Carbonyl Condensation Reactions

The following reaction involves a conjugate addition reaction followed by an intramolecular Claisen condensation. Write both steps, and show their mechanisms.

The following reaction involves an intramolecular aldol reaction followed by a retro aldol-like reaction. Write both steps, and show their mechanisms.

Propose a mechanism for the following base-catalyzed isomerization:

The Mannich reaction of a ketone, an amine, and an aldehyde is one of the few three-component reactions in organic chemistry. Cyclohexanone, for example, reacts with dimethylamine and acetaldehyde to yield an amino ketone. The reaction takes place in two steps, both of which are typical carbonyl-group reactions.

(a) The first step is reaction between the aldehyde and the amine to yield an intermediate iminium ion $\left(R_{2}C=N{R_2}^{+}\right)$ plus water. Propose a mechanism, and show the structure of the intermediate iminium ion.

(b) The second step is reaction between the iminium ion intermediate and the ketone to yield the final product. Propose a mechanism.

Propose a mechanism to account for the following reaction of an enamine with an alkyl halide:

Which of the following compounds would you expect to undergo aldol self-condensation? Show the product of each successful reaction.

(a) Trimethyl acetaldehyde                                

(b) Cyclobutanone

(c) Benzophenone (diphenyl ketone)                  

(d) 3-Pentanone 

(e) Decanal                                                           

(f) 3-Phenyl-2-propenal

How might you synthesize each of the following compounds using an aldol reaction? Show the structure of the starting aldehyde(s) or ketone(s) you would use in each case.

What product would you expect to obtain from aldol cyclization of hexanedial, $OHCC{H}_{2}C{H}_{2}C{H}_{2}C{H}_{2}CHO$

Intramolecular aldol cyclization of 2,5-heptanedione with aqueous NaOH yields a mixture of two enone products in the approximate ratio 9;1. Write their structures, and show how each is formed.

The major product formed by intramolecular aldol cyclization of 2,5-heptanedione (Problem 23-51) has two singlet absorptions in the 1H NMR spectrum, at 1.65 d and 1.90 d, and has no absorptions in the range 3 to 10 d. What is its structure?

Treatment of the minor product formed in the intramolecular aldol cyclization of 2,5-heptanedione (Problems 23-51 and 23-52) with aqueous NaOH converts it into the major product. Propose a mechanism to account for this base-catalyzed isomerization.

The aldol reaction is catalyzed by acid as well as the base. What is the reactive nucleophile in the acid-catalyzed aldol reaction? Propose a mechanism.

Cinnamaldehyde, the aromatic constituent of cinnamon oil, can be synthesized by mixed aldol condensation. Show the starting materials you would use, and write the reaction.

The bicyclic ketone shown below does not undergo aldol self-condensation even though it has two hydrogen atoms. Explain.

In the mixed Claisen reaction of cyclopentanone with ethyl format, a much higher yield of the desired product is obtained by first mixing the two carbonyl components and then adding a base, rather than by first mixing base with cyclopentanone and then adding ethyl format. Explain.

Ethyl dimethyl acetoacetate reacts instantly at room temperature when treated with ethoxide ion to yield two products, ethyl acetate, and ethyl 2-methyl propanoate. Propose a mechanism for this cleavage reaction.

In contrast to the rapid reaction shown in Problem 23-60, ethyl acetoacetate requires a temperature over 150 °C to undergo the same kind of cleavage reaction. How can you explain the difference in reactivity?

How might the following compounds be prepared using Michael reactions? Show the nucleophilic donor and the electrophilic acceptor in each case.

The so-called Wieland–Miescher ketone is a valuable starting material used in the synthesis of steroid hormones. How might you prepare it from 1,3-cyclohexanedione?

The Stork enamine reaction and the intramolecular aldol reaction can be carried out in sequence to allow the synthesis of cyclohexanones. For example, the reaction of the pyrrolidine enamine of cyclohexanone with 3-buten-2-one, followed by enamine hydrolysis and base treatment, yields the product indicated. Write each step, and show the mechanism of each.

How could you prepare the following cyclohexanones by combining a Stork enamine reaction with an intramolecular aldol condensation? (See Problem 23-64.)

The following reaction involves two successive intramolecular Michael reactions. Write both steps, and show their mechanisms.

What condensation products would you expect to obtain by treatment of the following substances with sodium ethoxide in ethanol?

(a) Ethyl butanoate 

(b) Cycloheptanone

(c) 3,7-Nonanedione 

(d) 3-Phenylpropanal

The following reactions are unlikely to provide the indicated product in high yield. What is wrong with each?

Fill in the missing reagents a–h in the following scheme:

How would you prepare the following compounds from cyclohexanone?

The compound known as Hagemann’s ester is prepared by treatment of a mixture of formaldehyde and ethyl acetoacetate with base, followed by acid-catalyzed decarboxylation.

(a) The first step is an aldol-like condensation between ethyl acetoacetate and formaldehyde to yield an α,β-unsaturated product. Write the reaction, and show the structure of the product.

(b) The second step is a Michael reaction between ethyl acetoacetate and the unsaturated product of the first step. Show the structure of the product.

The third and fourth steps in the synthesis of Hagemann’s ester from ethyl acetoacetate and formaldehyde (Problem 23-71) are an intramolecular aldol cyclization to yield a substituted cyclohexenone, and a decarboxylation reaction. Write both reactions, and show the products of each step.

When 2-methyl cyclohexanone is converted into an enamine, only one product is formed despite the fact that the starting ketone is unsymmetrical. Build molecular models of the two possible products and explain the fact that the sole product is the one with the double bond opposite the methyl-substituted carbon.