3-Methyl-4-nitrobenzoic acid
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Product Description
3-Methyl-4-nitrobenzoic acid is a yellow crystalline solid whose ortho-nitro group dramatically boosts carboxylic acidity via classical “ortho-effect” electron withdrawal; chemoselective reduction of the nitro unit delivers the key 3-methyl-4-aminobenzoic acid intermediate used to assemble the blockbuster antihypertensive telmisartan, making the compound a high-volume, high-value fine-chemical workhorse.
Other Information
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Thermodynamics of Solution: The dissolution process of 3-methyl-4-nitrobenzoic acid in organic solvents is spontaneous and endothermic. Mixing properties (Gibbs energy, enthalpy, entropy) are important for process design.
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Purification Science: Phase equilibrium studies (binary and ternary solid-liquid systems) and thermodynamic models (e.g., NRTL, Wilson) are essential for optimizing its crystallization and separation from isomers and by-products on an industrial scale.
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Chemical Stability: Stable under normal conditions but should be kept away from strong oxidizing or reducing agents due to the reactive nitro and carboxylic acid functional groups.
Synthesis and Production
Primary Route: Selective oxidation of 2,4-dimethylnitrobenzene (2,4-DMNB).
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Oxidizing Agents: Potassium permanganate (KMnO₄), potassium dichromate (K₂Cr₂O₇), chromium trioxide (CrO₃), nitric acid (HNO₃), or molecular oxygen (O₂).
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Catalytic Air Oxidation: Employing a catalyst like cobalt acetate [Co(OAc)₂] with sodium bromide (NaBr) in a solvent such as acetic acid under oxygen pressure (~0.8 MPa, 130°C). Yield is approximately 51%.
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Electrochemical Method: Utilizes electrolytically regenerated CrO₃ as the oxidant with a stepwise temperature control (50°C → 70°C → 90°C). This method offers a higher yield (~75%) but involves complex handling of chromium waste.
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Industrial Challenge & Purification: The synthesis typically yields less than 60% of the desired product, with by-products like 4-nitroisophthalic acid and 5-methyl-2-nitrobenzoic acid. Due to the high boiling points of these compounds, solvent crystallization is the critical purification step. Ternary solid-liquid phase diagrams (e.g., for the system with 3-methyl-2-nitrobenzoic acid in methanol/acetone) and detailed solubility data are used to design and optimize industrial separation processes.
Uses and Applications
Primary Use: Pharmaceutical Intermediate.
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Key Intermediate for Telmisartan: Serves as the crucial starting material in the multi-step synthesis of the antihypertensive drug Telmisartan (an angiotensin II receptor blocker). The nitro group is reduced to an amino group for further transformations.
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Other Pharmaceutical Intermediates: Acts as a precursor for synthesizing anti-cancer substances and AIDS drugs.
Other Applications:
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Organic Synthesis Building Block: Used in the synthesis of complex aromatic compounds, heterocycles, metal coordination complexes, and as a model compound for studying aromatic substitution and acidity effects.
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Dye and Pigment Synthesis: Functions as a precursor in the synthesis of azo dyes and pigments, where the nitro group influences chromophore properties.
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Research and Laboratory Reagent: Employed in organic reaction mechanism studies, catalysis evaluation, and polymer precursor preparation.
Chemical and Physical Properties
1. Chemical Identity:
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IUPAC Name: 3-Methyl-4-nitrobenzoic acid
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Synonyms: 4-Nitro-m-toluic acid, m-Methyl-p-nitrobenzoic acid
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CAS Number: 3113-71-1
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Molecular Formula: C₈H₇NO₄
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Molecular Weight: 181.15 g/mol
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SMILES: Cc1cc(ccc1N+=O)C(=O)O
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Structure: A benzene ring substituted with a carboxylic acid (-COOH) at position 1, a methyl group (-CH₃) at position 3, and a nitro group (-NO₂) at position 4.
2. Physical Properties:
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Appearance: Pale yellow to off-white crystalline solid.
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Melting Point: 216-218 °C (literature range also reported as 182-185°C).
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Boiling Point: ~356.0 ± 30.0 °C (estimated).
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Density: ~1.4 g/cm³.
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Flash Point: ~161.2 °C.
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Acidity: pKa estimated ~3.4-4.0. The nitro group ortho to the carboxylic acid enhances acidity via electron-withdrawal (ortho effect).
3. Solubility:
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In Water: Slightly soluble (<0.1 g/100 mL at 22°C).
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In Organic Solvents: Solubility increases with temperature. General order of solubility (high to low): N,N-Dimethylformamide (DMF), N-Methyl-2-pyrrolidone (NMP) > 1,4-Dioxane > Acetone > Toluene > Ethyl Acetate > Isopropanol > Methanol, Ethanol, n-Propanol, n-Butanol > Acetonitrile.
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Purification Solvent: Methanol is commonly used for recrystallization.
4. Computed/Structural Properties:
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LogP (Partition Coefficient): 1.60
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Topological Polar Surface Area (TPSA): 80.44 Ų
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Hydrogen Bond Donors: 1 (COOH)
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Hydrogen Bond Acceptors: 4 (2 from NO₂, 2 from COOH)
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Rotatable Bonds: 2
Safety and Handling
Toxicological Profile:
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Hazard Classification: Combustible solid. May cause skin, eye, and respiratory irritation (Xi, R36/37/38).
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Environmental Hazard: WGK 3 (Germany) – Highly hazardous to water. Nitro-aromatic compounds can be harmful to aquatic life.
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Personal Protective Equipment (PPE): Wear dust mask (N95), chemical safety goggles, gloves, and a lab coat.
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Handling: Avoid dust formation and inhalation. Use in a well-ventilated area or fume hood. Avoid contact with strong oxidizers and bases.
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Storage: Store in a cool, dry, well-ventilated place in a tightly sealed container.
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Emergency Measures:
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Skin Contact: Wash thoroughly with soap and water.
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Eye Contact: Rinse cautiously with water for several minutes. Seek medical attention.
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Fire: Use water spray, foam, dry powder, or CO₂ to extinguish.
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