CARBONYL CONDENSATION REACTIONS 2 (10 Mei 2013).ppt

7/28/2019 CARBONYL CONDENSATION REACTIONS 2 (10 Mei 2013).ppt

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CARBONYL

CONDENSATIONREACTIONS


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CARBONYL CONDENSATION REACTIONS

Aldol Reaction

Dehydration of Aldol Products

Intramolecular Aldol Reaction Claisen Condensation Reaction

Intramolecular Claisen

Condensation

Michael Reaction

Stork Enamine Reaction

Robinson Annulation Reaction


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General Mechanism of Carbonyl

Condensation

One carbonyl partner withan alpha hydrogen atom is

converted by base into its

enolate ion.

O

C

R C

H

OH


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C

O

C

C O

R

:

..

..

RC

O

C

OH2

C

O::

:

Electrophilic

Acceptor

NucleophilicDonor

This enolate ion acts as a

nucleophilic donor andadds to the electrophilic

carbonyl group of the

acceptor partner


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Protonation of the tetrahedral alkoxide ionintermediate gives the neutral condensation product.

OH2

R

C

C

C

OH -OH

O

+New C-C Bond


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Mechanism of the Aldol Reaction

HO:

HC

H H

C

O

H

Base removes an

acidic alpha hydrogen

from one aldehyde

molecule, yielding

a resonance-

stabilized eno-

late ion.


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CO

CH3 H

: : OH+2

CH

H

CH

O

..

CH3 C

H

O

C

HH H

OC

H

: :-..

The enolate ion attacks a

second aldehyde

molecule in a nucleophilic

addition reaction to give a

tetrahedral alkoxide ion

intermediate.


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H O2

C

O

CH

C CHHHH

OH

HO3

+ -

:

Protonation of the alkoxide ion intermediate yields neutral

aldol product and regenerates the base catalyst.


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Dehydration of Aldol Products:

Synthesis of Enones

-hydroxy aldehydes and -hydroxy ketones formed

in aldol reactions can be easily dehydrated to yield

conjugated enones

Dehydration is catalyzed by both acid and base

Reaction conditions for dehydration are only slightly

more severe than for condensation

Conjugated enones are more stable thannonconjugated enones


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C

O

CH

C

OHOH

Base-catalyzed

C

O

C

C

OH::

-..

Enolate ion

C

O

CC OH-+

Dehydration of Aldol Products


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C

C

CO OH

H

H+

Acid-catalyzed

C

C C

OHO

H

2+

Enol

C

O

CC H O+

3

+


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Intramolecular Aldol Reaction:

Treatment of certain dicarbonyl compounds

with base can lead to cyclic products

A mixture of cyclic products may result , but

the more strain-free ring is usually formed


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Intramolecular Aldol Reactions

Intramolecular aldol reactions are most successful for

formation of five- and six-membered rings.

Consider 2,7-octadione, which has two a-carbons.

a

a

O

O

O

O

a

a

KOH

KOH

O

HO

O

OH

-H2O

-H2O

O

O2,7-Octanedione

(not formed)

(formed)


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Intramolecular Aldol Reaction of 2, 5-

hexanedione yields 3-methyl-2-cyclopentenone

aC

H

HH H

C

O

H H OC

C

C

C 3

3 2,5- Hexanedioneb


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CH

HH

C

O

H H

C

C

C

C H H

O

3

-

-OHPath A

C

HH

H

C

O

H H

C

C

C

C

H

H

OH

3


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C

C

C

C C

C

H H

H

HH

H

O

H

H

O

HO

3

-:..

..

CH

OH O

3

2+

3-Methyl-2-cyclopentenone

NaOH, H2O


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Claisen Condensation, Ester Substitution

Esters also form enolate anions which participate in nucleophilicacyl substitution.

The product of a Claisen condensation is a -ketoester.

O

2CH3COEt1. EtO

-Na

+

2. H2O, HCl

O O

CH3CCH2COEt EtOH

EthanolEthyl 3-oxobutanoate(Ethyl acetoacetate)Ethyl ethanoate(Ethyl acetate)

+

CC C C ORO O

A -ketoester

a Recognition Element


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Claisen Condensation

Claisen condensation of ethyl propanoate

OEt

O

OEt

O

1. EtO-Na

+

2. H2O, HClOEt

OO

EtOH+

Ethylpropanoate

Ethyl 2-methyl-3-oxopentanoate

(racemic)

+

Ethylpropanoate

Here the enolate part of one ester molecule has

replaced the alkoxy group of the other ester molecule.


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Mechanism: Claisen CondensationStep 1: Formation of an enolate anion.

Step 2: Attack of the enolate anion on a carbonyl carbon

gives a TCAI.

EtO-

CH2-COEtH

O

EtOH CH2-COEt

O O -

CH2=COEt

pKa = 22(weaker acid)

pKa 15.9(stronger

acid)

Resonance-stabilized enolate anion

-++

CH3-C-OEtO O

CH2-COEtO

-

O

OEt

CH3-C-CH2 -C-OEt+

A tetrahedral carbonyladdition in termediate


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Mechanism: Claisen Condensation

Step 3: Collapse of the TCAI gives a -ketoester and an alkoxide ion.

Step 4: An acid-base reaction drives the reaction to completion. This

consumption of base must be anticipated.

