Chapter 25 — Exercises

Sixty problems on nucleophilic addition to aldehydes and ketones. Drawing required wherever a structure or mechanism is asked for. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — Predicting products

25.1∗ (routine) For each, predict the major product: (a) benzaldehyde + NaBH₄ in MeOH (b) acetone + CH₃MgBr, then aqueous workup (c) butanal + EtOH (excess) + H⁺ (d) acetone + HCN (e) 2-butanone + NH₂OH (hydroxylamine), trace acid (f) butanal + dimethylamine (excess), trace acid (g) cyclohexanone + LiAlH₄, then aqueous workup (h) 4-methyl-2-pentanone + Ph₃P=CHCH₃ (a Wittig ylide)

25.2 (routine) For each, predict the product: (a) acetaldehyde + 2 MeOH + H⁺ (b) 2-pentanone + NaBH₄ (c) 3-pentanone + NH₃ + NaBH₃CN (reductive amination) (d) cyclopentanone + ethylene glycol + H⁺ (e) propanal + Mg, then propanal again, then H₃O⁺

25.3∗ (routine) Predict the product of: methyl ester (e.g., methyl pentanoate) + 2 equivalents PhMgBr, then aqueous workup.

25.4 (moderate) Two carbonyls react in different ways. Predict the major product of: cyclohexanone + L-Selectride (a bulky borohydride). What stereochemistry results?

25.5 (challenge) Predict the product of: 2,2-dimethylpropanal (pivaldehyde) + EtMgBr + H₃O⁺. Why is the yield much lower than for a less hindered aldehyde?

25.6∗ (challenge) A ketone has α-Hs. Predict what happens with NaH (a strong, non-nucleophilic base) instead of NaBH₄ (a nucleophilic hydride).

Section B — Mechanism drawing

25.7∗ (routine) Draw the full mechanism for the addition of CN⁻ to acetone, forming acetone cyanohydrin. Show all arrows.

25.8 (routine) Draw the full mechanism for the formation of a hemiacetal from butanal + ethanol (no acid catalyst, slow but reversible).

25.9∗ (routine) Draw the full mechanism for the acid-catalyzed formation of acetal from butanal + 2 ethanol + H⁺. Show all 7 elementary steps including the oxocarbenium intermediate.

25.10 (routine) Draw the mechanism for: cyclohexanone + ethylene glycol + H⁺ → cyclic acetal. Identify the electrophilic carbon and the leaving group at each step.

25.11∗ (moderate) Draw the mechanism for the formation of the imine from acetaldehyde + methylamine. Include the hemiaminal intermediate and the loss of water step.

25.12 (moderate) Draw the mechanism for the formation of the enamine from cyclohexanone + pyrrolidine + trace acid. Why does the C=C end up at the α-position rather than the β-position?

25.13 (moderate) Draw the mechanism for the formation of the cyanohydrin from benzaldehyde + HCN. Why is base catalyst (e.g., KCN) better than just HCN alone?

25.14∗ (moderate) Draw the full mechanism for cyclohexanone + EtMgBr → 1-ethylcyclohexanol. Include the alkoxide intermediate and the workup step.

25.15 (moderate) Draw the mechanism for NaBH₄ + cyclohexanone in MeOH. Show the H⁻ delivery and the subsequent protonation.

25.16 (challenge) Draw the mechanism of the Wittig reaction: methyltriphenylphosphonium ylide + acetone → 2-methyl-1-propene + triphenylphosphine oxide. Include the betaine and the oxaphosphetane intermediates.

Section C — Equilibria and reversibility

25.17∗ (routine) Why is the hydration of formaldehyde nearly complete (>99.9% gem-diol) while the hydration of acetone is minor (~0.14%)?

25.18 (routine) Predict whether the hydration equilibrium of: (a) propanal, (b) 2,2,2-trifluoroacetone, (c) cyclopentanone, (d) chloral. Rank by gem-diol fraction at equilibrium.

25.19 (moderate) A student claims hemiketal formation from a ketone is reversible. Why does glucose (a hemiacetal) sit so far on the cyclic side at equilibrium? Hint: intramolecular vs. intermolecular.

25.20 (challenge) Calculate the equilibrium constant for the formation of glucose's pyranose form, given that it constitutes 99.98% of glucose at 25 °C in water. Use $K_{eq} = [\text{cyclic}]/[\text{open}]$.

