Electrophilic Aromatic Substitution

Part 1
H E E (an electrophile)

Generic reaction:

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?

dd+

Br

Br

Br

Br

d Br

+ d Br

DEN = 0 No bond dipole

Weak C=C/Br-Br repulsion Weak Br-Br polarization

Strong Br-Br polarization

Addition to Benzene Pi Bonds?

Question: Benzene has pi bonds...also adds Br2?
Br2

X
Br

Br

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 H H Br H d Br d Br

Resonance-stabilized carbocation
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So What It Up With Benzene?

How else is benzene different from an alkene?
Br d Br d Br H Br H Br H

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
Br Br

e- acceptor
d

Permanent d

FeBr3

Br

Br

FeBr3

Electrophile = deficient Therefore take e- away from Br

e-

More electrophilic than Br2 alone

Reaction and Mechanism

Br2 FeBr3 product

Mechanism?
Br Br FeBr3 d Br Br FeBr3

Useful reminder
H Br Br Br FeBr3 H Br H Br

Arenium ion
d H Br d d

Arenium ion resonance hybrid:

Arenium Ion Fate?

Arenium ion = a carbocation, so carbocation fates apply
H H Br Br + FeBr3 Br FeBr3 Br

Capture a nucleophile:

Aromaticity not restored

Br Br

FeBr3

Br + HBr + FeBr3

Be deprotonated; form pi bond: Weak base adequate

Aromaticity restored

Reaction Name and Kinetics

Overall reaction
Br Br2 FeBr3 + HBr + FeBr3

Electrophilic aromatic substitution (EAS)

Mechanism
Br Br FeBr3

d Br Br FeBr3

Kinetics: Which is rds?

H Br

Br

Br

FeBr3

Carbocation formed Aromaticity lost Rate-determining step

H Br

Br

FeBr3

Br + HBr + FeBr3

Carbocation quenched Aromaticity restored

Reaction rate depends on: Nucleophilicity of benzene ring Arenium ion stability Strength of electrophile

What If Benzene Ring Has Substituent(s)?

Br Br2 FeBr3

Only one product possible

Benzene
CH3
CH3
CH3

CH3

H
Br2 FeBr3

Br

+
Br

+
Br

H
H

Toluene

2-Bromotoluene Ortho-bromotoluene

3-Bromotoluene Meta-bromotoluene

4-Bromotoluene Para-bromotoluene

Which Product is Major?

Number of positions (probability)
CH3

Steric hindrance to electrophilic attack Ortho attack (between CH3 and H) More hindered Meta attack (between H and H) Less hindered

Two ortho positions Two meta positions One para position Product ratio conclusion: 40% ortho, 40% meta, 20% para

Para attack (between H and H) Less hindered

Product ratio conclusion: meta, para > ortho

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Which Product is Major?

Arenium ion stability
CH3 d Br Br FeBr3 CH3 H Br CH3 H Br CH3 H Br

Ortho attack:

2o
CH3 d Br CH3 Br FeBr3 Br

2o
CH3

3o
CH3

More stable

Meta attack:
2o
CH3 CH3
H

Br

Br

Less stable

2o
CH3

2o
CH3

Para attack:
d Br H Br FeBr3 Br H Br H Br

More stable
2o 3o
2o

Product ratio conclusion: ortho, para > meta

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Which Product is Major?

Summary Number of positions: ortho, meta > para Steric effects: meta, para > ortho Arenium ion stability: ortho, para > meta
CH3

Which factor dominates? Ask Mother Nature...

CH3 Br2 FeBr3

CH3 Br +

CH3 +

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 -NH2, -NHR, -NR2 Electron donation (resonance) -F, -Cl, -Br, -I outweighs 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: CH3 Nucleophile: CH3 is electron-donating group (EDG) H is neither EDG or EWG > Arenium ion stability: Arenium ion: CH3 is electron-donating group H is neither EDG or EWG
H CH3 Br

>
H

Br

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: alkene, alkyne, aromatic rings Electron donation (resonance) Lone pairs (-X:) -OH, -OR outweighs -NH2, -NHR, -NR2 electron withdrawing (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 Br2 FeBr3 OCH3 Br + OCH3

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

F F Br2 FeBr3 F Br +

F is ortho/para director F is deactivator 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 Br2 FeBr3 Br Br
O O N O O

NO2 Br +

NO2 +

Nitro group structure?

