1. Electrophilic Aromatic Substitution
Chapter 16
Chemistry of Benzene:
Electrophilic Aromatic Substitution

2. Introduction
Electrophilic aromatic substitution is the most common reaction of aromatic compounds
It replaces a proton (H+) on an aromatic ring with another electrophile (E+)
It leads to the retention of the aromatic core

3. Some electrophilic aromatic substitution reactions

4. 1. Bromination of Aromatic Rings
Benzene is a site of electron density
Its 6  electrons are in a cyclic conjugated system
Its 6  electrons are sterically accessible to other reactants because they are located above or below the plane

5. Benzene acts as an electron donor (a Lewis base or nucleophile)
It reacts with electron acceptors (Lewis acids or electrophiles)
Benzene’s  electrons participate as a Lewis base in reactions with Lewis acids

6. Bromination of benzene occurs in two steps:
Step 1: The  electrons act as a nucleophile toward Br2 (in a complex with FeBr3) to form a nonaromatic carbocation intermediate
Step 2: The resonance-stabilized carbocation intermediate loses H+ to regenerate the aromatic ring

7. Electrophilic Alkene Addition

8. Electrophilic Aromatic Bromination
Aromatic rings are less reactive toward electrophiles than alkenes
Unlike alkenes, benzene does not react rapidly with Br2 in CH2Cl2
For bromination, benzene requires FeBr3 as a catalyst to polarize the bromine reagent and make it more electrophilic

9. Step 1: The  electrons act as a nucleophile and attack the polarized Br2 (in a complex with FeBr3) to form a nonaromatic carbocation intermediate
It is a slow, rate-limiting step (high DG‡)
The carbocation is doubly allylic (nonaromatic) and has three resonance forms

10. The carbocation intermediate is not aromatic and is high in energy (less stable than benzene)

11. Step 1 is endergonic, has a high DG‡ and is a slow reaction

12. Step 2: The resonance-stabilized carbocation intermediate loses H+ to regenerate the aromatic ring and yield a substitution product in which H+ is replaced by Br+
It is similar to the 2nd step of an E1 reaction
The carbocation intermediate transfers a H+ to FeBr4- (from Br- and FeBr3)
This restores aromaticity (in contrast with addition in alkenes)

13. Step 2 is exergonic, has a low DG‡ and is a fast reaction

14. Electrophilic Aromatic Bromination: Mechanism

15. Why is there electrophilic aromatic substitution rather than addition?
Substitution reaction retains the stability of the aromatic ring and is exergonic
Addition
Loss of aromaticity
Endergonic
Substitution
Retention of aromaticity
Exergonic

16. Practice Problem: Monobromination of toluene gives a mixture of
Practice Problem: Monobromination of toluene gives a mixture of three bromotoluene products. Draw and name them.

17. 2. Other Aromatic Substitutions
The reaction with bromine involves a mechanism that is similar to many other reactions of benzene with electrophiles
The cationic intermediate was first proposed by G. W. Wheland and is often called the Wheland intermediate

18. Electrophilic Aromatic Substitution
An electrophilic aromatic substitution reaction involves two steps:
reaction of an electrophile E+ with an aromatic ring
loss of H+ from the resonance-stabilized carbocation intermediate to regenerate the aromatic ring

19. The same general mechanism is used by other aromatic substitutions including:
Chlorination
Iodination
Nitration
Sulfonation
F is too reactive for monofluorination

20. Aromatic Chlorination
Benzene ring reacts with Cl2 in the presence of FeCl3 catalyst to yield chlorobenzene
It requires FeCl3 to polarize Cl2 (make it more electrophilic)

21. Aromatic Iodination
Benzene ring reacts with I2 in the presence of an oxidizing agent (H2O2 or CuCl2) to yield iodobenzene
Iodine must be oxidized to form a more powerful electrophilic I+ species (with Cu2+ or peroxide)

22. Aromatic Nitration
Benzene ring reacts with a mixture of concentrated nitric and sulfuric acids (HNO3 and H2SO4) to yield nitrobenzene
The combination of nitric acid and sulfuric acid produces NO2+ (nitronium ion), an electrophile

23. The electrophile NO2+ is produced when HNO3 is protonated by H2SO4 and loses H2O

24. NO2+ reacts with benzene to give a carbocation intermediate which loses H+ to yield nitrobenzene

25. Aromatic nitration is useful in the pharmaceutical industry because the nitro-substituted product can be reduced by Fe or SnCl2 to yield arylamine

