Chapter 17

Other groups in addition to carbonyl groups enhance the acidities of adjacent \(\mathrm{C}-\mathrm{H}\) bonds. For instance, nitromethane, \(\mathrm{CH}_{3} \mathrm{NO}_{2}\), has \(\mathrm{p} K_{a}=10\); ethanenitrile, \(\mathrm{CH}_{3} \mathrm{CN}\), has a \(\mathrm{p} K_{a} \cong 25 .\) Explain why these compounds behave as weak acids. Why is \(\mathrm{CH}_{3} \mathrm{COCH}_{3}\) a stronger acid than \(\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{CH}_{3} ?\)

Explain why the \(D\) or \(L\) enantiomer of a chiral ketone such as 4 -phenyl-3-methyl-2-butanone racemizes in the presence of dilute acid or dilute base.

a. Would you expect the enol or the enolate anion of 2 -propanone to be more reactive toward bromine if each were present at the same concentration? Why? b. Would you expect the enolate anion to react with bromine at the oxygen? Explain. (Consider the bond energies involved!)

A detailed study of the rate of bromination of 2 -propanone in water, in the presence of ethanoic acid and ethanoate \(\quad\) ions, \(\quad\) has \(\quad\) shown \(\quad\) that \(v=\left\\{6 \times 10^{-9}+5.6 \times 10^{-4}\left[\mathrm{H}_{3} \mathrm{O}^{+}\right]+1.3 \times 10^{-7}\left[\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{H}\right]+7\left[\mathrm{OH}^{-}\right]+3.3 \times 10^{-6}\left[\mathrm{CH}_{3} \mathrm{CO}_{2}^{-}\right]+3.5 \quad\right.\) in which \(\left.\times 10^{-6}\left[\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{H}\right]\left[\mathrm{CH}_{3} \mathrm{CO}_{2}^{-}\right]\right\\}\left[\mathrm{CH}_{3} \mathrm{COCH}_{3}\right]\) the rate \(v\) is expressed in \(\mathrm{mol} \mathrm{L}^{-1} \mathrm{sec}^{-1}\) when the concentrations are in \(\mathrm{mol} \mathrm{L}^{-1}\). a. Calculate the rate of the reaction for a 1 M solution of 2 -propanone in water at \(\mathrm{pH} 7\) in the absence of \(\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{H}\) and \(\mathrm{CH}_{3} \mathrm{CO}_{2}^{-}\) b. Calculate the rate of the reaction for \(1 \mathrm{M} 2\) -propanone in a solution made by neutralizing \(1 \mathrm{M}\) ethanoic acid with sufficient sodium hydroxide to give \(\mathrm{pH} 5.0\) ( \(K_{a}\) of ethanoic acid \(=1.75 \times 10^{-5}\) ). c. Explain how the numerical values of the coefficients for the rate equation may be obtained from observations of the reaction at various \(\mathrm{pH}\) values and ethanoate ion concentrations. d. The equilibrium concentration of enol in 2 -propanone is estimated to be \(\sim 1.5 \times 10^{-4} \% .\) If the rate of conversion of \(1 \mathrm{M}\) 2-propanone to enol at \(\mathrm{pH} 7\) (no \(\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{H}\) or \(\mathrm{CH}_{3} \mathrm{CO}_{2}^{-}\) present) is as calculated in Part a, calculate the rate of the reverse reaction from enol to ketone at \(\mathrm{pH} 7\) if the enol were present in \(1 \mathrm{M}\) concentration. e. Suggest a mechanistic explanation for the term \(3.5 \times 10^{-6}\left[\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{H}\right]\left[\mathrm{CH}_{3} \mathrm{CO}_{2}^{-}\right]\) in the rate expression.

a. Explain why 2 -butanone is halogenated preferentially on the ethyl side with an acidic catalyst. (Review of Section \(11-\) 3 should be helpful.) b. What product would predominate in the acid-catalyzed bromination of 1 -phenyl-2-propanone? Give your reasoning.

The direct halogenation of aldehydes under either acidic or basic conditions is complicated by side reactions involving either oxidation of the aldehyde \(-\mathrm{CHO}\) group or additions to the \(-\mathrm{CH}=\mathrm{O}\) double bond. Therefore the synthesis of \(\alpha\) -halo aldehydes by the procedure described for ketones is not of much practical value. The enol ethanoate is made by treating the aldehyde with ethanoic anhydride and potassium ethanoate. The overall sequence follows: Write the structures of the intermediate products, \(\mathbf{B}\) and \(\mathbf{C}\), and the steps involved in each of the reactions to produce \(\mathbf{A}, \mathbf{B}, \mathbf{C}\) and 2-bromopropanal. What is the function of potassium ethanoate in the formation of \(\mathrm{A}\) ? (You may wish to review Sections \(15-4 \mathrm{D}\) and \(15-4 \mathrm{E}_{.}\) )

Trichloromethane (chloroform) at one time was synthesized commercially by the action of sodium hypochlorite on ethanol. Formulate the reactions that may reasonably be involved. What other types of alcohols may be expected to give haloforms with halogens and base?

