Jones M., Fleming S.A. Organic Chemistry

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13.11 Introduction to the Chemistry of Benzene 609

The mechanism of the Birch reduction is similar to that for dissolving metal

reduction of alkynes (p. 452), and starts in the same way, with a transfer of an

electron from the metal to one of the empty antibonding orbitals of benzene. The

product is a resonance-stabilized radical anion (Fig. 13.67).

Na/NH

A resonance-stabilized radical anion

etc.

–

FIGURE 13.67 Transfer of an electron

from sodium to benzene leads to a

resonance-stabilized radical anion.

Protonation by alcohol gives a radical that can undergo a second electron

transfer–protonation sequence to complete the reduction (Fig. 13.68).

A resonance-stabilized radical

–

––

–

H OEt

OEt

A resonance-stabilized anion

OEt

EtO

FIGURE 13.68 The radical anion is

protonated to give a resonance-

stabilized cyclohexadienyl radical

that goes on to produce the

1,4-cyclohexadiene through another

reduction–protonation sequence

(Et  CH

Substituted benzenes can also be reduced using these conditions. Electron-

releasing groups such as alkyl or alkoxy always wind up on one of the double bonds,

but electron-withdrawing groups, such as a carboxylic acid (COOH), invariably

appear on the methylene positions of the product dienes (Fig. 13.69).

O CH

1. Na/NH

/EtOH

2. H

O/H

COOH COOH

1. Na/NH

/EtOH

2. H

O/H

FIGURE 13.69 In the Birch reduction

of substituted benzenes, electron-

releasing groups appear on one of

the double bonds, but electron-

withdrawing groups are located at

the methylene position.

610 CHAPTER 13 Conjugation and Aromaticity

13.12 The Benzyl Group and Its Reactivity

Thus far we have been looking at processes directly involving the benzene ring of

an aromatic compound. Here we sketch out some reactions in which benzene plays

a major role, but in which the action takes place on the outskirts of the ring. The

carbon adjacent to a benzene ring is called the benzylic carbon,or the benzylic posi-

tion. Remember from p. 596, the benzyl group is . Any group attached

to a benzylic carbon is referred to as being in a benzylic position. In many ways, the

reactivity of the benzylic position resembles that of the allylic position. Indeed, an

orbital at the benzylic position is stabilized by overlap with adjacent orbitals in much

the same way as is an orbital at the allylic position (Fig. 13.70).

13.12a Substitution Reactions of Benzyl Compounds Benzyl compounds

are unusually active in both the S

1 and S

2 reactions. Clearly, the benzene ring

helps enormously to stabilize the carbocation formed in the rate-determining ioniza-

tion of an S

1 reaction. For example, the benzylic chloride in Figure 13.71 reacts

more than 100,000 times faster than isopropyl chloride in a typical S

1 process.

Both involve secondary cations as intermediates, but the secondary cation that is also

benzylic is significantly more stable, as is the transition state leading to it.

The benzyl group

The benzylic position The benzylic position

The allyl group

The allylic position

FIGURE 13.70 The position

adjacent to a benzene ring is quite

analogous to the allylic position.

EtOH

OEt

Relative rate = 1.37 ⫻ 10

Resonance-stabilized

benzylic cation

Relative rate = 1

25 ⬚C

1. EtOH

2. deprotonate

EtOH

25 ⬚C

HC Cl

HC OEt

1. EtOH

2. deprotonate

FIGURE 13.71 The resonance stabilization of the benzylic cation makes its formation relatively easy.

Accordingly, S

1 reactions of benzylic compounds containing good leaving groups are quite fast.

13.12 The Benzyl Group and Its Reactivity 611

In the benzyl cation itself (Fig. 13.72), the positive charge is borne by 4 carbons,

in the benzhydryl cation (Ph



H) (the benzhydryl group is Ph

CH) by 7 carbons,

and in the trityl cation (Ph



) by a whopping 10 carbons.

The benzhydryl cation—7 resonance formsBenzhydryl chloride

The trityl cation—10 resonance formsTrityl chloride

In this composite representation

of the benzhydryl cation, the

positions sharing the positive

charge are shown as

(+)

In this composite representation of

the trityl cation, the positions sharing

the positive charge are shown as

(+)

(+) (+)

(+)

(+)(+)

(+)

(+) (+)

(+)(+) (+)(+)

(+)

A composite picture in which the positions

sharing the positive charge are shown as

(+)

The benzyl cation— 4 resonance formsBenzyl chloride

FIGURE 13.72 Resonance

stabilization of the benzyhydryl and

trityl cations.

PROBLEM 13.25 Why is triptycenyl chloride not nearly as reactive in the S

reaction as trityl chloride?