26. Aromatic Sulfonation
Benzene ring reacts with fuming sulfuric acid (a mixture of H2SO4 and SO3) to yield benzenesulfonic acid
The reactive electrophile is either HSO3+ or neutral SO3 depending on reaction conditions

27. The reactive electrophile is either sulfur trioxide SO3 or its conjugate acid HSO3+

28. The reaction occurs via the Wheland intermediate (carbocation)

29. The reaction is reversible (Sulfonation is favored in strong acid; desulfonation, in hot, dilute aqueous acid)

30. Aromatic sulfonic acids are useful as intermediates in the synthesis of dyes and pharmaceuticals.
Example: Sulfadrugs
A sulfadrug

31. Aromatic sulfonic acids undergo alkali fusion reaction
Heating with NaOH at 300 ºC followed by neutralization with acid replaces the SO3H group with an OH
Example: Synthesis of p-cresol

32. Practice Problem: How many products might be formed on
Practice Problem: How many products might be formed on chlorination of o-xylene (o-dimethylbenzene), m-xylene, and p-xylene?

33. Practice Problem: When benzene reacts with D2SO4, deuterium
Practice Problem: When benzene reacts with D2SO4, deuterium slowly replaces all six hydrogens in the aromatic ring. Explain.

34. 3. Alkylation of Aromatic Rings: The Friedel-Crafts Reaction
Benzene ring reacts with an alkyl chloride in the presence of AlCl3 catalyst to yield an arene
Alkylation was first reported by Charles Friedel and James Crafts in 1877

35. Friedel-Crafts alkylation – is an electrophilic aromatic substitution in which the electrophile is a carbocation, R+.
AlCl3 catalyst promotes the formation of the alkyl carbocation, R+, from the alkyl halide, RX
The Wheland (carbocation) intermediate forms
Alkylation is the attachment of an alkyl group to benzene; R+ substitutes for H+

36. Friedel-Crafts Alkylation Reaction: Mechanism

37. Limitations of the Friedel-Crafts Alkylation
Only alkyl halides can be used (F, Cl, Br, I)
Aryl halides and vinylic halides do not react (their carbocations are too high in energy to form)

38. No reaction occurs if the aromatic ring has an amino group or a strongly electron-withdrawing group substituent
Amino groups react with AlCl3 catalyst in an acid-base reaction

39. It is difficult to control the reaction
It is difficult to control the reaction. Multiple alkylations can occur because the first alkylation is activating
Polyalkylation is often observed

40. Carbocation rearrangements occur during alkylation, particularly when a 1o alkyl halide is used
Catalyst, temperature and solvent affect the amount of rearrangement
Rearranged Unrearranged

41. Carbocation rearrangements of Friedel-Crafts alkylation
are similar to those that occur during electrophilic additions to alkenes
can involve hydride (H:-) or alkyl shifts
More Stable

43. Limitations of the Friedel-Crafts Alkylation
Only alkyl halides can be used (F, Cl, Br, I)
No reaction occurs if the aromatic ring has an amino group or a strongly electron-withdrawing group substituent
It is difficult to control the reaction. Multiple alkylations can occur because the first alkylation is activating
Carbocation rearrangements occur during alkylation, particularly when a 1o alkyl halide is used

44. Practice Problem: The Friedel-Crafts reaction of benzene with 2-
Practice Problem: The Friedel-Crafts reaction of benzene with chloro-3-methylbutane in the presence of AlCl occurs with carbocation rearrangement. What is the structure of the product?

45. Practice Problem: Which of the following alkyl halides undergo
Practice Problem: Which of the following alkyl halides undergo Friedel-Crafts reaction without rearrangement? Explain.
CH3CH2Cl
CH3CH2CH(Cl)CH3
CH3CH2CH2Cl
(CH3)3CCH2Cl
Chlorocyclohexane

46. Practice Problem: What is the major monosubstitution product
Practice Problem: What is the major monosubstitution product from Friedel-Crafts reaction of benzene with chloro-2-methylpropane in the presence of AlCl3?

