In Solved 22-9, the target molecule was synthesized using

Predict the major products of the following reactions. 1. \(\frac{(1) L D A}{(2) C H_{2}=C H C H_{2} B r}\) 2. \(\frac{(1) L D A}{(2) C H_{3} C H_{2} I}\) 3. \(\frac{(1) L D A}{(2) C H_{3} I}\) Equation transcription: Text transcription: frac{(1) L D A}{(2) C H{2}=C H C H_{2} B r} frac{(1) L D A}{(2) C H{3} C H{2} I} frac{(1) L D A}{(2) C H{3} I}

A student intends to carry out the following synthesis: \(\frac{(1) b a s e}{(2) P h C H_{2} B r}\) \(\mathrm{CH}_{2} \mathrm{Ph}\) He adds sodium ethoxide to cyclohexanone (in ethanol solution) to make the enolate ion; then he adds benzyl bromide to alkylate the enolate ion, and heats the solution for half an hour to drive the reaction to completion. (a) Predict the products of this reaction sequence. (b) Suggest how this student might synthesize the correct product. Equation transcription: Text transcription: \frac{(1) b a s e}{(2) P h C H_{2} B r} \mathrm{CH}_{2} \mathrm{Ph}

Problem 2P (a) Show each step in the mechanism of the acid-catalyzed interconversion of (R)- and (S)-3-methylpentan-2-one. (b) When cis-2,4-dimethylcyclohexanone is dissolved in aqueous ethanol containing a trace of NaOH, a mixture of cis and trans isomers results. Propose a mechanism for this isomerization.

Show reaction sequences (not detailed mechanisms) that explain these transformations: 1. \(\mathrm{CH}_{2} \mathrm{O}+2\) \(\frac{(1) \mathrm{NaOEt}}{(2) \mathrm{H}^{+}}\) \(\mathrm{COOH}\) 2. \(\mathrm{CH}_{2}(\mathrm{COOEt})_{2}) \(\frac{\mathrm{NaOEt}}{\mathrm{H}_{3} \mathrm{O}^{+}}\) Equation transcription: Text transcription: {CH}{2}{O}+2 frac{(1){NaOEt}}{(2){H}^{+}} {COOH} {CH}{2}({COOEt}){2} frac{{NaOEt}}{{H}{3}{O}^{+}}

Problem 6P Propose a mechanism for the acid-catalyzed reaction of cyclohexanone with pyrrolidine.

Problem 8P Give the expected products of the following acid-catalyzed reactions. (a) acetophenone + methylamine (b) acetophenone + dimethylamine (c) cyclohexanone + aniline (d) cyclohexanone + piperidine

Problem 7P Without looking back, propose a mechanism for the hydrolysis of this iminium salt to the alkylated ketone. The first step is attack by water, followed by loss of a proton to give a carbinolamine. Protonation on nitrogen allows pyrrolidine to leave, giving the protonated ketone.

Show how you would accomplish each conversion using an enamine synthesis with pyrrolidine as the secondary amine. (a) cyclopentanone -allylcyclopentanone (b) pentan-3-one -methyl-1-phenylpentan-3-one \(P h-C-C H_{2}-C-P h\) Equation transcription: Text transcription: P h-C-C H{2}-C-P h

Problem 11P Propose a mechanism to show how acetophenone undergoes base-promoted chlorination to give trichloroacetophenone.

Problem 14P Which compounds will give positive iodoform tests? (a) 1-phenylethanol (b) pentan-2-one (c) pentan-2-ol (d) pentan-3-one (e) acetone (f) isopropyl alcohol

Problem 12P Propose a mechanism for the reaction of cyclohexyl methyl ketone with excess bromine in the presence of sodium hydroxide.

Problem 15P Propose a mechanism for the acid-catalyzed bromination of pentan-3-one.

Problem 17P Show the products of the reactions of these carboxylic acids with PBr3/Br2 before and after hydrolysis. (a) pentanoic acid (b) phenylacetic acid (c) succinic acid (d) oxalic acid

Problem 18P Propose a mechanism for the aldol condensation of cyclohexanone. Do you expect the equilibrium to favor the reactant or the product?

Acid-catalyzed halogenation is synthetically useful for converting ketones to \(\alpha, \beta\)-unsaturated ketones, which are useful in Michael reactions (Section 22-18). Propose a method for converting cyclohexanone to cyclohex-2-en-1-one, an important synthetic starting material. Equation transcription: Text transcription: alpha, beta

Problem 19P Give the expected products for the aldol condensations of (a) propanal (b) phenylacetaldehyde (c) pentan-3-one

Problem 21P Propose a complete mechanism for the acid-catalyzed aldol condensation of acetone.

