Jones M., Fleming S.A. Organic Chemistry

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14.9 Disubstituted Benzenes: Ortho, Meta, and Para Substitution 659

As a result, we can expect para (or ortho) substitution to occur more rapidly than

the other two reactions (Fig. 14.67). In fact, the chlorination of anisole gives only

Reaction progress

Energy

Transition state for formation

of the meta intermediate

(higher energy)

Intermediate in para

substitution of anisole

(lower energy)

OCH

Intermediate in meta

substitution of anisole

(higher energy)

OCH

Transition state for

formation of the

para intermediate

(lower energy)

FIGURE 14.67 The intermediate

for para substitution, with four

resonance forms, is lower in energy

than the intermediate for meta

substitution (three forms) or that for

substitution of benzene (also three

forms).The transition state for para

substitution of anisole will also be

lower in energy than the transition

state for meta substitution.

o-chloroanisole and p-chloroanisole as

products (Fig. 14.68). The relatively low

energy of the intermediate formed by addi-

tion to anisole at the ortho or para substi-

tution (four resonance forms, Fig. 14.66)

means that this reaction will prevail over

meta attack (the intermediate has only three

resonance forms, Fig. 14.64). Moreover, if

we compare the rate of formation of the

lower-energy intermediate to the formation

of the benzene intermediate (also only three

resonance forms), we would expect the

lower-energy intermediate from anisole to

be formed faster, as is indeed observed.

OCH

Anisole

OCH

FeCl

p-Chloroanisole

(65.1%)

o-Chloroanisole

(34.9%)

m-Chloroanisole

(0%)

WEB 3D WEB 3D WEB 3D

PROBLEM 14.28 Provide a possible explanation for why ortho substitution is often

less favorable than para substitution, even though ortho substitution is favored

statistically by a 2:1 factor?

FIGURE 14.68 The chlorination of anisole.

660 CHAPTER 14 Substitution Reactions of Aromatic Compounds

There is another resonance form

for this intermediate! Remember

hyperconjugation

The meta substitution of toluene

Toluene

This resonance form

is a tertiary carbocation

All resonance forms secondary

The para substitution of toluene

FIGURE 14.69 The intermediates for meta

and para substitution of toluene. In the

intermediate for meta substitution, all three

resonance forms are secondary. In the

intermediate for para substitution, two

resonance forms are secondary but one

resonance form is a tertiary carbocation.

Let’s now look at the substitution of toluene. Figure 14.69 shows the interme-

diates formed by meta and para substitution using a generic electrophile, E



. This

time there is no obvious fourth resonance form,as there was in the para (and ortho)

substitution of anisole.Why is ortho/para substitution still preferred, and why does

toluene react faster than unsubstituted benzene (Table 14.2 p. 656)? Look at the

positions sharing the positive charge. In the intermediate formed from meta sub-

stitution, the three positions sharing the positive charge are all secondary. In the

intermediate formed by para substitution, one of the three positions is a tertiary

carbon and is therefore more effective in stabilizing a positive charge. So there real-

ly is a fourth resonance form! Recall the description of the stabilization of adjacent

positive charge by alkyl groups (p. 376). An alkyl group can stabilize an adjacent

positive charge in a hyperconjugative way.

PROBLEM 14.29 Hold it! Explain exactly why we “expect”that attack on anisole by

an electrophilic reagent to form a relatively low energy, resonance-stabilized inter-

mediate will be faster than attack on benzene? Are we not confusing thermody-

namics with kinetics?

14.9 Disubstituted Benzenes: Ortho, Meta, and Para Substitution 661

The intermediate for para substitution,and the transition state leading to it,are lower

in energy than those involved in meta substitution (Fig. 14.70). The transition state

Reaction progress

Energy

Transition state for formation

of the meta intermediate

(higher energy)

Intermediate in para

substitution of toluene

(lower energy)

Intermediate in meta

substitution of toluene

(higher energy)

Transition state for

formation of the

para intermediate

(lower energy)

FIGURE 14.70 The intermediate and

transition states for para substitution

of toluene are lower in energy than

those for meta substitution.

25 ⬚C

(59%) (36%) (4.5%)

AlCl

, 25 ⬚C

(89.2%) (9.3%) (1.5%)

COPh

FIGURE 14.71 Some substitution

reactions of toluene.

is also lower than the transition state for substitution of benzene. When a group on

an aromatic ring lowers the transition state compared to that for benzene, the ring

is said to be activated.This theoretical analysis is borne out in practice. Figure 14.71

shows some typical substitution reactions of toluene.

