3.Aldolica Claisen En

7/29/2019 3.Aldolica Claisen En

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Nucleophilic additions of enolates to carbonyl

compounds

The addition of nucleophiles based on oxygen, nitrogen, sulfur to carbonylcompounds is a reaction we met before. Carbon nucleophiles such as

carbanions (Grignard reagents, alkyl lithium) orenolates can also react with

carbonyl derivatives leading to a new C-C bond.

This class of reactions is called aldol condensation orClaisen

condensation according to whether the electrophile is a ketone/aldehyde or

an ester/thioester.

S Ch 21


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Apart from the diversity of products that are obtained w.r.t. the addition to C=O of

an alkyl lithium or Grignard reagent, what is the fundamental difference in enolate

additions?Enolates may also be formed in aqueous environment, unlike carbanions, and at

relatively high temperatures (r.t.).

Hence, enolates are the nucleophilic reagents present in nature, where the solvent

is H2O and reactions take place in narrow temperature ranges.

The aldol condensation is the self-condensation of an aldehyde

The reaction was so named by Charles Wurtz in 1872, who prepared 3-hydroxybutanal

(aldol) treating acetaldehyde with dilute HCl. The reaction was then studied by others,

including Hans Schmidt who was the first to employ basic, rather than acidic, conditions.

Aldol condensation

S1034


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Base-catalyzed aldol condensation

In basic environment the enolate is formed. In water the amount of enolate is

very low because carbonyl protons are less acidic than those of water by

several orders of magnitude.

Therefore in the reaction mixture there is a high amount of acetaldehyde

which may react with the enolate, forming the new C-C bond

S1034


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The -hydroxyaldehyde so produced has more acidic protons in to a

carbonyl: if OH- removes another proton, generating the corresponding

enolate, two reactions are possible:

Finally, the resulting alkoxide removes a proton from water, yielding a -

hydroxyaldehyde and regenerating the catalyst OH-

Condensation with another aldehyde molecule, leading to trimers or

oligomers

Elimination of H2O to an ,-unsaturated aldehyde

S1035

Base-catalyzed aldol condensation


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Dehydration of the product of the aldol condensation

A double bond conjugated with the carbonyl group is formed.

The elimination mechanism is different from the more common (E1 and E2) because theinitial event a carbanion is formed, which is allowed by the carbonyl function. Moreover,

the leaving group (OH-) is not particularly good.

The dehydration of the product of an aldol condensation occurs via an E1cb

mechanism

S1035

Unimolecular elimination, conjugate base (E1cb)


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Exercise: write the structures of the two products that are obtained from the

aldol condensation of propanal, catalyzed by OH-. Show the electron

movements that take place at every step.

S1036-7

H 3 CC

H

O

O H-

H 3 CC

H

O

+ H 2 O

C

H

O

HH

H

H

- O

H

C H O

H

O H

H

C H O+ H 2 O

+ O H -

H 3 C C H 2

O H

H

C H 3

H

C H O H 3 C C H 2

O H

H

C H 3

C H O

H 3 C C H 2

H

C H 3

C H O

- O H -

O H -


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In acidic environment an enol is formed, which is a much weaker nucleophile

than an enolate. However, the acid environment makes C=O a stronger

electrophile, owing to protonation at the carbonyl oxygen

Acid-catalyzed aldol condensation

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Deprotonation leads to the -hydroxyaldehyde

Stopping the process at the -hydroxyaldehyde is difficult. The acidic

environment favors elimination (E1 or E2)

S1036-7

Acid-catalyzed aldol condensation


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The aldol condensation, both acid- and base-catalyzed, is reversible. The

reverse process is called retroaldol reaction.

Retroaldol reaction

The ease with which this process occurs depends on steric effects at the and

positions.

S1037


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Aldol condensation of ketones

Enolizable and reactive ketones may undergo aldol condensation.

However, most often steric factors render the retroaldol reaction more

favorable.

The reaction can be displaced to the right if water is eliminated and the

,-unsaturated derivative is formed (acidic conditions).

The most important application of the aldol condensation of ketones is the

intramolecular Robinson annulation.

S1038


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Mixed aldol condensation

Using two enolizable

aldehydes leads to acomplex reaction

mixture deriving from

reaction of both

enolates with both

aldehydes (4 products)

and eliminationproducts the

corresponding ,-

unsaturated derivatives

(4 products).

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In order to make the mixed aldol condensation a useful process

we need to employ:

A non-enolizable aldehyde

A specific enolate

An enzymatic method

Non-enolizable aldehyde: benzaldehyde

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How is the ,-unsaturated derivative formed?

