Jones M., Fleming S.A. Organic Chemistry

Подождите немного. Документ загружается.

(a)

(b)

(c)

20.6 The Cope Rearrangement 1059

20.6 The Cope Rearrangement

As we saw in Problem 20.13, not all shift reactions are [1,x] shifts. One very com-

mon sigmatropic shift reaction is called the Cope rearrangement, and is named for

Arthur C. Cope (1909–1966, the same Cope of the Cope elimination, p. 914) who

spent most of his professional life at MIT.

The Cope rearrangement is a [3,3]

sigmatropic shift that occurs in almost any 1,5-hexadiene. In this sigmatropic shift

the new bond is formed between the two number 3 atoms, which is the reason it is

called a [3,3] shift (Fig. 20.49). In its simplest form, the Cope rearrangement is

degenerate and must be revealed through a labeling experiment.

Cope didn’t actually discover this reaction; C.Hurd of Northwestern University (1897–1998) apparently did.

It was Cope’s research group that thoroughly studied the reaction, however.

This degenerate,

“invisible” reaction…

…is revealed by this

labeling experiment

A [3,3] shift—a Cope rearrangement

90 ⬚C

FIGURE 20.49 The degenerate Cope rearrangement, a [3,3] shift, can be revealed by a

labeling experiment.

Like the [1,5] shifts we looked at first, the Cope rearrangement is intramol-

ecular, uncatalyzed, and shows no strong dependence on solvent polarity.The acti-

vation energy for the Cope rearrangement is about 34 kcal/mol, a value far below

what one would estimate for the simple bond breaking into two separated allyl

1060 CHAPTER 20 Reactions Controlled by Orbital Symmetry

radicals (Fig. 20.50). If the mechanism of the Cope rearrangement did involve two

independent allyl radicals,the labeled 1,5-hexadiene would have to give two prod-

ucts, which it does not.

Two independent

allyl radicals

(starting material)

recombine

3,3

recombine

1,1

recombine

Not found

1,3

FIGURE 20.50 A labeling experiment

shows that the Cope rearrangement

does not involve formation of a pair

of free allyl radicals because the

radical recombination products are

not all formed.

Reattachment at the two C(3) positions is allowed because the interaction of

the two lobes on the two C(3) carbons is bonding.This picture is consistent with

the near ubiquity of the Cope rearrangement when 1,5-dienes of all kinds are

heated (Fig. 20.52).

The Cope rearrangement has a nonpolar transition state (Fig. 20.51), but this

time it is not a simple hydrogen atom that migrates but a whole allyl radical. An

analysis of the symmetry of the orbitals involved shows why this reaction is a

relatively facile thermal process but is not commonly observed on photochemical

activation. As we break the bond, the phases of the overlapping lobes

must be the same.The HOMO of the allyl radical is

,and that information allows

us to fill in the symmetries of the two allyl groups making up the transition state.

C(1)

Transition state

(migration of an

allyl radical)

FIGURE 20.51 The transition state

for the Cope rearrangement involves

the migration of one allyl radical

across another.

Bonding Bonding

Transition state (two partially

bonded allyl radicals—Φ

the singly occupied HOMO

for each)

FIGURE 20.52 An orbital symmetry

analysis shows that the thermal Cope

rearrangement is allowed.

20.6 The Cope Rearrangement 1061

So we now have a general picture of the transition state for the Cope rearrange-

ment. But much more detail is possible if we work a bit at it. How might the two

migrating allyl radicals of the transition state arrange themselves in space during the

reaction? Two things are certain. First, the two C(1) atoms must start out close

together, because they are bonded. Second, the two C(3) positions must also be

within bonding distance, because in the transition state there is a partial bond

between them (Fig. 20.52).

