Chapter 30 — Exercises

Fifty-five problems on amines, their nucleophilicity, basicity, and reactions. Drawing required wherever a structure or mechanism is asked for. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — Classification and basicity

30.1∗ (routine) Classify each amine as 1°, 2°, 3°, or 4° (quaternary): (a) methylamine (b) dimethylamine (c) trimethylamine (d) tetramethylammonium chloride (e) aniline (f) N-methylaniline (g) pyridine (h) imidazole

30.2 (routine) Predict the pKaH of each amine in 30.1. Rank from most basic to least basic.

30.3∗ (routine) Why is aniline (pKaH 4.6) less basic than methylamine (pKaH 10.6)? Give the structural reason.

30.4 (routine) Why is pyridine (pKaH 5.2) less basic than pyrrolidine (pKaH 11.3)? Connect to the orbital character of the lone pair.

30.5 (routine) Why is pyrrole essentially non-basic (pKaH ~ -4)? Hint: where is the N lone pair?

30.6 (moderate) 4-Nitroaniline has pKaH 1.0 — much lower than aniline's 4.6. Why? Use a Hammett-style argument.

30.7 (moderate) 4-Methoxyaniline has pKaH 5.3 — slightly higher than aniline. Why? Hint: methoxy is a π donor.

30.8 (moderate) Why is an amide N essentially non-basic (pKaH < 0)? Connect to the resonance from Ch 24.

30.9 (challenge) Imidazole has two nitrogen atoms with very different pKaH values: one (the "pyridine-like") is basic (pKaH 7.0); the other (the "pyrrole-like") is acidic (pKa 14). Sketch imidazole and identify each N. Why are they different despite both being part of the same aromatic ring?

Section B — Amine nucleophilicity

30.10∗ (routine) Predict the products of: (a) methylamine + iodomethane (1 equiv) (b) methylamine + iodomethane (excess) (c) aniline + acetic anhydride (d) trimethylamine + iodomethane (e) ethylenediamine + 2 acetic anhydride

30.11 (routine) Why does direct alkylation of NH₃ by iodomethane give a mixture of methylamine, dimethylamine, trimethylamine, and tetramethylammonium iodide? Identify the over-alkylation problem.

30.12 (moderate) Predict whether ethylenediamine reacts mainly with one or both of two equivalents of acetic anhydride. What is the major product?

30.13 (moderate) Compare the rates of: (a) methylamine + iodoethane, (b) aniline + iodoethane. Which is faster, and why?

30.14 (challenge) A student wants to make N-methylaniline from aniline + iodomethane. The reaction gives a mixture (N-methyl, N,N-dimethyl, N,N,N-trimethylanilinium iodide). Suggest a strategy to obtain clean N-methylaniline.

Section C — Imine, enamine, amide formation

30.15∗ (routine) Predict the product: (a) methylamine + butanal + cat. acid (b) dimethylamine + cyclohexanone + cat. acid (c) methylamine + acetic anhydride (d) dimethylamine + acetyl chloride (e) ammonia + butanoyl chloride

30.16 (routine) Draw the mechanism for: methylamine + acetic anhydride → N-methylacetamide + acetic acid.

30.17 (routine) A student's reaction: methylamine + acetone + cat. HCl. Predict the product (an imine). Why is acid catalysis used?

30.18 (moderate) A student's reaction: dimethylamine + cyclohexanone + cat. HCl. Predict the product (an enamine). Why does the regiochemistry differ from imine formation?

30.19 (moderate) Reductive amination is a 2-step process: imine formation + reduction. Why is NaBH₃CN preferred over NaBH₄ for the reduction step? Hint: chemoselectivity.

30.20 (challenge) Amino acid coupling for peptide synthesis: glycine + alanine + DCC → Gly-Ala dipeptide + DCU. Identify the role of DCC and the mechanism (Section 26.6).

Section D — Synthesis methods

30.21∗ (routine) Design a synthesis of N-butylamine using the Gabriel synthesis. Show all steps.

30.22 (routine) Design a synthesis of N-methyl-2-aminoheptane via reductive amination. Identify the starting carbonyl and amine.

30.23 (routine) Design a synthesis of cyclohexylamine from cyclohexanone via reductive amination with ammonia.

30.24 (moderate) Design a synthesis of 2-aminobutane: (a) by Gabriel, (b) by reductive amination, (c) by reduction of a nitrile (use propanenitrile as starting material, $LiAlH_4$ for reduction).

30.25 (moderate) Design a synthesis of N-benzylpiperidine using a reductive amination approach.

30.26 (moderate) Design a synthesis of an aromatic primary amine (4-methylaniline) via reduction of the corresponding nitro compound (4-methylnitrobenzene + $H_2/Pd$).

30.27 (challenge) Design a stereoselective synthesis of (S)-2-aminobutane. (Hint: use a chiral source like an amino acid as starting material.)

30.28 (challenge) Compare the reductive amination of a ketone with a primary amine vs. with a secondary amine. Predict the products in each case and explain the difference.

Section E — Hofmann elimination and rearrangement

30.29∗ (routine) Predict the product of: tetrabutylammonium hydroxide + heat → ?

30.30 (routine) Predict the regiochemistry: 2-methyl-1-butyltrimethylammonium hydroxide + heat → ? (Hofmann or Zaitsev product?)

30.31 (moderate) Why does Hofmann elimination give the Hofmann (less-substituted) alkene rather than Zaitsev (more-substituted)? Identify the steric origin.

