Transcript Organic Chemistry - City University of New York

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
(a diene)
3-Buten-2-one
(a dienophile)
Diels -Alder adduct
24-1
Diels-Alder Reaction
• Alkynes also function as dienophiles.
C O OEt
C O OEt
+
C O OEt
C O OEt
1,3-butadiene
(a diene)
Diethyl
2-butynedioate
(a dienophile)
Diels-Alder adduct
• 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
Dienophile
Adduct
• 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 ra n s
co n f o rm a ti o n
(l o w e r i n e n e rg y )
s -c i s
co n fo rm a ti o n
(h i g h e r i n e n e rg y )
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.
m e th y l grou p s
f orce d cl os e r th an
al l o w e d b y van
d e r W aal s rad i i
s -t ra ns co n f orm ati on
(l ow e r e n e rg y)
s -c i s co n f orm ati on
(h i gh e r e n e rg y)
(2Z ,4Z )-2,4-H e xad i e n e
24-5
Diels-Alder Reaction
• Reaction is facilitated by a combination of electronwithdrawing substituents on one reactant and
electron-releasing substituents on the other.
200° C
+
1,3-Butadie ne
press ure
Ethylene
Cyclohexene
O
O
140° C
+
1,3-Butadie ne
3-Buten-2-one
O
O
30° C
+
2,3-Dimethyl1,3-butadiene
3-Buten-2-one
24-6
Diels-Alder Reaction
Electron-Releasing
Electron-Withdrawing
Groups
Groups
- CH 3 , al k y l g ro u p s
- CH O (al d e h y d e , k e to n e )
- O R (e th e r)
- CO O H (c arb oxy l )
- O O C R (e s te r)
- CO O R (e s te r)
- NO2
-C
N
(n i tro )
(cy an o )
24-7
Diels-Alder Reaction
• The Diels-Alder reaction can be used to form bicyclic
systems.
+
room
temperature
H
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
the diene
exo (outside)
endo (ins ide)
relative to
the double
bond
24-9
Diels-Alder Reaction
• For a Diels-Alder reaction under kinetic control, endo
orientation of the dienophile is favored.
O
+
Cyc lope nt adie ne
OCH3
Me t hyl
prope noat e
7
C O OC H 3
H
re draw
6
5
1
4
2
3
C O OC H 3
Methyl bicyclo[2.2.1]hept-5-enendo-2-carboxylate
(racemic)
24-10
Diels-Alder Reaction
• The configuration of the dienophile is retained.
C O OC H 3
C O OC H 3
C O OC H 3
C O OC H 3
+
A ci s
dienophile)
Dimethyl
ci s- 4-cyclohexene1,2-dicarboxylate
H3 COOC
C O OC H 3
+
C O OC H 3
A trans
dienophile)
C O OC H 3
Dimethyl
trans- 4-cyclohexene1,2-dicarboxylate
(racemic)
24-11
Diels-Alder Reaction
• The configuration of the diene is retained.
CH 3
O
+
H3 C
H
O
Check
that this
O is endo.
O
O
CH 3
H3 C
O
CH 3
+
H3 C
H
H
O
O
O
CH 3
O
O
H
H 3C
O
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
H
O
O
O
C
O
(A cyclic s ix-membered
trans ition s tate)
O
+ CO2
O
enol of
a ketone
• Cope elimination of amine N-oxides.
C
C
C H3
N+
H
O
C H3
heat
C
C
C H3
An alkene
A cyclic six-membered
trans ition state
+
N
H
O
C H3
N,N- dimethylhydroxylamine
24-16
Aromatic Transition States
• the Diels-Alder reaction
Diene
Dienophile
Adduct
• 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
A l l y l p h e n y l e th e r
2-A l l yl p h e n o l
24-18
Claisen Rearrangement
O
O
heat
Allyl phenyl
ether
Trans ition
state
OH
O
keto-enol
tautomeris m
H
A cyclohexadienone
intermediate
o-Allylphenol
24-19
Cope Rearrangement
 Cope
rearrangement: A thermal isomerization of
1,5-dienes.
heat
3,3-Dimethyl1,5-hexadiene
2-Methyl-2,6heptadiene
24-20
Cope Rearrangement
Example 24.8 Predict the product of these Cope
rearrangements.
350°C
(a)
OH
320°C
(b)
H
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
s e v e ral
s te p s
HO
Me
M e n th ol
(e n an ti om e ri cal l y p u re )
Me
Ph
Me
HO
Me
8-Ph e n yl m e n th o l
(an e n an ti o m e ri c al l y
p u re ch i ral au xi l l ary)
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.
Me
O Bn
Ph
Me
O
+
O
A c h i ral
Me
E n an ti o m e ri cal l y
p u re
D i e l s -A l d e r
89%
BnO
O Bn
+
O
97%
OR
RO
O
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 Derythrose.
• 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 -E ry th ro s e
24-26