Substituted benzenes Friedel-Crafts electrophiles

Electrophilic substitution at carbon, in simple pyridines at least, is very difficult in contrast to the reactions of benzene - Friedel-Crafts acylations, for example, do not occur at all with pyridines. This unreactivity can be traced to two factors ... 

The iR NMR spectrum of pyrrole is slightly less convincing as the two types of proton on the ring resonate at higher field (6.5 and 6.2 ppm) than those of benzene or pyridine but they still fall in the aromatic rather than the alkene region. Pyrrole is also more reactive towards electrophiles than benzene or pyridine, but it does the usual aromatic substitution reactions (Friedel— Crafts, nitration, halogenation) rather than addition reactions pyrrole is also aromatic. 

The mechanism of each of the reactions in the synthesis of phenol from benzene and propene via cumene hydroperoxide requires some comment. The first reaction is a familiar one. The isopropyl cation generated by the reaction of propene with the acid (H3PO4) alkylates benzene in a typical Friedel-Crafts electrophilic aromatic substitution ... 

Representative Electrophilic Aromatic Substitution Reactions of Benzene 457 Mechanistic Principles of Electrophilic Aromatic Substitution 458 Nitration of Benzene 459 Sulfonation of Benzene 461 Halogenation of Benzene 462 Biosynthetic Halogenation 464 Friedel-Crafts Alkylation of Benzene Friedel-Crafts Acylation of Benzene Synthesis of Alkylbenzenes by Acylation-Reduction 469 Rate and Regioselectivity in Electrophilic Aromatic Substitution 470 Rate and Regioselectivity in the Nitration ofToluene 472... 

The most widely used reactions are those of electrophilic substitution, and under controlled conditions a maximum of three substituting groups, e.g. -NO2 (in the 1,3,5 positions) can be introduced by a nitric acid/sul-phuric acid mixture. Hot cone, sulphuric acid gives sulphonalion whilst halogens and a Lewis acid catalyst allow, e.g., chlorination or brom-ination. Other methods are required for introducing fluorine and iodine atoms. Benzene undergoes the Friedel-Crafts reaction. ... 

The nitration, sulphonation and Friedel-Crafts acylation of aromatic compounds (e.g. benzene) are typical examples of electrophilic aromatic substitution. 

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. 

Anthraquinone dyes are derived from several key compounds called dye intermediates, and the methods for preparing these key intermediates can be divided into two types (/) introduction of substituent(s) onto the anthraquinone nucleus, and (2) synthesis of an anthraquinone nucleus having the desired substituents, starting from benzene or naphthalene derivatives (nucleus synthesis). The principal reactions ate nitration and sulfonation, which are very important ia preparing a-substituted anthraquiaones by electrophilic substitution. Nucleus synthesis is important for the production of P-substituted anthraquiaones such as 2-methylanthraquiQone and 2-chloroanthraquiaone. Friedel-Crafts acylation usiag aluminum chloride is appHed for this purpose. Synthesis of quinizatia (1,4-dihydroxyanthraquiQone) is also important. 

Pyridine lies near one extreme in being far less reactive than benzene toward substitution by electrophilic reagents. In this respect it resembles strongly deactivated aromatic compounds such as nitrobenzene. It is incapable of being acylated or alkylated under Friedel-Crafts conditions, but can be sulfonated at high temperature. Electrophilic substitution in pyridine, when it does occur, takes place at C-3. 

The most notable chemistry of the biscylopen-tadienyls results from the aromaticity of the cyclopentadienyl rings. This is now far too extensively documented to be described in full but an outline of some of its manifestations is in Fig. 25.14. Ferrocene resists catalytic hydrogenation and does not undergo the typical reactions of conjugated dienes, such as the Diels-Alder reaction. Nor are direct nitration and halogenation possible because of oxidation to the ferricinium ion. However, Friedel-Crafts acylation as well as alkylation and metallation reactions, are readily effected. Indeed, electrophilic substitution of ferrocene occurs with such facility compared to, say, benzene (3 x 10 faster) that some explanation is called for. It has been suggested that. 

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... 

Another drawback to the use of amino-substituted benzenes in electrophilic aromatic substitution reactions is that Friedel-Crafts reactions are not successful (Section 16.3). The amino group forms an acid-base complex with the AICI3 catalyst, which prevents further reaction from occurring. Both drawbacks can be overcome, however, b3 carrying out electrophilic aromatic substitution reactions on the corresponding amide rather than on the free amine. 

Unlike benzene, pyridine undergoes electrophilic aromatic substitution reactions with great difficulty. Halogenation can be carried out under drastic conditions, but nitration occurs in very low yield, and Friedel-Crafts reactions are not successful. Reactions usually give the 3-substituted product. 

Friedel-Crafts-type polyalkylations of alkyl-substituted benzenes with Ic become less difficult as the number of electron-donating methyl groups on the benzene ring increases. This is consistent with the fact that the alkylation occurs via an electrophilic substitution. The tendency of starting methylbenzenes to form rearranged products also increases in the same order from toluene to mesitylene. 

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... 

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. 

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. 

Substituents on the benzene rings exert their usual influence on the orientation and ease of electrophilic substitution reactions. For example, further nitration (HN03-H2S04-S03) of nitroquino-lines occurs meta to the nitro group as shown in diagrams (593) and (594). Friedel-Crafts acylation of 8-methoxyquinoline succeeds (cf. 595) although this reaction fails with quinoline itself. 

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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