Chapter 29 — Exercises

Fifty-five problems on conjugate (Michael) addition and the Robinson annulation. Drawing required wherever a structure or mechanism is asked for. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — 1,2 vs 1,4 addition

29.1∗ (routine) Predict 1,2 or 1,4 addition for each: (a) methyl vinyl ketone + CH₃MgBr at -78 °C (b) methyl vinyl ketone + (CH₃)₂CuLi (Gilman) at -78 °C (c) cyclohex-2-enone + LiAlH₄ (d) cyclohex-2-enone + NaSEt (sodium ethanethiolate) (e) methyl crotonate + NH₃ (f) acrolein + diethyl malonate (with NaOEt)

29.2 (routine) Justify each prediction in 29.1 using HSAB principles.

29.3∗ (routine) Why does NaBH₄ give 1,2-addition (allylic alcohol) on cyclohex-2-enone, while a Gilman reagent (R₂CuLi) gives 1,4-addition (saturated ketone with R at the β-C)?

29.4 (moderate) Predict the product of: cyclohex-2-enone + 1 equiv MeLi → ? vs. cyclohex-2-enone + 1 equiv (Me)₂CuLi → ? Why is the difference dramatic?

29.5 (moderate) A student claims that LDA + cyclohex-2-enone gives only 1,2-addition. Critique this claim. What product forms?

29.6 (challenge) Use computational analysis (DFT, frontier orbital): the LUMO of cyclohex-2-enone has its largest coefficient at the β-C, supporting 1,4 attack. The carbonyl C also has significant LUMO amplitude. Explain why the orbital arguments are consistent with the HSAB predictions.

Section B — Michael addition mechanism

29.7∗ (routine) Draw the full mechanism for: ethyl acetoacetate + methyl vinyl ketone + NaOEt → Michael adduct.

29.8 (routine) Draw the full mechanism for: malonic ester + acrolein + NaOEt → 1,5-dicarbonyl product.

29.9 (routine) Draw the full mechanism for: nitromethane + methyl vinyl ketone + NaOH → β-nitro ketone.

29.10 (moderate) Draw the mechanism for the Stork enamine version of a Michael addition: cyclohexanone + pyrrolidine → enamine; enamine + acrolein → 1,5-diketone; hydrolysis → final product.

29.11 (moderate) Compare the mechanism of LDA-enolate Michael with Stork-enamine Michael. Identify three differences.

29.12 (challenge) Why does a Michael adduct produce a 1,5-dicarbonyl pattern, regardless of which donor and acceptor are used?

Section C — Michael donors and acceptors

29.13∗ (routine) Identify which is the Michael donor and which is the acceptor in each: (a) ethyl acetoacetate + methyl vinyl ketone + base (b) diethyl malonate + acrolein + base (c) nitromethane + chalcone + base (d) cyclohexanone (LDA) + ethyl crotonate

29.14 (routine) Why is diethyl malonate (pKa ~13) a better Michael donor than ethyl acetate (pKa ~25)? Connect to enolate stability.

29.15 (moderate) Predict the rate of Michael addition for: methyl vinyl ketone vs. methyl acrylate vs. methyl crotonate (with the same Michael donor). Why does the rate differ? Consider both the LUMO energy and steric effects.

29.16 (moderate) A student tries to use ethyl benzoate (no α-H) as a Michael donor. Predict what happens. Why does this not work?

29.17 (challenge) Compare the reactivity of an α,β-unsaturated nitro compound (a nitroalkene) as a Michael acceptor to that of an α,β-unsaturated ester. Which is more electrophilic?

Section D — Robinson annulation

29.18∗ (routine) Design a Robinson annulation to make a fused 6-6 ring system (octalone, Wieland-Miescher-style) from cyclohexanone + methyl vinyl ketone.

29.19 (routine) Predict the Robinson product of: cyclohexanone + methyl vinyl ketone + NaOH → ?

29.20 (routine) Predict the Robinson product of: 2-methylcyclohexanone + methyl vinyl ketone → ? (Identify the new ring junction stereochemistry.)

29.21 (moderate) Why does Robinson annulation give a 6-membered ring (and not a 5- or 7-membered)? Identify the geometric reason.

29.22 (moderate) Design a Robinson annulation to make a 6-5 ring system (like a fused bicyclic). What changes in the substrate are needed?

29.23 (moderate) A student does the Michael step of a Robinson annulation but stops there (no aldol). Predict what happens upon longer base treatment. Why does the aldol step usually follow the Michael spontaneously?

29.24 (challenge) The Wieland-Miescher ketone is a Robinson annulation product. Sketch its structure. Why is it an important steroid synthesis precursor?

29.25 (challenge) Design a Robinson annulation to install the A-ring of an estrone-like steroid. What is the starting fused ring system, and what is the methyl vinyl ketone analog?

Section E — Stork enamine Michael

29.26∗ (routine) Design a Stork enamine Michael addition: cyclohexanone + pyrrolidine + acid (form enamine), then methyl vinyl ketone, then aqueous workup. Predict the product.

29.27 (routine) Why is the Stork enamine method preferred over LDA-enolate Michael in some cases? Identify two advantages.

29.28 (moderate) A student tries to do an LDA-enolate Michael with a substrate that has an OH group elsewhere. Predict what happens. Why is the Stork enamine method better here?

Section F — Heteroatom Michael

29.29∗ (routine) Predict the product: cysteine + acrylamide + base → thia-Michael adduct.

29.30 (routine) Predict the product: pyrrolidine (a secondary amine) + methyl crotonate + heat → β-amino ester. What is the regiochemistry?

