Nucleophilic additions of enolates to carbonyl compounds

The addition of nucleophiles based on oxygen, nitrogen, sulfur to carbonyl compounds is a reaction we met before. Carbon nucleophiles such as carbanions (Grignard reagents, alkyl lithium) or enolates can also react with carbonyl derivatives leading to a new C-C bond.

This class of reactions is called aldol condensation or Claisen condensation according to whether the electrophile is a ketone/aldehyde or an ester/thioester.
S Ch 21

Aldol condensation
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.
2

S1034

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

Base-catalyzed aldol condensation

Finally, the resulting alkoxide removes a proton from water, yielding a hydroxyaldehyde and regenerating the catalyst OH-

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: Condensation with another aldehyde molecule, leading to trimers or oligomers Elimination of H2O to an ,-unsaturated aldehyde
4

S1035

Dehydration of the product of the aldol condensation

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

A double bond conjugated with the carbonyl group is formed. The elimination mechanism is different from the more common (E1 and E2) because the initial event a carbanion is formed, which is allowed by the carbonyl function. Moreover, the leaving group (OH-) is not particularly good.

Unimolecular elimination, conjugate base (E1cb)

S1035

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.
O H
-

H H H H 3C H H C O H C O H -O CHO H
-

H 3C

C O

+ H 2O

H C HO

+ H 2O

+ O H

O H

O H H 3C CH
2

CH

O H CHO H 3C CH
2

CH

- O H
CHO H

H 3C

CH

CH

CHO

O H
S1036-7

Acid-catalyzed aldol condensation

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

S1036

Acid-catalyzed aldol condensation

Deprotonation leads to the -hydroxyaldehyde Stopping the process at the -hydroxyaldehyde is difficult. The acidic environment favors elimination (E1 or E2)

S1036-7

Retroaldol reaction
The aldol condensation, both acid- and base-catalyzed, is reversible. The reverse process is called retroaldol reaction.

The ease with which this process occurs depends on steric effects at the and positions.
S1037

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

10

Mixed aldol condensation

Using two enolizable aldehydes leads to a complex reaction mixture deriving from reaction of both enolates with both aldehydes (4 products) and elimination products the corresponding ,unsaturated derivatives (4 products).
S1039

11

Mixed aldol condensation

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

S1040

12

Mixed aldol condensation

How is the ,-unsaturated derivative formed?

S1040

13

Mixed aldol condensation

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

S1041

14

Mixed aldol condensation promoted by Lewis acids

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 = CF3SO3-

S1042

15

Mixed aldol condensation promoted by Lewis acids

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

S1042

16

Mixed aldol condensation promoted by Lewis acids

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.
17

S1042-3

Mixed aldol condensation promoted by Lewis acids

Oxidation with H2O2 in base leads to the -hydroxyaldehyde Even if both carbonyl compounds are enolizable, self-condensation can be avoided

S1043

18

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

OBBu2 +O CHO O BO H O OH

BO H

H2O2 / OHHO O

S1044

19

Addition of an ester enolate to an aldehyde or ketone

A variant of aldol condensation assisted by a Lewis acid

Generation of the enolate, nucleophilic addition to carbonyl and protonation to alcohol

S1045

20

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?

O CH C NMe2 Ph OH C Ph CH3 C H C H N

S1046

21

The Claisen condensation

Besides aldehydes and ketones, esters can also generate enolates and behave 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

22

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)

23

The Knoevenagel reaction: mechanism

CHO CO O Et

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

CO O Et

C H 3C O O
N H
2

C H 2 (C O O E t)2

C H (C O O E t)2
H E tO O C C O O Et E tO O C H C O O Et

C H O
-

H
H

C H

O H

C H (C O O E t)2

E tO O C

C O O Et

E tO O C

C O O Et

C H

O H

- O H

C H

+ H 2O

24

The Knoevenagel reaction: products

25

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

26

The Claisen condensation

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:

S1060

28

The Claisen condensation

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 it again, 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.
S1060

29

The Claisen condensation

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 The deprotonation of the intermediate in the basic environment is irreversible and leads to complete conversion. The final product can only be obtained in an acidic environment.
S1061

30

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

S1061-2

31

Retro Claisen

In the presence of EtO- a further nucleophilic attack occurs at the carbonyl, instead of deprotonation. The reaction reverts to the reactants

S1062

32

Avoiding retro Claisen

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.

