Chapter 14: Benzene Chemistry

Table of Contents Chapter 14: Benzene Chemistry........................................................................................59 14.1 Naming Substituted Benzene....................................................................................59 14.2 Electrophilic Addition: It Can Happen to Benzene!...............................................62 14.3 Electrophilic Aromatic Substitution.........................................................................63 14.3.1 General Reaction and Mechanism........................................................................63 14.3.2 Halogenation.........................................................................................................65 14.3.3 Nitration................................................................................................................66 14.3.4 Sulfonation............................................................................................................68 14.4 Directing Effects of Monosubstituted Benzene........................................................70 14.4.1 Ortho/Para Directing Effect of the R Group........................................................70 14.4.2 Ortho/Para Directing Effect of the X Group........................................................73 14.4.3 Meta Directing Effect of the Z Group..................................................................76 14.5 Directing Effect Rules in Disubstituted Benzene.....................................................78 14.6 Friedel-Crafts Alkylation..........................................................................................80 14.7 Friedel Crafts Acylation............................................................................................86 14.7.1 Synthesis of Linear Alkylbenzenes......................................................................87 14.7.2 Carboxylation of Phenols.....................................................................................88 14.8 Electrophilic Aromatic Substitution of Polycyclic and Heterocyclic Aromatics....89 14.9 Reactions of the Alkyl Group in Alkylbenzenes......................................................90 14.9.1 Radical Bromination.............................................................................................91 14.9.2 Side Chain Oxidation............................................................................................93 93 14.10 Diazonium Salts: Synthesis and Chemistry...........................................................94 14.10.1 Synthesis of Diazonium Salts.............................................................................94 14.10.2 Azo Dye Synthesis..............................................................................................94 14.10.3 Sandmeyer Reaction...........................................................................................96 14.10.4 Other Nucleophilic Substitution Reactions .......................................................96 14.11 Nucleophilic Aromatic Substitution.......................................................................97 14.12 Benzynes: Synthesis and Chemistry......................................................................98 Chapter 14 Exercises.......................................................................................................100 Answers to Chapter 14 Exercises...................................................................................106

Chapter 14: Benzene Chemistry

14.1 Naming Substituted Benzene
If a benzene ring has only one substituent (monosubstituted), the compound may be named as the substituent prefix followed by benzene:
NO2 Br

nitrobenzene

bromobenzene

However, common names are often used for the following monosubstituted benzenes (Fig. 14.1). The functional group basis for the name is automatically position #1. Figure 14.1 Common Names for Monosubstituted Benzenes.
O OH NH2 HN CH3 OCH3

phenol O

aniline CO2H

acetanilide SO3H

toluene

anisole

acetophenone

benzoic acid

benzenesulfonic acid

biphenyl

59

On disubstituted benzene, the groups can be named with either position number + prefix name in alphabetical order or with o (ortho) designation for 1,2-disubstituted, m (meta) for 1,3-disubstituted, and p (para) for 1,4-disubstituted: Examples
CH3
1 2 3 4

OH
1

CO2H Cl
1

NO2 2-chlorotoluene or o-chlorotoluene OH

1

3-nitrobenzoic acid or m-nitrobenzoic acid OH

4

4-isopropylphenol or p-isopropylphenol

same as
4 1

CH3 4-methylphenol or p-methylphenol 4-hydroxytoluene or p-hydroxytoluene

NO2
1

Br
1 2 3

NO2

NO2 1,3-dinitrobenzene or m-dinitrobenzene 1-bromo-2-nitrobenzene or o-bromonitrobenzene

There are even a few important common names for disubstituted benzenes (Fig. 14.2). The functional group basis for the name is automatically the lowest numbered positions.

Figure 14.2 Common Names for Some Disubstituted Benzenes.

60

OH
1 2

OH OH
1 2 3

OH
1 2

OH
2 1

CO2H

OH catechol CH3
1 2

3 4

resorcinol CH3 CH3

1

OH hydroquinone

salicylic acid CH3

1

2 3

2 3

CH3 o-xylene m-xylene

CH3 p-xylene

For tri- and tetrasubstituted benzenes, only numbers give the positions of the groups, which are placed in alphabetical order:
OH Br
6 1 2

OCH3 Br
1 2

NO2

Br 2,4,6-tribromophenol

Br 4-bromo-2-nitroanisole or 4-bromo-1-methoxy-2-nitrobenzene

Finally, for substituted biphenyl, each ring is numbered differently. One ring has numbers 1-6 and the other has numbers 1'-6' (read as "one prime to six prime"). Only use 1'-6' when necessary:
6 5 4

Cl

4'

1'

Cl

3'

2'

4,4'-dichloro-2,6-dimethyl-1,1'-biphenyl

61

14.2 Electrophilic Addition: It Can Happen to Benzene!

As you read in Chapter 13, even though they contain C=C bonds, benzene and other aromatic compounds do not easily perform the addition reactions of typical alkenes. However, this does not mean addition to benzene is impossible! For example, in the presence of air and nutrient broth, a strain of the bacterium Pseudomonas putida adds two adjacent OH groups onto benzene in a syn (same side) orientation (Scheme 14.1): Scheme 14.1 Syn-1,2-dihydroxylation of benzene catalyzed by P. putida P. putida O2, broth OH