Transition state

for the [3,3] shift

WORKED PROBLEM 20.17 Use orbital symmetry to analyze the photochemical

[3,3] shift in 1,5-hexadiene. Be careful! Photons are absorbed one at a time.It

requires specialized equipment to form a singly excited molecule and then have it

absorb a second photon. So we need only consider the singly excited state.

ANSWER The transition state for the [3,3] shift involves two interacting allyl

radicals.

If one electron is promoted on irradiation, the transition state must have one

electron in

, the photochemical HOMO.£

Antibonding!

Bonding

If a rotation were energetically feasible, if one C(3) carbon could rotate, a bond-

ing interaction could be achieved where the figure notes the antibonding inter-

action. However, for these sp

hybridized carbons, this rotation involves a large

energy cost.

Now an orbital analysis shows that there is no easy path for the photochemical

[3,3] shift. One antibonding interaction is always present.

1062 CHAPTER 20 Reactions Controlled by Orbital Symmetry

The question now comes down to determining

the position of the two C(2) atoms in the transition

state.Two possibilities are shown in Figure 20.53.The

two C(2) atoms might be close together as in the boat-

like transition state originally called the six-center

transition state. Or, they can be rather far apart, as in

the chairlike or four-center transition state. The fig-

ure shows a number of views of these two possibili-

ties, but this is probably a time to get out the models.

In 1962, W. von E. Doering and W. R Roth car-

ried out a brilliant experiment that determined which

of these two possible transition states was favored for

this [3,3] sigmatropic shift.They used a stereolabeled

molecule, 3,4-dimethyl-1,5-hexadiene (Fig. 20.54).

Notice first that there are three forms of this molecule,a meso,achiral form and a racemic

pair of enantiomers (p. 156). It all depends on how the methyl groups are attached.

Boatlike, or “six-center” arrangement

= C(2)

Chairlike, or four-center arrangement

FIGURE 20.53 Several views of the

chairlike and boatlike arrangements

for the transition state of the Cope

rearrangement.

CCH

HCH

Mirror

Racemic mixture

Meso form

FIGURE 20.54 The meso and

chiral forms of 3,4-dimethyl-1,5-

hexadiene.

In the following figures,we have drawn only one enantiomer of the racemic pair.

Be sure to keep in mind that the actual experiment used a 50:50 racemic mixture of

the two enantiomers.

Both the meso and racemic forms of 3,4-dimethyl-1,5-hexadiene can adopt

either the boat or chair arrangement. Figure 20.55 shows the results for the

CONVENTION ALERT

Meso compound in the boatlike arrangement

trans,trans

(E,E )

cis,cis

(Z,Z )

Meso compound in the chairlike arrangement

trans,cis

(E,Z )

cis,trans

(Z,E )

WEB 3D

FIGURE 20.55 The products formed from the boatlike and chairlike arrangements of meso-3,4-dimethyl-1,5-hexadiene.

20.7 A Molecule with a Fluxional Structure 1063

meso compound. The key to Doering and Roth’s experiment is that the chair

and boat arrangements give different products for both the meso and chiral

forms.

The results showed that it is the chairlike form that is favored,and that it is pre-

ferred to the boatlike arrangement by at least 6 kcal/mol. Presumably, some of the

factors that make chair cyclohexane more stable than the boat form (p. 198) oper-

ate to stabilize the related chairlike transition state.

There are many things that are important about this work. First of all, it is a

prototypal example of the way labeling experiments can be used to dig out the

details of a reaction mechanism.The second reason is more subtle,but perhaps more

important. As we will see in Section 20.7, the study of the Cope rearrangement

leads directly to an extraordinarily intellectually creative idea.

CHORISMATE TO PREPHENATE: A BIOLOGICAL COPE

REARRANGEMENT

The Cope rearrangement is by no means restricted to the

laboratory. Nature uses Cope-like processes as well. For

example, in bacteria and plants a critical step in the

production of the essential amino acids tyrosine and

phenylalanine is the rearrangement of chorismate to

prephenate, catalyzed by the enzyme chorismate mutase.

