Transcript 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.

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
Br2, FeBr3
Br
+ HBr
H
Cl2, FeCl3
Cl
+ HCl
Bromination Mechanism
Reaction Profile
Nitration
NO2
+ H2O
HNO3, H2SO 4
Formation of e le ctroph ile
HNO3 + H2SO 4
+
-
NO2 + H2O + HSO4
Nitration Mechanism
Nitration of Toluene
Sulfonation is Reversible
H
fuming sulfuric acid
SO 3, H2SO 4
O
S
O
O
H
OSO3H
SO 3H
H
OSO 3H
SO 3H
Desulfonation
Friedel-Crafts Acylation
O
O
RCCl, AlCl3
C
R
+ HCl
1st, Formaton of Electrophile
O
C
R
O
+

Cl

AlCl3
C
R
R
acylium ion
C O
AlCl4
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
T iCl4 in CH2Cl2
CH3
O
CH3
Friedel-Crafts Alkylation
many more limitations
RX, AlCl3
R
+ HCl
Mechanism
CH3
CH3 C
CH3
Cl
AlCl3
CH3 C
CH3
CH3
CH3 C
AlCl4
CH3
t-butyl carbocation
(CH3)3C
(CH3)3C
(CH3)3C
H
CH3
resonance stabilized intermediate
Cl
AlCl3
(CH3)3C
+ HCl
(+ AlCl3)
Carbocation Generated From
Alkene
Unexpected Product?
CH2CH2CH2CH3
CH3CH2CH2CH2Cl, AlCl3
minor product
CH3
CHCH2CH3
major product
Carbocations Rearrange…
H
CH3CH2CH2CH2
Cl
AlCl3
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
AlCl3
O
CH3CH2CCl
AlCl3
CH2CH2CH3
minor +
H2, Pd/C
O
CCH2CH3
CH(CH3)2
major
2) Oxidation of Alkyl Substituents
O
CH3
COH
KMnO4, H2O
CO 2H
KMnO4
H 2O
CH3
CO2H
KMnO4, H2O
CH(CH3)2
CO 2H
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, 300C
+
2) H3O
phe n ol
5) Reduction of Nitro Groups
NO2
1) SnCl2, HCl
2) NaOH
or H2 on Pt
NH2
Directing Effects
EDG
electron donating groups
activate ring
atom attached is
usually sp 3
EWG
electron withdrawing groups
de activate ring
at om at t ached is
2 or sp
usually 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, H2SO 4
+
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 de activate dt oward
EAS
Electron-Withdrawing Nitro
Group Directs meta
meta Directors
Comparison
CH3
Brom in ate d produ ct
ortho
meta
63
3
para
34
25
rat e rel. to
benzene
Br2, FeBr3
CF3
rel. rat e
ortho
meta
6
91
para
3
0.000025
More Limitations with
Friedel Crafts Reactions
Ring must be at least as
act ivat ed (reactive) as
Cl
CH3CH2Cl, T iCl4
O
NO2
ClCCH3, AlCl3
Cl
+ ortho
CH2CH3
No Re acti on
Substituent Summary
Halogens are the Anomoly
Deactivators and o,p-Directors
Br
Br
CH3CH2Cl
Br
CH2CH3
+
AlCl3
rel. rate = 0.5
CH2CH3
Inductive ly withdrawing, he nce de activating
Re sonance donation cause s o,p dire cting
Reactions of Rings With
Two or More Substituents
Activating Group Controls Reaction
OCH3
OCH3
Cl
Cl2, FeCl3
NO2
NO2
The (More) Activated Ring Reacts
SO 3
H2SO 4
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
ClCCH2CH2CH2CH3
AlCl3
H2, P t /C
NO2
HNO3
H2SO 4
O meta direct or
O
Sulfonic Acid Blocks para
Position C(CH )
3 3
Br
H
(CH3)3CBr
AlCl3
C(CH3)3
C(CH3)3
SO 3, H2SO 4
H 3O
+
C(CH3)3
Br
Br2, FeBr3
blocks para
SO3H
SO3H
Give the Reagents
CO2H
CH3
Cl
O
Provide the Reagents
CH2CH3
Br
OH
O
CH2CH3
1) ClCCH3, AlCl3
2) SO3, H2SO 4
3) Br2, FeBr3
Br
4) H2 P d/C
o
5) NaOH, 300 C
+
6) H3O
1)
O
O
2)
OH
5,6)
O
3)
SO 3H
4)
Br
SO3H Br
SO 3H
Provide the Reagents
HO2C
Cl
HO2C
1) AlCl3
2) Cl
O AlCl3
3) KMnO4, H2O
6) workup w/
+
H3O
HO2C
4) H2, P d/C
5) NBS, h
6) NaOCH3 in CH3OH, 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