1. Chemistry of Benzene: Electrophilic Aromatic Substitution
Chapter 16
Chemistry of Benzene: Electrophilic Aromatic Substitution
Suggested Problems – 1-23,34,37-8,40,46-7,49,51,53-8

2. Electrophilic Aromatic Substitution
The most common reaction of aromatic compounds is electrophilic aromatic substitution, in which an electrophile (E+) reacts with an aromatic ring and substitutes for one of the hydrogens.
Indeed, the ability of a compound to undergo electrophilic substitution is a good test of aromaticity.
Many different substituents can be introduced onto an aromatic ring through electrophilic substitution.

3. Electrophilic Aromatic Substitution Reactions: Bromination
An electrophile reacts with an aromatic ring to substitute a hydrogen on the ring
The beginning of the reaction is similar to that of electrophilic alkene reactions
The difference is that alkenes react more readily with electrophiles than aromatic rings
In the bromination of benzene, a catalyst such as FeBr3 is used
Aromatic rings are less reactive toward electrophiles than alkenes. For example, while bromine in dichloromethane solution reacts instantly with most alkenes, it does not react readily with benzene at room temperature. For bromination of benzene to take place, a catalyst such as FeBr3 is needed. The catalyst makes the Br2 molecule more electrophilic by polarizing it to give an FeBr4-Br+ species that reacts as if it were Br+. The polarized Br2 molecule then reaccts with the nucleophilic benzene ring to yield a nonaromatic carbocaation intermediate that is doubly allylic and has three resonance forms.

4. Electrophilic Aromatic Substitution Reactions: Bromination
Stability of the intermediate in electrophilic aromatic substitution is lesser than that of the starting benzene ring
Reaction of an electrophile is endergonic, possesses substantial activation energy, and is comparatively slow
Although more stable than a typical alkyl carbocation because of resonance, the intermediate in electrophilic aromatic substitution is nevertheless much less stable than the starting benzene ring itself, with its 150 kJ/mol of aromatic stability. Thus, the reaction of an electrophile with a benzene ring is endergonic, has a substantial activation energy, and is rather slow.

5. Electrophile Reactions With an Alkene and With Benzene
The benzene reaction is slower than that of an alkene because the starting material is more stable.

6. Electrophilic Bromination of Benzene
Another difference between alkene addition and aromatic substitution occurs after the carbocation intermediate has formed. Instead of adding Br- to give an addition product, the carbocation intermediate loses H+ from the bromine-bearing carbon to give a substitution product. The net effect of reaction with Br2 with benzene is substitution of H+ by Br+ by the overall mechanism shown.

7. Electrophile Reactions With an Alkene and With Benzene
Why does the reaction with Br2 take a different course than its reacction with an alkene?
Answer: If an addition occurs, the 150 kJ/mol stabilization energy of the aromatic ring would be lost and the overall reacction would be endergonic. When substitution occurs, though, the stability of the aromatic ring is retained and the reaction is exergonic.

8. Worked Example
Monobromination of toluene gives a mixture of three bromotoluene products
Draw and name them
Solution:
In practice, bromination of toluene often only leads to the ortho and para isomers and very little if any of the meta isomer.

9. Other Aromatic Substitutions
Chlorine, bromine, and iodine can be introduced into aromatic rings by electrophilic aromatic substitution reactions.
Fluorine is too reactive to be introduced directly
Can be introduced using Selectfluor.
Selectfluor contains a fluorine atom bonded to a positively charged nitrogen.

10. Other Aromatic Substitutions
Aromatic rings produce chlorobenzenes when they react with Cl2 using FeCl3 as a catalyst
Pharmaceutical agents such as Claritin are manufactured by a similar reaction

11. Other Aromatic Substitutions
Since iodine is unreactive toward aromatic rings, oxidizing agents such as CuCl2 are used as a catalyst
CuCl2 oxidizes I2 resulting in the production of a substitute
Additionally hydrogen peroxide oxidizes iodine to H-O-I which is a source of I+ that can be used to effect iodination.

12. Natural Electrophilic Aromatic Halogenations
Widely found in marine organisms
Occurs in the biosynthesis of thyroxine in humans
Thyroxine is a hormone involved in regulating growth and metabolism.

