Electrophilic Aromatic Substitution

Part 1

H E
E (an electrophile)
Generic reaction:

Optional reading: OCATSA email for access: harding@chem.ucla.edu

1
 Introduction
Fact: Alkenes undergo electrophilic addition
•Addition reaction: Increases the number of groups attached to the substrate at the
expense of a pi bond

Nucleophile (pi bond)

Br
Br Br

Br

Electrophile (induced dipole)

How is the Br-Br dipole induced?

Br Br
- + Br- Br+
Br Br

EN = 0 Weak C=C/Br-Br repulsion Strong Br-Br

No bond dipole Weak Br-Br polarization polarization
2
 Addition to Benzene Pi Bonds?
Question: Benzene has pi bonds...also adds Br2?

Br

X
Br2
No reaction occurs (NR)
Br

Why NR? What is special about benzene?

•Is benzene a nucleophile? Benzene has pi electrons  Benzene is a nucleophile
•Is Eact too large? Benzene + Br2 gives a stable intermediate  Eact probably ok
Br Br Br

  H H H
Br Br

Resonance-stabilized carbocation

3
 So What It Up With Benzene?
How else is benzene different from an alkene?
Br Br Br

  H H H
Br Br

Aromatic Not aromatic

•Aromaticity - worth 36 kcal mol-1 of stabilization
•Loss of aromaticity = large increase in Eact = mechanism step too expensive

How to solve this problem?

•Make Br2 more electrophilic e- acceptor Permanent 


Br Br FeBr3 Br Br FeBr3

More electrophilic
Electrophile = e deficient
-
than Br2 alone
Therefore take e- away from Br 4
 Reaction and Mechanism
Br2
product
FeBr3

Mechanism?

Br Br FeBr3 Br Br FeBr3

Useful reminder
H H H

Br Br Br
Br Br FeBr3

Arenium ion
 H

Br
Arenium ion resonance hybrid: 

5
 Arenium Ion Fate?
Arenium ion = a carbocation, so carbocation fates apply

H H

Br Br
Capture a nucleophile: + FeBr3

Br FeBr3 Br

Aromaticity not restored

H Br FeBr3
Br
Be deprotonated; form pi bond: Br
+ HBr + FeBr3
•Weak base adequate

Aromaticity restored

6
 Reaction Name and Kinetics
Overall reaction
Br
Br2

FeBr3
+ HBr + FeBr3 Electrophilic aromatic substitution (EAS)

Mechanism Kinetics: Which is rds?


Br Br FeBr3 Br Br FeBr3

Br
•Carbocation formed
Br Br FeBr3 •Aromaticity lost
Rate-determining step
H Br FeBr3
Br
Br
+ HBr + FeBr3
•Carbocation quenched
•Aromaticity restored
Reaction rate depends on: Nucleophilicity of benzene ring
Arenium ion stability
Strength of electrophile 7
 What If Benzene Ring Has Substituent(s)?
Br
Br2
FeBr3
Only one product possible

Benzene

CH3 CH3 CH3 CH3

H H Br
Br2

FeBr3
+ +
H H Br

H Br

Toluene 2-Bromotoluene 3-Bromotoluene 4-Bromotoluene

Ortho-bromotoluene Meta-bromotoluene Para-bromotoluene

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 Which Product is Major?
Number of positions (probability) Steric hindrance to electrophilic attack

CH3 Ortho attack

(between CH3 and H)
Two ortho positions More hindered
Two meta positions
One para position Meta attack
(between H and H)
Less hindered
Product ratio conclusion: Para attack
40% ortho, 40% meta, 20% para (between H and H)
Less hindered

Product ratio conclusion:

meta, para > ortho

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 Which Product is Major?
Arenium ion stability
CH3 CH3 CH3 CH3
 H H H
Br Br FeBr3
Ortho attack: Br Br Br
More
stable
2o 2o 3o
CH3 CH3 CH3 CH3

Br Br FeBr3
Less
Meta attack: Br Br Br stable
H H H
2o 2o 2o
CH3 CH3 CH3 CH3

More
Para attack:
stable
 H Br H Br H Br
Br Br FeBr3
2o 3o 2o

Product ratio conclusion: ortho, para > meta 10

 Which Product is Major?
Summary
•Number of positions: ortho, meta > para
•Steric effects: meta, para > ortho
•Arenium ion stability: ortho, para > meta
CH3
CH3
Which factor dominates? CH3 CH3

Ask Mother Nature... Br2 Br

+ +
FeBr3

Br
Br

60% <1% 40%

Conclusion: arenium ion stability >>> number of positions > steric effects

Reversed when steric effects are large enough

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 Directing Effects
CH3 is an ortho/para director
•Why? Arenium ion stability
CH3 stabilizes adjacent carbocation by electron-donating inductive effect

Extension: Any carbocation stabilizing group = ortho/para director

Ortho/para directors
Alkyl groups (-CH3, -CH2CH3, etc.)
Pi bonds: alkene, alkyne, aromatic rings

}
Lone pairs (-X:) -OH, -OR Electron donation (resonance)
-NH2, -NHR, -NR2 outweighs
-F, -Cl, -Br, -I electron withdrawing (induction)
Others...
In general... If it stabilizes a carbocation it is an ortho/para director.
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 Substituent Effects: Kinetics
CH3

Which reacts faster with Br2/FeBr3: or ?

