1. Chapter 18 Electrophilic Aromatic Substitution
Organic Chemistry, Second Edition
Janice Gorzynski Smith
University of Hawai’i
Chapter 18 Electrophilic Aromatic Substitution
Prepared by Rabi Ann Musah
State University of New York at Albany
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

2. Electrophilic Aromatic Substitution
Chapter 18 Topics:
Electrophilic Aromatic Substitution (EAS).
Common EAS Reactions.
EAS uses a two step mechanism.
Energy diagram for the two step mechanism.
Halogenation, Nitration, Sulfonation, Friedel-Crafts Alkylation and Acylation.
EAS of Substituted Benzenes.
Reactivity of the aromatic ring.
Directing effect of the substituent on the ring.
o, p directors and m directors.
Benzylic vs aromatic halogenation.
Oxidation/reduction reactons.

3. Electrophilic Aromatic Substitution
Background:
The characteristic reaction of benzene is electrophilic aromatic substitution: a hydrogen atom is replaced by an electrophile.

4. Electrophilic Aromatic Substitution
Background:
Benzene does not undergo addition reactions like other unsaturated hydrocarbons, because addition would yield a product that is not aromatic.
Substitution of a hydrogen keeps the aromatic ring intact.
There are five common examples of electrophilic aromatic substitution.

5. Figure 18.1
Five examples
of electrophilic
aromatic
substitution

6. Electrophilic Aromatic Substitution
Mechanism of EAS:
Regardless of the electrophile used, all electrophilic aromatic substitution reactions occur by the same two-step mechanism:
Step 1: addition of an electrophile E+ to the aromatic ring forming a resonance-stabilized carbocation (sigma complex). This step requires the input of ~36 kcal of energy and the ring loses aromatic character.
Step 2: deprotonation of the carbocation intermediate regenerates aromaticity. The proton lost comes from the same carbon that was attacked by the electrophile.

7. Electrophilic Aromatic Substitution
Mechanism:

8. Electrophilic Aromatic Substitution
Background:
The first step in electrophilic aromatic substitution forms a carbocation, for which three resonance structures can be drawn. To help keep track of the location of the positive charge:

9. Electrophilic Aromatic Substitution
Background:
The energy changes in electrophilic aromatic substitution are shown below:
Figure Energy diagram for electrophilic aromatic substitution:
PhH + E+ → PhE + H+

10. Electrophilic Aromatic Substitution
Halogenation:
In halogenation, benzene reacts with Cl2 or Br2 in the presence of a Lewis acid catalyst, such as FeCl3 or FeBr3, to give the aryl halides chlorobenzene or bromobenzene respectively.
Analogous reactions with I2 and F2 are not synthetically useful because I2 is too unreactive and F2 reacts too violently.

11. Electrophilic Aromatic Substitution
Halogenation:
Chlorination proceeds by a similar mechanism.

12. Electrophilic Aromatic Substitution
Nitration and Sulfonation:
Nitration and sulfonation introduce two different functional groups into the aromatic ring.
Nitration is especially useful because the nitro group can be reduced to an NH2 group.

13. Electrophilic Aromatic Substitution
Nitration and Sulfonation:
Generation of the electrophile in nitration requires strong acid.
Generation of the electrophile in sulfonation requires strong acid.

14. Electrophilic Aromatic Substitution
Friedel-Crafts Alkylation and Friedel-Crafts Acylation:
In Friedel-Crafts alkylation, treatment of benzene with an alkyl halide and a Lewis acid (AlCl3) forms an alkyl benzene.

15. Electrophilic Aromatic Substitution
Friedel-Crafts Alkylation and Friedel-Crafts Acylation:
In Friedel-Crafts acylation, a benzene ring is treated with acid chloride (RCOCl) and AlCl3 to form a ketone.
Because the new group bonded to the benzene ring is called an acyl group, the transfer of an acyl group from one atom to another is an acylation.

16. Electrophilic Aromatic Substitution
Friedel-Crafts Alkylation:

17. Electrophilic Aromatic Substitution
Friedel-Crafts Alkylation:

18. Electrophilic Aromatic Substitution
Friedel-Crafts Acylation:
In Friedel-Crafts acylation, the Lewis acid AlCl3 ionizes the carbon-halogen bond of the acid chloride, thus forming a positively charged carbon electrophile called an acylium ion, which is resonance stabilized.
The positively charged carbon atom of the acylium ion then goes on to react with benzene in the two step mechanism of electrophilic aromatic substitution.