13. Aromatic Nitration
Combination of concentrated nitric acid and sulfuric acid results in NO2+ (nitronium ion)
Reaction with benzene produces nitrobenzene
Electrophilic nitration of an aromatic ring does not occur in nature but is an important reaction in the laboratory because the nitro group can be reduced to yield an arylamine, such as aniline.

14. Aromatic Sulfonation
Occurs by a reaction with fuming sulphuric acid, a mixture of H2SO4, and SO3
The reactive electrophile is either HSO3+ or neutral SO3
In contrast to other electrophilic aromatic substitution reactions, electrophilic aromatic sulfonation is readily reversible. The forward reaction is favored in strong acid. The reverse reaction is favored in hot dilute aqueous acid.
Aromatic sulfonation does not occur naturally.

15. Aromatic Hydroxylation
Direct hydroxylation of an aromatic ring is difficult in the laboratory
Usually occurs in biological pathways
In biological systems the enzyme is responsible for an OH+ which hydroxylates the aromatic ring.

16. Mechanism for the Electrophilic Hydroxylation of p-hydroxyphenylacetate
Oxygen adds to FADH2 which constitutes the positive source of the hydroxyl group.

17. Worked Example
Propose a mechanism for the electrophilic fluorination of benzene with F-TEDA-BF4 (Selectfluor).
Solution:

18. Worked Example
The pi electrons of benzene attack the fluorine of F-TEDA-BF4
The nonaromatic intermediate loses –H to give the fluorinated product

19. Alkylation of Aromatic Rings: The Friedel-Crafts Reaction
Alkylation: Introducing an alkyl group onto the benzene ring
Also called the Friedel-Crafts reaction
Involves treatment of an aromatic compound with an alkyl chloride in the presence of AlCl3
An alkyl carbocation electrophile, R+, is the intermediate that adds to the aromatic ring
Aluminum chloride catalyzes the reaction by helping the alkyl halide to dissociate in much the same way that FeBr3 catalyzes aromatic brominations by polarizing Br2.

20. Mechanism of the Friedel-Crafts Reaction

21. Limitations of the Friedel-Crafts Reaction
Only alkyl halides can be used (F, Cl, I, Br)
High energy levels of aromatic and vinylic halides are not suitable to Friedel-Crafts requirements (carbocations do not form)
Not feasible on rings containing an amino group substituent or a strong electron-withdrawing group
Aryl and vinyl carbocations are too high in energy to form.
Substituents on aromatic rings have a large effect on the reactivity and regioselectivity of products generated in many electrophilic aromatic substitution reactions.
Basic amino groups that can be protonated and strong electron-withdrawing groups decrease the reactivity of aromatic rings toward the Friedel-Crafts reaction

22. Limitations of the Friedel-Crafts Reaction
Termination of the reaction allowing a single substitution is difficult
Polyalkylation occurs
Introduction of one alkyl substituent on an aromatic ring employing the Friedel-Crafts reaction increases the reactivity of the product relative to the starting material.

23. Limitations of the Friedel-Crafts Reaction
Occasional skeletal rearrangement of the alkyl carbocation electrophile
Occurs more often with the use of a primary alkyl halide
As might be expected, if a carbocation is an intermediate is formed, as it is in the formation of the electrophile in this reaction, rearrangements to form more stable carbocations are possible, with the result that the alkylating species may not be as expected.

24. Acylation of Aromatic Rings
Acylation: Reaction of an aromatic ring with a carboxylic acid chloride in the presence of AlCl3 resulting in an acyl group substitution

25. Mechanism of Friedel-Crafts Acylation
Similar to Freidel-Crafts alkylation and also possesses the same limitations on the aromatic substrate
The reactive species is the resonance stabilized acyl cation.
In contrast to the case for Friedel-Craft alkylation, rearrangements of the electrophilic partner do not occur with Friedel-Craft acylations.
Friedel-Craft acylations on aromatic rings containing amine substituents or strong electron withdrawing substituents do not occur in analogy to the case with Friedel-Craft alkylations.
In contrast to the case for Friedel-Craft alkylations, once an acyl group is introduced onto an aromatic ring, a second acylation will not occur; the product acylbenzene is less reactive than the nonacylated starting material.

