Friedel-Crafts alkylation limitations

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... 

It IS sometimes difficult to limit Friedel-Crafts alkylation to monoalkylation... 

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)... 

Despite its utility, the Friedel-Crafts alkylation has several limitations. For one thing, only alkyl halides can be used. Aromatic (atyl) halides and vinylic halides do not react because aryl and vinylic carbocations are too high in energy to form 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. 

The Friedel-Crafts alkylation reaction does not proceed successfully with aromatic reactants having EWG substituents. Another limitation is that each alkyl group that is introduced increases the reactivity of the ring toward further substitution, so polyalkylation can be a problem. Polyalkylation can be minimized by using the aromatic... 

This involvement of carbocations actually limits the utility of Friedel-Crafts alkylations, because, as we have already noted with carbocations, rearrangement reactions complicate the anticipated outcome (see Section 6.4.2). For instance, when a Lewis acid... 

An amine group limits Friedel-Crcifts reactions because it reacts with the catalyst so the reaction can t proceed. Friedel-Crafts alkylation or acylation doesn t take place with groups more deactivating than halogen. 

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. 

Here we report the synthesis and catalytic application of a new porous clay heterostructure material derived from synthetic saponite as the layered host. Saponite is a tetrahedrally charged smectite clay wherein the aluminum substitutes for silicon in the tetrahedral sheet of the 2 1 layer lattice structure. In alumina - pillared form saponite is an effective solid acid catalyst [8-10], but its catalytic utility is limited in part by a pore structure in the micropore domain. The PCH form of saponite should be much more accessible for large molecule catalysis. Accordingly, Friedel-Crafts alkylation of bulky 2, 4-di-tert-butylphenol (DBP) (molecular size (A) 9.5x6.1x4.4) with cinnamyl alcohol to produce 6,8-di-tert-butyl-2, 3-dihydro[4H] benzopyran (molecular size (A) 13.5x7.9x 4.9) was used as a probe reaction for SAP-PCH. This large substrate reaction also was selected in part because only mesoporous molecular sieves are known to provide the accessible acid sites for catalysis [11]. Conventional zeolites and pillared clays are poor catalysts for this reaction because the reagents cannot readily access the small micropores. 

Limitations of the Friedel-Crafts Alkylation Although the Friedel-Crafts alkylation looks good in principle, it has three major limitations that severely restrict its use. 

Limitation 2 Like other carbocation reactions, the Friedel-Crafts alkylation is susceptible to carbocation rearrangements. As a result, only certain alkylbenzenes can be made using the Friedel-Crafts alkylation. fm-Butylbenzene, isopropylbenzene, and ethylbenzene can be synthesized using the Friedel-Crafts alkylation because the corresponding cations are not prone to rearrangement. Consider what happens, however, when we try to make n-propylbenzene by the Friedel-Crafts alkylation. 

Limitation 3 Because alkyl groups are activating substituents, the product of the Friedel-Crafts alkylation is more reactive than the starting material. Multiple alkylations are hard to avoid. This limitation can be severe. If we need to make ethylbenzene, we might try adding some A1C13 to a mixture of 1 mole of ethyl chloride and 1 mole of benzene. As some ethylbenzene is formed, however, it is activated, reacting even faster than benzene itself. The product is a mixture of some (ortho and para) diethylbenzenes, some triethylbenzenes, a small amount of ethylbenzene, and some leftover benzene. 

HPAs, however, is their solubility in polar solvents or reactants, such as water or ethanol, which severely limits their application as recyclable solid acid catalysts in the liquid phase. Nonetheless, they exhibit high thermal stability and have been applied in a variety of vapor phase processes for the production of petrochemicals, e.g. olefin hydration and reaction of acetic acid with ethylene [100, 101]. In order to overcome the problem of solubility in polar media, HPAs have been immobilized by occlusion in a silica matrix using the sol-gel technique [101]. For example, silica-occluded H3PW1204o was used as an insoluble solid acid catalyst in several liquid phase reactions such as ester hydrolysis, esterification, hydration and Friedel-Crafts alkylations [101]. HPAs have also been widely applied as catalysts in organic synthesis [102]. 

Within the limits imposed there exists a number of available procedures for introducing alkyl substituents onto the pyridine ring. All of these involve either nucleophilic or homolytic substitution since alkylation via electrophilic substitution, e.g. Friedel Crafts alkylation, is not possible with the TT-deficient pyridine nucleus. 

A third limitation to the Friedel-Crafts alkylation is that it s often difficult to stop the reaction after a single substitution. Once the first alkyl group is on the ring, a second substitution reaction is facilitated for reasons we ll discuss in the nc.xt section. Thus, we often observe polyalkylation. Reaction of benzene with 1 mol equivalent of 2-chloro-2-inethylpropane, for example, yieldsp-di-A"t-butvlbenzene as the major product, along with small amounts of fc//-butyl-benzene and unreacted benzene. A high yield of monoalkylation product is obtained only when a large excess of benzene is used. 

Another limitation of the Friedel-Crafts alkylation arises because of polyalkylation. Treatment of benzene with an alkyl halide and AICI3 places an electron-donor R group on the ring. Because R groups activate a ring, the alkylated product (CeHsR) is now more reactive than benzene itself towards further substitution, and it reacts again with RCl to give products of polyalkylation. 

We have encountered three limitations to the use of Friedel-Crafts alkylation (a) the danger of polysubstitution (b) the possibility that the alkyl group will rearrange and (c) the fact that aryl halides cannot take the place of alkyl halides. Besides these, there are several other limitations. 

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