© e.v. blackburn, 2011 electrophilic aromatic substitution
TRANSCRIPT
© E.V. Blackburn, 2011
Substitution?
The characteristic reactions of benzene involve substitution in which the resonance stabilized ring system is maintained:
NO2
HNO3/H2SO4
© E.V. Blackburn, 2011
Reactivity
- an electron source, benzene reacts with electron deficient reagents - electrophilic reagents.
© E.V. Blackburn, 2011
1. Nitration
ArH + HNO3/H2SO4 ArNO2 + H2O
2. Sulfonation
ArH + H2SO4/SO3 ArSO3H + H2O
3. Halogenation
ArH + X2/FeX3 ArX + HX
Electrophilic aromatic substitution
© E.V. Blackburn, 2011
4. Friedel - Crafts alkylation
ArH + RCl/AlCl3 ArR + HCl
5. Friedel - Crafts acylation
ArH + RCOCl/AlCl3 ArCOR + HCl
Friedel - Crafts reactions
Ar R
O
© E.V. Blackburn, 2011
Substituent effects
Toluene is more reactive than benzene.....
CH3
HNO3
H2SO4
CH3
NO225C
+
CH3NO2
+
CH3
NO2
34% 63% 3%
© E.V. Blackburn, 2011
Reactivity
• Compare the time required for reactions to occur under identical conditions.
• Compare the severity of reaction conditions.
• Make a quantitative comparison under identical reaction conditions.
How is “reactivity” determined in the lab?
© E.V. Blackburn, 2011
Substituent effects
It also directs the attacking reagent to the ortho and para positions on the ring.
In some way, the methyl group makes the ring more reactive than that of the unsubstituted benzene molecule.
© E.V. Blackburn, 2011
Substituent effects
Nitrobenzene undergoes substitution at a slower rate than does benzene. It yields mainly the meta isomer.
NO2
HNO3
H2SO4
NO2
NO225C
+
NO2NO2
+
NO2
NO2
2% 7% 91%
© E.V. Blackburn, 2011
Substituent effects
A group which makes the ring less reactive than benzene is called a deactivating group.
A group which makes the ring more reactive than that of benzene is called an activating group.
A group which leads to the predominant formation of ortho and para isomers is called an “ortho - para directing group.”
A group which leads to the predominant formation of the meta isomer is called a “meta directing group.”
© E.V. Blackburn, 2011
Activating, o,p directors
-OH -NH2 -NHR -NR2
moderately activating
-OR -NHCOR
weakly activating
-aryl -alkyl
strongly activatingA
All activating groups are o,p directors.
© E.V. Blackburn, 2011
Deactivating, m directors
-NO2 -SO3H -CO2H -CO2R
-CONH2 -CHO -COR -CN
+ +-NH3 -NR3
A
All m directors are deactivating.
O or N
© E.V. Blackburn, 2011
Orientation in disubstituted benzenes
Here the two directing effects are additive.
CH3
NO2
H2SO4
HNO3
CH3
NO2
NO2
© E.V. Blackburn, 2011
Orientation in disubstituted benzenes
When two substituants exert opposing directional effects, it is not always easy to predict the products which will form. However, certain generalizations can be made....
© E.V. Blackburn, 2011
Orientation in disubstituted benzenes
• Strongly activating groups exercise a far greater influence than weakly activating and all deactivating groups.
OH
CH3
HNO3/H2SO4
OHNO2
CH3
© E.V. Blackburn, 2011
• If there is not a great difference between the directive power of the two groups, a mixture results:
CH3
Cl Cl
NO2
CH3 CH3
NO2
Cl
+HNO3
H2SO4
58% 42%
Orientation in disubstituted benzenes
© E.V. Blackburn, 2011
• Usually no substitution occurs between two meta substituents due to steric hindrance:
Cl
Br
1%
62%
37%
......nitration
Orientation in disubstituted benzenes
© E.V. Blackburn, 2011
Synthesis of m-bromonitrobenzene
In order to plan a synthesis, we must consider the order in which the substituents are introduced.......
If, however, we brominate and then nitrate, the o and p isomers will be formed.
NO2
HNO3
H2SO4
Br2/FeBr3NO2
Br
© E.V. Blackburn, 2011
Orientation and synthesis
Let’s look at converting a methyl group into a carboxylic acid:
Now let’s see how we can make the three nitrobenzoic acids:
If a synthesis involves the conversion of a substituants into another, we must decide exactly when to do the conversion.
H
H or R
H or R
1. KMnO4, OH-,
2. H3O+
CO2H
© E.V. Blackburn, 2011
The nitrobenzoic acids
m-nitrobenzoic acid
CH3
KMnO4
HNO3
H2SO4
CO2HHNO3
H2SO4
CO2H
NO2
CH3 CH3NO2
NO2
+
bp 225oC bp 238oC
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The nitrobenzoic acids
o-nitrobenzoic acid p-nitrobenzoic acid
CH3 CH3NO2
NO2
+
K2Cr2O7
CO2HNO2
K2Cr2O7
CO2H
NO2
© E.V. Blackburn, 2011
Nitration
HONO2 + 2H2SO4 H3O+ + 2HSO4- + NO2
+
nitronium ion - a Lewis acid
NO2+ H
NO2
+
HNO2
+ HSO4-
NO2H2SO4 +
© E.V. Blackburn, 2011
The structure of the intermediate carbocation
O2N H
+
The positive charge is not localized on any one carbon atom.
It is delocalized over the ring but is particularly strong on the carbons ortho and para to the nitro bearing carbon.
