1. ELECTROPHILIC ATTACK ON
DERIVATIVES OF BENZENE
What are the effects of the substituent?
a. Reactivity of the benzene ring
b. Regiochemistry of EAS: ortho, meta, para
R
E+
?

2. Donors and Acceptors
Donors
activate
Acceptors
deactivate
Activators: Direct
electrophilic attack
to the ortho and
para positions
Deactivators: Direct
electrophilic attack to
the meta positions

3. Induction and Resonance
Inductive effect:
-Occurs through the
σ framework
- Tapers off rapidly
with distance
-Governed by
electronegativity of
atoms and resulting
polarization of bonds
Both can operate, not always in the same direction

4. Resonance effect:
-Takes place through
π bonds
-Longer range
-Strong in charged
systems

5. Benzene Methylbenzene Benzenamine Nitrobenzene
(Toluene) (Aniline)
Electrostatic Potentials

6. A. Induction
Same results with HNO3, SO3, Friedel-Crafts
reagents: Mainly ortho (less, because of sterics)
and para substitution. Why?
1. Donors: R = alkyl, activate by hyperconjugation,
ortho/para directing
Faster than
benzene
No further bromination, because Br deactivates

7. Mechanism:
Steric effect larger with large alkyl group: tert-Bu gives only para

8. Friedel-Crafts reagents too slow, only the strongest
E+ work. Why meta?
2. Acceptors: R = -CF3, -CCl3, -
C(OR)3, deactivate by electronegativity, meta
directing
Slower than
benzene

9. Mechanism:

10. B. Resonance
1. Donors: R = -NH2, -NR’R”, -NHCR’, -OR,
activate by resonating lone pairs, ortho/para-
directing, do not need catalyst
O
Why ortho/para? Resonance > induction

11. Mechanism:
EASNH2

12. Br2, Friedel-Crafts reagents too slow. Why meta?
2. Acceptors: R = COOH, CR, NO2 ,SO3H,
C N, deactivate by resonance, meta-directing
O

13. Mechanism:
EASCO2H

14. 3. Exception: R = X (halogen), deactivate (slightly)
by electronegativity, inductive > resonance, but
nevertheless ortho/para-directing!
Why?

15. Mechanism:

16. Summary of Substituent Effects

17. Summary of Relative Rates

18. Disubstituted Benzenes-
Higher Substitution
R'
R"
R'
R"
Substituent Effects are Additive
R'
R"
EASCO2HEASNH2

19. The Strongest Activator Wins
GUIDELINE 1.
The most powerful activator controls the position of attack
GUIDELINE 2.
Three classes of substituents in the order of
diminishing control when in competition:
1. Resonance activators are best NR2, OR;
2. Halogens X and inductive activators, such as R
3. Deactivators CO2R < CF3 < NO2

20. When there is competition for regioselectivity
between members of each group, difficult to
predict (unless they both point to the same
position): Need to look up tables.
NHC6H5 ~ 106

21. GUIDELINE 3.
When product mixtures are predicted on the basis of
guidelines 1 and 2, products from ortho attack to
bulky groups or between two substituents are disfavored
(dashed lines): Sterics!

22. GUIDELINE 4.
Guidelines 1 through 3 apply to even more highly
substituted benzenes. Note: Higher substitution in the
starting material reduces the number of possible products.
Problem:
OCH3
C(CH3)3
F3C
HNO3, H2SO4
?

23. OCH3
C(CH3)3
F3C
HNO3, H2SO4
OCH3
C(CH3)3
F3C
NO2
Answer:

24. 1. NO2 NH2
Reduction: Zn(Hg), HCl; or H2, Ni; or Fe, HCl
O
Oxidation: CF3 COOH
Strategies in EAS
We can change the sense of the
directing power of substituents
(meta
director)
(ortho/para
director)
Reduction
Oxidation

25. Examples:
Retrosynthesis: Think of N substituent as NO2

26. 2. –CR -CH2R
Reducing agents:
H2, Pd, CH3CH2OH (hydrogenates carbonyl to
alcohol, then cleaves the benzylic OH) or
Clemmensen Reduction Zn(Hg), HCl, Δ
Oxidizing agents:
CrO3, H2SO4, H2O
O
(meta
director)
(ortho/para
director)
Reduction
Oxidation

27. Direct butylation gives (1-methylpropyl)benzene (sec-butylbenzene) and overalkylation.

28. 3. Friedel-Crafts reactions do not
work with strongly deactivated
benzenes
Consider making 1-(3-nitrophenyl)ethanone:

29. 4. Use reversible sulfonation for
blocking certain positions

30. 5. Protection of NH2 and OH functions
NH2 is quite basic, interferes with electrophiles; OH is
quite acidic, interferes with bases (organometallics).
OH
Phenol
NaOH, CH3I
conc. HI
OCH3
Methoxybenzene
Protection
Protection
Deprotection
Deprotection

31. 6. EAS in polycyclic benzenoids: An
exercise in resonance.
Example: Naphthalene
The molecule is
activated and
selective for attack
at C1:
?
Why?

32. Let us look at resonance in the
respective intermediate cations:
Two resonance forms with
intact benzene rings
Attack at C1
Three resonance forms with
disrupted cyclic conjugation

33. Attact at C2
Only one resonance form with an intact benzene ring
10 : 1

34. EAS on Substituted Naphthalenes
A. Activators:
-Direct
electrophile to
the same ring
-Ortho/para
Example:

35. B. Deactivators:
-Direct electrophile away (to other ring) and
to α- positions (C5 and C8)
For other benzenoid systems: Always write out the complete
set of resonance forms at all possible unique positions.
Sterics