4-Ethynyl-3-fluorobenzoic acid - ≥95% , CAS No.1862427-77-7

CAS: 1862427-77-7 Cat. No.: E964793 Formula: C₉H₅FO₂ Molecular Weight: 164.130 EC Number: 888-521-7

GRADE & PURITY ≥95%

Storage

Room temperature

Specifications

Specifications & Purity

≥95%

Storage

Room temperature

Purity

≥95%

Names and Identifiers

Canonical Smiles

C#CC1=C(C=C(C=C1)C(=O)O)F

IUPAC Name

4-ethynyl-3-fluorobenzoic acid

InChIKey

JAUFNXVOUWCYNW-UHFFFAOYSA-N

INCHI

1S/C9H5FO2/c1-2-6-3-4-7(9(11)12)5-8(6)10/h1,3-5H,(H,11,12)

Molecular Weight

164.130

Chemical and Physical Properties

• Molecular Weight: 164.130 g/mol
• XLogP3: 1.800
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 3
• Rotatable Bond Count: 2
• Exact Mass: 164.027 Da
• Monoisotopic Mass: 164.027 Da
• Topological Polar Surface Area: 37.300 Ų
• Heavy Atom Count: 12
• Formal Charge: 0
• Complexity: 228.000
• 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 antibody/assay kit applications are defined for this small molecule.

• Practical usage examples (general, not item-specific):
  • Preparing a 100 mM DMSO stock: Accurately weigh the solid, dissolve in dry DMSO to volume, and store small aliquots at −20°C; equilibrate to RT before opening to minimize moisture ingress.
  • Aqueous handling: Convert to the sodium salt in situ by adding equimolar NaHCO3 to an aqueous suspension; extract unreacted acid into EtOAc if needed.
  • CuAAC demo: Dissolve alkyne and azide (1:1) in t-BuOH/H2O (1:1), add CuSO4 (5 mol%) and sodium ascorbate (10 mol%), stir at RT until completion (TLC/LCMS), then chelate copper (EDTA) and extract/purify.

For detailed, application-specific procedures, consult peer-reviewed literature and adapt to your substrates and scale.

Biological Roles

This product is a synthetic aromatic building block and is not known as a natural metabolite or cofactor.

• Item-specific (Product Data): Research Use Only — not for diagnostic, therapeutic, or in vivo use.

• Literature/general context (not item-specific):

  • Aryl-alkynes and benzoic acid derivatives appear in probe design and bioconjugation due to the terminal alkyne enabling CuAAC “click” attachment of azide-bearing biomolecules, polymers, or surfaces.
  • The fluorine atom can modulate electronic properties in medicinal chemistry scaffolds (e.g., tuning lipophilicity and metabolic stability), but this compound itself is a tool/intermediate rather than a bioactive agent per se.
  • Carboxylates at physiological pH are largely deprotonated; if this compound is introduced into aqueous biological systems, it would exist mainly as the benzoate anion (assuming typical benzoic acid pKa ~4), affecting membrane permeability.

No specific endogenous biological roles or pathways are associated with 4-ethynyl-3-fluorobenzoic acid. Any biological studies should treat it as a synthetic intermediate used to construct or attach functional motifs.

Buffer Applications

This compound is not a dedicated buffering agent and is not typically used to prepare laboratory buffers.

• General note (literature): Benzoic acids have pKa values around 4, so they could, in principle, contribute to buffering capacity near pH ~3–5 when paired with their conjugate base. However, specialized buffers (acetate, citrate, MES) are preferred for reproducibility and biocompatibility.

• Practical guidance: If an aqueous stock is needed for screening, dissolve by basification (e.g., with Na2CO3/NaOH) to form the benzoate salt, or prepare DMSO stocks for subsequent dilution. For true buffer preparation, use established buffering agents instead.

Green Alternatives

While the molecule itself is a specialized building block, greener choices relate to how you use and transform it (literature-based process intensification guidance).