OH

(You'll read more about electrophilic addition to benzene to make single enantiomers of 1,2-diols later.) Thus, benzene's stability doesn't make electrophilic addition impossible. But with the exception of adding O or H atoms under special conditions, addition to aromatic compounds does not occur. For example, Br2 will react with benzene in the presence of the catalyst FeBr3, but you get substitution of one hydrogen by one Br atom instead of addition of both Br atoms (Scheme 14.2): Scheme 14.2
Br H H H H Br2, FeBr3 (cat.) H H H H Br H H Br H H H
+

HBr

H H

If you calculate the free energy of bromine addition to benzene, Go is positive, so addition of Br2 to benzene will not happen. But for bromine substitution, Go is negative, so this reaction will occur.

62

14.3 Electrophilic Aromatic Substitution

14.3.1 General Reaction and Mechanism When benzene and other aromatic compounds react with an electrophile (E+), the electrophile substitutes for a proton (H+) attached to the aromatic ring (Scheme 14.3). This reaction is called electrophilic aromatic substitution. Scheme 14.3 General Reaction of Electrophilic Aromatic Substitution

H H H E Y H

E H
+

HY

H H

H H

The accepted mechanism of the reaction is shown below (Scheme 14.4): Scheme 14.4 General Mechanism of Electrophilic Aromatic Substitution

E Y H H H slow H E H

Y H fast H

E H
+

HY

H H

H H arenium ion

H H

63

For clarity, the benzene picture in Scheme 14.4 has individual double bonds, even though we know better. In the first step, the electrophile, looking for a source of electrons, attacks the electrons in benzene. Destruction of the aromaticity costs about 36 kcal/mol, which is why this step is slow and why the electrophile has to be more reactive than the ones that attack simple alkenes. The intermediate is called an arenium ion, which is a resonancestabilized carbocation. Since the first step of the reaction is rate-determining, the rate expression for electrophilic aromatic substitution is: Rate = k [ArH] [E+] [ArH] is the concentration of the aromatic compound and [E+] is the concentration of the electrophile. In the second step, Y-, the conjugate base of the electrophile, always removes the proton from the same carbon that E+ is attached to, reforming the benzene ring. Since benzene is so stable and easy to make, the second step is the fast step of the mechanism. The concentration of Y- has no effect on the overall rate of the reaction because is involved in the fast step. Scheme 14.5 depicts the reaction energy diagram of electrophilic aromatic substitution. Scheme 14.5 Reaction Energy Diagram of Electrophilic Aromatic Substitution
E H H H

E n e r g y
H

H H

E H
H H

H
+

HY

H H

E Y

H H

Progress of reaction

Now we will examine several important examples of electrophilic aromatic substitution. ALL of these reactions use the same mechanism shown in Scheme 14.4. The only difference is how we make the electrophile itself, which will involve the catalyst for the reaction.

64

14.3.2 Halogenation Halogenation of benzene is defined as the substitution of H on a benzene ring (or other aromatic ring) by Cl, Br, or I. Direct reaction of benzene with F2 is useless because fluorine is too reactive. The overall reactions of chlorination and bromination are shown in Scheme 14.6: Scheme 14.6
CHLORINATION: H H H Cl Cl H Cl H
+

H BROMINATION: H H H

FeCl3 (cat.) (or Fe)

HCl

H H Br

Br

Br

H
+

H H

FeCl3 (cat.) (or Fe)

HBr

H H

In halogenation, the electrophile E+ = Cl+, Br+, or I+. For chlorination (E+ = Cl+) and bromination (E+ = Br+), the catalyst that forms the electrophile is either FeCl 3 or just Fe, since Fe will spontaneously react with Cl2 (eq. 1) and Br2 (eq. 2) to make the catalysts FeCl3 and FeBr3, respectively: (1) 2Fe + 3Cl2 2FeCl3 (2) 2Fe + 3Br2 2FeBr3

The mechanism of chlorination and bromination requires formation of Cl+ or Br+ by the catalyst, then reaction of the electrophile with the aromatic ring. Since both chlorination and bromination work exactly the same way, only the mechanism of chlorination will be illustrated (Scheme 14.7):

65

Scheme 14.7
MAKING Cl : Cl Cl FeCl3 Cl FeCl3 Cl FeCl3

Cl

Cl

SUBSTITUTION STEPS: Cl H H H slow H Cl FeCl3 Cl H H fast H H arenium ion

+

Cl

FeCl3 H

Cl H

H H

H H HCl
+

FeCl3

For iodination (E+ = I+), the catalyst is HNO3, nitric acid. It is suspected that I+ is formed by oxidation of I2 by nitric acid. Because the true nature of the electrophile in iodination is unknown, only the overall reaction is shown below (Scheme 14.8): Scheme 14.8
IODINATION: H H I I H I H
+

H H

HNO3 (cat.)

