12.15 Multiple Substituent Effects

1
12.15Multiple Substituent Effects
2
The Simplest Case

• all possible EAS sites may be equivalent

CH3
CCH3
AlCl3

CH3
99
3
Another Straightforward Case
CH3
Br
NO2
86-90

• directing effects of substituents reinforceeach
  other substitution takes place orthoto the
  methyl group and meta to the nitro group

4
Generalization

• regioselectivity is controlled by themost
  activating substituent

5
The Simplest Case

• all possible EAS sites may be equivalent

strongly activating
Br2
aceticacid
87
6
When activating effects are similar...
CH3
NO2
C(CH3)3
88

• substitution occurs ortho to the smaller group

7
Steric effects control regioselectivity
whenelectronic effects are similar
98

• position between two substituents is
  lastposition to be substituted

8
12.16Regioselective Synthesis of Disubstituted
Aromatic Compounds
9
Factors to Consider

• order of introduction of substituents to ensure
  correct orientation

10
Synthesis of m-Bromoacetophenone

• Which substituent should be introduced first?

11
Synthesis of m-Bromoacetophenone
para

• If bromine is introduced first,
  p-bromoacetophenone is major product.

meta
12
Synthesis of m-Bromoacetophenone
Br2
AlCl3
AlCl3
13
Factors to Consider

• order of introduction of substituents to ensure
  correct orientation
• Friedel-Crafts reactions (alkylation, acylation)
  cannot be carried out on strongly deactivated
  aromatics

14
Synthesis of m-Nitroacetophenone

• Which substituent should be introduced first?

15
Synthesis of m-Nitroacetophenone

• If NO2 is introduced first, the next step
  (Friedel-Crafts acylation) fails.

16
Synthesis of m-Nitroacetophenone
O2N
HNO3
H2SO4
AlCl3
17
Factors to Consider

• order of introduction of substituents to ensure
  correct orientation
• Friedel-Crafts reactions (alkylation, acylation)
  cannot be carried out on strongly deactivated
  aromatics
• sometimes electrophilic aromatic substitution
  must be combined with a functional group
  transformation

18
Synthesis of p-Nitrobenzoic Acid from Toluene

• Which first? (oxidation of methyl group or
  nitration of ring)

19
Synthesis of p-Nitrobenzoic Acid from Toluene
nitration givesm-nitrobenzoicacid
oxidation givesp-nitrobenzoicacid
20
Synthesis of p-Nitrobenzoic Acid from Toluene
HNO3
Na2Cr2O7, H2O H2SO4, heat
H2SO4
21
12.17Substitution in Naphthalene
22
Naphthalene
H
H
1
H
H
2
H
H
H
H

• two sites possible for electrophilicaromatic
  substitution
• all other sites at which substitution can
  occurare equivalent to 1 and 2

23
EAS in Naphthalene
AlCl3
90

• is faster at C-1 than at C-2

24
EAS in Naphthalene
E
E
H
H

• when attack is at C-1
• carbocation is stabilized by allylic resonance
• benzenoid character of other ring is maintained

25
EAS in Naphthalene
E
H

• when attack is at C-2
• in order for carbocation to be stabilized by
  allylic resonance, the benzenoid character of the
  other ring is sacrificed

26
12.18Substitution inHeterocyclic Aromatic
Compounds
27
Generalization

• There is none.
• There are so many different kinds of
  heterocyclicaromatic compounds that no
  generalizationis possible.
• Some heterocyclic aromatic compoundsare very
  reactive toward electrophilicaromatic
  substitution, others are very unreactive..

28
Pyridine

• Pyridine is very unreactive it
  resemblesnitrobenzene in its reactivity.
• Presence of electronegative atom (N) in
  ringcauses p electrons to be held more strongly
  thanin benzene.

29
Pyridine
SO3, H2SO4
HgSO4, 230C
71

• Pyridine can be sulfonated at high temperature.
• EAS takes place at C-3.

30
Pyrrole, Furan, and Thiophene

• Have 1 less ring atom than benzene or pyridine
  to hold same number of p electrons (6).
• p electrons are held less strongly.
• These compounds are relatively reactive toward
  EAS..

31
Example Furan
BF3

CCH3
O
O
75-92

• undergoes EAS readilyC-2 is most reactive
  position