Triptycenyl chlorideTrityl chloride

WEB 3D

612 CHAPTER 13 Conjugation and Aromaticity

PROBLEM SOLVING

In a Problem like 13.25, in which the parts of two molecules are just about the

same (here, three benzene rings and a chlorine bonded to a tertiary carbon are

common to the two molecules), it is a good bet that the answer lies in geometry.

In most such problems it is the geometrical relationship between the various

parts that leads to the crucial difference.

Transition state for S

displacement of an allyl halide

–

Transition state for S

displacement of a benzyl halide

–

FIGURE 13.73 The transition state

for S

2 displacement at the benzylic

position is stabilized through orbital

overlap with the ring.

Table 13.2 compares the rates of reaction for benzyl iodide and other alkyl iodides

in an S

2 reaction.

13.12b Radical Reactions at the Benzylic Position A benzene ring will also

stabilize an adjacent half-filled orbital (a free radical) through resonance (Fig. 13.74).

TABLE 13.2 Some Relative

Rates of S

2 Displacements

in the Reaction of

with Iodide Ion at 50 °C in

Ethyl Alcohol Solvent

R Group Relative Rate

Ethyl 1.0

Propyl 0.6

Butyl 0.4

Allyl 33

Benzyl 78

FIGURE 13.74 The resonance forms

for benzyl radical.

Benzyl halides are also especially reactive in the S

2 reaction.The reason is the

same as that for the enhanced reactivity of allyl chloride (p.543).The transition state

for S

2 displacement is delocalized, and therefore especially stable. If the transition

state for a reaction is at relatively low energy, the activation energy for the reaction

will also be relatively low and the reaction will be fast (Fig. 13.73).

13.12 The Benzyl Group and Its Reactivity 613

CCl

, hν

Toluene Benzyl

bromide

NBS =

FIGURE 13.75 The radical bromina-

tion of toluene.

CHCH

⌬ or hν

␣␤

FIGURE 13.76 The thermal or

photochemical decomposition of

bromine in ethylbenzene leads to

1-bromo-1-phenylethane through

radical bromination at the benzylic

position.

In Chapter 11 (p. 497), we discussed radical reactivity at the allylic position,

and very little need be added to get a description of benzylic reactivity. Toluene,

for example, can be brominated by N-bromosuccinimide (NBS) to give benzyl

bromide (Fig. 13.75).

13.12c Oxidation at the Benzylic Position Both free radicals and

the special activity of the benzylic position play a role in the reaction of

alkylbenzenes with KMnO

or H

to give benzoic acid, which is benzene

with a carboxylic acid (COOH) attached. Side chains are “chewed down” to

carboxylic acids no matter what their length. The details are vague, but the

key observation is that tertiary side chains are untouched by oxidizing agents.

As you should be able to deduce from Problem 13.27, abstraction of hydro-

gen is especially easy at the α position of ethylbenzene. This abstraction occurs

easily because of the resonance stabilization of the benzylic radical (Fig. 13.74).

Because bromine will not attack the benzene ring without a catalyst, benzylic posi-

tions can often be brominated by simply heating or photolyzing bromine in their

presence (Fig. 13.76).

PROBLEM 13.26 Write a mechanism for the reaction between toluene and NBS.

Hint: See Chapter 11 (p. 500) for a description of the reaction of NBS with allylic

compounds.

PROBLEM 13.27 Ethylbenzene yields only the product of bromination at the α

position (the position adjacent to the ring) when treated with NBS in CCl

Explain.

Benzylic oxidation

614 CHAPTER 13 Conjugation and Aromaticity

Summary

The chemistry of benzenes is summed up by the imperative: “Preserve the circle!”

In plain English, that statement means that there is a strong thermodynamic

driving force to preserve the delocalization energy—more than 30 kcal/mol—that

the circle represents. In this chapter, the classic aromatic substitution reaction

in which an electrophile replaces (substitutes for) one of the hydrogens on the

ring is introduced. In Chapter 14, this prototypal reaction will be expanded in

many ways.

Other aromatic chemistry features a few reactions in which aromaticity is lost

(the Birch reduction is one example) and the special influence of the aromatic

ring on the benzylic position.

KMnO

COOH

Benzoic acid

C(CH

)

CH(CH

)

WEB 3D

FIGURE 13.77 Oxidizing agents

convert most alkyl side chains on

benzene rings into the acid group,

COOH. However, for the oxidation

to succeed there must be at least one

benzylic hydrogen.Thus, tert-butyl-

benzene does not react.

