Aromatic Electrophilic Substitution Reactions (1).pdf

This is the contents of this presentation-
• The arenium ion mechanism,
• Orientation and reactivity,
• Energy profile diagrams.
• o/p ratio,
• Orientation in benzene ring with more than one substituent, orientation in other ring systems.
• ipso attack
• Diazonium coupling,
• Gatterman-Koch reaction,
• Reimer-Tiemann reaction,
• Pechman reaction,
• Houben –Hoesch reaction,
• Kolbe Schmitt reaction,
• Recapitulation of halogenation, nitration, sulphonation, and F.C. reaction.

1. Lecture Delivered By
Mr. Nilkesh K. Dhurve
Assistant Professor
Department of Chemistry
Shri Pundlik Maharaj Mahavidyalaya Nandura Rly, Dist-Buldana 22-Jan-22 1

2. 2 22-Jan-22
•The arenium ion mechanism,
•Orientation and reactivity,
•Energy profile diagrams.
•o/p ratio,
•Orientation in benzene ring with more than one substituents, orientation in other ring system.
•ipso attack
•Diazonium coupling,
•Gatterman-Koch reaction,
•Reimer-Tiemann reaction,
•Pechman reaction,
•Houben –Hoesch reaction,
•Kolbe Schmitt reaction,
•Recapitulation of halogenation, nitration, sulphonation and F.C. reaction.

3. 3 22-Jan-22
When aromatic compounds react with electrophiles they generally do so by electrophilic aromatic
substitution(EAS).
General Mechanism for Electrophilic Substitution Reaction
1.Benzene is a planar
symmetrical hexagon with 6
trigonal C
sp
2
-atoms, each
having 1H-atom in the
plane.
2.Bond length- 1.39 A
0

3.
13
C Shift are same(δ
c128.5)

4. Aromaticity(Exceptional
Stability)

4. 4 22-Jan-22
Simple alkene reacts rapidly with electrophile.
Under the same conditions benzene reacts with
neither reagent.
Benznen can be react with bromine if Lewis acid catalyst such as
AlCl
3 is added.
The product contains bromine but is not from either cis or trans
addition.

5. 5 22-Jan-22
Benzene is very unreactive.
1.It combine only with very reactive (usually cationic) electrophiles.
2.It gives substitution and not addition product.

6. 6 22-Jan-22
General Reaction:
Mechanism:

7. 7 22-Jan-22
1.The intermediate in electrophilic aromatic substitution is a delocalized cation.
2.Arenium ion or Wheland intermediate or σ-complexes as a delocalized cyclohexadienyl cation.
There are two factors are responsible the formation of arenium ion:
1.The energy liberated by the complete formation of the new bond to the attacking electrophile, and,
2.The positively charged σ-complexes can be stabilize itself, i.e. lower its energy level, by delocalisation.

8. 8 22-Jan-22
1.π-Complex Formation:
i.A complexation of the electrophile with the electron
system of the aromatic ring. This species, called the π-
complex.
ii.Complex formation is, in general, rapidly reversible and in
many cases the equilibrium constant is small.
2. σ-Complex Formation:
i.The term σ-complex is a cationic intermediate in which
the carbon at the site of substitution is bonded to both the
electrophile and the hydrogen. As the term implies, a
bond is formed at the site of substitution.
ii.The intermediate is a cyclohexadienylium cation.
iii.Formation of the σ-complex can be reversible. It is
depends on the ease with which the electrophile can be
eliminated, relative to a proton

9. 9 22-Jan-22

10. 10 22-Jan-22

11. 11 22-Jan-22
For most electrophiles, it is easier to eliminate the proton, in which case the formation of the σ-complex is
essentially irreversible.
The electrophiles in group A are the least likely to be reversible, whereas those in group C are most likely to
undergo reversible -complex formation.