47. 4. Acylation of Aromatic Rings: The Friedel-Crafts Reaction
Benzene ring reacts with a carboxylic acid chloride, RCOCl, in the presence of AlCl3 catalyst to yield an acylbenzene
Acylation is the attachment of an acyl group,-COR, to benzene; RCO+ substitutes for H+

48. Friedel-Crafts acylation – is an electrophilic aromatic substitution in which the reactive electrophile is a resonance-stabilized acyl cation, RCO+.
AlCl3 catalyst promotes the formation of the acyl cation, RCO+, from the acyl chloride, RCOCl
The acyl cation, RCO+, does not rearrange; it is resonance-stabilized
The Wheland (carbocation) intermediate forms

49. Friedel-Crafts Acylation Reaction: Mechanism
The mechanism of Friedel-Crafts acylation is similar to Friedel-Crafts alkylation

50. In Friedel-Crafts acylation, there is no carbocation rearrangement nor multiple substitution
No carbocation rearrangement: The acyl cation, RCO+, does not rearrange because it is resonance-stabilized by interaction of the vacant orbital on C with lone pair of electrons on O
No multiple substitution: Acylated benzene is less reactive than nonacylated benzene

51. Practice Problem: Identify the carboxylic acid chloride that might
Practice Problem: Identify the carboxylic acid chloride that might be used in a Friedel-Crafts acylation reaction to prepare each of the following acylbenzenes

52. 5. Substituent Effects in Substituted Aromatic Rings
A substituent present on an aromatic ring affects:
the reactivity of the aromatic ring
the orientation of the reaction

53. Substituents affect the reactivity of the aromatic ring
Substituents may
activate the ring, make it (much) more reactive than benzene or
deactivate the ring, make it (much) less reactive than benzene

54. Substituents affect the orientation of the reaction
Substituents present on the ring determine the position of the 2nd substitution: ortho, meta, and para

55. Classification of Substituent Effect
Substituents can be classified as:
ortho- and para-directing activators,
ortho- and para-directing deactivators, and
meta-directing deactivators

56. The directing effects of the groups correlate with their reactivities:
All meta-directing groups are strongly deactivating
Most ortho- and para-directing groups are activating
Halogens are unique being ortho- and para-directing but weakly deactivating

57. Origins of Substituent Effects
Reactivity and orientation in electrophilic aromatic substitutions are controlled by an interplay of inductive effects and resonance effects:
Inductive effect - withdrawal or donation of electrons through a s bond
Resonance effect - withdrawal or donation of electrons through a  bond

58. Inductive Effects
Inductive effects - withdrawal or donation of electrons through a s bond due to electronegativity and polarity of bonds in functional groups
Halogens, C=O, CN, and NO2 groups inductively withdraw electrons through s bond connected to ring
Alkyl groups inductively donate electrons

59. Halogens, C=O, CN, and NO2 inductively withdraw electrons through s bond connected to ring

60. Alkyl groups inductively donate electrons

61. Resonance Effects
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
C=O, CN, and NO2 groups withdraw electrons from the aromatic ring by resonance
Halogen, OH, alkoxyl (OR), and amino substituents donate electrons to the aromatic ring by resonance

62. C=O, CN, and NO2 groups withdraw electrons from the aromatic ring by resonance
 electrons flow from the ring to the substituents, placing a positive charge in the ring

63. C=O, CN, and NO2 groups withdraw electrons from the aromatic ring by resonance placing a positive charge in the ring
Effect is greatest at ortho and para
– Z is more electronegative than Y

64. Halogen, OH, alkoxyl (OR), and amino substituents donate electrons to the aromatic ring by resonance
 electrons flow from the substituents to the rings placing a negative charge in the ring

65. Halogen, OH, alkoxyl (OR), and amino substituents donate electrons to the aromatic ring by resonance placing a negative charge in the ring
Effect is greatest at ortho and para
– Y has a lone pair of electrons

66. Contrasting Effects: Inductive vs Resonance
When the two effects act in opposite direction, the strongest effects dominate.
Halogens have electron-withdrawing inductive effects due to electronegativity
Halogens have electron-donating resonance effects due to lone-pair electrons
Resonance interactions are generally weaker, affecting orientation. Thus, halogens deactivate the ring

67. Practice Problem: Predict the major product of the monosulfonation
Practice Problem: Predict the major product of the monosulfonation of toluene.

68. Practice Problem: Write resonance structures for nitrobenzene to
Practice Problem: Write resonance structures for nitrobenzene to show the electron-withdrawing resonance effect of the nitro group.

69. Practice Problem: Write resonance structures for chlorobenzene
Practice Problem: Write resonance structures for chlorobenzene to show the electron-donating resonance effect of the chloro group.

