Carey - Organic Chemistry - chapt21

Carey - Organic Chemistry - chapt21

(Parte 1 de 3)


You have already had considerable experience with carbanionic compounds and their applications in synthetic organic chemistry. The first was acetylide ion in Chapter 9, followed in Chapter 14 by organometallic compounds—Grignard reagents, for example—that act as sources of negatively polarized carbon. In Chapter 18 you learned that enolate ions—reactive intermediates generated from aldehydes and ketones—are nucleophilic, and that this property can be used to advantage as a method for carbon–carbon bond formation.

The present chapter extends our study of carbanions to the enolate ions derived from esters. Esterenolatesare important reagents in synthetic organic chemistry. The stabilized enolates derived from -keto estersare particularly useful.

Aproton attached to the -carbon atom of a -keto ester is relatively acidic. Typical

at this site is highly stabilized. The electron delocalization in the anion of a -keto ester is represented by the resonance structures

-Keto ester: a ketone carbonyl is to the carbonyl group of the ester.

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We’l begin by describing the preparation and properties of -keto esters, proceed to a discussion of their synthetic applications, continue to an examination of related species, and conclude by exploring some recent developments in the active field of synthetic carbanion chemistry.


Before describing how -keto esters are used as reagents for organic synthesis, we need to see how these compounds themselves are prepared. The main method for the preparation of -keto esters is a reaction known as the Claisen condensation:

On treatment with alkoxide bases, esters undergo self-condensation to give a -keto ester and an alcohol. Ethyl acetate, for example, undergoes a Claisen condensation on treatment with sodium ethoxide to give a -keto ester known by its common name ethyl acetoacetate(also called acetoacetic ester):

The systematic IUPAC name of ethyl acetoacetate is ethyl 3-oxobutanoate.The presence of a ketone carbonyl group is indicated by the designation “oxo” along with the appropriate locant. Thus, there are four carbon atoms in the acyl group of ethyl 3-oxobutanoate, C-3 being the carbonyl carbon of the ketone function.

The mechanism of the Claisen condensation of ethyl acetate is presented in Figure 21.1. The first two steps of the mechanism are analogous to those of aldol addition (Section 18.9). An enolate ion is generated in step 1, which undergoes nucleophilic addition to the carbonyl group of a second ester molecule in step 2. The species formed in this step is a tetrahedral intermediate of the same type that we encountered in our discussion of nucleophilic acyl substitution of esters. It dissociates by expelling an ethoxide ion, as shown in step 3, which restores the carbonyl group to give the -keto ester. Steps 1 to 3 show two different types of ester reactivity: one molecule of the ester gives rise to an enolate; the second molecule acts as an acylating agent.

Claisen condensations involve two distinct experimental operations. The first stage concludes in step 4 of Figure 21.1, where the base removes a proton from C-2 of the -keto ester. Because this proton is relatively acidic, the position of equilibrium for step 4 lies far to the right.

Ethyl acetate 2CH3COCH2CH3

Ethyl acetoacetate (75%) (acetoacetic ester)



-Keto ester


Principal resonance structures of the anion of a -keto ester


Ludwig Claisen was a German chemist who worked during the last two decades of the nineteenth century and the first two decades of the twentieth. His name is associated with three reactions. The Claisen–Schmidt reactionwas presented in Section 18.10, the Claisen condensationis discussed in this section, and the Claisen rearrangementwill be introduced in Section 24.13.

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Overall reaction:

Step 1: Proton abstraction from the carbon atom of ethyl acetate to give the corresponding enolate.


1. NaOCHCH 2. HO

Ethyl 3-oxobutanoate(ethyl acetoacetate) Ethanol


Ethyl acetate CH3CH2OHEthanol

Enolate of ethyl acetate

Step 2: Nucleophilic addition of the ester enolate to the carbonyl group of the neutral ester. The product is the anionic form of the tetrahedral intermediate.

CH3COCH2CH3 Ethyl acetate

Enolate of ethyl acetate


Anionic form of tetrahedral intermediate

Step 3: Dissociation of the tetrahedral intermediate.


Anionic form of tetrahedral intermediate

Ethyl 3-oxobutanoate


Ethoxide ion

Step 4: Deprotonation of the -keto ester product.

Ethyl 3-oxobutanoate (stronger acid)


Ethoxide ion (stronger base)

Conjugate base of ethyl 3-oxobutanoate (weaker base)

Ethanol (weaker acid)


X X —Cont.

