o-Anisidine (2-Methoxyaniline): Chemical Properties, Synthesis, Applications, and Safety Considerations

o-Anisidine CAS 90-04-0

o-Anisidine, also known as 2-methoxyaniline, is an aromatic amine with the chemical formula C7H9NO. It is a colorless to yellowish liquid with a characteristic odor, used primarily as an intermediate in the synthesis of various dyes, pigments, and pharmaceuticals.

1. Chemical Properties

IUPAC Name: 2-Methoxyaniline

CAS Number: 90-04-0

Molecular Formula: C7H9NO

Molecular Weight: 123.15 g/mol

Structure: The chemical structure consists of a benzene ring substituted with a methoxy group (-OCH3) at the ortho position and an amino group (-NH2) at the para position.

Appearance: Colorless to yellowish liquid

Boiling Point: 218-219°C

Melting Point: -2°C

Density: 1.088 g/cm³ at 20°C

Solubility: Soluble in organic solvents like ethanol, ether, and chloroform; slightly soluble in water.

2. Synthesis

1) Reduction of o-Nitroanisole

One of the primary methods for synthesizing o-anisidine is the reduction of o-nitroanisole (2-nitroanisole). This process can be carried out using various reducing agents, each offering distinct advantages depending on the scale and specific requirements of the synthesis.

Catalytic Hydrogenation: This method involves the reduction of o-nitroanisole using hydrogen gas in the presence of a suitable catalyst. Common catalysts include palladium on carbon (Pd/C), platinum (Pt), or Raney nickel.

Reaction Conditions: The reaction is typically performed in an appropriate solvent such as ethanol, methanol, or acetic acid. The mixture is subjected to hydrogen gas under controlled pressure and temperature.

Advantages: Catalytic hydrogenation provides a high yield of o-anisidine with minimal by-products. The process is efficient and can be scaled up for industrial production.

Mechanism: The nitro group (-NO2) in o-nitroanisole is reduced to an amino group (-NH2) through successive stages involving the formation of intermediate nitroso and hydroxylamine species.

Chemical Reduction: Alternatively, o-nitroanisole can be reduced using chemical reducing agents such as iron filings in the presence of hydrochloric acid (Bechamp reduction), zinc dust, or sodium sulfide.

Bechamp Reduction: Iron filings and hydrochloric acid reduce o-nitroanisole to o-anisidine. This method is historically significant and is still used in certain applications.

Advantages: Chemical reduction methods are cost-effective and suitable for large-scale synthesis, especially in environments where catalytic hydrogenation infrastructure is not available.

2) Methylation of Aniline

Another approach to synthesizing o-anisidine involves the methylation of aniline (phenylamine) followed by selective demethylation.

Methylation with Dimethyl Sulfate: Aniline can be methylated using dimethyl sulfate to form N-methylaniline and subsequently N,N-dimethylaniline.

Reaction Conditions: Aniline is reacted with dimethyl sulfate in the presence of a base such as sodium hydroxide or potassium carbonate. The reaction is typically conducted in an organic solvent like acetone or dimethylformamide (DMF).

Demethylation: The resulting N,N-dimethylaniline is subjected to selective demethylation to yield o-anisidine. This step can be achieved using reagents like hydrobromic acid (HBr) or boron tribromide (BBr3).

3) Direct Etherification

A less common but viable method for synthesizing o-anisidine involves the direct etherification of aniline with methanol or dimethyl ether under acidic conditions.

Etherification Process: Aniline is reacted with methanol in the presence of an acid catalyst such as sulfuric acid or hydrochloric acid.

Reaction Conditions: The mixture is heated under reflux to promote the formation of the methoxy group (-OCH3) at the ortho position relative to the amino group (-NH2).

Advantages: This method provides a straightforward route to o-anisidine, though it may require stringent control of reaction conditions to minimize side reactions and achieve high selectivity.

4) Nitration and Reduction Sequence

A more elaborate synthetic route involves the nitration of anisole followed by selective reduction.

Nitration of Anisole: Anisole (methoxybenzene) is nitrated using a mixture of concentrated nitric acid and sulfuric acid to yield a mixture of nitroanisole isomers.

Reaction Conditions: The nitration is conducted at controlled temperatures to favor the formation of the ortho-nitroanisole isomer.

Separation: The isomers are separated using techniques such as fractional distillation or chromatography.

Reduction to o-Anisidine: The ortho-nitroanisole is then selectively reduced to o-anisidine using catalytic hydrogenation or chemical reduction methods, as described earlier.

3. Applications

Dye and Pigment Industry:

o-Anisidine is a crucial intermediate in the synthesis of various dyes and pigments, particularly:

a) Azo dyes: Used extensively in textile, leather, and paper industries

b) Triphenylmethane dyes: Employed in inks, paints, and biological stains

c) Indigo dyes: Used in denim and other textile applications

d) Quinoline dyes: Applied in various industrial and consumer products

Pharmaceutical Industry:

o-Anisidine serves as a starting material or intermediate in the synthesis of:

a) Analgesics and anti-inflammatory drugs

b) Antihypertensive agents

c) Antihistamines

d) Local anesthetics

e) Antimicrobial compounds

Agrochemical Sector:

The compound is utilized in the production of:

a) Herbicides: As a precursor in triazine-based herbicides

b) Insecticides: Particularly in the synthesis of some organophosphate compounds

c) Fungicides: As an intermediate in certain azole-based fungicides

Flavor and Fragrance Industry:

o-Anisidine is a key precursor in the synthesis of:

a) Vanillin: The primary component of vanilla flavor

b) Ethylvanillin: A more potent synthetic vanilla flavoring

c) Guaiacol: Used in the production of various flavors and fragrances

Polymer and Rubber Industry:

The compound finds applications in:

a) Antioxidants for rubber and plastics

b) Curing agents for epoxy resins

c) Stabilizers in polymer production

Corrosion Inhibitors:

o-Anisidine derivatives are used as corrosion inhibitors in:

a) Industrial cooling systems

b) Oil and gas pipelines

c) Metal processing industries

Research and Analytical Chemistry:

o-Anisidine serves as:

a) A reagent in various organic syntheses

b) A standard in analytical chemistry for method development and validation

Specialty Chemicals:

The compound is utilized in the production of:

a) Optical brighteners for textiles and paper

b) UV absorbers for plastics and cosmetics

c) Antioxidants for fuels and lubricants

4. Safety

o-Anisidine is classified as a hazardous substance due to its toxicological properties. It can be absorbed through the skin, inhalation, or ingestion, causing various health effects.

Health Hazards: Exposure to o-anisidine can cause irritation to the skin, eyes, and respiratory tract. Prolonged exposure may lead to methemoglobinemia, a condition where hemoglobin is unable to effectively release oxygen to body tissues. It is also considered a potential carcinogen.

5. Handling and Storage

Personal Protective Equipment (PPE): When handling o-anisidine, appropriate PPE such as gloves, goggles, and lab coats should be worn to minimize exposure.

Storage: It should be stored in a cool, well-ventilated area away from sources of ignition. Containers should be tightly sealed to prevent leakage and contamination.