Jones M., Fleming S.A. Organic Chemistry

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12.12 The Diels–Alder Reaction of Conjugated Dienes 549

If the mechanism is stepwise, it should lead to stereochemical scrambling of the

groups originally attached to the dienophile (Fig. 12.60).

H R

rotate

Diradical with trans R groups

cis Product

trans Product

Diradical with cis R groups

FIGURE 12.60 A two-step

mechanism predicts a mixture of

stereoisomers.

In fact, retention of stereochemistry is observed. The reaction is a concerted,

one-step process (Fig. 12.61).

WEB 3D

COOH

trans Alkene, the dienophile trans Product

cis Alkene, the dienophile cis Product

COOH

140 ⬚C

benzene

140 ⬚C

benzene

HOOC

FIGURE 12.61 The preservation of

stereochemistry in the Diels–Alder

reaction favors the concerted

mechanism.

PROBLEM 12.28 The experiment described in Figures 12.59–12.61

is usually easy to understand, but there is another stereochemical

experiment possible. It tests the same thing, but is harder to see

without models. So, if this problem is difficult to follow, by all means

work it through with models. Let’s follow the stereochemical fate of

groups attached to the ends of the diene, not the alkene. Consider

the Diels–Alder reaction between a trans,trans-conjugated diene

and ethylene. Only a single cyclohexene product is formed and it

has the R groups cis. Explain how this result shows that the mecha-

nism of cycloaddition cannot be a two-step process.

trans,trans Diene cis Cycloalkene

550 CHAPTER 12 Dienes and the Allyl System: 2p Orbitals in Conjugation

In the preceding pages, mechanistic points have been illustrated using very sim-

ple examples.Actually,the simplest Diels–Alder reaction,ethylene and 1,3-butadiene,

has a rather high activation enthalpy of about 27 kcal/mol and requires high pres-

sure and temperature for success. Even 200 °C and a reaction pressure of 4500 psi

yields only 18% cyclohexene after 17 hours. Other Diels–Alder reactions proceed

under milder conditions. Reactions are more facile when the dienophile bears one

or more electron-withdrawing groups and if the diene can easily achieve the required

s-cis conformation. Two examples of these relatively fast Diels–Alder reactions are

shown in Figure 12.62.

100 ⬚C

1 h

(100%)

(88%)

25 ⬚C

benzene, 15 h

FIGURE 12.62 Two efficient

Diels–Alder reactions.

Why is the Diels–Alder reaction so important and so useful? Six-membered rings

are very common, and the reaction builds six-membered rings from relatively sim-

ple building blocks. Moreover, the reaction is very general. Most dienes react with

most dienophiles to give Diels–Alder products.From now on,every cyclohexene you

see must trigger the thought “can be made by a Diels–Alder reaction” in your mind.

That’s an important concept for both synthesis and problem solving.

Like most reactions in organic chemistry, the Diels–Alder reaction is not a one-

way street. Reverse Diels–Alder reactions are common, especially at high tempera-

ture. Remember: ¢G  ¢H  T¢S (Eq. 8.6, p. 337), and at high temperature the

temperature-dependent ¢S term can overwhelm the temperature-independent ¢H

term. The reverse Diels–Alder reaction makes two molecules from one and there-

fore is favored by entropy, ¢S. Cyclohexenes are formed in a reaction of a diene and

a dienophile, but they can be used as sources of dienes through the reverse Diels–

Alder reaction (Fig. 12.63).

(

87%

)

⌬

800 ⬚C,

12 mm

0.02 s

THE GENERAL CASE A SPECIFIC EXAMPLE

FIGURE 12.63 The reverse Diels–Alder reaction.

Now let’s press on to look at other uses of the Diels–Alder reaction, which is

surely one of the most synthetically useful of all the reactions in organic chemistry.

12.12 The Diels–Alder Reaction of Conjugated Dienes 551

Bicyclo[2.2.1]hept-2-ene

AcetyleneEthylene CyclopentadieneCyclopentadiene Bicyclo[2.2.1]hepta-

2,5-diene

200 ⬚C

23 h

280–300 ⬚C

10–12 atm

FIGURE 12.64 The Diels–Alder reaction between cyclic dienes and alkenes (or alkynes) gives

bicyclic molecules.

Chemists often use bicyclic molecules to investigate effects requiring a fixed geo-

metrical arrangement of orbitals or groups. Consider the simple Diels–Alder reaction

between ethylene or acetylene and a common cyclic diene, cyclopentadiene (Fig.12.64).

