Chapter 22 — Exercises

Forty-eight problems on substituent effects in electrophilic aromatic 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 — Classifying substituents

22.1∗ (routine) Classify each substituent as activating or deactivating, and as ortho/para-directing or meta-directing: (a) -OH (b) -NO₂ (c) -CH₃ (d) -CN (e) -Br (f) -NH₂ (g) -COOH (h) -OCH₃ (i) -CF₃ (j) -SO₃H (k) -CHO (l) -O⁻

22.2 (routine) Rank the following groups in order of activating strength toward EAS (most activating → least): -CH₃, -OCH₃, -NH₂, -O⁻, -OH.

22.3 (routine) Rank the following groups in order of deactivating strength toward EAS (most deactivating → least): -COOH, -NO₂, -CN, -SO₃H, -COOR.

22.4 (moderate) Why is -O⁻ (phenoxide) a stronger activator than -OH? Why is -NH₂ a stronger activator than -NHCOCH₃ (acetanilide)?

22.5 (challenge) Predict the activator/deactivator behavior of -N(CH₃)₂ vs -NH₂ vs -NH₃⁺. Connect to lone pair availability and protonation.

Section B — Predicting regiochemistry of mono-substituted rings

22.6∗ (routine) Predict the major product(s) of the following nitrations: (a) toluene + HNO₃/H₂SO₄ → ? (b) nitrobenzene + HNO₃/H₂SO₄ → ? (c) anisole (methoxybenzene) + HNO₃/H₂SO₄ → ? (d) bromobenzene + HNO₃/H₂SO₄ → ? (e) benzoic acid + HNO₃/H₂SO₄ → ? (f) benzonitrile + HNO₃/H₂SO₄ → ?

22.7 (routine) Predict the major product of: (a) toluene + Br₂/FeBr₃ → ? (b) nitrobenzene + Br₂/FeBr₃ → ? (c) phenol + Br₂ (no Lewis acid needed!) → ? (d) acetophenone + Br₂/FeBr₃ → ?

22.8 (moderate) When toluene is brominated, the para:ortho ratio is roughly 60:40 (para favored). When chlorination is performed, the para:ortho ratio is closer to 65:35. Why does the larger halogen give more para selectivity?

22.9 (moderate) Anisole + Br₂ gives 4-bromoanisole + 2-bromoanisole in roughly 95:5 ratio. Why is anisole so para-selective compared to toluene (60:40)?

22.10 (moderate) Predict ortho:meta:para distribution from nitration of: (a) ethylbenzene (b) methyl benzoate (PhCOOCH₃) (c) chlorobenzene

Section C — Drawing arenium ions

22.11∗ (moderate) Draw all three resonance structures of the arenium ion that forms when toluene is attacked at the para position by NO₂⁺. Identify which structure is most stable and explain.

22.12 (moderate) Repeat 22.11 for the meta position. Explain why the para arenium is more stable than the meta arenium.

22.13 (moderate) Draw all three resonance structures for the arenium ion that forms when nitrobenzene is attacked at the ortho position. Show why a positive charge ends up adjacent to the -NO₂ group, and why this destabilizes the intermediate.

22.14 (challenge) Compare the arenium ions for ortho, meta, and para attack on: (a) anisole (methoxybenzene) (b) chlorobenzene (c) acetanilide (PhNHCOCH₃)

Show the fourth resonance structure (with lone pair donation from O, Cl, or N) for ortho and para attacks. Why is no analogous structure available for meta attack?

Section D — The halogen exception

22.15∗ (routine) Halogens (-F, -Cl, -Br, -I) are deactivating yet ortho/para-directing. Explain in two parts: (a) Why deactivating? (inductive/electronegativity argument) (b) Why ortho/para-directing? (resonance argument)

22.16 (moderate) Of -F, -Cl, -Br, -I, which is the strongest deactivator? Why? Connect to electronegativity and to π-donation efficiency (orbital size match).

22.17 (moderate) Predict the product of nitration of fluorobenzene. Compare with nitration of chlorobenzene. Are the two products in similar yields, or does one give substantially more para selectivity? Why?

22.18 (challenge) -CF₃ is strongly deactivating and meta-directing — quite different from -Cl. Why? (Hint: the C of CF₃ has no lone pair to donate.)

Section E — π-donor vs π-acceptor classification

22.19 (routine) Classify each as a π-donor (lone pair on the atom attached to the ring) or π-acceptor (π* orbital extending from the atom attached to the ring) or neither: (a) -NO₂ (b) -OH (c) -CHO (d) -NH₂ (e) -CH₃ (f) -CN (g) -OCH₃ (h) -SO₃H (i) -COOR

22.20 (moderate) Some groups are σ-acceptors (electron-withdrawing inductively) AND π-acceptors (electron-withdrawing by resonance). Identify three from problem 22.19. Why are these the strongest deactivators?

22.21 (moderate) -NHCOCH₃ (amide) and -NH₂ (amine) are both π-donors. Why is the amine a stronger activator? Connect to lone pair availability and the C=O competition for the N lone pair.

22.22 (challenge) -OCOCH₃ (ester) and -OH (hydroxyl) are both π-donors. Compare their activating strengths. Which is more activating? Why?

Section F — Multi-substituted rings

22.23∗ (routine) Predict the major product of bromination of: (a) p-xylene (1,4-dimethylbenzene) (b) m-xylene (1,3-dimethylbenzene) (c) o-xylene (1,2-dimethylbenzene)

22.24 (moderate) Predict the major product of nitration of: (a) p-cresol (4-methylphenol) (b) p-bromotoluene (1-bromo-4-methylbenzene) (c) p-nitrotoluene (1-methyl-4-nitrobenzene) (d) m-nitrotoluene (1-methyl-3-nitrobenzene)

22.25 (moderate) When the two existing substituents on a ring give conflicting predictions, which wins? Apply this to: 4-methylanisole + Br₂. The methyl directs ortho/para to itself (positions 3 and 5); methoxyl directs ortho/para to itself (positions 2 and 6). Which group wins?