• Greener solvent choices for common transformations:

  | Use case | Conventional | Greener alternative(s) | Notes | |---|---|---|---| | Amide coupling | DMF, DCM | EtOAc, 2-MeTHF, CPME | 2-MeTHF/CPME reduce toxicity; ensure solubility. | | CuAAC | DMSO/t-BuOH | Water/t-BuOH (1:1), PEG-400 | Aqueous/PEG media often work with sodium ascorbate to generate Cu(I). | | Esterification | DCM | EtOAc, Me-THF | Maintain catalytic DMAP; azeotropic water removal as needed. | | Sonogashira | DMF/amine | 2-MeTHF or toluene/i-Pr2NH | Choose less hazardous amines (DIPEA) and lower Pd loadings. |

• Reagent selection:

  • Prefer OxymaPure over HOBt (safety), T3P (in EtOAc) over DCC to minimize urea waste.
  • Use aqueous CuSO4/ascorbate for CuAAC and immobilized copper scavengers to reduce Cu waste.

• Energy and workup:

  • Employ room-temperature couplings where possible; use flow or microwave for intensified but shorter processes.
  • Replace brine-heavy washes with minimal aqueous workups and direct crystallizations.

• Waste minimization:

  • Protect the carboxyl only when necessary; avoid protection–deprotection cycles.
  • Choose catalytic over stoichiometric routes (e.g., catalytic esterifications with isopropenyl acetate as water scavenger).

Trade-offs: Some greener solvents have different polarity/boiling points that can impact rates and selectivity; reoptimize base/catalyst loadings accordingly.

Pharmaceutical Uses

No pharmacopeial/excipient role is specified for this item; it is provided for research and synthetic use only.

• General formulation context (literature; not item-specific):

  • Aryl carboxylic acids often serve as intermediates in medicinal chemistry campaigns. The terminal alkyne allows rapid triazole formation (CuAAC) to generate libraries for SAR.
  • The carboxylic acid can be converted to amides/esters to tune physicochemical properties of candidate molecules during lead optimization.

• Compliance note: There is no claim of GMP status or pharmacopoeial compliance for this product. For any application related to clinical development or manufacture, procure GMP-grade material and follow appropriate regulatory guidelines.

Physical Properties

• Item-specific (Product Data):

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

• Literature/general (for the described structure; not item-specific):

  • Physical state: typically a crystalline solid for related aryl-ethynyl benzoic acids (literature observation)
  • Acid dissociation (pKa): benzoic acids ~4.0–4.5; meta-fluoro substitution generally lowers pKa modestly (often ~3.8–4.2) due to –I effect; terminal alkyne is weakly acidic (pKa ~25) and not ionized under aqueous conditions (literature trends)
  • Solubility profile:
    • Low solubility in neutral water; soluble in basic aqueous media as the carboxylate (literature behavior of benzoic acids)
    • Good solubility in polar aprotic solvents (DMSO, DMF, NMP) and in alcohols upon warming; moderate solubility in acetone/EtOAc; limited in nonpolar hydrocarbons (literature)
  • LogP/logD: benzoic acid derivatives with single F and an ethynyl typically show moderate lipophilicity (literature expectation, logP often ~1–2 for analogous structures)
  • UV: aromatic acids typically show π→π* absorption near 230–270 nm with extended tailing due to conjugation with the alkyne (literature)

• Not provided here: boiling point, melting point, density, refractive index, water content, residual metals, UV cutoff. Not specified for this item; refer to CoA/Spec Sheet.

Quality & Grades

• Item-specific (Product Data):

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

• Interpretation and guidance (general; not item-specific):

  • Research-use reagent: Suitable for synthetic chemistry, assay development, and materials research. Not for human or veterinary use.
  • If offered in “>98%” or similar assay on CoA: This typically reflects HPLC/GC purity on area% basis. For rigorous medicinal chemistry, consider confirming water content (KF), residual solvents, and identity (1H NMR, 13C NMR, HRMS) on receipt.
  • Stabilizers: None are typically required for benzoic acids and terminal aryl-alkynes; absence/presence of stabilizers will be declared on the CoA if used.
  • UV/LC suitability: If an HPLC grade is indicated on the Spec Sheet, it implies low UV-absorbing impurities and suitability for analytical detection at common aromatic wavelengths (254–280 nm).
  • Trace inorganic/organics: For metal-catalyzed couplings downstream (e.g., CuAAC), low metal background can matter. If specifications for residual metals or halides are important, request the CoA lot data or an expanded specification.

