This compound belongs to the class of organic compounds known as phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring.
External Descriptors
Not available
1. Djoumbou Feunang Y, Eisner R, Knox C, Chepelev L, Hastings J, Owen G, Fahy E, Steinbeck C, Subramanian S, Bolton E, Greiner R, and Wishart DS. ClassyFire: Automated Chemical Classification With A Comprehensive, Computable Taxonomy. Journal of Cheminformatics, 2016, 8:61.
Zertifikate (CoA, COO, BSE/TSE und Analyse-Diagramm)
C of A & Other Certificates(BSE/TSE, COO):
Analytical Chart:
Chemische und physikalische Eigenschaften
Molekulargewicht
183.150 g/mol
XLogP3
2.200
Hydrogen Bond Donor Count
0
Hydrogen Bond Acceptor Count
4
Rotatable Bond Count
2
Exact Mass
183.05 Da
Monoisotopic Mass
183.05 Da
Topological Polar Surface Area
33.000 Ų
Heavy Atom Count
13
Formal Charge
0
Complexity
201.000
Isotope Atom Count
0
Defined Atom Stereocenter Count
0
Undefined Atom Stereocenter Count
0
Defined Bond Stereocenter Count
0
Undefined Bond Stereocenter Count
0
The total count of all stereochemical bonds
0
Covalently-Bonded Unit Count
1
Lösungsrechner
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Application Protocols
No tested bioassay or diagnostic application protocols are provided for this item. As a synthetic building block, typical “protocols” correspond to organic reaction procedures (see Reaction Conditions and Reaction & Applications tabs).
General lab handling suggestions:
Weigh quickly and cap immediately to minimize environmental moisture ingress during setup.
For solution dosing into parallel reactions, prepare a stock in dry DMSO, MeCN, or THF, verify concentration by weight/volume, and store aliquots under inert atmosphere if used over multiple days.
Biological Roles
This compound is a synthetic, fluorinated aryl nitrile and does not have a known endogenous biological role.
General/literature context (non-clinical):
Aryl nitriles are common motifs in chemical biology probes and medicinal chemistry due to their compact polarity and ability to act as metabolically robust bioisosteres of carbonyl or halogenated aromatics. The nitrile can also serve as a weak hydrogen bond acceptor and electrophile in covalent-enzyme design when adjacent activating groups are present.
The 2,6-difluoro substitution pattern creates a hindered, conformationally biased arene that can influence binding geometry in fragment-based design, while the para-ethoxy group can be leveraged as a solubilizing or pro-moiety handle in derivatization campaigns.
Caveats:
No biological activity, targets, or potency data are provided for this catalog item. Any biological testing should be conducted in accordance with institutional safety protocols and recognizing this product is for research use only.
Buffer Applications
Not typically applicable. 4-Ethoxy-2,6-difluorobenzonitrile is a neutral, hydrophobic organic building block with low aqueous solubility and no acid/base buffering functionality in physiological pH ranges.
Practical note:
If used in biochemical assays, it is usually dissolved in an organic co-solvent (e.g., DMSO) before dilution into buffer. Keep final organic content low (commonly ≤1–2% v/v) to avoid perturbing biological systems.
Green Alternatives
Green chemistry considerations focus on solvent and base choices and energy input; the substrate itself is a fluorinated aromatic, which carries inherent EHS tradeoffs.
Greener process options (literature guidance):
Solvent substitution:
Replace DMF/DMSO with 2-MeTHF, CPME, or propylene carbonate where compatible. Note that SNAr often benefits from polar aprotics; propylene carbonate can be a greener high-permittivity option but has viscosity and workup tradeoffs.
Use MeCN or ethanol for nitrile reductions to ease solvent recovery.
Bases/nucleophiles: Favor inorganic carbonates (K2CO3, Cs2CO3) over strong alkoxides to minimize hazards, accepting longer reaction times or higher temperatures.
Energy efficiency: Employ microwave-assisted SNAr to reduce time/energy compared to long refluxes.
Workup/waste: Aim for telescoped sequences (e.g., SNAr followed by nitrile transformation) to reduce solvent exchanges and purifications.
Illustrative comparison (general):
DMF vs. Propylene carbonate: Similar ability to solvate ions; propylene carbonate is less volatile and has improved EHS profile, but removal can be more difficult.
THF vs. 2-MeTHF: 2-MeTHF derives from renewable sources and has better safety metrics; may require slightly higher temperatures to match SNAr rates observed in DMF/THF.
Note: Always validate greener substitutions on small scale; reaction kinetics and selectivity can change with solvent/base choices.
Pharmaceutical Uses
No pharmacopeial status or excipient role is specified for this item; refer to CoA/Spec Sheet for any regulatory notations.
