Chem 335 - Winter 2002
Organic Chemistry II
Dr. Carl C. Wamser

Chapter 12 Notes - Aromatic Substitution

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
• acyl chlorides prepared from RCOOH + SOCl2

• Clemmensen reduction: Zn(Hg) / HCl - reduces C=O to CH2
• Wolff-Kishner reduction: NH2NH2 / KOH / 180° - reduces C=O to CH2
• acylation followed by reduction makes primary alkylbenzenes without rearrangement

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

• see Table 12.2
• 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)

Partial Rate Factors

• rate of reaction at one position relative to benzene
• activating and o,p-directing:
  CH3 : o= 42 , m = 2.5 , p = 58
• deactivating and m-directing:
  CF3 : o = 0.0000045 , m = 0.000067 , p = 0.0000045
• deactivating but o,p-directing:
  Cl : o = 0.029 , m = 0.0009 , p = 0.137

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
• note both substituents are m-directors

Synthesis Example

Substitution on Other Aromatic Systems

• naphthalene - 1-position (activated)
• furan, pyrrole, thiophene - 2-position (activated)
• pyridine - 3-position (deactivated)