70. Practice Problem: Predict the major products of the following
Practice Problem: Predict the major products of the following reactions
Mononitration of bromobenzene
Monobromination of nitrobenzene
Monochlorination of phenol
Monobromination of aniline

71. 6. An Explanation of Substituent Effects
Activating groups donate electrons to the ring, stabilizing the Wheland intermediate (carbocation)
OH, OR, NH2 and R
Deactivating groups withdraw electrons from the ring, destabilizing the Wheland intermediate
CN, C=O, NO2 and X

73. An electron-withdrawing group makes the ring more electron-poor (eg
An electron-withdrawing group makes the ring more electron-poor (eg. CN and Cl)
An electron-donating group makes the ring more electron-rich (eg. CH3 and NH2)

74. Practice Problem: Rank the compounds in each group in order of
Practice Problem: Rank the compounds in each group in order of their reactivity to electrophilic substitution
Nitrobenzene, phenol, toluene, benzene
Phenol, benzene, chlorobenzene, benzoic acid
Benzene, bromobenzene, benzaldehyde, aniline

75. Practice Problem: Explain why Friedel-Crafts alkylations often
Practice Problem: Explain why Friedel-Crafts alkylations often give polysubstitution but Friedel-Crafts acylations do not

76. Practice Problem: Would you expect trifluoromethylbenzene to be
Practice Problem: Would you expect trifluoromethylbenzene to be more reactive or less reactive than toluene toward electrophilic substitution? Explain.

77. Ortho- and Para-Directing Activators: Alkyl Groups
Alkyl groups are activating
They have an electron-donating inductive effect
Alkyl groups are ortho and para directors
The ortho and para intermediates are the most stabilized (lower in energy)
The positive charge is directly on the alkyl-substituted carbon (3o carbon) and is stabilized by the inductive electron-donating effect of the alkyl group

78. The positive charge is directly on the alkyl-substituted carbon (3o carbon) and is stabilized by the inductive electron-donating effect of the alkyl group

79. Ortho- and Para-Directing Activators: OH and NH2
OH, OR and NH2 groups are activating
They have a strong electron-donating resonance and a weak electron-withdrawing inductive effect
OH, OR and NH2 groups are ortho and para directors
The ortho and para intermediates are the most stabilized (lower in energy)
The positive charge is stabilized by resonance donation of an electron pair from O or N

80. The ortho and para intermediates are more stable because of resonance donation of an electron pair from O or N

81. Practice Problem: Acetanilide is less reactive than aniline toward
Practice Problem: Acetanilide is less reactive than aniline toward electrophilic substitution. Explain.

82. Ortho- and Para-Directing Deactivators: Halogens
Halogens are deactivating
They have a strong electron-withdrawing inductive and a weak electron-donating resonance effect
Halogens are ortho and para directors
The ortho and para intermediates are the most stabilized (lower in energy)
Halogens stabilize the positive charge by resonance donation of a lone pair of electrons

83. The ortho and para intermediates are more stable because of resonance donation of an electron pair from X

84. Meta-Directing Deactivators
All meta-directing groups are strongly deactivating
They have electron-withdrawing inductive and resonance effects that reinforce each other
The ortho and para intermediates are destabilized
The positive charge of the carbocation intermediate in ortho and para attack is directly on the carbon that bears the deactivating group and resonance cannot produce stabilization

85. The meta intermediate is more stable because resonance does not place the positive charge directly on the carbon that bears the deactivating group

86. Summary of Substituent Effects in Aromatic Substitution

87. Practice Problem: Draw resonance structures for the intermediates
Practice Problem: Draw resonance structures for the intermediates from reaction of an electrophile at the ortho, meta, and para positions of nitrobenzene. Which intermediates are most stable?

88. 7. Trisubstituted Benzenes: Additivity of Effects
Three rules for the additive effects of two different groups:
If the directing effects of the two groups are the same, the result is additive
If the directing effects of two groups oppose each other, the more powerful activating group determines the principal outcome
The position between the two groups in meta-disubstituted compounds is unreactive

89. If the directing effects of the two groups are the same, the result is additive
It gives a single product

90. If the directing effects of two groups oppose each other, the more powerful activating group determines the principal outcome
It usually gives mixtures of products

91. The position between the two groups in meta-disubstituted compounds is unreactive
The reaction site is too hindered
To make aromatic rings with three adjacent substituents, it is best to start with an ortho-disubstituted compound

93. Practice Problem: What product would you expect from bromination
Practice Problem: What product would you expect from bromination of p-methylbenzoic acid?

94. Practice Problem: At what positions would you expect electrophilic
Practice Problem: At what positions would you expect electrophilic substitution to occur in the following substances?

