4-Ethoxy-3,5-difluorobenzonitrile , CAS No.1017779-27-9

CAS: 1017779-27-9 Cat. No.: E1028337 Summenformel: C₉H₇F₂NO Molekulargewicht: 183.15 PubChem CID: 46737607

Storage

Room temperature

Specifications

Storage

Room temperature

Namen und Kennungen

• Kanonisches Lächeln: CCOC1=C(C=C(C=C1F)C#N)F
• IUPAC Name: 4-ethoxy-3,5-difluorobenzonitrile
• InChIKey: QSLWOCXSGQJUSS-UHFFFAOYSA-N
• INCHI: 1S/C9H7F2NO/c1-2-13-9-7(10)3-6(5-12)4-8(9)11/h3-4H,2H2,1H3
• Isomere SMILES: CCOC1=C(C=C(C=C1F)C#N)F
• PubChem CID: 46737607
• Molekulargewicht: 183.15

Taxonomic Classification

Taxonomy Tree

• Kingdom Organic compounds
  • Superclass Benzenoids
    • Klasse Phenol ethers

• Kingdom: Organic compounds
• Superclass: Benzenoids
• Klasse: Phenol ethers
• Subclass: Not available
• Intermediate Tree Nodes: Not available
• Direct Parent: Phenol ethers
• Alternative Parents: Phenoxy compounds Benzonitriles Fluorobenzenes Alkyl aryl ethers Aryl fluorides Nitriles Organofluorides Hydrocarbon derivatives
• Molecular Framework: Aromatic homomonocyclic compounds
• Substituents: Benzonitrile - Phenol ether - Phenoxy compound - Alkyl aryl ether - Fluorobenzene - Halobenzene - Aryl fluoride - Aryl halide - Monocyclic benzene moiety - Ether - Carbonitrile - Nitrile - Organofluoride - Organonitrogen compound - Organic nitrogen compound - Organooxygen compound - Hydrocarbon derivative - Cyanide - Organic oxygen compound - Organohalogen compound - Aromatic homomonocyclic compound
• Beschreibung: 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

Data sources

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.

DOI: 10.1186/s13321-016-0174-y

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

Application Protocols

Not applicable.

• No tested bioassay protocols (e.g., WB, IHC, IF, FC) are associated with this small-molecule building block. For synthetic applications, refer to the Reaction Conditions tab for representative procedures.

Biological Roles

This product is a synthetic organic building block rather than a biological metabolite.

• No endogenous biological role is expected for 4-ethoxy-3,5-difluorobenzonitrile. It is used in research synthesis to construct bioactive candidates or functional materials.
• Aryl nitriles and fluorinated aromatics are common motifs in medicinal chemistry due to their effects on lipophilicity, metabolic stability, and binding interactions; however, any biological activity depends entirely on the final scaffold and context.

Notes

• No biological function, pathway involvement, or enzyme interactions are specified for this item. Any testing with biological systems should be performed under appropriate institutional approvals and is strictly for research use only.

Buffer Applications

Not typically applicable.

• 4-Ethoxy-3,5-difluorobenzonitrile is a neutral, hydrophobic organic building block and is not used as a buffering agent or pH modifier.
• For experimental work in aqueous systems, dissolve in an appropriate organic cosolvent (e.g., DMSO, MeCN) before dilution; select biological buffers (PBS, HEPES) independently according to assay needs.

Green Alternatives

Opportunities to improve sustainability when using this fluorinated aryl nitrile focus on solvent/catalyst choice and step economy rather than altering the core reagent (which is itself chosen for performance in SNAr and for electronic effects).

Greener choices (literature-based, not product specs):

• Solvents for SNAr and functionalization:
  • Prefer 2-MeTHF or CPME over DMF/DMSO when feasible; they offer lower toxicity, easier recovery, and better EHS profiles.
  • MeCN or acetone can balance kinetics vs. environmental impact; often require higher T or stronger bases.
• Bases and catalysts:
  • Use inorganic carbonates (K2CO3, Cs2CO3) or organically recyclable superbases (DBU) rather than harsher, waste-intensive reagents.
• Demethylation/dealkylation:
  • Replace BBr3 in chlorinated solvents with catalytic demethylations or oxidative protocols where compatible, or perform hydrolysis routes via nitrile to phenol when strategically acceptable.
• Energy and step reduction:
  • Microwaves or flow reactors can cut reaction times/energy.
  • Direct SNAr to install the final substituents (avoid temporary handles).

Comparison snapshot (general):

• DMF/DMSO: Fast kinetics; problematic from EHS standpoint; difficult solvent removal.
• 2-MeTHF/CPME: Renewable/benign; may require higher temperature/longer time.
• MeCN/acetone: Moderate EHS; broad availability; good for scale-up.

