Chapter 24 — Exercises

Fifty-five problems on the carbonyl group, its structure, the three reactivity families, the reactivity ordering, and the diagnostic spectroscopy. Drawing required wherever a structure or mechanism is asked for. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — Identification and classification

24.1∗ (routine) Classify each compound as aldehyde, ketone, carboxylic acid, ester, amide, acid halide, anhydride, or nitrile. For each, draw the structural formula and circle the carbonyl carbon. (a) $CH_3CHO$ (b) $CH_3COCH_3$ (c) $CH_3COOH$ (d) $CH_3COOC_2H_5$ (e) $CH_3CONH_2$ (f) $CH_3COCl$ (g) $(CH_3CO)_2O$ (h) $CH_3CN$ (i) $C_6H_5CHO$ (benzaldehyde) (j) $HCOOH$ (formic acid)

24.2 (routine) For each compound in 24.1, predict the formal name of the molecule including the parent chain and the suffix that identifies the carbonyl class.

24.3 (routine) Aspirin (acetylsalicylic acid) contains two carbonyl groups. Draw the molecule and label each carbonyl by its functional class (one is a carboxylic acid; one is an ester). Why does aspirin's reactivity in the body depend on the ester rather than the COOH?

24.4 (routine) Identify and classify every carbonyl group in: (a) ibuprofen, (b) acetaminophen, (c) thalidomide, (d) penicillin G. Draw each molecule and label.

24.5 (moderate) A student says "all C=O groups are the same — they're all just carbonyls." Critique this statement using specific examples of how reactivity differs across the family.

24.6∗ (moderate) Glucose in solution exists ~99% as a 6-membered ring (pyranose). Draw both the open-chain (aldehyde) and the cyclic (hemiacetal) forms. Why does the cyclic form not have a free C=O? Where did it go?

24.7 (challenge) Vitamin C (ascorbic acid) contains a 5-membered ring with an enol next to a carbonyl. Draw the structure. How many carbonyl-related functional groups does it have? Hint: there are subtleties.

24.8 (challenge) A natural product has the formula $C_{12}H_{16}O_3$ and shows IR peaks at 1740, 1700, and 3400 cm⁻¹. What functional groups are likely present? Sketch a candidate structure.

Section B — Polarization, dipole, and electronics

24.9∗ (routine) Draw the two main resonance structures of $C=O$. Which one shows the carbon as electrophilic? What does the dipole arrow look like?

24.10 (routine) Compute the approximate dipole moment of acetaldehyde (CH₃CHO) given the C-O dipole is ~2.7 D and the C-H dipoles are ~0.4 D. Justify why acetaldehyde has a measured dipole of ~2.75 D.

24.11 (moderate) Why is the C=O bond shorter (1.21 Å) than the C=C bond (1.34 Å)? Use the concept of polar covalent character and atomic radius.

24.12 (moderate) Why is the C=O bond stronger (178 kcal/mol) than the C=C bond (146 kcal/mol)? Polar bonds are usually said to be stabilized by ionic resonance — explain this idea.

24.13 (challenge) Compare the dipole moment of acetone (~2.9 D) to that of dimethyl sulfoxide (DMSO, ~3.96 D). Why is the S=O dipole larger? Hint: think about which atom holds more positive character and the bond polarity.

24.14 (challenge) Compute (qualitatively) why an ester has a smaller dipole moment than the corresponding ketone. Hint: the ester has two oxygens with overlapping dipole vectors.

Section C — Reactivity ordering

24.15∗ (routine) Rank the following five compounds in order of increasing reactivity toward nucleophilic attack at the carbonyl: acetic acid, methyl acetate, acetyl chloride, acetic anhydride, acetamide.

24.16 (routine) Justify the reactivity order in 24.15 using two arguments: (a) the leaving-group ability of the substituent and (b) the resonance donation of the substituent into the carbonyl C.

24.17 (moderate) Why is an amide so much less reactive than an ester, despite both having two heteroatoms attached to the carbonyl C? Use resonance to show why.

24.18 (moderate) Carboxylate anion ($RCOO^-$) is even less reactive than amide. Why? Draw the resonance structure that explains the very low electrophilicity of the central carbon.

24.19 (challenge) A student claims acid halides should be slower than aldehydes because the chlorine has lone pairs that should donate into the carbonyl. Critique this claim using the inductive vs. resonance argument.

24.20 (challenge) Compare the relative reactivity of a thioester ($R-CO-S-R'$) to that of an oxoester ($R-CO-O-R'$). Hint: sulfur is a much better leaving group than oxygen but a much worse π donor. Predict the experimental observation that thioesters are about 10⁵ times more reactive than esters.

