Limitations of Friedel-Crafts Reactions

The acylium ion, acting as an eiectrophile, reacts with benzene to form the arenium ion. 

A proton is removed from the arenium ion, forming the aryl ketone. 

The ketone, acting as a Lewis base, reacts with aluminum chloride (a Lewis acid) to form a complex. 

Treating the complex with water liberates the ketone and hydrolyzes the Lewis acid. 

Several important synthetic applications of the Friedel-Crafts reaction are given in Section 15.9. 

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Limitations of Friedel-Crafts Reactions The remaining steps in the Friedel-Crafts acylation of benzene are the following ... 

Several restrictions limit the usefulness of Friedel-Crafts reactions ... 

The third limitation of Friedel-Crafts alkylation reaction is the structural rearrangement of the alkyl carbocation generated from the alkyl halide. A rearrangement of the alkyl group gives a different product than the one desired. For example, the reaction with 1-chloropropane in the presence of AlCl yields a small amount of propylbenzene, but a larger amount of the isomer, isopropylbenzene. 

The presence of one or more molar equivalents of AlGlg can bring about a remarkable acceleration of diene syntheses.—E Anthracene allowed to react for 5 min. with an equimolar amount of dimethyl fumarate in the presence of 2 molar equivalents of AlClg frans-dimethyl ester adduct. Y ca. 100%.— Reaction in the absence of AlGlg when carried out in boiling dioxane requires 2-3 days and affords a less pure product. Limitations are imposed by the instability of some dienes and dienophiles under the reaction conditions and by the preferential occurrence of Friedel-Crafts reactions in some cases. F. e. s. P. Yates and P. Eaton, Am. Soc. 82, 4436 (1960) also with other Friedel-Grafts type catalysts cf. G. I. Fray and R. Robinson, Am. Soc. 83, 249 (1961). 

Neither Friedel-Crafts acylation nor alkylation reactions can be earned out on mtroben zene The presence of a strongly deactivating substituent such as a nitro group on an aromatic ring so depresses its reactivity that Friedel-Crafts reactions do not take place Nitrobenzene is so unreactive that it is sometimes used as a solvent m Friedel-Crafts reactions The practical limit for Friedel-Crafts alkylation and acylation reactions is effectively a monohalobenzene An aromatic ring more deactivated than a mono halobenzene cannot be alkylated or acylated under Friedel-Crafts conditions... 

Zirconium monochloride reacts with sodium ethoxide to form additional adducts which hydrolyze in water. The monochloride does not react with benzene in a Friedel-Crafts reaction, and does not enter into intercalation reactions similar to those of zirconium disulfide. Both monohaUdes add hydrogen reversibly up to a limiting composition of ZrXH (131). 

Yet a final limitation to the Friedel-Crafts reaction is that a skeletal rearrangement of the alkyl carbocation electrophile sometimes occurs during reaction, particularly when a primary alkyl halide is used. Treatment of benzene with 1-chlorobutane at 0 °C, for instance, gives an approximately 2 1 ratio of rearranged (sec-butyl) to unrearranged (butyl) products. 

Aromatic hydrocarbons substituted by alkyl groups other than methyl are notorious for their tendency to disproportionate in Friedel-Crafts reactions. This tendency has previously limited the application of the isomerization of para- or ortho-) m ky -benzenes to the corresponding meta compounds. At the lower temperature of the present modification, disproportionation can be minimized. 

This involvement of carbocations actually limits the utility of Friedel-Crafts alkylations, because, as we have already noted with carbocations, rearrangement reactions complicate the anticipated outcome (see Section 6.4.2). For instance, when a Lewis acid... 

Exploring electrophilic substitution Checking out what happens in benzene reactions Tackling Friedel-Crafts reactions two ways Figuring out how to modify the reactivity of an aromatic Understanding the limitations of electrophilic substitution... 

The Friedel-Crafts reaction has limited application in pyrazole chemistry, as the acyl group can be introduced only in the 4-position. The reaction is easier with 1-arylpyrazoles which are less inclined to form pyrazole cations.822,828 Heating N-substituted pyrazoles with benzoyl chloride at 200-230° for some hours gives high yields of 4-benz-oylpyrazoles (60) even in the absence of catalysts.48,505,647,624,825... 

Chiral titanium complexes are also employed as effective asymmetric catalysts for other carbon-carbon bond-forming reactions, for example addition of diketene (Sch. 66) [154c,162], Friedel-Crafts reaction (Sch. 67) [163] (Sch. 68) [164], iodocar-bocyclization (Sch. 69) [165], Torgov cyclization (Sch. 70) [166], and [2 -i- 1] cycloaddition (Sch. 71) [167]. Asymmetric functional group transformations can also be catalyzed by chiral titanium complexes. These transformations, for example the Sharpless oxidation [168] or hydride reduction [169] are, however, beyond the scope of this review because of space limitations. Representative results are, therefore, covered by the reference list. 

Friedel—Crafts reactions with halomethyl aromatic compounds have been used to prepare several types of polymers. The reaction is usually unsatisfactory because of the formation of either low-molecular-weight or crosslinked polymers. Rate studies are complicated by the multifunctional nature of the reactants, and often by limited solubility of the products. The kinetics of the first two steps of the reaction between benzene and p-bis-chloromethylbenzene with SnC catalysts were investigated by Grassie and Meldrum [212]. The activation energy was found to be about 10 kcal mole . ... 

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