Problem 20P A student wanted to dry some diacetone alcohol and allowed it to stand over anhydrous potassium carbonate for a week. At the end of the week, the sample was found to contain nearly pure acetone. Propose a mechanism for the reaction that took place.

Problem 22P Propose a mechanism for the dehydration of diacetone alcohol to mesityl oxide (a) in acid (b) in base

Problem 26P When acetone is treated with excess benzaldehyde in the presence of base, the crossed condensation adds two equivalents of benzaldehyde and expels two equivalents of water. Propose a structure for the condensation product of acetone with two molecules of benzaldehyde.

Problem 23P When propionaldehyde is warmed with sodium hydroxide, one of the products is 2-methylpent- 2-enal. Propose a mechanism for this reaction.

Problem 24P Predict the products of aldol condensation, followed by dehydration, of the following ketones and aldehydes. (a) butyraldehyde (b) acetophenone (c) cyclohexanone

Problem 25P Propose mechanisms for the following base-catalyzed condensations, with dehydration. (a) 2,2-dimethylpropanal with acetaldehyde (b) benzaldehyde with propionaldehyde

Problem 28P Predict the major products of the following base-catalyzed aldol condensations with dehydration. (a) benzophenone (PhCOPh) + propionaldehyde (b) 2,2-dimethylpropanal + acetophenone

Problem 27P In the problem-solving feature above, methylcyclohexanone was seen to react at its unsubstituted ? carbon. Try to write a mechanism for the same reaction at the methyl-substituted carbon atom, and explain why this regiochemistry is not observed.

Cinnamaldehyde is used as a flavoring agent in cinnamon candies. Show how cinnamaldehyde is synthesized by a crossed aldol condensation followed by dehydration.

Problem 30P Show how octane-2,7-dione might cyclize to a cycloheptenone. Explain why ring closure to the cycloheptenone is not favored.

Problem 31P When cyclodecane-1,6-dione is treated with sodium carbonate, the product gives a UV spectrum similar to that of 1-acetyl-2-methylcyclopentene. Propose a structure for the product, and give a mechanism for its formation.

The following compound results from base-catalyzed aldol cyclization of a 2-substituted cyclohexanone. (a) Show the diketone that would cyclize to give this product. (b) Propose a mechanism for the cyclization.

Problem 35P Esters with only one ? hydrogen generally give poor yields in the Claisen condensation. Propose a mechanism for the Claisen condensation of ethyl isobutyrate, and explain why a poor yield is obtained.

Problem 34P Ethoxide is used as the base in the condensation of ethyl acetate to avoid some unwanted side reactions. Show what side reactions would occur if the following bases were used. (a) sodium methoxide (b) sodium hydroxide

Show how each compound can be dissected into reagents joined by an aldol condensation, then decide whether the necessary aldol condensation is feasible.

Predict the products of self-condensation of the following esters. (a) methyl propanoate + \(\mathrm{NaOCH}_{2}\) (b) ethyl phenylacetate + \(\mathrm{NaOCH}_{2} \mathrm{CH}_{2}\) Equation transcription: Text transcription: {NaOCH}{2} {NaOCH}{2}{CH}{2}

Problem 37P Propose a mechanism for the self-condensation of methyl 3-phenylpropionate catalyzed by sodium methoxide.

Show what esters would undergo Claisen condensation to give the following esters.

Problem 39P Propose mechanisms for the two Dieckmann condensations just shown.

Some (but not all) of the following keto esters can be formed by Dieckmann condensations. Determine which ones are possible, and draw the starting diesters.

Problem 41P Propose a mechanism for the crossed Claisen condensation between ethyl acetate and ethyl benzoate.

Show how Claisen condensations could be used to make the following compounds.

Problem 47P Show how the following compounds can be made using the malonic ester synthesis. (a) 3-phenylpropanoic acid (b) 2-methylpropanoic acid (c) 4-phenylbutanoic acid (d) cyclopentanecarboxylic acid

Problem 46P Show the resonance forms for the enolate ions that result when the following compounds are treated with a strong base. (a) ethyl acetoacetate (b) pentane-2,4-dione (c) ethyl ?-cyanoacetate (d) nitroacetone

Show how crossed Claisen condensations could be used to prepare the following esters.

Predict the major products of the following crossed Claisen condensations.

Predict the products from crossed Claisen condensation of the following pairs of esters. Indicate which combinations are poor choices for crossed Claisen condensations.

