16.7 Benzyne

Benzyne is a highly reactive intermediate formed from benzene derivatives. It's characterized by a strained triple bond between adjacent carbon atoms, making it unstable and eager to react with various compounds.

In nucleophilic aromatic substitution, benzyne plays a crucial role. Its unique structure allows it to undergo reactions with nucleophiles, forming substituted aromatic compounds that might be tricky to make through other methods.

Benzyne

Formation and structure of benzyne

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• Benzyne is a highly reactive intermediate formed from benzene derivatives
  • Commonly formed by elimination of two adjacent substituents from benzene ring (aryl halides, benzenediazonium salts)
  • Possesses a formal triple bond between two adjacent carbon atoms
    • Consists of one σ bond and two π bonds
    • Adopts a linear geometry with a bond angle of 180°
  • Exhibits significant ring strain and instability due to deviation from typical aromatic structure
    • Estimated strain energy of 63 kcal/mol compared to benzene
  • Behaves as an electrophile due to low-lying LUMO
    • Readily undergoes addition reactions with nucleophiles (amines, enolates)

Benzyne in nucleophilic aromatic substitution

• Benzyne undergoes nucleophilic aromatic substitution reactions ([object Object],[object Object]Ar) with various nucleophiles
  • Nucleophiles can be neutral (amines, alcohols) or anionic (enolates, alkoxides)
• Mechanism involves initial nucleophilic attack on benzyne
  • Nucleophile adds to the highly strained and electrophilic triple bond
  • Forms a negatively charged cyclohexadienyl anion intermediate
• Subsequent protonation of the cyclohexadienyl anion yields the substituted aromatic product
  • Proton source can be the solvent or an added acid
• Overall result is substitution of a hydrogen atom with the nucleophile
  • Provides access to substituted aromatic compounds that may be difficult to obtain through other methods (direct halogenation, Friedel-Crafts alkylation)

Regioselectivity of benzyne reactions

• Benzyne reactions with substituted arenes can lead to multiple isomeric products
  • Regioselectivity depends on the nature and position of substituents on the arene
• Electron-donating groups (EDG) on the arene direct nucleophilic attack to the ortho and para positions
  • Examples of EDGs include alkyl, alkoxy, and amino groups
  • EDGs increase electron density at ortho and para positions through resonance
  • Nucleophile preferentially attacks at these electron-rich positions (ortho-anisidine, para-toluidine)
• Electron-withdrawing groups (EWG) on the arene direct nucleophilic attack to the meta position
  • Examples of EWGs include nitro, cyano, and carbonyl groups
  • EWGs decrease electron density at ortho and para positions through resonance
  • Nucleophile preferentially attacks at the less deactivated meta position (meta-nitroaniline, meta-cyanoaniline)
• Steric effects can also influence regioselectivity
  • Bulky substituents on the arene may hinder nucleophilic attack at nearby positions (2,6-di-tert-butylaniline)
  • Nucleophile may preferentially attack at less hindered positions

Aromaticity and Reactivity

• Benzyne formation disrupts the aromaticity of the benzene ring
  • Loss of aromaticity contributes to the high reactivity of benzyne
• Resonance structures play a crucial role in understanding benzyne's reactivity
  • Resonance stabilization is reduced compared to benzene, increasing reactivity
• Benzyne acts as both an electrophile and a nucleophile in reactions
  • Its electrophilic nature allows it to react with nucleophiles
  • Its nucleophilic character enables reactions with electrophiles