24.21 (challenge) Acetyl-CoA in metabolism is a thioester. Why is biology evolved to use a thioester (CoA) rather than an oxoester for acyl transfer reactions? Use 24.20 to argue.

Section D — Spectroscopy

24.22∗ (routine) Predict the IR C=O stretch frequency (in cm⁻¹) for each: (a) propanal (b) acetone (c) propionic acid (d) methyl propionate (e) propionamide (f) propionyl chloride (g) acetic anhydride

24.23 (routine) A compound shows IR C=O at 1715 cm⁻¹. Is it an aldehyde, ketone, ester, amide, or acid halide? Justify.

24.24 (routine) A compound shows IR C=O at 1660 cm⁻¹ and a broad N-H around 3300 cm⁻¹. Identify the functional class.

24.25 (moderate) A compound shows IR peaks at 2820 and 2720 cm⁻¹ (the "aldehyde doublet") plus C=O at 1720 cm⁻¹. What functional class is this? Why are the 2820/2720 peaks diagnostic?

24.26 (moderate) Cyclopropanone has an IR C=O stretch at ~1815 cm⁻¹. Why is this much higher than acetone's (1715 cm⁻¹)? Hint: ring strain and orbital character.

24.27 (moderate) Conjugated carbonyls (e.g., methyl vinyl ketone, $CH_2=CHCOCH_3$) absorb at lower wavenumber (~1680 cm⁻¹) than saturated ones (~1715 cm⁻¹). Why? Hint: π conjugation lengthens C=O.

24.28∗ (moderate) ¹³C chemical shifts (ppm): (a) acetone carbonyl C: ___ (estimate) (b) acetic acid carbonyl C: ___ (c) methyl acetate carbonyl C: ___ (d) acetamide carbonyl C: ___ (e) acetyl chloride carbonyl C: ___ Predict and justify the order from highest to lowest field.

24.29 (challenge) Two compounds have the molecular formula $C_4H_8O$. One is an aldehyde with IR at 1720 cm⁻¹ and ¹H NMR with a peak at δ 9.7. The other is a ketone with IR at 1715 cm⁻¹. Without further data, can you determine which compound is which? What additional spectrum would clinch it?

24.30 (challenge) A compound has mass spectrum with M⁺ at 86, peak at 71 (M-15), peak at 43 (M-43), and intense peak at 43 itself. Propose a structure.

Section E — Three reactivity families

24.31∗ (routine) For each carbonyl compound, predict which of the three families of reactivity (addition, acyl substitution, α-carbon chemistry) is the dominant pathway when reacted with a generic nucleophile $Nu^-$: (a) cyclohexanone + $Nu^-$ (b) methyl benzoate + $Nu^-$ (c) propanoyl chloride + $Nu^-$ (d) propionic acid + $Nu^-$ (e) butan-2-one + $LDA$ (a non-nucleophilic, very strong base)

24.32 (routine) Why does an aldehyde follow the addition pathway (with the nucleophile staying on C) while an ester follows the acyl substitution pathway (with the nucleophile replacing the OR group)? Hint: think about leaving groups.

24.33 (moderate) Predict the product of each reaction: (a) acetone + $NaBH_4$ (b) methyl acetate + $NaBH_4$ (c) acetic acid + $LiAlH_4$ (d) acetamide + $LiAlH_4$ Compare the outcomes and explain why $LiAlH_4$ is needed for COOH/amide while $NaBH_4$ works on aldehydes/ketones.

24.34 (moderate) $\alpha$-Carbon chemistry (Ch 27-29) requires that the carbonyl have an $\alpha$-hydrogen — a hydrogen on the carbon adjacent to the C=O. Identify all $\alpha$-hydrogens in: (a) acetone (b) cyclohexanone (c) acetaldehyde (d) ethyl acetate (e) acetamide Why does $\alpha$-carbon chemistry depend on the presence of these hydrogens?

24.35 (challenge) Acetic anhydride can react with a nucleophile via either acyl substitution or some other pathway. Predict the dominant outcome for $(CH_3CO)_2O + RNH_2$ and justify.

24.36 (challenge) When acetone is treated with a strong base like $NaOH$, it can undergo an aldol reaction. Draw the enolate of acetone and explain why this enolate is the key reactive species in $\alpha$-carbon chemistry.