12. 12 22-Jan-22
Experimental Evidence :
1.The arenium ion is a true
intermediate in electrophilic
substitution reactions.
2.It is not a transition state.
3.This means that in a free-energy
diagram the arenium ion lies in an
energy valley between two
transition states.
1.The reaction leading from benzene and an electrophile to the arenium ion is highly endothermic, because the
aromatic stability of the benzene ring is lost.
2.The reaction leading from the arenium ion to the substituted benzene, by contrast, is highly exothermic because
it restores aromaticity to the system.

13. 13 22-Jan-22
Step 1 (the formation of the arenium ion): The rate-determining step in electrophilic aromatic substitution because of
its higher free energy of activation:
Step 2: The removal of a proton, occurs rapidly relative to step 1 and has no effect on the overall rate of reaction.

14. 14 22-Jan-22
The case for the cyclohexadienylium ion intermediates is cations can exist as stable entities under suitable conditions.
Substituted cyclohexadienylium ions can be observed by NMR under stable ion conditions. They are formed by
protonation of the aromatic reactant. (X
-
=SbF
6
-
, non-nucleophilic or non-basic counterion.)

15. 15 22-Jan-22
General Reaction:
Mechanism:
1. Generation of Electrophile
2. Attack of Electrophile and Deprotonation:

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General Reaction:
Mechanism:
1. Generation of Electrophile

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2. Attack of Electrophile and Deprotonation:

18. 18 22-Jan-22
General Reaction:
Mechanism:
1. Generation of Electrophile
2. Attack of Electrophile and Deprotonation:

19. 19 22-Jan-22
General Reaction:
Mechanism:

20. 20 22-Jan-22
General Reaction: Bromination
FeBr
3
Mechanism:

21. 21 22-Jan-22
Energy Profile Diagram comparing substitution and addition pathways for benzene

22. 22 22-Jan-22
General Reaction: Chlorination
Mechanism:

23. 23 22-Jan-22
General Reaction: Iodine is so unreactive that a special technique has to be used to effect direct iodination; the reaction
has to be carried out in the presence of an oxidizing agent such as nitric acid.
Biochemical iodination, as in the biosynthesis of thyroxine, occurs with enzymatic catalysis.
Reactivity Order: I
2 < Br
2 < Cl
2 < F
2

24. 24 22-Jan-22
Azole-Antifungal Agents
Antihistamines
Azo Dyes used for fruity Pebbles

25. 25 22-Jan-22
General Reaction:
Mechanism:
Generation of electrophile

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Example: 1
Example: 2
Friedel-Craft alkylation is effective when ethyl chloride is used, most
other primary alkyl halides cannot be used effectively. Because their
complexes with AlCl
3 readily undergoes rearrangement to form secondary
or tertiary carbocation.
Example: 3
Rearrangement of Carbocation

27. 27 22-Jan-22
Example: 4
Example: 5
Example: 6

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Example: 7
Problems:

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General Reaction:
Mechanism:
Generation of
Electrophile:
Acylium ion
(Resonance stabilized)

30. 30 22-Jan-22
Example: 1
Problems:

31. 31 22-Jan-22
•Rearrangements of carbon chain do not occur in F-C acylation, because acylium ion stabilized by resonance, is
more stable than the other carbocations. Therefore FC acylation followed by reduction give much better routes to
unbranched alkylbenzens than do FC allkylation.
Friedel-Craft Alkylations:

32. 32 22-Jan-22
Wolff-Kishner Reduction
Clemmensen Reduction
Friedel-Craft Acylations:

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Example: Synthesis of α-Tetralone using FC alkylation followed by reduction.

34. 34 22-Jan-22
P:1
P:2

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•When the carbocation formed from an alkyl halide, alkene, or alcohol can rearrange to one or more carbocations
that are more stable, it usually does so, and the major products obtained from the reaction are usually those from
the more stable carbocations.

36. 36 22-Jan-22
•Friedel–Crafts alkylation and acylation reactions usually give poor yields when powerful electron-withdrawing
groups are present on the aromatic ring.

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•Aryl and vinylic halides cannot be used as the halide component because they do not form carbocations readily.
•Polyalkylations often occur.

