Enols and Enolates

8/4/2019 Enols and Enolates

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Enols and Enolates

A major type of reaction with carbonyl compounds is an -substitution

O O

E

In the preceding chapters we were concerned

with the carbonyl reacting as an electrophile

O

OH

NUC


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Enols

As observed previously an enol and a ketone are tautomers

O OH

Usually the ketone is far more stable than the enol and it predominates

Under either slightly basic or acidic conditions the concentration of enol can be increasedThe keto form still predominates

With aldehydes there is relatively more enol form than with ketones


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Reactions of Enols

The enol form can react with electrophiles

A common reaction is halogenation

O OHNaOH/H2O Br BrOH

Br

under basic conditions it is hard to stop at one addition because

hydrogen abstraction of product is more favored than starting material

O

Br

OH

Br

O

Br

Br

Br2


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Haloform Reaction

This polyhalogenation is exploited with a haloform reaction

A methyl ketone will react until three halogens have been substituted on -carbon

O O

CI3

I2

NaOH

with three halogens attached to the carbon it becomes a good leaving group

O

CI3

O

O

NaOH

HCI3

iodoform

the three halogens stabilize the negative charge of the leaving group


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Acid Catalyzed Enol Formation

Under acidic conditions the enol can react with halogen and stop after one addition

O OH O

Br

H+ Br2

with acidic conditions we do not form anion adjacent to halogen as in basic mechanism

therefore the reaction can be stopped after one addition


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Enolizable Positions

A consequence of the ability to form enols is that chiral carbons can racemize

O

Et

OH

Et

O

Et

H+ or NaOH

chiral achiral racemic

since the -position can form an enol, and the enol is achiral, chiral atoms that are to

carbonyls will lose chiralty whenever enol formation is favored


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Bromination of Acids

Carboxylic acids can also be brominated

First need to convert carboxylic acid into acid halide (labile H would interfere)

O

OH

PBr3/Br2

O

Br

this acid bromide can form enol under these conditions, which will react with Br2

O

Br

OH

Br

O

Br

Br Br

O

OH

Br2 H2O


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Enolates

Enolates are similar to enols but they are far more nucleophilic

In order to generate an enolate need a base to abstract an -hydrogen

H3C

O

CH3

pKa of-hydrogens ~ 20

the -hydrogens are more acidic than normal alkane hydrogens due to electron

withdrawing carbonyl group that can delocalize the resultant negative charge

O O


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Base Abstraction

Since the pKa of an -hydrogen of a ketone is ~20 the choice of base will determine

extent of enolate formation

H3C

O

CH3

NaOH

H3C

O

CH2

both water (pKa of ~15.7) or alcohols (pKa ~>16) are less acidic

therefore with these bases the majority of the compounds will be in the keto form


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Basicity vs. Nucleophilicity

Most strong bases are also strong nucleophiles - remember SN2 vs. E2

With carbonyls need to balance two different type of reactions:

A strong nucleophile reacting with the carbonyl and a strong base abstracting -hydrogen

H3C

O

CH3

H3C

O

CH3

NUC

H3C

O

NUC

CH3

B

H3C

O

CH2


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Enolate

To generate enolate need to use a base that will not act as a nucleophile

Common choice is to use lithium diisopropylamine (LDA)

HN N

Li

BuLi

LDA

LDA is a strong base (pKa of conjugate is close to 40)

At the same time it is very bulky so it will not react as a nucleophile


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LDA will quantitatively form enolate

H3C

O

CH3

LDA

H3C

O

CH2

using LDA the enolate will be formed quantitatively

with weaker bases will only form the enolate in a small fraction


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Enolate as a Nucleophile

We have already seen many reactions with a nucleophile reacting

-see any SN2 reaction

an enolate is simply another type of nucleophile

it can react in exactly the same manner we have observed other nucleophiles react

H3C

O

CH2 H3C

O

E

E+


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Alkylation of Enolates

One common reaction is to alkylate the enolate

H3C

O

CH2 H3C

O

CH3

CH3Br

This reaction will place an alkyl substituent at the -position of a carbonyl

Any electrophile that will react in an SN2 reaction can be used in this reaction


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Unsymmetrical Carbonyls

With an unsymmetrical carbonyl can obtain two different enolates

O O O

O O

LDA

CH3Br CH3Br

how to obtain one product preferentially?


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Thermodynamic vs. Kinetic Control

The key is which enolate is generated

The enolate can be preferentially generated at either site depending upon conditions

O O OLDA

kinetic enolate thermodynamic enolate

more stable double bondeasier hydrogen to abstract

lower temperatures favor kinetic product

higher temperatures (in this case usually room temp. and above) favor thermodynamic


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Product Formation

By controlling which enolate is generated,

where the -substitution occurs can be controlled

O 1) LDA, -78C

2) CH3BrO

O1) LDA. RT2) CH3Br

O


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Cannot follow this procedure with Aldehydes

