3,5-Difluorothioanisole: Properties, Uses & Lab Guide

3,5-Difluorothioanisole is a fluorinated aromatic thioether widely valued in synthetic and medicinal chemistry as a versatile building block for constructing bioactive molecules and advanced intermediates.

Chemical Name

3,5-Difluorothioanisole (1,3-difluoro-5-(methylthio)benzene)

Molecular Formula

C7H6F2S

Molecular Weight

160.18 g/mol

CAS Number

100858-32-0

Appearance

Colorless to pale yellow liquid

Key Functional Groups

Aryl fluorides (C–F) and thioether (C–S–CH3)

Primary Application

Intermediate in pharmaceutical and agrochemical synthesis

Chemical Identity and Physical Properties

3,5-Difluorothioanisole, systematically named 1,3-difluoro-5-(methylthio)benzene, is an organofluorine aromatic compound bearing two fluorine substituents at the 3- and 5-positions of the benzene ring and a methylthio (–SCH₃) group at the 1-position. Its molecular formula is C₇H₆F₂S with a molecular weight of approximately 160.18 g/mol.

The compound typically presents as a colorless to pale yellow liquid at ambient conditions. The electron-withdrawing nature of the two fluorine atoms significantly modulates the electron density of the aromatic ring, influencing both reactivity and physicochemical parameters such as lipophilicity (logP) and metabolic stability. These properties make it particularly attractive in the design of pharmaceutical intermediates.

The C–F bonds in the molecule contribute characteristic stability toward metabolic oxidation, a property routinely exploited in drug discovery programs. The methylthio group, while amenable to further functionalization (e.g., oxidation to sulfoxide or sulfone), also acts as a directing and activating group in electrophilic aromatic substitution chemistry.

Synthesis and Functionalization Strategies

3,5-Difluorothioanisole is commonly prepared via nucleophilic aromatic substitution (S_NAr) or thioetherification reactions starting from appropriate difluorobenzene precursors. The presence of two fluorine substituents in the meta-positions substantially activates the ring toward nucleophilic attack, enabling efficient introduction of the sulfide moiety under mild conditions.

Alternatively, the compound may be accessed through palladium-catalyzed cross-coupling methodologies, such as the coupling of a suitable aryl halide with thiomethyl nucleophiles, or via direct fluorination of a thioanisolyl precursor using reagents such as Selectfluor or DAST under controlled conditions.

Once in hand, 3,5-Difluorothioanisole can be further elaborated by:

• Lithiation: Treatment with n-BuLi at low temperature generates aryllithium intermediates suitable for reaction with electrophiles.
• Oxidation of sulfur: Controlled oxidation with mCPBA or H₂O₂ yields the corresponding sulfoxide or sulfone derivatives, which may possess distinct bioactivity profiles.
• Cross-coupling: Borylation via Miyaura borylation followed by Suzuki–Miyaura coupling enables the introduction of diverse aryl or heteroaryl fragments.

These strategies underscore the compound's utility as a versatile synthetic building block.

Research and Industrial Applications

The unique combination of fluorine atoms and a thioether group makes 3,5-Difluorothioanisole a sought-after intermediate in multiple research domains:

Pharmaceutical Chemistry: Fluorinated aryl thioethers are recurrent motifs in drug candidates targeting a wide variety of biological pathways. The fluorine atoms improve membrane permeability, metabolic stability, and binding affinity to protein targets by modulating electronic and steric profiles. Medicinal chemists routinely incorporate difluorothioanisole scaffolds when designing kinase inhibitors, CNS-active agents, and anti-infective compounds.

Agrochemical Research: Organofluorine building blocks are extensively used in the synthesis of modern pesticides and herbicides. The metabolic resistance conferred by C–F bonds and the lipophilicity adjustments from the thioether moiety are equally exploited in agrochemical lead optimization.

Materials Science: Sulfur-containing fluorinated aromatic compounds have found niche applications in liquid crystal formulations and specialty polymer synthesis, where precise tuning of dielectric properties is required.

Probe and Tracer Synthesis: The scaffold can serve as a precursor for PET imaging tracers or fluorescent probes where selective labeling of biological targets is desired.

Safety, Handling and Storage

As with most organofluorine thioether compounds, appropriate precautions should be taken when handling 3,5-Difluorothioanisole in the laboratory setting. Users are advised to consult the current Safety Data Sheet (SDS) supplied by Aladdin Scientific before use.

