2-Fluoro-3-nitrobenzoic acid
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Product Description
2-Fluoro-3-nitrobenzoic acid is an exceptionally versatile building block for installing fluorinated, nitro-aromatic or benzoic-acid motifs into more complex targets. Prepared on scale by low-temperature nitration of 2-fluorobenzoic acid, it is soluble in hot water and common polar organic solvents and is traded commercially as a high-purity intermediate. Its reactivity profile is exploited across three main sectors: in medicinal chemistry it is a key precursor to kinase inhibitors and other fluorinated targeted therapeutics; in crop science it is converted into specialty benzoic-acid herbicides and insecticides; and in materials research it serves as a fluorinated monomer or linker for liquid-crystalline and high-performance polymeric systems.
Synthesis and Production
Main Synthesis Routes:
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Chromic Acid Oxidation (Industrial Scale)
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Starting Material: 2-Fluoro-3-nitrotoluene
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Conditions: Acetic acid solvent, concentrated H₂SO₄, dropwise addition of CrO₃ in water at 95 °C, maintained for 3 hours.
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Yield: 62–65%.
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Salicylic Acid Multi-Step Derivatization
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Salicylic acid → Esterification → Nitration → Chlorination → Chloro-fluoro exchange → Hydrolysis.
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Suitable for large-scale production; lower cost and easier separation of intermediates.
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Nitration Method
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Nitration of 2-fluorobenzoic acid using mixed acid (HNO₃/H₂SO₄).
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Temperature control (0–10 °C) required to avoid over-nitration.
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Production Notes: An industrially relevant fluorinated aromatic acid used as a fine chemical intermediate in both laboratory and industrial settings.
Uses and Applications
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Pharmaceutical Intermediate
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Key building block for fluorinated targeted drugs (e.g., kinase inhibitors such as Dabrafenib).
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Starting material for quinolone and benzimidazole antibacterial/antiviral agents.
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Used in constructing fluorinated bioactive molecules.
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Agrochemical Intermediate
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Synthesis of fluorinated benzoic acid-based herbicides, fungicides, and insecticides.
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Can be reduced and rearranged to prepare fluorinated aniline pesticides.
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Materials and Dyes
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Precursor for fluorinated liquid crystal monomers and polymer materials.
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Used in fluorescent dye synthesis (nitro group reducible to amino for coupling).
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Research Building Block
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Aromatic module for Suzuki, Buchwald, nucleophilic substitution, and other coupling reactions.
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Valuable for structure–activity relationship (SAR) optimization.
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Chemical and Physical Properties
| Property | Description |
|---|---|
| Molecular Formula | C₇H₄FNO₄ |
| Molecular Weight | 185.11 g/mol |
| CAS No. | 317-46-4 (also listed: 4715-07-3, 401-96-7) |
| Appearance | Pale yellow to off-white crystalline powder |
| Melting Point | ~138–160 °C (literature varies, commonly 145–160 °C) |
| Boiling Point | ~347.6 °C (predicted) |
| Solubility | Slightly soluble in water; soluble in ethanol, methanol, ethyl acetate, DMF, DMSO |
| Acidity (pKa) | ~2.32–4.2 (stronger acid due to electron-withdrawing fluoro and nitro groups) |
| LogP | 1.3–1.43 (moderate lipophilicity) |
| Hydrogen Bond Donor/Acceptor | 1 / 5 |
| Polar Surface Area | ~83.1 Ų |
| Chemical Stability | Slowly decarboxylates if heated above 180 °C; avoid prolonged melting. |
Key Chemical Features:
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Ortho-fluoro and meta-nitro groups are strong electron-withdrawing substituents, enhancing electrophilicity.
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Nitro group can be reduced to an amine (e.g., using SnCl₂/HCl or Pd/C-H₂).
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Fluorine atom can undergo nucleophilic substitution under forcing conditions (e.g., with NaOH or amines).
Safety and Handling
GHS Hazard Classification:
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Pictogram: ⚠️ (Irritant)
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Signal Word: Warning
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Hazard Statements:
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H315: Causes skin irritation
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H319: Causes serious eye irritation
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H335: May cause respiratory irritation
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Precautionary Measures:
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Use personal protective equipment: gloves, safety goggles, dust mask.
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Handle in a well-ventilated area to avoid dust inhalation.
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Avoid contact with strong oxidizers, reducing agents, and bases.
Storage:
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Store in a tightly sealed container in a cool, dry place (recommended 2–8 °C).
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Keep away from heat, sparks, and light.
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Store separately from metal powders and incompatible materials.
Environmental & Toxicity:
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Toxic to aquatic life.
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Prevent release into the environment.