General formulation/manufacturing context (non-clinical; literature-based):
Role as an intermediate: Fluorinated aryl nitriles are frequently used as advanced intermediates in the synthesis of active pharmaceutical ingredient (API) candidates. The 2,6-difluoro array enables convergent SNAr to install functionally diverse ortho substituents, while the nitrile can be elaborated to amides/acids/amines.
Process advantages: The ethoxy substituent can modulate crystallinity and solubility of intermediates, aiding isolation and purification during process development.
Analytical considerations: 19F NMR provides a sensitive handle for in-process control; IR ν(C≡N) is diagnostic for endpoint confirmation when converting the nitrile.
Compliance note:
This product is supplied strictly for R&D and process development. It is not intended for human or veterinary use and should not be used in drug products without appropriate qualification and regulatory assessment.
Physical Properties
Item-specific specifications:
Molecular Formula: Not specified for this item; refer to CoA/Spec Sheet.
Molecular Weight: Not specified for this item; refer to CoA/Spec Sheet.
Appearance: Not specified for this item; refer to CoA/Spec Sheet.
Literature/general properties (reference values; not specifications of this lot):
Expected state at ambient conditions: low-volatility organic compound; many aryl nitriles of comparable size are crystalline solids or low-melting solids/liquids.
Polarity/solubility profile: Moderately lipophilic; typically low solubility in water and good solubility in common organic solvents (e.g., DMSO, DMF, acetonitrile, dichloromethane, toluene, ethers) due to aryl ring and ether; nitrile imparts some polarity.
Spectroscopy (typical): strong IR ν(C≡N) band around 2220–2260 cm⁻¹ (literature); aromatic C–F stretches in 1000–1400 cm⁻¹ region; 19F NMR shows two aromatic F signals (often ortho to CN) with characteristic coupling to aromatic protons.
Partitioning: aryl nitriles of similar substitution often exhibit logP in the ~2–3 range (literature trend), consistent with organic solvent preference.
Thermal behavior: aromatic nitriles and aryl ethers are generally thermally robust; avoid prolonged exposure above 150–200 °C to limit decomposition.
Practical notes:
Drying: may be dried under vacuum at ambient to mild temperatures if needed for moisture-sensitive applications.
Hygroscopicity: typically low for aryl nitriles/ethers, but handle in a dry environment for SNAr chemistry.
For exact BP/MP, density, refractive index, and solubility of this catalog item, consult the CoA/Spec Sheet.
Quality and Grades
Item-specific quality information:
Grade/Purity: Not specified for this item; refer to CoA/Spec Sheet.
General guidance on quality for electrophilic aryl building blocks:
Purity needs depend on application. For SNAr, coupling, or multistep synthesis, impurities such as hydrolyzed phenols, residual halogenated isomers, or solvents can impact rate/selectivity. High assay (≥95–98%) is typically preferred for reproducible reactivity.
Water/peroxides/metal limits: Not specified for this item; refer to CoA/Spec Sheet. For moisture-sensitive nucleophiles, drying the material prior to use can improve outcomes.
Stabilizers: None are typically required for aryl nitriles/ethers. If any stabilizer is used, it will be disclosed on the CoA; its presence can influence chromatographic baselines and should be removed during workup if necessary.
Documentation: For precise specifications (HPLC purity method, residual solvents by GC, NMR identity, and exact impurity profile), consult the CoA/Spec Sheet corresponding to your lot.
Practical tips:
Verify identity by 1H/13C NMR, 19F NMR, and IR (C≡N band) prior to scale-up.
If using in sensitive transformations (e.g., organometallics), consider an additional purification (flash chromatography or recrystallization) to ensure batch-to-batch consistency.
Reaction and Applications
Core reactivity of 4-ethoxy-2,6-difluorobenzonitrile (literature/general guidance):
Nucleophilic Aromatic Substitution (SNAr): The nitrile strongly deactivates the ring toward electrophilic substitution but activates it toward SNAr at ortho/para positions. The two ortho fluorides are excellent leaving groups in SNAr. Nucleophiles such as amines, thiols, and alkoxides can replace F under basic conditions, enabling rapid access to 2- and 6-disubstituted anilines/phenyl ethers/thioethers.
Chemoselectivity: The para ethoxy substituent is relatively inert under SNAr conditions, providing a handle for later manipulation (deprotection or cleavage under strong conditions if needed).
Nitrile transformations: The –C≡N can be
Hydrolyzed to the corresponding amide or carboxylic acid (acidic or basic conditions).
Reduced to the primary amine (catalytic hydrogenation, borane, or DIBAL for partial reduction to aldehyde).
Converted to tetrazoles with azide under Lewis acid catalysis (e.g., ZnCl2), useful as carboxylate bioisosteres.
Cross-coupling: While aryl–F bonds are challenging, nickel-catalyzed couplings or specialized ligand systems can functionalize aryl fluorides, though SNAr is typically more practical for this substrate class.
