Jones M., Fleming S.A. Organic Chemistry

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20.10 Additional Problems 1079

(b) Although cycloaddition reactions of this type are not concerted,

they are often stereospecific, as in the following example:

Only isomer formed

(CH

)

(CH

)

CCO

NPh

20 ⬚C

PROBLEM 20.48 Reaction of bicyclopropenyl (1) and

s-tetrazine (2) gives the semibullvalene (3). Provide an

arrow formalism mechanism for this transformation. Hint:

There is at least one nonisolable intermediate involved. Also,

explain the relatively simple

H and

C NMR spectra of

compound 3, summarized below.

Compound 3

H NMR (CDCl

): δ 1.13 (s, 3H)

3.73 (s, 3H)

4.79 (s, 2H)

C NMR (CDCl

): δ 14.9 (q)

51.4 (q)

60.6 (s)

93.7 (d)

127.2 (s)

164.7 (s)

Attempt to explain the stereochemistry observed in the

reaction above. Start by minimizing the steric interactions in

your proposed dipolar intermediate. Then, see if you can

find a concerted process that converts your proposed inter-

mediate into the observed β-lactam. Hint:A tert-butyl

group is much bigger than a cyano group.

PROBLEM 20.47 Heating α-phenylallyl acetate (1) affords

isomeric compound 2. Spectral data for compound 2 are sum-

marized below. Deduce the structure of 2 and provide an arrow

formalism mechanism for this isomerization.

Compound 2

IR (film): 1740 (s), 1225 (s), 1025 (m), 960 (m), 745 (m),

690 (m) cm



H NMR (CDCl

): δ 2.08 (s, 3H)

4.71 (d, J  5.5 Hz, 2H)

6.27 (dt, J  16, 5.5 Hz, 1H)

6.63 (d, J  16 Hz, 1H)

7.2–7.4 (m, 5H)

C NMR (CDCl

): δ 20.9 (q)

65.0 (t)

123.1 (d)

126.5 (d)

128.0 (d)

128.5 (d)

134.1 (d)

136.1 (s)

170.6 (s)

25 ⬚C

COOCH

COOC

PROBLEM 20.49 Figure 20.55 shows the products of the

Cope rearrangement of meso-3,4-dimethyl-1,5-hexadiene from

both the chairlike (four-center) and boatlike (six-center) transi-

tion states. Work out the products expected from the other pos-

sible form of the diene, racemic 3,4-dimethyl-1,5-hexadiene.

Predict what products will actually be formed.

1080

21.1 Preview

21.2 Heteroatoms as Neighboring

Groups

21.3 Neighboring π Systems

21.4 Single Bonds as Neighboring

Groups

21.5 Coates’ Cation

21.6 Summary

21.7 Additional Problems

Special Topic

Intramolecular Reactions

and Neighboring Group

Participation

WATER BARRIER Electrons are like water. There are few barriers that stop

movement of available electrons to electrophilic centers in intramolecular

reactions.

21.1 Preview 1081

(a)

KOH

KBr

(see p. 283)

(b)

(c)

(see p. 925)

(see p. 912)

C C

⌬

FIGURE 21.1 Neighboring group

interactions.

Our race would not have gotten far,

Had we not learned to bluff it out

And look more certain than we are

Of what our motion is about.

—W. H. AUDEN

21.1 Preview

Here we introduce the chemistry of polyfunctional molecules. This chapter by no

means contains an exhaustive treatment. The chemistry of di- and polyfunctional

compounds could easily be the subject of an advanced course in organic chemistry,

and we will only catch some highlights here.

In principle, two functional groups in a single molecule might not interact at all,

and the chemistry of the molecule would be the simple combination of the

chemistries of the two separated functional groups.This occurrence is rare, because

groups in molecules often do interact, even if they are quite remote from each other.

Through inductive and resonance effects, one functional group in a molecule can

affect the chemistry of another group at a distant point in the molecule. Sometimes,

groups interact even more strongly, and the chemistry is best described not as a sum

of the two individual chemistries, but as something quite new. These examples are

the most interesting ones.