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If the ketone can form a single enolate, the reaction proceeds smoothlyand a single product is obtained in high yield.

S1041



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Mixed aldol condensation promoted by Lewis acids

S1042

Using dialkylboron triflates (R2B-OTf), in the presence of a weak base

such as EtN(i-Pr)2 (DIEA) a boron enolate is obtained:

OTf = CF3SO

3

-


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The boron derivative, a Lewis

acid, coordinates to the

carbonyl oxygen

The base removes the acidic proton, generating the double bond with

loss of triflate ion

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Then the boron enolate is added to an aldehyde and coordinates to it.

Thus boron acts both as carbonyl activator (Lewis acid) and as template,bringing the two reagents close to each other

The enolate now attacks the carbonyl and the new C-C bond is formed.

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Oxidation with H2O2 in base leads to the -hydroxyaldehyde

Even if both carbonyl compounds are enolizable, self-condensation can be

avoided

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Exercise: what is the major product expected for each of the following

reactions:

S1044

OBBu2

CHO

O

B-

O

H

+O

B-

O

H

H2O2 / OH-

O OH

O

HO


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A variant of aldol condensation assisted by a Lewis acid

Generation of the enolate,

nucleophilic addition to

carbonyl and protonation toalcohol

Addition of an ester enolate to an aldehyde or ketone

S1045


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Exercise. A carbanion derived from an imine or a tertiary amide may also

react with a carbonyl compound. What is the expected main product of

the following reactions?

S1046

CH C

O

NMe2 Ph C

Ph

CH

OH CH3

C

N

H


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The Claisen condensation

Besides aldehydes and ketones, esters can also generate enolates andbehave as electrophiles. When an ester is treated with a base a transformation

similar to the aldol condensation occurs the Claisen condensation.

The Claisen condensation leads to the formation of -ketoesters after acidic

workup.

S1060


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The Knoevenagel reaction

A variant of aldol condensation, in which the nucleophile is the

conjugate base of an active methylene compound

The product is an alkene containing two geminal acceptor groups

The reaction occurs under wakly basic (organic bases like piperidine)

or neutral (piperidinium acetate) conditions

S1091 (es. 21.27)


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C H O

+ C H 2 ( C O O E t ) 2

C O O E t

C O O E t

C H 2 ( C O O E t ) 2

NH 2

C H 3 C O O-

- C H ( C O O E t ) 2

C H O

- C H ( C O O E t ) 2

C

E t O O C C O O E t

H

OC

E t O O C C O O E t

H

O H

H +

C

E t O O C C O O E t

H

- O H -

H H

C

E t O O C C O O E t

H

O H

+ H 2 O

The Knoevenagel reaction: mechanism


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The Knoevenagel reaction: products


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Henry reaction

A variant of the aldol condensation in which the nucleophile is the

conjugate base of a nitroalkane (pKa < 10)

mechanism

S1091 (es. 21.26) es. nitroethane + PhCHO


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The mechanism is similar to that of the aldol condensations, with some

differences:

Low concentration of the enolate (pKa 24)

A stoichiometric (not catalytic) amount of base is needed

The enolate reacts with another ester molecule leading to a tetrahedral

intermediate:

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The carbonyl function is regenerated with an ethoxide as leaving group

The reaction might stop here. However, since the newly formed compound has

an active methylene, in the reaction conditions the base can deprotonate itagain, generating a new stabilized enolate.

For this reaction to take place, at least 1 eq of base must be present. This is

another difference w.r.t. the aldol condensation, which requires only a catalytic

amount of base.

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After acid workup the -ketoester is obtained:

If the reagent is ethyl acetate, this reaction is called acetoacetic

condensation or acetoacetic synthesis

In the Claisen condensation, formation of a resonance-stabilized enolate

shifts the equilibrium to the right

S1061

The deprotonation of the intermediate inthe basic environment is irreversible and

leads to complete conversion. The final

product can only be obtained in an acidic

environment.



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Claisen condensation: retro Claisen

All steps of the Claisen condensation are reversible; the formation of a

dicarbonyl enolate brings the reaction to completion. If this process cannot

take place, the equilibrium favors the reactants.

ethyl isobutyrate vs. ethyl acetate

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In the presence of EtO- a further nucleophilic attack occurs at the carbonyl,

instead of deprotonation. The reaction reverts to the reactants

Retro Claisen

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A method to prevent retro Claisen from occurring is to use strong bases to

generate the enolate

The enolate is then treated with one equivalent of ester or, better, the

corresponding acyl chloride.

Avoiding retro Claisen

S1062-3


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Exercise. What is the main product of the following reaction?