• Practical note: For structure–activity studies or conjugation workflows, consider lot-to-lot verification by NMR to ensure the terminal alkyne remains intact (terminal proton at ~3.0–3.2 ppm in DMSO-d6 for aryl–C≡CH, literature) and that no oligomerization/byproducts are present.

Reaction & Applications

The 4-ethynyl-3-fluorobenzoic acid scaffold combines three orthogonal handles: a carboxylic acid, a terminal alkyne, and an aryl–F. This enables diverse downstream transformations in materials and medicinal chemistry (literature/general guidance).

• Carboxylic acid manifold:

  • Amide formation with amines via HATU, EDCI/HOBt (or OxymaPure), T3P; mild bases (DIPEA, NMM). Enables linker installation, polymer conjugation, or PROTAC-like motif assembly.
  • Esterification (Fischer or Steglich, DCC/DMAP) to generate esters as protecting groups or for pro-moiety studies.
  • Activation to acid chloride (SOCl2, oxalyl chloride) for acylations; handle terminal alkyne carefully to avoid side reactions.

• Terminal alkyne manifold:

  • Cu-catalyzed azide–alkyne cycloaddition (CuAAC) to 1,4-disubstituted triazoles for tagging and conjugation.
  • Sonogashira coupling with aryl/vinyl halides to form internal aryl–alkynes; use Pd(0)/CuI and amine bases (Et3N, i-Pr2NH). Protect acid as ester or run under buffered conditions.
  • Glaser–Hay oxidative homocoupling to symmetric diynes (Cu(I), TMEDA, O2).
  • Hydrofunctionalizations (hydrosilylation, hydroboration/protodeboration) under metal catalysis for diversification.

• Aryl–F manifold:

  • SNAr with strong nucleophiles (e.g., alkoxides, amines) under forcing conditions due to meta-F deactivation being modest; alternative: metal-catalyzed C–F activation (specialized).

• Applications:

  • Building block for fluorescent linkers (triazoles), crosslinked materials, surface grafting via alkyne–azide chemistry, and SAR libraries via rapid amide diversification.

• Practical tips:

  • If performing Pd/Cu catalysis, consider transiently protecting the acid (methyl/tert-butyl esters) to improve solubility and suppress acid–base side reactions.
  • Scrupulously exclude thiols/strong chelators during CuAAC to maintain Cu(I) activity.

Reaction Conditions

General literature conditions for common transformations of this scaffold (guidance; adjust to your system and consult primary references):

• Amide coupling (acid → amide):

  • HATU (1.1 eq), amine (1.2 eq), DIPEA (2–3 eq) in DMF or MeCN, 0–25°C, 1–4 h. Workup by dilution and aqueous wash. Alternatively, EDCI (1.2 eq) + OxymaPure (1.2 eq) + NMM (3 eq) in DMF or EtOAc.

• Esterification (Steglich):

  • DCC (1.2 eq), ROH (2–4 eq), DMAP (0.1 eq) in DCM or EtOAc, 0°C to RT, 2–16 h; filter DCU. Greener option: T3P (50% in EtOAc), catalytic DMAP in EtOAc.

• CuAAC (terminal alkyne → triazole):

  • CuSO4·5H2O (5–10 mol%), sodium ascorbate (10–20 mol%) in t-BuOH/H2O (1:1) or DMSO/H2O at RT to 50°C, 1–6 h. Use ligand (TBTA, THPTA) to accelerate and suppress side reactions when bioconjugating.

• Sonogashira (to internal alkyne):

  • Aryl/vinyl halide (1.0 eq), this alkyne (1.2 eq), Pd(PPh3)2Cl2 (2–3 mol%), CuI (5–10 mol%), Et3N or i-Pr2NH as base, in DMF, MeCN, or 2-MeTHF, 25–80°C, 2–12 h. Consider protecting –CO2H as ester if basic precipitation occurs.

• Glaser–Hay coupling (diyne formation):

  • CuI (5–10 mol%), TMEDA (1.0 eq), O2/air, in DCM/MeOH or THF, RT, 2–8 h; monitor to avoid overoxidation.