A neighboring group effect can change the rates of formation of products as

well as the structures of the molecules produced.Don’t be put off by the fancy name.

All of intramolecular chemistry involves interactions between neighboring groups.

You have already seen lots of intramolecular chemistry. Figure 21.1 gives some famil-

iar, or at least old, examples of such reactions, and we will see more as we go along.

Wystan Hugh Auden (1907–1973) was one of the most influential British poets of his generation.“Reflections

of the Estate of W. H. Auden, from Collected Poems by W. H. Auden. Used by permission of Curtis Brown,

Ltd., Faber and Faber Ltd., and Random House, Inc.

Intramolecular S

1082 CHAPTER 21 Intramolecular Reactions and Neighboring Group Participation

addition elimination deprotonation

–

Cl H

WORKED PROBLEM 21.1 Write mechanisms for the reactions of Figure 21.1.

ANSWER (a) The first step is certainly loss of the hydroxyl proton to give an

alkoxide. Intramolecular S

2 displacement gives the product, a cyclic ether.

–

deprotonation

–

Alkoxide

(b) Addition–elimination gives the lactone (a cyclic ester).

ing the part of the nucleophile and the neighboring hydrogen acting as the elec-

trophile for the reaction.

The exploitation of the intuitively obvious notion that groups might interact in

a synergistic fashion constituted one of the most fascinating areas of chemical

exploration during the middle of the twentieth century, and it continues even today.

As we examine this area,we will encounter some sociology as well as chemistry. One

of the most heated arguments in the history of organic chemistry centered on this

subject, and it is worth our time to see what we can learn about science from a look

at this intensely emotional issue. There will be some opinion here, but we’ll try to

keep it labeled as such.

ESSENTIAL SKILLS AND DETAILS

1. There are three clues to the operation of a neighboring group effect. Learning to

recognize them is critical to understanding this chemistry. Fortunately, at least one

of these clues is always present, and usually quite easy to find.This material is

of the “looks hard—is easy”variety.

The clues are

a. An unusual stereochemical result, usually retention where inversion is expected.

b. A strange rearrangement, often involving a labeled molecule.

c. An unexpectedly fast rate.

C C

21.2 Heteroatoms as Neighboring Groups 1083

(6.1%)

A hemiacetal

(93.9%)

WEB 3D WEB 3D

FIGURE 21.3 Cyclic hemiacetal

formation involves an intramolecular

hydroxyl group acting as a neigh-

boring group on a ketone or

aldehyde.

2. Be certain you are completely clear on the difference between an intermediate

described by a set of equilibrating structures and an intermediate described by

a set of resonance forms. Figure 21.40 gives an example.

21.2 Heteroatoms as Neighboring Groups

In its simplest form, the study of neighboring group effects notes that a heteroatom

with a pair of nonbonding electrons can act as a nucleophile in an intramolecular

displacement reaction, just as external nucleophiles can participate in intermolecu-

lar S

2 reactions.In an example we have seen (p. 317), oxiranes can be formed from

halohydrins in base (Fig. 21.2).

Intermolecular S

Intramolecular S

2 by

“neighboring” alkoxide

–

FIGURE 21.2 Formation of an oxirane

by treatment of a bromohydrin with

hydroxide involves an alkoxide acting

as a neighboring group.

First, base removes the hydroxyl hydrogen to make the alkoxide. Intramolecular

2 displacement of the bromide generates the oxirane. Here the alkoxide is the

neighboring group, and the whole process couldn’t be simpler.

Another example is intramolecular hemiacetal formation. If a relatively

unstrained ring can be formed, compounds containing both a carbonyl group and a

hydroxyl group exist in equilibrium with the cyclic hemiacetal (p. 783; Fig. 21.3).

PROBLEM 21.2 Write a mechanism for the reaction of Figure 21.3.

Other reactions are more subtle than these straightforward intramolecular

processes, but there are always clues when a neighboring group effect is involved.

For example, consider the reaction of the optically active α-bromocarboxylate in

methyl alcohol (Fig. 21.4).

