1. Electrophilic Aromatic Substitution Multiple Substituent Effects: Activation-Deactivation / Direction (Regio-selectivity) 1

2. Activation & all possible sites are equivalent
The Simplest Case
Activation & all possible sites are equivalent
CH3 O
AlCl3
CH3COCCH3 +
CH3
CCH3
99% 2

3. Another Straightforward Case
CH3
NO2
CH3
NO2 Br
86-90%
Br2 Fe
directing effects of substituents reinforce each other; substitution takes place ortho to the methyl group and meta to the nitro group 2

4. regioselectivity is controlled by the most activating substituent
Generalization
regioselectivity is controlled by the most activating substituent 6

5. Question
Which positions are activated for chlorination on the compound shown below?
A) 2 and 3
B) 1 and 3
C) 2 and 4
D) 1 and 4

6. Example
strongly activating
NHCH3 Cl
Br2
87%
acetic acid
NHCH3 Cl Br 2

7. When activating effects are similar...
CH3
C(CH3)3
CH3
C(CH3)3
NO2
HNO3
H2SO4
88%
substitution occurs ortho to the smaller group 5

8. position between two substituents is last position to be substituted
Steric effects control regioselectivity when electronic effects are similar
CH3
HNO3
H2SO4
98%
NO2
CH3
position between two substituents is last position to be substituted 5

9. Question
Which compound undergoes electrophilic aromatic substitution with (CH3)3CCl and AlCl3 at the slowest rate (or not at all)?
A) B)
C) D)
CH3

10. Regioselective Synthesis of Disubstituted Aromatic Compounds7

11. Synthesis of m-Bromoacetophenone
Which substituent should be introduced first?
CCH3 O 8

12. Synthesis of m-Bromoacetophenone
para
If bromine is introduced first, p-bromoacetophenone is major product.
CCH3 O
meta 8

13. Synthesis of m-Bromoacetophenone
AlCl3
CCH3 O Br O
CH3COCCH3
CCH3 O
AlCl3 8

14. order of introduction of substituents to ensure correct orientation
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 6

15. Synthesis of m-Nitroacetophenone
Which substituent should be introduced first?
CCH3 O 8

16. Synthesis of m-Nitroacetophenone
If NO2 is introduced first, the next step (Friedel-Crafts acylation) fails.
CCH3 O 8

17. Synthesis of m-Nitroacetophenone
HNO3
H2SO4
CCH3 O
O2N O
CH3COCCH3
CCH3 O
AlCl3 8

18. order of introduction of substituents to ensure correct orientation
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 6

19. Question
Which of the following is the most reasonable way to begin an effective synthesis of the
compound shown?
A) Treat benzene with isopropyl chloride and AlCl3.
B) Treat chlorobenzene with propene and AlCl3.
C) Treat benzene with 2-chloropropene and AlCl3.
D) Treat benzene with 3-chloropropene and AlCl3.

20. Synthesis of p-Nitrobenzoic Acid from Toluene
CO2H
CH3
Which first? (oxidation of methyl group or nitration of ring)
NO2
CH3 8

21. Synthesis of p-Nitrobenzoic Acid from Toluene
CO2H
nitration gives m-nitrobenzoic acid
CH3
NO2
CH3
oxidation gives p-nitrobenzoic acid 8

22. Synthesis of p-Nitrobenzoic Acid from Toluene
NO2
CO2H
Na2Cr2O7, H2O
H2SO4, heat
CH3
NO2
CH3
HNO3
H2SO4 8

23. Substitution in Naphthalene1

24. two sites possible for electrophilic aromatic substitution
Naphthalene H H 1 H H 2 H H H H
two sites possible for electrophilic aromatic substitution
all other sites at which substitution can occur are equivalent to 1 and 2 2

25. is faster at C-1 than at C-2
EAS in Naphthalene
CCH3 O O
CH3CCl
AlCl3
90%
is faster at C-1 than at C-2 2

26. carbocation is stabilized by allylic resonance
EAS in Naphthalene E H E H + +
when attack is at C-1
carbocation is stabilized by allylic resonance
benzenoid character of other ring is maintained 2

27. EAS in Naphthalene E H + 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 2

28. Substitution in Heterocyclic Aromatic Compounds1

29. Generalization There is none.
There are so many different kinds of heterocyclic aromatic compounds that no generalization is possible.
Some heterocyclic aromatic compounds are very reactive toward electrophilic aromatic substitution, others are very unreactive.. 2

30. Pyridine N
Pyridine is very unreactive; it resembles nitrobenzene in its reactivity.
Presence of electronegative atom (N) in ring causes  electrons to be held more strongly than in benzene. 2

31. Pyridine can be sulfonated at high temperature.
SO3, H2SO4
SO3H N N
HgSO4, 230°C
71%
Pyridine can be sulfonated at high temperature.
EAS takes place at C-3. 2

32. Pyrrole, Furan, and Thiophene•• O •• S ••
Have 1 less ring atom than benzene or pyridine to hold same number of  electrons (6).
 electrons are held less strongly.
These compounds are relatively reactive toward EAS. 31

33. undergoes EAS readily C-2 is most reactive position
Example: Furan O
CH3COCCH3 O
BF3 +
CCH3 O O
75-92%
undergoes EAS readily C-2 is most reactive position 2