662 CHAPTER 14 Substitution Reactions of Aromatic Compounds

So, for many groups, meta substitution does not present a problem. However,

separation of ortho and para products is a problem, especially because the two are

often formed in comparable amounts. Happily, physical methods such as crystalliza-

tion and distillation can generally be used successfully to separate the products.

Electrophilic aromatic substitution is a practical source of many ortho and para

disubstituted benzenes.

N(CH

)

N(CH

)

N(CH

)

N(CH

)

N(CH

)

In this resonance form, two positive charges

are very close; this form is very high energy

and will contribute little

N(CH

)

N(CH

)

N(CH

)

N(CH

)

N(CH

)

Meta substitution of the trimethylanilinium ion

Para substitution of the trimethylanilinium ion

Trimethyl-

anilinium

ion

Trimethyl-

anilinium

ion

FIGURE 14.72 Meta and para substitution of the trimethylanilium ion. Both intermediates have three resonance

forms, but the adjacent positive charges in the intermediate for para substitution are especially destabilizing.

What about groups that direct substitution to the meta position and slow the

rate? Why are the effects we have seen so far not general? Once more, the way to

attack this problem is to write out the various possibilities and look for points of

difference. Let’s look first at the intermediates formed by reaction of the trimethyl-

anilinium ion in Figure 14.72.

Both meta and para substitution give an intermediate with three resonance forms,

so there is no gross difference here. Note that we are introducing a second positive

charge when we do any electrophilic aromatic substitution reaction on this molecule.

PROBLEM 14.30 Write a mechanism for the ortho substitution of toluene by an

electrophile, E



. Compare this reaction to meta substitution.

PROBLEM 14.31 Explain why bromobenzene and aniline direct electrophilic aro-

matic substitution reactions ortho/para.

14.9 Disubstituted Benzenes: Ortho, Meta, and Para Substitution 663

This second charge is bound to slow the reaction relative to substitution of benzene

itself.In this case the aromatic ring is strongly deactivated with respect to electrophilic

substitution. Now we know why this substitution reaction is especially slow, but we

can’t yet explain why the meta position is preferred. The difficulty in para substitu-

tion is that the reaction places the two positive charges especially close together. In

para substitution,the positive charge produced by reacting with the electrophile resides

partly on the carbon bearing the original substituent. When this substituent can sta-

bilize the charge through resonance, as in anisole or toluene, para substitution will

be favored. When it brings two positive charges together, as in the trimethylanilinium

ion, para substitution is decidedly disfavored for electrostatic reasons.

So the situation is clear for the trimethylanilinium ion.Meta substitution,which

does not place two like charges on adjacent carbons,is favored over para (or ortho)

substitution, which does. Figure 14.73 shows one example: bromination of the

trimethylanilinium ion.

O, 25 ⬚C

“Br

”

N(CH

)

N(CH

)

(100%)

Trimethylanilinium

ion

WEB 3D

FIGURE 14.73 Bromination of the

trimethylanilinium ion.

What about the other meta-directing groups? They do not bear obvious positive

charges. Nitrobenzene is a good example. Nitrobenzene is so deactivated with respect

to electrophilic substitution that it can be used as a solvent for Friedel–Crafts reactions

of other aromatic compounds and not suffer attack itself.When substitution does occur

on nitrobenzene, it is invariably largely in the meta position (Table 14.2; Fig. 14.74).

HNO

0 ⬚C

Nitrobenzene

m-Dinitrobenzene

(93.2%)

p-Dinitrobenzene

(0.3%)

o-Dinitrobenzene

(6.4%)

FIGURE 14.74 Nitrobenzene nitrates

very slowly at 0 °C, and almost

entirely in the meta position.

Yet there is no obvious positive charge in the starting material, as there is in the

trimethylanilinium ion we analyzed before. However, a close look at the structure

of the nitro group reveals the problem, which has been hidden by the obfuscation

PROBLEM 14.32 Draw all of the resonance structures of the intermediate formed

by ortho substitution of the trimethylanilinium ion.

PROBLEM 14.33 Use an Energy versus Reaction progress diagram to compare

ortho and meta substitution on the trimethylanilinium ion.

664 CHAPTER 14 Substitution Reactions of Aromatic Compounds

of nitro as NO

. If you draw out a nitro group carefully, you will see (1) that there is

no good uncharged structure,and (2) that the nitrogen always bears a positive charge:

Meta substitution of nitrobenzene is favored over…

Para substitution of nitrobenzene

–

In this resonance form, two positive charges are

very close; this form is very high energy and will

contribute little to the stability of the intermediate

FIGURE 14.75 The resonance description for the nitro group reveals that nitrogen bears a full positive charge. Electrophilic

aromatic substitution will be directed to the meta position.The ring is deactivated.