At the heart of this rearrangement is a Cope-like process

called the Claisen

rearrangement. The research groups of

Jeremy Knowles (1935–2008) at Harvard and Glenn

Berchtold (1932–2008) at MIT collaborated on a tritium

(

H  T, a radioactive isotope of hydrogen) labeling exper-

iment, related to that used by Doering and Roth, to deter-

mine that the enzymatic reaction also proceeds through a

chairlike transition state. Notice that the chairlike transi-

tion state must take the compound with a (Z) double bond

to a product in which the stereogenic carbon is (S), not

(R). The conversion of chorismate into prephenate is a

Cope-like rearrangement. The chair transition state is

shown in the top reaction and a boat transition state is

shown in the bottom reaction.

(Z ) Double bond

This carbon is (S)

This carbon would be (R )

–

OOC

COO

–

chorismate

mutase

Chorismate

Chairlike transition

state for chorismate

Prephenate

–

OOC

COO

–

(Z ) Double bond

COO

–

COO

–

...the tritium-labeled

carbon would be (R)

lf this boatlike transition

state were used…

–

OOC

COO

–

COO

–

20.7 A Molecule with a Fluxional Structure

We spent some time in Section 20.6 working out the details of the structure of the

transition state for the Cope rearrangement. This rearrangement is a most general

reaction of 1,5-hexadienes, and appears in almost every molecule incorporating the

1,5-diene substructure.In this section we will examine the consequences of the Cope

rearrangement and will work toward a molecule whose structure differs in a funda-

mental way from anything you have seen so far in this book. At room temperature

it has no fixed structure; instead it has a fluxional structure,in which nearest neigh-

bors are constantly changing. Along the way to this molecule there is some extraor-

dinary chemistry and some beautiful insights. This section shows not only clever

ideas and beautiful chemistry, but also how much fun this subject can be.

The same Claisen of the Claisen condensation (p. 987) and the Claisen–Schmidt reaction (p. 984).

Cope rearrangement

1064 CHAPTER 20 Reactions Controlled by Orbital Symmetry

The degenerate

Cope rearrangement

of 1,5-hexadiene

An electrocyclic

rearrangement, a

modified Cope

rearrangement

1,3-Cyclohexadienecis-1,3,5-Hexatriene

FIGURE 20.56 The electrocyclic ring closure of cis-1,3,5-hexatriene to 1,3-cyclohexadiene is similar to a Cope

rearrangement.

The simple 1,5-hexadiene at the heart of the Cope rearrangement can be elab-

orated in many ways, and in fact we’ve already seen one. If we add a central π bond

we get back to cis-1,3,5-hexatriene (Fig. 20.56), a molecule we saw when we con-

sidered electrocyclic reactions (p.1040).The arrow formalism of the Cope rearrange-

ment leads to 1,3-cyclohexadiene.

trans-1,3,5-Hexatriene

(a)

(b)

1,4-Cycloheptadienecis-1,2-Divinyl-

cyclopropane

trans-1,2-Divinyl-

cyclopropane

No Cope

WEB 3DWEB 3D

WEB 3D

FIGURE 20.57 (a) trans-1,3,5-

Hexatriene cannot undergo this

rearrangement because the ends

of the molecule (dots), where

bonding must occur, are too far apart.

(b) trans-1,2-Divinylcyclopropane

cannot undergo the Cope rearrange-

ment, but the cis isomer can.

But there is a stereochemical problem. This reaction is only possible for the

stereoisomer with a cis central double bond.In the trans isomer, the ends of the triene

system are too far apart for bond formation (Fig. 20.57a). That’s an easy concept,

and it appears again in a slightly different modified 1,5-hexadiene: 1,2-divinylcy-

clopropane (Fig. 20.57b). The Cope rearrangement is possible in this molecule and

here, too, it is only the cis molecule that is capable of rearrangement. In the trans

compound, the ends cannot reach.

