Chem 336 - Spring 1999 - Organic Chemistry III
Portland State University - Dr. Carl C. Wamser

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Chapter 20 - Aromatic Substitution Reactions

Electrophilic Aromatic Substitution

• benzene can be made to react with very strong electrophiles (E+)
• intermediate is a carbocation
  (like addition to one of the pi bonds)
• nucleophiles don't add to the cation
  (H+ leaves, regenerates benzene ring)
• reaction is substitution (E+ for H+)

Mechanism of Aromatic Substitution



Mechanism - why slower than alkenes ?

• Ea for electrophilic attack on benzene is greater than Ea for electrophilic attack on an alkene
• although the cation intermediate is delocalized and more stable than an alkyl cation, benzene is much more stable than an alkene

Mechanism - why substitution ?

• the substitution product regains the aromatic stability
• an addition product would be a conjugated diene, not as stable

Bromination of Benzene

• electrophile is Br+
• generated from Br2 + FeBr3

Chlorination of Benzene

• electrophile is Cl+
• generated from Cl2 + FeCl3

Nitration of Benzene

• electrophile is NO2+
• generated from H2SO4 + HNO3

Sulfonation of Benzene

• electrophile is HSO3+
• generated from H2SO4 + SO3

Friedel-Crafts Alkylation

• electrophile is an alkyl cation (R+)
• generated from RCl + AlCl3

• limitations of the Friedel-Crafts reaction
  • cation rearrangements may occur
  • doesn't work with deactivated aromatic rings
• extensions of the Friedel-Crafts reaction
  • other sources of cations, e.g., alkene + H+

Friedel-Crafts Acylation

• electrophile is an acyl cation (RCO+)
• generated from RCOCl + AlCl3

Substituent Effects

• substituents on the benzene ring can affect the reaction in two ways:
  reactivity - substituted benzene may react faster or slower than benzene itself reacts
  orientation - the new group may be oriented ortho, meta, or para with respect to the original substituent

Reactivity Effects

• activating - reaction is faster
  observed with electron-donating groups that make the ring more electron-rich
• deactivating - reaction is slower
  observed with electron-withdrawing groups that make the ring less electron-rich

Orientation Effects

• substituent already present on the benzene ring determines the location of the new group
• ortho,para-directors: electron-donating groups direct the new group mainly to ortho & para
• meta-directors: electron-withdrawing groups direct new group mainly meta

Ortho, Para Directors

• the best cation is formed when the electrophile adds either ortho or para
  (better than unsubstituted)

Meta Directors

• the best cation is formed when the electrophile adds meta
  (but this is worse than unsubstituted)

Classifying Substituents

• activating and o,p-directing:
  alkyl, aryl, O and N groups
• deactivating and m-directing:
  N+ groups, polar multiple bonds
• deactivating but o,p-directing:
  the halogens (F, Cl, Br, I)
  (electron-withdrawing atoms, but lone pairs can stabilize the cation when it is ortho or para)

Synthetic Strategy

• synthesis of complex compounds requires attention to the order in which groups are attached
• retrosynthetic analysis - think backwards one step at a time
  (What reaction could have made this target compound?)

Synthesis Example

• target compound: p-nitrobenzoic acid

Synthesis Example

Nucleophilic Aromatic Substitution - Benzyne (Elimination/Addition)

• elimination from an aryl halide with a very strong base (usually NaNH2 in NH3)
• intermediate is benzyne, highly reactive
• benzyne adds nucleophiles, e.g., NH3
• note different substitution patterns that can result

Nucleophilic Aromatic Substitution - Anion Intermediate (Addition/Elimination)

• addition of nucleophile to an aryl halide ( at the ipso position )
• intermediate is a delocalized anion, analogous to the cation in electrophilc substitution
• usually workls only with strong electron-withdrawing groups ortho & para (e.g., nitro)
• loss of leaving group returns the aromaticity