22.26 (challenge) Predict the major product of nitration of m-nitroaniline (1-amino-3-nitrobenzene). Where does the new -NO₂ go? Justify with resonance arguments.

22.27 (challenge) Mucic acid analog: predict the major product of nitration of 1-chloro-3-methoxybenzene.

Section G — Hammett equation

22.28∗ (moderate) The Hammett equation: log(k/k₀) = ρσ. Define each variable and explain its physical meaning.

22.29 (moderate) Hammett σ values: - σ_para(NO₂) = +0.78 - σ_para(Cl) = +0.23 - σ_para(CH₃) = -0.17 - σ_para(OCH₃) = -0.27

Predict whether each para-substituted benzoic acid is more or less acidic than benzoic acid: (a) p-nitrobenzoic acid (b) p-chlorobenzoic acid (c) p-methoxybenzoic acid (d) p-toluic acid (4-methylbenzoic acid)

22.30 (moderate) A reaction has ρ = +2.5. Does it favor electron-donor or electron-withdrawing substituents? What does this say about the buildup of charge in the transition state?

22.31 (moderate) A reaction has ρ = -3.0. Does it favor electron-donor or electron-withdrawing substituents? What does this say about the transition state? Connect to a possible example (cation-stabilizing reaction).

22.32 (challenge) Saponification (hydrolysis) of methyl benzoate has ρ = +2.4. EAS bromination has ρ = -12 (much more negative!). Why is bromination so much more sensitive to substituent effects?

Section H — Multi-step synthesis design

22.33∗ (moderate) Design a synthesis of 3-bromobenzoic acid from benzene. Show each EAS step and rationalize the order.

22.34∗ (moderate) Design a synthesis of 4-bromobenzoic acid from benzene. Show each EAS step.

22.35 (moderate) Design a synthesis of 4-bromonitrobenzene from benzene.

22.36 (moderate) Design a synthesis of 2-bromo-4-methylbenzoic acid from toluene.

22.37 (challenge) Design a synthesis of 4-aminobenzoic acid (PABA) from toluene. Sequential nitration + side chain oxidation + reduction.

22.38 (challenge) Design a synthesis of 3-bromo-4-nitrobenzoic acid from toluene. (4 EAS steps in a careful order!)

22.39 (challenge) Design a synthesis of 3,5-dinitrobenzoic acid from toluene. The two nitro groups must end up meta to each other and meta to a -COOH that you derive from the methyl.

Section I — Substituent modification

22.40 (routine) -NO₂ → -NH₂ via reduction. Common reagents: (a) Sn/HCl (b) Fe/HCl (c) H₂/Pd or H₂/Pt (d) SnCl₂ (e) Zn/HCl

Which is preferred industrially? Why?

22.41 (moderate) A diazonium salt (Ar-N₂⁺) can be converted to many functional groups (Sandmeyer reactions, etc.). List five conversions: (a) Ar-N₂⁺ → Ar-Cl (Sandmeyer) (b) Ar-N₂⁺ → Ar-Br (Sandmeyer) (c) Ar-N₂⁺ → Ar-CN (Sandmeyer) (d) Ar-N₂⁺ → Ar-OH (hot aqueous acid) (e) Ar-N₂⁺ → Ar-H (hypophosphorous acid, H₃PO₂)

What is the source of the diazonium? (Hint: Ar-NH₂ + HNO₂ at 0 °C.)

22.42 (moderate) Use diazonium chemistry to design a synthesis of 3-fluorobenzoic acid from toluene. (Diazonium → fluoride via Schiemann reaction: Ar-N₂⁺ BF₄⁻ → Ar-F + BF₃ + N₂.)

22.43 (challenge) Use diazonium chemistry to design a synthesis of 3,5-dibromoaniline from aniline. Strategy: protect the amine, brominate, then unprotect.

Section J — Industrial / practical applications

22.44 (moderate) TNT (2,4,6-trinitrotoluene) requires three sequential nitrations of toluene. Why is each nitration progressively harder? What conditions are needed for the third nitration?

22.45 (moderate) Aspirin synthesis (Kolbe-Schmitt route): phenol + CO₂ → salicylic acid → aspirin. Predict the major product of phenol + CO₂ + base. Why does CO₂ go ortho to -OH?

22.46 (challenge) Acetaminophen synthesis: aniline → acetanilide → 4-nitroacetanilide → 4-aminophenol → acetaminophen. Why protect the amine before nitration? Why does -NHCOCH₃ direct para?

22.47 (challenge) A pharmaceutical chemist needs to make 3-amino-4-hydroxybenzoic acid in 4 steps. Design the synthesis from a benzene starting material.

Section K — Open-ended

22.48 (challenge) Compare the substituent effects framework with (a) Hammett σ values for sigma bond reactions (e.g., aryl halide solvolysis), and (b) substituent effects in pKa of phenols (Ch 6). Why does the same σ value predict trends in such different reactions? What does this say about the framework's universality?

Notes for instructors: Common stumbling blocks for Chapter 22: (1) confusing inductive vs. resonance contributions; (2) forgetting the halogen exception; (3) order of steps in multi-step synthesis (substituent installed first determines where the next goes); (4) confusing protonated -NH₃⁺ (deactivating) with neutral -NH₂ (activating). Computational exercises: visualize HOMO of toluene vs nitrobenzene to see π-donor / π-acceptor effects directly.