95. Practice Problem: Show the major product(s) from reaction of the
Practice Problem: Show the major product(s) from reaction of the following substances with (i) CH3CH2Cl, AlCl and (ii) HNO3, H2SO4

96. 8. Nucleophilic Aromatic Substitution
Nucleophilic aromatic substitution is a reaction that aryl halides with electron-withdrawing substituents undergo
It replaces a halide ion (X-) on an aromatic ring with another nucleophile (Nu-)

97. Nucleophilic Aromatic Substitution
A nucleophilic aromatic substitution reaction occurs in two steps by the addition/elimination mechanism:
Step 1: Addition of the nucleophile (Nu-) to the electron-deficient aryl halide, forming a resonance stabilized carbanion intermediate (Meisenheimer complex)
Step 2: Elimination of a halide ion (X-) from the carbanion intermediate to regenerate the aromatic ring

98. Nucleophilic Aromatic Substitution: Mechanism

99. Nucleophilic aromatic substitution occurs ONLY if the aryl halide has an electron-withdrawing substituent in ortho and/or para position
The more such substituents, the faster the reaction
Only ortho and para electron-withdrawing substituents can stabilize the anion intermediate through resonance

100. Only ortho and para intermediate carbanions (Meisenheimer complex) are resonance stabilized by electron-withdrawal

101. A nucleophilic aromatic substitution reaction is neither an Sn1 nor an Sn2 reaction:
Not Sn1: Aryl cations are unstable for dissociation to occur
Not Sn2: Backside displacement is sterically blocked

102. Electrophilic vs Nucleophilic Aromatic Substitution
Electrophilic Aromatic Substitution
is favored by electron-donating groups
involves a carbocation intermediate
replaces a H with an electrophile
Nucleophilic Aromatic Substitution
is favored by electron-withdrawing groups
involves a carbanion intermediate
replaces a leaving group with a nucleophile

103. Electron-donating groups Electron-withdrawing groups
favor electrophilic aromatic substitution
stabilize carbocation intermediate
are ortho-para directors in electrophilic reaction
Electron-withdrawing groups
favor nucleophilic aromatic substitution
stabilize carbanion intermediate
are ortho-para directors in nucleophilic reaction but meta-directors in electrophilic substitution

104. Practice Problem: Propose a mechanism for the reaction of 1-
Practice Problem: Propose a mechanism for the reaction of chloroanthraquinone with methoxide ion to give the substitution product 1-methoxyanthraquinone Use curved arrows to show the electron flow in each step.

105. 9. Benzyne
Aryl halides without electron-withdrawing substituents undergo substitution with a benzyne intermediate
Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressure

106. The synthesis of phenol occurs in two steps by the elimination/addition mechanism rather than addition/elimination:
Step 1: Elimination of a HX from halobenzene in an E2 reaction catalyzed by a strong base, forming a highly reactive benzyne intermediate
Step 2: Addition of a nucleophile (Nu-) to the benzyne intemediate

107. Evidence for Benzyne as an Intermediate
Bromobenzene with 14C only at C1 gives substitution product with label scrambled between C1 and C2
The reaction proceeds through a symmetrical intermediate in which C1 and C2 are equivalent
The intermediate must be benzyne

108. Trapping experiments further demonstrate that benzyne was the intermediate
Benzyne is too reactive to be isolated and thus can be intercepted in a Diels-Alder reaction

109. Structure of Benzyne Benzyne is a highly distorted alkyne
The triple bond uses sp2-hybridized carbons, not the usual sp
The triple bond has one  bond formed by p–p overlap and one  bond formed by weak sp2–sp2 overlap

110. Practice Problem: Treatment of p-bromotoluene with NaOH at 300oC
Practice Problem: Treatment of p-bromotoluene with NaOH at 300oC yields a mixture of two products, but treatment of m-bromotoluene with NaOH yields a mixture of three products. Explain

111. 10. Oxidation of Aromatic Compounds
There are two reactions of alkylbenzene side chains:
Oxidation of Alkylbenzene Side Chains
Bromination of Alkylbenzene Side Chains
Aromatic ring activates neighboring benzylic (C-H) position toward oxidation

112. Oxidation of Alkylbenzene Side Chains
Alkyl side chains can be oxidized to carboxyl groups, -CO2H, by strong oxidizing agents such as KMnO4 and Na2Cr2O7
The alkyl side chains must have a C-H next to the ring
This converts an alkylbenzene into a benzoic acid, Ar-R  Ar-CO2H

113. The mechanism of side-chain oxidation involves reaction of C-H next to the ring to form intermediate benzylic radicals
t-butylbenzene is inert (no benzylic H’s)

114. Practice Problem: What aromatic products would you obtain from the
Practice Problem: What aromatic products would you obtain from the KMnO4 oxidation of the following substances?

