Condensation Reactions of Esters

Introduction

In our discussion of the aldol reaction we saw that competing reactions occur when aldehydes and ketones are treated with hydroxide ion. One the one hand, the hydroxide ion may add to the carbonyl carbon in a nucleophilic addition reaction, while on the other it may abstract an a-hydrogen. As the color coding in Figure 1 indicates that duality of reaction pathways stems from the fact that both the carbonyl carbon and the a-hydrogen of the aldehyde or ketone are electrophilic. For purposes of the following discussion it is important to note that addition of hydroxide ion to the carbonyl carbon generates a tetrahedral intermediate labeled T-1 in Figure 1.

Figure 1

Alternative Reaction Pathways for Aldehydes and Ketones

Aldehydes and Ketones vs. Esters

Esters are structurally related to aldehydes and ketones: all three classes of compounds contain a carbonyl group. It shouldn't be surprising then that esters display similar reactivity patterns to aldehydes and ketones. As we shall see, they also display some interesting and significant differences. Figure 2 presents an analogous scheme to that shown in Figure 1 for the reaction of simple esters with hydroxide ion. Nucleophilic addition of hydroxide to the carbonyl carbon generates a tetrahedral intermediate T-2.

Figure 2

Alternative Reaction Pathways for Esters

One of the most favorable pathways available to these tetrahedral intermediates involves regeneration of the carbonyl group. This is favorable because the carbonyl group is an especially stable entity. Figure 3 compares the alternative ways in which the tetrahedral intermediates T-1 and T-2 might regenerate the carbonyl group.

Figure 3

Alternative Fates of Tetrahedral Intermediates

In the case of aldehydes and ketones, regeneration of the carbonyl group is a reasonable alternative only when it results in expulsion of hydroxide ion from T-1. As we have seen, regeneration of the starting material by this path allows for the less likely alternative, abstraction of an a-hydrogen and the formation of aldol condensation products which follow that event.

Figure 4

Additional Equilibria

The equilibrium constant for expulsion of alkoxide ion from T-2 is approximately 1. Note that the product of this pathway is a carboxylic acid. Since this acid is formed in a strongly basic solution, it will be deprotonated rapidly. Given that the pK_a of a carboxylic acid is about 5, the equilibrium constant for its deprotonation is approximately 10¹¹. In other words, while the expulsion of hydroxide ion from T-2 (Figure 3) is about as likely as expulsion of alkoxide ion, the latter pathway is greatly preferred because a subsequent reaction has a much larger equilibrium constant. Consequently, treatment of an ester with aqueous sodium hydroxide results in the formation of the conjugate base of a carboxylic acid. More information is available.

Summary

In our discussion of the reactions of aldehydes and ketones with hydroxide ion, we saw that addition to the carbonyl carbon was more probable than abstraction of an a-hydrogen, but that the latter pathway was the one followed because the addition reaction was non-productive. In the case of structurally similar esters, i.e. esters containing at least one a-hydrogen, the more probable reaction is a productive reaction. It produces carboxylic acids. The process is called saponification.

Saponification of Esters

The formation of carboxylic acids by treatment of esters with sodium hydroxide is known as saponification. Equation 1 summarizes the net transformation for the saponification of methyl salicylate, a fragrant component in oil of wintergreen.

The general procedure involves refluxing the ester in 6M NaOH until the mixture becomes homogeneous, indicating complete formation of the water-soluble carboxylate salt, RCO₂^-. Acidification of the mixture during the work-up produces the carboxylic acid.

Equation 2 provides another example of saponification of an even simpler ester, ethyl acetate.

Exercise 3 Saturated fats are esters that may be represented by the general formula . Typically the values of x, y, and z range from 8-20. Saponifaction of fats produces glycerol (1,2,3-propanetriol) and three molecules of sodium carboxylates. The mixture of these compounds is used as soap. Acidification of the saponification mixture produces fatty acids. Draw the structures of glycerol and the three fatty acids that would be formed when x=8, y=10, and z=12.

Exercise 4 Saponification of esters is a specific example of a more general reaction type called nucleophilic acyl substitution. It is typical of derivatives of carboxylic acids- esters, acyl halides, amides, and anhydrides- and may be summarized in general terms by the following scheme:

Write equations for nucleophilic acyl substitution reactions where X = OH, and G = OCH₃, Cl, N(CH₃)₂, and OC(=O)CH₃. Estimate the equilibrium constant for each reaction. Hint- You need to know the pK_a values of the conjugate acids of each G group.

Exercise 5 Predict the relative reactivities of esters, acyl halides, amides, and anhydrides in nucleophilic acyl substitution reactions.

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NaOH vs NaOCH₂CH₃

Suppose that you were to treat ethyl acetate with sodium ethoxide rather than sodium hydroxide. What would happen? The answer; the Claisen condensation.

Exercise 7 Following the example given in Figure 3, draw the structures of the species that would be formed from T-3 upon regeneration of the carbonyl group by paths A3-1, A3-2, and A3-3.

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