13.13 Special Topic: The Bio-Downside,

the Mechanism of Carcinogenesis by

Polycyclic Aromatic Compounds

We mentioned earlier that some polycyclic aromatic hydrocarbons are strongly car-

cinogenic. Although all the details of this carcinogenesis are not worked out, the

broad outlines are known for some molecules. Deoxyribonucleic acid (DNA) and

ribonucleic acid (RNA) are huge biomolecules that contain and help transcribe

genetic information (Chapter 23). Both DNA and RNA are phosphate-linked

sequences of nucleotides, which are sugar molecules attached to heterocyclic bases.

There must be at least one hydrogen in the benzylic position for the reaction to

succeed (Fig. 13.77).

13.13 Special Topic: The Bio-Downside 615

Alkylation changes the size and shape of the DNA molecule and makes mis-

matched base pairing through hydrogen bonding more likely (see Chapter 23 for

more details of base pairing).This mismatch can lead to errors in replication and to

mutations. Most mutations are harmless to the organism, because they lead to the

death of only the individual cell. On rare occasions, however, a mutation can lead to

uncontrolled cell division and cancer.

The polyaromatic hydrocarbons (PAHs) are only indirectly responsible for the

chemical processes that lead to cancer. Aromatic hydrocarbons are not very reactive

and there is no obvious way for them to react chemically with the nucleophilic bases

in DNA or RNA (Fig. 13.79).

However, there are enzymes that can modify the PAH rings. Nonpolar mol-

ecules such as aromatic hydrocarbons accumulate in fat cells and natural methods

have been evolved to purge our bodies of such molecules. These methods gener-

ally involve making the hydrocarbons more water soluble by adding polar groups.

No reaction

Guanine Benz[a ]pyrene

Sugar

FIGURE 13.79 Aromatic

hydrocarbons do not react with

nucleophiles, and there is no way for

a molecule like benz[a]pyrene to

alkylate one of the bases directly.

SugarSugar

The structures of the four bases found in DNA attached to sugars

Adenine

Sugar

Guanine

Sugar

Cytosine Thymine

Sugar

Alkylated

1. S

2 alkylation

2. deprotonate

Base

Sugar

Base

Sugar

P O

Sugar

–

Base

Sugar

Base

Sugar

–

H-bonding

π stacking

FIGURE 13.78 The DNA polymer is composed of phosphate-linked sugar-base units.Two strands of DNA

are held together by hydrogen bonding between pairs of bases and by π stacking between the aromatic

bases. Alkylation of the bases changes the size and shape of one of the units.This change can interfere with

hydrogen bonding and base pairing. In turn, this interference can lead to mutations and cancer.

These molecules bear large numbers of nucleophilic groups that can be alkylated by

other molecules (electrophiles) in what seem to be simple S

2 reactions (Fig.13.78).

616 CHAPTER 13 Conjugation and Aromaticity

P-450

monooxygenase

Benz[a ]pyrene

epoxide

hydratase

WEB 3D

FIGURE 13.80 Benz[a]pyrene is enzymatically epoxidized and ring opened to give a polar trans 1,2-diol.

A second enzymatic epoxidation, again by P-450 monooxygenase, gives a mol-

ecule that reacts with guanine, one of the DNA bases, to give DNA that is severe-

ly encumbered by the large, alkylated guanine (Fig. 13.81). This modified base has

difficulty in maintaining normal hydrogen bonding with another complementary

base, and this mismatch can lead to mutations.

Guanine

Sugar

P-450

monooxygenase

–

Sugar

NHNH

Sugar

FIGURE 13.81 A second epoxide is

formed.This epoxide is opened by

guanine to give a highly encumbered

molecule, A, that has problems

maintaining proper hydrogen

bonding.

For example,benz[a]pyrene is epoxidized by the enzyme P-450 monooxygenase and

the product epoxide is then opened enzymatically to give a trans diol (Fig. 13.80).

This alkylation of guanine is not a new reaction. You already know of the open-

ing of epoxides in both base and acid (p. 426), and this process is nothing more than

a complicated version of that simple reaction.

13.14 Summary 617

13.14 Summary

New Concepts

Equilibrium

Resonance

Dewar resonance

form (minor contributor)

Kekule´ resonance

form (important)

Benzene Dewar benzene

(unstable species)

FIGURE 13.82 Equilibrium versus resonance.

Reactions, Mechanisms, and Tools

equilibrating molecules have different geometries—different

arrangements of atoms in space. Benzene and Dewar

benzene are different molecules; the Kekulé and Dewar

resonance forms contribute to the real structure of benzene

(Fig. 13.82).

The material in this chapter is composed almost entirely of

concepts. There are few new reactions or synthetic procedures.