WEB 3D

–

OCH

The * indicates

a stereogenic

carbon

Still (R)—retention

(R)

FIGURE 21.4 Treatment of

α-bromopropionate in methyl

alcohol. Notice that the reaction

involves retention of configuration.

–

(R) Now (S)

deprotonation

–

(S)—Inversion

FIGURE 21.5 A straightforward mechanism in which the bromide is displaced by methyl alcohol would give

the wrong stereochemical result.This inversion is not observed.

The observation of a strange stereochemical result is the first kind of clue to

the operation of a neighboring group effect.The simple mechanism of Figure 21.5

must be wrong, because it cannot accommodate the observed retention of con-

figuration in the product. In this reaction, the carboxylate anion acts as an inter-

nal nucleophile, displacing bromide to give an intermediate called an α-lactone

(Fig. 21.6). These smallest cyclic esters cannot be isolated, but they are known

as reactive intermediates. In this case, methoxide or methyl alcohol adds to the

α-lactone in an intermolecular S

2 displacement to give the actual product of

the reaction. Now examine the stereochemistry of the reaction with care. The first

1084 CHAPTER 21 Intramolecular Reactions and Neighboring Group Participation

–

(R)

–

OCH

Still (R)—

overall

retention

–

HOCH

α-lactone

Intramolecular

inversion

Intermolecular

2 inversion

Deprotonation

FIGURE 21.6 If the carboxylate anion acts as a neighboring group and displaces the

bromide in an intramolecular fashion, methyl alcohol can open the resulting α-lactone.

The overall result of this double inversion mechanism is retention.

The product is formed with the stereochemistry opposite to what we might

naively expect. An S

2 displacement of the bromide from the optically active start-

ing material by methyl alcohol or methoxide must give an optically active product

(Fig. 21.5), but notice that the stereochemistry of the product is exactly the reverse

of what is observed!

21.2 Heteroatoms as Neighboring Groups 1085

Brosylate

(OBs) Acetate

(OAc)

OCH

COOH

(AcOH)

FIGURE 21.7 Acetolysis of the

brosylate of 4-methoxy-1-butanol

gives the corresponding acetate.

displacement is an intramolecular S

2 reaction with the carboxylate anion acting

as the nucleophile and the bromide as the leaving group. As with all S

2 reactions,

inversion must be the stereochemical result. A second S

2 displacement, this time

intermolecular, occurs as the α-lactone is opened by methyl alcohol. Once again

inversion is required.The end result of two inversions (or any even number of inver-

sions) is retention of configuration.

Summary

Whenever you see an unexpected stereochemical result (usually retention where

inversion is expected),look for an intramolecular displacement reaction—a neigh-

boring group effect. You will almost always find it.

Oxygen need not be negatively charged to participate in an intramolecular

displacement reaction. The reaction of the “brosylate” (p-bromobenzenesul-

fonate) of 4-methoxy-1-butanol in acetic acid gives the corresponding acetate

(Fig. 21.7).

deprotonation

OCH

OBs

OCH

HOBs

BsO

–

FIGURE 21.8 A simple S

2 displacement of the brosylate by acetic acid might explain the

reaction of Figure 21.7.

Acetic acid, CH

COOH, is often abbreviated as “HOAc” or “AcOH.” The

acetates formed as products in many reactions of acetic acid are often written as

“ROAc.”

CONVENTION ALERT

Sulfonates are excellent leaving groups,and a reasonable mechanism for the reac-

tion involves intermolecular displacement by acetic acid or acetate (Fig. 21.8).

When this reaction is run with a similar, but methyl-labeled brosylate (Fig.21.9),

we can see that something more complicated than the simple S

2 reaction of Figure

21.8 is going on.There are two products formed. Our first mechanism can accom-

modate one of the products but not the other, which is the second clue to neigh-

boring group participation—the observation of an unusual rearrangement reaction.