26. Alkylation of Aromatic Rings: The Friedel-Crafts Reaction
Natural aromatic alkylations are a part of many biological pathways
Catalyzing effect of AlCl3 is replaced by organodiphosphate dissociation
In biological systems, the carbocation electrophile is typically formed by dissociation of an organodiphosphate (with assistance from a magnesium cofactor).

27. Biosynthesis of Phylloquinone from 1,4- dihydroxynaphthoic Acid
In this biological reaction, phytyl diphosphate first dissociates to a resonance stabilized allylic carbocaton, which then substitutes onto the aromatic ring in the typical way.

28. Worked Example
Identify the carboxylic acid that might be used in a Friedel-Crafts acylation to prepare the following acylbenzene

29. Worked Example Solution:
Identification of the carboxylic acid chloride used in the Friedel-Crafts acylation of benzene involves:
Breaking the bond between benzene and the ketone carbon
Using a –Cl replacement

30. Substituent Effects in Substituted Aromatic Rings
Reactivity of the aromatic ring is affected
Substitution can result in an aromatic ring with a higher or a lower reactivity than benzene
Substituents affect the orientation of the reaction
Some substituents direct reactions at ortho and para positions
Some substituents direct reactions at meta positions

31. Substituent Effects in Substituted Aromatic Rings
Reactivity of the aromatic ring is affected
Substitution can result in an aromatic ring with a higher or a lower reactivity than benzene
Some substituents activate the ring, making it more reactive than benzene.
Some substituents deactivate the ring, making it less reactive than benzene.
In aromatic nitration, for example, an –OH substitutent makes the ring 1000 times more reactive than benzene, while an –NO2 substituent makes the ring more than 10 million times less reactive.

32. Orientation of Nitration in Substituted Bezenes
The three possible disubstituted products – ortho, meta, and para – are usually not formed in equal amounts.
Instead the nature of the substituent initially present on the benzene ring determines the positin of the second substitution. An –OH group directs substitutuion toward the ortho and para positions, for instance, while a carbonyl group such as –CHO directs substitution primarily toward the meta position.
Substituents can be classified into three groups: ortho- and para-directing activators, ortho- and para-directing deactivators, and meta-directing deactivators. There are no meta-directing activators.

33. Classification of Substituent Effects in Electrophilic Aromatic Substitution
Notice how the directing effect of a group correlates with its reactivity. All meta-directing groups are strongly deactivatint, and most orth- and para-directing groups are activating. The halogens are unique in being ortho- and para-directing but weakly activating.

34. Worked Example
Predict the major product in the nitration of bromobenzene
Solution:
Even though bromine is a deactivator, it is used as an ortho-para director

35. Activating or Deactivating Effects
Activating groups contribute electrons to the aromatic ring
The ring possesses more electrons
The carbocation intermediate is stabilized
Activation energy is lowered
Deactivating groups withdraw electrons from the aromatic ring
The ring possesses fewer electrons
The carbocation intermediate is destabilized
Activation energy is increased

36. Activating or Deactivating Effects

37. Origins of Substituent Effects
Inductive effect: Withdrawal or donation of electrons through a sigma bond due to electronegativity
Prevalent in halobenzenes and phenols
The withdrawal or donation of electrons by a substituent group is controlled by an interplay of inductive effects and resonance effects.
Halogens, hyddroxyl groups, carbonyl groups, cyano groups, and nitro groups inductively withdraw electrons through the sigma bond linking the substituent to a benzene ring. This effect is most pronounced in halobenzenes and phenols, in which the electronegative atom is directly attached to the ring, but is also significant in carbonyl compounds, nitriles, and nitro compounds, in which the electronegative atom is farther removed.
Alkyl groups, on the other hand, inductively donate electrons. This is the same hyperconjugative donating effect that causes alkyl substituents to stabilize alkenes and carbocations.

38. Resonance Effects - Electron Withdrawal
Resonance effect: Withdrawal or donation of electrons through a  bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring
Carbonyl, cyano, and nitro substituents withdraw electrons from the aromatic ring by resonance. The pi electrons flow from the ring to the substituent, leaving a positive charge in the ring.
Note that substituents with an electron-withdrawing resonance effect have the general structure –Y=Z, where the Z atom is more electronegative than Y.