S1063

H3

C C

O C H 3

C H 3

C O O E t

H 3 C C

O C H 3

C H 3

C O O E t

E t O -

( r e t r o - C l a i s e n )

C H 3 C O O E t + ( C H 3 ) 2 C H C O O E t


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The Dieckmann cyclization

The mechanism is fully analogous to that of the Claisen condensation: generation

of the enolate, formation of the tetrahedral intermediate, expulsion of the leavinggroup, formation of the stabilized carbanion

An intramolecular Claisen condensation

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Acidic workup allows to obtain the neutral product, in which the

carbonyl function is within the ring

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Since -ketoesters can be easily decarboxylated, this is a synthetic strategy

to obtain cycloalkanones.

S1064

E t O O C C O O E t

E t O - / E t O H

C O O E t

O E t

O

C O O E t

- O

E t O

C O O E t

O

+ E t O -

C O O E t

O

C O O E t

OH 3 O

+



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Mixed Claisen condensation

Like in the aldol condensation, two different esters can be used in the Claisen

condensation. The reaction works best when one of the esters does not have

hydrogens

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An example of mixed Claisen condensation is a Dieckmann cyclization, when

one of the ester functions does not have protons. This allows for theformation of a single product.

A single product can be obtained even in the presence of two enolizable ester

functions, if the reaction is reversible.

Single product

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One of the two products does not have enolizable protons; therefore the

retro-Claisen is favored. The equilibrium is displaced towards the formationof the 2,6-disubstituted regioisomer.

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In the mixed Claisen condensation the enolizable partner may also be a

ketone. Ketones are 4 orders of magnitude more acidic than esters and will

preferentially form the enolate.A non-enolizable ester is preferred, even if ketones undergo self-condensation

slowly.

A common application of this reaction is the hydroxymethylenation of ketones

with ethyl formate:

Mixed Claisen condensation with ketones

S1067


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Acid workup yields theproduct, which exists

mainly as enol

Hydroxymethylenation of ketones

S1067-8


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Exercise. Explain the following

processes:

S1068

O

O

O

H

H C O O E t

O

O E t

O -

H

O

O

H

- E t O

-

O

H

H

O E t

- O

O

H

H

O

OH

O

OH

O


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Aldol condensation

Base-catalyzed aldol, possibly dehydration E1cbAcid-catalyzed: aldol dehydration E1/E2

Summary

H3C C

O

H2

cat. OH-

H3C CH

OH

CH2 CHO

cat. H+

H3C CH

CH CHOH3C CH

OH

CH2 CHO

H3C CH

CH CHOE1cb

E1 o E2

Condensation of ketones less favored

Mixed condensation requires a non-enolizable partner (e.g. PhCHO)

The enolizable component may be an ester, amide or imine


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Aldol condensation promoted by Lewis acids

Summary

R C

O

CH2 R'

n-Bu2BOTf / DIEA

R C

OBBu2

CHR'

+ DIEAH+

TfO-

R C

OBBu2

CHR'

PhCHO

R C

O

CH

B

O

Bu

Bu

R'

C

Ph

H

H2O2/OH-

R C

O

CH CH

OH

Ph

R'

No self-condensation


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Claisen condensation 2 mol. ester -ketoesterLow concentration of enolate, 1 equiv. base

Reversible reaction: equilibrium is displaced to the right by deprotonation,

otherwise retro Claisen

H 3 C C O O E t2E t O N a / E t O H

H 3 C C

O

C H C O O E t H 3 C C

O

C H 2 C O O E t

C C O O E t2E t O N a / E t O H

C C

O

C C O O E t

C H 3

C H 3

H

H

C H 3

C H 3 C H 3

C H 3

In such cases, use a strong base to generate the enolate with ester or

acyl halide

Dieckmann cyclization: intramolecular variant (cyclic -ketoester)

Summary


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Mixed Claisen condensation: to achieve regioselectivity, use a non-

enolizable component

ketone+HCOOEt hydroxymethylenationO

H C O O E t

O

H

C H O

O

C H O H

Carboxylatione of enolates: ketone-ketoacidwith CO2 reversible reactionPossible with equivalents such as ClCOOEt or CO(OEt)2

Summary


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Knoevenagel reaction: variant of aldol cond.

aldehyde + active methylene alkene with 2 geminal acceptor groups

C H O

+ C H 2 ( C O O E t ) 2

C O O E t

C O O E t

Henry reaction

aldehyde + nitroalkane nitroalkene

C H O

+ C H 3 N O 2

N O 2

Summary

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3.Aldolica Claisen En