Friedel-Crafts reactions, limitations

F-L (Fig. 2). The Friedel-Crafts reaction (limited in the 1-benzazepine series), Dieckmann, acyloin, and aldol condensations, Bischler-Napieralski, Vilsmeyer, and Pictet-Spengler-type reactions, and phenolic oxidative... 

Other limitations to Friedel-Crafts reactions will be encountered in this chap ter and are summarized in Table 12 4 (page 511)... 

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). 

Another limitation is that Friedel-Crafts reactions don t succeed on aromatic rings that are substituted either by a strongly electron-withdrawing group... 

Figure 16.8 Limitations on the aromatic substrate in Friedel-Crafts reactions. No reaction occurs if the substrate has either an electron-withdrawing substituent or an amino group.

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. 

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... 

There are several limitations to using the Friedel-Crafts reaction. 

Although electrophilic aromatic substitution worics well with most substituted benzenes, halogena-tion and the Friedel-Crafts reactions have some additional limitations that must be kept in mind. 

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 . ... 

Despite these numerous limitations, the Friedel-Crafts reaction, in its various modifications (for example, acylation, Sec. 19.6), is an extremely useful synthetic tool. 

A second limitation is that the Friedel-Crafts reaction doesn t succee on an aromatic ring that is substituted either by an amino group or by a strongly electron-withdrawing group. We ll see in Section 16.5 that the pres-... 

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