FIGURE 21.1 The mechanism of the Claisen condensation of ethyl acetate. BackForwardMain MenuTOCStudy Guide TOCStudent OLCMHHE Website

In general, the equilibrium represented by the sum of steps 1 to 3 is not favorable for condensation of two ester molecules to a -keto ester. (Two ester carbonyl groups are more stable than one ester plus one ketone carbonyl.) However, because the -keto ester is deprotonated under the reaction conditions, the equilibrium represented by the sum of steps 1 to 4 does lie to the side of products. On subsequent acidification (step 5), the anion of the -keto ester is converted to its neutral form and isolated.

Organic chemists sometimes write equations for the Claisen condensation in a form that shows both stages explicitly:

Like aldol condensations, Claisen condensations always involve bond formation between the -carbon atom of one molecule and the carbonyl carbon of another:

PROBLEM 21.1One of the following esters cannot undergo the Claisen condensation. Which one? Write structural formulas for the Claisen condensation products of the other two.

Unless the -keto ester can form a stable anion by deprotonation as in step 4 of

Figure 21.1, the Claisen condensation product is present in only trace amounts at equilibrium. Ethyl 2-methylpropanoate, for example, does not give any of its condensation product under the customary conditions of the Claisen condensation.

Ethyl propanoate


Ethyl 2-methyl-3-oxopentanoate (81%)


Ethyl acetate


Ethyl acetoacetate

Sodium salt of ethyl acetoacetate


Step 5: Acidification of the reaction mixture. This is performed in a separate synthetic operation to give the product in its neutral form for eventual isolation.

Conjugate base of ethyl 3-oxobutanoate (stronger base)

Hydronium ion (stronger acid)

Ethyl 3-oxobutanoate (weaker acid)

Water (weaker base)

FIGURE 21.1 (Continued)

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At least two protons must be present at the carbon for the equilibrium to favor prod-


Esters of dicarboxylic acidsundergo an intramolecular version of the Claisen condensation when a five- or six-membered ring can be formed.

This reaction is an example of a Dieckmann cyclization.The anion formed by proton abstraction at the carbon to one carbonyl group attacks the other carbonyl to form a five-membered ring.

PROBLEM 21.2Write the structure of the Dieckmann cyclization product formed on treatment of each of the following diesters with sodium ethoxide, followed by acidification.



Diethyl hexanedioate

Ethyl (2-oxocyclopentane)- carboxylate (74–81%)

Ethyl 2-methylpropanoate

Ethyl 2,2,4-trimethyl-3-oxopentanoate (cannot form a stable anion; formed in no more than trace amounts)

Enolate of diethyl hexanedioate

Ethyl (2-oxocyclopentane)carboxylate

Walter Dieckmann was a German chemist and a contemporary of Claisen.

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SAMPLE SOLUTION(a) Diethyl heptanedioate has one more methylene group in its chain than the diester cited in the example (diethyl hexanedioate). Its Dieckmann cyclization product contains a six-membered ring instead of the fivemembered ring formed from diethyl hexanedioate.


Analogous to mixed aldol condensations, mixed Claisen condensations involve carbon–carbon bond formation between the -carbon atom of one ester and the carbonyl carbon of another.

The best results are obtained when one of the ester components is incapable of forming an enolate. Esters of this type include the following:

The following equation shows an example of a mixed Claisen condensation in which a benzoate ester is used as the nonenolizable component:

PROBLEM 21.3Give the structure of the product obtained when ethyl phenyl- acetate (C6H5CH2CO2CH2CH3) is treated with each of the following esters under conditions of the mixed Claisen condensation:

(a)Diethyl carbonate(c)Ethyl formate (b)Diethyl oxalate

Methyl benzoate (cannot form an enolate)

Methyl propanoate CH3


Methyl 2-methyl-3-oxo- 3-phenylpropanoate (60%)

Formate esters

Carbonate esters

Oxalate esters

Benzoate esters


Another ester

-Keto ester

Diethyl heptanedioate



Ethyl (2-oxocyclohexane)- carboxylate



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SAMPLE SOLUTION(a) Diethyl carbonate cannot form an enolate, but ethyl phenylacetate can. Nucleophilic acyl substitution on diethyl carbonate by the enolate of ethyl phenylacetate yields a diester.

The reaction proceeds in good yield (86%), and the product is a useful one in further synthetic transformations of the type to be described in Section 21.7.


In a reaction related to the mixed Claisen condensation, nonenolizable esters are used as acylating agents for ketone enolates. Ketones (via their enolates) are converted to -keto esters by reaction with diethyl carbonate.