HI

H H

14.3.3 Nitration Nitration is defined as the substitution of H on a benzene ring (or other aromatic ring) by NO2 (nitro) (Scheme 14.9):

66

Scheme 14.9
NITRATION: H H H O H H H H2SO4 H H H O N OH H NO2 H

In nitration, the electrophile E+ = NO2+. NO2+ comes from the reaction of nitric acid (HNO3) with the catalyst sulfuric aid (H2SO4). NO2+ then reacts with benzene in the standard two-step substitution mechanism (Scheme 14.10). Scheme 14.10
MAKING NO2 : O N O OH H O S O O O O N OH2 O S O SUBSTITUTION STEPS: O N H H O H slow O S O H O O O N H H fast H H arenium ion H H H
+ H

O O N O
+

O O S O H2O

O O S O H O O N H

H H

H O O S O

67

14.3.4 Sulfonation Sulfonation is defined as the substitution of H on a benzene ring (or other aromatic ring) by SO3H (sulfonic acid) (Scheme 14.11): Scheme 14.11
SULFONATION: H H H O H H H H2SO4 H H benzenesulfonic acid H O S O H SO3H H

In sulfonation, the electrophile E+ = +SO3H. +SO3H comes from the reaction of sulfur trioxide (SO3) with the catalyst sulfuric acid (H2SO4). This mixture is called fuming sulfuric acid. +SO3H then reacts with benzene in the standard two-step substitution mechanism (Scheme 14.12). Scheme 14.12
MAKING SO3H: O S O O H O S O O O O S O O S O SUBSTITUTION STEPS: O S HO H H slow H OH HO O S O H H fast H H arenium ion H H H
+ H

H O

O S O O O

H O S O

O O S O H O O S OH H

H H

H O O S O

68

Sulfonation is reversible. This means that reacting benzenesulfonic acid with steam will form benzene and sulfuric acid in a process called desulfonation (Scheme 14.13): Scheme 14.13

DESULFONATION: SO3H H H dilute H2SO4 H H H2O, 135-200 oC H H H H H H

+

O S O O

H benzenesulfonic acid

The mechanism of desulfonation is the reverse of sulfonation: first you attach H+, then you knock off SO3H (Scheme 14.14): Scheme 14.14

SUBSTITUTION STEPS: H O S OH H H H O H slow H H O O S O O H H H fast H H arenium ion

+

O H

H H H

H H

H O S O H

H H H

O + H O

69

14.4 Directing Effects of Monosubstituted Benzene

When benzene has one substituent attached to the ring, it is called monosubstituted benzene. This substituent will direct where an incoming electrophile will preferentially attack the benzene ring. There are three kinds of substituents: 1. R (C with single bonds, C=C, CC) 2. X (an atom with one or more lone pairs, e.g., N, O, F, Cl, Br, and I) 3. Z (an atom with full positive charge or large partial positive charge, e.g., C in CCl 3, N in NO2, S in SO3H, C in C=O, and C in CN) To understand this directing effect, you must always heed this rule: The electrophile will most quickly make the most stable arenium ion. 14.4.1 Ortho/Para Directing Effect of the R Group When monosubstituted benzene has an R group, the electrophile is directed mostly ortho and para to the R group (Scheme 14.15): Scheme 14.15

R E Y

R E
+

HY

ortho product

E para product

MAJOR PRODUCTS
The arenium ion that you get when E+ attaches to the ortho or para position is more stable than when E+ attaches to the meta position. The Reason: When E+ attaches ortho or para to an R group, the positive charge can resonate to a 3o position (Scheme 14.16): 70

Scheme 14.16

Ortho Substitution: R H E R 3o carbocation E R H E H R E H

R E H Y

R E
+

HY

ortho product Para Substitution: R E 3o carbocation

H R

H R

HY

E para product

71

However, when E+ attaches meta to an R group, the positive charge can only resonate to the less stable 2o positions (Scheme 14.17): Scheme 14.17
Meta Substitution: R E H R R E H H E H E R R R

HY

E H

E meta product

Example
CH3 SO3 H2SO4 SO3H CH3 SO3H
+

CH3

MAJOR PRODUCTS

72

14.4.2 Ortho/Para Directing Effect of the X Group When monosubstituted benzene has an X group, the electrophile is directed mostly ortho and para to the X group (Scheme 14.18). Except for the halogens (F, Cl, Br, I), the X group is electron-releasing, making the benzene ring more reactive to electrophiles than benzene itself. The halogens make the benzene ring less reactive to electrophiles than benzene by itself. OH and NH2 make the ring so reactive that halogenation occurs without any catalyst and at EVERY available ortho and para position:
OH Br OH Br Br2 H2O Br NH2 Cl2 H2O Cl Cl NH2 Cl

Scheme 14.18
X E Y X E
+ +

HY

ortho product

E para product

MAJOR PRODUCTS

The arenium ion that you get when E+ attaches to the ortho or para position is more stable than when E+ attaches to the meta position. The Reason: When E+ attaches ortho or para to an X group, the arenium ion will be stabilized by four resonance structures (Scheme 14.19).