⌬

X pointing away from the

double bond (called exo)

X pointing toward the

double bond (called endo)

FIGURE 12.65 In principle, this kind

of Diels–Alder reaction can give

either endo or exo products.

Presto! Bicyclic compounds! But this instant synthetic expertise is not without its price,

because now there is a new stereochemical effect to be considered.When a substitut-

ed alkene reacts with a cyclic diene,there are two possible stereoisomeric products even

though the two new σ bonds are formed simultaneously. The substituents on the

alkene must retain their stereochemical relationship during the reaction, but there are

still two possible products.The substituents on the alkene can point toward the newly

formed double bond or away from it (Fig. 12.65). In this molecule, the isomer with

the substituents aimed toward the double bond is called endo and that with the groups

aimed away from the double bond is called exo. More generally, a substituent that is

on the same side as the smaller bridge of a bicyclic system is exo.The exo isomers are

usually more stable,but the endo compounds are kinetically favored in the Diels–Alder

reaction (Fig. 12.66).

WEB 3DWEB 3D

⌬

(60%)

(81%)shorthand = (19%)

(40%)

OAc

endo Products exo Products

FIGURE 12.66 It is the endo product

that is favored in most Diels–Alder

reactions. In each case, the percentage

of endo product is greater than the

percentage of exo product.

552 CHAPTER 12 Dienes and the Allyl System: 2p Orbitals in Conjugation

The exo compounds formed from a substituted dienophile are more stable for

steric reasons:The substituent points away from the more congested part of the mol-

ecule.Indeed, the transition state for exo product formation must also be less crowd-

ed than the transition state for endo product formation. But the transition state for

the endo product benefits from other factors that overwhelm steric considerations.

Chemists have performed high-level molecular orbital calculations and have found

that in the endo transition state, but not in the exo transition state, there can be

“secondary orbital overlap.” This fancy-sounding phrase simply means that there can

be interaction between the “back” diene orbitals and orbitals on the substituent X

only in the endo transition state. Figure 12.67 shows this effect for the first example

of Figure 12.66. Another explanation that has been suggested for the endo selectivity

relates to solvent interactions.Whatever the cause, the endo product is usually formed

preferentially and sometimes with very high selectivity (Fig. 12.68).

Even more complicated polycyclic structures can be made from the Diels–Alder

reaction between two ring compounds. In the simplest case, the reaction of a cyclic

1,3-diene with a cycloalkene (Fig. 12.68), notice that the endo addition is preferred.

endo Product

exo Product

endo Transition state exo Transition state has

no possible secondary

interactions

New bonds New bonds

Secondary

interactions

FIGURE 12.67 Secondary orbital interactions stabilize the endo transition states.

endo Product

(98%)

exo Product

(2%)

⌬

FIGURE 12.68 The Diels–Alder

reaction between a cyclic diene and a

cyclic dienophile gives a polycyclic

product. Once again, it is the endo

form that is favored.

12.12 The Diels–Alder Reaction of Conjugated Dienes 553

WORKED PROBLEM 12.29 You attempt to prepare 1,3-cyclopentadiene from the

base-catalyzed loss of hydrogen bromide (E2 reaction) from 3-bromocyclopen-

tene, but instead of isolating a compound having the formula C

, you get a

high yield of a compound with the formula C

base

)

The hoped-for product

)

The isolated product

Two cyclic dienes can also react in Diels–Alder fashion. The self-condensation

of cyclopentadiene is the classic example.We’ll illustrate this reaction with a pair of

problems.

Fame, fortune,and the Nobel prize await you if you can explain this result (at least

if you were explaining it in 1928). Be careful—although this question is obviously

set up in the text, it is not so easy to write a structure correct in every detail.

ANSWER The formula of C

is a clue. Clearly,two C

molecules have joined

to make the C

product.The reaction is, in fact, successful.The problem is that

cyclopentadiene dimerizes in a Diels–Alder reaction very quickly.The molecule you

isolate is the Diels–Alder dimer. Note formation (mainly) of the endo adduct.

Anytime you see a 1,3-diene, especially a cyclic one, think Diels–Alder.

