At the end of our comparison of the reactions of aldehydes and ketones and esters with hydroxide ion, we posed the question "Suppose that you were to treat ethyl acetate with sodium ethoxide rather than sodium hydroxide. What would happen?"
Two alternatives are likely: 1. The ethoxide ion will abstract a proton from the methyl carbon a to the carbonyl group forming an enolate ion. 2. The ethoxide ion will add to the carbonyl carbon to form a tetrahedral intermediate. The latter possibility is more likely. As can be seen in Figure 1, this intemediate contains two identical ethoxy groups. Consequently, reformation of the carbonyl group has to regenerate the starting ester. As in the case of the aldol reaction, the more likely reaction is a non-productive one. And for the same reason a less likely alternative, abstraction of an a-hydrogen, becomes the productive reaction.
Alternative Paths for the Reaction of Ethyl Acetate with Sodium Ethoxide
Again, as in the case of the aldol condensation, abstraction of an a-hydrogen produces a low concentration of a highly reactive enolate ion. What happens when this highly reactive nucleophilic species finds itself surrounded by ethyl acetate molecules that have not been deprotonated? It reacts.
The Claisen Condensation
The nucleophilic carbon of the enolate ion adds to the electrophilic carbon of a molecule of ethyl acetate that has not been deprotonated. A carbon-carbon bond is formed. The reaction produces yet another tetrahedral intemediate as shown in Equation 1.
Since the newly formed tetrahedral center has an electronegative atom attached to it, reformation of the carbonyl group, as shown in Equation 2, is a reasonable process.
Exercise 1 What is the approximate equilibrium constant for reaction 2? Keq =
This step results in the formation of a b-ketoester, which in this case is called ethyl acetoacetate. In the same way that b-hydroxyaldehydes and b-hydroxyketones are signature structures of the aldol reaction, b-ketoesters suggest the Claisen condensation.
A complete description of the mechanism of the Claisen condensation is, in fact, a bit more complicated than indicated in Equations 1 and 2, so, if you'd like to know more...
Exercise 2 Draw the structure of the major product you would expect to be formed in each of the following situations:
Exercise 3 The best answer for some of the reactions in Exercise 2 is No Reaction. Enter the number of any equation for which No Reaction is the best answer.
Exercise 4 Select the structures that are b-ketoesters:
To a synthetic organic chemist who is planning the synthesis of a target molecule, the presence of a b-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 2 demonstrates this retrosynthetic approach for a generic b-ketoester.
Taking Another Step Backwards
There are three points worth remembering about the retrosynthesis animated in Figure 2. First, R, R', and R'' may be the same or they may be different. Second, while R and R' may be H, R'' may not. Third, when R and R' are not the same, the condensation is called a crossed Claisen condensation.
Exercise 5 Each of the following compounds was prepared by a Claisen condensation. In each case, select the structure of the starting material from the list of choices in the box below. Enter the appropriate letter into the text field.
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Exercise 6 Each of the following compounds may be prepared by a crossed Claisen condensation involving two of the esters A-H above. Enter the letters of the reactants in the appropriate text field. Enter the letter of the nucleophilic component first, followed by that of the electrophilic component. Note-There are 3 acceptable combinations for the first target.
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An intramolecular version of the Claisen condensation is known as the Dieckmann condensation. Equation 3 shows how this reaction was put to good use as part of the total synthesis of the prostaglandin PGA2.
Equation 4 offers another example of the Dieckmann condensation that was involved in the synthesis of tropinone, a degradation product that was produced during the determination of the structure of the physiologically active alkaloid atropine.
An early synthesis of cholesterol involved the "mixed Claisen reaction" shown if Equation 5.
Exercise 7 Devise a mechanism to show how the product of reaction 5 was formed. Use curved arrows to indicate the movement of electrons. Your mechanism must account for the role of the base. It should show any tetrahedral intermediates that are formed.