Substitution Reactions of Carbonyl Compounds at the α Carbon

Question: Draw the enol or keto tautomer(s) of each compound.

Question: During the metabolism of glucose, glyceraldehyde 3-phosphate is converted to dihydroxyacetone phosphate by a process that involves two keto-enol tautomerizations. Draw a stepwise mechanism for this reaction in the presence of acid.

Question: When phenylacetaldehyde ( C₆H₅CH₂CHO) is dissolved in   with added DCl, the hydrogen atoms α to the carbonyl are gradually replaced by deuterium atoms. Write a mechanism for this process that involves enols as intermediates.

Question: Which C-H bonds in the following molecules are acidic because the resulting conjugate base is resonance stabilized?

Question: Rank the protons in the labeled CH₂  groups in order of increasing acidity, and explain why you chose this order.

Question: Draw the product formed when each starting material is treated with LDA in THF solution at –78⁰ C.

Question: As we learned in Chapter 20, organolithium reagents (RLi) are strong bases that readily react with acidic protons. Why aren’t organolithium reagents used to generate enolates?

Question: What enolate is formed when each ketone is treated with LDA in THF solution? What enolate is formed when these same ketones are treated with  NaOCH₃ in CH₃OH  solution?

Question: Explain each observation: (a) When (R)-2-methylcyclohexanone is treated with NaOH in H₂O , the optically active solution gradually loses optical activity. (b) When (R)-3-methylcyclohexanone is treated with NaOH in H₂0 , the solution remains optically active.

Question: Draw the products of each reaction.

Question: Draw the products of each reaction. Assume excess halogen is present.

Question: Draw the organic products formed when 2-bromopentan-3-one ( CH₃CH₂COCHBrCH₃) is treated with each reagent: (a) Li₂CO₃, LiBr, DMF; (b) CH₃CH₂NH₂ ; (c) CH₃SH.

Question: Identify the product M of the following two-step reaction sequence. M was converted to the hallucinogen LSD (Figure 18.4) in several steps.

Question: What product is formed when each compound is treated first with LDA in THF solution at low temperature, followed by CH₃CH₂l ?

Question: Draw the products obtained (including stereochemistry) when each compound is treated with LDA, followed by  CH₃l.

Question: The analgesic naproxen can be prepared by a stepwise reaction sequence from ester A. Using enolate alkylation in one step, what reagents are needed to convert A to naproxen? Write the structure of each intermediate. Explain why a racemic product is formed.

Question: How can pentan-2-one be converted into each compound?

Question: Identify A, B, and C, intermediates in the synthesis of the five-membered ring called an $\alpha$ -methylene- $\gamma$-butyrolactone. This heterocyclic ring system is present in some antitumor agents.  

Question: Which of the following compounds will readily lose CO₂ when heated?

Question: Draw the product of each reaction.

Question: What cyclic product is formed from each dihalide using the malonic ester synthesis?

Question: What alkyl halides are needed to prepare each ketone using the acetoacetic ester synthesis?

Question: Explain why each of the following carboxylic acids cannot be prepared by a malonic ester synthesis.

Question: What ketones are prepared by the following reactions?

Question: What alkyl halides are needed to prepare each ketone using the acetoacetic ester synthesis?

Question: Treatment of ethyl acetoacetate with NaOEt (2 equiv) and BrCH₂CH₂Br  forms compound X. This reaction is the first step in the synthesis of illudin-S, an antitumor substance isolated from thejack-o’-lantern, a poisonous, saffron-colored mushroom. What is the structure of X?

Question: Nabumetone is a pain reliever and anti-inflammatory agent sold under the brand name of Relafen.

a. Write out a synthesis of nabumetone from ethyl acetoacetate.

b. What ketone and alkyl halide are needed to synthesize nabumetone by direct enolate alkylation?

Question: Draw enol tautomer(s) for each compound. Ignore stereoisomers.

Question: The cis ketone A is isomerized to a trans ketone B with aqueous NaOH. A similar isomerization does not occur with ketone C. (a) Draw the structure of B using a chair cyclohexane. (b) Label the substituents in C as cis or trans, and explain the difference in reactivity.

Question: Draw enol tautomer(s) for each compound.

Question: Both pentane-2,4-dione and ethyl acetoacetate have two carbonyl groups separated by a single carbon atom. Although an equilibrium mixture of pentane-2,4-dione tautomers contains 76% of the enol forms, an equilibrium mixture of ethyl acetoacetate tautomers contains only 8% of the enol forms. Suggest a reason for this difference.

Question: Which carbonyl compound in each pair exhibits the higher percentage of the enol tautomer?

Question: What hydrogen atoms in each compound have a pk_a ≤ 25?

Question: Rank the labeled protons in each compound in order of increasing acidity.

Question: What is the major enolate (or carbanion) formed when each compound is treated with LDA?

Question: Why is the pKa of the Ha protons in 1-acetylcyclohexene higher than the pK_a  of the Hbprotons?

Question: Acyclovir is an effective antiviral agent used to treat the herpes simplex virus. (a) Draw the enol form of acyclovir, and explain why it is aromatic. (b) Why is acyclovir typically drawn in its keto form, despite the fact that its enol is aromatic?

Question: Explain why pentane-2,4-dione forms two different alkylation products (A or B) when the number of equivalents of base is increased from one to two.

Question: Vitamin C is a stable enediol. Draw the structure of the two keto tautomers in equilibrium with the enediol and explain why the enediol is more stable than the other tautomer.

Question: Acid-catalyzed bromination of pentan-2-one (CH₃COCH₂CH₂CH₂ ) forms two products: BrCH₂COCH₂CH₂CH₃  (A) and CH₃COCH₂(Br)CH₂CH₃  (B). Explain why the major product is B, with the Br atom on the more substituted side of the carbonyl group.

Question: Draw a stepwise mechanism for the following reaction.

Question: What alkyl halides are needed to prepare each carboxylic acid using the malonic ester synthesis?

Question: Use the malonic ester synthesis to prepare each carboxylic acid.

Question: Devise a synthesis of valproic acid [(CH₃CH₂CH₂)₂ CHC0₂H], a medicine used to treat epileptic seizures, using the malonic ester synthesis.

Question: Synthesize each compound from diethyl malonate. You may use any other organic or inorganic reagents.

Question: The enolate derived from diethyl malonate reacts with a variety of electrophiles (not just alkyl halides) to form new carbon-carbon bonds. With this in mind, draw the products formed when Na^{+ –}CH(CO₂Et)₂ reacts with each electrophile, followed by treatment with H₂O.

Question: What alkyl halides are needed to prepare each ketone using the acetoacetic ester synthesis?

Question: Synthesize each compound from ethyl acetoacetate. You may use any other organic or inorganic reagents.

Question: Draw the organic products formed in each reaction

Question: Draw the products formed (including stereoisomers) in each reaction.