Chapter 27 — Exercises

Sixty problems on enols, enolates, and α-carbon chemistry. Drawing required wherever a structure or mechanism is asked for. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — Acidity and resonance

27.1∗ (routine) Draw the two main resonance structures of the enolate of acetone. Indicate which atom carries the negative charge in each form.

27.2 (routine) Rank the following carbonyls by α-H pKa (most acidic first): acetone, methyl acetate, acetaldehyde, 2,4-pentanedione (acetylacetone), diethyl malonate, cyclohexanone.

27.3∗ (routine) Why is the α-H of a ketone (pKa ~20) so much more acidic than the H of an alkane (pKa ~50)? Use the concept of conjugate-base stability.

27.4 (routine) Why is the α-H of a 1,3-dicarbonyl (pKa ~10) so much more acidic than the α-H of a simple ketone (pKa ~20)? Draw the resonance structures.

27.5 (moderate) Acetonitrile (CH₃CN, pKa ~25) is more acidic than methane but less acidic than acetone. Explain.

27.6 (moderate) A nitro compound, nitromethane (CH₃NO₂), has α-H pKa of ~10. Explain why this is comparable to a 1,3-dicarbonyl. Draw the resonance structures of the nitromethyl anion.

27.7 (challenge) Compute (qualitatively) why an aldehyde α-H (e.g., propanal, pKa 17) is more acidic than a ketone α-H (e.g., acetone, pKa 20). Hint: think about the effective electronegativity of the carbonyl C.

Section B — Tautomerism

27.8∗ (routine) Draw the keto and enol forms of: (a) acetone, (b) acetaldehyde, (c) cyclohexanone, (d) acetic acid, (e) 2-acetylphenol, (f) 2,4-pentanedione.

27.9 (routine) What percent enol of 2,4-pentanedione is present in pure liquid at 25 °C? What percent of acetaldehyde? Why are these so different?

27.10 (moderate) Draw the enol of methyl acetoacetate. Why is the enol form unusually stable? Identify the intramolecular H-bond.

27.11 (moderate) Phenol is technically an enol of cyclohexa-2,4-dien-1-one. Why does phenol not tautomerize back to the keto form? Draw both structures.

27.12 (moderate) Vitamin C (ascorbic acid) is an enediol. Sketch its structure. Why is the enediol form stable?

27.13 (challenge) Acetylation of acetylacetone with AcOH/HCl gives a mixed anhydride that converts the enol to a stable enol ester. Sketch the chemistry. Why does this fix the molecule in the enol form?

Section C — Bases and enolate formation

27.14∗ (routine) Predict whether each base will completely deprotonate acetone (pKa 20): (a) NaOEt (pKaH 16) (b) NaH (pKaH 35) (c) LDA (pKaH 36) (d) NaOH (pKaH 16).

27.15 (routine) Why is LDA preferred over NaH for selective formation of a kinetic enolate?

27.16 (routine) Why is LDA bulky? What does the bulkiness achieve?

27.17 (moderate) Predict the product of: 2-methylcyclohexanone + LDA at -78 °C → ? Then + CH₃I → ? Identify the kinetic enolate and the alkylation product.

27.18 (moderate) Predict the product of: 2-methylcyclohexanone + NaOEt + EtOH at 25 °C → ? Then + CH₃I → ? Identify the thermodynamic enolate.

27.19 (challenge) A student tries to use NaOH (in MeOH) to deprotonate acetone to form an enolate, then adds methyl iodide. Predict what happens. Why does this not give the desired α-alkylation? What goes wrong?

27.20 (challenge) The pKaH of LiHMDS is ~30. Compare its kinetic vs thermodynamic enolate selectivity to LDA's. Why might LiHMDS be preferred for some substrates?

Section D — α-Halogenation and the haloform reaction

27.21∗ (routine) Predict the product: acetone + Br₂ + acid → ?

27.22 (routine) Predict the product: acetophenone + Br₂ + acetic acid → ? Specify regiochemistry.