Esters of nonenolizable monocarboxylic acids such as ethyl benzoate give -diketones on reaction with ketone enolates:

Intramolecular acylation of ketones yields cyclic -diketones when the ring that is formed is five- or six-membered.

Ethyl 4-oxohexanoate CH3

Ethyl benzoate


1,3-Diphenyl-1,3- propanedione (62–71%)

Diethyl carbonate



Ethyl (2-oxocycloheptane)- carboxylate (91–94%)

Diethyl 2-phenylpropanedioate (diethyl phenylmalonate)

Sodium hydride was used as the base in this example. It is often used instead of sodium ethoxide in these reactions.

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PROBLEM 21.4Write an equation for the carbon–carbon bond-forming step in the cyclization reaction just cited. Show clearly the structure of the enolate ion, and use curved arrows to represent its nucleophilic addition to the appropriate carbonyl group. Write a second equation showing dissociation of the tetrahedral intermediate formed in the carbon–carbon bond-forming step.

Even though ketones have the potential to react with themselves by aldol addition, recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18.9). On the other hand, acylation of ketone enolates gives products ( -keto esters or -diketones) that are converted to stabilized anions under the reaction conditions. Consequently, ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base in the presence of esters.

The carbon–carbon bond-forming potential inherent in the Claisen and Dieckmann reactions has been extensively exploited in organic synthesis. Subsequent transformations of the -keto ester products permit the synthesis of other functional groups. One of these transformations converts -keto esters to ketones; it is based on the fact that -keto acids (not esters!) undergo decarboxylation readily (Section 19.17). Indeed, -keto acids, and their corresponding carboxylate anions as well, lose carbon dioxide so easily that they tend to decarboxylate under the conditions of their formation.

Thus, 5-nonanone has been prepared from ethyl pentanoate by the sequence

Ethyl pentanoate


Ethyl 3-oxo-2-propylheptanoate (80%)

5-Nonanone (81%)

3-Oxo-2-propylheptanoic acid (not isolated; decarboxylates under conditions of its formation)


Ketone heat CO2

-Keto acid

C Enol form of ketone


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The sequence begins with a Claisen condensation of ethyl pentanoate to give a -keto ester. The ester is hydrolyzed, and the resulting -keto acid decarboxylates to yield the desired ketone.

PROBLEM 21.5Write appropriate chemical equations showing how you could prepare cyclopentanone from diethyl hexanedioate.

The major application of -keto esters to organic synthesis employs a similar pattern of ester saponification and decarboxylation as its final stage, as described in the following section.


Ethyl acetoacetate (acetoacetic ester), available by the Claisen condensation of ethyl acetate, has properties that make it a useful starting material for the preparation of ketones. These properties are

1.The acidity of the proton 2.The ease with which acetoacetic acid undergoes thermal decarboxylation

Ethyl acetoacetate is a stronger acid than ethanol and is quantitatively converted to its anion on treatment with sodium ethoxide in ethanol.

The anion produced by proton abstraction from ethyl acetoacetate is nucleophilic. Adding an alkyl halide to a solution of the sodium salt of ethyl acetoacetate leads to alkylation of the carbon.

The new carbon–carbon bond is formed by an SN2-type reaction. The alkyl halide must therefore be one that is not sterically hindered. Methyl and primary alkyl halides work best; secondary alkyl halides give lower yields. Tertiary alkyl halides react only by elimination, not substitution.

Saponification and decarboxylation of the alkylated derivative of ethyl acetoacetate yields a ketone.

Sodium halide

2-Alkyl derivative of ethyl acetoacetate

Sodium salt of ethyl acetoacetate; alkyl halide

Ethyl acetoacetate (stronger acid)


Sodium ethoxide(stronger base)Sodium salt of ethyl acetoacetate

(weaker base)

Ethanol (weaker acid)

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This reaction sequence is called the acetoacetic estersynthesis.It is a standard procedure for the preparation of ketones from alkyl halides, as the conversion of 1- bromobutane to 2-heptanone illustrates.

The acetoacetic ester synthesis brings about the overall transformation of an alkyl halide to an alkyl derivative of acetone.

We call a structural unit in a molecule that is related to a synthetic operation a synthon.The three-carbon unit is a synthon that alerts us to the possibility that a particular molecule may be accessible by the acetoacetic ester synthesis.

PROBLEM 21.6Show how you could prepare each of the following ketones from ethyl acetoacetate and any necessary organic or inorganic reagents:

(Parte 1 de 3)