Waste handling:

• Fluorinated organics and nitrile-containing wastes should be segregated and incinerated per local regulations; avoid aqueous discharge.

Pharmaceutical Uses

Formulation/industry context (general; no therapeutic claims):

• Role: synthetic intermediate/building block for discovery and process chemistry; may be used to prepare fluorinated aryl nitrile motifs incorporated into APIs or performance materials.
• Excipient status: Not a pharmacopeial excipient; not intended for direct formulation use.
• Regulatory: No compendial monograph known for this specific compound. Any use in GMP settings would require internal specifications, validated analytical methods, and impurity controls.

Item-specific note:

• No pharmaceutical grade or special compliance claims are provided for this item; refer to CoA/Spec Sheet for available quality documentation.
• For clinical manufacturing or regulated use, source control and full characterization (residual solvents, genotoxic impurities assessment) must be established by the end user.

Physical Properties

Item-specific specifications (this listing):

• Appearance: Not specified for this item; refer to CoA/Spec Sheet.
• Exact MP/BP, density, refractive index, UV cutoff, water/peroxide/metals: Not specified for this item; refer to CoA/Spec Sheet.

General/literature or computed information (for context; NOT product specifications):

• Molecular formula (derived): C9H8F2NO
• Molecular weight (calculated): ~184.16 g/mol
• Physical state expectation: small, neutral aromatic nitriles of this size are typically low-melting solids or high-boiling liquids.
• Polarity/partitioning: moderately lipophilic; cLogP commonly in the ~2–3 range for analogous 3,5-difluoro-4-alkoxy benzonitriles (literature trend/fragment estimate).
• Solubility profile:
  • Expected good solubility in polar aprotic and moderately polar organic solvents (e.g., DMSO, DMF, DMAc, MeCN, acetone, EtOAc, CH2Cl2, THF) and in nonpolar aromatics (toluene) (literature behavior of aryl nitriles/ethers).
  • Negligible solubility in water is typical for fluorinated aryl nitriles.

Notes:

• Use the product’s CoA for batch-specific values when needed for analytical or regulatory purposes.
• Values herein are informational and should not be used as specifications.

Quality and Grades

• Grade/Purity: Not specified for this item; refer to CoA/Spec Sheet for exact assay and impurity profile.
• Stabilizers/Inhibitors: Not specified for this item; refer to CoA/Spec Sheet.

How to interpret common grades (general guidance):

• Research/technical grade: Suitable for most synthetic applications and screening. Impurity levels adequate for discovery chemistry; verify for sensitive catalysis.

• 98% (typical for building blocks, literature): Minimizes side-products in cross-coupling/SNAr and improves analytical clarity. Confirm by NMR/GC/HPLC.

• HPLC grade solvents vs. reagents: For this solid/liquid building block, low-UV “HPLC grade” designation is usually applied to solvents, not to aryl nitriles. When using in photochemical or trace analysis contexts, review UV background of impurities.

Assurance and documentation:

• For structure confirmation and quality, request or consult CoA (NMR, LC/GC purity, MS) and, if needed, ask for residual solvent and elemental analysis. Batch-specific specs, including appearance and assay, are provided on the CoA.

Reaction and Applications

4-Ethoxy-3,5-difluorobenzonitrile is a versatile electron-poor arene useful as a building block in medicinal chemistry, materials (e.g., liquid-crystal motifs), and discovery synthesis.

Key application themes (literature guidance):

• SNAr diversification at C–F: The 3,5-difluoro pattern adjacent to a para nitrile activates the ring toward nucleophilic aromatic substitution. Amines, thiols, and phenoxides can displace one or both fluorides under basic, polar-aprotic conditions to install amino/alkoxy/aryloxy groups. Regioselectivity often favors positions activated by the para-CN.
• Ether manipulation: The para-ethoxy can be cleaved to the phenol (–OH) with Lewis acids (e.g., BBr3) for further diversification (etherification, esterification, silylation).
• Nitrile transformations:
  • Reduction to benzylamine analogs (e.g., catalytic hydrogenation, LiAlH4, BH3).
  • Hydrolysis to amide or carboxylic acid (acidic or basic conditions), enabling entry to 4-ethoxy-3,5-difluorobenzoic acid derivatives.
  • Nitrile-as-directing-group for ortho-lithiation/metalation, followed by electrophile quench.
• Cross-coupling strategies: While C–F activation is challenging for Pd-catalysis, SNAr-installed aryl chlorides/boronates enable Suzuki, Buchwald–Hartwig, or Ullmann-type couplings from the scaffold.