39. Resonance Effects - Electron Donation
Halogen, hydroxyl, alkoxyl (-OR), and amino substituents donate electrons to the aromatic ring by resonance. Lone-pair electrons flow from the substituents to the ring, placing a negative charge on the ring. Substituents with an electron-donating resonance effect have the general structure –Y:, where the Y atom has a lone pair of electrons available for donation to the ring.
Note: inductive effects and resonance effects don’t necessarily act in the same direction. Halogen, hydroxyl, alkoxyl, and amino substituents, for instance, have electron-withdrawing inductive effects because of the electronegativity of the –X, -O, or –N atom bonded to the aromatic ring but have electron-donating resonance effects because of the lone-pair electrons on those –X, -O, or –N atoms.
When the two effects work in opposition, the stronger one dominates.
The hydroxyl, alkoxyl, and amino substituents are activators because their stronger electron-donating resonance effect outweighs their weaker electon-withdrawing inductive effect.
Halogens, in contrast, are deactivators because their stronger electron-withdrawing inductive effect outweighs their weaker electron-donating resonance effect.

40. Worked Example
Explain why Freidel-Crafts alkylations often give poly-substitution reactions but Freidel-Crafts acylations do not

41. Worked Example Solution An acyl substituent is deactivating
Once an aromatic ring has been acylated, it is less reactive to further substitution
An alkyl substituent is activating; thus, an alkyl-substituted ring is more reactive than an unsubstituted ring
Polysubstitution occurs readily

42. Ortho- and Para-Directing Activators: Alkyl Groups
Alkyl groups possess an electron-donating inductive effect
Inductive and resonance effects account not only for reactivity but also for the orientation of electrophilic aromatic substitutions.
Alkyl groups have an electron-donating inductive effect and are ortho and para directors.
Although all three intermediates are resonance-stabilized, the ortho and para intermediates are more stabilized than the meta intermediate in the nitration of toluene.
For both the ortho and para reactions, but no for the meta reaction, a resonance form places the positive charge directly on the methyl-substituted carbon, where it is in a tertiary posibion and can be stabilized by the electron-donating inductive effect of the methyl group. The ortho and para intermediates are thus lower in energy than the meta intermediate and form faster.

43. Ortho- and Para-Directing Activators: OH and NH2
Hydroxyl, alkoxyl, and amino groups possess a strong, electron-donating resonance effect
Hydroxyl, alkoxyl, and amino groups are also ortho-para activators, but for different a different reason than for alkyl groups.
Hydroxyl, alkoxyl, and amino groups have a strong, electron-donating resonance effect that outweighs a weaker electron-withdrawing inductive effect.
When phenol is nitrated, for example, the ortho and para intermediates are more stable than the meta intermediate because they have more resonance forms, including one particularly favorable form that allows the positve charge to be stabilized by electron donation from the substituent oxygen atom. The intermediate from the meta reaction has no such stabilization.

44. Worked Example
Explain why acetanilide is less reactive than aniline toward electrophilic substitution

45. Worked Example
Solution:

46. Worked Example
For acetanilide, resonance delocalization of the nitrogen lone pair electrons to the aromatic ring is less favoured
Positive charge on nitrogen is next to the positively polarized carbonyl group
The electronegativity of oxygen favors resonance delocalization to the carbonyl oxygen
In acetanilide, the decreased availability of nitrogen lone pair electrons results in decreased reactivity of the ring toward electrophilic substitution
Acetanilide kicks its lone pair into the carbonyl group rather than the benzene ring. Oxygen is more electronegative than the benzene ring and the negative charge is best accommodated by it.

47. Ortho- and Para-Directing Deactivators: Halogens
Deactivation is caused by the dominance of the stronger electron-withdrawing inductive effect over the weaker electron-donating resonance effect
Electron donating resonance effect is present only at the ortho and para positions
Ortho and para reactions can cause stabilization of the positive charge in the carbocation intermediates
Meta intermediates take more time to form
Although weak, the electron-donating resonance effect of halogens is felt only at the ortho and para positions and not at the meta position.