•Rate-determining step: electrophile + nucleophile  arenium ion

•Electrophile: same in both cases
Nucleophilicity:
•Nucleophile: CH3 is electron-donating group (EDG) CH3

H is neither EDG or EWG >

Arenium ion stability:

CH3
•Arenium ion: CH3 is electron-donating group
H is neither EDG or EWG >
Br Br

H H

Conclusion: Br2/FeBr3 reacts faster with toluene than with benzene

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 Activating Effects
CH3 is an EAS activator

Why? Relative to H...

•CH3 enhances benzene ring nucleophilicity
•CH3 increases arenium ion stability
•CH3 is electron-donating group; stabilizes adjacent carbocation

Extension: Any carbocation-stabilizing group is an activator

EAS Activating Groups

•Alkyl groups (-CH3, -CH2CH3, etc.)
••Pi bonds:
pairsalkene,
(-X:) alkyne, aromatic rings Electron donation (resonance)
Lone -OH, -OR
-NH2, -NHR, -NR2 }electron withdrawing
outweighs
(induction)

Better electron donors = more powerful activators

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 Activating Effects: An Exception
Are all ortho/para directors also activators?
Yes, except F, Cl, Br, and I
Why? Balance of electron-donation versus electron-withdrawal
Does transition state look more like benzene ring or arenium ion?
Net effect: F, Cl, Br, I are ortho/para directors, but deactivators

Example: OCH3
OCH3 OCH3
Br2
•OCH3 is ortho/para director
Br
FeBr3
+
•OCH3 is activator
Reaction faster than benzene + Br2/FeBr3
Br

F
F F

Br2
•F is ortho/para director
Br
+ •F is deactivator
FeBr3
Reaction is slower than benzene + Br2/FeBr3
Br
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 Substituent Effects: the Nitro Group (NO2)
Predict major product:
Nitro group
NO2
NO2 NO2 NO2

Br2 Br
+ +
FeBr3

Br
Br

O O

Nitro group structure? N N

O O

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Electrophilic Aromatic Substitution
Part 2
O O

S
Na O

OH

N
N

OCH3

CH3

O S
O Na
O

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 Part 1 Summary
Electrophilic aromatic substitution (EAS): electrophilic attack on aromatic ring leads to hydrogen
atom replacement
CH3
CH3 CH3 CH3
Br2
Example: FeBr3
+ +

Br Br
Br

ortho meta para

Mechanism: Br Br FeBr3 Br Br FeBr3

CH3 CH3 CH3 CH3

Br Br FeBr3 H H H

rds Br Br Br arenium ion

CH3 CH3
H Br FeBr3
Br
Br

Substituent effects: CH3 is an ortho/para director and activator 18

 Substituent Effects: the Nitro Group (NO2)
Predict major product:
Nitro group
NO2
NO2 NO2 NO2

Br2 Br
+ +
FeBr3

Br
Br

O O

Nitro group structure? N N

O O

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 Substituent Effects: the Nitro Group (NO2)
Arenium ion stability O O
NO2 NO2 NO2 NO
N 2 Bad !
H H H
Br Br FeBr3
Br Br Br
Ortho attack:

2o 2o 2o

NO2 NO2 NO2 NO2

Br Br FeBr3
Meta attack: Br Br
Br
H H H
2o 2o 2o

NO2 NO2 NO2 NO2

Para attack:

H Br H o Br H Br
Br Br FeBr3 2o 2 2o

Product ratio conclusion: meta > ortho > para 20

 Directing Effects
NO2 is an meta director
•Why? Arenium ion stability
NO2 destabilizes adjacent carbocation by electron-withdrawing inductive effect

Extension: Any carbocation destabilizing group = meta director

Meta directors
-NO2
O
-+NH3, -+NH2R, -+NHR2, -+NR3
-C=O (ketone, aldehyde, ester, carboxylic acid, etc.)
-CN O
-CF3 S
O

-SO3H sulfonic acid OH

Others... In general: If it destabilizes a carbocation it is a meta director.

