Jones M., Fleming S.A. Organic Chemistry

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14.11 Synthesis of Polysubstituted Benzenes 669

An example of this kind of reaction is the

nitration of 4-nitrotoluene (Fig. 14.86).

In the example in Figure 14.86, we

really didn’t have to worry much about

the directing effect of the nitro group on

the disubstituted ring, because it is a

rate-retarding substituent that will be

overwhelmed by the activating and ortho/

para-directing methyl group. However,

there are less obvious situations. If the

benzene ring bears ortho/para-directing

groups at both the 1- and the 4-positions,

the position of further substitution is not

immediately clear. Sometimes steric

effects determine the outcome.For exam-

ple, Friedel–Crafts acylation of 4-iso-

propyltoluene gives reaction only at the

less encumbered position adjacent to the

methyl group (Fig. 14.87). In other cases,

electronic factors of one of the groups may

determine the outcome, and further

reaction will be at the position activated

by the more strongly activating group.

For example,the Friedel–Crafts alkylation

of 4-methylphenol gives almost entirely

substitution ortho to the strongly ortho/para-directing hydroxyl group, and only

traces of substitution ortho to the less activating methyl group (Fig. 14.87).

Here, electronic effects decide the issue

OH OH

2-Isopropyl-4-methylphenol

(20.5%)

3-Isopropyl-4-methylphenol

(a trace)

CH(CH

)

CH(CH

)

AlCl

, CS

, 5 ⬚C

The steric influence

of the large isopropyl

group dominates

CH(CH

)

CH(CH

)

(50%)

(CH

)

CHBr

AlCl

, 15–25 ⬚C

4-Methylphenol

-Isopropyltoluene

FIGURE 14.87 Two examples of

reactions of benzenes substituted

1,4 with both groups ortho/para-

directing. Steric effects decide the

first case, electronic effects the

second.

o/p = ortho/para directing

m = meta directing

o/p o/p directs hereo/p directs here

o/p

2,4-Dinitrotoluene

(99.8%)

3,4-Dinitrotoluene

(0.2%)

m directs here m directs here

p-Nitrotoluene

A SPECIFIC EXAMPLE

GENERAL CASE

FIGURE 14.86 Substitution is directed to a single position if a benzene ring is

substituted 1,4 with one ortho/para-directing group and one meta-directing group.

Other situations are more difficult to predict.Generally,the result will be determined

by the sum of the steric and electronic effects of the groups already present on the ring.

670 CHAPTER 14 Substitution Reactions of Aromatic Compounds

3-Amino-2,4,6-tribromo-

benzoic acid

(~100%)

COOH COOH

BrBr

excess Br

O, 40–50 ⬚C

3-Aminobenzoic

acid

2,4,6-Tribromophenol

(97%)

BrBr

excess Br

CCl

, 0 ⬚C

Phenol

WEB 3D

FIGURE 14.88 The bromination of anilines and phenols often leads to multiple additions of several bromines. The

strongly activating groups, amino and hydroxyl, direct substitution to the ortho and para positions.

Arene halogenation

pyridine

HCl

Acetamidobenzene

(acetanilide)

NaOH

CCOO

–

p-Nitroacetamido-

benzene

(79%)

HNO

o-Nitroacetamido-

benzene

(19%)

m-Nitroacetamido-

benzene

(2%)

WEB 3D

FIGURE 14.89 Acylated aniline is a

less activated molecule than aniline.

Monosubstitution can be achieved.

Some substituents are so strongly activating that no catalyst is needed, and it is

often difficult to stop substitution before more than one new substituent has been

added to the ring. For example, many anilines are brominated with Br

alone to give

2,4,6-tribromoanilines (Fig.14.88). Phenols are also highly activated toward further

substitution to give polysubstituted products. Mild conditions are needed to restrict

the reaction to monosubstitution.

The hydroxyl group of phenol or the amino group of aniline are so strongly acti-

vating that neither monobromo nor dibromo compounds can be isolated unless great

care is taken. Note that when the first bromine is added in the para position, we

have the general situation of Figure 14.87. In this case, the OH (or NH

) and the

Br direct further substitution to different positions.The more powerfully activating

OH or NH

groups win out (bromine is actually deactivating), and the second and

third bromines add ortho to the amino or hydroxyl group as shown in Figure 14.88.

The overly active amino group can be deactivated, as shown in Figure 14.89,

by acylating it through reaction with acetyl chloride to give acetamidobenzene.

