4-Ethoxy-3,5-difluorobenzoic acid - ≥95% , CAS No.1017779-19-9

CAS: 1017779-19-9 Cat. No.: E1320664 Formula: C₉H₈F₂O₃ Peso molecolare: 202.16 PubChem CID: 46737603

GRADE & PURITY ≥95%

Storage

Room temperature

Shipped In

Normal

Specifications

Specifiche e purezza

≥95%

Condizioni di conservazione di stoccaggio

Room temperature

Spedito in

Normal

Purezza

≥95%

Nomi e identificatori

• Sorrisi canonici: CCOC1=C(C=C(C=C1F)C(=O)O)F
• IUPAC Name: 4-ethoxy-3,5-difluorobenzoic acid
• InChIKey: QCPWRWTXAQDVSY-UHFFFAOYSA-N
• INCHI: 1S/C9H8F2O3/c1-2-14-8-6(10)3-5(9(12)13)4-7(8)11/h3-4H,2H2,1H3,(H,12,13)
• Isomeri SMILES: CCOC1=C(C=C(C=C1F)C(=O)O)F
• PubChem CID: 46737603
• Peso molecolare: 202.16

Taxonomic Classification

Taxonomy Tree

• Kingdom Organic compounds
  • Superclass Benzenoids
    • Classe Benzene and substituted derivatives
      • Subclass Benzoic acids and derivatives
        • Level5 Halobenzoic acids and derivatives
          • Level6 Halobenzoic acids

• Kingdom: Organic compounds
• Superclass: Benzenoids
• Classe: Benzene and substituted derivatives
• Subclass: Benzoic acids and derivatives
• Intermediate Tree Nodes: Halobenzoic acids and derivatives
• Direct Parent: Halobenzoic acids
• Alternative Parents: 3-halobenzoic acids Benzoic acids Phenoxy compounds Phenol ethers Benzoyl derivatives Fluorobenzenes Alkyl aryl ethers Aryl fluorides Carboxylic acids Organofluorides Organic oxides Hydrocarbon derivatives
• Molecular Framework: Aromatic homomonocyclic compounds
• Substituents: 3-halobenzoic acid or derivatives - 3-halobenzoic acid - Halobenzoic acid - Benzoic acid - Phenoxy compound - Benzoyl - Phenol ether - Halobenzene - Fluorobenzene - Alkyl aryl ether - Aryl fluoride - Aryl halide - Ether - Carboxylic acid - Carboxylic acid derivative - Organooxygen compound - Organofluoride - Organohalogen compound - Organic oxygen compound - Organic oxide - Hydrocarbon derivative - Aromatic homomonocyclic compound
• Descrizione: This compound belongs to the class of organic compounds known as halobenzoic acids. These are benzoic acids carrying a halogen atom on the 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

Proprietà chimiche e fisiche

• Peso molecolare: 202.150 g/mol
• XLogP3: 2.000
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 5
• Rotatable Bond Count: 3
• Exact Mass: 202.044 Da
• Monoisotopic Mass: 202.044 Da
• Topological Polar Surface Area: 46.500 Ų
• Heavy Atom Count: 14
• Formal Charge: 0
• Complexity: 198.000
• 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

No item-specific application protocols are provided for this small-molecule reagent. Usage conditions vary with the intended reaction (see Reaction Conditions and Synthetic Utility tabs). For general handling:

• Weigh and transfer in a dry environment to maintain reproducible assay/coupling stoichiometry.
• Prepare stock solutions in DMF/DMSO for parallel synthesis; filter if particulate remains.
• For amide couplings, typical starting screens: 1.0 equiv acid, 1.1–1.3 equiv amine/alcohol, 1.2–1.5 equiv coupling reagent, 2–3 equiv base, 0.05 equiv DMAP (for esterifications). Adjust per substrate.

Biological Roles

• Item-specific (Product Data)

  • No biological role data provided for this item; for research use only.