27.23 (moderate) Predict the product: 2-butanone + 3 Br₂ + 3 NaOH → ? Identify the haloform.

27.24 (moderate) A student tries to do a haloform reaction on cyclohexanone (an α-CH₂ but not a methyl ketone). Predict whether this works. Why or why not?

27.25 (moderate) Why does the haloform reaction need 3 equivalents of X₂ rather than just 1?

27.26 (challenge) Iodoform test: identify which of the following give a positive (yellow precipitate) iodoform test: (a) acetone (b) 2-butanone (c) 3-pentanone (d) ethanol (e) 2-propanol (f) 1-butanol (g) acetaldehyde Justify each answer.

Section E — α-Alkylation

27.27∗ (routine) Predict the product: cyclohexanone + LDA in THF at -78 °C, then methyl iodide.

27.28 (routine) Predict the product: 2-methylcyclohexanone + LDA at -78 °C, then methyl iodide. Specify regiochemistry.

27.29 (moderate) A student claims they can α-alkylate cyclohexanone with tert-butyl chloride after LDA deprotonation. Critique this approach. What happens instead?

27.30 (moderate) A student wants to make 2,2-dimethylcyclohexanone from cyclohexanone. Design the synthesis. How many alkylation steps are needed? Should each be kinetic or thermodynamic?

27.31 (moderate) Design a synthesis of 2-benzyl-3-methylcyclopentan-1-one from cyclopentanone. Identify the alkylation steps.

27.32 (challenge) Use the acetoacetic ester synthesis to make: (a) 2-methyl-2-propanyl methyl ketone (3,3-dimethyl-2-butanone), (b) 2-pentyl methyl ketone (2-octanone). Show all steps including decarboxylation.

27.33 (challenge) Use the malonic ester synthesis to make: (a) cyclopentanecarboxylic acid (one alkyl group + ring closure?), (b) 2-methylpentanoic acid. Show all steps including decarboxylation.

Section F — Stork enamine and silyl enol ethers

27.34∗ (routine) Predict the product of the Stork enamine alkylation: cyclohexanone + pyrrolidine + acid catalyst (form enamine), then add methyl iodide, then hydrolyze.

27.35 (routine) Why is the Stork enamine method preferred over LDA-enolate alkylation in some situations? Identify two advantages.

27.36 (moderate) Form the silyl enol ether of cyclohexanone using TMSCl + LDA. Predict the structure.

27.37 (moderate) Use a silyl enol ether in a Mukaiyama aldol with TiCl₄ as Lewis acid catalyst. Predict the product.

27.38 (challenge) Why does the Mukaiyama-type aldol work with a Lewis acid that wouldn't normally cause an aldol? Hint: the silyl group activates the enol ether to attack the activated electrophile.

Section G — Biology of α-C chemistry

27.39∗ (routine) Identify the α-carbon chemistry in: (a) glycolysis (which step?), (b) fatty acid β-oxidation (which step?), (c) amino acid racemization (which enzyme class?), (d) thalidomide racemization (which carbon?).

27.40 (routine) PLP-dependent enzymes catalyze a Schiff base + α-H removal. Sketch the structure of an amino acid bound to PLP via Schiff base. Why is the α-H so acidic in this complex?

27.41 (routine) Identify why fatty acid β-oxidation proceeds with α-H abstraction rather than β-H abstraction. (The E2-like elimination requires α-H removal, then loss of the β-COR leaving group.)

27.42 (moderate) Thalidomide's α-C is α to two carbonyls (an imide). Estimate its pKa using the analogy to 2,4-pentanedione (pKa 9). Discuss the racemization timescale at physiological pH.

27.43 (moderate) The "asymmetric carbon" of an amino acid (the α-C) is the one that's α to the carboxylic acid. Its pKa is much lower than a typical amine's α-H. Why?