HNO

, 0 ⬚C

COOEt

meta

(68.4%)

para

(3.3%)

ortho

(28.3%)

OEt

Ethyl

benzoate

WEB 3D

FIGURE 14.76 The nitration of ethyl

benzoate gives mainly meta product.

So there really is a positive charge adjacent to the ring in nitrobenzene.Therefore the

same factors that lead to meta substitution and a slow rate in the trimethylanilinium

ion will operate for nitrobenzene as well (Fig. 14.75).

We still need to discuss the other meta directors in Table 14.2, those with a car-

bonyl group attached to the ring. Ethyl benzoate (C

COOCH

) is a good

example.It too substitutes slowly, and predominantly in the meta position (Fig. 14.76).

In nitrobenzene, there

is a positive charge

adjacent to the ring

–

14.9 Disubstituted Benzenes: Ortho, Meta, and Para Substitution 665

The explanation for this behavior again comes from a close look at the struc-

ture of the group substituting the benzene ring, in this case, the carbonyl group.

Although there are no hidden full positive charges as in the nitro group, the

carbon–oxygen double bond is highly polar. Because oxygen is much more elec-

tronegative than carbon, the dipole in the bond will place a partial positive charge

on the carbonyl carbon attached to the ring (Fig. 14.77).

OEt

–

.. ..

....

FIGURE 14.77 The carbonyl group

is polar, with the carbon bearing a

partial positive charge.

So, once again, ortho or para substitution of an electrophile results in a less sta-

ble intermediate.This time it is not two full positive charges that must be adjacent,

but a full and partial positive charge. No matter—meta substitution, which keeps

the charges further apart, will still be favored (Fig. 14.78). The rate of the reaction

will be slow relative to that for benzene. An aromatic ring with a carbonyl group

attached is deactivated.

COOEt

COOEt COOEt

The meta substitution of ethyl benzoate

The para substitution of ethyl benzoate

EtO

–

In this resonance form, a positive charge and a partial positive charge

are very close; this form is very high energy and will contribute little

FIGURE 14.78 Meta substitution is preferred to para substitution. In the intermediate for para (or ortho) substitution,

a full and partial positive charge are opposed on adjacent carbons.

PROBLEM 14.34 Explain why cyanobenzene (benzonitrile, C

CN) substitutes

preferentially in the meta position.

666 CHAPTER 14 Substitution Reactions of Aromatic Compounds

Summary

A group (G) on the benzene ring determines the position of the next electrophilic

aromatic substitution reaction. Generally, groups that direct ortho/para also

increase the rate of substitution. In such cases, the ring is said to be activated.

If substitution is in the ortho or para position (but not the meta position), G

provides additional stabilization to the cyclohexadienyl cation intermediate, and

thus increases the rate. Meta-directing groups make the best of an energetically

bad set of choices. Meta substitution is slow and wins by default—it is the least-

bad alternative for some substituents. In this case the ring is said to be deactivated

with respect to electrophilic aromatic substitution.

These σ bonds are

strongly polarized

so as to make

introduction of a

positive charge into

the ring difficult

N(CH

)

(CH

)

–

Shows a dipole in the

direction indicated by

the

and δ

–

FIGURE 14.79 In the

trimethylanilinium ion and

nitrobenzene, the σ bond from the

ring to the substituent is polarized

by the electron-withdrawing group.

Further substitution is difficult.

These subsituents will reduce the electron density in the ring, making the aro-

matic compound a weaker nucleophile, and thus a less active participant in any

reaction with an electrophilic reagent. More important is the destabilizing effect

of electron withdrawal on the charged intermediate and the partially charged tran-

sition state leading to the intermediate. So, it is no surprise to find that both

trimethylanilinium ion and nitrobenzene are very slow to react in electrophilic aro-

matic substitution. Similar rate-retarding effects might be expected to operate

whenever an atom more electronegative than carbon is attached to the ring.

If that is the case, what is one to make of the rate

accelerating effect of the methoxy group? Anisole reacts

much faster than benzene, and yet the methoxy group

is certainly withdrawing electrons from the ring

through induction.The dipole in the carbon–oxygen

σ bond surely points toward the electronegative

oxygen atom (Fig. 14.80).

