Diels-Alder Reaction

 Diels-Alder reaction: A cycloaddition reaction of

a conjugated diene and certain types of double
and triple bonds.
• dienophile: Diene-loving.
• Diels-Alder adduct: The product of a Diels-Alder
reaction.
O
O

1,3-Butadiene 3-Buten-2-one Diels-Alder adduct

(a diene) (a dienophile)

24-1
Diels-Alder Reaction
• Alkynes also function as dienophiles.
COOEt COOEt
+
COOEt
COOEt
1,3-butadiene Diethyl Diels-Alder adduct
(a diene) 2-butynedioate
(a dienophile)

• Cycloaddition reaction: A reaction in which two

reactants add together in a single step to form a cyclic
product.

24-2
Diels-Alder Reaction
• We write a Diels-Alder reaction in the following way:

Diene Dieno- Adduct

phile

• The special value of D-A reactions are that they:

1. form six-membered rings.
2. form two new C-C bonds at the same time.
3. are stereospecific and regioselective.
Note the reaction of butadiene and ethylene gives only
traces of cyclohexene.

24-3
Diels-Alder Reaction
• The conformation of the diene must be s-cis.

s-t rans s-cis

conformation con formation
(lower in en ergy) (higher in en ergy)

24-4
Diels-Alder Reaction Steric Restrictions

• (2Z,4Z)-2,4-Hexadiene is unreactive in Diels-Alder

reactions because nonbonded interactions prevent it
from assuming the planar s-cis conformation.
methyl grou ps
forced clos er th an
allow ed by van
der Waals radii

s-t rans conformation s-cis conformation

(low er energy) (h igh er energy)
(2Z,4Z)-2,4-Hexadiene

24-5
Diels-Alder Reaction
• Reaction is facilitated by a combination of electron-
withdrawing substituents on one reactant and
electron-releasing substituents on the other.
200°C
+ pressure
1,3-Butadiene Ethylene Cyclohexene
O O
140°C
+
1,3-Butadiene 3-Buten-2-one
O O

+ 30°C

2,3-Dimethyl- 3-Buten-2-one
1,3-butadiene 24-6
Diels-Alder Reaction

Electron-Releasing Electron-Withdrawing
Groups Groups
- CH 3 , alkyl group s - CH O (ald ehyde, ketone)
- OR (ether) - COOH (carb oxyl)
- OOCR (es ter) - COOR (es ter)
- NO 2 (nitro)
-C N (cyano)

24-7
Diels-Alder Reaction
• The Diels-Alder reaction can be used to form bicyclic
systems.
room H
temperature
+
170°C
Diene Dienophile H
Dicyclopentadiene
(endo form)

24-8
Diels-Alder Reaction
• Exo and endo are relative to the double bond derived
from the diene.
the double bond
derived from exo (outside)
the diene relative to
the double
endo (inside) bond

24-9
Diels-Alder Reaction
• For a Diels-Alder reaction under kinetic control, endo
orientation of the dienophile is favored.
O
+ OCH3

Cyclopentadiene Methyl
propenoate
7
COOCH 3 H
redraw 6 1
2
5
3 COOCH 3
4
Methyl bicyclo[2.2.1]hept-5-en-
endo-2-carboxylate
(racemic)

24-10
Diels-Alder Reaction
• The configuration of the dienophile is retained.
COOCH 3 COOCH 3
+
COOCH 3 COOCH 3
A cis Dimethyl cis-4-cyclohexene-
dienophile) 1,2-dicarboxylate

H3 COOC COOCH 3
+
COOCH 3 COOCH 3
A trans Dimethyl trans- 4-cyclohexene-
dienophile) 1,2-dicarboxylate
(racemic)

24-11
Diels-Alder Reaction
• The configuration of the diene is retained.
CH3 O H3 C O
H
Check
that this
+ O O is endo.

O H O
CH3 H3 C

O H3 C O
CH3 H

+ O O
CH3
O H O
H3 C

24-12
Diels-Alder Reaction
 Mechanism
• No evidence for the participation of either radical of
ionic intermediates.
• Chemists propose that the Diels-Alder reaction is a
concerted pericyclic reaction.
 Pericyclic reaction: A reaction that takes place in
a single step, without intermediates, and involves
a cyclic redistribution of bonding electrons.
 Concerted reaction: All bond making and bond
breaking occurs simultaneously.