48. Carbocation Intermediates in the Nitration of Chlorobenzene
A halogen substituent can stabilize the positve charge of the carbocation intermediates from ortho and para reaction in the same way that hydroxyl and amino substituents can. The meta intermediate, however, has no such stabilization and is therefore formed more slowly.
Halogens have a stronger electron-withdrawing inductive effect but a weaker electron-donating resonance effect and are thus deactivators. Hydroxyl, alkoxyl, and amino groups have a weaker electron-withdrawing inductive effecct but a stronger electron-donating resonance effect and are thus activators. All are ortho and para directors, however, because of the lone pair of electrons on the atom bonded to the aromatic ring.

49. Meta-Directing Deactivators
The meta intermediate has three favorable resonance forms
Ortho and para intermediates possess only two
The carbonyl group is deactivating and directs nitration to the meta position in benzaldehyde.
In both ortho and para intermediates, one resonance form is highly unfavorable because it places the positive charge directly on the carbon that bears the aldehyde group, where it is disfavored by a repulsive interaction with the positively polarized carbon of the C=O group.
Hence, the meta intermediate has no such unstable resonance form, is more favored, and is formed faster than the ortho and para intermediates.
In general, any substituent that has a positively polarized atom directly attached to the ring will make one of the resonance forms of the ortho and para intermediates unfavorable and will thus act as a meta director.

50. Worked Example
Draw resonance structures for the intermediates from the reaction of an electrophile at the ortho, meta, and para positions of nitrobenzene
Determine which intermediates are most stable

51. Worked Example Solution:
While deactivating, the nitro group directs substitution to the meta position.

52. Substituent Effects in Electrophilic Aromatic Substitution
This slide provides a summary of activating and directing effects of substituents in electrophilic aromatic substitution.

53. Trisubstituted Benzenes: Additivity of Effects
Additivity effects are based on three rules:
The situation is straightforward if the directing effects of the groups reinforce each other
Electrophilic substitution of a disubstituted benzene ring is governed by the same resonance and inductive effects that influence monosubstituted rings.
The only difference is that ist’s necessary to consider the additive effects of two different groups.
In the case above, both groups direct substitution to the same position and only one isomer is formed.

54. Trisubstituted Benzenes: Additivity of Effects
If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome
Usually gives mixtures of products
Both the hydroxyl and methyl group are ortho and para activators. The hydroxyl group is the more powerful and nitration ortho to it is the favored product.

55. Trisubstituted Benzenes: Additivity of Effects
Substitution between two groups is rare when they are in a meta-disubstituted compound as the site is too hindered
An alternate route must be taken in the preparation of aromatic rings with three adjacent substituents
The best way to prepare an aromatic ring with three adjacent substituents is to effect substituion on an ortho disubstituted compound.

56. Worked Example
Determine the position at which electrophilic substitution occurs in the following substance

57. Worked Example Solution:
Both groups are ortho-para directors and direct substitution to the same positions
Attack does not occur between the two groups for steric reasons

58. Nucleophilic Aromatic Substitution
Aryl halides with electron-withdrawing substituents can also undergo a nucleophilic substitution reaction

59. Nucleophilic Aromatic Substitution
Not very common
Use
Reaction of proteins with Sanger’s reagent results in a label being attached to one end of the protein chain
p. 592b

60. Nucleophilic Aromatic Substitution
Reaction is superficially similar to the SN1 and SN2 nucleophilic substitutions
Aryl halides are inert to both SN1 and SN2 conditions
Mechanism must be different
SN1 reactions do not occur with aryl halides because dissociation of the halide is energetically unfavorable, due to the instability of the potential aryl cation product.
SN2 reactions do not occur with aryl halides because the halo-substituted carbon of the aromatic ring is sterically shielded from a backside approach. For a nucleophile to react with an aryl halide, it would have to approach directly through the aromatic ring and invert the stereochemistry of the aromatic carbon – a geometric impossibility.
p. 592c

61. Mechanism of Nucleophilic Aromatic Substitution
In nucleophilic aromatic substitution, the nucleophile first adds to the electron-deficient aryl halide, forming a resonance-stabilized, negatively charged intermediate called a Meisenheimer complex. Halide ion is then eliminated.

62. Nucleophilic Aromatic Substitution of Nitrochlorobenzenes
Nucleophilic aromatic substituion occurs only if the aromatic ring has an electron-withdrawing substituent in a position ortho or para to the leaving group to stabilize the anion intermediate through resonance. A meta substituent offers no such resonance stabilization.