Personal Protective Equipment (PPE): Wear chemically resistant gloves (nitrile or neoprene), safety goggles, and a laboratory coat. Work in a well-ventilated fume hood to avoid inhalation of vapors.

Storage: Store in a tightly sealed container in a cool, dry, well-ventilated location, away from incompatible materials such as strong oxidizers and strong bases. Refrigerated storage (2–8 °C) is typically recommended to maintain purity and prevent decomposition over extended periods.

Disposal: Dispose of waste material in accordance with all applicable local, regional, and national regulations governing organosulfur and halogenated compounds. Do not pour down the drain.

First Aid: In the event of skin or eye contact, rinse immediately with copious water for at least 15 minutes and seek medical attention. If inhaled, move to fresh air immediately.

Note: Always refer to the current product SDS for authoritative hazard and first-aid information.

Quality Specifications and Ordering Information

Aladdin Scientific offers 3,5-Difluorothioanisole (SKU: D692744) as a high-purity research reagent suitable for use in demanding synthetic applications. Key quality parameters typically monitored include:

• Purity: Assessed by GC or HPLC; research-grade material is generally ≥97% pure (verify with current certificate of analysis).
• Identity Confirmation: Verified by ¹H NMR, ¹⁹F NMR, and/or mass spectrometry.
• Appearance: Colorless to pale yellow clear liquid, free from visible particulates.

Researchers requiring bulk quantities or custom purity grades are encouraged to contact Aladdin Scientific's technical sales team for tailored quotations. Certificates of Analysis (CoA) are available upon request for each production lot, ensuring full traceability and compliance with laboratory quality management requirements.

For procurement teams, 3,5-Difluorothioanisole is typically available in multiple pack sizes. Lead times are subject to current inventory; please check the Aladdin Scientific website or contact customer service for real-time availability.

Frequently asked questions

What is 3,5-Difluorothioanisole used for in research?

3,5-Difluorothioanisole is primarily used as a synthetic building block in pharmaceutical and agrochemical research. Its fluorinated thioether scaffold is valuable for constructing bioactive intermediates, including drug candidates targeting kinases and CNS pathways, as well as in materials science applications.

How should 3,5-Difluorothioanisole be stored to maintain its stability?

The compound should be stored in a tightly sealed container under cool, dry, and well-ventilated conditions. Refrigerated storage at 2–8 °C is generally recommended to preserve purity over extended periods. Always keep it away from strong oxidizers and strong bases.

Can the methylthio group in 3,5-Difluorothioanisole be further functionalized?

Yes. The methylthio group can be selectively oxidized to a sulfoxide or sulfone using reagents such as mCPBA or hydrogen peroxide, providing derivatives with distinct electronic and biological properties. The group can also participate in transition-metal-catalyzed cross-coupling reactions under appropriate conditions.

What purity grade is available for 3,5-Difluorothioanisole from Aladdin Scientific?

Aladdin Scientific offers 3,5-Difluorothioanisole (SKU: D692744) as a research-grade reagent. Purity is typically ≥97% as determined by GC or HPLC. A Certificate of Analysis for the specific production lot can be requested to confirm exact purity and quality specifications.

Why are fluorine substituents important in drug discovery scaffolds like 3,5-Difluorothioanisole?

Fluorine substituents improve key drug-like properties including metabolic stability, membrane permeability, and binding affinity to biological targets. The strong C–F bond resists oxidative metabolism, and fluorine's high electronegativity modulates the pKa and lipophilicity of the molecule, making fluorinated scaffolds highly desirable in lead optimization.

References

1. Hagmann, W. K. The Many Roles for Fluorine in Medicinal Chemistry. Journal of Medicinal Chemistry, 2008, 51(15), 4359–4369. doi:10.1021/jm800219f
2. Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. Journal of Medicinal Chemistry, 2015, 58(21), 8315–8359. doi:10.1021/acs.jmedchem.5b00258
3. Patai, S.; Rappoport, Z. (Eds.) The Chemistry of Organic Sulfur Compounds. Wiley, 1993.
4. Aladdin Scientific. Product Page: 3,5-Difluorothioanisole, SKU D692744. Aladdin Scientific Corporation.

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