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Alkylation of Enolate Ions



In our discussions of the aldol condensation and the Claisen condensation we saw how deprotonation of a carbon atom α to a carbonyl group generated an enolate ion. Suppose for the moment that you wanted to react such a nucleophilic species with an alkyl halide as suggested in Figure 1 for the specific case of acetone. In other words, you want to synthesize 2-butanone from acetone.

Figure 1

A Viable Synthesis?

Scheme 1

Is this a viable process? Let's consider the nature of this reaction. First, recall that treatment of acetone with aqueous NaOH establishes an equilibrium with an equilibrium constant of approximately 10-3. In other words, the solution contains comparatively high concentrations of acetone and NaOH and a relatively low concentration of the enolate ion. When you add CH3I to this mixture there is a chance that it will react with the enolate ion as shown in Figure 1. However alternative pathways are more likely. One alternative is an aldol condensation. Another is an Sn2 reaction of hydroxide ion with methyl iodide. Both of these possibilities are more likely than the desired reaction. So the answer to the question posed earlier is no, the synthesis proposed in Figure 1 is not viable. Fortunately it is possible to accomplish the transformation outlined in Figure 1 by alternative methods. We will consider two, the first a direct method, the second indirect. Then we will extend our discussion of the second method to a related system. All three approaches accomplish the same goal- alkylation of an enolate ion.

Exercise 1 Draw the structures of the compounds that would be formed in the alternative processes to the reaction outlined in Figure 1.





Direct Alkylation of Enolate Ions

Consider the consequences of using a stronger base than hydroxide ion to deprotonate acetone in Figure 1. First, the concentration of enolate ion at equilibrium would be higher. This would increase the likelihood of a reaction with the methyl iodide. Second, the concentration of acetone would be lower. This would reduce the probability of an aldol condensation. Both of these factors increase the likelihood of alkylation.

When lithium diisopropylamide, LDA, is used as the base to deprotonate acetone, Equation 1, the equilibrium constant for the reaction is approximately 1016. Virtually all of the acetone is deprotonated. The chances of an aldol reaction are reduced to essentially zero.

Equation 1

Because LDA is such a strong base, it is possible to use a stoichiometric amount of it to deprotonate all of the acetone. Thus, at equilibrium, there is no unreacted LDA to compete for any alkyl halide that might be added to the reaction mixture. Therefore the reaction of the enolate ion with added methyl iodide, Equation 2, becomes the most probable event under these conditions.

Equation 2

Exercise 2 Draw the structure of the major product (s) expected in each of the following alkylation reactions:





The Acetoacetic Ester Synthesis

Before the direct alkylation of lithium enolates was developed, chemists used an alternative, indirect method to achieve transformations such as that illustrated in Figure 1. Recall that the Claisen condensation of ethyl acetate produces a β-keto ester called ethyl acetoacetate. Recall, too, that the pKa of such compounds is approximately 10.

Figure 2

The Claisen Condensation (Again)

Figure 2

Under the reaction conditions the ethyl acetoacetate is deprotonated by the sodium ethoxide present in the mixture. The equilibrium constant for this acid-base reaction is approximately 106. In other words, the concentration of sodioacetoacetic ester is high. Addition of methyl iodide to the reaction mixture results in methylation of the enolate ion as shown in Equation 3.

Equation 3

The ester fragment of the product of reaction 3 is shown in blue to emphasize the idea that if we could replace that fragment with a hydrogen atom, we would have 2-butanone, the same product that was formed by direct methylation of acetone. Such a transformation is possible. It involves a 2-step, 1-pot reaction. The first step is the saponification of the ester. This results in the formation of the conjugate base of a β-ketocarboxylic acid. Acidification of the reaction mixture, followed by heating, results in the decarboxylation of the β-keto acid and the formation of the corresponding ketone. These steps are outlined in Figure 3.

Figure 3

It's a Gas

Figure 3

Figure 4 compares the outcomes of the direct alkylation of acetone with the indirect alkylation-saponification-decarboxylation sequence. Because the latter approach yields the desired target molecule, ethyl acetoacetate is considered to be the synthetic equivalent of acetone. Such a reagent is called a synthon. We'll see another example of a synthon when we discuss the malonic ester synthesis at the end of this topic.