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•Polyacylations are not problem in Friedel–Crafts acylations.
•Following reaction does not takes place. Give the reason.
1. 2.
•Polyacylations do not take place in Friedel–Crafts acylation. Why?

39. 39 22-Jan-22
In this nitration reaction, the presence of the methyl group raises two issues:
(1)The effect of the methyl group on the rate of reaction and
(2)The effect of the methyl group on the regiochemical outcome of the reaction.
Nitration of Toluene:

40. 40 22-Jan-22

41. 41 22-Jan-22
Energy diagram comparing the relative energy level of the possible sigma complexes

42. 42 22-Jan-22
Nitration of Anisole:
Inductive Effect Resonating Effect
Resonating Effect is dominant over inductive effect.

43. 43 22-Jan-22

44. 44 22-Jan-22
Energy diagram comparing the relative energy level of the possible sigma complexes
We have seen that both a methyl group and methoxy group activate the ring and are ortho-para director.
All activators are ortho-para director.

45. 45 22-Jan-22
Nitration of Nitrobenzene:
Inductive Effect Resonating Effect
Both factors suggest that the nitro group is strong electron withdrawing group.

46. 46 22-Jan-22

47. 47 22-Jan-22
Nitro group deactivates the ring and are meta-director.
Most deactivators are meta director.
Energy diagram comparing the relative energy level of the possible sigma complexes

48. 48 22-Jan-22
Inductive Effect Resonating Effect
Nitration of Chlorobenzene:
Induction suggest that halogen is a electron withdrawing while resonance suggest that halogen is electron
donating.
Induction is dominant factor for halogens but they are o, p-directors even though they are deactivators.
Its depend on stability of sigma complex.

49. 49 22-Jan-22 Therefore, halogens are ortho-para directors, despite the fact that they are deactivators.

50. 50 22-Jan-22
All the halobenzenes react more slowly than benzene.
The percentage of the ortho product increases from fluorobenzene to
iodobenzene as the size of the halide increases (No relation with steric
effect/hindrance at the o-position).
The greater inductive effect of the more electronegative atoms (F, Cl)
withdraws electron density mostly from the ortho positions, lessening
their reactivity.
o/p-Ratio

51. 51 22-Jan-22
Ortho
-
para
directing

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meta directing

o-p directing

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Problem: For each of the following compounds, predict whether the ring is activated or deactivated, then predict the
strength of activation/deactivation, and finally predict the expected directing effects.

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Problem: State whether the group is an ortho–para or meta director.

55. 55 22-Jan-22
Problem: Comment on reactivity of following compounds on the basis of NMR data.
Electron density
Chemical shift (δ-value)
Reactivity

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Mechanism:
Reaction: Benzene does not react with bromine
except lewis acid catalysis.
Phenols react rapidly with bromine.

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4-bromophenol(85% yield)
Reaction:
Reaction at low temperature
Use just one equivalent of bromine.
Reaction:
It can be separated by steam distillation.

58. 58 22-Jan-22
Reaction:
Ortho product only 

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Reaction:
Mechanisms:
A nitrogen lone pair activates even more
strongly.
1
H NMR shifts
in phenol and
aniline

60. 60 22-Jan-22
How then could we prevent oversubstitution from occurring?  Making aromatic amine less reactive.
Making aromatic amines less reactive:

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Anilines react rapidly with electrophiles to give polysubstituted products. Their amide derivatives react in more
controlled manner to give para-substituted product.

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Mechanism:
p-Toluene sulphonic acid
(PTSA/TsOH/Tosic acid)

63. 63 22-Jan-22
Mechanism:

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If the reaction is reversible, as is the case with sulfonation, the position of substitution may be determine by
temperature.
Sulfonation at low temperatures gives o-product by kinetic control, while sulfonation at high temperatures gives p-
product by thermodynamic control.
Chlorosulfonic acid is used to synthesis of saccharin.

