Friedel-Crafts acylation

What is Friedel-Crafts acylation?

In 1877, Friedel and Crafts first reported a reaction that involves electrophilic aromatic substitution by an acyl group derived from carboxylic acid derivatives in the presence of a Lewis acid or Brønsted acid. This reaction is commonly referred to as the Friedel-Crafts acylation. The reaction typically involves four components: aromatics, acylating agents, catalysts, and solvents. The electron density on the aromatic ring affects the reaction, with electron-donating groups facilitating the reaction and electron-withdrawing groups hindering it.

Friedel-Crafts acylation - general reaction scheme
Friedel-Crafts acylation

X = halogen, OC(O)R’, OR’, NHR’, OH, etc.
Nitrobenzene, which has a strong electron-withdrawing nitro group, is often used as the solvent to inhibit acylation. Acyl halides (mostly acyl chloride) and acyl anhydrides are commonly used as acylating agents, with the latter requiring effective catalysts such as AgClO4, BF3, CF3CO2H, (CF3CO)2O, HClO4, HF, H3PO4, SnCl4, SOCl2, or ZnCl2. The use of at least 1 eq. of Lewis acid, such as AlCl3, AlBr3, BeCl2, CuCl2, FeBr3, HgCl2, MbCl5, SbBr3, SbCl5, TiCl4, UCl4, WCl6, or ZrCl4, can increase the electrophilicity of the acylating agents. While there are various solvents that can be used, nonpolar carbon disulfide and polar nitrobenzene are commonly used for heterogeneous and homogeneous acylation, respectively.

The Lewis acid can react with an acylating agent that is sufficiently electrophilic to form a complex that can react with an aromatic ring. The resulting product is a ketone-Lewis acid complex that prevents further reactions and yields a high-purity product. Therefore, the ketone-Lewis acid complex can be decomposed by using water or dilute HCl. At least one equivalent of Lewis acid is needed for acylation with an acyl halide, while other acylating agents may require more than one equivalent. From this perspective, Lewis acids are promoters, not catalysts, although recent developments have made acylation catalytic.

The Friedel-Craft acylation is usually considered irreversible, but if the acyl group is tilted out of the plane of the aromatic ring by a neighboring bulky group, isomers can form from reversible acylation. Intermolecular acylation can provide aromatics with long hydrocarbon chains without rearrangement after carbonyl group reduction, whereas intramolecular acylation can synthesize benzocyclic ketones, including 1-indanones, 1-tetralones, and 1-benzosuberones. The direction of acylation follows the Crum-Brown-Gibson substitution rule, which means that acylation often occurs at the para-position of the electron-donating group and much less at the ortho-position due to steric hindrance. When both amino and thioether groups exist on the same aromatic ring, the amino group is the determining group for acylation direction.

Recent developments for Friedel-Crafts acylation include the application of ionic liquids as recyclable catalyst and media for acylation, new catalysts such as AgSbF6, Bi2O3, Bi(OTf)3, [(CuOTf)2PhH], Envirocats, EtAlCl2, Nafion-H, zeolite, and ZnO, the use of acylals as acylating agents, which produce different products depending on the conditions and the amount of catalyst, and the acylation of alkenes to make β,γ-unsaturated ketones.

References

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