24a synthesis

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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

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• 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

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• 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

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• The conformation of the diene must be s-cis.

s-trans conformation

(lower in energy)

s-cis conformation

(higher in energy)

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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 groupsforced closer thanallowed by vander Waals radii

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• Reaction is facilitated by a combination of electron-withdrawing substituents on one reactant and electron-releasing substituents on the other.

CyclohexeneEthylene1,3-Butadiene

200°Cpressure

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

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Electron-WithdrawingGroups

Electron-ReleasingGroups

-C N (cyano)

- OR (ether)

- OOCR (ester)

- CHO (aldehyde, ketone)

- COOH (carboxyl)

- COOR (ester)

- NO2 (nitro)

- CH3 , alkyl groups

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• The Diels-Alder reaction can be used to form bicyclic systems.

+

roomtemperature

170°CDiene Dienophile

Dicyclopentadiene(endo form)

H

H

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• Exo and endo are relative to the double bond derived from the diene.

the double bondderived fromthe diene

endo (inside)

exo (outside) relative tothe doublebond

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• 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)

Methylpropenoate

Cyclopentadiene

+ OCH3

O

H

COOCH3

COOCH3redraw 1 23

45

6

7

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• The configuration of the dienophile is retained.

COOCH3

COOCH3 COOCH3

COOCH3A cis

dienophile)Dimethyl cis-4-cyclohexene- 1,2-dicarboxylate

+

COOCH3

H3COOC COOCH3

COOCH3A trans

dienophile)Dimethyl trans-4-cyclohexene-

1,2-dicarboxylate(racemic)

+

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• The configuration of the diene is retained.CH3

CH3

CH3

O

O

O

O

O

O

O

O

O

H3C

H3C

O

O

OH3C

H3C

CH3

+

+

H

H

H

H

Check that this is endo.

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� 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.

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• Mechanism of the Diels-Alder reaction

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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.

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Aromatic Transition States, Aromatic Transition States, ExamplesExamples

• Decarboxylation of β-keto acids and β-dicarboxylic acids.

• Cope elimination of amine N-oxides.

O OH

O

OH

C

O

O

OCO2+

enol ofa ketone

(A cyclic six-membered transition state)

O

heat+

A cyclic six-memberedtransition state

N,N-dimethyl-hydroxylamine

C C

H NCH3

CH3

NCH3

CH3

OHC C

An alkene

+

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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

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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

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Claisen RearrangementClaisen Rearrangement

O

Allyl phenyl ether

heat

OH

o-Allylphenol

O

H

A cyclohexadienone intermediate

keto-enoltautomerism

O

Transition state

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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

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Cope RearrangementCope Rearrangement

Example 24.8Example 24.8 Predict the product of these Cope rearrangements.

(a)

(b)

350°C

OH

H

320°C

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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.

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� 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.

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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 MePh

8-Phenylmenthol(an enantiomericallypure chiral auxillary)

Menthol(enantiomerically pure)

several steps

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• 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 MePh

O

ORO

BnO

RO O

OBn

+

Diels-Alder+

Enantiomericallypure

97% 3%

89%

Achiral

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• 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.

HOH

O

OH

OH

D-Erythrose

24a synthesis

Technology

dielsalder reactions

dielsalder adductdiethyl

dielsalder adduct3buten

cycloaddition reaction

reaction of butadiene

conjugated diene

butadienea diene o o24

butadienea diene o o3buten