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Reactions of Aromatic Compounds (overall)

Friedel-Crafts Acylation

Friedel-Crafts acylation is, to a greater extent, in accordance with Friedel-Crafts alkylation. Similar to Friedel-Crafts alyklation, it is a method of introducing carbon side chains into aromatic compounds through electrophilic aromatic substitution. However, the electrophilic reagent is not an alkyl halide but an acyl halide or a carboxylic acid anhydride. In these reagents, the carbonyl carbon is the electrophilic center, which is attacked by the aromatic π electrons. As a result, Friedel-Crafts acylation yields an aromatic ketone. In order to obtain a satisfactory reaction rate, a Lewis acid catalyst, such as AlCl3, must be applied in Friedel-Crafts acylation, as well. The Lewis acid and the acyl halide yield a polarized complex. The electrophile that actually reacts may be the polarized complex or a resonance-stabilized acylium ion, which is formed through dissociation of the polarized complex.

Fig.1
Formation of the polarized complex and the acylium ion.
Fig.2
Formation of the polarized complex and the acylium ion illustrated by electrostatic potential surfaces.

Results of a semiempirical-quantum-mechanical calculation of the reaction between acetyl chloride and AlCl3 (red means a more negative potential, blue means a more positive potential).

In contrast to Friedel-Crafts alkylation, the acylated aromatic compound, which is formed by Friedel-Crafts acylation, is also complexed by the Lewis acid. Thus, the Lewis acid is not available for a further Friedel-Crafts acylation. The Lewis acid catalyst must therefore be applied in stoichiometric amounts. The aromatic ketone is released from its complex with the Lewis acid by working up with water.

Fig.3
Friedel-Crafts acylation by an attack on an acylium ion.

Analogous to Friedel-Crafts alyklation, the transition state's energy and, thus, the activation energy in Friedel-Crafts acylation decrease with an increase in the strength of the interaction between the aromatic compound's HOMO and the acyl halide's LUMO. The interaction is all the more stronger the smaller the energy difference between the frontier molecular orbitals (HOMO / LUMO) is. The energy of the acyl halide's LUMO is considerably decreased by complexation with a Lewis acid. As a result, it approaches the energy of the aromatic compound's HOMO. Consequently, the transition state's energy and, thus, the activation energy are reduced. In other words, the reaction is noticeably speeded up through the application of a Lewis acid catalyst.

The acylium ion is much more reactive than the two possible polarized complexes, as its LUMO energy is considerably lower and closer to the aromatic compound's HOMO energy. The LUMO energies of the two alternative polarized complexes do not dramatically differ. However, the complexation of the acyl halide's carbonyl oxygen influences the extent to which the LUMO's energy is decreased much more than the complexation of the acyl halide's halogen does.

Fig.4
HOMO - LUMO energy diagram.
Hint
N O T E ! The relatively low energy of the acylium ion's LUMO does not mean that the Friedel-Crafts acylation always consistently proceeds via an acylium ion. Compared to the polarized complexes, the acylium ion is, namely, an extremely energy-rich species, which is generated only in miniscule amounts.

One variation of Friedel-Crafts acylation is the application of a carboxylic acid, or a carboxylic acid anhydride which has been protonated by a mineral acid. The cations that are produced by the protonation react analogously to the polarized Lewis acid-acyl halide complexes.

Fig.5
Protonation of carboxylic acids and their anhydrides.

Compared to Friedel-Crafts alkylation, the acylation seems to have some advantages. In contrast to the activating alkylation, the aromatic compound is deactivated for further electrophilic aromatic substitution by an acylation. Thus, multiple Friedel-Crafts acylations usually do not occur. Isomerization, which is undesirable in Friedel-Crafts alkylation, does not occur with acyl substituents. Aromatic compounds with terminal linear alkyl substituents that cannot be produced through Friedel-Crafts alkylation may, therefore, be synthesized through Friedel-Crafts acylation and a subsequent reduction of the carbonyl group.

Fig.6
Alkylation by acylation and subsequent Clemmensen reduction.

Practically speaking, a Friedel-Crafts formylation is extremely difficult to manage because of the high instability of the electrophilic reagent that is required, such as, for example formyl chloride or formic anhydride. The formylation of benzene and alkylbenzenes may be achieved by the Gattermann-Koch reaction with CO / HCl / AlCl3 / CuCl instead. The Gattermann-Koch reaction does not function with phenols, phenolethers and especially not with benzene derivatives that contain meta-directing substituents. Another alternative formylation method that is suitable for activated aromatic compounds, such as aniline and phenol derivatives, is the Vilsmeier-Haack synthesis, which is carried out in a mixture of dimethylformamide (DMF) and phosphoryl chloride (POCl3).

Fig.7
Gattermann-Koch formylation.

Some acylium ions are relatively easily decarbonylated if the resulting carbenium ion is considerably stabilized. In such cases, treating an aromatic compound with an acyl halide and a Lewis acid does not lead to a Friedel-Crafts acylation. Rather, the aromatic compound is alkylated by the carbenium ion that has been formed by the acylium ion's decarbonylation.

Fig.8
Decarbonylation and subsequent alkylation.

Similar to the Friedel-Crafts alkylation, the Friedel-Crafts acylation is prevented by electron-withdrawing, deactivating substituents in the aromatic starting product. Furthermore, in the case of OH- and NH2-substituted aromatic compounds, it is not the aromatic ring that is acylated, but the substituent. However, the resulting phenolic esters may subsequently be converted into o- and p-acylphenols, respectively, through treatment with a Lewis acid, such as AlCl3. In this so-called Fries rearrangement, the o/p ratio can often be accordingly controlled by the reaction conditions. In this case, one of the isomers would then predominate. The Fries rearrangement is a Lewis acid-catalyzed isomerization.

Fig.9
Fries rearrangement of phenolic esters.
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