The Haller-Bauer cleavage of } 2,2 \text { -dimethyl-1-phenyl-1-propanone with sodium amide forms }\end{array}$ benzenecarboxamide and 2-methylpropane. Write a mechanism for the Haller-Bauer reaction analogous to the haloform cleavage reaction.

Predict the principal products to be expected in each of the following reactions; give your reasoning: a. \(\mathrm{CH}_{3} \mathrm{CHO}+\left(\mathrm{CH}_{3}\right)_{2} \mathrm{CO} \stackrel{\mathrm{NaOH}}{\longrightarrow}\) b. \(\left(\mathrm{CH}_{3}\right)_{2} \mathrm{C}(\mathrm{OH}) \mathrm{CHCOCH}_{3} \stackrel{\mathrm{NaOH}}{\longrightarrow}\) c. \(\mathrm{CH}_{2} \mathrm{O}+\left(\mathrm{CH}_{3}\right)_{3} \mathrm{CCHO} \stackrel{\mathrm{NaOH}}{\longrightarrow}\) d. \(\mathrm{CH}_{2} \mathrm{O}+\left(\mathrm{CH}_{3}\right)_{2} \mathrm{CHCHO} \stackrel{\mathrm{Ca}(\mathrm{OH})_{2}}{\longrightarrow}\)

a. A useful modification of aldol addition to methanal, known as the Mannich reaction, uses a secondary amine (usually as its hydrochloride salt) to selectively introduce one carbon atom at the alpha position of an aldehyde or ketone. The actual product is the salt of an amino ketone. For example, $$ \mathrm{C}_{6} \mathrm{H}_{5} \mathrm{COCH}_{3}+\mathrm{CH}_{2} \mathrm{O}+\left(\mathrm{CH}_{3}\right)_{2} \mathrm{NH}_{2} \stackrel{\ominus}{\mathrm{Cl}} \underset{\text { (solvent) }}{\mathrm{C}_{2} \mathrm{H}_{\mathrm{b}} \mathrm{OH}}{\longrightarrow} \mathrm{C}_{6} \mathrm{H}_{5} \mathrm{COCH}_{2} \mathrm{CH}_{2} \stackrel{\oplus}{\mathrm{NH}}\left(\mathrm{CH}_{3}\right)_{2} \stackrel{\ominus}{\mathrm{C}} 1 $$ Write the steps involved in this reaction, assuming that an intermediate imminium ion, \(\left(\mathrm{CH}_{3}\right)_{2} \stackrel{\oplus}{\mathrm{N}}=\mathrm{CH}_{2}\), is formed from the amine and methanal. b. Show how the reaction product - the so-called Mannich base - could be converted to \(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{COCH}=\mathrm{CH}_{2}\)

Explain why many \(\beta\) -halo ketones undergo \(E 2\) elimination with considerable ease. What kinds of \(\beta\) -halo ketones do not undergo such elimination readily?

Aldol additions also occur in the presence of acidic catalysts. For example, 2-propanone with dry hydrogen chloride slowly yields \(\left(\mathrm{CH}_{3}\right)_{2} \mathrm{C}=\mathrm{CHCOCH}_{3}\) (mesityl oxide) and \(\left(\mathrm{CH}_{3}\right)_{2} \mathrm{C}=\mathrm{CHCOCH}=\mathrm{C}\left(\mathrm{CH}_{3}\right)_{2}\) (phorone). Write mechanisms for the formation of these products, giving particular attention to the way in which the new carbon-carbon bonds are formed.

What features of the base-catalyzed dehydration of 3 -hydroxybutanal make it a more favorable and faster reaction than would be expected for a base-catalyzed dehydration of 2 -butanol? Give your reasoning.