PROBLEM 20.18 The Cope rearrangement of cis-1,2-divinylcyclopropane is very

easy. It is rapid at room temperature. Why should it be so much easier than the

other versions we have seen?

There is another stereochemical problem in the reaction of cis-1,2-divinyl-

cyclopropane that is a bit more subtle. The most favorable arrangement for

20.7 A Molecule with a Fluxional Structure 1065

cis-1,2-divinylcyclopropane is shown in Figure 20.58.

The two vinyl groups are directed away from the

ring, and in particular, away from the cis ring hydro-

gen.Yet this extended form cannot undergo the Cope

rearrangement at all! The less stable, coiled form

must be adopted where the two vinyl groups point

back toward the ring and are closer to the offending

cis hydrogen.

The problem is that the extended form must pro-

duce a 1,4-cycloheptadiene product with two trans

double bonds. Although the paper puts up with these

trans double bonds without protest, the molecule

will not. Remember, trans double bonds in small

rings are most unstable. trans-Cycloheptene is a barely

detectable reactive intermediate that can be intercept-

ed only at low temperature.The constraints of the ring

lead to severe twisting about the π bond and destabi-

lization. A seven-membered ring containing two trans double bonds is unthinkably

unstable.

By contrast, the higher energy coiled form yields a seven-membered ring con-

taining two cis double bonds, and that presents no problem. Be certain you see why

the two forms give different stereochemistries. Figure 20.59 shows the Energy ver-

sus Reaction progress diagram for the Cope rearrangement of cis-1,2-divinylcyclo-

propane.

Less stable, “coiled” form

Bump

cis H

rotate

Cope Cope

More stable, “extended” form

Both trans

Both cis

FIGURE 20.58 Only the less stable,

coiled arrangement of cis-1,2-

divinylcyclopropane can undergo the

Cope rearrangement.The more

stable, extended form must produce a

hideously unstable trans,trans-

cyclohepta-1,4-diene.

Energy

Reaction progress

Coiled form

Extended form

cis,cis Diene

trans,trans Diene

FIGURE 20.59 The energy diagram

for the Cope rearrangement of cis-

1,2-divinylcyclopropane.

1066 CHAPTER 20 Reactions Controlled by Orbital Symmetry

Still homotropilidene

Homotropilidene

WEB 3D

FIGURE 20.60 The degenerate Cope

rearrangement of homotropilidene.

Now let’s make another addition to the 1,5-diene system. Let’s add a methyl-

ene group joining the two double bonds to give the molecule named “homotropili-

dene.” We can still draw the arrow formalism, and the Cope rearrangement still

proceeds rapidly. As Figure 20.60 shows,we are back to a degenerate Cope rearrange-

ment, because the starting material and product are the same.

PROBLEM 20.19 The rapid Cope rearrangement of homotropilidene led to prob-

lems for W. R Roth, who first made the molecule. Can you explain in general

terms the three perplexing

H NMR spectra for this molecule that are shown?

Note that both low- and high-temperature spectra have sharp peaks, whereas at

an intermediate temperature the spectrum consists of two “blobs.” You are not

required to analyze the spectra in detail—just give the general picture of what

must be happening.

76543210

7654321

7654

Chemical shift (

δ) (ppm)

321

–50 ⬚C

20 ⬚C

180 ⬚C

20.7 A Molecule with a Fluxional Structure 1067

There are also stereochemical problems for homotropilidene (Fig. 20.61). Like

1,2-divinylcyclopropane, the most stable extended form of homotropilidene is unable

to undergo the Cope rearrangement, and it must be the higher-energy coiled

arrangement that is active in the reaction. Here the destabilization of the coiled

arrangement is especially obvious, because the two methylene hydrogens badly

oppose each other. As before,the extended form must give an unstable molecule with

a pair of trans double bonds incorporated into a seven-membered ring.The less sta-

ble, coiled arrangement has no such problem, because it can give a product contain-

ing two cis double bonds.

