16.3 Alkylation and Acylation of Aromatic Rings: The Friedel–Crafts Reaction

Friedel-Crafts reactions are key players in organic synthesis, allowing us to add alkyl or acyl groups to aromatic rings. These reactions use Lewis acid catalysts to create electrophiles that attack the ring, forming new carbon-carbon bonds.

Understanding the mechanisms and factors affecting Friedel-Crafts reactions is crucial. From regioselectivity to potential rearrangements, these reactions offer both challenges and opportunities for creating diverse aromatic compounds in the lab and in nature.

Friedel-Crafts Alkylation

Mechanism of Friedel-Crafts alkylation

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• Electrophilic aromatic substitution reaction introduces an alkyl group onto an aromatic ring
• Involves an alkyl halide (R-X) and an aromatic compound with a Lewis acid catalyst ($AlCl_3$)
• Lewis acid ($AlCl_3$) reacts with alkyl halide (R-X) forming a carbocation electrophile ($R^+$) and $AlCl_4^-$
• Electrophilic carbocation attacks the aromatic ring forming a resonance-stabilized arenium ion intermediate
• Proton loss from arenium ion restores aromaticity yielding the alkylated aromatic product
• Lewis acid catalyst generates the electrophilic carbocation species by reacting with the alkyl halide
• Catalyst serves as an electron pair acceptor stabilizing the arenium ion intermediate
• Rearrangement of carbocations can lead to a mixture of products (isomers)
• Multiple alkylations can occur resulting in polyalkylated products (xylenes)
• Intramolecular alkylation can form cyclic products (indanes)
• Deactivated aromatic rings with electron-withdrawing groups (nitrobenzene) are less reactive towards alkylation
• Regioselectivity of the reaction is influenced by the substituents on the aromatic ring

Comparison of Friedel-Crafts Alkylation and Acylation

Alkylation vs acylation in Friedel-Crafts

• Both are electrophilic aromatic substitution reactions requiring a Lewis acid catalyst ($AlCl_3$)
• Both involve the formation of a resonance-stabilized arenium ion intermediate
• Alkylation uses an alkyl halide (R-X) as the electrophile while acylation uses an acyl halide (RCO-X)
• Alkylation forms a new C-C single bond while acylation forms a new C-C(O) bond (ketone)
• Acylation is more selective and does not typically result in multiple substitutions or rearrangements
• Friedel-Crafts alkylation yields an alkylated aromatic compound (ethylbenzene)
• Friedel-Crafts acylation yields an aromatic ketone (acetophenone)

Biological Aromatic Alkylations

Biological aromatic alkylations

• Occur without the need for metal catalysts like $AlCl_3$
• Enzymes catalyze these reactions by:
  1. Activating the electrophile through the formation of reactive intermediates
  2. Stabilizing the transition state and arenium ion intermediate
  3. Providing a specific orientation for the substrates to facilitate the reaction
• Biosynthesis of vitamin K1 (phylloquinone) involves an aromatic alkylation step
• Catalyzed by the enzyme 1,4-dihydroxy-2-naphthoate prenyltransferase
• Alkylation of 1,4-dihydroxy-2-naphthoate with geranylgeranyl diphosphate (isoprenoid) forms 2-phytyl-1,4-naphthoquinone
• Enzyme active site facilitates the reaction by:
  • Binding and orienting the substrates for optimal reaction
  • Activating the isoprenoid electrophile through the formation of a carbocation intermediate
  • Stabilizing the arenium ion intermediate formed during the alkylation step

Factors Affecting Friedel-Crafts Reactions

Key considerations in Friedel-Crafts reactions

• Aromaticity of the substrate is crucial for the reaction to proceed
• Resonance stabilization of the arenium ion intermediate affects reaction rate and product distribution
• Carbocation rearrangement can occur, leading to unexpected products
• The nature of the electrophile (alkyl or acyl) influences reaction outcome and selectivity