Will not obtain -substitution with aldehydes through enolate chemistry

The aldehyde carbonyl is too reactive and it will interfere

with the formation of the enolate

O

H

O

H

self condenses


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-Alkylation of Aldehydes

to alkylate an aldehyde we first need to convert the aldehyde to a less reactive system

an imine or imine derivative is used most frequently

O

H

NH2

N

H

N

H

N

H

O

H

1) CH3Br

2) H+/H2OLDA


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Enamines

Another option instead of enolate formation is to form an enamine

React carbonyl with 2 amine

O

HN

N N OCH3Br H+/H2O

the enamine is not as reactive as an enolate but it is more reactive than an enol


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Aldol Condensation

Instead of reacting the enolate with an alkyl halide

We can also react the enolate with a carbonyl compound

The carbonyl can react as an electrophile

O

OO OH

upon work-up obtain a -hydroxy ketone


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Dehydration of Aldol Product

The -hydroxy ketone that is formed can also loss water

to form an ,-unsaturated ketone

O OH O

-H2O

the loss of water can sometimes occur during work-up,

it can be driven to this product through heat and either acidic or basic conditions


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Procedure for Aldol Reaction

When reacting in a self-condensation can use an alkoxide base

OO O OHCH3

ONa

O

the alkoxide base will only deprotonate a small proportion of ketone,

but those enolates will react quickly with keto forms in an aldol reaction

can drive the reaction to completion


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Using Different Carbonyl Compounds

If there are different carbonyl compounds (a mixed aldol or crossed aldol)

then conditions need to be considered

CH3ONaO O O OH

O OH

if using unsymmetrical ketones than will obtain four regioproducts for this reaction


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A couple of options to reduce number of products

Use one carbonyl that does not have -hydrogens

Therefore there are no hydrogens to abstract and can only react as electrophile

O

O

H CH3ONa

O OH

want to add compound with -hydrogens (acetone in above example)

slowly to basic benzaldehyde solution


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Another option: quantitatively form enolate first

If need to use two carbonyls that both contain -hydrogens need to first generate the

enolate quantitatively (strong base) and then add the second carbonyl compound

O LDA OLi

OO OH

can generally obtain high yield of the desired aldol product with this method

remember that with weak base will obtain a mixture of products with these reactants


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Claisen Condensation

There are many "Name" reactions that are modifications of the aldol condensation

A Claisen condensation is an aldol where one carbonyl is an ester

By using an ester this changes the chemistry due to the presence of a leaving group

CH3ONaO O

O

O O

O

O O

can run this reaction with both carbonyls present and a weak base

due to differences in pKa (ketones are ~20 and esters are ~24)


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Reactions are Driven to Completion

Unlike other aldol reactions, which are under equilibrium control, Claisen condensations

give very high yield without adjusting equilibrium conditions

The last step generates an alkoxide with a -diketone

O OCH3ONa

O ONa

diketones have a pKa ~10, therefore methoxide will quantitatively abstract the hydrogen


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Dieckmann

A Dieckmann condensation is an intramolecular Claisen condensation

O

O

O

O

O

O

O

O

CH3ONaOO

O

convenient method to form 5- or 6-membered rings


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-Dicarbonyls

both Claisen and Dieckmann condensations form -dicarbonyl compounds

-keto esters are another type of dicarbonyl systems that are very useful synthetically

O O

OCH3

CH3ONaONa O

OCH3

O O

OCH3

R

RBr

due to the acidity of the methylene position alkylation reactions are easy to perform,

with only one carbonyl often need to use LDA to quantitatively form enolate


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Decarboxylation

After alkylation, the ester group can be hydrolyzed and then decarboxylated

O O

OCH3

R

O O

O

R

H

1) NaOH2) W-U

O

H

R

-CO2

O

R

allows alkylation of ketone in much milder method than starting with ketone


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Michael Addition

If we add enolate to ,-unsaturated system the reaction often reacts with 1,4-addition

Called Michael addition

O

NUC

O

NUC

O1

2

3

4


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Calicheamicin 11: An Example of Michael Addition in Drug Action

In chapter 4 we first saw a drug that uses a Michael addition

O

I

OCH3

OCH3

O

SO

OHO

H3CO OH

OH

ON

O

O

O

O

NHCO2CH3

H3CSSS

HO

O

H3CO

HN

HO

binding group

reactive functionality

H


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After the sugar binding group binds in the minor groove of DNA a sulfide is generated

O

O

NHCO2CH3S

HO

binding groupO

O

NHCO2CH3

HO

binding group

S

HO

S

Obinding group

O

NHCO2CH3 HO

S

Obinding group

O

NHCO2CH3

Bergmancycloaromatization

DNA

DNA diradical

DNA double strand cleavageO2

Michael

After the Michael addition occurs, the conformational change causes the Bergman

cyclization to occur eventually leading to cell death after DNA cleavage


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Robinson Annulation

This is a very convenient method to form 6-membered rings

Perform a Michael addition followed by an aldol condensation

CH3ONa

O ONa O O ONa

O OO ONa

O

CH3OH

CH3ONa


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Convenient Method to Synthetically Produce Multi-Ring Systems

steroid ring system

HO

H

H H

H

cholesterol

nature has more efficient ways to synthesize steroids but you can see how Robinson

Annulation can be used to prepare 6-6 and 6-5 ring junctions in a one pot reaction

Documents

Enols and Enolates