Friedel-Crafts alkylation reaction limitations

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... 

The Friedel-Crafts alkylation reaction has some limitations. It cannot be applied to an aromatic ring that already has on it a nitro or sulfonic acid group, because these groups form complexes with and deactivate the aluminum chloride catalyst. 

A second limitation of the Friedel-Crafts alkylation reaction is the difficulty of stopping the reaction after the introduction of a single alkyl group. Alkyl groups make the benzene ring more reactive, so the alkylated product reacts more readily in subsequent substitution reactions than the original reactant. In contrast, Friedel-Crafts acylation yields a less reactive product than the original reactant and multiple acylations do not occur. 

The third limitation of Friedel-Crafts alkylation reaction is the structural rearrangement of the alkyl carbocation generated from the alkyl halide. A rearrangement of the alkyl group gives a different product than the one desired. For example, the reaction with 1-chloropropane in the presence of AlCl yields a small amount of propylbenzene, but a larger amount of the isomer, isopropylbenzene. 

As mentioned above, a range of enantioselective transformations have been established using chiral phosphoric acids via the activation of imines and related nitrogen-substituted substrates. In contrast, the activation of carbonyl compounds, including a,P-unsaturated carbonyl compounds, by chiral phosphoric acids has been limited. In 2008, Zhou, He, and coworkers achieved the asymmetric Friedel-Crafts alkylation reaction of indole derivatives with 1,3-diaryl a,p-unsaturated... 

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... 

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)... 

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. 

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. 

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. 

So far, most of the reactions presented in the book that are useful in synthesis have made C-O, C-N, or C-halogen bonds and only a few (Wittig, Friedel-Crafts, and reactions of cyanides and alkynes) make C-C bonds. This limitation has severely restricted the syntheses that we can discuss in this chapter. This is by design as we wanted to establish the idea of synthesis before coming to more complicated chemistry. The next four chapters introduce the main C-C bond-forming reactions in the chemistry of enols and enolates. You met these valuable intermediates in Chapter 21 but now you are about to see how they can be alkylated and acylated and how they add directly to aldehydes and ketones and how they do conjugate addition to unsaturated carbonyl compounds. Then in Chapter 30 we return to a more general discussion of synthesis and develop a new approach in the style of the last synthesis in this chapter. 

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]. 

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. 

When the Hammett plot bends the other way, so that the rate of the reaction decreases as it passes the discontinuity, we have a single mechanism with a change in rate-determining step. A reaction goes by the fastest possible mechanism but its rate is limited by the slowest of the steps in that mechanism. An example is the intramolecular Friedel-Crafts alkylation of a diphenyl derivative where the alkylating agent is a diaryhnethanol attached to one of the benzene rings in the ortho position. 

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