24-13
Diels-Alder Reaction
• Mechanism of the
Diels-Alder reaction

24-14
Aromatic Transition States
 Hückel criteria for aromaticity: The presence of
(4n + 2) pi electrons in a ring that is planar and
fully conjugated.
 Just as aromaticity imparts a special stability to
certain types of molecules and ions, the
presence of (4n + 2) electrons in a cyclic
transition state imparts a special stability to
certain types of transition states.
• Reactions involving 2, 6, 10, 14.... electrons in a cyclic
transition state have especially low activation energies
and take place particularly readily.

24-15
Aromatic Transition States, Examples
• Decarboxylation of -keto acids and -dicarboxylic
acids.
H
O O H
O O O
+ CO 2
O C
O
(A cyclic six-membered enol of
trans ition s tate) a ketone

• Cope elimination of amine N-oxides.

C C CH3 heat CH3

H N+ C C + H N
O CH3
O CH3
An alkene N,N-dimethyl-
A cyclic s ix-membered hydroxylamine
transition state
24-16
Aromatic Transition States
• the Diels-Alder reaction

Diene Dieno- Adduct

phile

• pyrolysis of esters (Problem 22.42)

 We now look at examples of two more reactions
that proceed by aromatic transition states:
• Claisen rearrangement.
• Cope rearrangement.

24-17
Claisen Rearrangement
 Claisen rearrangement: A thermal rearrangement
of allyl phenyl ethers to 2-allylphenols.
O OH
200-250°C

Allyl ph enyl ether 2-A llylp henol

24-18
Claisen Rearrangement
O O
heat

Allyl phenyl Transition

ether state

O OH
keto-enol
tautomerism
H

A cyclohexadienone o-Allylphenol
intermediate

24-19
Cope Rearrangement
 Cope rearrangement: A thermal isomerization of
1,5-dienes.
he at

3,3-Dimethyl- 2-Methyl-2,6-
1,5-hexadiene heptadiene

24-20
Cope Rearrangement
Example 24.8 Predict the product of these Cope
rearrangements.

(a) 350°C

OH
320°C
(b)

24-21
Synthesis of Single Enantiomers
• We have stressed throughout the text that the
synthesis of chiral products from achiral starting
materials and under achiral reaction conditions of
necessity gives enantiomers as a racemic mixture.
• Nature achieves the synthesis of single enantiomers
by using enzymes, which create a chiral environment
in which reaction takes place.
• Enzymes show high enantiomeric and diastereomeric
selectivity with the result that enzyme-catalyzed
reactions invariably give only one of all possible
stereoisomers.

24-22
Synthesis of Single Enantiomers
 How do chemists achieve the synthesis of single
enantiomers?
 The most common method is to produce a
racemic mixture and then resolve it. How?
• the different physical properties of diastereomeric
salts.
• the use of enzymes as resolving agents.
• chromatographic on a chiral substrate.

24-23
Synthesis of Single Enantiomers
• In a second strategy, asymmetric induction, the achiral starting
material is placed in a chiral environment by reacting it with a
chiral auxiliary. Later it will be removed.
• E. J. Corey used this chiral auxiliary to direct an asymmetric
Diels-Alder reaction.
• 8-Phenylmenthol was prepared from naturally occurring
enantiomerically pure menthol.

Me Me Ph
Me Me
several
HO step s HO

Me Me
Menth ol 8-Phen ylmenthol
(enan tiomerically p ure) (an enan tiomerically
pure chiral auxillary)
24-24
Synthesis of Single Enantiomers
• The initial step in Corey’s prostaglandin synthesis was
a Diels-Alder reaction.
• By binding the achiral acrylate with enantiomerically
pure 8-phenylmenthol, he thus placed the dienophile in
a chiral environment.
• The result is an enantioselective synthesis.
Ph
Me Me
OBn O D iels-A lder
+
89%
O
BnO OBn
Me
Achiral Enantiomerically
pure +

O OR RO O
97% 3% 24-25
Synthesis of Single Enantiomers
• A third strategy is to begin a synthesis with an
enantiomerically pure starting material.
• Gilbert Stork began his prostaglandin synthesis with
the naturally occurring, enantiomerically pure D-
erythrose.
• This four-carbon building block has the R
configuration at each stereocenter.
• With these two stereocenters thus established, he then
used well understood reactions to synthesize his
target molecule in enantiomerically pure form.
OH O
HO
H
OH
D-Erythrose
24-26