Post on 17-Jan-2016
BenZene Ractions
Dr Md Ashraful Alam
Assistant Professor
Department of Pharmaceutical Sciences
• Benzene does not undergo electrophilic addition
• It undergoes electrophilic aromatic substitution maintaining the aromatic core
• Electrophilic aromatic substitution replaces a proton on benzene with a.nother electrophile
2
3
electrophilic aromatic substitution
Electrophilic Aromatic Substitution
HE
E
HE
+ H-base:base
Ortho-Para and Meta Directing Substituents
• When substituted benzenes undergo further substituents, the substituent group present in the benzene derivative will influence electrophilic substitution in 2 ways which are:
i) Reactivity
ii)Orientation
EFFECTS OF SUBSTITUENTS ON THE REACTIVITY OF ELECTROPHILIC
AROMATIC SUBSTITUTION• Substituent group present in the benzene ring can
influence the rate of reaction of further substitutions.
• Electron-donating groups make the ring more reactive (called activating groups) thus influence the reaction become faster.
• Electron-withdrawing groups make the ring less reactive (called deactivating groups) thus influence the reaction become slower.
• A substituents group already in the ring influences the position of further electrophilic substitution whether at ortho, meta or para position.
• Ortho-para directors: the groups that tend to direct electrophilic substitution to the C2 and C4 positions.
• Meta directors: the groups that tend to direct electrophilic substitution to the C3 position.
EFFECTS OF SUBSTITUENTS ON THE ORIENTATION OF ELECTROPHILIC
AROMATIC SUBSTITUTION
Effetcs of substituent groups on the benzene ring
Activating groups (electron donating)
Deactivating groups
(electron-withdrawing)
-NH2 -R
-OH
-OR
-NHCOCH3
-F
-Cl
-Br
-I
ortho-para directors ortho-para directors
meta directors
C
O
R
C
O
OH
C
O
OR
SO3H
C N
NO2
NR3
Disubstituted Benzenes : Orientation
Orientation Effects of Substituents in Electrophilic Aromatic Substitution :
Ortho , para directors Meta directors
-OH, -OR-NH2, -NHR, -NR2-C6H5-CH3, -R (alkyl)-F, -Cl, -Br, -I
-NO2-SO3H-COOH, -COOR-CHO, -COR-CN
OH OH
NO2
NO2
nitration
NO2
NO2
nitration+
OH
NO2o-Nitrophenol p-Nitrophenol
53 47
10
Substituent Effects in Aromatic Rings • Substituents can cause a compound to be (much)
more or (much) less reactive than benzene• Substituents affect the orientation of the reaction
– the positional relationship is controlled– ortho- and para-directing activators, ortho- and para-
directing deactivators, and meta-directing deactivators
11
Activators/Deactivators
Specific Electrophilic Aromatic : Substitution Reactions
X2 , FeX3
Halogenation
X
+ HX (X=Cl, Br)
RCl, AlCl 3
Alkylation
R
+ ClH
HONO2 , H2SO4
Nitration
NO2
+ OH2
SO3 , H2SO4
Sulfonation
SO3H
EAS Reactions of Benzene
Br
NO2
SO3H
CR
O
Cl
IR
CHO
• Benzene’s electrons participate as a Lewis base in reactions with Lewis acids
– Lewis acid: electron pair acceptor
– Lewis base: electron pair donor
• The product is formed by loss of a proton, which is replaced by a halogen
14
Bromination / Chlorination
H BrBr2, FeBr3
+ HBr
H ClCl2, FeCl3
+ HCl
Bromination Mechanism
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
N-Bromosuccinimide
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
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+
65
Reactions of Benzene