2,2-Difluorobenzo[d][1,3]dioxol-5-ol: Properties & Applications

2,2-Difluorobenzo[d][1,3]dioxol-5-ol is a fluorinated phenolic building block featuring a gem-difluoro-substituted 1,3-dioxole ring fused to a benzene core, making it a versatile intermediate for medicinal chemistry and agrochemical research.

IUPAC Name

2,2-Difluoro-1,3-benzodioxol-5-ol

SKU

D734667

Molecular Formula

C7H4F2O3

Key Functional Groups

gem-Difluoro dioxole ring, free phenolic hydroxyl

Supplier

Aladdin Scientific

Primary Use

Synthetic intermediate in medicinal and agrochemical research

Chemical Structure and Properties

2,2-Difluorobenzo[d][1,3]dioxol-5-ol (CAS registry; SKU D734667) consists of a 1,3-benzodioxole scaffold in which the two methylene hydrogens at the 2-position have been replaced by fluorine atoms, and a free hydroxyl group is present at the 5-position of the aromatic ring. The molecular formula is C₇H₄F₂O₃, giving a molecular weight of approximately 176.10 g/mol.

The gem-difluoro substitution at the acetal carbon significantly alters the electronic and metabolic profile relative to the parent methylenedioxy analogue. The strong electron-withdrawing character of the two fluorine atoms reduces the electron density of the dioxole oxygen lone pairs, which in turn modulates the electron density across the fused aromatic ring. The free phenolic –OH group at C-5 provides a handle for further derivatization via O-alkylation, O-acylation, or coupling reactions.

The compound is expected to be a solid or low-melting solid at room temperature, with limited water solubility due to its largely lipophilic aromatic core, and reasonable solubility in common organic solvents such as DMSO, DMF, acetonitrile, and ethyl acetate.

Significance of the gem-Difluoro Motif

The replacement of a methylenedioxy (–OCH₂O–) group with a difluoromethylenedioxy (–OCF₂O–) group is a well-established bioisosteric strategy in drug discovery. The parent methylenedioxy group is metabolically labile; cytochrome P450 enzymes can oxidize the methylene carbon to form a reactive carbene-like intermediate that can irreversibly inhibit the enzyme. Introduction of two fluorine atoms at this position blocks this oxidative metabolic pathway, conferring improved metabolic stability to the resulting drug candidate.

In addition to blocking metabolism, the difluoro substitution modulates lipophilicity and membrane permeability. Because fluorine is highly electronegative and the C–F bond is among the strongest in organic chemistry, the fluorinated analogue typically exhibits altered pKa values for the phenolic hydroxyl and distinct solid-state and solution-phase properties relative to its non-fluorinated counterpart.

These properties have made –OCF₂O– containing scaffolds of considerable interest in the design of pharmaceuticals, agrochemicals, and materials with tailored electronic properties.

Research and Synthetic Applications

2,2-Difluorobenzo[d][1,3]dioxol-5-ol serves primarily as a versatile synthetic building block. The free phenolic hydroxyl group at the 5-position enables a wide range of downstream transformations:

• O-Alkylation: Reaction with alkyl halides or under Mitsunobu conditions to install ethers, enabling access to more complex fluorinated aryl ether libraries.
• O-Acylation: Esterification to produce phenyl ester derivatives for prodrug strategies or as protected phenol intermediates.
• Cross-coupling reactions: After conversion of the phenolic –OH to a triflate or other leaving group, palladium-catalyzed Suzuki, Negishi, or Buchwald–Hartwig reactions can introduce diverse aryl, heteroaryl, or amino substituents.
• Directed C–H functionalization: The phenolic hydroxyl can direct ortho-selective C–H activation reactions for further ring elaboration.

The compound is of interest to researchers working on CNS-active compounds, anti-infective agents, and crop-protection chemicals, where the difluoromethylenedioxy motif confers both metabolic stability and tunable physicochemical properties. It is also useful as a reference standard or analytical standard in quantitative assays.

Handling, Storage, and Safety Considerations

As with all fluorinated organic compounds and phenolic reagents, appropriate laboratory safety practices should be observed when handling 2,2-Difluorobenzo[d][1,3]dioxol-5-ol:

• Personal Protective Equipment (PPE): Wear nitrile gloves, safety glasses, and a laboratory coat. Use a fume hood when weighing or handling the compound in open containers.
• Storage: Store in a tightly sealed container in a cool, dry, well-ventilated area away from strong oxidizing agents and strong bases. Refrigerated storage (2–8 °C) is recommended to maintain long-term stability.
• Disposal: Dispose of waste in accordance with local institutional and governmental regulations for halogenated organic waste.

Users should consult the Safety Data Sheet (SDS) provided by Aladdin Scientific for compound-specific hazard classifications, first-aid measures, and regulatory information prior to use. Specific toxicological data for this compound may be limited; exercise caution accordingly.

Frequently asked questions

What is the molecular formula and molecular weight of 2,2-Difluorobenzo[d][1,3]dioxol-5-ol?

The molecular formula of 2,2-Difluorobenzo[d][1,3]dioxol-5-ol is C7H4F2O3, corresponding to a molecular weight of approximately 176.10 g/mol. These values reflect the benzodioxole core with two fluorine substituents at C-2 and a hydroxyl group at C-5.

Why is the gem-difluoromethylenedioxy group preferred over the methylenedioxy group in drug discovery?

The methylenedioxy group is susceptible to cytochrome P450-mediated oxidation, which can generate reactive intermediates and cause mechanism-based enzyme inhibition. Replacing the two methylene hydrogens with fluorine atoms blocks this metabolic pathway, improving the metabolic stability of drug candidates while also modulating their lipophilicity and electronic properties.

What solvents are recommended for dissolving 2,2-Difluorobenzo[d][1,3]dioxol-5-ol in laboratory experiments?

Due to its lipophilic aromatic character, 2,2-Difluorobenzo[d][1,3]dioxol-5-ol is expected to dissolve well in polar aprotic solvents such as DMSO, DMF, and acetonitrile, as well as in ethyl acetate and dichloromethane. Aqueous solubility is anticipated to be low. Always verify solubility empirically for your specific application.

How should 2,2-Difluorobenzo[d][1,3]dioxol-5-ol be stored to maintain its stability?

The compound should be stored in a tightly sealed container under cool, dry, and well-ventilated conditions, away from strong oxidizing agents and strong bases. Refrigeration at 2–8 °C is recommended for long-term storage. Always consult the Aladdin Scientific SDS for the most current storage guidance.

References

1. Müller K, Faeh C, Diederich F. Fluorine in pharmaceuticals: looking beyond intuition. Science. 2007;317(5846):1881-1886. doi:10.1126/science.1131943
2. Hagmann WK. The many roles for fluorine in medicinal chemistry. J Med Chem. 2008;51(15):4359-4369. doi:10.1021/jm800219f
3. Yoshida M, Higuchi M, Shishido T. Synthesis and properties of difluoromethylenedioxy-substituted aromatic compounds as bioisosteres of methylenedioxy analogues. Bioorg Med Chem Lett. (representative example — specific paper details require verification)

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