Practical tips:

• Ensure dryness for strong-base SNAr; water suppresses nucleophilicity.
• For diamino/diaryloxy products, stepwise substitution often affords better control; monitor by LC/MS.
• Workup: neutralize bases, extract into EtOAc or MTBE, charcoal polish to remove colored by-products.

Reaction Conditions

The following conditions are representative literature guidance for 3,5-difluoro-4-alkoxy benzonitriles and closely related substrates; they are not product specifications.

• SNAr (amine installation):
  • Substrate + R2NH (1.1–2.0 equiv), K2CO3 or Cs2CO3 (2–3 equiv)
  • Solvent: DMSO, DMF, or NMP (0.1–0.5 M)
  • Temperature: 60–120 °C (oil bath or sealed tube)
  • Time: 2–18 h; often complete within 4–8 h
  • Notes: Electron-poor ring from –CN enhances rates; secondary amines often higher reactivity. Monitor by LC/MS; vent pressure for high-boiling polar solvents.
• SNAr (aryloxy/alkoxy installation):
  • Nucleophile: sodium or potassium phenoxide/alkoxide (1.5–2.5 equiv)
  • Base: same or added carbonate; crown ether or phase-transfer may help in less polar solvents (2-MeTHF, toluene)
  • 80–140 °C; 4–24 h
• Nitrile reduction to amine:
  • H2 (30–60 bar) with Pd/C or Raney Ni, solvent EtOH/THF, 25–80 °C, 6–24 h; or LiAlH4 (THF, 0–25 °C to reflux) with careful quench.
• Nitrile hydrolysis:
  • To amide: H2SO4 (aq) or HCl (aq), 60–100 °C, 4–16 h; or NaOH/KOH (aq/MeOH), 50–90 °C followed by neutralization.
  • To acid: stronger/longer conditions (reflux) or two-step via amide.
• Ether dealkylation (to phenol):
  • BBr3 (1–3 equiv), CH2Cl2 or toluene, −78 to 0 °C then to RT, 2–16 h; quench carefully with MeOH/water.

Typical outcomes:

• SNAr single substitution often 60–90% isolated yield; disubstitution feasible with excess nucleophile/extended time. Actual yields depend on nucleophile strength and solvent.

Safety: Strong bases, high temperatures, and pressurized hydrogen require appropriate engineering controls and risk assessment.

Safety and Handling

Item-specific hazard data (this listing):

• GHS Classification, Signal Word, H-statements, Pictograms: Not specified for this item; refer to the SDS for authoritative information.

General laboratory safety guidance for aryl nitrile/fluorinated ether compounds (informational; not a substitute for the SDS):

• Hazards: Aromatic nitriles may cause irritation to skin/eyes/respiratory tract. Fluorinated aromatics and nitriles can exhibit acute toxicity if ingested or inhaled. Avoid dust/vapor formation. Combustible organic.
• PPE: Wear lab coat, safety glasses or face shield, and suitable gloves (e.g., nitrile). Use in a fume hood to control vapors/aerosols.
• Handling: Avoid heat, sparks, open flames. Prevent contact with strong bases/nucleophiles unless intended for reaction (risk of SNAr). Avoid strong oxidizers and strong reducing agents.
• Incompatibilities: Strong bases/nucleophiles can displace aryl fluoride under forcing conditions; Lewis acids (e.g., BBr3) may demethylate/dealkylate aryl ethers.
• 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 for irritation.
  • Ingestion: Rinse mouth; do not induce vomiting; seek medical attention.
• Spills: Absorb with inert material, collect in chemical waste. Ventilate area.
• Fire: Use CO2, dry chemical powder, or foam. Combustion may produce irritating/ toxic fumes (HF, NOx, CO/CO2).

Always consult the product SDS for definitive hazard classification and response procedures.

Solvent Selection

This compound is a moderately lipophilic, polarizable aryl nitrile/aryl ether. Solvent choice typically targets dissolution and compatibility with planned transformations (SNAr, reductions, hydrolysis, coupling).

• Polarity/miscibility (literature expectations):

  • Good solubility: DMSO, DMF/DMAc, NMP, MeCN, acetone, THF/2-MeTHF, EtOAc, CH2Cl2, toluene.
  • Poor solubility: water and highly protic, very polar media without cosolvent.

• Selection by application:

  • SNAr with amines/phenoxides: polar aprotics (DMSO, DMF, NMP) enhance rates; consider K2CO3, Cs2CO3, or DBU as base. For greener options, 2-MeTHF or CPME with phase-transfer/base may work at elevated T.
  • Reductions of nitrile (to amine): EtOH, iPrOH, or THF under catalytic hydrogenation; or ethereal solvents for hydride reagents (THF, 2-MeTHF).
  • Hydrolysis of nitrile: aqueous-organic mixtures (MeOH/H2O, MeCN/H2O) under acid or base catalysis.
  • Demethylation/dealkylation of aryl ether (to phenol): halogenated solvents are often used with BBr3; alternatives include toluene or CH2Cl2 at low T (literature practice).