19. Electrophilic Aromatic Substitution
Friedel-Crafts Alkylation:
Four additional facts about Friedel-Crafts alkylation should be kept in mind:
[1] Vinyl halides and aryl halides are less reactive than alkyl halides so do not react in Friedel-Crafts alkylation.
[2] Alkyl groups activate the benene ring toward further EAS so polyalkylation can occur.

20. Electrophilic Aromatic Substitution
Friedel-Crafts Alkylation:
[3] Carbocation rearrangements can occur.
These results can be explained by carbocation rearrangements.

21. Electrophilic Aromatic Substitution
Friedel-Crafts Alkylation:

22. Electrophilic Aromatic Substitution
Friedel-Crafts Alkylation:
Rearrangements can occur even when no free carbocation is formed initially.

23. Electrophilic Aromatic Substitution
Friedel-Crafts Alkylation:
[4] Other functional groups that form carbocations can also be used as starting materials.

24. Electrophilic Aromatic Substitution
Friedel-Crafts Alkylation and Friedel-Crafts Acylation:
Each carbocation can then go on to react with benzene to form a product of electrophilic aromatic substitution. For example:
Starting materials that contain both a benzene ring and an electrophile are capable of intramolecular Friedel-Crafts reactions.

25. Electrophilic Aromatic Substitution
Substituted Benzenes:
Many substituted benzene rings undergo electrophilic aromatic substitution.
Each substituent either increases or decreases the electron density in the benzene ring, and this affects the course of electrophilic aromatic substitution.

26. Electrophilic Aromatic Substitution
Substituted Benzenes:
Considering the inductive effect, the NH2 group withdraws electron density. The CH3 donates electron density through hyperconjugation.

27. Electrophilic Aromatic Substitution
Substituted Benzenes:
Resonance effects are only observed with substituents containing lone pairs or  bonds.
An electron-donating resonance effect is observed whenever an atom Z having a lone pair of electrons is directly bonded to a benzene ring.

28. Electrophilic Aromatic Substitution
Substituted Benzenes:
An electron-withdrawing resonance effect is observed in substituted benzenes having the general structure C6H5-Y=Z, where Z is more electronegative than Y.
Seven resonance structures can be drawn for benzaldehyde (C6H5CHO). Because three of them place a positive charge on a carbon atom of the benzene ring, the CHO group withdraws electrons from the benzene ring by a resonance effect.

29. Electrophilic Aromatic Substitution
Substituted Benzenes:
To predict whether a substituted benzene is more or less electron rich than benzene itself, one must consider the net balance of both the inductive and resonance effects.
For example, alkyl groups donate electrons by an inductive effect, but they have no resonance effect because they lack nonbonded electron pairs or  bonds.
Thus, any alkyl-substituted benzene is more electron rich than benzene itself.

30. Electrophilic Aromatic Substitution
Substituted Benzenes:
The inductive and resonance effects in compounds having the general structure C6H5-Y=Z (with Z more electronegative than Y) are both electron withdrawing.

31. Electrophilic Aromatic Substitution
Substituted Benzenes:
These compounds represent examples of the general structural features in electron-donating and electron withdrawing substituents.

32. Electrophilic Aromatic Substitution
EAS and Substituted Benzenes:
Electrophilic aromatic substitution is a general reaction of all aromatic compounds, including polycyclic aromatic hydrocarbons, heterocycles, and substituted benzene derivatives.
A substituent affects two aspects of the electrophilic aromatic substitution reaction:
The rate of the reaction: A substituted benzene reacts faster or slower than benzene itself.
The orientation: The incoming group is located either ortho, meta, or para to the substituent already present. The identity of the existing substituent determines the position of the new substituent.

33. Electrophilic Aromatic Substitution
EAS and Substituted Benzenes:
First, consider toluene—Toluene reacts faster than benzene in all substitution reactions.
The electron-donating CH3 group activates the benzene ring to electrophilic attack.
Ortho and para products predominate.
The CH3 group is called an ortho, para director.