25.21 (challenge) A peptide aldehyde (the C-terminus is an aldehyde) is unusually reactive in solution because it forms a very stable cyclic hemiaminal with an upstream amino group. Sketch the structure. Why is this useful for designing protease inhibitors?

Section D — Stereochemistry

25.22∗ (routine) Predict the stereochemistry of NaBH₄ reduction of 4-tert-butylcyclohexanone. Which face is preferred?

25.23 (routine) L-Selectride (a bulky boronate) shows the opposite face preference from NaBH₄ on the same substrate. Why?

25.24 (moderate) Use the Felkin-Anh model to predict the major diastereomer formed by attacking 2-methylpropanal at the C=O with a phenyl Grignard.

25.25 (moderate) Use the Bürgi-Dunitz angle to explain why nucleophiles approach the C=O at 107° rather than perpendicular to the C=O axis.

25.26 (challenge) A chiral auxiliary on the α-carbon directs nucleophilic addition to give one diastereomer with high selectivity. Sketch the transition state and explain.

25.27 (challenge) Cyclohexanone's reduction by NaBH₄ in MeOH gives the equatorial alcohol. Explain mechanistically using the Bürgi-Dunitz approach.

Section E — Imines and amines

25.28∗ (routine) Predict the product: butanone + methylamine + NaBH₃CN at pH 5 (reductive amination).

25.29 (routine) Predict the product: cyclohexanone + dimethylamine (excess) + trace acid. What kind of N-containing functional group is formed?

25.30 (moderate) Why is reductive amination performed with NaBH₃CN rather than NaBH₄? What does NaBH₃CN do that NaBH₄ doesn't?

25.31 (moderate) Imines hydrolyze under acidic aqueous conditions. Explain mechanistically — show the reverse of imine formation.

25.32 (challenge) Hemoglobin glycation is the slow imine formation between glucose's C1 aldehyde and the N-terminal valine amine of hemoglobin. Sketch the structure of glycated hemoglobin (HbA1c). Why is this useful as a clinical diabetes marker?

25.33 (challenge) Pyridoxal-5'-phosphate (PLP) is an aldehyde cofactor that forms Schiff bases with amino acids. Sketch the PLP-amino acid Schiff base. Why is this configuration set up for transamination, decarboxylation, and racemization at the α-carbon?

Section F — Grignard and organometallic

25.34∗ (routine) Design a synthesis of 3-pentanol using only propanal and ethyl bromide as carbon sources. Use a Grignard addition.

25.35 (routine) Design a synthesis of 2-methyl-2-butanol using a Grignard addition.

25.36 (moderate) Why does an alkyl halide that has an OH group on the chain cannot be made into a Grignard? (Hint: Grignard's basicity.)

25.37 (moderate) Predict the product: methyl benzoate + 2 PhMgBr + H₃O⁺. Why does this give triphenylmethanol?

25.38 (challenge) Design a synthesis of 1,3-diphenyl-1-propanol from benzaldehyde and benzyl bromide. Use a Grignard.

25.39 (challenge) A student tries to do a Grignard reaction on a substrate that has both a ketone and an ester. Predict what happens. How could the student protect the ketone first to selectively make the ester react with the Grignard? (Trick: usually the other way around.)

25.40 (challenge) Diisobutylaluminum hydride (DIBAL-H) at -78 °C with 1 equivalent reduces an ester to an aldehyde (not all the way to an alcohol). Why? What does the partial reduction tell you about the mechanism and how to avoid over-reduction?

Section G — Wittig and alkene synthesis

25.41∗ (routine) Predict the product: cyclohexanone + Ph₃P=CHCH₃ (a stabilized ylide) → ?

25.42 (routine) Predict the product: butanal + Ph₃P=CH₂ (an unstabilized ylide) → ?

25.43 (moderate) Compare the geometry of the alkene produced by: (a) butanal + Ph₃P=CHCH₃ and (b) butanal + Ph₃P=CHCO₂CH₃ (a stabilized ylide). Why does the cis vs trans preference differ?

25.44 (moderate) A Wittig reaction is run between (E)-2-butenal and Ph₃P=CHCH₃. Predict the product. Why is the Wittig selective for the aldehyde over the alkene C=C?