• SNAr on aryl–F (challenging at meta):

  • Strong nucleophiles (e.g., alkoxides, amines) in DMSO/DMF at elevated temperatures (100–160°C); yields are substrate-dependent and may be low without additional activating groups.

These conditions are indicative ranges from literature for similar substrates; optimization is advised for your specific coupling partners.

Safety & Handling

• Item-specific (Product Data):

  • GHS classification / Signal word / H-statements / Pictograms: Not specified for this item; refer to SDS.
  • Storage conditions: Room temperature.

• General safety guidance (literature/good laboratory practice; not item-specific):

  • Likely hazards: Aromatic carboxylic acids are typically irritants to skin/eyes; dust may irritate respiratory tract. Terminal alkynes can form metal acetylides under strong basic/metalating conditions (handle accordingly). No peroxide-formation risk expected.
  • PPE: Use lab coat, safety glasses, and suitable chemical-resistant gloves (e.g., nitrile). Handle powders in a fume hood to minimize dust inhalation.
  • Incompatibilities: Avoid strong bases unless deprotonation to the carboxylate or acetylide is intended; avoid strong oxidizers; keep away from reactive acid chlorides/anhydrides unless performing derivatization.
  • First aid (overview; defer to SDS):
    • Inhalation: Move to fresh air; seek medical advice if symptoms persist.
    • Skin/eye contact: Rinse with water for at least 15 minutes; remove contaminated clothing; obtain medical attention for persistent irritation.
    • Ingestion: Rinse mouth; do not induce vomiting; seek medical attention.
  • Fire: Combustible organic solid; use CO2, dry chemical, or foam. Combustion may produce CO/CO2 and HF traces from fluorinated aromatics—firefighters wear SCBA.
  • Spill: Avoid dust, collect with inert absorbent, place in suitable waste container. Prevent entry into waterways.

Always consult the product-specific SDS for authoritative hazard classifications and response measures.

Solvent Selection

This compound is an aromatic carboxylic acid with a terminal alkyne. Solvent choice depends strongly on whether you need it protonated (acid form) or deprotonated (carboxylate) and whether the alkyne will be engaged in metal-mediated reactions.

• Polarity/miscibility (literature/general):

  • Water: Low solubility when protonated; becomes soluble upon basification (carbonate, bicarbonate, or NaOH) as the carboxylate.
  • Polar aprotic: DMSO, DMF, NMP solubilize well at room temperature and are preferred for coupling or click setups.
  • Moderately polar organics: EtOAc, acetone, MeCN provide moderate solubility; heating/sonication may help.
  • Alcohols: MeOH/EtOH solubilize on warming; may participate in esterification under acidic conditions.
  • Nonpolar: Hexanes/toluene show limited solubility at RT; toluene/xylene may be used at reflux for coupling reactions.

• When to choose what:

  • Amidation/esterification: Use DMF, DCM, or MeCN depending on coupling system; for carbodiimide couplings, DMF or DCM are common.
  • CuAAC (“click”): DMSO, DMF, t-BuOH/H2O, or MeOH/H2O mixtures; maintain some water if azide is inorganic/ionic.
  • SNAr on the aryl-F (if attempted): Polar aprotic (DMSO, DMF) with strong bases/nucleophiles.
  • Glaser–Hay/oxidative couplings: O2 or air in DCM/MeOH/THF with Cu catalysts; avoid excessive protic solvents if acetylide formation is desired.

• Practical tips:

  • Pre-neutralize with base (e.g., DIPEA, NaHCO3) to improve solubility and reactivity in amide couplings.
  • For moisture/oxygen-sensitive metal-catalyzed steps, degas solvents and use anhydrous grades.

Storage & Reconstitution

• Item-specific (Product Data):

  • Storage conditions: Room temperature.

• General guidance (literature/best practice; not item-specific):

  • Store in a tightly closed container, in a dry place, protected from prolonged light. A desiccator or dry cabinet is recommended to limit moisture uptake and potential acid-catalyzed side reactions.
  • For long-term storage, keep original packaging sealed; if frequent access is expected, split into working aliquots to reduce ambient exposure.
  • Reconstitution/stock solutions:
    • Organic stocks: Prepare in anhydrous DMSO, DMF, MeCN, or EtOAc depending on use. Typical concentrations: 10–200 mM. Filter (0.2 µm PTFE) if needed.
    • Aqueous stocks: Dissolve by basification (e.g., NaOH/NaHCO3) to form the benzoate salt; adjust pH cautiously to avoid CO2 absorption shifts.
  • Solution storage: For DMSO/DMF stocks, store aliquots at −20°C to −30°C, protected from moisture. Avoid repeated freeze–thaw; use single-use aliquots when possible.