34. Electrophilic Aromatic Substitution
EAS and Substituted Benzenes:
Now consider nitrobenzene—It reacts more slowly than benzene in all substitution reactions.
The electron-withdrawing NO2 group deactivates the benzene ring to electrophilic attack.
The meta product predominates.
The NO2 group is called a meta director.

35. Electrophilic Aromatic Substitution
EAS and Substituted Benzenes:
All substituents can be divided into three general types:

36. Electrophilic Aromatic Substitution
EAS and Substituted Benzenes:

37. Electrophilic Aromatic Substitution
EAS and Substituted Benzenes:
Keep in mind that halogens are in a class by themselves.
Also note that:

38. Electrophilic Aromatic Substitution
EAS and Substituted Benzenes:
To understand how substituents activate or deactivate the ring, we must consider the first step in electrophilic aromatic substitution.
The first step involves addition of the electrophile (E+) to form a resonance stabilized carbocation.
The Hammond postulate makes it possible to predict the relative rate of the reaction by looking at the stability of the carbocation intermediate.

39. Electrophilic Aromatic Substitution
EAS and Substituted Benzenes:
The principles of inductive effects and resonance effects can now be used to predict carbocation stability.

40. Electrophilic Aromatic Substitution
EAS and Substituted Benzenes:
The energy diagrams below illustrate the effect of electron-withdrawing and electron-donating groups on the transition state energy of the rate-determining step.
Figure Energy diagrams comparing the rate of
electrophilic substitution of substituted benzenes

41. Electrophilic Aromatic Substitution
EAS and Substituted Benzenes:

42. Electrophilic Aromatic Substitution
Orientation Effects in Substituted Benzenes:
There are two general types of ortho, para directors and one general type of meta director.
All ortho, para directors are R groups or have a nonbonded electron pair on the atom bonded to the benzene ring.
All meta directors have a full or partial positive charge on the atom bonded to the benzene ring.

43. Electrophilic Aromatic Substitution
Orientation Effects in Substituted Benzenes:
To evaluate the effects of a given substituent, we can use the following stepwise procedure:

44. Electrophilic Aromatic Substitution
Orientation Effects in Substituted Benzenes:
A CH3 group directs electrophilic attack ortho and para to itself because an electron-donating inductive effect stabilizes the carbocation intermediate.

45. Electrophilic Aromatic Substitution
Orientation Effects in Substituted Benzenes:
An NH2 group directs electrophilic attack ortho and para to itself because the carbocation intermediate has additional resonance stabilization.

46. Electrophilic Aromatic Substitution
Orientation Effects in Substituted Benzenes:
With the NO2 group (and all meta directors) meta attack occurs because attack at the ortho and para position gives a destabilized carbocation intermediate.

47. Electrophilic Aromatic Substitution
Orientation Effects in Substituted Benzenes:
Figure The reactivity and
directing effects of common
substituted benzenes

48. Electrophilic Aromatic Substitution
Relative rates of reaction for some monosubstituted benzenes
Aniline Toluene Benzene ChloroΦ NitroΦ
Strong Strong Activator Deactivator

49. Electrophilic Aromatic Substitution
Limitations in Electrophilic Aromatic Substitutions:
Benzene rings activated by the strong electron-donating groups, OH, NH2, and their derivatives (OR, NHR, and NR2), undergo polyhalogenation when treated with X2 and FeX3.

50. Electrophilic Aromatic Substitution
Limitations in Electrophilic Aromatic Substitutions:
A benzene ring deactivated by strong electron-withdrawing groups (i.e., any of the meta directors) is not electron rich enough to undergo Friedel-Crafts reactions.
Friedel-Crafts reactions also do not occur with NH2 groups because the complex that forms between the NH2 group and the AlCl3 catalyst deactivates the ring towards Friedel-Crafts reactions.

51. Electrophilic Aromatic Substitution
Limitations in Electrophilic Aromatic Substitutions:
Treatment of benzene with an alkyl halide and AlCl3 places an electron-donor R group on the ring. Since R groups activate the ring, the alkylated product (C6H5R) is now more reactive than benzene itself towards further substitution, and it reacts again with RCl to give products of polyalkylation.
Polysubstitution does not occur with Friedel-Crafts acylation.