HNO2
+ HNO2
+
HNO2
+
© E.V. Blackburn, 2011
Sulfonation
2H2SO4 H3O+ + HSO4- + SO3
S OO
OSO3
-+
H
SO3-+
H
HSO4-
H2SO4 +SO3
-
© E.V. Blackburn, 2011
Halogenation
Br Br FeBr3 Br Br FeBr3
+ -Br Br FeBr3
+ -
Br Br FeBr3+ - Br
+
H + FeBr4-
Br+
HBr FeBr3
- + HBr + FeBr3
Br
© E.V. Blackburn, 2011
Friedel - Crafts alkylation
R X AlX3 R+ + AlX4-
R+R
+
H
R+
HX AlX3
- + AlX3
R
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An electrophilic carbocation?
(CH3)3COH + H+ (CH3)3COH2
+
(CH3)3COH2
+H2O + (CH3)3C+
(CH3)3COH/H+ C(CH3)3
© E.V. Blackburn, 2011
An electrophilic carbocation?
(CH3)2C=CH2 + H+ (CH3)3C+
(CH3)2C=CH2/H+ C(CH3)3
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An electrophilic carbocation?
+
CH2CH2CH3
CH3CH2CH2Cl
AlCl3
CH(CH3)2
~33% ~67%
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An electrophilic carbocation?
When RX is primary, a simple carbocation does not form. The electrophile is a complex:
H3C Cl AlCl3
-
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Limitations
• A polysubstitution is possible - the reaction introduces an activating group!
• Aromatic compounds bearing -NH2, -NHR or -NR2 do not undergo Friedel - Crafts substitution. Why?
• Aromatic rings less reactive than the halobenzenes do not undergo Friedel - Crafts reactions.
© E.V. Blackburn, 2011
Friedel - Crafts acylation
acylium ion
RC O+
+ AlX3
O
R X + AlX4-
RC O+
RC O+
+
HR
O
+
HX AlX3
-R
O
+ HX + AlX3R
O
© E.V. Blackburn, 2011
The mechanism
slow, rate determining step
fast
Evidence - there is no significant deuterium isotope effect.
+ E+
E H
+
E H
+ Nu:+
E
© E.V. Blackburn, 2011
Isotope effects
A difference in rate due to a difference in the isotope present in the reaction system is called an isotope effect.
© E.V. Blackburn, 2011
Isotope effectsIf an atom is less strongly bonded in the transition state than in the starting material, the reaction involving the heavier isotope will proceed more slowly.
C H + ZkH
C H Z C + HZ
The isotopes of hydrogen have the greatest mass differences. Deuterium has twice and tritium three times the mass of protium. Therefore deuterium and tritium isotope effects are the largest and easiest to determine.
© E.V. Blackburn, 2011
Primary isotope effectsThese effects are due to breaking the bond to the isotope.
C H + ZkH
C H Z C + HZ
C D + ZkD
C D Z C + DZ
kH
kD = 5 - 8
Thus the reaction with protium is 5 to 8 times faster than the reaction with deuterium.
© E.V. Blackburn, 2011
CH3CHCH3
Br NaOEt
kH
CH3CH=CH2
CD3CHCD3
Br NaOEt
kD
CD3CH=CD2
kH/kD = 7
Evidence for the E2 mechanism - a large isotope
effect
© E.V. Blackburn, 2011
The mechanism
slow, rate determining step
fast
Evidence - there is no significant deuterium isotope effect.
+ E+
E H
+
E H
+ Nu:+
E
© E.V. Blackburn, 2011
The reactivity of aromatic rings
The transition state for therate determining step:
Factors which stabilize carbocations by dispersal of the positive charge will stabilize the transition state which resembles a carbocation; it is a nascent carbocation.
HE
+
+
© E.V. Blackburn, 2011
Carbocation stability
electron donation stabilizes the carbocation
electron withdrawal destabilizes the carbocation
HE
+
HE
+
CH3
HE
+
NO2
© E.V. Blackburn, 2011
Orientation
A deactivating group deactivates all positions on the ring but deactivates the ortho and para positions more than the meta position.
Why? Examine the transition state for the rate determining step for ortho, meta and para attack.
An activating group activates all positions on the ring but directs the attacking reagent to the ortho and para positions because it makes these positions more reactive than the meta position.
© E.V. Blackburn, 2011
CH3 - an o/p director
para attack
ortho attack
meta attack
E H
+CH3
E HE H+
+
CH3 CH3
E H+
CH3
E HE H+
+CH3 CH3
E H+
CH3
E HE H+
CH3 CH3
+
3°
3°
© E.V. Blackburn, 2011
NO2 - a m director
para
ortho
meta
E H E HE H
++
+
NO2 NO2 NO2
E H E HE H+ +
+NO2 NO2 NO2
E H E HE H+ +
NO2 NO2 NO2
+
© E.V. Blackburn, 2011
NO2 - a m director
para
E H E HE H+ +
NO2 NO2 NO2
+
E H
CH3C O
+
E H
NO O
++
-
© E.V. Blackburn, 2011
NH2 - an o/p director??E H E HE H
++
+
NH2 NH2 NH2
E H E HE H+ +
+NH2 NH2 NH2
E H E HE H+ +
NH2 NH2 NH2
+
E H
+NH2 :
E H +NH2
© E.V. Blackburn, 2011
Deactivation results from electron withdrawal:
Halogen - a deactivating group
HE
+
HE
+
Cl
© E.V. Blackburn, 2011
Halogen - an o/p directing group
o/p directors are electron donating. How can a halogen substituent donate electrons?
© E.V. Blackburn, 2011
Halogen - an o/p directing group
E H E HE H+ +
Cl Cl Cl
+
E H E HE H
++
+
Cl Cl Cl
E H E HE H+ +
+Cl Cl Cl
E H +Cl
E H
Cl+