Friedel-Crafts alkylation and acylation

1 FRIEDEL-CRAFTS ALKYLATION AND ACYLATION (SEE ALSO SECTION 12.2.2) 

FIGURE 13.42 Friedel-Crafts reaction with ferf-butyl chloride. 

FIGURE 13.43 Alkylation of benzene using ferf-butanol. 

FIGURE 13.44 Friedel-Crafts acylation of a polycyclic compound. 

FIGURE 13.46 Gattermann-Koch formylation of benzene. PROBLEM 13.9 

In the previous sections, we saw how to install several different groups (Br, Cl, I, or NO2) on a benzene ring, using an electrophilic aromatic substitution. In each case, the meehanism was the same E on the ring, and then H off. In this section, we will learn how to install an alkyl group. 

Let s start with the simplest of aU alkyl groups a methyl group. So, the question is what reagents would we need to achieve the following transformation  

Using the logic that we have developed in this chapter, we would want to use CHs as our electrophile. But you should probably cringe when you see CHs . After all, you probably remember the trend in the stability of carbocations—that tertiary carboeations are more stable than secondary carbocations, and so on. Certainly a methyl carbocation would not be very stable at all. In fact, we deliberately avoid using methyl or primar y carbocations when drawing mechanisms. But here we are, trying to make a methyl carbocation. Is it even possible The answer is yes. In fact, we will make it using the same method we have used in the previous sections. 

If we take methyl chloride and we mix it with a pinch of AICI3, we wiU have a source of CH3+ CH3 

The truth is that we are NOT really forming a free methyl carbocation that can float off into solution. A free CH3 would be too imstable to form. So, instead, we must view this as a complex that can serve as a source of CH3+. 

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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)... 

An important difference between Friedel-Crafts alkylations and acylations is that acyl cations do not rearrange. The acyl group of the acyl chloride or acid anhydride is transfened to the benzene ring unchanged. The reason for this is that an acyl cation is so strongly stabilized by resonance that it is more stable than any ion that could conceivably arise from it by a hydride or alkyl group shift. 

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. 

Friedel-Crafts alkylations and acylations of N-arylamides also proceed normally. For example, benzoylation of acetanilide (iV-acetylaniline) under Friedel-Crafts conditions gives 4-aminobenzophenone in 80% yield after hydrolysis. 

These alkylation and acylation reactions are important because Friedel-Crafts alkylation and acylation (11-12, 11-14) cannot be applied to most nitrogen heterocycles. See also 13-15. 

Zinc chloride exchanged clay catalysts have been reported to be highly active for the Friedel-Crafts alkylation and acylation reactions these are commercially sold by Contract Catalysts under the name Envirocats. These are montmorillonite catalysts modified by ZnCU and FeCli. Some of the reported examples of Friedel-Crafts reactions are given below there are claims that some of the processes are commercially practised. 

Intermodular Alkylation by Carbocations. The formation of carbon-carbon bonds by electrophilic attack on the ir system is a very important reaction in aromatic chemistry, with both Friedel-Crafts alkylation and acylation following this pattern. These reactions are discussed in Chapter 11. There also are useful reactions in which carbon-carbon bond formation results from electrophilic attack by a carbocation on an alkene. The reaction of a carbocation with an alkene to form a new carbon-carbon bond is both kinetically accessible and thermodynamically favorable. 

Bismuth tra-tri lluoromcthancsulfonate, Bi(OTf)3, and BiCh were found to be effective catalysts for the Friedel-Crafts acylation of both activated and deactivated benzene derivatives such as fluorobenzene.19 Ga(III) triflate is also effective for Friedel-Crafts alkylation and acylation in alcohols and can tolerate water.20 This catalyst is water-stable... 

Near-critical water has been used as a medium for various C-C bond formation reactions including Friedel-Crafts alkylation and acylation (Eq. 7.12).30 In these reactions, near-critical water solubilizes the organics and acts as a source of both hydronium and hydroxide ions, thereby replacing the normally required hazardous solvents and catalysts that require subsequent neutralization and disposal. 

BF3 is an effective reagent for various kinds of reaction such as Friedel-Crafts alkylation and acylation reactions (Scheme 63),291 cyclization reactions, rearrangement,292 Diels-Alder reactions,293 and aldol reactions. 

It is well known (March, 1977) that an important synthetic application of Friedel Crafts alkylation and acylation is to effect ring closure. These reactions are most successful when 6-membered rings are formed, but 5- and 7-membered rings can be sythesised as well, although less readily. Quantitative data are not available, but the indication is strong that formation of... 

Particularly useful reactions resnlt from Friedel-Crafts alkylations and acylations, in which the... 

A 1 2 mixture of l-methyl-3-ethylimidazolium chloride and aluminum trichloride, an ionic liquid that melts below room temperature, has been recommended recently as solvent and catalyst for Friedel-Crafts alkylation and acylation reactions of aromatics (Boon et al., 1986), and as solvent for UV/Vis- and IR-spectroscopic investigations of transition metal halide complexes (Appleby et al., 1986). The corresponding 1-methyl-3-ethylimidazolium tetrachloroborate (as well as -butylpyridinium tetrachlo-roborate) represent new molten salt solvent systems, stable and liquid at room temperature (Williams et al., 1986). 

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). 

Tricarbonylcyclopentadienyl manganese undergoes Friedel-Crafts alkylation and acylation and sulfonation competition experiments 18) gave the reactivity order ferrocene >anisole>C5H5Mn(CO)3>C6H6, but again no comparative calculations of ring-electron densities are available. 

The importance of aluminum trichloride (and AlBr3 which is more soluble in hydrocarbons) as a catalyst, particularly for Friedel-Crafts alkylation and acylation of aromatic compounds,... 

A considerable difference between Friedel-Crafts alkylation and acylation is the amount of the Lewis acid necessary to induce the reaction. Friedel-Crafts alkylation requires the use of only catalytic amounts of the catalyst. Lewis acids, however, form complexes with the aromatic ketones, the products in Friedel-Crafts acylations, and the catalyst is thus continuously removed from the system as the reaction proceeds. To achieve complete conversion, therefore, it is necessary to use an equimolar amount of Lewis acid catalyst when the acylating agent is an acyl halide. Optimum yields can be obtained using a 1.1 molar excess of the catalyst. With... 

The mechanism of the chloromethylation reaction is related to that of Friedel-Crafts alkylation and acylation and probably involves an incipient chloro-methyl cation, CH2C1 ... 

Friedel-Crafts alkylation and acylation of aromatics A1C13, AlBr3... 

Study of the reactivity of aromatic C-H bonds in the presence of transition metal compounds began in the 1960s despite the quite early discovery of Friedel-Crafts alkylation and acylation reactions with Lewis acid catalysts. In 1967, we reported Pd(II)-mediated coupling of arenes with olefins in acetic acid under reflux [1], The reaction involves the electrophilic substitution of aromatic C-H bonds by a Pd(II) species, as shown in Scheme 2, and this is one of the earliest examples of aromatic C-H bond activation by transition metal compounds. Al-... 

The Friedel-Crafts alkylation and acylation are of very little, if any, synthetic interest when applied to heterocyclic aromatic bases the substitution of protonated heterocycles by nucleophilic carbon-centered radicals is instead successful. This reaction, because of the dominant polar effect which is mainly related to the charge-transfer character of the transition state (Scheme 1), reproduces most of the aspects of the Friedel-Crafts aromatic substitution, but reactivity and selectivity are the opposite. 

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