14.11 Synthesis of Polysubstituted Benzenes 671

N-Acylated aromatic amines still direct ortho/para, but substitution is slower than

for the unsubstituted aniline,and the reaction can be stopped after a single new sub-

stitution.The protecting acyl group can be removed later by treatment with acid or

base. We will see the mechanisms for these reactions in Chapter 18.

excess Br

, 0 ⬚C

CCl

COOH, H

O, 25 ⬚C

-Bromophenol

(100%)

Phenol 2,4,6-Tribromophenol

(97%)

FIGURE 14.90 Direct bromination of phenol cannot give pure o-bromophenol.

100 ⬚C, 3 h H

O, 100 ⬚C

nitrobenzene

40–50 ⬚C

Phenol o-Bromophenol

FIGURE 14.91 The para and one ortho position can be reversibly blocked by the sulfonic acid groups. Once

these groups are attached, only one ortho position remains for further substitution. After bromination, the

sulfonic acid groups can easily be removed to give the pure ortho isomer.

Effective use can sometimes be made of removable blocking groups on the ring.

Suppose you are set the task of making pure o-bromophenol. Simple bromination

of phenol will fail because of the dominant formation of the para isomer or of poly-

brominated compounds (Fig. 14.90). A solution to this problem is first to sulfonate

the ring to give the 2,4-disulfonic acid of phenol (Fig.14.91).The deactivating effect

of the sulfonic acid groups prevents further sulfonation. This compound can now

be brominated at the position ortho to the activating hydroxyl group and meta to

the deactivating groups. The sulfonic acids have acted to block substitution at the

other ortho and para positions. Removal of the blocking sulfonate groups with acidic

steam completes the reaction. (Note that the SO

OH group is an acid.) This

approach allows the formation of a single isomer of bromophenol.

PROBLEM 14.35 Through a mechanistic analysis of the electrophilic aromatic sub-

stitution of acetamidobenzene, explain why this compound substitutes mainly

para. Suggest a reason why the reaction rate of acetamidobenzene with elec-

trophiles is slower than the rate of the reaction of aniline with electrophiles.

672 CHAPTER 14 Substitution Reactions of Aromatic Compounds

“

Br,” H

O, 25 ⬚C

m-Bromonitrobenzene

100% meta isomer

Nitrobenzene

FIGURE 14.92 Nitrobenzene cannot

be brominated in the ortho or para

positions. Substitution is entirely meta.

The ability to interconvert nitro and amino groups is also useful in synthesis of

aromatic compounds. The synthesis of p-bromonitrobenzene from nitrobenzene is

an example. Nitrobenzene cannot be brominated in the para position because the

meta-directing nitro group will force formation of only the meta isomer (Fig. 14.92).

100% para isomer

pyridine

, CH

COOH,

25 ⬚C

/Pd/C

COOOH

NaOH

COOH

Nitrobenzene

-Bromonitrobenzene

FIGURE 14.93 Conversion of the

nitro group into the ortho/para-

directing amino group followed by

acylation allows the introduction of a

single para bromine. Regeneration of

the amine, followed by oxidation back

to nitro, completes the reaction

sequence.

The synthesis of a disubstituted benzene in which two meta-directing groups

are substituted ortho or para to each other constitutes a general synthetic problem.

To solve such a problem, the ability to convert a meta-directing group into an

ortho/para director and back again is crucial. A similar difficulty is encountered in

the construction of disubstituted benzenes bearing ortho/para-directing groups in

meta positions.

The solution is to convert nitrobenzene into aniline by a reduction step, acetylate,

and then brominate. Bromination now goes 100% in the para position. Now the

amino group can be regenerated by removal of the acyl group and then oxidized to

a nitro group (Fig. 14.93). The initial reduction of nitro to amino can be carried out

using catalytic hydrogenation, or by a variety of other reducing agents.The oxidation

step is usually accomplished with trifluoroperacetic acid or m-chloroperbenzoic acid.

14.11 Synthesis of Polysubstituted Benzenes 673

Anilinium ion

FAST

slow

This arrow is the key; as long as some free amine

is present, the high rate of its substitution reactions

will lead to the formation of ortho and para product

(a)

(b)

(c)

(d)

ANSWER Aniline will protonate in acid,and the anilinium ion will substitute meta.

However, as long as there is some unprotonated aniline present at equilibrium, it

will continue to substitute ortho and para. It is estimated that some anilines react

at 10

times the rate of the deactivated anilinium ions! So, even if there is only a

little free amine present there can still be a great deal of product formed from it.

PROBLEM 14.37 Devise syntheses of the following substituted benzenes. You may

start from benzene, organic reagents containing no more than two carbons, and

any inorganic reagents you may need.

Summary

When the reacting benzene ring is di- or polysubstituted,the original substituents

may reinforce each other or compete. One has to determine the relative influ-

ences, resonance, inductive, and steric of each substituent in assessing where the

next substitution will occur. Resonance effects usually dominate inductive effects.