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 Substituent Effects: Kinetics
NO2

Which reacts faster with Br2/FeBr3: or ?

•Rate-determining step: electrophile + nucleophile  arenium ion

•Electrophile: same in both cases
Nucleophilicity:
•Nucleophile: NO2 is electron-withdrawing group (EWG) NO2

H is neither EDG or EWG <

Arenium ion stability:

NO2
•Arenium ion: NO2 is electron-withdrawing group
H is neither EDG or EWG Br
<
Br
H H

Conclusion: Br2/FeBr3 reacts more slowly with nitrobenzene than with benzene
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 Other Electrophiles: Bromination
Ar-H  Ar-Br

Origin of electrophile: Br Br FeBr3 Br Br FeBr3

--or--

Br Br FeBr3 Br + FeBr4

o/p director: NH2

NH2 NH2

Br2 Br
Example: +
FeBr3

Br

Write out the complete mechanism for yourself

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 Other Electrophiles: Chlorination
Ar-H  Ar-Cl

Origin of electrophile: Cl Cl AlCl3 Cl Cl AlCl3

--or--

Cl Cl AlCl3 Cl + AlCl4

o/p director
EDG CH3 CH3 CH3 more hindered
Cl2 Cl Cl
Example: ** ** AlCl3
+

CH3 CH3
**
CH3

major minor

Write out the complete mechanism for yourself

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 What is the Electrophile?
A useful pattern for remembering EAS reactions...
NH2 NH2

Br Br + electrophile
Bromination: comes from

CH3 CH3

Cl + Cl
Chlorination: comes from

CH3 CH3

Elec Elec +
General EAS: comes from

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 Other Electrophiles: Nitration
Ar-H  Ar-NO2
Electrophile: +NO2 O N O

O O O

Origin of electrophile: N OH H OH2 N OH2 N

O O O
--or--
O O

N OH N OH

O H OH2 HO

o/p director: Br
Br Br

aq. HONO2 NO2

+
Example: aq. H2SO4

NO2

Write out the complete mechanism for yourself

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 Just Who Is In Charge Here?
ortho/para director Br
Br Br

aq. HONO2 NO2

Nitration of bromobenzene: +
aq. H2SO4

NO2
meta director
NO2 NO2

Br2

Bromination of nitrobenzene: FeBr3

Br
director
G

Elec
Generic EAS reaction:

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 Other Electrophiles: Sulfonation
Ar-H  Ar-SO3H (sulfonic acid)
O

Electrophile: +SO3H S OH

O O

Origin of electrophile: S O H OSO3H S OH

O O
--or--
O

S O

meta director
EWG O

O
SO3
Example: H2SO4 O
S
O
OH

Write out the complete mechanism for yourself

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 Other Electrophiles: Friedel-Crafts Alkylation
Ar-H  Ar-R (R = alkyl group)

Electrophile: R+ (a carbocation)

Origin of electrophile: R Cl AlCl3 R Cl AlCl3 R + AlCl4

Less stable More stable

carbocations carbocations

•Carbocation rearrangements possible

Cl How?
C(CH3)3
Example: AlCl3
C(CH3)3 Electrophile = +C(CH3)3

Write out the complete mechanism for yourself

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 Other Electrophiles: Friedel-Crafts Acylation
O

Ar H Ar (a ketone)
R
O O

Electrophile: C C Acylium ion

R R

O O O

Origin of electrophile: C C C
R Cl AlCl3 R Cl AlCl3
R

O
OCH3
OCH3 CH3
How? Cl
Example: CH3
CH3 Electrophile =
AlCl3
O

Write out the complete mechanism for yourself

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 Other Electrophiles: Diazo Coupling
Ar N
Ar H
N Ar

Electrophile: Ar N N Ar N N Diazonium cation

Na O N O
Origin of electrophile: Ar NH2
aq. HCl
Ar N N

•Mechanism? An OWLS problem

OH

Example:

NaNO2 N
NH2 N N
aq. HCl N OH

Write out the complete mechanism for yourself

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 EAS Application Example:
Synthesis of Allura Red C
O O

S •Allura Red AC (an azo dye)

Na O
•Color due to extensive conjugation
•Many dyes are diazo compounds
OH

N
Ar-N=N-Ar suggests N
synthesis via diazo
OCH3
coupling

CH3

O S
O Na
O

Strawberry soda colored

with Allura Red AC
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 Synthesis of Allura Red C
N
EWG
Nucleophile
Electrophile Deactivated Activated
NH2 N

OCH3 OCH3 HO3S

NaNO2
+ *
aq. HCl
CH3 CH3 OH EDG
SO3H SO3H * o/p director

HO3S

OH

N
Na2CO3 N
Allura Red AC
OCH3

CH3

SO3H
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