Chapter 26 — Exercises

Sixty problems on nucleophilic acyl substitution. 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

26.1∗ (routine) Predict the major product of each: (a) acetyl chloride + ethanol (b) acetyl chloride + methylamine (c) acetic anhydride + 1-butanol (d) acetic anhydride + ammonia (e) methyl acetate + NaOH (excess) + water + heat (f) methyl acetate + NH₃ + heat (g) propanoyl chloride + sodium acetate (h) acetamide + HCl + water + reflux

26.2 (routine) Predict the major product: (a) benzoyl chloride + 2-propanol (b) phenol + acetic anhydride + H⁺ (c) ethyl benzoate + LiAlH₄, then aqueous workup (d) propyl propanoate + 2 PhMgBr, then aqueous workup (e) 4-methylbenzoyl chloride + dimethylamine

26.3∗ (routine) Salicylic acid + acetic anhydride + H₂SO₄ → ? Identify the product (aspirin) and the byproduct (acetic acid). Predict the IR shift for the new C=O.

26.4 (moderate) Pivaloyl chloride (2,2-dimethylpropanoyl chloride) + ethanol → ester. Why is this slower than acetyl chloride + ethanol despite both being acid halides? Identify the steric origin.

26.5 (moderate) Trifluoroacetic acid (CF₃COOH) reacts with methanol much faster than acetic acid does. Why? Identify the electronic origin.

26.6 (challenge) A dipeptide ($H_2N$-Gly-Ala-COOH) is hydrolyzed in 6N HCl + reflux. Predict the products and the chemoselectivity.

Section B — Mechanism drawing

26.7∗ (routine) Draw the full mechanism with arrows for: acetic anhydride + methanol + acid → methyl acetate + acetic acid.

26.8 (routine) Draw the full mechanism for: methyl acetate + NaOH → sodium acetate + methanol (saponification). Show the tetrahedral intermediate.

26.9∗ (moderate) Draw the full mechanism for the Fischer esterification: acetic acid + ethanol + H⁺ ⇌ ethyl acetate + H₂O. Include all six elementary steps and identify the rate-determining step.

26.10 (moderate) Draw the mechanism for: acetyl chloride + dimethylamine → N,N-dimethylacetamide + HCl. Show the tetrahedral intermediate.

26.11 (moderate) Draw the mechanism for the aspirin synthesis: salicylic acid + acetic anhydride + H₂SO₄ → aspirin + acetic acid. Identify each step.

26.12 (challenge) Draw the mechanism for amide hydrolysis under acidic conditions: acetamide + HCl + heat → acetic acid + ammonium chloride. Why does this require harsh conditions? Identify the rate-determining step.

26.13 (challenge) Draw the mechanism for amide hydrolysis under basic conditions: acetamide + NaOH + heat → sodium acetate + ammonia.

26.14 (challenge) Draw the mechanism for DCC coupling of acetic acid + methylamine + DCC → N-methylacetamide + dicyclohexylurea (DCU). Show the O-acylisourea intermediate.

Section C — Reactivity ordering

26.15∗ (routine) Rank the rate of hydrolysis (in water, no catalyst) of: acetyl chloride, acetic anhydride, methyl acetate, acetamide.

26.16 (routine) Rank the rate of reaction with methylamine of: methyl acetate, methyl trifluoroacetate, methyl benzoate.

26.17 (moderate) Why is the carboxylate (RCOO⁻) the slowest acyl substrate? Use resonance arguments.

26.18 (moderate) Draw a reaction-coordinate diagram showing the relative energies of: acid chloride + Nu⁻ < anhydride + Nu⁻ < ester + Nu⁻ < amide + Nu⁻. Identify the rate-determining step in each.

26.19 (challenge) Predict the half-life of an amide in water at 25 °C without catalyst (use Wolfenden's 2011 data: ~600 years). Convert to a rate constant. Compare to acetyl chloride hydrolysis (t₁/₂ ~10 sec).

26.20 (challenge) A 4-nitrobenzoate ester is much more reactive than a regular benzoate. Why? Use a Hammett analysis (Ch 22 if needed).