27.44 (challenge) Compute the equilibrium ratio of (R)- to (S)-thalidomide at physiological pH given a racemization rate constant of $k = 0.087 \text{ h}^{-1}$. (Hint: ratio is 1:1 at equilibrium; reach time depends on k.)

27.45 (challenge) A drug designer wants to make a single-enantiomer thalidomide-like drug that is stable to racemization. Suggest one strategy. (Hint: replace the α-H with something else — a quaternary carbon, a fluorine, etc.)

Section H — Mechanism drawing

27.46∗ (routine) Draw the full mechanism for: acetone + LDA in THF at -78 °C → enolate. Show LDA's structure (Li-N(iPr)₂) and the deprotonation arrows.

27.47 (routine) Draw the full mechanism for: cyclohexanone + Br₂ + acid → 2-bromocyclohexanone.

27.48 (routine) Draw the full mechanism for: cyclohexanone + LDA, then iodomethane → 2-methylcyclohexanone.

27.49 (moderate) Draw the mechanism of the acetoacetic ester synthesis: ethyl acetoacetate + NaOEt + R-X → α-alkyl ester → hydrolysis → diacid → decarboxylation → methyl ketone. Show every step.

27.50 (moderate) Draw the mechanism of the malonic ester synthesis: diethyl malonate + NaOEt + R-X → α-alkyl malonate → diester → diacid → decarboxylation → carboxylic acid.

27.51 (challenge) Draw the mechanism of the haloform reaction: 2-butanone + 3 Cl₂ + 4 NaOH → CHCl₃ + propanoate. Identify the trihalogenated intermediate.

27.52 (challenge) Draw the mechanism of the Stork enamine synthesis: cyclohexanone + pyrrolidine + H⁺ → enamine; enamine + R-X → iminium ion; hydrolysis → α-alkyl ketone.

Section I — Spectroscopy

27.53∗ (routine) A compound has IR 1715 cm⁻¹ and ¹H NMR triplet at δ 1.0 (3H, J = 7 Hz), quartet at δ 2.4 (2H, J = 7 Hz), singlet at δ 2.1 (3H). Identify the compound and the α-position.

27.54 (routine) A compound has IR 1715 + 3300 (broad). After treatment with NaOH/Cl₂, the IR shows new C=O at 1620 (broad) and a strong absorption at 1430. Identify the haloform reaction; what's the product?

27.55 (moderate) Acetylacetone shows an unusually broad ¹H NMR peak at δ 14–15 ppm. Why is it broad? What does the chemical shift indicate?

27.56 (challenge) A compound has ¹³C NMR peaks at 200 (one carbonyl C), 180 (another carbonyl), 90 (one CH between them), 35 (one CH₂), 22 (one CH₃). Propose the structure (a 1,3-diketone).

Section J — Multistep synthesis

27.57∗ (routine) Design a synthesis of 2-methylcyclohexanone from cyclohexanone using α-alkylation with LDA + CH₃I.

27.58 (routine) Design a synthesis of 2,2-dimethyl-3-pentanone from 3-pentanone using two sequential α-alkylations.

27.59 (moderate) Design a synthesis of 2-methylpentanoic acid using the malonic ester route.

27.60 (challenge) Combine α-alkylation with α-halogenation: starting from acetone, make 1-bromo-3-methyl-2-butanone in 2 steps. Show the sequence and the mechanism of each step.

Notes for instructors: This chapter is essential for understanding aldol/Claisen (Ch 28). Common stumbling blocks: (1) mixing up α-position with carbonyl C — the α-C is adjacent to C=O. (2) Using NaOH to fully deprotonate a ketone — only ~5% goes to enolate; need stronger base. (3) Trying to alkylate with a tertiary halide — that's E2 elimination, not alkylation. (4) Forgetting that the enolate's nucleophilic site is the α-C, not the O. Computational exercises: use Avogadro to optimize the enol of acetylacetone and compute the intramolecular H-bond geometry; compare to acetone's keto form energy.