Carbonyl Alpha-Substitution Reactions

Draw structures for all monoenol forms of the following molecule. Which would you expect to be the most stable? Explain.

Question: Identify the most acidic Hydrogens in each of the following molecules:

(a) CH₃CH₂CHO

(b) (CH₃)₃CCOCH₃

(c) CH₃CO₂H

(d) Benzamide

(e) CH₃CH₂CH₂CN 

(f) CH₃CON(CH₃)₂

Why do you suppose ketone halogenations in acidic media are referred to as being acid-catalyzed, whereas halogenations in basic media are base-promoted? In other words, why is a full equivalent of base required for halogenation?

How could you use a malonic ester synthesis to prepare the following compound?

Question: How would you prepare the following compound using an acetoacetic ester synthesis?

Show how you might prepare the following compounds using an alkylation reaction as the key step:

Show the steps in preparing each of the following substances using either a malonic ester synthesis or an acetoacetic ester synthesis:

Unlike most β-diketones, the following β-diketone has no detectable enol content and is about as acidic as acetone. Explain.

For each reaction below, give the corresponding keto/enol tautomer and provide the complete mechanism.

Predict the product(s) and provide the mechanism for each reaction below.

Predict the product(s) and provide the mechanism for each reaction below.

The two optically beta-keto acids below were decarboxylated using the conditions typically used for the acetoacetate synthesis. Will the ketone products also be optically active? Provide the complete mechanism to explain your answer.

In the Hell–Volhard–Zelinskii reaction, only a catalytic amount of PBr₃ is necessary because of the equilibrium below. Review the mechanism for the reaction of a carboxylic acid with thionyl chloride and propose a mechanism for the equilibrium.

When a ketone is treated with acid and a halogen, the a-monohalogenated product can be obtained in high yield. However, under basic conditions it is extremely difficult to isolate the mono halogenated product. Provide an explanation for this reactivity.

Draw structures for the enol tautomers of the following compounds: 

(a) Cyclopentanone 

(b) Methyl thioacetate 

(c) Ethyl acetate 

(d) Propanal 

(e) Acetic acid 

(f) Phenylacetone

How many acidic Hydrogens does each of the molecules listed in Problem 22-1 have? Identify them.

Write the complete mechanism for the deuteration of acetone on treatment with D₃O⁺.

Show how you might prepare 1-penten-3-one from 3-pentanone.

If methanol rather than water is added at the end of a Hell–Volhard–Zelinskii reaction, an ester rather than an acid is produced. Show how you would carry out the following transformation, and propose a mechanism for the ester forming step.

Draw a resonance structure of the acetonitrile anion, 

 and account for the acidity of nitriles. 

Ketones react slowly with benzene selenenyl chloride in the presence of HCl to yield a-phenyl seleno ketones. Propose a mechanism for this acid-catalyzed a-substitution reaction.

The key step in a reported laboratory synthesis of sativene, a hydrocarbon isolated from the mold Helminthosporium sativum, involves the following base treatment of a keto tosylate. 

What kind of reaction is occurring? How would you complete the synthesis?

Sodium pentothal is a short-acting barbiturate derivative used as a general anesthetic and known as a truth serum in popular culture. It is synthesized like other barbiturates (see the Something Extra at the end of this chapter), using thiourea, (H₂N)₂C=S, in place of urea. How would you synthesize sodium pentothal?

Using curved arrows, propose a mechanism for the following reaction, one of the steps in the metabolism of the amino acid alanine.

Using curved arrows, propose a mechanism for the following reaction, one of the steps in the biosynthesis of the amino acid tyrosine.

Treatment of a cyclic ketone with diazomethane is a method for accomplishing a ring-expansion reaction. For example, treatment of cyclohexanone with diazomethane yields cycloheptanone. Propose a mechanism.

The final step in attempting to synthesize Laurene, a hydrocarbon isolated from the marine alga Laurencia glandulifera, involved the Wittig reaction shown. The product obtained, however, was not Laurene but an isomer. Propose a mechanism to account for these unexpected results.

Amino acids can also be prepared by a two-step sequence that involves Hell–Volhard–Zelinskii reaction of a carboxylic acid followed by treatment with ammonia. Show how you would prepare leucine, (CH₃)₂CHCH₂CH(NH₂)CO₂H, and identify the mechanism of the second step.

Heating carvone with aqueous sulfuric acid converts it into carvacrol. Propose a mechanism for the isomerization.

Rank the following compounds in order of increasing acidity:

Write resonance structures for the following anions:

Predict the product(s) of the following reactions:

Which, if any, of the following compounds can be prepared by a malonic ester synthesis? Show the alkyl halide you would use in each case.

(a) Ethyl pentanoate                                  (b) Ethyl 3-methylbutanoate

(c) Ethyl 2-methylbutanoate        (d) Ethyl 2,2-dimethylpropanoate

Which, if any, of the following compounds can be prepared by an acetoacetic ester synthesis? Explain.

How would you prepare the following ketones using an acetoacetic ester synthesis?

How would you prepare the following compounds using either an Acetoacetic ester synthesis or a malonic ester synthesis?

Which of the following substances would undergo the haloform reaction?

(a) CH₃COCH₃        (b) Acetophenone  (c) CH₃CH₂CHO

(d) CH₃CO₂H           (e) ${\mathbf{CH}}_{\mathbf{3}}\mathbf{C}\mathbf{\equiv }\mathbf{N}$

How might you convert geraniol into either ethyl geranylacetate or geranylacetone?

One way to determine the number of acidic hydrogens in a molecule is to treat the compound with NaOD in D₂O, isolate the product, and determine its molecular weight by mass spectrometry. For example, if cyclohexanone is treated with NaOD in D₂O, the product has MW =102. Explain how this method works.

When optically active (R)-2-methylcyclohexanone is treated with either aqueous base or acid, racemization occurs. Explain.

Would you expect optically active (S)-3-methylcyclohexanone to be racemized on acid or base treatment in the same way as 2-methylcyclohexanone (Problem 22-51)? Explain.

When an optically active carboxylic acid such as (R)-2-phenylpropanoic acid is brominated under Hell–Volhard–Zelinskii conditions, is the product optically active or racemic? Explain.

Fill in the reagents a–c that are missing from the following scheme:

Although 2-substituted 2-cyclopentenones are in a base-catalyzed equilibrium with their 5-substituted 2-cyclopentenone isomers (Problem 22-55), the analogous isomerization is not observed for 2-substituted 2-cyclohexenones. Explain.

Although 2-substituted 2-cyclopentenones are in a base-catalyzed equilibrium with their 5-substituted 2-cyclopentenone isomers (Problem 22-55), the analogous isomerization is not observed for 2-substituted 2-cyclohexenones. Explain.

All attempts to isolate primary and secondary nitroso compounds result solely in the formation of oximes. Tertiary nitroso compounds, however, are stable. Explain.

How would you synthesize the following compounds from cyclohexanone?

More than one step may be required.

The two isomers cis- and trans-4-tert-butyl-2-methylcyclohexanone are interconverted by base treatment. Which isomer do you think is more stable, and why?