenol exhibits higher acidity compared to unsubstituted phenol due to the electron-withdrawing effect of the ortho-fluorine atoms, which stabilize the phenoxide ion upon deprotonation. The hydroxyl proton can participate in acid–base reactions, forming salts with bases, or undergo esterification with acyl chlorides and anhydrides. The fluorine substituents reduce the reactivity of the aromatic ring toward electrophilic substitution at the ortho and para positions, while slightly activating the meta positions relative to the hydroxyl group.

The compound is typically a solid at room temperature and exhibits moderate solubility in polar organic solvents such as ethanol, acetone, and dimethylformamide. Its chemical stability is generally good under ambient conditions, although strong bases or nucleophiles can react with the phenolic hydroxyl group or induce substitution of the fluorine atoms under harsh conditions. The presence of two ortho fluorine atoms also introduces steric hindrance that can influence the molecule’s interactions in both chemical and biological systems.

In practical applications, 2,6-difluorophenol is commonly used as a building block in organic synthesis, pharmaceuticals, and agrochemical development. The molecule’s hydroxyl group allows derivatization, while the fluorine atoms can modify electronic properties, lipophilicity, and metabolic stability in bioactive compounds. It serves as a precursor for the preparation of ethers, esters, and other functionalized derivatives, enabling the design of molecules with targeted chemical and biological properties.

The combination of a reactive hydroxyl group and sterically hindered fluorine-substituted aromatic ring makes 2,6-difluorophenol a valuable intermediate for synthetic chemistry. Its defined electronic and steric characteristics support controlled functionalization and selective reactivity, allowing it to be incorporated into more complex molecular frameworks for research, development, and applied chemical purposes.

References

2010. Modulation of the Aerobic Oxidative Polymerization in Phenylazomethine Dendrimers Assembling Copper Complexes. Chemistry - A European Journal.
DOI: 10.1002/chem.201001516

2010. A Diverse Series of Substituted Benzenesulfonamides as Aldose Reductase Inhibitors with Antioxidant Activity: Design, Synthesis, and in Vitro Activity. Journal of Medicinal Chemistry.
DOI: 10.1021/jm101008m

2004. Degradation of 2-fluorophenol by the brown-rot fungus Gloeophyllum striatum : evidence for the involvement of extracellular Fenton chemistry. Applied Microbiology and Biotechnology.
DOI: 10.1007/s00253-003-1445-x