25.45 (challenge) Design a synthesis of 5-decene starting from pentanal and an appropriate phosphorus ylide.

25.46 (challenge) Why does the Wittig reaction generate triphenylphosphine oxide as a byproduct? What is the thermodynamic driving force? (Hint: P=O bond energy.)

Section H — Spectroscopy and identification

25.47∗ (routine) A compound is reduced with NaBH₄. Before: IR 1720 cm⁻¹, δ 9.8 (singlet). After: IR 3300 broad, no 1720 peak; δ 3.6 (CH-OH region). What was the starting compound?

25.48 (routine) A compound has IR 1720 and ¹H NMR singlet at δ 2.2. After treatment with EtMgBr + H₃O⁺, the IR shows broad 3400 and the ¹H shows new CH₃ peaks. What was the starting compound and what was the product?

25.49 (moderate) A compound has IR 1720 cm⁻¹ + 2820/2720 doublet (aldehyde C-H). After treatment with HCN, the IR loses the 1720 peak and the carbonyl is replaced by a C-O alcohol stretch. What is the product? Predict ¹³C chemical shifts of the new compound.

25.50 (moderate) Distinguish between: (a) the cyclic acetal of acetone with ethylene glycol (1,3-dioxolane derivative) and (b) the open-chain acetal of acetone with 2 methanol equivalents. What ¹³C and ¹H differences do you expect?

25.51 (challenge) Three compounds with formula C₅H₁₀O. (a) IR 1720, δ 9.8 → an aldehyde, pentanal? (b) IR 1715, no aldehyde H → a ketone, 3-pentanone or 2-pentanone? (c) IR 3400 broad, δ 3.6 (CH-OH) → an alcohol. Identify each and propose a synthesis from a single starting material.

Section I — Biology and applications

25.52∗ (routine) Identify the carbonyl-addition step in: (a) glycolysis, (b) gluconeogenesis, (c) fatty acid biosynthesis, (d) amino acid metabolism (PLP enzymes).

25.53 (routine) The Maillard browning reaction (in toast, roasted coffee) starts with imine formation between a sugar and an amine. Sketch the imine intermediate. Why is the product brown? Hint: heterocyclic aromatics form downstream.

25.54 (moderate) Vision: the chromophore in rhodopsin is retinal bound to opsin via a Schiff base (imine). When a photon hits, retinal isomerizes from 11-cis to all-trans, and the imine eventually hydrolyzes. Why is the imine reversibility important for vision?

25.55 (moderate) A drug is made by Grignard addition to a ketone, installing a quaternary carbon. Identify potential side reactions and how to suppress them.

25.56 (challenge) Design a synthesis of dl-alanine from acetaldehyde + ammonia + HCN (Strecker synthesis). Show every step including the hydrolysis of the α-aminonitrile to the α-amino acid.

25.57 (challenge) Pyruvate + NADH → lactate. Identify the mechanism (carbonyl reduction by hydride source) and the enzyme (lactate dehydrogenase). Compare to NaBH₄ + ketone in vitro.

25.58 (challenge) Aldolase enzymes (Ch 28) catalyze a Mannich/aldol reaction in glycolysis (step 4). The first part is hemi-aminal formation between fructose-1,6-bisphosphate and a lysine on the enzyme. Describe the imine/enamine intermediate and predict the next step (retro-aldol cleavage).

25.59 (challenge) Aspirin's ester carbonyl is too electrophilic to be a stable hemiacetal — but cyclohexanone's hemiacetal with methanol is a marginal equilibrium species. Why? Connect to the Ch 24 reactivity ranking.

25.60 (challenge) Combine three reactions in a single synthesis: aldehyde → imine → reduction → amine → alkylation. Use this to plan a synthesis of N,N-dimethylbenzylamine starting from benzaldehyde.

Notes for instructors: This is the foundational chapter for nucleophilic addition. Common stumbling blocks: (1) confusing addition (Family I) with acyl substitution (Family II) — addition leaves the nucleophile bonded to C; substitution displaces a leaving group. (2) Mixing up NaBH₄ vs LiAlH₄ selectivity — emphasize the milder/aggressive distinction. (3) Forgetting that imine formation is reversible (vision biology) while Grignard addition is not. Computational exercises: optimize cyclohexanone in Avogadro; use it to predict the Bürgi-Dunitz approach angle and the equatorial vs axial face preferences.