Et OCH3-C-CH2 -C-OEt

O OO

CH3-C-CH2-C-OEt

O

OEt

+

Et O

H

CH3-C-CH-C-OEtO O

CH3-C-CH-C-OEt

OO

Et OH

pKa 15.9(weaker acid)

pKa 10.7(stronger acid)

++


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Intramolecular Claisen condensation: Dieckman

Condensation

+

Diethyl hexanedioate

(Diethyl adipate)

Ethyl 2-oxocyclo-pentanecarboxylate

1 . EtO-

Na+

2 . H2 O, HCl

EtOH

OEt

O

EtO

O

OEt

O O

Acidic


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Crossed Claisen Condsns

Crossed Claisen condensations between two

different esters, each with a-hydrogens, give

mixtures of products and are usually not useful.

But if one ester has no a-hydrogens crossed Claisenis useful.

O

HCOEt EtOCOEt

O

COEt

OO

EtOC-COEt

Diethyl ethanedioate(Diethyl oxalate)

Diethylcarbonate

Ethylformate

Ethyl ben zoate

O

No a-hydrogens


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Crossed Claisen Condsns

The ester with no a-hydrogens is generally used in

excess.

Ph OCH3

O

OCH3

O1. CH3O

-Na

+

2. H2O, HClPh OCH3

O O

Methylpropanoate

Methylbenzoate

+

Methyl 2-methyl-3-oxo-3-phenylpropanoate

(racemic)Used in

excess


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Michael Reaction

Conjugate addition of a carbon nucleophile to an

alpha, -unsaturated acceptor

Best Michael Reactions:

Between unusually acidic donors (-ketoesters or-diketones)

Unhindered alpha,-unsaturated acceptors

Stable enolates are Michael donors, and alpha,-unsaturated compounds are Michael acceptors


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The Michael Reaction

EtO

O

C

C

C

O

CH3

HH

Na+ - OEt

The base catalyst

removes an acidic alpha

proton from the starting

beta-keto ester to

generate a stabilized

enolate ion nucleophile.


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The nucleophile adds

to the alpha,beta-ketounsaturated ketone

electrophile in a

Michael reaction to

generate a new enolate

as product.

EtO

C

O

C

C

O

CH3H

-

EtOH

C

H

C

C

H3C H

O

C

H3C C

C

H H

C

HHCO

2Et

C

CH3

OO

.. +

..


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O

EtOH

H3C

C

C

C

H H

C

C

O

CH3

H HCO

2Et

H

EtO-+

The enolate product

abstracts an acidic

proton, either fromsolvent or from starting

keto ester, to yield the

final addition product.


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Some Michael Acceptors and Michael

Donors

H2C CHCHO

H2C CHCO

2Et

H2C CHC N

H2C CHCOCH

3

H2C CHNO2

H2C CHCONH

2

Propenol

Ethyl Propanoate

Propenenitrile

3-Buten-2-one

NitroethylenePropenamide

RCOCH2COR'

RCOCH2CO2Et

EtO2CCH2CO

2Et

RCOCH2C N

RCH2NO2

Beta-Diketone

Beta-Keto Ester

Malonic Ester

Beta-Keto nitrile

Nitro compound

MichaelAcceptors Michael Donors


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Stork Enamine Reaction

enamine adds to an alpha,-unsaturated carbonylacceptor in a Michael- type process

Overall reaction is a three-step sequence:

Step 1: Enamine formation from a ketoneStep 2: Michael-type addition to an alpha, -

unsaturated carbonyl compound

Step 3: Enamine Hydrolysis back to ketone net effect of Stork Enamine reaction sequence is

the Michael addition of a ketone to an alpha,-unsaturated carbonyl compound


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Example of Stork Enamine Reaction

ON

H

-H2O

NH

2C CHCCH3

O..

Cyclohexanone An enamine

NCH

2CHCCH

3

-.. O NCH

2CH

2CCH

3

O+ OH2

O

CH2CH2CCH3

O

N

H

+

A 1,5-diketone


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Enamines (and imines, Schiff bases)Recall primary amines react with carbonyl compounds to give Schiff bases (imines),

RN=CR2.

Primary amine

Secondary Amine

But secondary amines react to give enamines


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Formation of Enamines

Examples:

+H

+

NH

O

An enamine

-H2

ON

OHN

+O

An enamine

N

O

OHN

O

N

O

H

H+

H+

-H2 O

H+


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Compare mechanisms of acid catalyzed aldol and enamine

O

CH3-C-H

H

CH2=C-H

HO

:A-

CH3-CH-CH2-C-H

OH O

H-A+ ++

(racemic)

An iminiumbromide(racemic)

The morpholineenamine of

cyclohexanone

+

Br

N

O

BrSN2

N

O

3-Bromopropene(Ally l bromide)


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Enamines - Alkylation

Hydrolysis of the iminium halide gives an alkylated

aldehyde or ketone.

Morpholiniumchloride

2-Allylcyclo-hexanone

+HCl/ H2O

+Br

-N

O

O

+Cl

-N

O

H H

Overall process is to render the alpha carbonss of ketone nucleophilic enough

so that substitution reactions can occur.

CARBONYL CONDENSATION REACTIONS 2 (10 Mei 2013).ppt

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