Medicinal chemistry building block: Installation of polar side chains via SNAr on the ortho positions, combined with divergent nitrile elaboration, provides rapid library synthesis around a rigid difluoro-aryl core.
Practical tips:
Ensure anhydrous conditions for reactions with strong nucleophiles/bases.
Monitor by LC-MS or 19F NMR; disappearance of F signals is a convenient handle.
If bis-substitution is undesired, use stoichiometry and stepwise protecting strategies to control mono- vs. disubstitution.
Reaction Conditions
The following are literature/general conditions commonly used with difluoro-activated aryl nitriles; they are provided as guidance only and are not specific to this catalog item.
SNAr with amines (Ar–F → Ar–NR2):
Solvent: DMF, DMSO, or NMP (0.1–0.5 M).
Base: K2CO3 or Cs2CO3 (2–3 equiv) or organic base (DIPEA for more nucleophilic amines).
Temperature: 60–120 °C (microwave 80–140 °C for 10–60 min).
Notes: Order of substitution at C-2 vs. C-6 can be influenced by nucleophile, temperature, and sterics; monitor by 19F NMR.
SNAr with thiols/alkoxides (Ar–F → Ar–SR/OR):
Solvent: DMSO, DMF, or MeCN.
Base: NaH or KOtBu for alkoxides (1.1–1.5 equiv); K2CO3/Cs2CO3 for thiolates formed in situ.
Temperature: 25–100 °C (thiolates often proceed at lower temperatures than amines).
Notes: Minimize oxygen for thiolates; consider inert atmosphere.
Nitrile hydrolysis to amide/acid:
Acidic: Aqueous H2SO4 or HCl (3–6 M), 80–120 °C; amide intermediate may be isolable.
Basic: NaOH/KOH (2–6 equiv) in EtOH/H2O or dioxane/H2O, 80–120 °C; work up acidic to obtain acid.
Nitrile reduction:
To primary amine: H2 (1–5 bar) with Pd/C or Raney Ni in EtOH/MeOH, 25–60 °C; or BH3·THF at 0–25 °C then quench.
To aldehyde: DIBAL-H (1.5–2.0 equiv) in toluene/THF at −78 to −20 °C; careful quench to prevent over-reduction.
Typical outcomes:
SNAr conversions often 70–95% isolated yields on small scale with optimized conditions; nitrile transformations vary (50–90%) depending on substrate and workup.
Always confirm compatibility of conditions with the ethoxy substituent and desired chemoselectivity.
Safety and Handling
Item-specific hazard data:
GHS Classification: Not specified for this item; refer to SDS.
Signal Word: Not specified for this item; refer to SDS.
Hazard (H-) Statements: Not specified for this item; refer to SDS.
Pictograms: Not specified for this item; refer to SDS.
General safety considerations for aryl nitriles/aryl fluorides (literature guidance; not product-specific):
Hazards: May cause irritation to skin, eyes, and respiratory tract. Aromatic nitriles can be harmful if swallowed or inhaled; avoid aerosol formation. Combustible organic compound.
PPE: Wear lab coat, safety glasses or goggles, and appropriate chemical-resistant gloves (e.g., nitrile). Use in a chemical fume hood to avoid inhalation.
Incompatibilities: Strong bases can induce SNAr and/or ether cleavage; strong oxidizers may react vigorously with organics. Avoid strong reducing agents unless intended (nitrile reductions). Fluoride release is not expected under normal handling but can occur under harsh conditions.
First aid (overview): Inhalation—move to fresh air, seek medical attention if symptoms persist. Skin/eye contact—rinse with water for at least 15 minutes, remove contaminated clothing, seek medical attention if irritation persists. Ingestion—rinse mouth, do not induce vomiting, seek medical attention.
Fire safety: Use CO2, dry chemical, or foam. Combustion may produce CO/CO2 and HF traces if C–F bonds are degraded under extreme conditions; firefighters should wear SCBA.
Stability: Stable under recommended storage (room temperature, dry, away from light). Store tightly closed.
Always consult the product’s SDS for authoritative safety and regulatory information.
Solvent Selection
Relevance: 4-Ethoxy-2,6-difluorobenzonitrile is a moderately polar aromatic substrate. Solvent choice should balance substrate solubility with the demands of the transformation (e.g., SNAr vs. nitrile hydrolysis or reduction).
General solvent behavior (literature trends):
Solubility: Typically high in polar aprotic solvents (DMSO, DMF, NMP, acetonitrile) and in less polar organics (THF, 2-MeTHF, dioxane, toluene, chlorinated solvents). Poorly soluble in water.
Polarity class: Polar aprotic compatible; aromatic-coordinating solvents (toluene) can be useful for high-temperature processes.
Selection by application:
SNAr with amines/thiols/alkoxides: DMF, DMSO, NMP, or DME/THF with added base (Cs2CO3, K2CO3, NaOtBu). For heterogeneous bases, polar aprotics often give best rates.
