Benzene derivatives Friedel-Crafts acylation

Friedel-Crafts Acylation of Aromatic Rings In the presence of aluminum chloride, acyl halides acylate benzene, halobenzenes, and activated benzene derivatives. Friedel-Crafts acylation is discussed in detail in Section 17-11. 

Friedel-Crafts Acylation. The Friedel-Crafts acylation procedure is the most important method for preparing aromatic ketones and thein derivatives. Acetyl chloride (acetic anhydride) reacts with benzene ia the presence of aluminum chloride or acid catalysts to produce acetophenone [98-86-2], CgHgO (1-phenylethanone). Benzene can also be condensed with dicarboxyHc acid anhydrides to yield benzoyl derivatives of carboxyHc acids. These benzoyl derivatives are often used for constmcting polycycHc molecules (Haworth reaction). For example, benzene reacts with succinic anhydride ia the presence of aluminum chloride to produce P-benzoylpropionic acid [2051-95-8] which is converted iato a-tetralone [529-34-0] (30). 

Anthraquinone dyes are derived from several key compounds called dye intermediates, and the methods for preparing these key intermediates can be divided into two types (/) introduction of substituent(s) onto the anthraquinone nucleus, and (2) synthesis of an anthraquinone nucleus having the desired substituents, starting from benzene or naphthalene derivatives (nucleus synthesis). The principal reactions ate nitration and sulfonation, which are very important ia preparing a-substituted anthraquiaones by electrophilic substitution. Nucleus synthesis is important for the production of P-substituted anthraquiaones such as 2-methylanthraquiQone and 2-chloroanthraquiaone. Friedel-Crafts acylation usiag aluminum chloride is appHed for this purpose. Synthesis of quinizatia (1,4-dihydroxyanthraquiQone) is also important. 

Partial rate factors may be used to estimate product distributions in disubstituted benzene derivatives. The reactivity of a particular position in o-bromotoluene, for example, is given by the product of the partial rate factors for the corresponding position in toluene and bromobenzene. On the basis of the partial rate factor data given here for Friedel-Crafts acylation, predict the major product of the reaction of o-bromotoluene with acetyl chloride and aluminum chloride. 

As in the alkylation reaction, the reactive intermediate in Friedel-Crafts acylation can be a dissociated acylium ion or a complex of the acid chloride and Lewis acyl.49 Recent mechanistic studies have indicated that with benzene and slightly deactivated derivatives, it is the protonated acylium ion that is the kinetically dominant electrophile.50... 

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... 

In-situ IR-spectroscopic characterization of the Friedel-Crafts acylation of benzene in ionic liquids derived from AICI3 and FeCl3 showed that the mechanism of the reaction in ionic liquids was the same as that in 1,2-dichloroethane (128). The immobilization of ferric chloride-containing ionic liquid onto solid supports (e.g., silica and carbon) however failed to catalyze the acylation reaction, because leaching was a serious problem. When the reaction was carried out with gas-phase reactants, catalyst deactivation was observed. 

Nitration of coumarin gives the 6-nitro derivative and a small amount of 8-nitrocoumarin. Similarly, Friedel-Crafts acylation and sulfonation give 6-substitution but in the presence of a hydroxyl group in the benzene ring, the incoming group usually enters a position ortho to it. 

Substrates of Friedel-Crafts acylations are benzene and naphthalene, as well as their halogen, alkyl, aryl, alkoxy, or acylamino derivatives. Acceptor-substituted aromatic compounds are inert. Because Friedel-Crafts acylations introduce an acceptor into the aromatic substrate, no multiple substitutions take place. This distinguishes them from Friedel-Crafts alkylations. Free OH and NH2 groups in the aromatic compound prevent Friedel-Crafts acylations because they themselves are acylated. However, the O-acylphenols available in this way can later be rearranged with A1C1, into orf/zo-acylated isomers (Fries rearrangement). 

In the presence of aluminum chloride, an acyl chloride reacts with benzene (or an activated benzene derivative) to give a phenyl ketone an acylbenzene. The Friedel-Crafts acylation is analogous to the Friedel-Crafts alkylation, except that the reagent is an acyl chloride instead of an alkyl halide and the product is an acylbenzene (a phenone ) instead of an alkylbenzene. 

The mechanism of Friedel-Crafts acylation (shown next) resembles that for alkylation, except that the electrophile is a resonance-stabilized acylium ion. The acylium ion reacts with benzene or an activated benzene derivative via an electrophilic aromatic substitution to form an acylbenzene. 

The Gatterman-Koch synthesis is a variant of the Friedel-Crafts acylation in which carbon monoxide and HC1 generate an intermediate that reacts like formyl chloride. Like Friedel-Crafts reactions, the Gatterman-Koch formylation succeeds only with benzene and activated benzene derivatives. 

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... 

However, in contrast to benzene, ferrocene is sensitive to oxidation, and the ferrocenium cation, FeCpj, a paramagnetic 17-electron species, is readily formed in the presence of various oxidants. The ferrocenium cation is reluctant to undergo electrophilic substitution, and therefore reactions such as halogenation and nitration, which are important routes to substituted benzene derivatives, cannot be used for the synthesis of substituted ferrocenes. Only electrophilic substitution under nonoxidizing conditions (e.g., Friedel-Crafts acylation, Mannich reaction, borylation, lithiation or mercuration), and radical substitution are available as an entry into the chemistry of substituted ferrocenes. 

Instead, these heterocycles and their derivatives most commonly undergo electrophilic substitution nitration, sulfonation, halogenation. Friedel-Crafts acylation, even the Reimer-Tiemann reaction and coupling with diazonium salts. Heats of combustion indicate resonance stabilization to the extent of 22-28 kcal/ mole somewhat less than the resonance energy of benzene (36 kcal/mde), but much greater than that of most conjugateci dienes (about Tlccal/mole). On the basis of these properties, pyrrole, furan, and thiophene must be considered aromatic. Clearly, formulas I, II, and III do not adequately represent the structures of these compounds. 

Like other aromatic compounds, these five-membered heterocycles undergJ nitration, halogenation, sulfonation, and Friedel-Crafts acylation. They are mucji more reactive than benzene, and resemble the most reactive benzene derivatives (amines and phenols) in undergoing such reactions as the Reimer-Tiemann reaction, nitrosation, and coupling with diazonium salts. 

Essentially every analog and derivative prepared in the project was ultimately derived from the corresponding 3-chloro-pyri-dazine. With the exception of a few 3-chloropyridazines which originated from a Friedel-Crafts acylation of benzene, the large majority of chloropyridazines were prepared by a sequence based on the addition of the masked acyl anion equivalent of a benzaldehyde to the appropriately substituted acrylate ester. 

A Acetophenone derivatives can be prepared from benzene by a Friedel-Crafts acylation. The derived oxime, formed using hydrox-ylamine, undergoes a Beckmann rearrangement to produce the amide hydrolysis yields the amine (Scheme 8.4). 

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