Chapter 28 — Exercises

Sixty problems on aldol reactions and Claisen condensations. Drawing required wherever a structure or mechanism is asked for. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — Aldol mechanism and products

28.1∗ (routine) Draw the full mechanism for the self-aldol of acetaldehyde under NaOH/H₂O catalysis. Show every step including enolate formation, attack on the second aldehyde, tetrahedral alkoxide, and protonation.

28.2 (routine) Predict the product of the aldol condensation: 2 acetone + NaOH + heat.

28.3∗ (routine) Predict the products of the aldol of: (a) 2 propanal + NaOH; (b) 2 cyclohexanone + NaOH; (c) propanal + butan-2-one + NaOH (a crossed aldol).

28.4 (routine) Why is the aldol product (β-hydroxy aldehyde) often dehydrated to the α,β-unsaturated carbonyl (enone) under warm conditions?

28.5 (moderate) A student claims: "The aldol of acetaldehyde stops at the β-hydroxy aldehyde and never goes to the enone." Critique this claim — when is the aldol product stable, and when does it condense?

28.6 (moderate) Predict the major product of the crossed aldol between benzaldehyde (no α-H) and acetone (α-H present), under base catalysis. Why is benzaldehyde an effective electrophile?

28.7 (challenge) A student wants to do a self-aldol of propanal to make 3-hydroxy-2-methylpentanal. Predict the product. Why is the regiochemistry of self-aldol unambiguous in this case?

Section B — Aldol mechanism in detail

28.8∗ (routine) Draw the full mechanism (including arrows) for the base-catalyzed aldol of 2 acetaldehyde + NaOH → 3-hydroxybutanal.

28.9 (routine) Draw the mechanism for the aldol condensation: 2 acetone + NaOH + heat → 4-methyl-3-penten-2-one (mesityl oxide). Show the dehydration step (E1cb).

28.10 (moderate) Draw the mechanism for the crossed aldol between benzaldehyde and acetone with NaOH catalysis → (E)-4-phenyl-3-buten-2-one. Why is this clean (no benzaldehyde-only enolate possible)?

28.11 (moderate) Draw the mechanism for the directed aldol using LDA: 2-methylcyclohexanone + LDA, then add benzaldehyde, then aqueous workup. Predict the product and its regiochemistry.

28.12 (challenge) Draw the mechanism for the Mukaiyama aldol: silyl enol ether of acetone + benzaldehyde + TiCl₄ → β-hydroxy ketone. Identify the role of the Lewis acid.

Section C — Crossed aldol and directed strategies

28.13∗ (routine) Predict the major crossed-aldol product: (a) acetone + benzaldehyde + NaOH → ? (b) acetone + paraformaldehyde (CH₂O equivalent) + NaOH → ? (c) propanal + 2,2-dimethylpropanal (pivaldehyde) + NaOH → ?

28.14 (routine) Why does using a non-enolizable aldehyde (e.g., benzaldehyde, pivaldehyde, formaldehyde) as the electrophile work for crossed aldol?

28.15 (moderate) A student needs to do a crossed aldol of two enolizable carbonyls (e.g., 2-butanone + acetaldehyde). Suggest two strategies to direct the reaction.

28.16 (moderate) Use LDA to perform a directed aldol: cyclohexanone + LDA at -78 °C, then add 4-methylbenzaldehyde, then aqueous workup. Predict the product and stereochemistry.

28.17 (moderate) Use the Stork enamine approach for a crossed aldol: cyclohexanone + pyrrolidine → enamine; then add 4-methoxybenzaldehyde → C-C bond. Predict the product after hydrolysis.

28.18 (challenge) Design a synthesis of (E)-4-(2-methoxyphenyl)-3-buten-2-one (a flavor compound) by aldol condensation. Identify the starting materials and the strategy.

Section D — Claisen condensation

28.19∗ (routine) Draw the full mechanism for the self-Claisen of ethyl acetate + NaOEt → ethyl 3-oxobutanoate (ethyl acetoacetate). Show every step including the final deprotonation that drives the equilibrium.