Section D — Acyl chlorides and Gilman reagents

26.21∗ (routine) Predict the product: butanoyl chloride + Ph₂CuLi (Gilman reagent) + cold workup. Why does this stop at a ketone rather than going to a tertiary alcohol?

26.22 (routine) Predict the product: acetyl chloride + 2 PhMgBr + H₃O⁺. Why does this go all the way to a tertiary alcohol?

26.23 (moderate) A student mixes acetyl chloride and ethyl Grignard in a 1:1 ratio. Predict the product distribution. Why is selectivity for the ketone hard to achieve with Grignard?

26.24 (challenge) Design a synthesis of 4-octanone from butanoyl chloride and a Grignard or organometallic. Explain your choice.

Section E — Esters and Fischer

26.25∗ (routine) Predict the product: butanoic acid + 1-butanol + H₂SO₄ catalyst, with water removed.

26.26 (routine) A Fischer esterification of acetic acid + methanol gives methyl acetate (not ethyl acetate). Why? What if you used ethanol instead?

26.27 (moderate) What is the equilibrium constant of a Fischer esterification, approximately? Why is this approximately the same regardless of the specific acid and alcohol?

26.28 (moderate) Design a synthesis of methyl 4-bromobenzoate. Compare a Fischer esterification approach to an acid-chloride-based approach.

26.29 (moderate) A transesterification: methyl acetate + ethanol + H⁺ ⇌ ethyl acetate + methanol. What is the equilibrium constant approximately? Why?

26.30 (challenge) Saponification of an ester is irreversible because the carboxylate product is unreactive. But the corresponding hydrolysis of an amide is also (partially) irreversible. Why? Hint: think about what happens after amide hydrolysis under basic conditions.

26.31 (challenge) Biodiesel production: vegetable oil (a triester of glycerol with three fatty acids) + 3 methanol + base catalyst → 3 fatty acid methyl esters + glycerol. Identify this as a transesterification. Why is this the preferred industrial method? What is the role of base?

Section F — Amides and peptide synthesis

26.32∗ (routine) Predict the product: glycine (an amino acid: H₂N-CH₂-COOH) + alanine (H₂N-CH(CH₃)-COOH) + DCC. Identify the product as a dipeptide.

26.33 (routine) Why is DCC preferred over an acid chloride for peptide bond formation? Identify two issues.

26.34 (moderate) A coupling reaction is performed at 0 °C in DMF using HBTU. Why are these conditions chosen?

26.35 (moderate) β-lactam antibiotics (penicillin, cephalosporin) contain a strained 4-membered amide. Why is the C=O of this amide much more reactive than a normal amide? Compare to ring-strain effects discussed in Chapter 24.

26.36 (challenge) Trans-amidation: an amide (RCONR'_2) + new amine (R''NH_2) → new amide + R'_2NH. Predict whether this is fast or slow. Explain.

26.37 (challenge) Design a synthesis of N-methylbenzamide using two different routes: (a) via benzoyl chloride + methylamine, (b) via Fischer-style amidation using benzoic acid + methylamine + DCC. Compare yield, conditions, and byproducts.

Section G — Thioesters and biology

26.38∗ (routine) Why is acetyl-CoA more reactive than methyl acetate toward attack by a serine OH? Use the reactivity arguments from Section 26.8.

26.39 (routine) Pyruvate + CoA-SH + NAD⁺ → acetyl-CoA + CO₂ + NADH (pyruvate dehydrogenase). Identify the acyl substitution step in this multi-step transformation.

26.40 (moderate) Fatty acid biosynthesis: acyl-ACP + malonyl-ACP → β-keto acyl-ACP + CO₂ + ACP-SH. Identify the acyl substitution step (one of the malonyl C=O is attacked by the acyl-ACP enolate; the malonyl-S-ACP is the leaving group).

26.41 (challenge) Cholesterol biosynthesis: HMG-CoA + 2 NADPH → mevalonate + CoA-SH (HMG-CoA reductase, the target of statin drugs). Identify the reduction step and the carbonyl-substitution step.

26.42 (challenge) Histone acetyltransferase (HAT) enzymes use acetyl-CoA to acetylate histone lysine residues. Sketch the mechanism — identify the acyl substitution.

