Electrophilic Aromatic Substitution
Activating and Directing effects of substituents already on the ring
Products of Nitration
CH3 CH3
NO2
CH3
NO2
CH3
O2N
+ +HNO3
H2SO4
ortho meta para
63% 3% 34%
CN CN
NO2
CN
NO2
CN
O2N
+ +HNO3
H2SO4
17% 81% 2%
OH OH
NO2
OH
NO2
OH
O2N
+ +HNO3
H2SO4
50% 0% 50%
1 hr
48 hr
0.0003 hr
Mechanism of Electrophilic Aromatic Substitution
E
H
E
H
E
H
E+
E
H
GE
H
GE
H
GE
+G
With a substituent group G
Depending on the nature of the substituent, the substituent G may stabilize the carbocation intermediate and therefore speed the reaction, or it may raise the energy of the carbocation and slow the reaction. Substituents that make the ring react faster (than benzene) with electrophiles are called activators; those that make the ring react slower (than benzene) are called deactivators.
Substituent effects
• All activators also direct incoming electrophiles to the ortho- and the para-positions.
• Most deactivators direct incoming electrophiles to the meta position. The exceptions are the halogens, which are weakly deactivating yet ortho-para directing.
Classification of Substituents
H
F
Cl
Br
I
Benzene
o,p-directingdeactivators
o,p-directingactivators
Ar
R
NHCOCH3
OR NH2
OH
CHOCO2H
COR
O
CR
O
CN
SO3HNO2
NR3+
m-directingdeactivators
more activatingmore deactivating
Product Distribution in Nitration
(Percent %) (Percent %) X ortho meta para X ortho meta para
(meta-directing Deactivators) (ortho- and para-directing Deactivators)
-N(CH3)3 2 89 11 -F 13 1 86
-NO2 7 91 2 -Cl 35 1 64
-CO2H 22 77 2 -Br 43 1 56
-CN 17 81 2 -I 45 1 54
-CO2CH2CH3 28 72 2 (ortho- and para-directing Activators)
-COCH3 26 72 2 -CH3 63 3 34
-CHO 19 72 9 -OH 50 0 50
-NHCOCH3 19 2 79
o,p-Activators (alkyl & aryl groups)
p
m
o
E
E
E
CH3
CH3
HE
CH3
H
H
E
CH3
H
HE
CH3
H
E
CH3
HE
CH3
H
H
E
CH3
H
H
E
CH3H
E
CH3
H
H
E
CH3
H
CH3
3º, especially stable
3º, especially stable
o,p-Activators with a lp of electrons
OH
H
E
OH
H
H
E
OH
H
H
E
OHH
E
OH
HE
OH
HHE HE
OH
HE
OH
H
OH
OH
E
E
EHE
OH
H
E
OH
H
H
E
OH
H
E
OH
H
4 resonance forms
4 resonance forms
o-
m-
p-
o,p-Deactivators (Halogens)
Cl
H
E
ClH
E
ClH
E
ClH
E
H
E
Cl
HE
Cl
H
E
Cl
HE HE
Cl
HE
Cl
Cl
Cl
E
E
EHE
Cl
Cl
Cl
H
E
4 resonance forms
4 resonance forms
o-
m-
p-
meta-directing DeactivatorsCN
H
E
CNH
E
CNH
E
CN
H
E
CN
HE
CN
H
E
CN
HE
CN
HE
H
E
CN
HE
CN
CN
CN
E
E
E
Especially UNSTABLE**
Especially UNSTABLE**
o-
m-
p-
Additivity of substituent effects in disubstituted aromatic rings
• Rule 1: If the directing effects of two substituents reinforce each other, the predicted product predominates.
CH3
CO2H
CH3
CO2H
NO2HNO3
H2SO4
(o,p)
(m)
Additivity of substituent effects…
• Rule 2: If the directing effects of two substituents oppose each other, the more activating group dominates, but mixtures often result.
NH2
CH3
NH2
CH3
BrBr2
(FeBr3 catnot needed)
(o,p; STRONG activator)
(o,p; weak activator)
Additivity of substituent effects…
• Rule 3: Substitution almost never occurs between two substituents meta to each other.
CH3
Cl
CH3
SO3H
Cl
SO3
H2SO4
CH3
Cl
HO3S
CH3
Cl
SO3H
+
but not:
(o,p)
(o,p)
X (too crowded)
Additivity of substituent effects…
• Rule 4: With a bulky o,p- director and/or a bulky electrophile, para substitution predominates.
OCCH3
O
SO3H
OCCH3
O
SO3
H2SO4
(o,p; BULKY)
(HSO3+ is a
BULKY electrophile)
Mechanism
Halogenation of Benzene
Requires a Lewis acid catalyst
Reactivity: F2 >> Cl2 > Br2 >> I2
Catalyst
Mechanism (Cont’d)
Nitration of Benzene
Electrophile = NO2
⊕ (nitronium ion)
Mechanism
Sulfonation
r.d.s
repeat next slide
repeat
Sulfonation & Desulfonation-useful!
(heat)
Friedel–Crafts Alkylation
Electrophile = R⊕ (not vinyl or aryl)
R = 2o or 3o
Friedel–Crafts Acylation
Acyl group:
Electrophile is R–C≡O⊕ (acylium ion)
RX and Mechanism
Ch. 15 - 33
Acid chlorides (or acyl chlorides)
Prep
Ch. 15 - 35
(not formed)
Limitations of Friedel–Crafts Reactions
carbocations rearrangement
Ch. 15 - 36
1o cation (not stable)
Reason
3o cation
Ch. 15 - 3
Questions?
Problems: Friedel–Crafts alkylations, acylations, etc. with withdrawing groups & amines (basic)
generally give poor yieldsdeactivating gps
Basic amino groups (–NH2,–NHR, & –NR2) form
strong electron withdrawing gps with acids
Not Friedel-Crafts reactive
Another problem: polyalkylations can occur
More common with activated aromatic rings
Substituents effect reactivity & regiochemistry of substitution
Y = EDG (electron-donating group) or EWG (electron-withdrawing group)
possibilities
metam
parap
Ch. 15 - 50
Ring is electron poor; Ring reacts slower than benzene with E+
Ring is electron rich; Ring reacts faster than benzene with E+
relative to benzene
Reactivity towards electrophilic aromatic substitution
Ch. 15 - 57
Regiochemistry: directing effect
General aspects Either o-, p- directing or m-directing
Rate-determining-step: aromatic ring -electrons attacking the E
Ch. 15 - 59
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