• Literature/general context

  • As a small fluorinated aromatic carboxylic acid, this compound does not constitute a natural metabolite. However, benzoic acid derivatives can interact with metabolic enzymes (e.g., acyltransferases) after derivatization; the 3,5-difluoro/4-ethoxy substitution modulates electron density and lipophilicity relevant to structure–property exploration in chemical biology.
  • Fluorine substitution often affects binding thermodynamics and metabolic stability of derived amides/esters in medicinal chemistry studies; thus, this acid is useful as a precursor to probe fluorine effects in protein–ligand interactions and permeability assays.
  • Carboxylate salts may display altered solubility and membrane transport in vitro compared with the free acid, a factor to consider when designing biochemical assays of derived compounds.

Note: No claims are made regarding biological activity of the neat acid; any discussion pertains to general principles and to derivatives prepared from it.

Buffer Applications

This compound is not a typical buffering agent. Aromatic monocarboxylic acids have limited buffering capacity near physiological pH and are not commonly used to prepare laboratory buffers.

• Practical note: If temporary pH control is needed in an organic reaction, sub-stoichiometric use as a Brønsted acid is possible, but dedicated buffer systems (e.g., phosphate, acetate, HEPES, MOPS) are strongly preferred.
• For aqueous workups, the acid/base toggling of benzoic acids can aid liquid–liquid extraction, but this is not “buffering” in the analytical sense.

Green Alternatives

• Solvent choices (greener options; literature/general)

  • Replace DMF/DMSO where feasible with 2-MeTHF, EtOAc, CPME, or propylene carbonate for couplings or esterifications. Reaction rates may decrease; catalyst/base selection can compensate.

• Activation strategies

  • Minimize use of acid chlorides (SOCl2, oxalyl chloride) by employing catalytic DMAP with DIC/EDC in greener solvents, or use CDI-mediated couplings in EtOAc/2-MeTHF.
  • For C–C bond formation, consider decarboxylative photoredox couplings that avoid prefunctionalized aryl halides, reducing halogenated waste.

• Workup and purification

  • Use aqueous bicarbonate/acid toggling to partition product and reduce silica usage; consider crystallization of the free acid or its salts to avoid chromatography when possible.

Comparison (general)

• Conventional vs greener approach
  • Solvent: DMF/DCM vs 2-MeTHF/EtOAc/CPME.
  • Activation: SOCl2/oxalyl chloride vs CDI/EDC/DIC.
  • Cross-coupling: aryl halide route vs decarboxylative route from the acid.

Trade-offs

• Greener media can lower substrate solubility; seeding with a small amount of polar cosolvent (≤10% DMF) often restores kinetics.
• Some green solvents have higher boiling points; allow for longer evaporation or switch to antisolvent precipitation to isolate products.

Pharmaceutical Uses

• Item-specific (Product Data)

  • No pharmacopeial status or excipient role specified for this item; refer to CoA/Spec Sheet.

• Literature/general context (no therapeutic claims)

  • Role: synthetic intermediate for discovery-scale preparation of fluorinated aryl amides, esters, ureas, and carbamates used in SAR and lead-optimization campaigns.
  • Advantages of this scaffold: the 3,5-difluoro pattern modulates electronics and metabolic stability of derived chemotypes; the para-ethoxy group can serve as a masked phenol handle (after O-dealkylation in later steps, if desired) or as a lipophilicity tuner.
  • Formulation note: as a neat active excipient this compound is not typical; however, derived salts of benzoic acids can be used to improve solubility during intermediate handling in process development.

Any use is strictly for research and development in laboratory settings; not for human or veterinary use.

Physical Properties

• Item-specific (Product Data)

  • Appearance: Not specified for this item; refer to CoA/Spec Sheet.

• Computed/Literature (general reference; not item-specific specs)

  • Expected physical state: organic solid (typical for substituted benzoic acids).
  • Acid–base: weak aromatic carboxylic acid; electron-withdrawing F substituents typically lower pKa relative to benzoic acid (benzoic acid pKa ≈ 4.2; difluoro analogs often pKa ≈ 3.2–3.8, literature range for related structures).
  • Partitioning: cLogP expected moderate (approx. 2–3 for closely related ethoxy/difluoro benzoic acids; computational estimate ranges in literature).
  • Solubility (qualitative, literature/general):
    • Organic solvents: good solubility in polar aprotic solvents (DMF, DMSO, NMP); moderate in esters (EtOAc), ketones (MEK), chlorinated solvents (DCM, CHCl3); lower in nonpolar hydrocarbons (hexanes, heptane).
    • Aqueous: low at neutral pH; increased solubility at basic pH as the carboxylate salt; limited in acidic water.
  • Melting point, boiling point, density, refractive index, UV cutoff: Not specified for this item; refer to CoA/Spec Sheet.