28.20 (routine) Predict the product of: 2 methyl propanoate + NaOMe → ?

28.21 (routine) Why does the Claisen condensation require a strong base (NaOEt or LDA) but the aldol can use NaOH? Hint: the α-H of an ester is much less acidic than the α-H of a ketone.

28.22 (moderate) A student tries to do a Claisen condensation of ethyl acetate with NaOH instead of NaOEt. Predict what happens. Why is NaOH ineffective?

28.23 (moderate) Draw the mechanism for a crossed Claisen: ethyl acetate (enolate-forming) + ethyl benzoate (no α-H, electrophile) + NaOEt → ethyl 3-oxo-3-phenylpropanoate.

28.24 (challenge) Compare the equilibrium constant of an aldol vs. a Claisen condensation. Why is the Claisen typically essentially irreversible (driven by the final deprotonation), while the aldol is often reversible?

Section E — Dieckmann cyclization

28.25∗ (routine) Draw the Dieckmann cyclization of diethyl adipate (a 1,6-diester, with -CO₂Et at both ends of a 4-CH₂ chain) to give a 5-membered cyclic β-keto ester.

28.26 (routine) Predict the Dieckmann product of diethyl pimelate (a 1,7-diester, with -CO₂Et at both ends of a 5-CH₂ chain).

28.27 (moderate) Why does the Dieckmann favor 5- and 6-membered ring formation? Identify the entropic and steric reasons.

28.28 (moderate) Design a synthesis of cyclohexanone by Dieckmann + hydrolysis + decarboxylation. Identify the starting diester.

28.29 (challenge) A student tries to do a Dieckmann on a 1,4-diester (a 2-CH₂ chain). Predict the outcome — what ring size would result, and why does this not work?

Section F — Knoevenagel and Mannich

28.30∗ (routine) Draw the Knoevenagel condensation: acetaldehyde + diethyl malonate + piperidine (as base) → ?

28.31 (routine) Predict the Knoevenagel product of: benzaldehyde + ethyl acetoacetate + base → ?

28.32 (moderate) Compare Knoevenagel to a regular aldol. Why is Knoevenagel cleaner (single product) when 1,3-dicarbonyl is used?

28.33 (moderate) Draw the Mannich reaction: acetone + dimethylamine + formaldehyde + acid → β-amino ketone. Identify the iminium intermediate.

28.34 (challenge) Use a Mannich reaction to synthesize tropinone (an alkaloid skeleton). What starting materials do you use? (Hint: tropinone synthesis by Robinson is a classic Mannich.)

Section G — Stereochemistry of aldol

28.35∗ (routine) What is the Zimmerman-Traxler transition state? Sketch it for a Z-enolate attacking an aldehyde.

28.36 (routine) Predict the product of a Z-enolate (made from LDA + a propanate ester) attacking propanal — syn or anti aldol product?

28.37 (moderate) A chiral oxazolidinone (Evans auxiliary) is used to direct the aldol with high diastereoselectivity. Sketch the product of an Evans propanate + benzaldehyde aldol.

28.38 (moderate) Why does the Mukaiyama aldol with chiral Lewis acid give different stereoselectivity than the Evans aldol? Identify the structural origin.

28.39 (challenge) Compute the relative energies of syn vs anti products of an aldol. Hint: think about substituent placement (axial vs equatorial in the chair-like TS).

Section H — Biology of aldol and Claisen

28.40∗ (routine) Identify the aldol or Claisen step in: (a) glycolysis (which enzyme?), (b) citric acid cycle (which enzyme?), (c) fatty acid biosynthesis (which enzyme?), (d) cholesterol biosynthesis (HMG-CoA reductase or earlier?).

28.41 (routine) Sketch the substrate (fructose-1,6-bisphosphate) and the products (DHAP + G3P) of glycolytic aldolase. Identify it as a retro-aldol.

28.42 (moderate) Sketch the substrate (acetyl-CoA + oxaloacetate) and product (citrate) of citrate synthase. Identify the aldol step.

