Preparation and Properties of Indole | Chemistry Optional Notes for UPSC PDF Download

Introduction

• Indole consists of a benzene ring fused to the Alpha and Beta positions of a pyrrole ring. 
• Indole occurs in coal-tar and in the oils of jasmine and orange blossoms. It is also found as a part of the total structure of a number of alkaloids and amino acids e.g., serotonin, reserpine, and tryptophan
  

Preparation Methods

Indole may be obtained;.

• By Fischer-indole synthesis: In this method, pyruvic acid is first treated with phenylhydrazine to form the corresponding phenylhydrazone. The hydrazone is heated with anhydrous zinc chloride to give indole-2-carboxylic acid which on decarboxylation yields indole.

• By the Reissert Synthesis. In this method o-nitrotoluene is condensed with diethyl oxalate in the presence of a base to form a 2-keto-ester. This is then reduced with zinc and glacial acetic acid to give indole-2-carboxylic acid which on decarboxylation gives indole.
  
• From o-Toluidine: This involves treatment of o-toluidine with formic acid to form N-formyl-o-toluidine. This undergoes dehydration on heating with potassium t-butoxide to yield indole.
  
• By the Lip Synthesis. In this method o-amino-w-chlorostyrene is heated with sodium ethoxide at l60-170°C
• From o-Nitrophenylacetaldehyde: This involves reduction of onitrophenylacetaldehyde with iron powder and sodium bisulphite to give o-aminophenylacetaldehyde which cyclises spontaneously to yield indole.

Physical Properties of Indole 

• Indole is a colorless, volatile solid,
• Melting point 52C
• It is sparingly soluble in cold water, but dissolves in hot water and most organic solvents.
• Indole has a powerful odour which is pleasant and flowery in low concentrations. It is, in fact, used commercially as a perfume base. In contrast, indole and its 3-methyl derivative (Skatole) are responsible for the strong offensive odour of faeces.

Chemical Properties of Indole

• Basic and Acidic Character: Like pyrrole, indole is a weak base and also a weak acid. It is polymerized by strong acids and reacts with potassium hydroxide and Grignard reagents.
• Electrophilic Substitutions: Unlike pyrrole, indole undergoes electrophilic substitution at C-3. This is because two resonance forms can be written for intermediate cation obtained from attack at C-3 (without disturbing the benzene ring), whereas only one such form is possible for substitution at C-2
  
  • a. Nitration: Indole may be nitrated at low temperature with ethyl nitrate in the presence of sodium ethoxide to yield 3-nitroindole
  • (b) Sulphonation: Indole undergoes sulphonation with sulphur trioxide in pyridine at 110°C to give indole-3-sulphonic acid.
    
  • C. Bromination: When treated with sodium methoxide and Methylene iodide, pyrrole undergoes ring expansion forming pyridine.
    
  • d. Friedel-Craft Acylation: Indole may be acetylated with acetyl chloride in the presence of SnCl4 (Tin tetrachloride) to yield 3-acetylindole.
    
  • e. Alkylation: Indole reacts with methyl iodide in dimethyl sulphoxide (DMSO) at about 80°C to give 3-methylindole (skatole).
    
    
• Reimer-Tiemann Formylation: Indole reacts with chloroform in the presence of alkali to yield indole-3- aldehyde (3-formylindole) and 3-chloroquinoline

• Diazo Coupling: Indole couples with benzenediazonium chloride in a weakly acidic solution to yield 3-phenylazoindole.
  
• Mannich Reaction: Indole undergoes Mannich reaction with formaldehyde and dimethylamine to give 3-dimethylaminomethylindole (Gramine).
  
• Oxidation: Indole may be oxidized by ozone in formamide to give 2-formamido-benzaldehyde.
  
• Reduction: Mild reduction of indole with zinc (or tin) and hydrochloric acid yields 2,3 dihydroindole (Indoline). Catalytic reduction hydrogenates both rings and produces ocatahydroindole.
  

Medicinal Importance of indole