63. Differences Between Electrophilic and Nucleophilic Aromatic Substitutions
Electrophilic substitutions
Nucleophilic substitutions
Favored by electron-donating substituents
Electron-withdrawing groups cause ring deactivation
Electron-withdrawing groups are meta directors
Replace hydrogen on the ring
Favored by electron-withdrawing substituents
Electron-withdrawing groups cause ring activation
Electron withdrawing groups are ortho-para directors
Replace a leaving group
In electrophilic aromatic substitutions, electron-donating substituents stabilize a carbocation intermediate.
In nucleophilic aromatic substitions, electron-withdrawing substituents stabilize a carbanion intermediate.
Thus, the electron-withdrawing groups that deactivate rings for electrophilic substituion (nitro, carbonykl, cyano, etc.) activate them for nucleophilic substituion.

64. Worked Example
Propose a mechanism for the preparation of oxyfluorfen, a herbicide, through the reaction between phenol and an aryl fluoride

65. Worked Example Solution: Step 1: Addition of the nucleophile
Step 2: Elimination of the fluoride ion

66. Benzyne
On a general basis, there are no reactions between nucleophiles and halobenzenes that do not have electron withdrawing substituents
High temperatures can be used to make chlorobenzene react

67. Benzyne A similar substitution reaction is observed with bromobenzene.
The reaction is not a nucleophilic substitution reaction, however.
Equal distribution of labeling at two adjacent positions suggests a symmetrical intermediate.
p. 595a

68. Benzyne
A Diels-Adler reaction occurs when bromobenzene reacts with KNH2 in the presence of a conjugated diene, such as furan
Elimination of HBr from bromobenzene forms a benzyne as the chemical intermediate
Benzyne is too reactive to be isolated as a pure compound, but in the presence of water, addition occurs to give a phenol.
In the presence of a diene, Diels-Alder cycloaddition takes place.

69. Benzyne
Benzyne has the electronic structure of a highly distorted alkyne
The benzyne triple bond uses sp2-hybridized carbon atoms

70. Worked Example
Explain why the treatment of p-toluene with NaOH at 300°C yields a mixture of two products, but treatment of m-bromotoluene with NaOH yields a mixture of two or three products

71. Worked Example
Solution:

72. Oxidation of Aromatic Compounds
In the presence of an aromatic ring, alkyl side chains are converted to carboxyl groups through oxidation
Alkylbenzene is converted to benzoic acid
The benzene ring is inert to strong oxidizing agents such as KMnO4 amd Na2Cr2O7, reagents that will cleave alkene carbon-carbon bonds.
The presence of an aromatic ring has a dramatic effect on alkyl side chains, however. These side chains react rapidly with oxidizing agents and are converted into carboxyl groups, -CO2H.
The net effect is conversion of an alkylbenzene into a benzoic acid, Ar-CO2H.

73. Oxidation of Aromatic Compounds
Side-chain oxidation involves a complex mechanism wherein C–H bonds next to the aromatic ring react to form intermediate benzylic radicals
Analogous side-chain reactions are a part of many biosynthetic pathways
Tert-Butylbenzen has no benzylic hydrogens, and is therefore inert.
Note the stereospecificity of the norepinephrine reaction – this is because of the chiral environment imparted by enzyme catalysis.

74. Worked Example
Mention the aromatic substance that is obtained if KMnO4 undergoes oxidation with the following substance

75. Worked Example Solution:
Oxidation takes place at the benzylic position
This reaction only works because there is a benzylic hydrogen. In it’s absence, with tert-butylbenzene for example, no reaction will occur.

76. Bromination of Alkylbenzene Side Chains
Occurs when an alkylbenzene is treated with N-bromosuccinimide (NBS)

77. Mechanism of NBS (Radical) Reaction
Abstraction of a benzylic hydrogen atom generates an intermediate benzylic radical
Benzylic radical reacts with Br2 to yield product and a Br. radical
Br. radical cycles back into reaction to carry on the chain reaction
Br2 is produced when HBr reacts with NBS
Bromination occurs exclusively next to the aromatic ring and does not give a mixture of products.