Bad steric

interaction

Extended form

rotate

Coiled form

Cope Cope

Two trans

double

bonds

Two cis

double

bonds

FIGURE 20.61 Only the higher-

energy, coiled form of

homotropilidene can give a stable

product in the Cope rearrangement.

The lower-energy, extended form

would produce a product containing

two trans double bonds in a seven-

membered ring.

Although cis-1,2-divinylcyclopropane and homotropilidene undergo the Cope

rearrangement quite rapidly even at room temperature and below, one might con-

sider how to make the reaction even faster. For the reaction to occur, an unfavorable

equilibrium between the more stable but unproductive extended form, and the less

stable but productive coiled form must be overcome. The activation energy for the

reaction includes this unfavorable equilibrium (Fig. 20.62).

Energy

Reaction progress

ΔG for Cope

rearrangement

from extended form

Extended

form

Extended

form

Coiled

form

Coiled

form

†

FIGURE 20.62 An Energy versus

Reaction progress diagram for

the Cope rearrangement of

homotropilidene.The activation

energy (ΔG

‡

) for the reaction

includes the energy difference

between the extended and coiled

forms.

1068 CHAPTER 20 Reactions Controlled by Orbital Symmetry

Energy

Reaction progress

Coiled

form

Coiled

form

(extended form

not present)

⌬G for

Cope from

coiled form

†

FIGURE 20.63 An Energy versus

Reaction progress diagram for

the Cope rearrangement of a

homotropilidene locked into the

coiled arrangement.The activation

energy is lower than in Figure 20.62

because it is no longer necessary to

fight an unfavorable equilibrium

from the extended form, shown here

as a phantom (dashes) just to remind

you of the previous figure.

If this unfavorable equilibrium could be avoided in some way, and the molecule

locked into a coiled arrangement, the activation energy would be lower, and the reac-

tion faster (Fig. 20.63).

Our next variation of the Cope rearrangement includes the clever notion of bridging

the two methylene groups of homotropilidene to lock the molecule in a coiled arrange-

ment (Fig.20.64).This modification greatly increases the rate of the Cope rearrangement

Extended form

Coiled form

This bridge locks

the molecule

into a coiled

arrangement

FIGURE 20.64 A homotropilidene locked into the coiled arrangement can be achieved if

the two methylene groups are connected with a bridge.

BarbaraloneDihydro-

bullvalene

Barbaralane

Semibullvalene

FIGURE 20.65 Four bridged

homotropilidenes. All undergo very

rapid Cope rearrangements.

Cope

Bullvalene Bullvalene

WEB 3D

FIGURE 20.66 If the new bridge

is a carbon–carbon double bond,

the resulting molecule is known as

bullvalene.

because being locked in the coiled form decreases the activation energy (Fig. 20.63). No

longer is it necessary to fight an unfavorable equilibrium in order for the Cope rearrange-

ment to occur; the coiled form is built into the structure of the molecule. Many bridged

homotropilidenes are now known, and some are shown in Figure 20.65.

Now bridging is a clever idea, and it has led to some fascinating molecules and

some very nice chemistry. But it’s only a good idea. What comes next is an extraor-

dinary idea; one of those insights that anyone would envy, and which define through

their example what is meant by creativity. Suppose we bridge the two methylene

groups with a double bond to give the molecule known as bullvalene.

At first, this

molecule seems like nothing special. As Figure 20.66 shows, the Cope rearrange-

ment is still possible in this highly modified 1,5-hexadiene.

What an odd name! If you are curious about its origin,see Alex Nickon and Ernest F. Silversmith’s nice book

on chemical naming, The Name Game (Pergamon, New York, 1987). You won’t find the systematic naming

scheme in there, but you will find hundreds of stories about the origins of the names chemists give to their

favorite molecules, including bullvalene.