The answer to this conundrum is simply that the

resonance effect must substantially outweigh the

inductive effect.The fourth resonance form in Figure

14.66 helps more in energy terms than the inductive

withdrawal of σ electrons by methoxy hurts.

This σ bond is also strongly

polarized so as to make

introduction of a positive

charge into the ring difficult;

yet, the reactions of anisole

are very fast

–

FIGURE 14.80 The carbon–oxygen bond in anisole is also electron-

withdrawing, yet substitution is directed ortho/para and the reactions

are fast.The resonance effect outweighs this inductive effect.

14.10 Inductive Effects in Aromatic Substitution

So far, we have mainly considered the way in which the group attached to a ben-

zene ring can affect further reaction through either resonance stabilization or elec-

trostatic destabilization of the intermediate cyclohexadienyl cation. We should also

consider the inductive effects of groups,which act by withdrawing or donating elec-

trons through the σ bonds. For example, both the trimethylammonium group and

the nitro group are strongly electron-withdrawing by induction (Fig. 14.79).

14.10 Inductive Effects in Aromatic Substitution 667

Cl Cl

–

This bond is strongly polarized

and the

on carbon acts to

retard any substitution reaction

that would place more positive

charge on the ring carbons

FIGURE 14.81 Chlorine and the

other halogens are strongly electron-

withdrawing and slow the rate of

electrophilic substitution.The net

result is an overall slowing of the rate.

However, ortho/para substitution is still favored over meta because the halogen

can stabilize an adjacent positive charge by resonance (Fig. 14.82).The rate of meta

The meta substitution of chlorobenzene—three resonance forms

The para substitution of chlorobenzene—there are four forms because the chlorine can help share the positive charge

There is another

resonance form

for this intermediate!

Here it is

FIGURE 14.82 Chlorine and other halogens

can help stabilize the intermediate for para

(and ortho) substitution through a fourth

resonance form.The halogens strongly

withdraw electrons from the ring through

an inductive effect, however, and

substitution is slow relative to benzene.

Thus,often we have two effects operating in opposition. In anisole,the resonance

effect stabilizes the intermediate for ortho or para substitution and the transition

states leading to them,accelerating the reaction and directing ortho/para.The induc-

tive effect is decelerating for any substitution reaction. For anisole and most groups,

the resonance effect wins out, but we can surely find examples where the two effects

are largely in balance; where substitution is still ortho/para because of a resonance

effect, but where an inductive effect slows the reaction relative to unsubstituted

benzene. A look at Table 14.2 shows that there are such cases.For example,haloben-

zenes direct substitution to the ortho/para positions but substitution proceeds at a

slower rate than that for the reaction of benzene. In halobenzenes, all electrophilic

aromatic substitution is retarded by the strong electron-withdrawing effect of the

electronegative halogens (Fig. 14.81). As a result, the ring is deactivated.

668 CHAPTER 14 Substitution Reactions of Aromatic Compounds

Cl Cl Cl Cl

HNO

, 25 ⬚C

m-Chloronitrobenzene

(0.9%)

Chlorobenzene p-Chloronitrobenzene

(69.5%)

o-Chloronitrobenzene

(29.6%)

nitromethane

FIGURE 14.83 The nitration of chlorobenzene gives almost entirely ortho and para products.

m = meta director

m = another meta director

m directs here

FIGURE 14.84 On a benzene ring

substituted 1,3 with a pair of meta-

directing groups, both substituents

direct further substitution to the

same position.

substitution, in which the stabilizing resonance effect cannot operate, is slowest of

all, and so meta product is greatly disfavored (Fig. 14.83).

14.11 Synthesis of Polysubstituted Benzenes

Sometimes it is easy to predict the position of electrophilic attack on a polysubstituted

benzene ring. For example, if we have a ring substituted 1,3 with meta-directing groups,

further substitution will surely occur at the position meta to both groups, although the

rate will be severely retarded by the presence of a pair of deactivating groups (Fig.14.84).

–

FSO

150 ⬚C, 4 h

1,3,5-Trinitrobenzene

~ 50% yield

100% this isomer

m-Dinitrobenzene

FIGURE 14.85 Nitration of 1,3-

dinitrobenzene gives a single

product, 1,3,5-trinitrobenzene.

Further substitution of a disubstituted aromatic ring containing an ortho/para

director and a meta director at the 1- and 4-positions is similarly easy to predict.

Both groups direct the next substitution ortho to the ortho/para-directing group.

Accordingly, nitration of 1,3-dinitrobenzene gives only meta substitution (Fig. 14.85).