WORKED PROBLEM 14.36 The nitration of aniline takes place in acid. Under

acidic conditions the amino group must be largely protonated to give an anilini-

um ion, a meta-directing group. In fact, if the amino group is not acetylated, the

product does contain substantial amounts of m-nitroaniline. Why is the product

not entirely m-nitroaniline? Hint: Think about the relative rates of the reactions

involved.

14.12 Nucleophilic Aromatic Substitution

14.12a Nucleophilic Additions to Benzenes Normally, alkenes are unaf-

fected by treatment with nucleophiles, and it is no surprise to find that benzene also

survives treatment with strong nucleophiles. In particular, no reaction occurs when

benzene or halobenzenes are treated with a nucleophile (Fig. 14.94).

However, a few specially substituted benzenes do undergo nucleophilic substi-

tution in base. Electron-withdrawing groups on the ring are necessary for this reac-

tion. For example, 1-chloro-2,4-dinitrobenzene is converted into 2,4-dinitrophenol

by treatment with sodium hydroxide in water (Fig. 14.95).

674 CHAPTER 14 Substitution Reactions of Aromatic Compounds

–

OCH

HOCH

No reaction

–

FIGURE 14.94 Benzenes and haloben-

zenes do not normally react with

nucleophiles to give substituted products.

–

OH/H

warming

2,4-Dinitrophenol

(95%)

1-Chloro-2,4-dinitrobenzene

FIGURE 14.95 Some substituted

benzenes are reactive toward

nucleophiles. 1-Chloro-2,4-

dinitrobenzene can be swiftly

transformed into the corresponding

phenol by hydroxide ion in water.

–

OCH

–

OCH

HOCH

, 50 ⬚C

–

OCH

HOCH

, 50 ⬚C

–

OCH

HOCH

, 50 ⬚C

No reaction

Relative Rate

115,000

3.4

1.0

HOCH

, 50 ⬚C

FIGURE 14.96 For nucleo-

philic aromatic substitution

to succeed, at least one

nitro group must be present.

2,4-Dinitro compounds

(represented by the first

molecule in this figure) react

much faster than mononitro

compounds.

At least one nitro group is essential for this substitution reaction, and it must be

in the right place relative to the chlorine.Chlorobenzene and m-chloronitrobenzene

do not react with nucleophiles, but p-chloronitrobenzene does, although it substi-

tutes much more slowly than the 2,4-dinitro compound (Fig. 14.96).

Nucleophilic aromatic

substitution

14.12 Nucleophilic Aromatic Substitution 675

Neither an S

2 nor an S

1 reaction seems

likely. Attack from the rear is impossible, as

the ring blocks the path of any entering

nucleophile, so an S

2 reaction is not

involved. Ionization would produce a most

unstable carbocation (Fig. 14.97), which pre-

cludes the S

1 reaction path.

The mechanism of this reaction involves addition to the benzene ring by methoxide

(or any nucleophile) to generate a resonance-stabilized anionic intermediate, called a

Meisenheimer complex,after Jakob Meisenheimer (1876–1934) (Fig.14.98).This mech-

anism is called the S

Ar reaction,because it is a Nucleophilic Aromatic Substitution.

An unstable phenyl cation—the

1 reaction will not be easy

The path of addition

in the S

2 reaction

is blocked—not S

–

FIGURE 14.97 Neither an S

2 nor

1 reaction occurs in substitution

of the halobenzenes.

A Meisenheimer complex

–

HOCH

–

OCH

FIGURE 14.98 Addition to the ring by

methoxide leads to a highly

resonance-stabilized anion. Both nitro

groups help bear the negative charge.

The nitro groups stabilize the negative charge through resonance, and therefore

exert their effect only when they are substituted at a carbon that helps to bear the neg-

ative charge.This stabilization by nitro is the reason that o- or p-chloronitrobenzene

undergoes the reaction, but the meta isomer does not (Fig. 14.99). The aromatic

Para addition

–

OCH

HOCH

–

Ortho addition

–

OCH

HOCH

–

Meta addition—here the nitro groups do not help stabilize the negative charge

–

OCH

HOCH

–

(–)

(–) (–)

–

FIGURE 14.99 The stabilizing nitro

group must be in the proper position.

A nitro group meta to the point of

nucleophilic attack cannot stabilize

the negative charge by resonance.

676 CHAPTER 14 Substitution Reactions of Aromatic Compounds

14.12b S

Ar Reactions of Heteroaromatics Pyridine is more active in

nucleophilic aromatic substitution than benzene. Not only is pyridine less reso-

nance stabilized than benzene (Table 14.1), but the electronegative nitrogen atom

provides an attractive place for an incoming negative charge (Fig. 14.101).