Devise a reasonable synthesis of each of the following compounds from the indicated starting materials. Assume that other needed reagents are available. (Not all of the syntheses involve aldol-addition reactions, but all involve at some stage or the other carbonyl-addition reactions.) a. propenenitrile from ethanal b. 1 -(trichloromethyl) cyclohexanol from cyclohexanone c. 2,2 -dimethyl- 1,3 -propanediol from 2 -methylpropanal d. 2 -(phenylmethylidene)cyclohexanone form cyclohexanone e. 2,3 -diphenylpropenenitrile from phenylethanenitrile f. \(\quad\) OH \(\quad 0\) from a compound with only one cyclohexane ring g. 3-methyl-2-cyclopentenone from an open-chain compound

If methyl iodide gives mainly \(\mathrm{C}\) -alkylation with the enolate anion of 2 -propanone, which of the following halides would you expect to be candidates to give \(\mathrm{O}\) -alkylation: tert-butyl chloride, phenylmethyl chloride, 3 -chloropropene, neopentyl chloride?

a. Alkylation of ketones is much less successful with ethyl and higher primary halides than for methyl halides. Explain why competing reactions may be particularly important for such cases. b. What would you expect to happen if you were to try to alkylate ethanal with \(\mathrm{KNH}_{2}\) and \(\mathrm{CH}_{3} \mathrm{I}\) ?

If you wished to prepare the methyl ether of 4 -hydroxy-3-penten- 2 -one by \(\mathrm{O}\) -alkylation, what base and which fo the methylating agents listed would you choose? \(\mathrm{CH}_{3} \mathrm{Cl}, \mathrm{CH}_{3} \mathrm{I}, \mathrm{CH}_{3} \mathrm{OCO}_{2} \mathrm{OCH}_{3},\left(\mathrm{CH}_{3}\right)_{3} \mathrm{OBF}_{4}\), or \(\left(\mathrm{CH}_{3}\right)_{2} \mathrm{O} .\) Give your reasoning.

On what basis can you account for the fact that \(\mathrm{HCN}\) adds to the carbonyl group of 3 -butenal and to the double bond of 3 -buten-2-one? Would you expect the carbonyl or the double-bond addition product of \(\mathrm{HCN}\) to 3 -buten- 2 -one to be more thermodynamically favorable? Give your reasoning.

Write reasonable mechanisms for the reaction of ketene with alcohols and amines. Would you expect these reactions to be facilitated by acids, or by bases?

Write a mechanism for the acid-catalyzed reaction of methanol with diketene that accords with the nature of the reagents involved.

If the keto form of 2,4 -pentanedione is more stable than the enol form in water solution, why does it also have to be a weaker acid than the enol form in water solution?

It is just as important to be able to recognize reactions which do not work as it is to recognize reactions that do work. The following equations represent "possible" synthetic reactions. Consider each carefully and decide whether it will proceed as written. Show your reasoning. If you think a different reaction will take place, write an equation for it. a. \(\mathrm{CH}_{3} \mathrm{COCH}_{3}+6 \mathrm{Br}_{2}+8 \mathrm{NaOH} \rightarrow 2 \mathrm{CHBr}_{3}+\mathrm{Na}_{2} \mathrm{CO}_{3}+6 \mathrm{NaBr}+6 \mathrm{H}_{2} \mathrm{O}\) b. \(\mathrm{CH}_{3} \mathrm{CHO}+\mathrm{NaNH}_{2}+\left(\mathrm{CH}_{3}\right)_{3} \mathrm{CCl} \rightarrow\left(\mathrm{CH}_{3}\right)_{3} \mathrm{CCH}_{2} \mathrm{CHO}+\mathrm{NH}_{3}+\mathrm{NaCl}\) c. \(\left(\mathrm{CH}_{3}\right)_{2} \mathrm{CHCOCH}_{3}+\mathrm{CH}_{2}=\mathrm{O} \stackrel{\mathrm{Ca}(\mathrm{OH})_{2}}{\longrightarrow}\left(\mathrm{CH}_{3}\right)_{2} \mathrm{C}\left(\mathrm{CH}_{2} \mathrm{OH}\right) \mathrm{COCH}_{3}\) d. \(\mathrm{CH}_{3} \mathrm{CHO}+\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{C}_{2} \mathrm{H}_{5} \stackrel{\text { ? }^{\circ}}{\longrightarrow} \mathrm{CH}_{3} \mathrm{CH}(\mathrm{OH}) \mathrm{CH}_{2} \mathrm{CO}_{2} \mathrm{C}_{2} \mathrm{H}_{5}\) e. \(\mathrm{CH}_{3} \mathrm{COCH}_{2} \mathrm{COCH}_{3}+\mathrm{CH}_{2}=\mathrm{C}=\mathrm{O} \rightarrow \mathrm{CH}_{3} \mathrm{COOC}\left(\mathrm{CH}_{3}\right)=\mathrm{CHCOCH}_{3}\)

Explain why \(\beta, \gamma\) -unsaturated aldehydes and ketones usually are relatively difficult to synthesize and are found to rearrange readily to the \(\alpha, \beta\) -unsaturated isomers, particularly in the presence of basic reagents: C=CCCC=CCC=O