Methyl cyclohexanecarboxylate

Introduction

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Methyl cyclohexanecarboxylate (CAS 4630-82-4), also known as methyl cyclohexanoate or cyclohexanecarboxylic acid methyl ester, is a carboxylic acid ester with the molecular formula C₈H₁₄O₂ and a molar mass of 142.20 g/mol. It appears as a clear, pale yellow liquid with a characteristic pleasant, ester-like odor, a boiling point of approximately 183–188°C, a flash point of around 60–67°C, and a density of about 1.00 g/cm³. Slightly soluble in water but miscible with most organic solvents, it is commonly synthesized via acid-catalyzed esterification of cyclohexanecarboxylic acid with methanol. Primarily used as a versatile organic synthetic intermediate, it serves in the preparation of pharmaceuticals, fragrances, flavors, and other fine chemicals through transformations such as hydrolysis, reduction, or Grignard reactions. It also finds application as a solvent for resins and polymers. While not classified as highly hazardous under GHS, it is combustible and requires proper handling, storage away from ignition sources, and use of personal protective equipment. It is distinct from structurally related compounds such as 2-oxocyclohexanecarboxylic acid methyl ester (CAS 41302-34-5) or substituted derivatives.

Uses of Methyl cyclohexanecarboxylate:

Methyl cyclohexanecarboxylate has a pleasant, fruity, berry-like odor and finds application primarily in the flavor and fragrance industries, as well as in chemical synthesis and research. Below is a summary of its key uses:

1. Flavor and Fragrance Agent

• Odor and Taste Profile: Exhibits a sweet, fruity aroma often described as berry-, pineapple-, or milky-like with estery nuances, making it valuable in sensory applications.
• FEMA GRAS Status: Recognized as Generally Recognized As Safe (GRAS) by the Flavor and Extract Manufacturers Association (FEMA #3568), permitting its use in food flavorings.
• Applications:
  • Used in artificial flavor formulations to impart fruity notes in beverages, confectionery, and dairy products.
  • Employed in perfumery for its fresh, slightly spicy-woody top notes and ability to enhance fruity accords.
  • Found in personal care products such as perfumes, colognes, soaps, shower gels, hair care products, and air fresheners.

2. Chemical Intermediate in Organic Synthesis

• Versatile Building Block: Serves as a synthon in multi-step organic reactions due to the reactivity of its ester functional group.
• Key Transformations:
  • Hydrolysis: Can be hydrolyzed back to cyclohexanecarboxylic acid.
  • Reduction: Reduced to cyclohexanemethanol (a primary alcohol) using reducing agents like LiAlH₄.
  • Aminolysis/Amide Formation: Converted into amides, including dimethylcyclohexanecarboxamide, for pharmaceutical or agrochemical intermediates.
  • Grignard Reactions: Reacts with organometallic reagents to form tertiary alcohols.
• Pharmaceutical Applications: Appears as an intermediate in patented synthetic routes for bioactive molecules, including SGLT2 inhibitors (e.g., WO2012025857) and β-lactamase inhibitors (e.g., WO2019221122).

3. Research and Analytical Applications

• Metabolomic Studies: Identified as an endogenous human metabolite present in body fluids, contributing to biochemical and metabolomics research.
• Mechanistic Studies: Used in kinetic studies of esterification and transesterification reactions under acid-catalyzed conditions.
• Reference Compound: Utilized in analytical chemistry as a standard for GC-MS or NMR calibration due to its well-defined structure and volatility.

4. Industrial and Specialty Uses

• Solvent Properties: Functions as a specialty solvent for resins, polymers, and organic reactions, though not widely used as a bulk solvent.
• Cleaning and Air Care: Its volatility and pleasant odor suggest potential use in industrial cleaning agents or fragranced consumer products, as indicated in fragrance-related patents.

Uses of Methyl cyclohexanecarboxylate:

Methyl cyclohexanecarboxylate is primarily synthesized through Fischer esterification, a well-established and widely used method. Additional synthetic routes include transesterification, decarboxylation, and indirect multi-step processes.

1. Fischer Esterification (Primary Method)

This is the most common and classical method for producing methyl cyclohexanecarboxylate.

• Reactants:

  • Cyclohexanecarboxylic acid
  • Methanol (CH₃OH)

• Catalyst:

  • Strong acid catalysts such as concentrated sulfuric acid (H₂SO₄), p-toluenesulfonic acid (p-TsOH), or hydrochloric acid (HCl)

• Reaction: C₆H₁₁COOH + CH₃OH ⇌ C₆H₁₁COOCH₃ + H₂O (Acid-catalyzed equilibrium reaction)

• Reaction Conditions:

  • The mixture is heated under reflux for approximately 19 hours.
  • Reflux temperature: ~65–70 °C (boiling point of methanol).
  • To drive the equilibrium toward the product, water is removed continuously using:
    • Dean-Stark apparatus (for azeotropic water removal), or
    • Molecular sieves (to absorb water in situ).

• Workup and Purification:

  1. After completion, cool the reaction mixture to room temperature.
  2. Neutralize the acidic catalyst by adding sodium hydrogen carbonate (NaHCO₃).
  3. Filter off any precipitated salts.
  4. Remove excess methanol and volatile components by evaporation under reduced pressure.
  5. Purify the crude product by distillation under reduced pressure, preferably using a Vigreux column.

• Yield:

  • Typically around 79–81%, as reported in standard organic synthesis procedures.

2. Alternative Synthetic Routes

While Fischer esterification is the standard, other methods exist:

A. Transesterification

• Involves exchanging the ester group of another ester with methanol.
• Example: Passing dimethyl 1,1-cyclohexanedicarboxylate over heated alumina (Al₂O₃) in methanol leads to decarboxylation and formation of methyl cyclohexanecarboxylate.

B. Indirect Route via Grignard Reaction

• Step 1: Synthesize cyclohexanecarboxylic acid by reacting cyclohexylmagnesium halide (Grignard reagent) with carbon dioxide (CO₂), followed by acidification.
• Step 2: Esterify the resulting acid with methanol under Fischer conditions as described above.

C. Acid Chloride Route

• React cyclohexanecarboxylic acid chloride with methanol:

  C₆H₁₁COCl + CH₃OH → C₆H₁₁COOCH₃ + HCl

• This method is fast and high-yielding but less commonly cited in standard preparations due to the need to handle corrosive acid chlorides.

D. Catalytic Hydrogenation

• Some patents suggest hydrogenation of methyl benzoate over a Ru/Al₂O₃ catalyst under H₂ pressure to yield methyl cyclohexanecarboxylate.
• This provides a direct route from aromatic precursors to the saturated aliphatic ester.