Science of Synthesis

Sellars, J. D., Science of Synthesis Knowledge Updates, (2014) 1, 397.

In 1877, Friedel and Crafts developed the synthesis of aryl ketones from benzene using a carboxylic acid chloride and aluminum trichloride.[‌1‌] This is an electrophilic aromatic substitution reaction that proceeds most effectively with electron-rich arenes. The reaction proceeds via attack on an acylium ion formed from reaction of the acid chloride with the Lewis acid. Addition of the acyl moiety decreases the electron density of the arene, hindering subsequent acylations of the product, and thus providing a monoacylated product cleanly. The regiochemical outcome of acylation is often very good, with electron-donating moieties favoring ortho/para substitution, whilst the steric size of the acyl group allows for preferential reaction at the para position. The solvent also plays a role in the reaction, with nitrobenzene, nitroalkanes, and the chlorinated alkanes dichloromethane and 1,2-dichloroethane being good solvents. This process is now of vital importance to academia and industry as it is used to produce chemical feedstocks, synthetic intermediates, and fine chemicals.[‌2‌] However, Friedel–Crafts reactions suffer from several drawbacks. These include limited substrate scope, being restricted to electron-rich ar­enes, harsh reaction conditions, and the need for stoichiometric amounts of Lewis acid. The last of these arises from the strong complexation of the aryl ketone product to the Lewis acid. Moreover, upon hydrolytic workup, the complex is destroyed and the Lewis acid is lost, producing large volumes of corrosive waste.

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References