Friedel-Crafts acylation electrophile formation

The synthesis of an alkylated aromatic compound 3 by reaction of an aromatic substrate 1 with an alkyl halide 2, catalyzed by a Lewis acid, is called the Friedel-Crafts alkylation This method is closely related to the Friedel-Crafts acylation. Instead of the alkyl halide, an alcohol or alkene can be used as reactant for the aromatic substrate under Friedel-Crafts conditions. The general principle is the intermediate formation of a carbenium ion species, which is capable of reacting as the electrophile in an electrophilic aromatic substitution reaction. 

Diels-Alder reaction, 493 El reaction, 391-392 ElcB reaction, 393 E2 reaction, 386 Edman degradation, 1032 electrophilic addition reaction, 147-148. 188-189 electrophilic aromatic substitution, 548-549 enamine formation, 713 enol formation, 843-844 ester hydrolysis, 809-811 ester reduction, 812 FAD reactions. 1134-1135 fat catabolism, 1133-1136 fat hydrolysis, 1130-1132 Fischer esterification reaction, 796 Friedel-Crafts acylation reaction, 557-558... 

A similar problem of complex formation may be encountered if either amino or phenol groups are present in the substrate, and the reaction may fail. Under such circumstances, these groups need to be blocked (protected) by making a suitable derivative. Nevertheless, Friedel-Crafts acylations tend to work very well and with good yields, uncomplicated by multiple acylations, since the acyl group introduced deactivates the ring towards further electrophilic substitution. This contrasts with Friedel-Crafts alkylations, where the alkyl substituents introduced activate the ring towards further substitution (see Section 8.4.3). 

In electrophilic catalysis, the metal ion acts as a Lewis acid. An example from organic chemistry is the formation of an acylium ion from aluminum chloride and an acid chloride in Friedel-Crafts acylation reactions (Figure 2). In this case substrate activation results in cleavage of the C—Cl bond. In most cases, however, substrate activation by Lewis acids involves electron redistribution without bond breaking (Figure 3). 

The reaction presented in this problem is known as a Friedel-Crafts acylation. Technically, this example belongs to a class of reactions referred to as electrophilic aromatic substitutions. Furthermore, the actual mechanism associated with this reaction, utilizing Lewis acid reagents as catalysts, proceeds through initial formation of an electrophilic acyl cation followed by reaction with an aromatic ring acting as a nucleophile. This mechanism, shown below, reflects distinct parallels to standard addition-elimination reaction mechanisms warranting introduction at this time. 

The acyl halides (RCOX) on treatment with anhydrous aluminium chloride (AICI3) give a complex, which decomposes to give acyl electrophile, an acylium ion (RCO+). Friedel-Crafts acylation of aromatic compounds involves the formation of a carbocation that acts as an electrophile (see section 2.1.3). 

Ferrocene reacts with acetyl chloride and aluminum chloride to afford the acylated product (287) (Scheme 84). The Friedel-Crafts acylation of (284) is about 3.3 x 10 times faster than that of benzene. Use of these conditions it is difficult to avoid the formation of a disubstituted product unless only a stoichiometric amount of AlCft is used. Thus, while the acyl substituent present in (287) is somewhat deactivating, the relative rate of acylation of (287) is still rapid (1.9 x 10 faster than benzene). Formation of the diacylated product may be avoided by use of acetic anhydride and BF3-Et20. Electrophilic substitution of (284) under Vilsmeyer formylation, Maimich aminomethylation, or acetoxymercuration conditions gives (288), (289), and (290/291), respectively, in good yields. Racemic amine (289) (also available in two steps from (287)) is readily resolved, providing the classic entry to enantiomerically pure ferrocene derivatives that possess central chirality and/or planar chirality. Friedel Crafts alkylation of (284) proceeds with the formation of a mixture of mono- and polyalkyl-substituted ferrocenes. The reaction of (284) with other... 

The formation of acylium ions by the fission of the hydroxyl group in strong acid provides a useful source of electrophilic carbon and this leads to an important series of methods for making C-C bonds (Scheme 3.59), similar to the Friedel-Crafts acylations based on acyl chlorides. The acylium ion obtains some stabilization from the lone pairs on the oxygen atom of the carbonyl group (see 3.23). 

By comparison with the reactions with aromatic substrates, the absence of the driving force of rearo-matization by proton loss in electrophilic acylations of alkenes leads to competition between alternative pathways for the carbocation intermediate. In particular, capture of halide to form 3-halo ketones can become dominant. Hence, the aliphatic Friedel-Crafts acylation reaction need not necessarily result in substitution of an acyl residue for a hydrogen atom in an alkene, nor in the formation of unsaturated ketones. Indeed, within this broader scope, acylations of alkynes and some classes of alkanes can be synthetically useful. 

The P-effect of silicon tends to direct the site of electrophilic attack on alkenylsilanes to the carbon bearing the silicon atom (Scheme 4). In comparison with a proton, the greater ease with which the tri-methylsilyl group is displaced from carbon leads more often to the formation of substitution products rather than those of addition. Thus vinyltrimethylsilane (b.p. 55 °C) is a convenient equivalent for ethylene in Friedel-Crafts acylations. The alkenyl ketone is formed directly, in contrast to the p-chloroethyl ketone formed in the acylation of ethylene. 

CAMEO failed to predict the formation of 2-benzoylthiophene (12) via Friedel-Crafts acylation of thiophene (13) with benzoyl chloride (14) in the presence of a Lewis acid (e.g., stannic chloride) using the Electrophilic Aromatic module. Thiophene is highly reactive under these conditions and would have been expected to undergo acylation readily, as previously reported (71) (Scheme 4). Instead, CAMEO predicted that stannic chloride (the catalyst) would replace a hydrogen in either the 2- or 3-position of... 

The hydroxylated anthraquinone chromophore of the anthracyclines would seem an ideal candidate for synthesis through two Friedel-Crafts acylations, either in a concurrent or a stepwise manner with formation of ring C. However, the fact that the first acylation deactivates the future ring B toward further electrophilic substitution necessitates vigorous reaction conditions, and this... 

Friedel-Crafts acylation is an electrophilic aromatic substitution with an acylium ion acting as the electrophile. Step I Formation of an acylium ion. 

Friedel-Crafts acylation (Scheme 6.2) is, in contrast to Friedel-Crafts alkylation, selective for the formation of monosubstituted ketones, which are deactivated for further electrophilic substitutions. 

Mechanism 18,7 Formation of the Electrophile in Friedel-Crafts Acylation... 

The mechanism of Friedel-Crafts acylation is believed to involve ratedetermining exo attack of the acylating species generating an intermediate 11, analogous to the Wheland intermediates generated during electrophilic substitution of arenes. Rapid loss of a proton from 11 results in formation of the neutral product 7. ... 

Reactions with Electrophiles. The structure of isoquinoline 1 is the result of fusing benzene and pyridine together. Electrophilic aromatic substitution predominately occurs on the benzene ring under acidic conditions and usually addition takes place at the 5-position but can sometimes add to the 8-position. The rate of electrophilic aromatic substitution is slower for isoquinoline compared to naphthalene. The nitrogen in isoquinoline reacts similar to a pyridine nitrogen and will add a variety of electrophilic species such as 0-(2,4-dinitrophenyl)hydroxylamine 2 to aminate the nitrogen (eq 1). Friedel-Crafts acylation and alkylation do not work due to the formation of IV-acyl or IV-alkyl isoquinolinium salts. 

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