73

Scheme 14.19
Ortho Substitution: X H E X E H X E H X E H

X E X E H Y X E
+

HY

ortho product Para Substitution: X E X X X

H X

HY

E para product

74

However, when E+ attaches meta to an X group, the arenium ion will be stabilized by only three resonance structures (Scheme 14.20): Scheme 14.20
Meta Substitution: X E H X X E H H E H E X X X

HY

E H

E meta product

Example
OCH3 HNO3 H2SO4 OCH3 NO2
+

OCH3

NO2

MAJOR PRODUCTS

75

14.4.3 Meta Directing Effect of the Z Group When monosubstituted benzene has a Z group, the electrophile is directed almost exclusively meta to the Z group (Scheme 14.21). The Z group is an electron-withdrawing group. The Z group makes the benzene ring react more slowly to electrophiles than benzene would react by itself. Scheme 14.21
Z E Y E meta product Z

HY

MAJOR PRODUCT

The arenium ion that you get when E+ attaches to the meta position is more stable than when E+ attaches to the ortho or para position. The Reason: When E+ attaches meta to the Z group, the positive charge never resonates next to the already positive Z group. This makes the arenium ion more stable (Scheme 14.22):
Meta Substitution: Z or Z E H Z or Z E H or H E H E or

Scheme 14.22
Z or Z or

HY

E H

E meta product

76

However, when E+ attaches ortho or para to the Z group, the positive charge resonates to the already positive Z group. This makes the arenium ion less stable (Scheme 14.23): Scheme 14.23
Ortho Substitution: Z or H or Z UNSTABLE! E H Z or E H Z or E H

or E H Y

or E
+

HY

ortho product Para Substitution: Z or Z E or Z or

UNSTABLE!

or

H Z

E or

H Z or

HY

E para product

Example

77

NO2 Br2 Fe

NO2

HBr

Br MAJOR PRODUCT

14.5 Directing Effect Rules in Disubstituted Benzene

If there are two substituents on a benzene ring, follow these three rules to predict the major position of attack by an electrophile: Rule 1: When ortho/para-directing groups (X, R) compete, because of resonance, X directs more strongly than R, except for the halogens. R is a stronger director than any halogen. Both X and R groups are stronger directors than meta-directing (Z) groups: Order of Influence:

O
R > F, Cl, Br, I > Z

NH2, OH, NR2, O- > O R , HN R , OR >

A mnemonic: X-Ray Zach's Right Hand

for X beats R, which beats Z, and R beats Halogens. Examples O a) X NH X beats R HNO3 H2SO4 CH3 R Examples (cont.) 78 CH3 O NH NO2

b)

Cl

Halogen Br2 Fe

Cl

Br CH3 Cl

R X c) Cl

CH3

R beats Halogen

X beats Z SO3 H2SO4 NO2 Z

NO2 SO3H major product

(see Rules 2 and 3)

Rule 2: When two groups are meta to each other, because of the tight fit (steric effect), an electrophile is less likely to come between these groups than to attach to another directed site. Example Under Rule 1, see Example (c). Rule 3: When Z groups are meta to X or R groups, the incoming electrophile will attack mostly ortho to the Z group rather than para. This is known as the ortho effect. Example Under Rule 1, see Example (c).

79

14.6 Friedel-Crafts Alkylation

Friedel-Crafts alkylation is defined as the substitution of H on a benzene ring (or other aromatic ring) by an alkyl group (Scheme 14.24). In Friedel-Crafts alkylation, the electrophile E+ = +CR3 (carbocation), where R can be H or C (Scheme 14.24): Scheme 14.24

FRIEDEL-CRAFTS ALKYLATION:

a)

Cl + AlCl3 HCl

b) H2SO4

c)

OH H2SO4

80

The carbocation is usually made in one of three ways: 1. Reaction of an alkyl halide with a Lewis acid catalyst, typically AlCl3. In terms of reactivity, F > Cl > Br > I (Scheme 14.25). Scheme 14.25

H Cl + HCl AlCl3 MAKING +CR3:

AlCl3 Cl SUBSTITUTION STEPS: Cl H Cl AlCl3 H + HCl AlCl3 Cl AlCl3 Cl AlCl3

AlCl3

81

2. Reaction of an alkene with strong acid, e.g., H2SO4 (Scheme 14.26): Scheme 14.26

H2SO4

H OH2

MAKING +CR3: H OH2 + H2O

SUBSTITUTION STEPS: OH2 H H

H OH2

82

3. Reaction of an alcohol with a strong acid, e.g., H2SO4 (Scheme 14.27): Scheme 14.27

H OH + H2SO4 H OH2

MAKING +CR3: + H2O OH2

H OH2 OH SUBSTITUTION STEPS:

OH2 H H

H OH2

As with ALL electrophiles, the reaction of the carbocation with the benzene ring follows the same two-step mechanism (see substitution steps in Scheme 14.27).