(a) Explain why the following substituted acetic acid cannot be formed by the malonic ester synthesis. (b) Sections 22-2B and 22-3 showed the use of lithium diisopropylamide (LDA) to depro- tonate a ketone quantitatively. Draw the acid-base reaction between LDA and the following ester, and use estimated \(p K_{a}\) values to decide whether the reaction favors the reactants or products at equilibrium. (c) Show how you might use a modern alternative to the malonic ester synthesis to make the acid shown in part (a). You may use the ester shown in part (b) as your starting material. Equation transcription: Text transcription: p K{a}

Show how the following ketones might be synthesized by using the acetoacetic ester synthesis. 1. \(\mathrm{PhCH}_{2} \mathrm{CH}_{2}-\mathrm{C}-\mathrm{CH}_{3}\) 2. \(H_{2} C=C H C H_{2} C H-C C H_{3}\) Equation transcription: Text transcription: {PhCH}{2}{CH}{2}-{C}-{CH}{3} H{2} C=C H C H{2} C H-C C H{3}

Show the ketones that would result from hydrolysis and decarboxylation of the following \(\beta\)-keto esters. Equation transcription: Text transcription: beta

(a) Although the following compound is a substituted acetone derivative, it cannot be made by the acetoacetic ester synthesis. Explain why (two reasons). (b) The use of LDA to make enolate ions (Sections 22-2B and 22-3) has provided alterna- tives to the acetoacetic ester synthesis. Show how you might make the compound shown in part (a), beginning with 1,3-diphenylacetone. (c) Enamine reactions (Section 22-4) occur under relatively mild conditions, and they often give excellent yields of compounds like the one shown in part (a). Show how you might use an enamine reaction for this synthesis, beginning with 1,3-diphenylacetone.

Problem 54P Show how an acetoacetic ester synthesis might be used to form a ?- diketone such as heptane- 2,6-dione.

Show how cyclohexanone might be converted to the following \(\delta\)-diketone (Hint: Stork). Equation transcription: Text transcription: delta

In Solved Problem 22-9, the target molecule was synthesized using a Michael addition to form the bond that is \(\beta, \gamma\) to the upper carbonyl group. Another approach is to use a Michael addition to form the bond that is \(\beta, \gamma\) to the other (lower) carbonyl group. Show how you would accomplish this alternative synthesis. Equation transcription: Text transcription: beta, gamma

Propose a mechanism for the conjugate addition of a nucleophile (Nuc: __) to acrylonitrile \(\left(H_{2} C=C H C N\right)\) and nitroethylene. Use resonance forms to show how the cyano and nitro groups activate the double bond toward conjugate addition. Equation transcription: Text transcription: (H{2} C=C H C N)

Show how you would use Robinson annulations to synthesize the following compounds. Work backward, remembering that the cyclohexenone is the new ring and that the double bond of the cyclohexenone is formed by the aldol with dehydration. Take apart the double bond, then see what structures the Michael donor and acceptor must have. \(\mathrm{CH}_{3}\) Equation transcription: Text transcription: {CH}{3}

Propose a mechanism for the following reaction. \(H_{2} C=C H\) \(\mathrm{CH}_{2} \mathrm{CH}_{2}\) \(\mathrm{CH}_{3}\) Equation transcription: Text transcription: H{2} C=C H {CH}{2}{CH}{2} {CH}{3}

Show how the following products might be synthesized from suitable Michael donors and Acceptors.

For each molecule shown below, 1. indicate the most acidic hydrogens. 2. draw the important resonance contributors of the anion that results from removal of the most acidic hydrogen.

The base-catalyzed reaction of an aldehyde (having no hydrogens) with an anhydride is called the Perkin condensation. Propose a mechanism for the following example of the Perkin condensation. (Sodium acetate serves as the base.)

1. Rank the following compounds in order of increasing acidity. 2. Indicate which compounds would be more than 99% deprotonated by a solution of sodium ethoxide in ethanol. \(\mathrm{OCH}_{3}\) \(\mathrm{COOH}\) \(O H\) Equation transcription: Text transcription: {OCH}_{3} {COOH} O H

Predict the products of the following aldol condensations. Show the products both before and after dehydration.

Predict the products of the following Claisen condensations.

Show how you would use the Robinson annulation to synthesize the following compounds. \(H_{3} C\) \(P h\) \(\mathrm{CH}_{3}\) Equation transcription: Text transcription: H{3} C P h {CH}{3}

Propose mechanisms for the reactions shown in Problems 22-62 parts (a) and (b) and 22-63 parts (a) and (b).

