Chemistry of Aromatic
Compounds
Electrophilic Aromatic Substitution
Directing Effects
Side-chain Reactions
Synthesis
Nucleophilic Aromatic Substitution
Electrophilic Aromatic
Substitution
E
H
E
H
:base
E
+ H-base
EAS Reactions of Benzene
NO2
CHO
Cl
O
CR
Br
R
I
SO3H
Bromination / Chlorination
H
Br 2, FeBr 3
Br
+ HBr
H
Cl2, FeCl3
Cl
+ HCl
Bromination Mechanism
Reaction Profile
Nitration
NO2
+ H2O
HNO3, H2SO4
Formation of electrophile
HNO3 + H2SO4
+
-
NO2 + H2O + HSO4
Nitration Mechanism
Nitration of Toluene
Sulfonation is Reversible
H
fuming sulfuric acid
SO3, H2SO4
O
S
O
O
H OSO3H
SO3H
H
OSO3H
SO3H
Desulfonation
Friedel-Crafts Acylation
O
O
RCCl, AlCl 3
C
R
+ HCl
1st, Formaton of Electrophile
O
C
R
O
+

Cl

AlCl 3
C
R
R
acylium ion
C O
AlCl 4
Acylation Mechanism
O
C
R
O
C
H
R
Cl
AlCl3
O
C
R + HCl
Intermediate is
Resonance-Stabilized
O
O
O
C
C
C
H
R
H
R
H
R
An Acylation
CH3
O
CH3
CCH2CH2CH2CH3
CH3CH2CH2CH2CCl
+ HCl
TiCl 4 in CH 2Cl2
CH3
O
CH3
Friedel-Crafts Alkylation
many more limitations
RX, AlCl 3
R
+ HCl
Mechanism
CH3
CH3 C
CH3
Cl
AlCl 3
CH3 C
CH3
CH3
CH3 C
AlCl 4
CH3
t-butyl carbocation
(CH3)3C
(CH3)3C
(CH3)3C
H
CH3
resonance stabilized intermediate
Cl
AlCl3
(CH3)3C
+ HCl
(+ AlCl 3)
Carbocation Generated From
Alkene
Unexpected Product?
CH2CH2CH2CH3
CH3CH2CH2CH2Cl, AlCl 3
minor product
CH3
CHCH2CH3
major product
Carbocations Rearrange…
H
CH3CH2CH2CH2
Cl
AlCl 3
CH3CH2CHCH2
o
1
hydride shift
CH3CH2CHCH3
2o
1o RX Typically Undergoes Shift
Side Chain Reactions
1) Reduction of Aromatic Ketones
O
H2, Pd/C
in ethanol
Straight-chain Alkylation can
be Accomplished in 2 steps:
Acylation, then Reduction
CH3CH2CH2Cl
AlCl 3
O
CH3CH2CCl
AlCl 3
CH2CH2CH3
minor
+
H2, Pd/C
O
CCH2CH3
CH(CH3)2
major
2) Oxidation of Alkyl Substituents
O
CH3
COH
KMnO 4, H2O
CO2H
KMnO 4
H 2O
CH3
CO2H
KMnO 4, H2O
CH(CH3)2
CO2H
3) Benzylic Bromination with NBS
benzylic hydrogen
H
Br
NBS, CCl4, h
O
NBS
NBr
O
4) Alkali Fusion of Sulfonic Acids
SO3H
OH
o
1) NaOH, 300 C
+
2) H3O
phenol
5) Reduction of Nitro Groups
NO2
1) SnCl 2, HCl
2) NaOH
or H2 on Pt
NH2
Directing Effects
EDG
EWG
electron donating groups
activate ring
electron withdrawing groups
deactivate ring
atom attached is
usually sp 3
atom attached is
usually sp2 or sp
ortho/para-Directing
Activating Groups
OCH3
OCH3
OCH3
+
 OCH3