83

Once the carbocation is made, it is very picky about the kind of benzene it likes. Only plain benzene or benzene "flavored" with X or R groups are acceptable. Carbocations dislike the "taste" of benzenes with Z groups. Why? As electrophiles go, carbocations are somewhat wimpy, so they only react with reasonably reactive benzenes. In addition, NH2 and NR2 (where R is an alkyl group) don't work for Friedel-Crafts alkylation because the catalyst turns them into Z groups (Scheme 14.28): Scheme 14.28
a) NH2 NO REACTION! H2SO4 Reason: NH2
+

Z GROUP H2SO4

NH3

b)

N Cl NO REACTION! AlCl3

Reason:

N
+

Z GROUP AlCl3

AlCl3

N attached to C=O (amide) is an excellent group for Friedel-Crafts reactions, because resonance of the lone pair of N into C=O keeps N from binding to the catalyst and turning into a Z group (Scheme 14.29):

84

Scheme 14.29

H Cl + HCl AlCl3 HN O HN O

Another important note about the carbocations for Friedel-Crafts reactions: DO NOT pick ones that undergo rearrangement (hydride or carbon shifts). For example, if you try to make n-propylbenzene with 1-chloropropane, AlCl3, and benzene, you'll mostly get isopropylbenzene because the propyl cation will rearrange to the more stable isopropyl cation (Scheme 14.30): Scheme 14.30
H Cl + AlCl3 isopropylbenzene n-propylbenzene (cumene) (Major Product) (Minor Product) MECHANISM LEADING TO THE MAJOR PRODUCT: MAKING +CR3: H AlCl3 Cl Cl Cl3Al Cl SUBSTITUTION STEPS: Cl H Cl AlCl3 H + HCl AlCl3 AlCl3 Cl AlCl3 H MORE STABLE H HCl

AlCl3

85

We can't make n-propylbenzene directly by Friedel-Crafts alkylation, but n-propylbenzene and longer, linear alkylbenzenes can be made in a two-step process described in the next section.

14.7 Friedel Crafts Acylation

Friedel-Crafts Acylation is defined as the substitution of H on a benzene ring (or other aromatic ring) by an acyl or RC=O group (Scheme 14.31). In Friedel-Crafts acylation, the electrophile E+ = [RC=O]+ (acylium ion), where R = alkyl, C=C, or CC. AlCl3 is a typical catalyst, and leaving groups include Cl (from acid chlorides) and O(C=O)R (from acid anhydrides). Scheme 14.31
O O H Cl or O O AlCl3 MAKING [RC=O] : O AlCl3 Cl SUBSTITUTION STEPS: O H Cl AlCl3 Cl H + HCl AlCl3 O Cl AlCl3 Cl AlCl3 Cl AlCl3 O O O
+

O + or HCl O OH

AlCl3

86

Friedel-Crafts acylations have two of the same restrictions as Friedel-Crafts alkylations: 1. The benzene ring cannot have a Z group. 2. The benzene ring cannot have an NH2 or NR2 group. However, in contrast to Friedel-Crafts alkylations, the R in RC=O can be a long alkyl chain because acylium ions do NOT rearrange; they are too stable for that. 14.7.1 Synthesis of Linear Alkylbenzenes As previously stated, acylium ions do not rearrange like their alkyl cousins. Thus, linear alkyl benzenes can be made by Friedel-Crafts acylation followed by reduction of C=O in the ketone to CH2 (Scheme 14.32): Scheme 14.32

O O H Cl or O O AlCl3 propiophenone + or HCl O OH

There are various ways to reduce C=O in a ketone to CH2 (Table 14.1): Table 14.1. Reduction Methods (C=O in Ketones to CH2) Name of Reaction Reagents Wollf-Kishner* N2H4 (hydrazine), KOH, heat Clemmensen* Zn-Hg, HCl *Both reactions also reduce C=O in aldehydes, but not in carboxylic acids or amides.

O Reduction

n-propylbenzene

87

14.7.2 Carboxylation of Phenols There are two ways to put CO2H directly onto a phenol. The most important method is the Kolbe-Schmitt reaction, in which CO2 in the presence of sodium or potassium phenoxide selectively carboxylates the ortho position, producing the salt of salicylic acid, the precursor to aspirin (acetylsalicylic acid):
O O CO2 OH CO2 O CO2H

salicylic acid salt

aspirin

To selectively carboxylate the para position of sodium or potassium phenoxide, use potassium carbonate and CO:
O CO K2CO3 CO2 OH

88

14.8 Electrophilic Aromatic Substitution of Polycyclic and Heterocyclic Aromatics

Two principles govern electrophilic aromatic substitution on polycyclic and heterocyclic aromatics: 1. Attach the electrophile where you get the most resonance stabilization of positive charge. 2. Resonance stabilization of positive charge should not have to sacrifice aromaticity in another ring. Example: Bromination of Naphthalene
H Br2 FeBr3 naphthalene Substitution Steps: H Br Br FeBr3 H Br Br FeBr3 1-bromonaphthalene Br

HBr

has to resonate in the other benzene ring to be Br stable

89

Example: Bromination of Furan

O H O
1

Br2 FeBr3

Br
2 +

HBr

furan Substitution Steps:

2-bromofuran

Br O H Br Br FeBr3 O H Br

FeBr3

not enough resonance stabilization!