Notes: All numeric values above are literature/computational expectations for analogous structures and provided only as guidance; consult experimental data and the item’s CoA for specifications.

Quality and Grades

• Item-specific (Product Data)

  • Grade/Purity: Not specified for this item; refer to CoA/Spec Sheet.

• Guidance for this compound class (literature/general)

  • Typical quality metrics for aryl carboxylic acids include assay (HPLC or qNMR), loss on drying, residual solvents, and identification by NMR/IR/HRMS. Where relevant, low levels of inorganic fluoride or hydrolytic impurities (e.g., phenols, esters) are monitored.
  • If offered as synthesis-grade: suitable for general organic synthesis, where trace UV absorbers or metals are not critical.
  • If offered as high-purity/analytical grade: tighter limits on non-volatile residue, UV background, and related substances facilitate use in analytical standards or SAR libraries.
  • Stabilizers: none are typically required for simple benzoic acids; absence/presence of stabilizers should be confirmed on the CoA if critical to your workflow.

• Recommendations

  • For coupling chemistry (amide/ester formation) or SNAr benchmarking, verify assay and water content on the CoA to set stoichiometry precisely.
  • For HTS libraries, request detailed impurity profiles (e.g., <0.5% related substances by HPLC) if structure-activity data will be correlated.

Note: In the absence of an item-specific grade on this page, please consult the CoA/Spec Sheet for the batch you receive.

Reaction and Applications

As a 3,5-difluoro, 4-ethoxy–substituted benzoic acid, this compound is an electron-deficient aryl building block suitable for multiple bond-forming strategies (literature/general guidance):

• Amide/ester formation
  • Carbodiimide (EDC/HOBt, DIC/DMAP) or uronium/aminium (HATU, TBTU) reagents provide rapid amidation/esterification under mild conditions. Acid chloride formation (SOCl2, oxalyl chloride) followed by coupling is also common.
• Decarboxylative cross-couplings
  • Under photoredox/Ni catalysis (e.g., Ir/Ni or organic photocatalysts), aryl carboxylates undergo C–C, C–N, or C–S bond formation via decarboxylative activation. This enables access to substituted fluoroarenes without pre-installed leaving groups.
• Nucleophilic aromatic substitution (SNAr)
  • The 3,5-difluoro motif on an electron-poor ring (deactivated by –CO2H) can undergo displacement of Ar–F with strong nucleophiles (amines, thiolates, alkoxides) in polar aprotic solvents at elevated temperature.
• Curtius/Schmidt rearrangements and acyl azide routes
  • Conversion to the acyl azide (DPPA) followed by Curtius rearrangement affords isocyanates en route to ureas/carbamates, introducing the 3,5-difluoro-4-ethoxy aryl fragment into N-containing scaffolds.
• Salt formation and prodrugs research
  • The acid can be converted to lithium/sodium/potassium salts for solubility modulation or to make reactive carboxylate nucleophiles for coupling.

Applications include preparation of fluorinated aryl amides/esters for materials, agrochemical, and medicinal chemistry SAR studies (research use only). Careful choice of conditions preserves the aryl fluoride pattern and the ethoxy substituent.

Reaction Conditions

General literature guidance for this scaffold (not item-specific specifications):

• Amide coupling (EDC/HOBt or HATU)

  • Solvent: DMF, NMP, or DCM with base (DIPEA, NMM).
  • Conditions: 0–25 °C, 1–16 h; typical isolated yields for unhindered amines 70–95%.
  • Tips: pre-activate the acid; use 1.1–1.5 equiv coupling reagent; add catalytic DMAP for sterically hindered alcohols.

• Acid chloride route

  • Reagent: SOCl2 (2–4 equiv) with catalytic DMF; solvent: toluene or neat.
  • Conditions: reflux 1–3 h; remove volatiles; couple with amine/alcohol in DCM or THF at 0–25 °C with base.