29.31 (moderate) Why is thia-Michael much faster than aza-Michael at the same conditions? Connect to softness of S vs. N.

29.32 (moderate) A drug warhead is an α,β-unsaturated amide ($-NH-CO-CH=CH_2$, an acrylamide). Predict whether this would react preferentially with a serine, cysteine, or lysine in a target protein. Why?

29.33 (challenge) Sketch the mechanism of ibrutinib's covalent binding to BTK kinase: ibrutinib's acrylamide warhead + Cys481-SH of BTK → covalent thioether bond. Identify the Michael donor and acceptor.

29.34 (challenge) Compute the rate constant for a generic thia-Michael at physiological pH given that glutathione (a tripeptide thiol) reacts with maleimide ($k = 10^4 \text{ M}^{-1}\text{s}^{-1}$). How long does a 100 nM Michael acceptor take to react with 5 mM glutathione?

Section G — Asymmetric Michael

29.35∗ (routine) Why might a chiral catalyst (proline, MacMillan imidazolidinone) be used in a Michael addition? Identify the goal.

29.36 (routine) Predict the product (with stereochemistry) of: cyclohexanone + methyl vinyl ketone + proline catalyst → asymmetric Michael adduct.

29.37 (moderate) Compare the Evans (chiral oxazolidinone) approach to Michael addition with the proline organocatalyst approach. What is the key difference?

29.38 (challenge) Explain why proline-catalyzed Michael is mechanistically different from a standard NaOH-catalyzed Michael. Hint: proline forms an iminium ion with the substrate.

Section H — Biology of Michael

29.39∗ (routine) Identify a biological Michael acceptor: (a) acrolein (a metabolic toxin), (b) coenzyme Q10 (in electron transport), (c) curcumin (anti-inflammatory natural product), (d) HMG-CoA (in cholesterol biosynthesis). Which of these are α,β-unsaturated and which are not?

29.40 (routine) Glutathione S-transferase catalyzes glutathione + Michael acceptor → glutathione adduct. Identify the Michael donor (glutathione's thiol) and the role of the enzyme.

29.41 (moderate) Curcumin's α,β-unsaturated diketone is the basis of its anti-inflammatory activity (it modifies NF-κB pathway proteins via Michael addition). Sketch curcumin's structure and identify the Michael acceptor portion.

29.42 (moderate) Many cancer chemotherapeutics work as Michael acceptors. What is the mechanism: covalent modification of a cysteine in a target protein. Sketch a generic example.

29.43 (challenge) Sotorasib (LUMAKRAS) covalently modifies K-Ras G12C (a specific cysteine mutation) via Michael addition. Sketch the chemistry: sotorasib's α,β-unsaturated amide attacks the Cys12-SH of K-Ras G12C. Why is this drug uniquely targeted to the G12C mutation?

Section I — Spectroscopy and identification

29.44∗ (routine) A compound shows IR 1715 cm⁻¹ + 2960 (saturated CH). Before reaction, it had IR 1670 + 1620 (conjugated enone). What happened?

29.45 (routine) A compound has ¹H NMR showing two singlets at δ 2.1 (acetyl), and a triplet/quartet pattern at δ 2.5/2.7 (1,5-dicarbonyl chain). Identify it as a Michael adduct.

29.46 (moderate) A Robinson annulation product has IR 1670 cm⁻¹ + ¹H at δ 5.9 (vinyl) and the rest aliphatic. Identify it as the cyclic α,β-unsaturated ketone.

Section J — Multistep and integrative

29.47∗ (routine) Design a synthesis of 4-methyl-2-octanone using a Michael addition between methyl ethyl ketone (donor) and methyl vinyl ketone (acceptor) + base.

29.48 (routine) Use a Michael addition + Mukaiyama aldol to make a complex β-hydroxy-1,5-dicarbonyl product. Show the synthesis.

29.49 (moderate) Design a Robinson annulation followed by reduction and dehydration to make a fully saturated bicyclic ring system.

29.50 (moderate) Design a synthesis of a polyketide natural product using iterative aldol + Michael cyclizations.

29.51 (challenge) Design a "Michael cascade" synthesis: a substrate with two Michael donor sites and one Michael acceptor → polycyclic product after intramolecular Michael additions.

29.52 (challenge) Design a synthesis of (R)-tropinone (the alkaloid skeleton) using a Mannich/Michael cascade. Hint: see Robinson's classical 1917 synthesis.

Section K — Challenge

29.53 (challenge) Combine knowledge from Chs 27, 28, 29: design a 4-step synthesis of an octalin enone (fused 6-6 ring) from cyclohexanone + 2 carbonyl partners. Show the sequence of α-alkylation → aldol condensation → Michael → Robinson.

29.54 (challenge) Compute the LUMO energy of cyclohexenone vs. methyl acrylate vs. nitromethane (all Michael acceptors). Predict the relative reactivity.

29.55 (challenge) Asymmetric Michael with chiral organocatalyst: explain why proline gives one enantiomer with high ee. Sketch the proline-substrate complex and the reactive trajectory.

Notes for instructors: Common stumbling blocks for Chapter 29: (1) confusing 1,2 vs 1,4 — students often get the HSAB rule reversed. (2) Failing to recognize the 1,5-dicarbonyl pattern as a Michael product. (3) Forgetting that Robinson is Michael + aldol — both steps must work for the cyclization. (4) Missing the cysteine chemistry of modern targeted drugs. Computational exercises: predict the LUMO coefficients of various enones using DFT; correlate with experimental Michael reactivity.