Substitution, electrophilic Friedel-Crafts alkylation

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. 

Electrophilic Aromatic Substitution Reactions. Friedel-Crafts alkylation, acylation, and the Vilsmeier-Haack formylation, shown below, are excellent reactions for the synthesis of substituted aromatic compounds. 

The alkylation of pyridine [110-86-1] takes place through nucleophilic or homolytic substitution because the 7C-electron-deficient pyridine nucleus does not allow electrophilic substitution, eg, Friedel-Crafts alkylation. Nucleophilic substitution, which occurs with alkali or alkaline metal compounds, and free-radical processes are not attractive for commercial applications. Commercially, catalytic alkylation processes via homolytic substitution of pyridine rings are important. The catalysts effective for this reaction include boron phosphate, alumina, silica—alumina, and Raney nickel (122). 

The selectivity of an electrophile, measured by the extent to which it discriminated either between benzene and toluene, or between the meta- and ara-positions in toluene, was considered to be related to its reactivity. Thus, powerful electrophiles, of which the species operating in Friedel-Crafts alkylation reactions were considered to be examples, would be less able to distinguish between compounds and positions than a weakly electrophilic reagent. The ultimate electrophilic species would be entirely insensitive to the differences between compounds and positions, and would bring about reaction in the statistical ratio of the various sites for substitution available to it. The idea has gained wide acceptance that the electrophiles operative in reactions which have low selectivity factors Sf) or reaction constants (p+), are intrinsically more reactive than the effective electrophiles in reactions which have higher values of these parameters. However, there are several aspects of this supposed relationship which merit discussion. 

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. 

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... 

A similar problem of complex formation may be encountered if either amino or phenol groups are present in the substrate, and the reaction may fail. Under such circumstances, these groups need to be blocked (protected) by making a suitable derivative. Nevertheless, Friedel-Crafts acylations tend to work very well and with good yields, uncomplicated by multiple acylations, since the acyl group introduced deactivates the ring towards further electrophilic substitution. This contrasts with Friedel-Crafts alkylations, where the alkyl substituents introduced activate the ring towards further substitution (see Section 8.4.3). 

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. 

Direct electrophilic substitution of benz- and dibenz-azepines remains relatively unexplored. Most substituted benzazepines have been prepared from benzene precursors bearing the desired substituents (74AHC(17)45). The bulk of the reported electrophilic substitutions have been carried out on 5//-dibenz[6,/]azepine (74CRV101), MO calculations on which predict that substitution should occur at the 2- and 4-positions, i.e. para and ortho to the azepine ring nitrogen. These predictions are borne out by Friedel-Crafts alkylation and acylation studies, although it is apparent that a second alkyl group enters at the 8- rather than at the 4-position. Formylation under Vilsmeier conditions yields the 2-aldehyde. As noted earlier (Section 5.16.3.4), however, the 10,11-dihydro system exhibits different behavior and acylates at the benzylic 10,11-positions. Nitration with mixed acids of the... 

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. 

The dicyclopentadienyl metal compounds undergo Friedel-Crafts alkylation and acylation, sulfonation, metalation, arylation, and formyla-tion in the case of ferrocene, dicyclopentadienyl ruthenium, and dicyclopentadienyl osmium, whereas the others are unstable to such reactions ( ). Competition experiments (128) gave the order of electrophilic reactivity as ferrocene > ruthenocene > osmocene and the reverse for nucleophilic substitution of the first two by n-butyl lithium. A similar rate sequence applies to the acid-catalysed cleavage of the cyclopentadienyl silicon bonds in trimethylsilylferrocene and related compounds (129), a process known to occur by electrophilic substitution for aryl-silicon bonds (130). 

The range of preparatively useful electrophilic substitution reactions is often limited by the acid sensitivity of the substrates. Whereas thiophene can be successfully sulfonated in 95% sulfuric acid at room temperature, such strongly acidic conditions cannot be used for the sulfonation of furan or pyrrole. Attempts to nitrate thiophene, furan or pyrrole under conditions used to nitrate benzene and its derivatives invariably result in failure. In the case of sulfonation and nitration milder reagents can be employed, i.e. the pyridine-sulfur trioxide complex and acetyl nitrate, respectively. Attempts to carry out the Friedel-Crafts alkylation of furan are often unsuccessful because the catalysts required cause polymerization. 

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,... 

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