In this case, it is the ether oxygen that acts as a neighboring group. The sulfonate

(OBs) is an excellent leaving group and a five-membered ring is relatively unstrained,

so the intramolecular displacement of p-bromobenzenesulfonate to give a cyclic oxo-

1086 CHAPTER 21 Intramolecular Reactions and Neighboring Group Participation

OCH

OBs

Methyl

label

OCH

OAc

(40%)

OAc

(60%)

This product could

be formed by a simple

2 displacement…

…but not this one

OCH

COOH

(AcOH)

FIGURE 21.9 Reaction of the methyl-labeled compound shows that the simple

mechanism of Figure 21.8 is inadequate.

WORKED PROBLEM 21.3 There are two possible nucleophiles for the S

2 displace-

ment in Figure 21.8, the acetate ion or acetic acid. In the displacement using

acetic acid, why is the carbonyl oxygen, not the hydroxyl oxygen, used as the dis-

placing agent?

ANSWER The carbonyl oxygen is the better nucleophile. Recall that protona-

tion of acetic acid occurs faster on the carbonyl oxygen (p. 837). A resonance-

stabilized intermediate is formed in this case, but not from protonation of the

hydroxyl oxygen. Reaction of any electrophile with acetic acid is similar. In

Figure 21.8, only one resonance form is shown; in each case there is another

form in which the carbon atom bears the positive charge—ordinary carbonyl

resonance.

Resonance stabilized!

Not resonance stabilized

21.2 Heteroatoms as Neighboring Groups 1087

OCH

OBs

OCH

–

OBs

Intramolecular

Intermolecular

Deprotonation

Product expected

from S

Rearranged

product

FIGURE 21.10 In this case the

methoxyl oxygen acts as neighboring

group. A cyclic ion is formed that can

open two ways. One mode of

opening leads to the product

expected from a simple S

2 reaction.

“Rearrangement” is the result of the

other possible mode of opening of

the intermediate oxonium ion.

nium ion takes place (Fig. 21.10). The cyclic oxonium ion can be opened by acetic

acid in two ways to give the two observed products. The result is an apparent

rearrangement.

PROBLEM 21.4 There is actually a third product in the reaction in Figure 21.9. It

is 2-methyltetrahydrofuran (see below). Can you explain the formation of a small

amount of this molecule? Hint: The intermediate ring is obviously retained in the

formation of this product.

2-Methyltetrahydrofuran

and 2-chloroethyl ethyl sulfide react in water to give the corresponding alcohols.The

rate of reaction of the sulfur-containing compound is about 10

faster than that of

the alkyl chloride, however. The mechanism of alcohol formation from the primary

halide must be a simple S

2 displacement with water acting as nucleophile

(Fig.21.12). It is difficult to see why the sulfide should be so much faster if the reac-

tion mechanism is analogous.

1088 CHAPTER 21 Intramolecular Reactions and Neighboring Group Participation

Sulfur atoms are often powerful nucleophiles, and the participation of sulfur as

a neighboring group is common. Figure 21.11 shows an example of the third kind

of clue, a reaction in which there is an unexpectedly rapid rate. Both hexyl chloride

Relative

Rate

~700

WEB 3D

FIGURE 21.11 If a sulfur atom is

substituted for the C(3) of hexyl

chloride, the formation of the related

alcohol is greatly accelerated.

deprotonation

–

HCl

FIGURE 21.12 The reaction of hexyl chloride must be a simple

2 displacement of chloride by water, followed by deprotonation.

In the reaction of the sulfide in Figure 21.11, it is the sulfur atom that dis-

places the leaving chloride (Fig. 21.13).This intramolecular reaction is much faster

than the intermolecular displacement of chloride by water either in the alkyl chlo-

ride or the chlorosulfide.The intermediate is an episulfonium ion. This interme-

diate is opened by water in a second, intermolecular S

2 displacement step to give

the product.

Episulfonium ion

fast

–

HCl

–

Intramolecular

Intermolecular

Deprotonation

FIGURE 21.13 Sulfur can act as a neighboring group, displacing chloride in an

intramolecular S

2 reaction. An episulfonium ion is formed and can be opened

in a second, intermolecular S

2 reaction to give the product.