Br

14.9 Reactions of the Alkyl Group in Alkylbenzenes

In an alkylbenzene, the position on the alkyl chain next to the benzene ring is called benzylic (Fig. 14.3). The benzylic position is also the position (alpha) to the benzene ring. Figure 14.3 Benzylic Position in Alkyl Benzene.
benzylic position

This is the only reactive position on the alkyl chain. There are two common reactions performed at the benzylic position: 1. Radical bromination 2. Side chain oxidation.

90

14.9.1 Radical Bromination Radical bromination at the benzylic position involves substitution of an H by Br (Scheme 14.33): Scheme 14.33
NBS O H H N Br O (PhCO2)2, CCl4 propylbenzene benzoyl peroxide (an ROOR compound) (1-bromopropyl)benzene (97%) O
+

Br

N O

succinimide

A tiny amount of bromine is originally generated by the reaction of N-bromosuccinimide (NBS) with a trace amount of HBr. A radical initiator (ROOR) stimulates bromine radical formation. In the mechanism (Scheme 14.34), benzoyl peroxide (a source of ROOR) decomposes with heat to form carbon dioxide and a phenyl radical. The phenyl radical breaks the weak Br-Br bond, initiating bromine radical formation. The bromine radical next abstracts a benzylic hydrogen atom, producing a benzylic radical and HBr. The benzylic radical makes the final product by breaking another Br-Br bond and regenerating a bromine radical. The HBr formed is used to generate Br2 from NBS.

91

Scheme 14.34
FORMATION OF Br2: O N O CHAIN INITIATION STEPS: O O O O benzoyl peroxide Br Br Br + Br

O Br
+

HBr

N O

Br2

(trace amount)

O 2 O phenyl radical + 2 O C O 2

CHAIN PROPAGATION STEPS: H H Br H

+

Br

benzylic radical H H Br
+

Br

Br

Br

Bromination only occurs at the benzylic position. The reason for this extreme selectivity is that a resonance-stabilized radical is formed when the benzylic C-H bond is broken (Fig.14.4): Figure 14.4 Resonance stabilization of the benzylic radical.
H H H H

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14.9.2 Side Chain Oxidation In the presence of potassium permanganate (KMnO4) in aqueous acid, the alkyl side chain is oxidatively cleaved to a carboxylic acid group (CO2H) (Scheme 14.35): Scheme 14.35

R R KMnO4 H3O

O OH

There must be at least one hydrogen at the position for the reaction to work (Scheme 14.36): Scheme 14.36

KMnO4 H3O HO O

93

14.10 Diazonium Salts: Synthesis and Chemistry

14.10.1 Synthesis of Diazonium Salts Diazonium salts are very valuable, particularly for the manufacture of dyes. The preparation of diazonium salts is a two-step process (Scheme 14.37): Scheme 14.37

N NO2 (1) reduction NH2 N (2) NaNO2, HX 0oC - 5 oC Reduction methods Zn, CH3CO2H SnCl2, HCl TiCl3, HCl Raney Ni, H2
The first step is the reduction of a nitrobenzene to aniline. The second step is the oxidation of the NH2 to the diazonium salt using nitrous acid (HNO2). An ice-cold solution of sodium nitrite (NaNO2) dissolved in dilute HCl or H2SO4 is a typical source of nitrous acid. Note: The solution must be kept cold, between 0-5 oC, to prevent the decomposition of the diazonium salt. 14.10.2 Azo Dye Synthesis Once you have a diazonium salt solution, you can convert it into an azo dye. Azo dyes contain the N=N (azo) group. Azo dyes are made by an electrophilic aromatic substitution reaction between aniline or phenol and the diazonium salt as the electrophile (Scheme 14.38):

diazonium salt

94

Scheme 14.38
OH

OH N N X N N X N H N

+ HX + ortho product

diazonium salt

NH2

NH2

N N + HX + ortho product

(As an electrophile, diazonium salts are incredibly weak; they only react with anilines and phenols.) Below are some examples of azo dyes used as biological stains:

Amido black 10B Orange G (used to stain the proteins collagen and (used to stain cells in the pancreas and reticulin) pituitary gland)

95

14.10.3 Sandmeyer Reaction Diazonium salts can also perform nucleophilic substitution reactions in which N2 gas is the leaving group. When the nucleophiles are Cl, Br, or CN, a copper (I) salt is employed. These substitutions are called Sandmeyer reactions (Scheme 14.39): Scheme 14.39
N N X CuY
+