Section F — Biology and applications

24.37∗ (routine) Identify the carbonyl groups in: (a) glucose (open-chain) (b) glycine (amino acid) (c) palmitate (16-carbon fatty acid) (d) acetyl-CoA (just the carbonyl portion) (e) testosterone

24.38 (routine) A peptide bond is an amide. Why does this matter for protein structure? List three structural consequences of the C-N partial double bond.

24.39 (moderate) Explain how glucose's open-chain aldehyde form is responsible for hemiacetal formation when glucose dissolves in water. What ring size results, and why?

24.40 (moderate) Aspirin's mechanism in the body is acyl transfer from the ester to a serine hydroxyl on the COX enzyme. Describe this reaction in the language of Section 24.2 (acyl substitution).

24.41 (challenge) Fatty acid biosynthesis is a series of Claisen condensations (Ch 28). Why must the substrates be thioesters (linked to ACP/CoA) rather than oxoesters? Connect to 24.20-24.21.

24.42 (challenge) Penicillin contains a strained 4-membered β-lactam (cyclic amide). The IR C=O stretch is ~1780 cm⁻¹ — much higher than a normal amide. Why? Connect to 24.26 (cyclopropanone). What does this say about penicillin's reactivity in the body?

Section G — Multistep and integrative

24.43∗ (routine) Acetone is converted into a cyclic hemiketal with ethylene glycol ($HOCH_2CH_2OH$). Draw the product and the mechanism. Compare to glucose's hemiacetal.

24.44 (moderate) A reaction is reported: methyl acetate + ammonia → acetamide + methanol. Predict the mechanism (acyl substitution) and predict the rate compared to a similar reaction with methylamine. Justify using nucleophilicity arguments.

24.45 (moderate) Two compounds with the same molecular formula $C_3H_6O_2$: methyl formate (HCOOCH₃) and acetic acid (CH₃COOH). Which is more reactive toward methylamine, and why?

24.46 (challenge) Predict: (a) the product of methyl benzoate + LiAlH₄ → ? (b) the IR of the product. (c) what classifies this as an example of the "addition" family despite the ester appearing in the acyl-substitution family.

24.47 (challenge) Design a synthesis of acetyl-coenzyme A starting from acetic acid and CoA-SH. Include the activation step (acetic acid is too unreactive; needs activation). Hint: in vivo biology uses ATP coupling.

Section H — Mechanism with arrows

24.48∗ (routine) Draw the full mechanism with curved arrows for the addition of $CN^-$ to acetone, forming acetone cyanohydrin.

24.49 (routine) Draw the full mechanism with curved arrows for the acyl substitution of methylamine into methyl acetate, forming N-methylacetamide and methanol.

24.50 (routine) Draw the full mechanism with curved arrows for the deprotonation of the α-carbon of acetone by $LDA$ to form the lithium enolate.

24.51 (moderate) Draw the full mechanism for the conversion of acetic acid to acetyl chloride using $SOCl_2$. Identify the electrophilic and nucleophilic atoms in each step.

24.52 (challenge) Write a careful mechanism for the hydrolysis of an amide ($RCONHR'$) under acidic conditions. Why is acid catalysis required? At what step is the rate-limiting transition state? (Hint: an amide is exceptionally stable and the resonance structure with C-N partial double bond is important.)

24.53 (challenge) A peptide bond hydrolyzes very slowly at neutral pH (half-life ~600 years). Yet enzymes (proteases) hydrolyze it in milliseconds. From a mechanistic perspective, what does the enzyme provide to accelerate this 10¹⁰-fold? Hint: catalysis pulls down the transition-state energy by stabilizing the tetrahedral intermediate.

24.54 (challenge) Predict the product and write the mechanism: cyclohexanone + LDA, then methyl iodide. (This is an enolate alkylation, Ch 27.) Identify the carbonyl family at work.

24.55 (challenge) Combine all three families in one molecule. Take 4-oxopentanoic acid (a γ-keto acid). Predict possible reactions if you treat it with: (a) NaBH₄, (b) NaOH then heat, (c) PCl₅ followed by NH₃. Identify which family of reactivity each scenario invokes.

Notes for instructors: Ch 24 is the foundational chapter for Part VI. Students who understand the polarization of C=O, the three families, and the reactivity ordering will succeed in Chs 25–31. Common stumbling blocks: confusing aldehydes (which add) with esters (which substitute); rationalizing why amides are slow (resonance, not just steric); confusing the "α" position with the carbonyl carbon. Computational exercises: optimize acetone, acetic acid, methyl acetate, and acetamide in Avogadro/WebMO; compute the C=O bond length and the natural bond orbital charges; correlate with the reactivity order from 24.15.