In Friedel-Crafts alkylation

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. 

Table 10.9. Substrate and Position Selectivity in Friedel-Crafts Alkylation Reactions...

Steric effects play a major role in determining the ortho para ratio in Friedel-Crafts alkylations. The amount of ortho substitution of toluene decreases as the size of the entering alkyl group increases along the series methyl, ethyl, /-propyl. No ortho product is found when the entering group is /-butyl. ... 

Ualike the multiple substitutions that often occur in Friedel-Crafts alkylations, acylations never occur more than once on a ring because the product acyl-benzene is less reactive than the nonacylated starting material. We ll account for this reactivity difference in the next section. 

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. 

Naphthalene and other fused ring compounds are so reactive that they react with the catalyst, and therefore tend to give poor yields in Friedel-Crafts alkylation. Heterocyclic rings are also tend to be poor substrates for the reaction. Although some furans and thiophenes have been alkylated, a true alkylation of a pyridine or a quinoline has never been described.However, alkylation of pyridine and other nitrogen heterocycles can be accomplished by a free radical (14-23) and by a nucleophilic method (13-15). 

From what has been said thus far, it is evident that the electrophile in Friedel-Crafts alkylation is a carbocation, at least in most cases. This is in accord with the knowledge that carbocations rearrange in the direction primary — secondary —> tertiary (see Chapter 18). In each case, the cation is formed from the attacking reagent and the catalyst. For the three most important types of reagent these reactions are... 

See Davister, M. Laszlo, P. Tetrahedron Lett., 1993, 34, 533 for examples of paradoxical selectivity in Friedel-Crafts alkylation. 

It is well known in the literature that aluminum chloride, a strong Lewis acid, is a very effective catalyst in Friedel-Crafts alkylations with silicon... 

The validity of Wheland intermediates such as (18) and (20) in Friedel-Crafts alkylation has been established by the actual isolation... 

Carbocations also feature as intermediates in electrophilic addition reactions (see Section 8.1) and in Friedel-Crafts alkylations (see Section 8.4.1). 

However, although we invoked a Lewis acid complex to provide the halonium electrophile, there is considerable evidence that, where appropriate, the electrophile in Friedel-Crafts alkylations is actually the dissociated carbocation itself. Of course, a simple methyl or ethyl cation is unlikely to be formed, so there we should assume a Lewis acid complex as the electrophilic species. On the other hand, if we can get a secondary or tertiary carbocation, then this is probably what happens. There are good stereochemical reasons why a secondary or tertiary complex cannot be attacked. Just as we saw with Sn2 reactions (see Section 6.1), if there is too much steric hindrance, then the reaction becomes SnI type. 

Here, the term no-solvent means the absence of a traditional solvent—the reactants are neat and may well be sohds. Where one reactant is in sufficiently large excess to qualify as a solvent, for example in Friedel-Crafts alkylations or acylations with excess benzene or toluene, the reactions are not normally classified as no-sol-vent. The phrase solid-phase (solid-state) reaction today often describes a reaction carried out on a solid phase, like a resin, to which the reaction intermediates are bound by adding reagents in solution. These reactions have become very important in combinatorial chemistry, but they do not meet the definition of no-solvent. The nosolvent reactions refer only to the primary reactions themselves and not to workup conditions which may or may not involve solvents (Dittmer, 1997). 

ZnCl2 supported in sol-gel-derived silica394 or aluminosilicates395 is effective in Friedel-Crafts alkylations. Significantly higher activities than over commercially available clayzic were observed, which were correlated with high total pore volume. 

Rearrangements of this type involving carbocation intermediates often occur in Friedel-Crafts alkylations with primary and secondary alkyl groups larger than C2 and C3. Related carbocation rearrangements are discussed in Sections 8-9B and 15-5E. 

Fujiwara et al.227 tested a nanocomposite material having Nafion immobilized in MCM-41 mesoporous silica in Friedel-Crafts alkylations with benzyl alcohol. Whereas Nafion-MCM-41 showed lower activity in the alkylation of toluene than 13% Nafion SAC-13 under identical conditions, it exhibited increased activity when used in the alkylation of para-xylene. 

The effective electrophiles in Friedel-Crafts alkylations are the species shown in Figure 5.26. 

Lewis acid complexes of alkyl halides and alkyl sulfonates (Figure 5.26, left) and proto-nated alcohols (Figure 5.26, middle) are additional reactive electrophiles in Friedel-Crafts alkylations. The aromatic compound displaces their respective leaving group in an SN2 process. This is in principle possible (Section 2.4.4) for primary or secondary alkylating agents and alcohols. 

Intramolecularly, certain secondary carbenium ions can be introduced without isomerization in Friedel-Crafts alkylations. An example is the last step in the bicyclization of Figure 3.56. 

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