Section H — Aspirin's mechanism

26.43∗ (routine) Aspirin's mode of action: aspirin + COX-Ser-OH → salicylate + acetyl-COX-Ser. Identify the carbonyl class involved (aspirin's ester carbonyl). Sketch the mechanism with arrows.

26.44 (routine) Why is aspirin's acetylation of COX irreversible (as long as new COX isn't synthesized)?

26.45 (moderate) A student claims that aspirin's COOH carbonyl is the one targeted in COX inhibition. Critique this claim by analyzing the relative reactivities of aspirin's ester C=O and COOH.

26.46 (moderate) Aspirin's effect on platelet COX (cyclooxygenase) lasts ~10 days because platelets cannot synthesize new protein. Connect this to the irreversibility of acyl substitution.

26.47 (challenge) Design a "second-generation aspirin" with similar mode of action but better COX-2 selectivity. (Hint: see celecoxib, a COX-2 selective inhibitor that does not work by acyl transfer but by reversible binding.)

Section I — Spectroscopy and analytical

26.48∗ (routine) A compound has IR 1735 cm⁻¹. After treatment with NaOH and aqueous workup, it gives a compound with IR 3300 broad and 1715 cm⁻¹ (with broad O-H). Identify both compounds.

26.49 (routine) Acetyl chloride absorbs at 1800 cm⁻¹; acetic acid at 1715 cm⁻¹; methyl acetate at 1745 cm⁻¹. Justify the trend.

26.50 (moderate) A compound has IR 1660 + 3300 (broad). After treatment with HCl + reflux, it gives IR 1715 + 3300 (broad). Identify both compounds and the transformation.

26.51 (moderate) ¹³C NMR of an ester: the ester C=O shifts to 165–175 ppm. After saponification, the carboxylate C is at 175–185 ppm. Why does the carboxylate appear higher field?

26.52 (challenge) A natural product has formula C₁₂H₁₅NO₃ and shows IR peaks at 1735 (ester), 1660 (amide), and 3400 (broad NH/OH). ¹³C peaks at 175 (ester C), 170 (amide C), and 56 (OCH₃). Propose a reasonable structure.

Section J — Multistep and integrative

26.53∗ (routine) Design a synthesis of phenylacetic acid from benzaldehyde, using a cyanohydrin (Strecker-style) intermediate.

26.54 (routine) Design a synthesis of N-acetylserine (an N-acetyl amino acid) from serine + acetic anhydride.

26.55 (moderate) Design a synthesis of an N-protected amino acid (Boc-glycine) from glycine + di-tert-butyl dicarbonate (Boc anhydride).

26.56 (moderate) Design a synthesis of glycerol triacetate (a triester) from glycerol + 3 equivalents of acetic anhydride.

26.57 (challenge) Design a synthesis of acetylsalicylic acid (aspirin) from anthranilic acid (2-aminobenzoic acid). Plan a 3-step route.

26.58 (challenge) Design a one-pot synthesis of an amide from a carboxylic acid + amine + an activating reagent. Compare DCC, EDC, and HBTU.

26.59 (challenge) A student claims that SOCl₂ + COOH gives the acid chloride directly without intermediates. Draw the mechanism showing the chlorosulfite intermediate. Why is this mechanism preferred over an SN1 or SN2 cleavage of COOH?

26.60 (challenge) Design a synthesis of an ester from a carboxylic acid using a "modern" method (e.g., DCC + DMAP catalyst). Compare to the classical Fischer method. When would you use each?

Notes for instructors: This chapter is critical for organic synthesis. Common stumbling blocks: (1) confusing acid catalysis (Fischer ester, reversible) with base catalysis (saponification, irreversible). (2) Forgetting that amide formation requires activation. (3) Failing to predict the leaving group in mixed substrates (e.g., aspirin synthesis: which C=O of acetic anhydride does the phenol attack? Both halves are equivalent). Computational exercises: optimize methyl acetate, acetamide, and acetyl chloride in Avogadro; calculate the C=O bond order and HOMO-LUMO gap; correlate with the experimental hydrolysis rate.