• Small comparison (literature):

  • DMSO/DMF: highest SNAr rates; challenging workup, higher EHS burden.
  • MeCN/acetone: cleaner workup; may require higher temperature/stronger bases.
  • 2-MeTHF/CPME: greener, hydrophobic; may need longer times or catalysts to match rates.

Note: Optimize solvent based on solubility screening, reaction kinetics, EHS profile, and downstream isolation.

Storage and Reconstitution

Item-specific guidance (from Product Data):

• Storage conditions: Room temperature.
• Shipped in: Not specified for this item; refer to CoA/Spec Sheet.
• Appearance: Not specified for this item; refer to CoA/Spec Sheet.

General handling recommendations (literature/common practice):

• Store tightly closed in a dry, well-ventilated place, away from strong oxidizers and strong bases.
• Protect from prolonged exposure to heat and light. While aryl nitriles/ethers are typically stable, maintain desiccation to prevent hydrolysis of reactive reagents used alongside it.
• No reconstitution is required; if solid at ambient conditions, warm gently or dissolve in a compatible organic solvent (e.g., DMSO, MeCN, THF) to prepare stock solutions. For biological testing, prepare concentrated DMSO stocks (e.g., 10–100 mM) and dilute into assay media with mixing to avoid precipitation.
• Shelf life/retention samples: Verify integrity periodically by NMR/LC-MS if stored long term.

Note: Always defer to the product’s CoA/SDS for batch-specific storage and handling instructions.

Structure and Identity

Brief description: 4-Ethoxy-3,5-difluorobenzonitrile is an electron-deficient, fluorinated aryl nitrile bearing a para-ethoxy substituent.

• Item-specific identifiers (from Product Data)

  • SKU: E1028337
  • Product name: 4-Ethoxy-3,5-difluorobenzonitrile
  • CAS: 1017779-27-9
  • PubChem CID: 46737607
  • InChIKey: 305337 (as provided)
  • Storage: Room temperature
  • Research use: For research use only

• Structure description (literature/computed; not item-specific specs)

  • Molecular formula (derived from name): C9H8F2NO
  • Molecular weight (calculated): ~184.16 g/mol (literature calculation)
  • SMILES (representative): CCOc1cc(F)cc(C#N)c1F
  • Core features: substituted benzene ring with a para-ethoxy group (–OCH2CH3), a nitrile (–C≡N) para to the ethoxy, and two ring fluorines at the 3- and 5-positions.
  • Functional groups: aryl ether, aryl nitrile, aryl C–F bonds.
  • 2D structure (verbal): a 1,3,5-trisubstituted benzene where positions 3 and 5 are fluoro, position 4 is ethoxy, and position 1 is cyano.

• Notes

  • Any missing or alternative identifiers (e.g., exact InChI, canonical SMILES) are not specified for this item; refer to CoA/Spec Sheet.

Synthetic Utility

Functional handles and their utility (literature overview):

• Aryl nitrile (–C≡N):
  • Convertible to amide, acid, aldehyde, or amine via hydrolysis, partial reduction (e.g., DIBAL-H), or full reduction (hydrogenation, LiAlH4).
  • Serves as a strong electron-withdrawing group to activate the ring to SNAr and can direct ortho-metalation.
• Aryl fluorides (3,5-positions):
  • Good leaving groups under SNAr with hard nucleophiles in polar aprotic media; enables rapid library generation of 3,5-disubstituted analogs.
  • Retentive of metabolic stability and modulate electronics.
• Aryl ether (para-ethoxy):
  • Tuning of electronics and solubility; convertible to phenol for divergent derivatization (BBr3, AlCl3, or other protocols).

Strategic value:

• Scaffolding for bis-substitution patterns key to kinase/inflammasome inhibitor series and liquid-crystal cores (literature precedents using 3,5-difluoro-4-alkoxybenzonitriles).
• Enables convergent SNAr-first, cross-coupling-second sequences to assemble densely substituted aromatics without harsh halogenation steps on sensitive intermediates.

Analytical notes:

• 19F NMR gives two characteristic aromatic F signals; disappearance upon SNAr is a quick progress indicator.
• CN stretch near ~2220–2240 cm−1 (IR, literature) confirms nitrile retention; loss indicates hydrolysis/reduction.

Target Specificity

Not applicable.

• This product is a small-molecule building block, not a biological macromolecule or affinity reagent. No antigen/epitope, species reactivity, clone, or isotype information applies.