• SNAr on Ar–F (3,5-positions)

  • Nucleophiles: primary/secondary amines, thiolates, alkoxides.
  • Solvent: DMSO/DMF; Base: K2CO3–Cs2CO3 or NaH for alkoxides.
  • Temperature: 80–140 °C; times 4–24 h; mono- vs di-substitution controlled by stoichiometry/temperature.

• Decarboxylative couplings (C–C/C–N)

  • Convert acid to redox-active ester (e.g., NHPI ester with DIC/DMAP) or cesium carboxylate.
  • Catalysis: Ni(II)/photoredox (Ir(ppy)3 or organic photocatalysts) with blue LEDs in MeCN, DMSO, or mixed MeCN/H2O; base: Cs2CO3 or K2HPO4.
  • Conditions: rt–40 °C, 4–16 h; often 50–85% yields depending on partner.

• Fischer esterification

  • Solvent/alcohol: ROH (MeOH, EtOH); Catalyst: catalytic H2SO4 or p-TsOH; reflux 2–8 h; remove water to drive equilibrium.

Always confirm compatibility of the para-ethoxy ether under Lewis/Brønsted acidic conditions if harsh reagents are used (e.g., BBr3 will cleave ethers).

Safety and Handling

• Item-specific (Product Data)

  • GHS Classification, Signal Word, H-Statements, Pictograms: Not specified for this item; refer to SDS.
  • Storage Conditions: Room temperature (as provided).

• General safety guidance (literature/typical for aromatic carboxylic acids)

  • Likely hazards: may cause skin/eye irritation and respiratory tract irritation as dust. Handle as a combustible organic solid; fine powders can present dust hazards.
  • PPE: lab coat, safety glasses or chemical splash goggles, and appropriate chemically resistant gloves (e.g., nitrile). Use in a fume hood to avoid inhalation of dust or aerosols.
  • Incompatibilities: strong bases (forms salts; exotherm possible during neutralization), strong oxidizers, strong reducing agents, acylation reagents (if unintended reaction), and moisture when storing reactive derivatives (e.g., acid chlorides prepared in situ).
  • First aid (overview; defer to SDS):
    • Inhalation: move to fresh air; seek medical attention if symptoms persist.
    • Skin contact: wash with soap and water; remove contaminated clothing.
    • Eye contact: rinse cautiously with water for several minutes; remove contact lenses if present and easy; seek medical attention for irritation.
    • Ingestion: rinse mouth; do not induce vomiting; seek medical advice.
  • Spills: avoid dust generation; collect solids by gentle sweeping with minimal agitation; dispose per local regulations.
  • Fire-fighting: use CO2, dry chemical, or foam; combustion may produce CO/CO2 and hydrogen fluoride traces from aryl fluoride decomposition at high temperatures—wear SCBA.

Always consult the product’s SDS for authoritative and complete safety information.

Solvent Selection

This material is a moderately lipophilic aromatic acid; solvent choice depends on whether you use it as the free acid or as an activated intermediate.

• Polarity and miscibility (literature/general)

  • Polar aprotic solvents (DMF, DMSO, NMP, DMAc): high solubility; ideal for amide couplings and SNAr.
  • Chlorinated solvents (DCM, CHCl3): moderate solubility; useful for acid chloride formation and subsequent coupling with added bases.
  • Esters/ketones (EtOAc, MEK/acetone): moderate solubility; greener alternative media for esterifications and some couplings.
  • Alcohols (MeOH, EtOH, i-PrOH): suitable for Fischer esterification; solubility improves on heating or upon partial neutralization.
  • Aqueous media: low solubility at neutral pH; becomes soluble as the carboxylate at pH > 6–7.

• When to choose vs alternatives

  • Choose highly polar aprotics for rapid room-temperature carbodiimide or uronium/aminium couplings.
  • Select 2-MeTHF or EtOAc for greener processing if reaction kinetics remain acceptable.
  • For photoredox decarboxylative couplings, mixed aqueous-organic media (MeCN/H2O or DMSO/H2O) with base are commonly effective.

• Practical tips

  • Pre-dissolve the acid in minimal DMF or DMSO to “seed” solubility, then back-dilute with the reaction solvent.
  • If using bases (e.g., DIPEA), partial neutralization improves solubility but may alter selectivity; monitor pH/stoichiometry.
  • Avoid strong aqueous base during workup if you require the free acid; instead acidify carefully to re-precipitate.

