1. 24-24-11
Diels-Alder ReactionDiels-Alder Reaction
Diels-Alder reaction:Diels-Alder reaction: A cycloaddition reaction
of a conjugated diene and certain types of
double and triple bonds.
• dienophile:dienophile: Diene-loving.
• Diels-Alder adduct:Diels-Alder adduct: The product of a Diels-Alder
reaction.
Diels-Alder adduct3-Buten-2-one
(a dienophile)
1,3-Butadiene
(a diene)
+
O
O
3-Buten-2-one
(a dienophile)
1,3-Butadiene
(a diene)
+
O
O

2. 24-24-22
Diels-Alder ReactionDiels-Alder Reaction
• Alkynes also function as dienophiles.
• Cycloaddition reaction:Cycloaddition reaction: A reaction in which two
reactants add together in a single step to form a
cyclic product.
Diels-Alder adductDiethyl
2-butynedioate
(a dienophile)
+
1,3-butadiene
(a diene)
COOEt
COOEt
COOEt
COOEt

3. 24-24-33
Diels-Alder ReactionDiels-Alder Reaction
• We write a Diels-Alder reaction in the following
way:
• 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.
Diene Dieno-
phile
Adduct

4. 24-24-44
Diels-Alder ReactionDiels-Alder Reaction
• The conformation of the diene must be s-cis.
s-trans
conformation
(lower in energy)
s-cis
conformation
(higher in energy)

5. 24-24-55
Diels-Alder Reaction Steric RestrictionsDiels-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.
(2Z,4Z)-2,4-Hexadiene
s-trans conformation
(lower energy)
s-cis conformation
(higher energy)
methyl groups
forced closer than
allowed by van
der Waals radii

6. 24-24-66
Diels-Alder ReactionDiels-Alder Reaction
• Reaction is facilitated by a combination of
electron-withdrawing substituents on one reactant
and electron-releasing substituents on the other.
CyclohexeneEthylene1,3-Butadiene
200°C
pressure
3-Buten-2-one
140°C
+
1,3-Butadiene
O O
+
2,3-Dimethyl-
1,3-butadiene
+ 30°C
3-Buten-2-one
O O

7. 24-24-77
Diels-Alder ReactionDiels-Alder Reaction
Electron-Withdrawing
Groups
Electron-Releasing
Groups
-C N (cyano)
- OR (ether)
- OOCR (ester)
- CHO (aldehyde, ketone)
- COOH (carboxyl)
- COOR (ester)
- NO2 (nitro)
- CH3, alkyl groups

8. 24-24-88
Diels-Alder ReactionDiels-Alder Reaction
• The Diels-Alder reaction can be used to form
bicyclic systems.
+
room
temperature
170°C
Diene Dienophile
Dicyclopentadiene
(endo form)
H
H

9. 24-24-99
Diels-Alder ReactionDiels-Alder Reaction
• Exo and endo are relative to the double bond
derived from the diene.
the double bond
derived from
the diene
endo (inside)
exo (outside) relative to
the double
bond

10. 24-24-1010
Diels-Alder ReactionDiels-Alder Reaction
• For a Diels-Alder reaction under kinetic control,
endo orientation of the dienophile is favored.
Methyl bicyclo[2.2.1]hept-5-en-
endo-2-carboxylate
(racemic)
Methyl
propenoate
Cyclopentadiene
+ OCH3
O
H
COOCH3
COOCH3
redraw 1 2
3
45
6
7

11. 24-24-1111
Diels-Alder ReactionDiels-Alder Reaction
• The configuration of the dienophile is retained.
COOCH3
COOCH3 COOCH3
COOCH3
A cis
dienophile)
Dimethyl cis-4-cyclohexene-
1,2-dicarboxylate
+
COOCH3
H3 COOC COOCH3
COOCH3
A trans
dienophile)
Dimethyl trans-4-cyclohexene-
1,2-dicarboxylate
(racemic)
+

12. 24-24-1212
Diels-Alder ReactionDiels-Alder Reaction
• The configuration of the diene is retained.
CH3
CH3
CH3
O
O
O
O
O
O
O
O
O
H3 C
H3 C
O
O
OH3C
H3 C
CH3
+
+
H
H
H
H
Check
that
this is
endo.

13. 24-24-1313
Diels-Alder ReactionDiels-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 reactionPericyclic 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.

14. 24-24-1414
Diels-Alder ReactionDiels-Alder Reaction
• Mechanism of the
Diels-Alder reaction

15. 24-24-1515
Aromatic Transition StatesAromatic Transition States
Hückel criteria for aromaticity: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.

16. 24-24-1616
Aromatic Transition States,Aromatic Transition States,
ExamplesExamples
• Decarboxylation of β-keto acids and β-
dicarboxylic acids.
• Cope elimination of amine N-oxides.
O O
H
O
O
H
C
O
O
O
CO2+
enol of
a ketone
(A cyclic six-membered
transition state)
O
heat
+
A cyclic six-membered
transition state
N,N-dimethyl-
hydroxylamine
C C
H N
CH3
CH3
N
CH3
CH3
O
HC C
An alkene
+

17. 24-24-1717
Aromatic Transition StatesAromatic Transition States
• the Diels-Alder reaction
• 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.
Diene Dieno-
phile
Adduct

18. 24-24-1818
Claisen RearrangementClaisen Rearrangement
Claisen rearrangement:Claisen rearrangement: A thermal
rearrangement of allyl phenyl ethers to 2-
allylphenols.
Allyl phenyl ether
200-250°C
2-Allylphenol
O OH

19. 24-24-1919
Claisen RearrangementClaisen Rearrangement
O
Allyl phenyl
ether
heat
OH
o-Allylphenol
O
H
A cyclohexadienone
intermediate
keto-enol
tautomerism
O
Transition
state

20. 24-24-2020
Cope RearrangementCope Rearrangement
Cope rearrangement:Cope rearrangement: A thermal
isomerization of 1,5-dienes.
3,3-Dimethyl-
1,5-hexadiene
2-Methyl-2,6-
heptadiene
heat

21. 24-24-2121
Cope RearrangementCope Rearrangement
Example 24.8Example 24.8 Predict the product of these Cope
rearrangements.
(a)
(b)
350°C
OH
H
320°C

22. 24-24-2222
Synthesis of Single EnantiomersSynthesis 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.

23. 24-24-2323
Synthesis of Single EnantiomersSynthesis 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. 24-24-2424
Synthesis of Single EnantiomersSynthesis of Single Enantiomers
• In a second strategy, asymmetric inductionasymmetric induction, the achiral
starting material is placed in a chiral environment by
reacting it with a chiral auxiliarychiral 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
HO
Me Me
Me
HO
Me Me
Ph
8-Phenylmenthol
(an enantiomerically
pure chiral auxillary)
Menthol
(enantiomerically pure)
several
steps

25. 24-24-2525
Synthesis of Single EnantiomersSynthesis 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.
OBn
Me
O
Me Me
Ph
O
ORO
BnO
RO O
OBn
+
Diels-Alder
+
Enantiomerically
pure
97% 3%
89%
Achiral

26. 24-24-2626
Synthesis of Single EnantiomersSynthesis 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.
HO
H
O
OH
OH
D-Erythrose