Y N N
+

CuX

(Y = Cl, Br, or CN) diazonium salt

14.10.4 Other Nucleophilic Substitution Reactions In addition to Sandmeyer reactions, nucleophilic displacement of N2 gas from diazonium salts can occur under a variety of other conditions to yield fluorobenzene, iodobenzene, and phenol (Scheme 14.40): Scheme 14.40
OH N N N X Cu(NO3)2 H2O KI diazonium salt NaBF4, H2O F (Schiemann reaction) H3PO3
+ +

Cu2O

CuX

I N
+

CuX

N N
+

CuX

H N
+

CuX

96

14.11 Nucleophilic Aromatic Substitution

Nucleophilic aromatic substitution is defined as the displacement of a leaving group (a departing nucleophile) from an aromatic ring by a nucleophile. Previously, we noted that diazonium salts will perform this reaction under various conditions. Benzene compounds containing NO2 ortho or para to a leaving group (F, Cl, Br, or I) will also undergo substitution. An example is the synthesis of p-nitroaniline from p-chloronitrobenzene (Scheme 14.41): Scheme 14.41
NO2 2NH3
+

NO2

NH4 Cl

Cl

NH2

If you take away the nitro group, there will be no reaction. You need the nitro group to stabilize the negative charge in the intermediate, which quickly decomposes to product (Scheme 14.42): Scheme 14.42
O O O O

NO2 fast

slow

fast

Cl

NH3

Cl

NH3

NH2 H

Cl
+

NH2 NH4 Cl

NH3

For nucleophilic aromatic substitution, the typical leaving group order (best to worst, left to right) is F, Cl, Br, and I. The reason for this order is that the first step in the mechanism is rate-determining. This means that the more partial positive the attacked carbon is, the more likely the nucleophile will "stick," and the faster the reaction will be.

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14.12 Benzynes: Synthesis and Chemistry

Benzyne is a strange creature. The reaction of fluoro-, chloro-, bromo-, or iodobenzene with sodium amide (NaNH2) produces benzyne (Scheme 14.43): Scheme 14.43

X H NaNH2

NaX +

NH2

X = F, Cl, Br, or I

benzyne
-

Is that really a CC in the ring? No. The so-called "triple" bond acts like +C=C . Benzyne reacts as a powerful dienophile in Diels-Alder reactions and also combines with nucleophiles (Scheme 14.44): Scheme 14.44

is really

Diels-Alder reaction with benzyne:

Nucleophilic addition to benzyne: Y Y H H Y

H Y = OH, RO, NH2, NR2

98

For substituted benzenes, the preferred resonance character of benzyne will put the negative charge closest to a highly electronegative groups (F, Cl, Br, OR, NO2, etc.) and the negative charge furthest away from electron-rich groups (C, CO2 , O ) (Scheme 14.45): Scheme 14.45
Cl Cl H NH2 Cl
-

most acidic proton H

best place for

+

NH2 +

Cl

Cl

Cl

Cl

OCH3 Br

OCH3 best place for

OCH3

NH2

CH3 Br

CH3

CH3

NH2

best place for

99

Thus, we can predict the major products of nucleophilic addition to benzynes (Scheme 14.46): Scheme 14.46

Cl H NH2

Cl H OH

Cl H

Cl m-dichlorobenzene H

OH
+

NH2
+

m-chlorophenol

Cl

Chapter 14 Exercises 1. Name each of the following compounds:

OCH3 a) Br b) SO3H c)

NO2

d)

e)

Cl

Cl F NO2 Cl

2. Draw each of the following compounds: a. m-nitrophenol b. 4-methylresorcinol c. o-cyanobenzoic acid d. 2,4,6-trichloroaniline e. p-isopropylbenzenesulfonic acid f. 2,3,5,6-tetrachlorohydroquinone g. 2,6-diethyl-4'-nitro-1,1'-biphenyl

100

3. Predict the major product(s) of each of the following reactions. Part 1:

O a) HN Br2 Fe CN Cl2 b) N Cl HNO3 H2SO4 N h) O O O AlCl3 H2SO4 d) H3CO NO2 I2 HNO3 O g) OCH3 Fe O f) SO3 H2SO4

c)

e)

OH

H2SO4 Br

101

Part 2:
Cl i) N2 n) HO OH

AlCl3 CCl3 j) o) CH3Cl AlCl3

NO2

1) TiCl3, HCl 2) NaNO2, HCl, 0oC 3) CuCN

k)

NO2 p) CH3O CH3OH F

Br
Cl 1) NaNH2 2) H2O

l)

Cl KMnO4 H3O

q)

Cl 1) NaNH2 2) O

m)

Cl NBS (PhCO2)2, CCl4

102

4.

Starting with benzene, propose a reasonable synthetic route to each of the following compounds:
OH a) CO2H b) c) d) CN

NH2

SO3H

5.

a) Starting with acetanilide, propose a reasonable synthetic route to the analgesic (painkiller) and anti-inflammatory agent, Tylenol. b) What is the chemical name of Tylenol?
O HN

OH Tylenol
R

6.