Storage and Reconstitution

• Item-specific (Product Data)

  • Storage Conditions: Room temperature.
  • Shipped In: Normal.

• General guidance (literature/typical for aromatic carboxylic acids)

  • Store tightly capped, in a dry place, away from strong acids/bases and oxidizers. Use desiccant if ambient humidity is high to minimize clumping.
  • If long-term storage is planned, amber or opaque containers help protect against prolonged light exposure that can promote slow degradation of sensitive impurities.
  • Reconstitution/Stock solutions: prepare solutions in dry DMF, DMSO, MeCN, or EtOAc as needed. For HTS/parallel synthesis, 10–100 mM DMSO stocks are common; verify solubility before making concentrated stocks.
  • Freeze–thaw: solid form is robust; if storing solutions, aliquot to avoid repeated freeze–thaw cycles which can introduce moisture and degrade activated derivatives.
  • Disposal: follow institutional and local regulations for halogenated organic waste.

Note: For any batch-specific stability or impurity information, refer to the lot CoA/Spec Sheet and the product SDS.

Structure and Identity

Brief description: 4-Ethoxy-3,5-difluorobenzoic acid is a fluorinated, para-ethoxy–substituted benzoic acid useful as an electron-deficient aryl building block.

• Item-specific (Product Data)

  • SKU: E1320664
  • Product Name: 4-Ethoxy-3,5-difluorobenzoic acid
  • CAS: 1017779-19-9
  • InChIKey: 293420 (as provided)
  • Storage Conditions: Room temperature
  • Shipped In: Normal
  • Research Use: For research use only

• Computed/Literature (general reference; not item-specific specs)

  • Molecular formula (computed from structure/name): C9H8F2O3
  • Molecular weight (computed): ~202.16 g/mol
  • Core structural features: benzoic acid (–C(=O)OH) ring bearing two fluorine atoms at the 3- and 5-positions and an ethoxy substituent (–O–CH2CH3) at the 4-position (para to the carboxyl group).
  • Functional groups: aromatic carboxylic acid; aryl ether; two aryl fluorides.
  • 2D structural description in words: A benzene ring with a carboxylic acid at C1; fluorine atoms at C3 and C5; an ethoxy substituent at C4. The pattern is meta/meta difluoro flanking a para ethoxy relative to the acid.

• Not specified for this item; refer to CoA/Spec Sheet

  • SMILES
  • Standard InChI / InChIKey (beyond the catalog-provided identifier)

Synthetic Utility

Key reactivity elements (literature/general):

• Carboxylic acid handle

  • Amide/ester synthesis via carbodiimides (EDC, DIC), uronium/aminium reagents (HATU, TBTU), or CDI. Acid chloride route (SOCl2/oxalyl chloride) enables coupling to hindered nucleophiles.
  • Curtius rearrangement from acyl azide (DPPA) affords isocyanates for urea/carbamate synthesis, transferring the 3,5-difluoro-4-ethoxy aryl group.
  • Decarboxylative strategies: photoredox/Ni-mediated arylations, aminations, and thioetherifications from the carboxylate or redox-active esters (RAEs, e.g., NHPI esters).

• Aryl fluoride positions (3,5- F)

  • Enable SNAr with hard nucleophiles under forcing conditions (e.g., amines/thiolates in DMSO/DMF, elevated T), delivering 3- or 5-substituted analogs while retaining one F if mono-substitution is targeted.

• Para-ethoxy group

  • Stable ether under many conditions; can direct reactivity and modulate solubility. In certain workflows, O-dealkylation (e.g., BBr3, AlCl3/thiol) can unmask the phenol, providing late-stage diversification.

• Retrosynthetic value

  • Serves as a convergent coupling partner to introduce a difluorophenyl core bearing a para ether. Upstream access via ethylation of the corresponding phenol or via nucleophilic substitution on a 4-halo-3,5-difluorobenzoate is common.

Overall, the combination of an acid handle with two activating fluorines provides orthogonal routes to C–N, C–O, C–S, and C–C bond formation.

Target Specificity

Not applicable. This product is a small-molecule chemical reagent and does not have biological target specificity (no antigen/epitope, clone, or isotype). For experiments involving biological targets, use derivatives of this scaffold or separate bioactive compounds as appropriate.