Pentane-2,4-dione (acetylacetone) exists as a tautomeric mixture of 8% keto and 92% enol forms. Draw the stable enol tautomer, and explain its unusual stability. \(\mathrm{CH}_{3}-\mathrm{C}-\mathrm{CH}_{2}-\mathrm{C}-\mathrm{CH}_{3}\) Equation transcription: Text transcription: {CH}{3}-{C}-{CH}{2}-{C}-{CH}{3}

Predict the products of the following reactions. (a) cyclopentanone Br2 in acetic acid (b) 1-phenylethanol excess I2 + + in base

Show how you would use an aldol, Claisen, or another type of condensation to make each compound. \(\text { CHO }\) \(C\left(C H_{3}\right)_{3}\) \(\text { COOEt }\) \(\mathrm{CH}_{3}\) \(\mathrm{CH}_{2} \mathrm{CH}_{3}\) Equation transcription: Text transcription: { CHO } C(C H{3}){3} { COOEt } {CH}{3} {CH}{2}{CH}{3}

Show how you would accomplish the following conversions in good yields. You may use any necessary reagents.

Show how you would use the malonic ester synthesis to make the following compounds. \(\mathrm{CH}_{2} \mathrm{CH}_{2}-\mathrm{C}-\mathrm{OH}\) \(\mathrm{COOH}\) \(\mathrm{CH}_{2} \mathrm{CH}_{3}\) \(C-O H\) Equation transcription: Text transcription: {CH}{2}{CH}{2}-{C}-{OH} {COOH} {CH}{2}{CH}{3} C-O H

The following compounds can be synthesized by aldol condensations, followed by further reactions. (In each case, work backward from the target molecule to an aldol product, and show what compounds are needed for the condensation.)

Show how you would use the acetoacetic ester synthesis to make the following compounds. \(\mathrm{CH}_{2}-\mathrm{CH}-\mathrm{C}-\mathrm{CH}_{3}\) \(\mathrm{CH}_{2} \mathrm{CH}_{3}\) \(C-C H_{3}\) \(\mathrm{CH}_{3}\) (Hint: Consider using heptane-2,6-dione as an intermediate.) Equation transcription: Text transcription: {CH}{2}-{CH}-{C}-{CH}{3} {CH}{2}{CH}{3} C-C H{3} {CH}{3}

Show how you would accomplish the following multistep conversions. You may use any additional reagents you need.

Problem 74SP Write equations showing the expected products of the following enamine alkylation and acylation reactions. Then give the final products expected after hydrolysis of the iminium salts. (a) pyrrolidine enamine of pentan-3-one + allyl chloride (b) pyrrolidine enamine of acetophenone + butanoyl chloride (c) piperidine enamine of cyclopentanone + methyl iodide (d) piperidine enamine of cyclopentanone + methyl vinyl ketone

Propose mechanisms for the following reactions.

(A true story.) Chemistry lab students added an excess of ethylmagnesium bromide to methyl furoate, expecting the Grignard reagent to add twice and form the tertiary alcohol. After water workup, they found that the product was a mixture of two compounds. One was the expected product having two ethyl groups, but the unexpected product had added three ethyl groups. Propose a mechanism to explain the formation of the unexpected product.

Propose a mechanism for the following reaction. Show the structure of the compound that results from hydrolysis and decarboxylation of the product. \(\mathrm{CHO}+\mathrm{CH}_{2}\left(\mathrm{COOCH}_{2} \mathrm{CH}_{3}\right)_{2}\) \(\mathrm{CH}=\mathrm{C}\left(\mathrm{COOCH}_{2} \mathrm{CH}_{3}\right)_{2}\) \(\mathrm{NaOCH}_{2} \mathrm{CH}_{3}\) Equation transcription: Text transcription: {CHO}+{CH}{2}({COOCH}{2}{CH}{3}){2} {CH}={C}({COOCH}{2}{CH}{3}){2} {NaOCH}{2}{CH}{3}

Biochemists studying the structure of collagen (a fibrous protein in connective tissue) found cross-links containing \(\alpha, \beta\)-unsaturated aldehydes between protein chains. Show the structures of the side chains that react to form these cross- links, and propose a mechanism for their formation in a weakly acidic solution. Equation transcription: Text transcription: alpha, beta

A reaction involved in the metabolism of sugars is the splitting of fructose-1,6-diphosphate to give glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. In the living system, this retro-aldol is catalyzed by an enzyme called aldolase; however, it can also be catalyzed by a mild base. Propose a mechanism for the base-catalyzed reaction.

Problem 13P Predict the products of the following reactions. (a) cyclopentyl methyl ketone + excess Cl2 + excess NaOH (b) 1-cyclopentylethanol + excess I2 + excess NaOH (c) propiophenone + excess Br2 + excess NaOH

Problem 1 Phenylacetone can form two different enols. (a) Show the structures of these enols. (b) Predict which enol will be present in the larger concentration at equilibrium. (c) Propose mechanisms for the formation of the two enols in acid and in base.

Give the important resonance forms for the possible enolate ions of: (a) acetone (b) cyclopentanone (c) pentane-2,4-dione