Figure 4

There's More Than One Way to Skin a Cat

Figure 4A

The decarboxylation of β-keto acids is a general phenomenon. It occurs readily because the carboxylic acid proton is transferred to the oxygen atom of the β-keto group intramolecularly. The transition state for the transfer is shown in Figure 5. Note the similarity to a chair conformation of cyclohexane.

Figure 5


Figure 4

The immediate product of this decarboxylation is an enol which rapidly tautomerizes to the isomeric ketone, i.e. 2-butanone.

Exercise 3 Draw the structure of the enol that would be formed from the transition state shown in Figure 4.


Exercise 4 Identify all those compounds from structures A-H that are β-ketoesters by entering the appropriate letters into the text box. Note-An incorrect answer many mean that you have selected a compound that is not a β-ketoester or that you have not entered a letter for every β-ketoester there is in compounds A-H. (Yes, you've seen this exercise before.)

Exercise 4

Exercise 5 Draw the structure of the major product that you would expect to be formed in each of the following reactions.







Retrosynthetic Analysis

To a synthetic organic chemist who is planning the synthesis of a target molecule, the presence of a β-ketoester fragment within that target should suggest the use of a Claisen condensation at some point during the synthesis. Retrosynthetic analysis of the target will then reveal the structure of the appropriate starting ester. Figure 6 demonstrates this retrosynthetic approach for a generic β-ketoester.

Figure 6

Taking Another Step Backwards

Claisen Retro

There are three points worth remembering about the retrosynthesis animated in Figure 6:

  1. R, R', and R'' may be the same or they may be different.
  2. While R and R' may be H, R'' may not.
  3. When R and R' are not the same, the condensation is called a crossed Claisen condensation.

The alkylation-decarboxylation sequence outlined in Figure 3 has a direct parallel in a related synthetic scheme called the malonic ester synthesis. We'll conclude this topic with a comparison of the malonic ester and the acetoacetic ester syntheses.

The Malonic Ester Synthesis

Malonic ester, sometimes called diethyl malonate, is the diethyl ester of malonic acid. The structures of these two compounds are shown in Figure 7. Notice the structural similarities between malonic ester and acetoacetic ester. The similarity of their chemical reactivity stems from their structural relationship.

Figure 7

Meet the Malonates

Malonic Ester

Malonic ester is a common starting material for the synthesis of carboxylic acids. Figure 8 describes a typical sequence.

Figure 8

A Malonic Ester Synthesis

Figure 8

Exercise 6 The following scheme is not a viable method for preparing propanoic acid because it will not yield significant amounts of ethyl propanoate. Why not? What alternative reactions are more likely?

Exercise 8

Draw the structure of the most likely product in the first step of this 2-step sequence.


Exercise 7 How could you convert ethyl acetate directly into ethyl propanoate? Write an equation describing the reaction you would perform.

Exercise 8 The transformation shown in Exercise 8 requires certain precautions if it is to be executed successfully. One complicating factor is that the ethyl propanoate is subject to further alkylation by methyl iodide:

Exercise 10

If you want to minimize the chances of di- and tri-methylation, which of the following approaches would you take?

Slowly add a solution of CH3I in EtOH to a mixture of ethyl acetate and NaOEt in EtOH.

Slowly add a mixture of ethyl acetate and NaOEt in EtOH to a solution of CH3I in EtOH.

Slowly add a solution of ethyl acetate in EtOH to a solution of CH3I and NaOEt in EtOH.

Malonic ester is a synthon of ethyl acetate. There is a close parallel between the malonic ester/ethyl acetate synthon pair and the acteoacetic ester/acetone synthon pair. Malonic ester is used to make substituted acetic acids, while acetoacetic ester is used to prepare derivatives of acetone.

Exercise 9 Each of the following carboxylic acids might be prepared from malonic ester using a 1o alkyl iodide as the alkylating agent. For each reaction Draw the structure of the alkyl iodide required. Hint-One way to think about these problems is to name the products as derivatives of acetic acid. For example, if you think of CH3CH2CO2H as methyl acetic acid, then it should become clear that you need methyl iodide as your alkylating agent.



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