Friedel–Crafts alkylation

Friedel–Crafts alkylation involves the alkylation of an aromatic ring with an alkyl halide using a strong Lewis acid catalyst.^[6] With anhydrous ferric chloride as a catalyst, the alkyl group attaches at the former site of the chloride ion. The general mechanism is shown below.

This reaction suffers from the disadvantage that the product is more nucleophilic than the reactant. Consequently, overalkylation occurs. Furthermore, the reaction is only very useful for tertiary alkylating agents, some secondary alkylating agents, or ones that yield stabilized carbocations (e.g., benzylic ones). In the case of primary alkyl halides, the incipient carbocation (R⁽⁺⁾—X—Al^(-)Cl₃) will undergo a carbocation rearrangement reaction.

Steric hindrance can be exploited to limit the number of alkylations, as in the t-butylation of 1,4-dimethoxybenzene.

Alkylations are not limited to alkyl halides: Friedel–Crafts reactions are possible with any carbocationic intermediate such as those derived from alkenes and a protic acid, Lewis acid, enones, and epoxides. An example is the synthesis of neophyl chloride from benzene and methallyl chloride:

H₂C=C(CH₃)CH₂Cl + C₆H₆ → C₆H₅C(CH₃)₂CH₂Cl

Friedel–Crafts acylation

Friedel–Crafts acylation involves the acylation of aromatic rings. Typical acylating agents are acyl chlorides. Typical Lewis acid catalysts are acids and aluminium trichloride. Friedel–Crafts acylation is also possible with acid anhydrides.^[11] Reaction conditions are similar to the Friedel–Crafts alkylation. This reaction has several advantages over the alkylation reaction. Due to the electron-withdrawing effect of the carbonyl group, the ketone product is always less reactive than the original molecule, so multiple acylations do not occur. Also, there are no carbocation rearrangements, as the acylium ion is stabilized by a resonance structure in which the positive charge is on the oxygen.

The viability of the Friedel–Crafts acylation depends on the stability of the acyl chloride reagent. Formyl chloride, for example, is too unstable to be isolated. Thus, synthesis of benzaldehyde through the Friedel–Crafts pathway requires that formyl chloride be synthesized in situ. This is accomplished by the Gattermann-Koch reaction, accomplished by treating benzene with carbon monoxide and hydrogen chloride under high pressure, catalyzed by a mixture of aluminium chloride and cuprous chloride.

Reaction mechanism

The reaction proceeds through generation of an acylium center:

The reaction is completed by deprotonation of the arenium ion by AlCl₄⁻, regenerating the AlCl₃ catalyst:

If desired, the resulting ketone can be subsequently reduced to the corresponding alkane substituent by either Wolff–Kishner reduction or Clemmensen reduction. The net result is the same as the Friedel–Crafts alkylation except that rearrangement is not possible.