Synthesis, Reactions, and Medicinal Uses of Acridine

 

Acridine is a three-membered fused heterocyclic system containing Nitrogen as a heteroatom at the 10th position. Two benzene rings are fused to the "b" and "e" sides of pyridine. Other names for acridine are 2,3-Benzoquinoline and Dibenzo[b,e]pyridine.

Physical properties:

Colour: white

State: powder(solid)

Melting point: 106 - 110 ^oC

Boiling point: 344.86 ^oC

Solubility: Slightly soluble in hot water and soluble in organic solvents.

Structure and Aromaticity:

Acridine is a planar molecule, all atoms are sp² hybridised. Unhybridised p-orbitals sidewise overlap to form pi bonds. Acridine contains seven double bonds and 14 delocalised pi electrons, following the huckles rule(4n+2)pi electrons (where n=3). Hence acridine is aromatic.

Synthesis of Acridine:

1. Ulmann synthesis: 

2-chlorobenzoic acid reacts with aniline in the presence of sodium hydroxide give diphenylamino-2-carboxylic acid(DPCA). 

(i) DPCA treated with strong acid give 9(10H)-acridinone, which upon reduced with Na in ethanol gives 9,10-dihydroacridine.

(ii) DPCA reacted with phosphorous oxychloride give 9-chloro-9,10-dihydroacridine, which upon reduced with hydrogen and nickel gives 9,10-dihydroacridine.

The formed 9,10-dihydroacridine upon oxidation give acridine.

2. Bernthsen acridine synthesis:

Diarylamine heated with a carboxylic acid or acid anhydride in the presence of Zinc chloride gives 9-substituted acridine.

3. From 2-benzyl aniline: 

2-benzyl aniline passed through a red hot tube gives acridine.

Electrophilic addition reactions to 'N' of Acridine.

1. Protonation:

 Acridine reacts with acids and gives acridinium salts.

2. N-alkylation: 

Acridine reacts with alkyl halides giving N-alkyl acridinium halides.

Electrophilic substitution reactions:

Electrophilic substitution reactions of acridine give a mixture of 2-substituted and 2,7-disubstituted derivatives.

1. Nitration: 

Acridine upon nitration gives a mixture of 2-nitro and 2,7-dinitro acridine.

2. Sulphonation:

Acridine upon sulphation gives acridine-2-sulphonic acid and acridine-2,7-sulphonic acid.

3. Halogenation: 

Acridine upon halogenation gives 2-halo and 2,7-dihalo acridine.

Nucleophilic substitution reactions:

Acridine readily reacts with nucleophiles. nucleophilic reactions take place at the 9th position.

Chichibabin reaction: Acridine reacts with Sodamide in liquid ammonia leading to 9-aminoacridine.

Oxidation reactions:

1. Acridine oxidized with sodium dichromate in acetic acid gives 9-(10H)-acridine.

2. Acridine is oxidised by potassium permanganate in an alkaline medium gives quionoline-2,3-dicarboxylic acid.

3. Acridine reacts with peroxy acids and gives acridine-N-oxides.

Reduction reactions:

1. Acridine reduced with hydrogen and pt as catalyst gives 1,2,3,4,5,6,7,8-octahydroacridine.

2. Acridine reduced with hydrogen and Ni as Catalyst or Zinc in Hcl gives 9,10-dihydroacridine.

3. Acridine reduced with Na in liquid ammonia gives 1,4,5,8-tetrahydroacridine.

Medicinal uses:

Drugs containing Acridine ring:

1. Tacrine: Anticholinesterase drug used in the treatment of Alzheimer's disease.

2. 9-Aminoacridine: Slow-acting germicide, used as an antiseptic and disinfectant. also used in the treatment of vaginal candidiasis.

3. Quinacrine: used in the treatment of malaria and tapeworm infections. also used in the treatment of cutaneous leishmaniasis and giardiasis.

4. Proflavine: A topical antiseptic agent used to prevent infections.

References (Latest editions):

Heterocyclic chemistry by Raj K. Bansal.

Heterocyclic chemistry by T.L. Gilchrist.

Organic chemistry by Morrison and Boyd.

A  textbook of organic chemistry - Arun Bahl. B.S. Bahl.