30.32 (moderate) Hofmann elimination is used in some industrial processes for selective alkene formation. Compare with E2 elimination of an alkyl halide. Which is more controllable?

30.33 (challenge) Hofmann rearrangement of an amide: butanamide + Br₂ + NaOH → propylamine + CO₂. Draw the mechanism showing the isocyanate intermediate. Why does the R group migrate from C to N?

30.34 (challenge) Compare the Hofmann rearrangement of butanamide with the Curtius rearrangement of butanoyl azide ($CH_3CH_2CH_2CON_3$). How are they similar mechanistically?

Section F — Diazonium chemistry

30.35∗ (routine) Design a synthesis of chlorobenzene from aniline using diazonium chemistry (Sandmeyer reaction).

30.36 (routine) Design a synthesis of phenol from aniline using diazonium chemistry (hydrolysis).

30.37 (routine) Design a synthesis of fluorobenzene from aniline using the Schiemann reaction.

30.38 (moderate) Design a synthesis of 4-bromoaniline from aniline. Hint: protect the amine, brominate, then deprotect; OR use Sandmeyer on a brominated diazonium intermediate.

30.39 (moderate) Predict the product: aniline + NaNO₂ + HCl + 0 °C, then warm to room T (no other reagent added) → ? (a phenol, via aryl cation intermediate).

30.40 (challenge) Design a synthesis of 4-bromo-2-iodoaniline from 4-bromonitrobenzene using diazonium chemistry.

30.41 (challenge) Sketch an azo dye synthesis: (a) 4-aminobenzenesulfonic acid + (b) 2-naphthol via diazonium coupling. Predict the structure of the dye and its color (yellow/orange/red region).

30.42 (challenge) Why does the diazonium salt explode at temperatures above 5 °C while the sulfonate or alkoxy salt does not? Hint: think about the stability of N₂ vs. C-N bond cleavage.

Section G — Heterocyclic amines

30.43∗ (routine) Identify whether each is an aromatic amine (pyridine-like, sp² N with lone pair available) or an aliphatic amine: (a) pyridine (b) piperidine (c) pyrrolidine (d) imidazole (e) tropine (f) 4-aminopyridine

30.44 (moderate) Compare the chemistry of pyridine + alkyl halide vs. piperidine + alkyl halide. What products result? Why?

30.45 (moderate) Draw the structure of nicotine (in tobacco) and identify the two amine nitrogens. What is their pKaH?

30.46 (challenge) Imidazole's protonation behavior: at pH 7, what fraction of histidine residues in proteins are protonated? Use the pKaH 6.0 of histidine's imidazole.

Section H — Biology and pharmacology

30.47∗ (routine) Identify the amine functional group(s) in: (a) dopamine (b) serotonin (c) epinephrine (d) GABA (e) acetylcholine

30.48 (routine) Draw the structure of morphine. Identify the amine and the phenol. What is morphine's pKaH and what is its protonation state at physiological pH?

30.49 (moderate) Why are most antihistamines tertiary amines? Connect to receptor binding and bioavailability.

30.50 (moderate) A student designs a drug with an amine pKaH of 12 (very basic). Predict whether this drug would be well-absorbed orally. Justify.

30.51 (challenge) A drug designer wants to "reduce" the pKaH of an amine in a lead compound. Suggest two structural modifications.

30.52 (challenge) The MAO (monoamine oxidase) enzyme oxidatively deaminates many neurotransmitters. Sketch the chemistry: amine → imine + H₂O₂ + NH₃. Identify the role of the enzyme.

Section I — Spectroscopy

30.53∗ (routine) A compound shows IR 3370 + 3290 (two peaks) and ¹H NMR 1.5 (broad, 2H, exchangeable). Identify the amine class.

30.54 (routine) A compound has IR 3320 (one peak) and ¹H NMR 2.4 (s, 3H, NCH₃). Identify the amine class.

30.55 (moderate) A compound has no N-H peaks in IR but shows ¹H NMR 2.3 (s, 9H, N(CH₃)₃). Identify the compound — likely a tertiary amine. What is the molecular formula if the molecular weight is 89?

Section J — Multistep and integrative

30.56 (routine) Design a synthesis of N,N-dimethylbenzylamine from benzaldehyde + dimethylamine via reductive amination.

30.57 (moderate) Combine SN2 alkylation + reductive amination to make a tertiary amine. Show a 3-step synthesis of N-ethyl-N-methylbenzylamine starting from benzaldehyde.

30.58 (challenge) Design a synthesis of an alkaloid (e.g., a tropane skeleton) using Robinson's tropinone synthesis. Identify the starting materials and the Mannich step.

30.59 (challenge) Design a synthesis of phenethylamine (the parent amphetamine) from benzaldehyde via two different methods.

30.60 (challenge) Design a synthesis of an N-acyl amino acid (like N-acetyl-L-alanine) from L-alanine + acetic anhydride. Identify the regiochemistry (the amine, not the COOH).

Notes for instructors: Common stumbling blocks for Chapter 30: (1) over-estimating amine basicity for aniline (it's much less basic than aliphatic amines because of resonance with the ring). (2) Confusing imine (1° amine + carbonyl) with enamine (2° amine + carbonyl). (3) Forgetting the over-alkylation problem with direct NH₃ + R-X. (4) Misidentifying which N atom of imidazole is the basic one. Computational exercises: predict pKaH of a series of heterocyclic amines (pyridine, pyrrole, imidazole, pyrazole) using DFT methods.