Acridine: Synthesis, Chemical Behaviour, and Therapeutic Applications

Acridine is an organic compound that plays a vital role in medicinal chemistry. Understanding its synthesis and reactions is essential for leveraging its therapeutic potential.

Methods of Synthesising Acridine

Bernthsen Synthesis

The Bernthsen method is a widely recognised approach for synthesising acridine. This process involves the condensation of diphenylamine with carboxylic acids in the presence of zinc chloride. For instance, o-chlorobenzene acid can react with aniline to yield diphenylamine-2-carboxylic acid. When this acid is treated with phosphorus oxychloride (POCl3), it produces 9-chloroacridine. Subsequent hydrogenation of 9-chloroacridine, followed by oxidation with ferric chloride, results in the formation of acridine.

Alternative Synthesis Approaches

Another method involves the Friedlander synthesis, where cyclohexane-2-enone is reacted with the salt of anthranilic acid at 120°C to generate 9-methyl acridine. Additionally, a first acylation of diphenylamine can lead to the production of 9-phenylacridine through a thermochemical reaction when heated in the presence of iodine and hydrogen iodide.

Chemical Reactions of Acridine

Basic Properties

Acridine is classified as a weak base and shares structural similarities with pyridine and quinoline. Its nitrogen atom possesses an available electron, contributing to its aromatic character. When protonated at the nitrogen atom, acridine forms soluble salts, with the first protonation occurring at the ring nitrogen in amino-acridine, resulting in a double salt.

Electrophilic and Nucleophilic Substitution

Acridine undergoes electrophilic substitution predominantly at the 2- or 7-positions, leading to di-substitution. In contrast, nucleophilic reagents exhibit a stronger interaction with quaternary salts of acridine, favouring attacks at the 9-position due to its lower electron density compared to other positions.

Oxidation and Reduction Processes

During oxidation with dichromate in acetic acid, acridine converts to acridone. Furthermore, oxidative ring cleavage using potassium permanganate (KMnO4) in alkaline conditions yields quinoline-2,3-dicarboxylic acid. Selective reductions can also be achieved; for instance, catalytic hydrogenation can reduce the benzene rings while zinc and hydrochloric acid can reduce the pyridine ring, producing 9,10-dihydroacridine. Additionally, exposure to ultraviolet light allows acridine to react with n-pentanoic acid, resulting in 9-n-butylacridine.

Therapeutic Applications of Acridine

Acridine derivatives are integral to various pharmaceutical formulations. Notable examples include:

• Bucricaine, an anaesthetic
• Quinacrine (also known as mepacrine), used for treating malaria
• 9-ammoacridine, a disinfectant
• Proflavin, an antibacterial agent
• Nitracine, employed in cancer therapies
• Acriflavine, which has antiseptic properties

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