S1062-3

33

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

O H 3C C

CH

C O O Et CH
3

O H 3C C

CH

(re tro -C la is e n )
CO O Et CH
3

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

E tO

S1063

34

The Dieckmann cyclization

An intramolecular Claisen condensation

The mechanism is fully analogous to that of the Claisen condensation: generation of the enolate, formation of the tetrahedral intermediate, expulsion of the leaving group, formation of the stabilized carbanion

S1063

35

The Dieckmann cyclization

Acidic workup allows to obtain the neutral product, in which the carbonyl function is within the ring

S1064

36

The Dieckmann cyclization

Since -ketoesters can be easily decarboxylated, this is a synthetic strategy to obtain cycloalkanones.

E tO - /E tO H
E tO O C C O O Et

O C O O Et O Et

CO O Et -O O E tO

CO O Et O

C O O Et

CO O Et

+ E tO

H 3O

S1064

37

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

S1064

38

Mixed Claisen condensation

S1065

39

Mixed Claisen condensation

An example of mixed Claisen condensation is a Dieckmann cyclization, when one of the ester functions does not have protons. This allows for the formation 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
S1065

40

Mixed Claisen condensation

One of the two products does not have enolizable protons; therefore the retro-Claisen is favored. The equilibrium is displaced towards the formation of the 2,6-disubstituted regioisomer.

S1066

41

Mixed Claisen condensation with ketones

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:

S1067

42

Hydroxymethylenation of ketones

Acid workup yields the product, which exists mainly as enol

S1067-8

43

Exercise. Explain the following processes:

O H

O H

- E tO
O
-

O O Et

O H

H C O O Et
H H -O O Et

O H H

S1068

44

Summary
Aldol condensation Base-catalyzed aldol, possibly dehydration E1cb Acid-catalyzed: aldol dehydration E1/E2

OH

cat. OH 2 H3C
C H

H3C

C H OH

CH2

CHO

E1cb

H3C

C H

CH

CHO

cat. H

H3C

C H

CH2

CHO

E1 o E2

H3C

C H

CH

CHO

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
47

Summary
Aldol condensation promoted by Lewis acids

n-Bu2BOTf / DIEA
R C CH2 R'

OBBu2 R C CHR'

+ DIEAH+ TfO-

Bu Bu OBBu2 R C CHR' R' O B O CH C Ph H O OH CH R' C H Ph

PhCHO

H2O2/OH

No self-condensation
48

Summary
Claisen condensation 2 mol. ester -ketoester Low concentration of enolate, 1 equiv. base
E tO N a /E tO H 2
H 3C CO O Et H 3C O C CH CO O Et H 3C O C C H
2

CO O Et

Reversible reaction: equilibrium is displaced to the right by deprotonation, otherwise retro Claisen
CH
3

E tO N a /E tO H 2
H C CH
3

CH H C CH

O C

CH C CH

CO O Et CO O Et
3

In such cases, use a strong base to generate the enolate with ester or acyl halide Dieckmann cyclization: intramolecular variant (cyclic -ketoester)
49

Summary
Mixed Claisen condensation: to achieve regioselectivity, use a nonenolizable component ketone + HCOOEt hydroxymethylenation
O O H O CHO H CHO

H C O O Et

Carboxylatione of enolates: ketone -ketoacid with CO2 reversible reaction Possible with equivalents such as ClCOOEt or CO(OEt)2

50

Summary
Knoevenagel reaction: variant of aldol cond. aldehyde + active methylene alkene with 2 geminal acceptor groups

CHO

CO O Et

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

CO O Et

Henry reaction aldehyde + nitroalkane nitroalkene

CHO NO
2

+ C H 3N O

51