• Shipping: Not specified for this item; refer to CoA/Spec Sheet. In general, shipping at ambient temperature is acceptable for stable aromatic carboxylic acids.

Always follow your institution’s chemical storage guidelines and consult the product SDS for any additional precautions.

Structure & Identity

Brief overview: 4-Ethynyl-3-fluorobenzoic acid is an aromatic carboxylic acid bearing a terminal alkyne para to the acid and a fluorine meta to the acid, providing orthogonal handles for coupling and conjugation.

• Item-specific (Product Data):

  • SKU: E964793
  • Product name: 4-Ethynyl-3-fluorobenzoic acid
  • CAS: 1862427-77-7
  • InChIKey: 155447 (as provided)
  • Storage conditions: Room temperature
  • Research use: For research use only

• Literature/computed (general identity; not item-specific):

  • Expected molecular formula for 4-ethynyl-3-fluorobenzoic acid: approximately C9H5FO2 (literature inference from structure)
  • Approximate molecular weight: ~164.1 g/mol (literature calculation from inferred formula)
  • SMILES (representative): OC(=O)c1cccc(F)c1C#CH (literature/derived)
  • Structural features:
    • Aromatic ring with a carboxylic acid (–CO2H) at C1 (benzoic acid core)
    • Fluorine substituent at C3 (meta to –CO2H)
    • Terminal ethynyl (–C≡CH) at C4 (para to –CO2H)
    • No stereocenters; planar aromatic core; linear terminal alkyne
  • 2D description in words: A benzoic acid ring substituted by F at the meta position and a linear –C≡CH at the para position relative to the acid; the acid carbonyls are conjugated with the ring, and the alkyne extends linearly from the ring.

• Not specified for this item; refer to CoA/Spec Sheet if an authoritative empirical formula/SMILES/InChIKey different from the above literature representation is required.

Synthetic Utility

From a retrosynthetic and forward-synthesis perspective (literature/general), 4-ethynyl-3-fluorobenzoic acid provides multiple, chemoselectively addressable handles:

• Orthogonal handles and typical disconnections:

  • –CO2H: Convert to acid chloride or activated ester for rapid amide/ester formation; can be masked as tert-butyl/methyl ester, then deprotected after alkyne chemistry.
  • –C≡CH: Engage in CuAAC with azides; extend to internal alkynes via Sonogashira with aryl/vinyl halides; perform Glaser dimerization to symmetrical diynes.
  • –F (meta): Potential for SNAr with strong nucleophiles; serves as an electronic modulator for downstream reactivity.

• Build/cascade strategies:

  • Sequence A (protect–functionalize–deprotect): Esterify the acid (t-Bu), perform Pd/Cu couplings on the alkyne, then deprotect with TFA.
  • Sequence B (click-first): CuAAC with azide-tag, followed by amidation to attach solubilizing amines.
  • Sequence C (amide-first): Form amide under mild coupling, then perform Glaser/Sonogashira to extend conjugation for materials applications.

• Materials and surface chemistry:

  • The terminal alkyne enables grafting onto azide-functionalized polymers/surfaces. The acid or amide can anchor to metal oxides or be converted to catechol/chelator motifs for stronger adhesion.

• Selectivity tips:

  • Maintain terminal alkyne integrity by avoiding strong bases/metallation unless acetylide formation is intended.
  • If acid chloride is formed, run reactions in dry solvents and quench carefully to prevent alkyne side reactions.

Target Specificity

Not applicable. This product is a small-molecule building block, not a biologic or affinity reagent.

• No antigen/epitope, clone, isotype, or species reactivity data are relevant.
• For target engagement studies, derivatize this scaffold (e.g., via amide or CuAAC) to install recognition elements, then assess specificity with appropriate biochemical assays.