52. Electrophilic Aromatic Substitution
Disubstituted Benzenes:
When the directing effects of two groups reinforce, the new substituent is located on the position directed by both groups.

53. Electrophilic Aromatic Substitution
Disubstituted Benzenes:
2. If the directing effects of two groups oppose each other, the more powerful activator controls the reaction.

54. Electrophilic Aromatic Substitution
Disubstituted Benzenes:
3. No substitution occurs between two meta substituents because of crowding.

55. Electrophilic Aromatic Substitution
Planning Synthesis of Benzene Derivatives:
In a disubstituted benzene, the directing effects indicate which substituent must be added to the ring first.
Let us consider the consequences of bromination first followed by nitration, and nitration first, followed by bromination.

56. Electrophilic Aromatic Substitution
Pathway I, in which bromination precedes nitration, yields the desired product. Pathway II yields the undesired meta isomer.

57. Electrophilic Aromatic Substitution
Halogenation of Alkyl Benzenes:
Benzylic C—H bonds are weaker than most other sp3 hybridized C—H bonds, because homolysis forms a resonance-stabilized benzylic radical.
As a result, alkyl benzenes undergo selective bromination at the weak benzylic C—H bond under radical conditions to form the benzylic halide.

58. Electrophilic Aromatic Substitution
Halogenation of Alkyl Benzenes:

59. Electrophilic Aromatic Substitution
Halogenation of Alkyl Benzenes:
Note that alkyl benzenes undergo two different reactions depending on the reaction conditions:
With Br2 and FeBr3 (ionic conditions), electrophilic aromatic substitution occurs, resulting in replacement of H by Br on the aromatic ring to form o and p isomers.
With Br2 and light or heat (radical conditions), substitution of H by Br occurs at the benzylic carbon of the alkyl group.

60. Electrophilic Aromatic Substitution
Oxidation and Reduction of Substituted Benzenes:
Arenes containing at least one benzylic C—H bond are oxidized with KMnO4 to benzoic acid.
Substrates with more than one alkyl group are oxidized to dicarboxylic acids. Compounds without a benzylic hydrogen are inert to oxidation.

61. Electrophilic Aromatic Substitution
Oxidation and Reduction of Substituted Benzenes:
Ketone products of Friedel-Crafts acylation can be reduced to alkyl benzenes by two different methods:
The Clemmensen reduction—uses zinc and mercury in the presence of strong acid.
The Wolff-Kishner reduction—uses hydrazine (NH2NH2) and strong base (KOH).

62. Electrophilic Aromatic Substitution
Oxidation and Reduction of Substituted Benzenes:
We now know two different ways to introduce an alkyl group on a benzene ring:
A one-step method using Friedel-Crafts alkylation.
A two-step method using Friedel-Crafts acylation to form a ketone, followed by reduction.
Figure Two
methods to prepare
an alkyl benzene

63. Electrophilic Aromatic Substitution
Oxidation and Reduction of Substituted Benzenes:
Although the two-step method is longer, it must be used to synthesize certain alkyl benzenes that cannot be prepared by the one-step Friedel-Crafts alkylation because of possible rearrangements.

64. Electrophilic Aromatic Substitution
Oxidation and Reduction of Substituted Benzenes:
A nitro group (NO2) that has been introduced on a benzene ring by nitration with strong acid can readily be reduced to an amino group (NH2) under a variety of conditions.

65. Electrophilic Aromatic Substitution
The Gatterman-Koch Reaction:
Formylation of benzene using the Gatterman-Koch reaction is similar to the Friedel Crafts acylation.

66. Nucleophilic Aromatic Substitution
Two common NAS mechanisms:
1. Addition-elimination requires strong electron withdrawing groups on the ring to render it suceptable to attack by a nucleophile.

67. Nucleophilic Aromatic Substitution
Two common NAS mechanisms:
2. The benzyne mechanism accounts for two possible products.

68. End Chapter 18 Organic Chemistry, Second Edition
Janice Gorzynski Smith
University of Hawai’i
End Chapter 18
Prepared by Rabi Ann Musah
State University of New York at Albany
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.