The classic example of nucleophilic aromatic substitution of pyridine is the

Chichibabin reaction, named for Alexei E. Chichibabin (1871–1945), in which

pyridine is converted into 2-aminopyridine through treatment with potassium amide

in liquid ammonia (Fig. 14.102).

–

–+

Na OCH

(a)

(b)

OCH

–

(a) (b)

FIGURE 14.100 The addition–elimination S

Ar mechanism starts with addition of the nucleophile; the

reaction is completed by elimination of chloride and regeneration of the aromatic ring. Loss of

methoxide only leads back to starting material.

–

FIGURE 14.101 Nucleophilic attack

on pyridine.

system can be regenerated by reversal of the attack of nucleophile or by elimination

of chloride to give 2,4-dinitroanisole (Fig.14.100).This is the addition–elimination

pathway of the S

Ar reaction.

2-Aminopyridine

(78%)

Pyridine

1. KNH

105–130 ⬚C

2. H

FIGURE 14.102 The Chichibabin

reaction.

addition to

the 3-position

addition to

the 2-position

–

FIGURE 14.103 Addition to the 3-position does not allow the ring nitrogen to help stabilize the negative charge.

Addition to the 2- or 4-position does.

The first step of the mechanism is consistent with the addition–elimination S

process. The strongly nucleophilic



adds to pyridine. Addition at the 2- or

4-position makes it possible for the negative charge to be shared by nitrogen and so

is preferred to attack at the 3-position (Fig. 14.103).

14.12 Nucleophilic Aromatic Substitution 677

–

2-Aminopyridine

WEB 3D

FIGURE 14.104 In this S

Ar reaction there is a loss of hydride followed by formation of

. Hydrolysis regenerates 2-aminopyridine.

addition

LiOH H

–

loss of

hydride

RLi

–

FIGURE 14.105 Addition of alkyllithium reagents also leads to substituted pyridines.

This conventional beginning is followed by a rather unconventional conclu-

sion, as aromaticity is regained through elimination of hydride (Fig. 14.104).This

step is unconventional because loss of hydride from an organic compound is rare.

Aminopyridine and potassium hydride are the initially formed products. These

react rapidly and irreversibly to form hydrogen gas and a nicely resonance-

stabilized amide ion. A final hydrolysis step regenerates aminopyridine. It is pre-

sumably the irreversible nature of hydrogen gas formation that helps drive this

reaction to completion.

Other strong nucleophiles such as organolithium reagents also undergo the

Ar reaction to form substituted pyridines. In these reactions, hydrogen gas can-

not be formed until the final hydrolysis step (Fig. 14.105).

Nucleophilic substitution provides a means of converting pyridines bearing a

leaving group at the 2- or 4-position into differently substituted molecules.Addition

to the position bearing the leaving group (called ipso attack) leads to an interme-

diate that can either revert to starting material or eliminate the leaving group to give

a new compound (Fig. 14.106).

elimination step

–

OCH

–

OCH

50 ⬚C

ipso attack

addition step

–

FIGURE 14.106 S

Ar reaction

of a pyridine through ipso attack.

A leaving group is displaced through

the addition–elimination process.

678 CHAPTER 14 Substitution Reactions of Aromatic Compounds

–

(–)

add to

2-position

–

(–)

(–) (–)

add to

4-position

no addition to

3-position

The charge is shared

by three carbons, but

not by nitrogen

WORKED PROBLEM 14.38 Explain why the S

Ar reaction works only for halopyr-

idines substituted at the 2- or 4-position and fails for 3-substituted halopyridines.

ANSWER The key to the relatively easy nucleophilic additions to pyridines is the

placement of the negative charge on nitrogen. If the leaving group is attached to

the 3-position, ipso addition of a nucleophile does not place the negative charge

on the electronegative nitrogen atom. Only if the leaving group is at the 2- or

4-position does this happen.

N-oxides are especially active in nucleophilic aromatic substitution because the

incoming nucleophile annihilates the positive charge on nitrogen as it adds.

Addition destroys aromaticity, but for the N-oxides, loss of a leaving group

regenerates the aromatic sextet and the aromatic N-oxide. An interesting twist to

this reaction is shown in Figure 14.107 where the S

Ar reaction is carried out in

removal of a

proton and loss

of the good

leaving group

addition

elimination

addition

An acid chloride

–

Good

leaving

group

FIGURE 14.107 Pyridine N-oxides

are relatively easily attacked by

nucleophiles. Loss of a leaving group

leads to a substituted pyridine.