28.43 (moderate) Sketch the iterative Claisen of fatty acid biosynthesis. How many carbons are added per cycle? What is the leaving group? What is the driving force?

28.44 (moderate) PLP-dependent enzymes (Ch 27 case study 2) catalyze α-carbon chemistry on amino acids. Are PLP enzymes performing aldol-like reactions?

28.45 (challenge) Design a "synthetic biology" pathway: take a natural Claisen-like enzyme and engineer it to make a specific β-keto ester not normally made in nature.

Section I — Multistep synthesis

28.46∗ (routine) Use an aldol condensation to make 3-hydroxy-2-methylpentanal from propanal. Show the mechanism and indicate the stereochemistry.

28.47 (routine) Design a synthesis of (E)-2-pentenal from propanal using a self-aldol + dehydration.

28.48 (moderate) Combine aldol + reduction: aldol of acetone + benzaldehyde, then NaBH₄ reduction → 1,3-diol. Predict the product and stereochemistry.

28.49 (moderate) Combine aldol + Mukaiyama: form a silyl enol ether of cyclohexanone, then react with benzaldehyde + TiCl₄ → β-hydroxy ketone. Predict the product.

28.50 (moderate) Use a Dieckmann cyclization + hydrolysis + decarboxylation to make cyclopentanone from a diester.

28.51 (challenge) Use a crossed Claisen of ethyl acetate + ethyl benzoate to make 1-phenyl-2-butanone (an aromatic methyl ketone) in 3 steps total (Claisen + hydrolysis + decarboxylation).

28.52 (challenge) Build the steroid skeleton (a 4-ring fused system) using iterative aldol condensations from cyclic precursors. Identify the disconnection strategy. Hint: look up the Wieland-Miescher ketone synthesis.

Section J — Spectroscopy and identification

28.53∗ (routine) A compound has IR 1670 cm⁻¹ + δ 7-8 (vinyl Hs in ¹H). Identify the functional group (an α,β-unsaturated carbonyl). Predict whether this could be from an aldol condensation.

28.54 (routine) A compound has IR 1715 + 1745 (two C=O peaks) and ¹H singlet at δ 3.5 (OCH₃). Identify the structure (a β-keto ester from a Claisen).

28.55 (moderate) Distinguish between: (a) an aldol product (β-hydroxy ketone) and (b) an aldol condensation product (α,β-unsaturated ketone) using IR alone.

28.56 (challenge) Three compounds with formula C₅H₈O. (a) Aldol of acetaldehyde (β-hydroxy aldehyde, 3-hydroxybutanal). (b) Cross-aldol of acetone + acetaldehyde. (c) An α,β-unsaturated ketone (mesityl oxide). Distinguish them spectroscopically.

Section K — Aldol condensation conditions

28.57∗ (routine) Why does base-catalyzed aldol stop at the β-hydroxy carbonyl (kinetic product) at low temperature, but proceed to the α,β-unsaturated carbonyl (thermodynamic product) at higher temperature?

28.58 (routine) What is the role of the dehydration step in the aldol condensation? Why is it irreversible?

28.59 (moderate) Compare the equilibrium constants of: (a) aldol (ketone + ketone → β-hydroxy diketone) and (b) aldol condensation (β-hydroxy → enone + H₂O). Which has the larger equilibrium constant favoring product?

28.60 (challenge) A student claims that aldol can be performed at very high pressure to drive the equilibrium toward product. Critique this claim. What would actually drive the reaction to product?

Notes for instructors: This chapter is the central engine of synthesis. Common stumbling blocks: (1) confusing aldol (with C=O substrate) and Claisen (with ester substrate) — they look similar but the leaving group and product type differ. (2) Forgetting the role of the final β-keto ester deprotonation in Claisen — it's what drives the equilibrium. (3) Missing the dehydration step in aldol condensation. (4) Not recognizing the crossed-aldol selectivity strategies (LDA, no-α-H electrophile). Computational exercises: predict the Zimmerman-Traxler transition state energies for syn vs anti aldol using DFT.