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Electrophilic Aromatic Substitution Part 2

O S Na O O OH N N OCH3

CH3 O O S O Na

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

Example:

ortho

meta
Br CH3 FeBr3 CH3 H Br H Br

para

Mechanism:

Br

Br CH3 Br

FeBr3

Br

CH3 H Br

Br

FeBr3

rds
CH3 H Br Br FeBr3 CH3

arenium ion

Br

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

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Substituent Effects: the Nitro Group (NO2)

Predict major product: Nitro group
NO2 NO2 Br2 FeBr3 Br Br
O O N O O

NO2 Br +

NO2 +

Nitro group structure?

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Arenium ion stability

NO2

Substituent Effects: the Nitro Group (NO2)

NO2 Br Br FeBr3 H Br NO2 H Br NO2 H Br

Bad !

Ortho attack:

2o
NO2 Br Br FeBr3 Br NO2

2o
NO2

2o
NO2

Meta attack:
2o
NO2 NO2
H

Br

Br

2o
NO2

2o
NO2

Para attack:
H Br Br FeBr3 Br H Br H Br

2o

2o

2o

Product ratio conclusion: meta > ortho > para

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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.) -CN O -CF3 O S -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: NO2 Nucleophile: NO2 is electron-withdrawing group (EWG) H is neither EDG or EWG < Arenium ion stability: Arenium ion: NO2 is electron-withdrawing group H is neither EDG or EWG
H NO2 Br

<
H

Br

Conclusion: Br2/FeBr3 reacts more slowly with nitrobenzene than with benzene
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Other Electrophiles: Bromination

Ar-H Ar-Br
Br

Origin of electrophile:

Br

Br

FeBr3

Br

FeBr3

--or-Br Br FeBr3 Br + FeBr4

o/p director : Example:

NH2 NH2 Br2 FeBr3 NH2 Br +

Br

Write out the complete mechanism for yourself

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Other Electrophiles: Chlorination

Ar-H Ar-Cl
Cl

Origin of electrophile:

Cl

Cl

AlCl3

Cl

AlCl3

--or-Cl Cl AlCl3 Cl + AlCl4

o/p director EDG Example:

CH3

CH3

CH3 Cl +

more hindered

** * *

**
CH3

Cl2 AlCl3

Cl

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

Bromination:

comes from

Br

electrophile

CH3

CH3

Chlorination:

Cl

comes from
CH3

Cl

CH3

Elec

Elec

General EAS:

comes from

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Other Electrophiles: Nitration

Ar-H Ar-NO2 Electrophile: +NO2
O N O

O N OH H OH2 O N OH2

O N O

Origin of electrophile:
O

--or-O N O OH H OH2 HO O N OH

o/p director : Example:

Br Br aq. HONO2 aq. H2SO4 Br NO2

NO2

Write out the complete mechanism for yourself

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Just Who Is In Charge Here?

ortho/para director
Br Br aq. HONO2 aq. H2SO4 NO2 + Br

Nitration of bromobenzene:
meta director
NO2

NO2
NO2 Br2

Bromination of nitrobenzene:
director
G

FeBr3 Br

Generic EAS reaction:

Elec

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Other Electrophiles: Sulfonation

Ar-H Ar-SO3H (sulfonic acid)
S O
O O S O O H OSO3H S O OH

Electrophile: +SO3H

OH

Origin of electrophile:

--or-O S O O

meta director EWG

O

Example:

SO3 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 carbocations

More stable carbocations

Carbocation rearrangements possible

Example:
Cl

How? C(CH3)3
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 R

(a ketone)

O C

Electrophile:

C R

Acylium ion

R O C Cl AlCl3 R
OCH3

O C Cl AlCl3 R

Origin of electrophile:
R

Example:

OCH3

CH3How? Cl AlCl3
CH3

CH3

Electrophile =
O
O

Write out the complete mechanism for yourself

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Other Electrophiles: Diazo Coupling

Ar Ar H N Ar N

Electrophile:

Ar

Ar

Diazonium cation
N O Ar N N

Origin of electrophile:

Ar

NH2

Na O

aq. HCl

Mechanism? An OWLS problem

OH

Example:
NaNO2 aq. HCl N N N N OH

NH2

Write out the complete mechanism for yourself

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EAS Application Example: Synthesis of Allura Red C

O S Na O O

Allura Red AC (an azo dye) Color due to extensive conjugation Many dyes are diazo compounds
OH N N OCH3

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

CH3

O O

S O Na

Strawberry soda colored with Allura Red AC

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Synthesis of Allura Red C

Electrophile
NH2 OCH3 NaNO2 + aq. HCl CH3 SO3H CH3 SO3H N N OCH3 HO3S

EWG

Nucleophile
Deactivated Activated

* *
OH

EDG

o/p director

HO3S

OH Na2CO3 N N OCH3

Allura Red AC

CH3 SO3H

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