78. Mechanism of NBS (Radical) Reaction
· ·

79. Bromination of Alkylbenzene Side Chains
The reaction of HBr with NBS occurs only at the benzylic position
The benzylic radical intermediate is stabilized by resonance
The p orbital of the benzyl radical overlaps with the ringed  electron system

80. Worked Example
Styrene, the simplest alkenylbenzene, is prepared for commercial use in plastics manufacture by catalytic dehydrogenation of ethylbenzene
Prepare styrene from benzene

81. Worked Example Solution:
A good synthesis – something you might want to remember.

82. Reduction of Aromatic Compounds
Aromatic rings are inert to catalytic hydrogenation under conditions that reduce alkene double bonds
Alkene double bonds can be selectively reduced in the presence of an aromatic ring employing standard conditions

83. Reduction of Aromatic Compounds
Reduction of an aromatic ring requires either:
A platinum catalyst and a pressure of several hundred atmospheres
A catalyst such as rhodium or carbon

84. Reduction of Aryl Alkyl Ketones
An aromatic ring activates a neighboring carbonyl group toward reduction
An aryl alkyl ketone can be converted into an alkylbenzene by catalytic hydrogenation over a palladium catalyst
In the same way that an aromatic ring activates a neighboring (benzylic) C-H toward oxidation, it also activates a benzylic carbonyl group toward reduction.
Since the net effect of Friedel-Crafts acylation followed by reduction is the preparation of a primary alkylbenzene, this two-step sequence of reactions makes it possible to circumvent the carbocation rearrangment problems associated with direct Friedel-Crafts alkylation using a primary alkyl halide.

85. Reduction of Aryl Alkyl Ketones
Only aryl alkyl ketones can be converted into a methylene group by catalytic hydrogenation
Nitro substituents hinder the catalytic reduction of aryl alkyl ketones
Nitro group undergoes reduction to form an amino group
Dialkyl ketone carbonyls are not converted to methylene groups under these conditions.
The catalytic reduction of aryl alkyl ketones is not compatible with the presence of a nitro substituent on the aromatic ring which is readily hydrogenated to an aniline under these conditions.

86. Worked Example
Prepare diphenylmethane, (Ph)2CH2, from benzene and an acid chloride
Solution:

87. Synthesis of Polysubstituted Benzenes
Working synthesis reactions is one of the best ways to learn organic chemistry
Knowledge on using the right reactions at the right time is vital to a successful scheme
Ability to plan a sequence of reactions in right order is valuable to synthesis of substituted aromatic rings

88. Worked Example Synthesize m-Chloronitrobenzene from benzene Solution:
In order to synthesize the product with the correct orientation of substituents, benzene must be nitrated before it is chlorinated

89. Practice Problems

90. Designing a Synthesis two routes for the synthesis of 2-phenylethanol
The preferred route depends on the number of steps, the complexity of each reaction, and the overall yield.
The first route is preferable.

91. The Order of the Reactions is Important

92. The Order of the Reactions is Important
The acetyl group must be added first because a Friedel–Crafts acylation will not occur with a meta director on the ring.

93. The Order of the Reactions is Important

94. Designing a Synthesis
The first alkyl group is added by Friedel–Crafts reaction.
A Friedel–Crafts reaction will not work with a meta director on the ring,
so the second alkyl group must be added by a coupling reaction.

95. Designing a Synthesis

96. The Synthesis of Trisubstituted Benzenes
The directing effects of both substituents on a disubstituted benzene
must be considered in deciding where the third group will add.
Both substituents direct to equivalent positions.

97. The Synthesis of Trisubstituted Benzenes
Both substituents direct to equivalent positions.
Addition between two substituents is a minor product because of steric hindrance.

98. The Synthesis of Trisubstituted Benzenes
Both substituents direct to different positions.
The strong activator wins out over the weak activator.

99. The Synthesis of Trisubstituted Benzenes
Both substituents direct to different positions.
The similar directing ability of the groups leads to addition at both positions.

100. The Synthesis of Cyclic Compounds
Cyclic compounds are formed from intramolecular reactions.
Formation of five- and six-membered rings are favored.

101. The Synthesis of Cyclic Compounds
The products obtained from an intramolecular reaction
can undergo further reactions.