Friedel-Crafts alkylation

What is Friedel-Crafts alkylation?

Although Wurtz first discovered this reaction, it is commonly known as the Friedel-Crafts alkylation after the work of Friedel and Crafts in 1877. It belongs to a special category of electrophilic aromatic substitution where the electrophile is a carbocation. Just like the Friedel-Crafts acylation, electron-donating groups aid the alkylation, while electron-withdrawing groups hinder it. Additionally, an acidic catalyst, either a Brønsted or Lewis acid, is required to enhance the electrophilicity of the alkylating agent. Usually, this alkylation occurs between aromatics and alkyl halides in the presence of a Lewis acid. The Lewis acid polarizes the alkyl halide, making the hydrocarbon section more electrophilic and saturated with electron deficiency from electron-rich aromatics by forming a π-complex that transforms into a σ-complex while sacrificing the aromaticity. The expulsion of a proton from this σ-complex helps regain the aromaticity.

Friedel-Crafts alkylation - general reaction scheme
Friedel-Crafts alkylation

= halogen, OH, OR, etc.

Apart from alkyl halides, other organic compounds such as alcohols, aldehydes, esters, ethers, imines, hydrozones, and olefins react with aromatics to give alkylated products. Among these, esters have proven advantageous over alkyl halides and have been thoroughly researched. The esters used in alkylation include alkyl sulfates, sulfites, phosphates, orthosilicates, carbonates, borates, chloroformates, hypochlorites, halosulfates, chlorosulfites, arenesulfonates, perchlorate, arenesulfinates, chloro- and fluorosulfates, triflates, pentafluorobenzenesulfonates, trifluoroacetates, acetates, formates, oxalate, silicate, and carboxylate.

Various solvents can be used in Friedel-Crafts alkylation, such as nitromethane, methylene chloride, carbon disulfide, 1,1,2-trichlorotrifluoromethane, and others. The Lewis acid catalysts commonly employed for this reaction can be ranked by decreasing Lewis acidity, with Al2Br6 being the strongest, followed by Al2Cl6, Al2I6, Ga2Br6, Ga2Cl6, Fe2Cl6, SbCl5, ZrCl4, SnCl4, and BCl3, BF3, SbCl3 being the weakest.

However, Friedel-Crafts alkylation has distinct differences from Friedel-Crafts acylation, including several limitations related to disproportionation, isomerization, overalkylation, sensitivity to water traces, and side reactions of alkylating agents. All these drawbacks are associated with the carbocation character in this reaction. For instance, disproportionation can result from the isomerization of a σ-complex to a more stable σ-complex during the alkylation when multiple alkyl groups are present on the aromatic ring. Isomerization of an alkylated group can stem from the rearrangement of a carbocation to form a more stable carbocation, as observed in the preparation of t-butyl aromatics from sec-butyl halide. Moreover, the alkyl group on the alkylated aromatics typically has an electron-donating effect that enriches the electron density on the aromatics, facilitating further alkylations.

When olefins are utilized as alkylating agents, they may undergo polymerization in the presence of a strong Lewis acid. Due to the acidic nature of Friedel-Crafts alkylation, acid-labile aromatics, including many heterocycles, are not suitable substrates for this reaction. However, some moderately inert aromatics can undergo alkylation with ethanol, ethyl, n-propyl, isopropyl, or n-butyl alcohol (excluding methanol and t-butyl alcohol) when sulfuric acid, PPA, or 85% phosphoric acid is employed as the catalyst. Nitrobenzene, known to be unreactive in Friedel-Crafts acylation, can undergo alkylation with ethanol in sulfuric acid. Similarly, highly electron-deficient pentafluorobenzene can react with methylene chloride or chloroform.

Recent advances in Friedel-Crafts alkylation include the development of new alkylating catalysts such as zeolite, cation-exchanged Montmorillonite, hetereobimetallic, and rare earth metal salts; the use of new reaction media, such as supercritical CO2; the design of new alkylating agents, such as vinyl chlorosilanes, nitrosoamide, and benzyl N-sulfamoylcarbamates (which can react with aromatics even in the absence of an acidic catalyst); and the establishment of an unsymmetrical alkylation system using chiral catalysts to produce enantiomerically pure products.

References

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