WORKED PROBLEM 12.30 In a fit of frustration or inspiration you decide to boil

(reflux) your unanticipated C

, and, in order to do that, you attach a long

condenser to a receiving vessel that is kept very cold. Your C

boils at about

165 °C, but you collect a product of the formula C

boiling at 40 °C. Moreover,

although this C

product is stable at low temperature for a long time, at room

temperature it rapidly reverts to your starting C

. Explain.

ANSWER At 165 °C, the Diels–Alder reaction reverses, and the low-boiling

cyclopentadiene can be collected and kept at low temperature. If it is allowed to

warm up, it again forms the Diels–Alder dimer.

⌬

)(C

)

WEB 3D

165 ⬚C

Cold

warm

554 CHAPTER 12 Dienes and the Allyl System: 2p Orbitals in Conjugation

PROBLEM SOLVING

Every cyclohexene that you see from now on—and there will be many—comes

with the messages: “Can be made through a Diels–Alder reaction,” and, “Think

reverse Diels–Alder.” Problem writers play the game called,“Hide the cyclohexene.”

Your job is to beat them at this game by recognizing all cyclohexenes, no matter

how well disguised. A very good way to become proficient at this game is to play

the other side, as it were. Set yourself the goal of disguising a cyclohexene so that it

is hard to see.

12.13 Special Topic: Biosynthesis of Terpenes

When we discussed cationic addition reactions in Chapter 9, we included a section

on the polymerization reactions of alkenes (p. 384). Dienes form quite stable inter-

mediates in addition reactions and are especially prone to polymerization.

Nature!

PolyisopreneIsoprene

PROBLEM 12.32 Notice the Z configuration of the alkenes in natural rubber.

There is another, stereoisomeric form of natural rubber, also a polymer of iso-

prene, called by the wonderful name gutta percha.

What do you suppose it is?

Gutta percha comes from the Malay, getah percha (gum of the percha tree).

PROBLEM 12.31 Write a mechanism for the radical-induced polymerization of

1,3-butadiene.

Nature uses related polymerization reactions (the cart is way before the horse

here; we make approximations of Nature, not the other way round!). One form

of natural rubber is polyisoprene, which is polymerized isoprene (2-methyl-1,3-

butadiene).

Polyisoprene is a limiting case—a molecule composed of a vast number of iso-

prene units. Many important natural products called terpenes are constructed of

smaller numbers of isoprene units put together in various ways. Terpenes are wide-

spread in nature and are still often extracted from plants. The smaller terpenes are

widely used as flavors and fragrances. Indeed, terpene chemistry is the very basis of

the fragrance industry.

12.13 Special Topic: Biosynthesis of Terpenes 555

3-Methyl-3-buten-1-ol pyrophosphate

(isopentenyl pyrophosphate)

3-Methyl-3-buten-1-ol Pyrophosphoric acid

FIGURE 12.69 In the biosynthesis of terpenes, 3-methyl-3-buten-1-ol is first converted

into the corresponding pyrophosphate.

Recall the discussion of various ways to change OH, a very poor leaving group,

into much better leaving groups (p. 281). We saw examples of protonation to make

the leaving group water, and of formation of a sulfonate ester (reviewed in Fig. 12.70).

Formation of the pyrophosphate ester serves exactly the same purpose and is wide-

ly used in Nature to generate a good leaving group from a poor one.

Most of the reactions used to make terpenes from diene units can be largely under-

stood in terms of reaction mechanisms we know well.For example, 3-methyl-3-buten-

1-ol is converted first into the corresponding 3-methyl-3-buten-1-ol pyrophosphate

(isopentenyl pyrophosphate) by reaction with pyrophosphoric acid (Fig. 12.69).

Pyrophosphoric acid

Water (an excellent

leaving group)

Hydroxide (a very

poor leaving group)

Tosylate, OTs

(another excellent leaving group)

Pyrophosphate, OPP

(still another excellent leaving group)

Tosyl chloride

FIGURE 12.70 Three ways of

converting OH, a poor leaving group,

into a good leaving group.

PROBLEM 12.33 Explain why the pyrophosphate ester in Figure 12.70 is an

excellent leaving group. The abbreviation OPP is used for the pyrophosphate

group.

556 CHAPTER 12 Dienes and the Allyl System: 2p Orbitals in Conjugation

3-Methyl-3-buten-1-ol pyrophosphate 3-Methyl-2-buten-1-ol pyrophosphate

enzyme

FIGURE 12.71 An enzyme

converts 3-methyl-3-buten-1-ol

pyrophosphate into a new,

allylic pyrophosphate.