115. Bromination of Alkylbenzene Side Chains
Reaction of an alkylbenzene with N-bromo-succinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain
Bromination occurs exclusively in the benzylic position

116. Mechanism of NBS (Radical) Reaction
Abstraction of a benzylic hydrogen atom generates an intermediate benzylic radical
This reacts with Br2 to yield product and Br·
Br· radical cycles back into reaction to carry on chain
Br2 is produced from reaction of HBr with NBS

117. Bromination occurs exclusively in the benzylic position because the benzylic radical intermediate is resonance-stabilized
The benzylic radical is stabilized by overlap of its p orbital with the ring p electron system

118. Practice Problem: Refer to Table 5. 3 for a quantitative idea of the
Practice Problem: Refer to Table 5.3 for a quantitative idea of the stability of a benzyl radical. How much stable (in kJ/mol) is the benzyl radical than a primary alkyl radical? How does a benzyl radical compare in stability to an allyl radical

119. Practice Problem: Styrene, the simplest alkenylbenzene, is prepared
Practice Problem: Styrene, the simplest alkenylbenzene, is prepared commercially for use in plastics manufacture by catalytic dehydrogenation of ethylbenzene. How might you prepare styrene from benzene?

120. 11. Reduction of Aromatic Compounds
There are two reduction reactions:
Catalytic hydrogenation of Aromatic Rings
Reduction of Aryl Alkyl Ketones

121. Catalytic hydrogenation of Aromatic Rings
Reduction of an aromatic ring requires more powerful reducing conditions (H2/Pt at high pressure or rhodium catalysts)

122. Aromatic rings are inert to catalytic hydrogenation under conditions that reduce alkene double bonds
It is possible to selectively reduce an alkene double bond in the presence of an aromatic ring

123. Reduction of Aryl Alkyl Ketones
Aromatic ring activates neighboring carbonyl group toward reduction
Aryl alkyl ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd catalyst

124. Conversion of a carbonyl group to a methylene group by catalytic hydrogenation (C=O  CH2)
is limited to aryl alkyl ketones
is not compatible with the presence of a nitro group

125. Practice Problem: Show how you would prepare diphenylmethane
Practice Problem: Show how you would prepare diphenylmethane (Ph)2CH2, from benzene and an appropriate acid chloride

126. 12. Synthesis of Trisubstituted Benzenes
These syntheses require planning and consideration of alternative routes
Compare the target and the starting material
Consider reactions that efficiently produce the outcome.
Look at the product and think of what can lead to it
A synthesis combines a series of proposed steps to go from a defined set of reactants to a specified product

127. Synthesis as a Tool for Learning Organic Chemistry
In order to propose a synthesis, one must be familiar with reactions:
What they begin with
What they lead to
How they are accomplished
What the limitations are
The order in which reactions are carried is critical in the synthesis of substituted aromatic rings
The introduction of a new substituent is strongly affected by the directing effects of other substituents
IE – is the energy required to remove an electron from an atom or ion in the gas phase
Atom in ground state (g) + energy  Atom+ (g) + e- Change in energy = ionization energy
EA – is the energy involved when a gaseous atom absorbs an electron to form a negative ion of the element. Atom (g) + e-  Atom- Change in Energy = EA

128. Practice Problem: Synthesize p-bromobenzoic acid from benzene
Br – Bromination using Br2/FeBr3
CO2H – Friedel-Crafts alkylation or acylation followed by oxidation

129. Practice Problem: Propose a synthesis of 4-chloro-1-nitro-2-
Practice Problem: Propose a synthesis of 4-chloro-1-nitro propylbenzene from benzene
Cl – Chlorination using Cl2/FeCl3
NO2 – Nitration using HNO3/H2SO4
CH2CH2CH3 – Friedel-Crafts acylation followed by reduction

132. m-Chloronitrobenzene m-Chloroethylbenzene p-Chloropropylbenzene
Practice Problem: Propose syntheses of the following substances from benzene:
m-Chloronitrobenzene
m-Chloroethylbenzene
p-Chloropropylbenzene

133. Practice Problem: In planning a synthesis, it is important to know
Practice Problem: In planning a synthesis, it is important to know what NOT to do as to know what do. As written, the following reaction schemes have flaws in them. What is wrong with each?

134. Chapter 16
The End