Electrophilic aromatic substitutions Friedel-Crafts alkylation

Friedel-Crafts reaction (Section 16.3) An electrophilic aromatic substitution reaction to alkylate or acylate an aromatic ring. 

One of the most useful of all electrophilic aromatic substitution reacUnig is alkylation, the attachment of an alkyl group to the benzene ring- Charles Friedel and James Crafts reported in 1877 that benzene rings can be alkylated by reaction with an alkyl chloride in the presence of aluminum chloride as catalyst. For example, benzene reacts with 2-chloropropaneand AJCI3 to yield isopropylbenzene, also called cumene. 

Friedel-Crafts alkylation is one of the most frequently used and widely studied reactions in organic chemistry. Since the initial discovery by Charles Friedel and James Mason Crafts in 1877, a large number of applications have emerged for the construction of substituted aromatic compounds. Friedel-Crafts alkylation processes involve the replacement of C—H bond of an aromatic ring by an electrophilic partner in the presence of a Lewis acid or Bronsted acid catalyst. Particularly, catalytic asymmetric Friedel-Crafts alkylation is a very attractive, direct, and atom-economic approach for the synthesis of optically active aromatic compounds. However, it took more than 100 years from the discovery of this reaction until the first catalytic asymmetric Friedel-Crafts (AFC) alkylation of naphthol and ethyl pyruvate was realized by Erker in 1990. Nowadays, owing to continued efforts in developing... 

Friedel-Crafts alkylation (Section 15.6) Installation of an alkyl group on a benzene ring by electrophilic aromatic substitution using an alkyl carbocation as the electrophile (generated in situ using a Lewis acid). 

Nitration in sulphuric acid is a reaction for which the nature and concentrations of the electrophile, the nitronium ion, are well established. In these solutions compounds reacting one or two orders of magnitude faster than benzene do so at the rate of encounter of the aromatic molecules and the nitronium ion ( 2.5). If there were a connection between selectivity and reactivity in electrophilic aromatic substitutions, then electrophiles such as those operating in mercuration and Friedel-Crafts alkylation should be subject to control by encounter at a lower threshold of substrate reactivity than in nitration this does not appear to occur. 

Other typical electrophilic aromatic substitution reactions—nitration (second entry) sul fonation (fourth entry) and Friedel-Crafts alkylation and acylation (fifth and sixth entnes)—take place readily and are synthetically useful Phenols also undergo elec trophilic substitution reactions that are limited to only the most active aromatic com pounds these include mtrosation (third entry) and coupling with diazomum salts (sev enth entry)... 

Friedel-Crafts alkylation (Section 12 6) An electrophilic aro matic substitution in which an aromatic compound reacts with an alkyl halide in the presence of aluminum chloride An alkyl group becomes bonded to the nng... 

The synthesis of an alkylated aromatic compound 3 by reaction of an aromatic substrate 1 with an alkyl halide 2, catalyzed by a Lewis acid, is called the Friedel-Crafts alkylation This method is closely related to the Friedel-Crafts acylation. Instead of the alkyl halide, an alcohol or alkene can be used as reactant for the aromatic substrate under Friedel-Crafts conditions. The general principle is the intermediate formation of a carbenium ion species, which is capable of reacting as the electrophile in an electrophilic aromatic substitution 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 Friedel-Crafts reaction after its discoverers, the reaction is carried out... 

Other electrophilic substitution reactions on aromatic and heteroaromatic systems are summarized in Scheme 6.143. Friedel-Crafts alkylation of N,N-dimethyl-aniline with squaric acid dichloride was accomplished by heating the two components in dichloromethane at 120 °C in the absence of a Lewis acid catalyst to provide a 23% yield of the 2-aryl-l-chlorocydobut-l-ene-3,4-dione product (Scheme 6.143 a) [281]. Hydrolysis of the monochloride provided a 2-aryl-l-hydroxycyclobut-l-ene-3,4-dione, an inhibitor of protein tyrosine phosphatases [281], Formylation of 4-chloro-3-nitrophenol with hexamethylenetetramine and trifluoroacetic acid (TFA) at 115 °C for 5 h furnished the corresponding benzaldehyde in 43% yield, which was further manipulated into a benzofuran derivative (Scheme 6.143b) [282]. 4-Chloro-5-bromo-pyrazolopyrimidine is an important intermediate in the synthesis of pyrazolopyrimi-dine derivatives showing activity against multiple kinase subfamilies (see also Scheme 6.20) and can be rapidly prepared from 4-chloropyrazolopyrimidine and N-bromosuccinimide (NBS) by microwave irradiation in acetonitrile (Scheme... 