-
-
OCH3
Nitration of Anisole
Nitration Affords
ortho and para Products
OCH3
OCH3
OCH3
NO2
HNO3, H2SO4
+
ortho
para
NO2
Activating ortho/para directors
Nitration of Toluene
meta-Directing
Deactivating Groups
O
O
O
O
CH
CH
CH
CH

O
CH

+

+
+
ortho and para positions
are deactivated toward
EAS
Electron-Withdrawing Nitro
Group Directs meta
meta Directors
Comparison
CH3
Brominated product
ortho
meta
para
rel. rate
63
3
34
25
rate rel. to
benzene
Br 2, FeBr 3
CF3
ortho
6
meta
91
para
3
0.000025
More Limitations with
Friedel Crafts Reactions
Ring must be at least as
activated (reactive) as
Cl
CH3CH2Cl, TiCl 4
O
NO2
ClCCH 3, AlCl 3
Cl
+ ortho
CH2CH3
No Reaction
Substituent Summary
Halogens are the Anomoly
Deactivators and o,p-Directors
Br
Br
CH3CH2Cl
Br
CH2CH3
+
AlCl 3
rel. rate = 0.5
CH2CH3
Inductively withdrawing, hence deactivating
Resonance donation causes o,p directing
Reactions of Rings With
Two or More Substituents
Activating Group Controls Reaction
OCH3
OCH3
Cl
Cl2, FeCl3
NO2
NO2
The (More) Activated Ring Reacts
SO3
H2SO4
O
CO
deactivated
activated
O
CO
SO3H
*
(+ some ortho)
Mixtures with Conflicting
Directing Effects
Provide the Reagents
NH2
C(CH3)3
Br
Must Acylate First
NH2
O
ClCCH 2CH2CH2CH3
AlCl 3
H2, Pt/C
NO2
HNO3
H2SO4
O meta director
O
Sulfonic Acid Blocks para
Position C(CH )
3 3
Br
H
(CH3)3CBr
AlCl 3
C(CH3)3
C(CH3)3
SO3, H2SO4
H3O
+
C(CH3)3
Br
Br 2, FeBr 3
blocks para
SO3H
SO3H
Give the Reagents
CO2H
CH3
Cl
O
Provide the Reagents
CH2CH3
Br
OH
O
CH2CH3
1) ClCCH 3, AlCl 3
2) SO3, H2SO4
3) Br 2, FeBr 3
Br
4) H2 Pd/C
o
5) NaOH, 300 C
+
6) H3O
1)
O
O
2)
OH
5,6)
O
3)
4)
SO3H Br
SO3H Br
SO3H
Provide the Reagents
HO2C
Cl
HO2C
1) AlCl 3
2) Cl
O AlCl 3
3) KMnO 4, H2O
6) workup w/
+
H3O
HO2C
4) H2, Pd/C
5) NBS, h
6) NaOCH3 in CH 3OH, heat
(E2 elim of HBr)
HO2C
1)
Br
5)
HO2C
3)
2)
O
4)
O
Nucleophlic Aromatic
Substitution
Not an SN1
Not an SN2
“SNA” criteria:
• Strongly deactivated ring
• Leaving group
• Deactivating group(s) ortho &/or para to
leaving group (preferably)
• Strong base (nucleophile) such as RO-, NH2-
Methoxide as a nucleophile
Mechanism
O
Cl
OCH3
O
OCH3
+ Cl
O
O
O Cl
O
O
OCH3
O
Cl
OCH3
With no EWG, reaction
conditions are more extreme
Elimination/Addition Mechanism
“Benzyne” Intermediate
Carbons are sp2
(not a second p bond)
Benzyne can be trapped by a Diene:
Undergoes a Diels-Alder rxn
Benzyne intermediate has 2
reactive sites
Mixture of Regioisomers
NH2
Br
H2N
NaNH2, NH3
+
OCH3
OCH3
major
OCH3
minor
+ NaBr