Alkylation and Acylation of Aromatic Rings The Friedel-Crafts Reaction

Alkylation and Acylation of Aromatic Rings The Friedel-Crafts Reaction 

Among the most useful electrophilic aromatic substitution reactions in the laboratory is alkylation—the introduction of an alkyl group onto the benzene ring. Called the Fricdel-Crafts reaction after its discoverers, the reaction is carried out 

Mechanism of the Friedel-Crafts alkylation reaction of benzene with 2-chloropropane to yield isopropylbenzene (cumene). 

The electrophile is a carbocation, generated by AICl3-assisted dissociation of an alkyl halide. 

Charles Friedel (1832-1899) was born in Strasbourg, France, and studied atthe Sorbonne in Paris. Trained as both a mineralogist and a chemist, he was among the first to attempt to manufacture synthetic diamonds. He was professor of mineralogy at the School of Mines before becoming professor of chemistry at the Sorbonne (1884-1899). 

I An electron pair from the aromatic ring attacks the carbocation, forming a C-C bond and yielding a new carbocation intermediate. 

Mechanism of the Friedel-Crafts alkylation reaction of benzene with 2-chloropropane to yield isopropylbenzene (cumene). The electrophile is a carbocation, generated by AlCl3-assisted dissociation of an alkyl halide. 

I Loss of a proton then gives the neutral alkylated substitution product. 

Despite its utility, the Friedel-Crafts alkylation has several limitations. For one thing, only alkyl halides can be used. Aromatic (aryl) halides and vinylic halides don t react because aryl and vinylic carbocations are too high in energy to form under Friedel-Crafts conditions. 

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ALKYLATION AND ACYLATION OF AROMATIC RINGS THE FRIEDEL-CRAFTS REACTION JJl... 

Discovered in 1877, the Friedel-Crafts reaction is one of the more important and useful organic transformations. This class of reactions is generally considered to include all Lewis acid-promoted electrophilic alkylations and acylations of aromatic rings. Due to their synthetic utility, Friedel-Crafts reactions have been extensively studied and used across a broad and diverse area of chemical research. 

The experiments in Sections 15.2 and 15.3 illustrate the Friedel-Crafts alkylation and acylation of aromatic hydrocarbons, respectively. A complication of Friedel-Crafts reactions is apparent in the alkylation experiment, wherein rearrangements of the carbo-cations generated from the alkyl halide provide mixtures of substitution products. The acylation reaction of Section 15.3 provides an example of how a combination of electronic and steric effects can affect the orientation of electrophilic attack on an aromatic ring. 

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... 

Many variations of the reaction can be carried out, including halogenation, nitration, and sulfonation. Friedel-Crafts alkylation and acylation reactions, which involve reaction of an aromatic ling with carbocation electrophiles, are particularly useful. They are limited, however, by the fact that the aromatic ring must be at least as reactive as a halobenzene. In addition, polyalkylation and carbocation rearrangements often occur in Friedel-Crafts alkylation. 

Aromatic compounds react mainly by electrophilic aromatic substitution, in which one or more ring hydrogens are replaced by various electrophiles. Typical reactions are chlorination, bromination, nitration, sulfonation, alkylation, and acylation (the last two are Friedel-Crafts reactions). The mechanism involves two steps addition of the electrophile to a ring carbon, to produce an intermediate benzenonium ion, followed by proton loss to again achieve the (now substituted) aromatic system. 

In comparison with molecular catalysts, solid catalysts can be isolated from the reaction mixtures by filtration or used in continuous processes this is both environmentally friendly and useful in laboratory-scale experiments. The most important reactions catalyzed by solid superbases are isomerization reactions and the alkylation of substituted arenes in the side chain (Scheme 2). They proceed at room temperature or below with high yield (typically >99%). The surperbase-cata-lyzed alkylation of aromatic compounds complements the acid-type Friedel-Crafts alkylation and acylation, because the latter results in ring alkylation, whereas the former results in side-chain alkylation. 

Another catalytic methodology that is widely used for C-C bond formation is the Heck and related coupling reactions [86, 87]. The Heck reaction [88] involves the palladium-catalysed arylation of olefinic double bonds (Fig. 1.31) and provides an alternative to Friedel-Crafts alkylations or acylations for attaching carbon fragments to aromatic rings. The reaction has broad scope and is currently being widely applied in the pharmaceutical and fine chemical industries. For example, Albemarle has developed a new process for the synthesis of the anti-in-... 

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