We concentrate here on the special stability of some planar,

cyclic, and fully conjugated polyenes.The special stability called

aromaticity is encountered when the cyclic polyene has a molec-

ular orbital system in which all degenerate bonding molecular

orbitals are completely filled.

These especially stable molecular orbital systems are

found in planar, cyclic, fully conjugated polyenes that contain

4n  2 π electrons (Hückel’s rule).

Heats of hydrogenation or heats of formation can be used

to calculate the magnitude of the stabilization. For benzene, the

delocalization energy or resonance energy amounts to more

than 30 kcal/mol.

It’s vital to keep clear the difference between resonance forms

and molecules in equilibrium. In this chapter, that difference is

exemplified by Dewar benzene, bicyclo[2.2.0]hexa-2,5-diene

(Problem 13.5), and the Dewar resonance forms contributing

slightly to the structure of benzene. As always, resonance forms

are related only by the movement of electrons, whereas

annulene (p. 594)

arene (p. 598)

aromatic character (p. 582)

aromaticity (p. 582)

benzene (p. 573)

benzhydryl group (p. 611)

benzoic acid (p. 613)

benzyl (p. 596)

Birch reduction (p. 608)

cycloheptatrienylium ion (p. 587)

cyclopentadienyl anion (p. 589)

delocalization energy (p. 581)

Dewar benzene (p. 573)

Dewar forms (p. 576)

Frost circle (p. 584)

furan (p. 599)

heteroaromatic compound (p. 599)

heterobenzene (p. 591)

Hückel’s rule (p. 583)

Kekulé forms (p. 575)

meta (p. 596)

ortho (p. 596)

para (p. 596)

phenyl (Ph) (p. 596)

polynuclear aromatic compound (p. 602)

pyridine (p. 598)

pyrrole (p. 592)

resonance energy (p. 581)

tropylium ion (p. 587)

Key Terms

In this chapter, the first reaction mechanism encountered is

the important and general electrophilic substitution of benzene.

A host of aromatic substitution reactions will be studied in

Chapter 14 and are exemplified here by deuterium exchange.

The aromatic ring is destroyed by an endothermic addition of



, but reconstituted by an exothermic loss of H



(Fig. 13.65).

There is little in the way of new synthetic procedures in this

chapter. You might remember the formation of the tropylium

ion by hydride abstraction and the Birch reduction of ben-

zenes to 1,4-cyclohexadienes. You also have a method of

Syntheses

synthesizing deuteriobenzene through the acid-catalyzed

exchange reaction of benzene. This reaction will serve as the

prototype of many similar substitution reactions to be found

in Chapter 14.

618 CHAPTER 13 Conjugation and Aromaticity

1 and S

2 reactions

–

Radical bromination at the benzyl position

NBS

Oxidation of benzyl positions bearing at least one hydrogen

CH(CH

)

COOH

KMnO

1. Benzylic Compounds

3. Deuteriobenzenes

2. Cyclohexadienes

4. Tropylium Ions

EtOH

Birch reduction of benzene

Na/NH

1,4-Cyclohexadiene

cid-catalyzed exchange of hydrogens on a benzene

ring; all hydrogens can eventually be exchanged

O/D

–

Hydride transfer from cycloheptatriene

to the trityl cation (

CPh

)

Tropylium

fluoborate

–

HCPh

CPh

Common Errors

Certainly the most common error is to overgeneralize

Hückel’s rule. We often forget to check each potentially

aromatic molecule to be certain it satisfies all the criteria.

The molecule must be cyclic or there cannot be the fully con-

nected set of p orbitals necessary (Fig. 13.18). The molecule

must be planar so that the p orbitals can overlap effectively

(Fig. 13.16). There may be no positions in the ring at which

p/p overlap is interrupted (Fig. 13.15). Finally, there must be

4n  2 π electrons. Be certain you are counting only π electrons.

Do not include in your count electrons not in the π system.

The classic example is pyridine, which contains a pair of elec-

trons in an sp

orbital that are often mistakenly counted as π

electrons (Fig. 13.47). If all four of these criteria are satisfied

we find aromaticity.

Do not misapply the Frost circle device.The most common

error is to forget to inscribe the circle with the vertex of the

appropriate polygon down. This requirement is hard to remem-

ber because at this level of discussion this point is arbitrary—

there is no easy way to figure it out if you don’t remember the

proper convention.

Do not confuse absolute and relative stability. For example,

the cyclopentadienyl anion is aromatic, and therefore exception-

ally stable, but only within the family of anions. The negatively

charged cyclopentadienyl anion is not as stable as benzene.

As always, you must be clear about the difference between

resonance and equilibrium. Be certain that you know the differ-

ence between the two Kekulé resonance forms for benzene and

the hypothetical molecule 1,3,5-cyclohexatriene.