65. 65 22-Jan-22
Orientation in benzene ring with more than one substituent's
Reaction 2:
Reaction 1:
Electronic Effect:

66. 66 22-Jan-22
Orientation in benzene ring with more than one substituent's
Reaction 2:
Reaction 3:
Consider electronic effects first and then steric effects.
For the electronic effects, in general, any activating effect are more important than deactivating ones.

67. 67 22-Jan-22
Orientation in benzene ring with more than one substituent's
Problem-1: In the following compound, identify the position that is most likely to undergo an electrophilic aromatic
substitution reaction.
(d)

68. 68 22-Jan-22
Orientation in benzene ring with more than one substituent's
Problem-2: For each compound below, identify which position(s) is/are most likely to undergo an electrophilic aromatic
substitution reaction.

69. 69 22-Jan-22
Orientation in benzene ring with more than one substituent's
Steric Effect:
For monosubstituted aromatic ring:




For disubstituted aromatic ring:

70. 70 22-Jan-22
Orientation in benzene ring with more than one substituent's
Problem-2: For the following compound, identify which position(s) is/are most likely to undergo an electrophilic
aromatic substitution reaction.
(e)

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Orientation in benzene ring with more than one substituent's
Blocking Groups:
Blocking Groups:
Example:

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Orientation in benzene ring with more than one substituent's
Problems:
Solution:

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Orientation in benzene ring with more than one substituent's
Problems: Determine whether a blocking group is necessary to accomplish each of the following transformation:

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Synthesis Strategies

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Synthesis Strategies
Functional Group conversions that change directing effect:

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Synthesis Strategies
Example:

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Synthesis Strategies
Problem-1: Starting with benzene and using any other necessary reagents of your choice, design synthesis for each of
the following compounds.

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Synthesis Strategies
Problem-2: Starting with benzene and using any other necessary reagents of your choice, design synthesis for each of
the following compounds.

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Synthesis Strategies
1)
2)
3)

80. 80 22-Jan-22
Ipso substitution: Substitution of an aromatic ring substituent (i.e., an attachment other than hydrogen).
The mechanism is usually nucleophilic aromatic substitution, but ipso substitution by an electrophilic aromatic
substitution mechanism is also possible.
Example-1:
Example-2:

81. 81 22-Jan-22
Ipso substitution: Substitution of an aromatic ring substituent (i.e., an attachment other than hydrogen).
The mechanism is usually nucleophilic aromatic substitution, but ipso substitution by an electrophilic aromatic
substitution mechanism is also possible.
Example-1:
Example-2:

82. 82 22-Jan-22
Arenediazonium ions are weak electrophiles; they react with highly reactive aromatic compounds—with phenols and
tertiary arylamines—to yield azo compounds. This electrophilic aromatic substitution is often called a diazo coupling
reaction.

83. 83 22-Jan-22
Example-1:

84. 84 22-Jan-22
Example-2:
Example-3:

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General Reaction: .
Mechanism: .
This reaction is limited to benzene and alkylbenzene.
Benzene Benzaldehyde

86. 86 22-Jan-22
General Reaction: .
Mechanism: .
Phenol Salicylaldehyde
Only for phenol

87. 87 22-Jan-22
Example-1:

88. 88 22-Jan-22
General Reaction: .
Mechanism: .
Phenol Ethyl acetoacetate
4-alkylcoumarin
(80-85% yield)
Coumarin Synthesis

89. 89 22-Jan-22
Example-1:
Example-2:
Example-3:

90. 90 22-Jan-22
General Reaction: .
Mechanism: .
Arene = Phenol/Aniline Arylketone
The reaction in which nitrile reacts with arene compound to form an arylketone.
The Hauben-Hoesch reaction refers specially to phenol as substrates, where the reaction is generally most useful.
Lewis Acid include ZnCl
2, AlCl
3, BCl
3

91. 91 22-Jan-22

92. 92 22-Jan-22
Example-1:
Example-2:

93. 93 22-Jan-22