To be really satisfactory, a Friedel-Crafts alkylation requires one relatively stable secondary or tertiary carbocation to be formed from the alkyl halide by interaction with the Lewis acid, i.e. cases where there is not going to be any chance of rearrangement. Note also that we are unable to generate carboca-tions from an aryl halide - aryl cations (also vinyl cations, see Section 8.1.3) are unfavourable - so that we cannot nse the Friedel-Crafts reaction to join aromatic gronps. There is also one further difficulty, as we shall see below. This is the fact that introduction of an alkyl substitnent on to an aromatic ring activates the ring towards fnrther electrophilic substitution. The result is that the initial product from Friedel-Crafts alkylations is more reactive than the... 

Despite the use of new catalys.s for manufacturing some industrial organic chemicals, many well-known classical reactions still abound. The Friedel-Crafts alkylation is one of the first reactions studied in electrophilic aromatic substitution. It is used on a large scale for making ethylbenzene. 

Electrophilic aromatic substitution is a reaction where a hydrogen atom in an aromatic system, e.g. benzene, is replaced by an electrophile. Some of the important electrophilic substitution reactions are Friedel-Crafts alkylation and acylation, nitration, halogenation and sulphonation of benzene. 

First introduced by Charles Friedel and James Crafts in 1877, the FC alkylation is an electrophilic aromatic substitution reaction where the electrophile is a carbocation, R. This carhocation is generated hy AICI3-catalysed ionization of alkyl halide. For example, benzene reacts with isopropylchloride in the presence of Lewis acid to produce isopropylbenzene. 

Alkylation of the C(2) or C(3) carbons of the pyrrole ring can be accomplished by electrophilic aromatic substitution. Such substitution reactions may be carried out on the neutral heterocycle or on a metal salt. The magnesium salts are of most synthetic importance for the alkylation of both pyrroles and indoles. As discussed in Section 3.05.1.2.7, there is a reversal of the preferred site of electrophilic substitution between pyrroles and indoles. Thus Friedel-Crafts-type substitution of pyrroles gives 2-aIkylpyrroles while similar reaction... 

One of the most common examples of an electrophilic aromatic substitution is Friedel-Crafts alkylation [40], These days, many important industrial processes are based on this type of Friedel-Crafts-chemistry [41]. The manufacture of high-octane gasoline, ethylbenzene, synthetic rubber, plastics and detergent alkylates are examples. Moreover, the Friedel-Crafts alkylation is among the most fundamental and convenient processes for C—C bond formation on arenes, especially for the synthesis of fine chemicals and agrochemicals containing functionalized arenes and heteroarenes. 

An alkyl group can be added to a benzene molecule by an electrophile aromatic substitution reaction called the Friedel-Crafts alkylation reaction. One example is the addition of a methyl group to a benzene ring. 

The Friedel-Crafts acylation reaction, another example of an electrophilic aromatic substitution reaction, is similar to the Friedel-Crafts alkylation reaction except that the substance that reacts with benzene is an acyl halide,... 

Friedel-Crafts type reactions of strongly deactivated arenes have been the subject of several recent studies indicating involvement of superelectrophilic intermediates. Numerous electrophilic aromatic substitution reactions only work with activated or electron-rich arenes, such as phenols, alkylated arenes, or aryl ethers.5 Since these reactions involve weak electrophiles, aromatic compounds such as benzene, chlorobenzene, or nitrobenzene, either do not react, or give only low yields of products. For example, electrophilic alkylthioalkylation generally works well only with phenolic substrates.6 This can be understood by considering the resonance stabilization of the involved thioalkylcarbenium ion and the delocalization of the electrophilic center (eq 4). With the use of excess Fewis acid, however, the electrophilic reactivity of the alkylthiocarbenium ion can be... 

This Lewis acid-catalyzed electrophilic aromatic substitution allows the synthesis of alkylated products via the reaction of arenes with alkyl halides or alkenes. Since alkyl substituents activate the arene substrate, polyalkylation may occur. A valuable, two-step alternative is Friedel-Crafts Acylation followed by a carbonyl reduction. 

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. 

Know the meaning of electrophilic aromatic substitution, halogenation, nitration, sulfonation, alkylation, acylation, Friedel-Crafts reaction. 

Study of the reactivity of aromatic C-H bonds in the presence of transition metal compounds began in the 1960s despite the quite early discovery of Friedel-Crafts alkylation and acylation reactions with Lewis acid catalysts. In 1967, we reported Pd(II)-mediated coupling of arenes with olefins in acetic acid under reflux [1], The reaction involves the electrophilic substitution of aromatic C-H bonds by a Pd(II) species, as shown in Scheme 2, and this is one of the earliest examples of aromatic C-H bond activation by transition metal compounds. Al-... 

Two of the reactions that are used in the industrial preparation of detergents are electrophilic aromatic substitution reactions. First, a large hydrocarbon group is attached to a benzene ring by a Friedel-Crafts alkylation reaction employing tetrapropene as the source of the carbocation electrophile. The resulting alkylbenzene is then sulfonated by reaction with sulfuric acid. Deprotonation of the sulfonic acid with sodium hydroxide produces the detergent. 

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