Ibuprofen (found in Advil, Nuprin, Motrin) is an analgesic (painkiller) sold as a racemate (50:50 mixture of R and S enantiomers). However, only (S)-ibuprofen actually blocks pain. Starting with (S)-2-phenylpropionic acid, propose a plausible synthetic route to (S)-ibuprofen:
O OH O OH

?
(S)-2-phenylpropanoic acid

(S)-ibuprofen

103

7. Write a plausible mechanism for each of the following transformations:

O

O a)

O OH O AlCl3 O OH H2SO4 (cat.) H2N

b) +

c)

N N HSO4 N N NH2

d)

O O NaNH2 (2 eq)

O O

Br e) O2N

F NH2NH2 (2 eq)

NH2 O2N

NH2 HN + NH2NH3 F

NO2

NO2

8. Why is compound A formed, but NOT compound B?

F AlCl3 Compound A F Cl Cl

Compound B NOT FORMED!

104

9. Why is compound C formed, but not compound D?

NO2 H N NO2 NO2

Cl Cl N

Cl Cl

Compound D NOT FORMED! Compound C

10. Why is compound E the major product?

Br Br Br

1) NaNH2 2) HBr

Compound E (major)

Compound F (minor)

11. Predict the major product of the reaction of indole with N-methyl-Nmethylenemethanaminium chloride (1), and EXPLAIN your prediction based on the stability of the reaction intermediate.
N 1 N H indole Cl

105

Answers to Chapter 14 Exercises 1. a. b. c. d. e. 2.

a) OH b) OH

2-bromo-4-methylanisole or 3-bromo-4-methoxytoluene 3-nitrobenzenesulfonic acid or m-nitrobenzenesulfonic acid 1,3-dimethyl-5-tert-butylbenzene or 5-tert-butyl-m-xylene 2-fluoro-4-iodo-1-nitrobenzene 2,4,6-trichloro-4'-cyclopentyl-1,1'-biphenyl
c) CN CO2H

NO2

OH

d) Cl

NH2 Cl

e)

SO3H

f) Cl

OH Cl

Cl Cl g) OH

Cl

O2N

106

3. Part 1:
O a) HN Br + HN O

f)

SO 3H

+ HO3S O O

Br

b) N Cl

CN g) Cl

OCH3
NO2
c) No reaction occurs, because the NR2 group will be protonated and become a Z group. Friedel-Crafts alkylation doesn't work when a Z group is present.
h) O +

O O

d) H3CO I NO2

e)

Br

107

Part 2:
i) n) N
N

OH

HO

j) No reaction. Friedel-Crafts alkylation cannot occur when a Z group (CCl3) is present.

o)

CN

k)

NO2 p)

Br

OH

l)

OCH3 Cl

q) O CO2H m) Cl

Br

108

4.
a) CH3Cl AlCl3 CO2H SnCl2, HCl NH2 b) O Cl AlCl3 Zn-Hg, HCl O CH3 KMnO4 H3O

CO2H HNO3 H2SO4

CO2H

NO2

SO3 H2SO4 SO3H

SO3H c) 1) Cl , AlCl3 OH

d)

2) HNO3, H2SO4 3) TiCl3, HCl 4) NaNO2, HCl 5) Cu2O, Cu(NO3)2 (aq) 1) CH3Cl, AlCl3 2) HNO3, H2SO4 NO2 3) TiCl3, HCl 4) NaNO2, HCl 5) CuCN

CN

109

5. a.
HN

OH

O HN

Cu2O, Cu(NO3)2 (aq)

N2

Cl

O HN 1)SnCl2, HCl 2)NaNO2, HCl, 0-5 oC HN

NO2

HNO3,H2SO4

b. p-hydroxyacetanilide or 4-hydroxyacetanilide 6.
O OH O Cl O OH TiCl3, HCl AlCl3 O OH

110

7.
a)

O O

O AlCl3 H O

O AlCl3 O O

AlCl3

O AlCl3 O

OH
+

AlCl3 H H

O O H3O O H O

b)

H
+

H3O

H H

H2O

111

c) H N N N NH2 HSO 4 H N NH2

N N
+

NH2

H2SO4 O O O O

d)

O O H NH2 2)H Br O O

NH2

NH2 O

NH2 e) O O N F O H2N NH2 O N

NH2 H F N NH2 H

NO2

O2N NH2

H N NH2 H

NO2 HN O2N

NH2

NH2NH3 F

H2N

NO2

NO2

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8. Compound A is formed because the C-F bond is broken much more rapidly by AlCl 3 than the C-Cl bond. 9. The leaving group must be ortho or para to NO2 for nucleophilic aromatic substitution to occur. The Cl which is not displaced is inert to this reaction because it is meta to NO2. 10. When benzyne is formed in the first step, the major resonance form places negative charge as far away as possible from the phenyl group, because phenyl is electron-rich. Thus, the - charge is para and the + charge is meta, so H+ attaches para and Br- attaches meta. 11.

Cl

N N H

N H indole N Cl

HCl

N H Cl

N H

N H Better resonancestabilization here

113