3-Methyl-3-buten-1-ol

pyrophosphate

3-Methyl-2-buten-1-ol pyrophosphate

Geranyl pyrophosphate

(geranyl–OPP)

OPP

New bond

FIGURE 12.72 Loss of the pyrophosphate gives an allylic cation that can be

attacked by a molecule of 3-methyl-3-buten-1-ol pyrophosphate to give a

new cation. Deprotonation gives geranyl pyrophosphate.

There is an enzyme that equilibrates 3-methyl-3-buten-1-ol pyrophosphate with

an isomeric pyrophosphate, 3-methyl-2-buten-1-ol pyrophosphate (Fig. 12.71).

Geranyl–OPP

OPP

New bond

OPP

Farnesyl pyrophosphate

(farnesyl–OPP)

OPP

FIGURE 12.73 The addition process can be repeated to give farnesyl pyrophosphate.

Note that this new pyrophosphate now has a good leaving group in an allylic posi-

tion.The combination of a good leaving group and the allylic position makes ioniza-

tion to form an allylic cation easy. The cation is attacked by 3-methyl-3-buten-1-ol

pyrophosphate to produce ultimately the C

compound, geranyl pyrophosphate

(Fig. 12.72).

Because geranyl pyrophosphate has a good leaving group in an allylic position,

this process can be repeated to produce the C

compound, farnesyl pyrophosphate

(Fig. 12.73).

12.13 Special Topic: Biosynthesis of Terpenes 557

Geranyl–OPP Geraniol

Farnesyl–OPP

OPP

Farnesol

FIGURE 12.74 The alcohols geraniol

and farnesol are formed by hydrolysis

of the related pyrophosphates.

Hydrolysis of geranyl pyrophosphate and farnesyl pyrophosphate produces the

terpenes geraniol and farnesol, respectively (Fig. 12.74).

Isoprene units can be characterized as having a head and a tail as shown in

Figure 12.75. Notice that both geranyl and farnesyl pyrophosphate are formed by

head-to-tail connections of isoprenes.

Geranyl–OPP

Farnesyl–OPP

OPP

Isoprene

OPP

comes from

HeadTail

Head

Tail

HeadTail

FIGURE 12.75 Head-to-tail attachment of isoprene units gives geranyl and farnesyl pyrophosphates.

The limit of head-to-tail combining is polyisoprene,natural rubber (p.554).Your

drawing of the polymer of isoprene called gutta percha (Problem 12.32) should also

have head-to-tail connections.

Molecules formed from isoprene units are made of multiples of five carbons. Dif-

ferent names are used corresponding to the number of isoprene units in the molecule.

Two units of isoprene combine to form terpenes,C

compounds such as geraniol.Three

isoprene units form sesquiterpenes,C

compounds such as farnesol.Diterpenes are C

compounds, triterpenes are C

compounds, and so on. Myriad terpenoid compounds

are known, and most can be traced to derivatives of isoprene as starting material. Most

terpenes follow the isoprene rule, which dictates the head-to-tail formation described

earlier. All of the terpenes shown in Figure 12.76 do not strictly follow the pattern, but

each has at least one head-to-tail connection.

558 CHAPTER 12 Dienes and the Allyl System: 2p Orbitals in Conjugation

WEB 3D

Limonene Menthol

Thujone

(1S )-(

–)-β-Pinene

(1R)-(

+)-Camphor

(1R)-(

+)-α-Pinene

(1S)-(

–)-Camphor

FIGURE 12.76 Some terpenes.

If you have experienced the rich odor

of a pine tree forest, then this photo

will remind you of that pleasant

smell. It comes from volatile terpenes

that fill the air.

WORKED PROBLEM 12.34 Dissect limonene and (1R)-()-camphor (Fig. 12.76)

into isoprene units.

ANSWER The isoprene units can usually be found by searching for the methyl

groups first. One of these problems is easy, the other is more complicated. Don’t

worry about oxygen atoms or double bonds, just look for carbon framework. The

two isoprenes for each compound are shown in red.

PROBLEM 12.35 Devise a mechanism for converting geranyl pyrophosphate into

racemic limonene (Fig. 12.76). Such processes are usually enzyme-mediated in

Nature. When you try this problem you should encounter a roadblock, because

the process can’t really be done without a cis/trans isomerization, very likely

carried out in Nature by the enzyme.