Metal-catalyzed couplings on aryl–F (if pursued): High-boiling polar aprotics (DMAc, NMP) or dioxane/toluene with tailored catalysts; note that SNAr is generally preferred over cross-coupling for activated aryl–F.
Nitrile hydrolysis: Aqueous alcohols or dioxane/water mixtures under acid/base catalysis.
Nitrile reductions: Alcoholic solvents (EtOH, iPrOH) with catalytic hydrogenation; or THF/EtOH with hydride reagents as appropriate.
2-MeTHF/CPME: Greener ethers; good for organometallic or hydride reductions; lower polarity may slow SNAr.
MeCN: Balanced polarity; good for moderate-temperature reactions; easier removal than DMF.
Always evaluate solvent compatibility with base/catalyst and downstream EHS constraints.
Storage and Reconstitution
Item-specific storage and shipping (from Product Data):
Storage Conditions: Room temperature
Shipped In: Normal
General storage guidance (literature/practice; not item-specific specs):
Keep container tightly closed in a dry, well-ventilated place. Protect from prolonged exposure to heat and light.
For long-term storage, consider desiccation (e.g., with silica or molecular sieves) to maintain dryness, especially if frequent SNAr chemistry is planned.
If supplied as a solid, no reconstitution is required. If supplied as a liquid/low-melting solid, store in glass with PTFE-lined cap to minimize permeation.
Solution handling:
Prepare stock solutions in dry organic solvents (e.g., DMSO, MeCN, THF) under inert atmosphere when moisture-sensitive bases/nucleophiles will be used subsequently.
Short-term solution storage at 2–8 °C may be acceptable in dry, sealed vials; for longer storage, freeze at ≤−20 °C and minimize freeze–thaw cycles by aliquoting.
Inspection:
Before use, check for discoloration, precipitated solids, or visible contamination. If present, consider purification (e.g., flash chromatography) prior to critical applications.
For exact appearance, stability limits, and any special handling for this lot, refer to the CoA/Spec Sheet and SDS.
Structure and Identity
Overview: 4-Ethoxy-2,6-difluorobenzonitrile is a difluorinated aryl nitrile bearing a para-ethoxy substituent. The combination of a nitrile and ortho-fluoro groups activates the ring toward nucleophilic aromatic substitution, making it a useful electrophilic building block.
Item-specific (from Product Data):
SKU: E1337850
Product Name: 4-Ethoxy-2,6-difluorobenzonitrile
CAS: 916483-58-4
CID: 20112210
InChIKey: 65592
SMILES: Not specified for this item; refer to CoA/Spec Sheet.
Storage Conditions: Room temperature
Shipped In: Normal
Research Use: For research use only
Literature/computed identifiers and features (for reference only; not item specifications):
2D structural description: A benzene ring bearing a nitrile (–C≡N) at C-1, fluorine atoms at C-2 and C-6 (ortho to the nitrile), and an ethoxy group (–O–CH2–CH3) at C-4 (para to the nitrile). No stereocenters; planar aromatic system.
Where exact identifiers/values are needed for regulatory or analytical purposes, consult the product’s CoA/Spec Sheet.
Synthetic Utility
Functional group logic (literature perspective):
Activated aryl–F bonds: The ortho-fluorides adjacent to a nitrile are excellent leaving groups under SNAr, enabling stepwise introduction of nucleophiles (R–NH2, R–S–, RO–). This allows rapid diversification to 2,6-disubstituted benzonitrile scaffolds.
Nitrile handle: Versatile for downstream transformations—hydrolysis to carboxylic acids/amides; reduction to primary amines or aldehydes; cycloadditions to tetrazoles; additions of organometallics (under control) to form imines/ketimines.
Orthogonal reactivity: The para-ethoxy group is generally inert under SNAr and mild reduction conditions, acting as a protecting/solubilizing group. Under strong Lewis acids or BBr3, it can be demethylated/dealkylated (ether cleavage) to give the corresponding phenol for further functionalization.
Retrosynthetic value:
Serves as a convergent branching point: build complexity via two independent SNAr events at C-2 and C-6, followed by nitrile elaboration to install carboxamide/amine functionality.
Enables polarity tuning: Introduction of polar nucleophiles ortho to CN can improve solubility and binding properties in lead optimization while maintaining the rigid aryl core.
Analytical/monitoring tips:
19F NMR cleanly tracks substitution at each ortho position; LC-MS readily detects mass shifts from F → Nu substitution (+(Nu−F)).
IR disappearance or shift of ν(C≡N) confirms nitrile transformation stages.
Target Specificity
Not applicable. This product is a small-molecule chemical building block and is not an antibody, enzyme, or targeted biological reagent. No antigen/epitope or species reactivity data apply.
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