chemistry of aromatic compounds electrophilic aromatic substitution directing effects side-chain...
TRANSCRIPT
Chemistry of Aromatic Compounds
Electrophilic Aromatic Substitution
Directing Effects
Side-chain Reactions
Synthesis
Nucleophilic Aromatic Substitution
Electrophilic Aromatic Substitution
HE
E
HE
+ H-base:base
EAS Reactions of Benzene
Br
NO2
SO3H
CR
O
Cl
IR
CHO
Bromination / Chlorination
H BrBr2, FeBr3
+ HBr
H ClCl2, FeCl3
+ HCl
Bromination Mechanism
Reaction Profile
Nitration
HNO3, H2SO4NO2
+ H2O
HNO3 + H2SO4 NO2+ + H2O + HSO4
-
Formation of electrophile
Nitration Mechanism
Nitration of Toluene
Sulfonation is Reversible
HSO3, H2SO4
SO3Hfuming sulfuric acid
S
O
OO H OSO3H
SO3H
HOSO3H
Desulfonation
Friedel-Crafts Acylation
RCCl, AlCl3
O C
O
R+ HCl
1st, Formaton of Electrophile
C
O
R Cl AlCl3
+ -
RC
O
R C O AlCl4
acylium ion
Acylation Mechanism
C
O
R
C
O
RH Cl AlCl3
CR
O
+ HCl
Intermediate is Resonance-Stabilized
C
O
RH
C
O
RH
C
O
RH
An Acylation
CH3
CH3
CH3CH2CH2CH2CCl
O
TiCl4 in CH2Cl2
CCH2CH2CH2CH3
OCH3
CH3
+ HCl
Friedel-Crafts Alkylationmany more limitations
RX, AlCl3R
+ HCl
Mechanism
CH3 C
CH3
CH3
Cl AlCl3 C
CH3
CH3
CH3
t-butyl carbocation
AlCl4
CH3 C
CH3
CH3
(CH3)3C
H
(CH3)3C (CH3)3C
resonance stabilized intermediate
Cl AlCl3 (CH3)3C
+ HCl(+ AlCl3)
Carbocation Generated From Alkene
Unexpected Product?
CH3CH2CH2CH2Cl, AlCl 3
CH2CH2CH2CH3
CHCH2CH3
CH3
minor product
major product
Carbocations Rearrange…
CH3CH2CH2CH2 Cl AlCl3 CH3CH2CHCH2
H
CH3CH2CHCH3
hydride shift
2o
1o
1o RX Typically Undergoes Shift
Side Chain Reactions
O
H2, Pd/C
in ethanol
1) Reduction of Aromatic Ketones
Straight-chain Alkylation can be Accomplished in 2 steps:
Acylation, then Reduction
CH2CH2CH3
CCH2CH3
O
CH3CH2CH2Cl
AlCl3 minor
CH(CH3)2
+
CH3CH2CCl
AlCl3
O
major
H2, Pd/C
2) Oxidation of Alkyl SubstituentsCH3
KMnO4, H2O
COH
O
KMnO4
H2O
CO2H
CH3
CH(CH3)2
KMnO4, H2OCO2H
CO2H
3) Benzylic Bromination with NBS
H
NBS, CCl4, h
Br
NBr
O
O
NBS
benzylic hydrogen
4) Alkali Fusion of Sulfonic Acids
phenol
SO3H1) NaOH, 300 C
2) H3O+
OHo
5) Reduction of Nitro Groups
NO21) SnCl2, HCl2) NaOH
or H2 on Pt
NH2
Directing Effects
EDG EWG
electron donating groups electron withdrawing groups activate ring deactivate ring
atom attached isusually sp3
atom attached isusually sp or sp2
ortho/para-Directing Activating Groups
OCH3 OCH3 OCH3 OCH3
OCH3
+
- -
-
Nitration of Anisole
Nitration Affords ortho and para Products
OCH3
HNO3, H2SO4
OCH3
NO2
OCH3
NO2
+
ortho para
Activating ortho/para directors
Nitration of Toluene
meta-Directing Deactivating Groups
CH
O
CH
O
CH
O
CH
O
CH
O
+
+ +
-
ortho and para positions
are deactivated toward
EAS
Electron-Withdrawing Nitro Group Directs meta
meta Directors
Comparison
CH3
CF3
Br2, FeBr3
ortho meta para
Brominated product
63 3 34
6 91 3
ortho meta para
rel. rate
25
0.000025
rate rel. to benzene
More Limitations with Friedel Crafts Reactions
Cl
Ring must be at least as activated (reactive) as
NO2 ClCCH3, AlCl3
O
No Reaction
Cl
CH2CH3
+ orthoCH3CH2Cl, TiCl4
Substituent Summary
Halogens are the AnomolyDeactivators and o,p-Directors
Br
CH3CH2Cl
AlCl3
Br
CH2CH3
CH2CH3
Br
+
rel. rate = 0.5
Inductively withdrawing, hence deactivatingResonance donation causes o,p directing
Reactions of Rings With Two or More Substituents
NO2
OCH3 OCH3
NO2
ClCl2, FeCl3
Activating Group Controls Reaction
The (More) Activated Ring Reacts
CO
OH2SO4
SO3
CO
O
SO3H
deactivated activated(+ some ortho)
*
Mixtures with Conflicting Directing Effects
Provide the Reagents
NH2
C(CH3)3
Br
Must Acylate FirstNH2
ClCCH2CH2CH2CH3
O
AlCl3
O meta director
HNO3
H2SO4
O
NO2
H2, Pt/C
Sulfonic Acid Blocks para Position C(CH3)3
Br
H(CH3)3CBr
AlCl3
C(CH3)3
SO3, H2SO4
SO3H
C(CH3)3
Br2, FeBr3
C(CH3)3
SO3H
Br
H3O+
blocks para
Give the Reagents
CO2H
O
CH3Cl
Provide the Reagents
CH2CH3
OHBr
CH2CH3
OHBr
1) ClCCH3, AlCl3
O
2) SO3, H2SO4
3) Br2, FeBr3
4) H2 Pd/C5) NaOH, 300 C
o
6) H3O+
O O
SO3H
O
SO3HBr SO3HBr
1)
2) 3) 4)
5,6)
Provide the Reagents
HO2C
HO2C1)
Cl
AlCl3
2) Cl
O AlCl33) KMnO4, H2O
4) H2, Pd/C
5) NBS, h6) NaOCH3 in CH3OH, heat
(E2 elim of HBr)
1)
O
2)
O
HO2C3)
HO2C
HO2C
Br
4)
5)
6) workup w/ H3O+
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
MechanismCl
O
OOCH3
Cl
O
O OCH3Cl
O
O OCH3
OCH3
O
O
+ Cl
With no EWG, reaction conditions are more extreme
Elimination/Addition Mechanism
“Benzyne” Intermediate
Carbons are sp2 (not a second bond)
Benzyne can be trapped by a Diene: Undergoes a Diels-Alder rxn
Benzyne intermediate has 2 reactive sites
Mixture of Regioisomers
Br
OCH3
NaNH2, NH3
NH2
OCH3
+
OCH3
H2N
majorminor
+ NaBr