Chapter 23 — Exercises

Forty-six problems on nucleophilic aromatic substitution, benzyne chemistry, and aromatic side-chain 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 — Why aryl halides resist SN1/SN2

23.1∗ (routine) Why does chlorobenzene fail to react with NaOH under the standard SN2 conditions that work for n-propyl chloride? Give two reasons.

23.2 (routine) Why is the phenyl cation (Ph⁺) too unstable to form via SN1 in chlorobenzene? Connect to the geometry of the empty orbital.

23.3 (moderate) Compare the C-X bond strengths and the C-X bond lengths of methyl chloride vs chlorobenzene. Which has the stronger C-Cl bond? Why?

23.4 (moderate) Iodobenzene is roughly 100× faster than chlorobenzene in SN1-like solvolysis (in superacid). Why?

Section B — SNAr mechanism

23.5∗ (routine) Predict the product of: 2,4-dinitrochlorobenzene + NaOH → ? Show the Meisenheimer complex.

23.6 (routine) Sketch the Meisenheimer complex when 2,4-dinitrochlorobenzene reacts with NH₃. Show all resonance structures with charge delocalized to the nitro groups.

23.7 (routine) Why is 2,4-dinitrochlorobenzene more reactive in SNAr than 4-nitrochlorobenzene?

23.8 (moderate) Order the following in increasing rate of SNAr with NaOH: (a) chlorobenzene (b) 4-nitrochlorobenzene (c) 2,4-dinitrochlorobenzene (d) 2,4,6-trinitrochlorobenzene (e) 3-nitrochlorobenzene

23.9 (moderate) 3-Nitrochlorobenzene is much less reactive in SNAr than 4-nitrochlorobenzene. Why?

23.10 (challenge) Predict the major SNAr product: (a) 2,4-dinitrochlorobenzene + sodium ethoxide → ? (b) 4-nitro-1-fluorobenzene + sodium azide → ? (c) 2-nitro-4-cyanofluorobenzene + dimethylamine → ?

Section C — Reactivity order (F > Cl > Br > I)

23.11∗ (routine) Why is fluorobenzene more reactive than iodobenzene in SNAr (when activated by NO₂ groups)? Compare with SN2 (where I > F).

23.12 (moderate) A student is told that "aryl fluorides are more reactive than aryl iodides in SNAr." She objects: "but C-F is the strongest bond! How can this be?" Resolve her confusion. (Hint: addition is rate-determining; departure is fast.)

23.13 (challenge) In SNAr of 2,4-dinitro-X-benzene with methoxide, the relative rates are: F (100) : Cl (3) : Br (2) : I (1). The ratio reflects that F's small size and high electronegativity boost both the rate of nucleophilic attack and the stability of the Meisenheimer. Estimate the rate ratio if -CN replaced -NO₂.

Section D — Benzyne mechanism

23.14∗ (routine) Sketch the benzyne mechanism for chlorobenzene + NaNH₂ in liquid NH₃. Show the carbanion intermediate, the benzyne, and the final amine product.

23.15 (routine) Why does the benzyne mechanism give a 1:1 mixture of two products (when the substrate has an asymmetric labeling)?

23.16 (moderate) Roberts' 1953 isotope-labeling experiment: chlorobenzene with ¹⁴C at C1 + NaNH₂ → mixture of aniline labeled at C1 (50%) + aniline labeled at C2 (50%). What does this prove?

23.17 (moderate) Predict the benzyne products: (a) p-chloroanisole + NaNH₂ → ? (b) m-chloroanisole + NaNH₂ → ?

For (a), explain why the methoxyl directs the nucleophile to a specific position.

23.18 (challenge) The Kobayashi protocol generates benzyne from 2-(trimethylsilyl)phenyl triflate + CsF. Sketch the mechanism. Why is this milder than NaNH₂ in liquid NH₃?

Section E — Side-chain halogenation

23.19∗ (routine) Predict the product of: ethylbenzene + Br₂ + light → ? Show the radical mechanism.

23.20 (routine) Why does benzyl bromide form preferentially over ring bromination when toluene is treated with Br₂/light?

23.21 (routine) Predict the major product of: (a) toluene + Br₂ + Lewis acid (no light) → ? (EAS) (b) toluene + Br₂ + light → ? (radical)

23.22 (moderate) NBS + ethylbenzene → ? Sketch the mechanism (N-bromosuccinimide releases Br slowly, giving radical bromination at low [Br₂]).

23.23 (moderate) Cumene (isopropylbenzene) + Br₂ + light gives PhC(CH₃)₂Br. Why does the bromination happen at the tertiary benzylic carbon and not the methyl carbons of the isopropyl?

23.24 (challenge) Tert-butylbenzene + Br₂ + light gives no reaction at the tert-butyl group. Why? Compare with cumene.

Section F — Side-chain oxidation

23.25∗ (routine) Predict the product of: ethylbenzene + KMnO₄ + heat + H⁺ → ?

23.26 (routine) Predict the product of n-propylbenzene + KMnO₄ + heat. Why does the chain length not matter?

23.27 (moderate) Predict the product of: (a) p-xylene + KMnO₄ + heat → ? (b) m-xylene + KMnO₄ + heat → ? (c) tert-butylbenzene + KMnO₄ + heat → ?

23.28 (challenge) Industrial: terephthalic acid (precursor to PET plastic) is made by oxidation of p-xylene. The Mid-Century process uses Co/Mn catalysts + O₂. Sketch the chemistry; why is this more efficient than KMnO₄?

Section G — Birch reduction

23.29∗ (routine) Predict the product of: benzene + Na/NH₃/EtOH → ?

23.30 (routine) Why does Birch reduction give 1,4-cyclohexadiene rather than 1,3-cyclohexadiene?

23.31 (moderate) Predict the product of: (a) anisole (PhOMe) + Na/NH₃/EtOH → ? (b) benzoic acid + Na/NH₃/EtOH → ? (Hint: -COOH is an acceptor; Birch reduces at C2/C4 leaving acceptor on sp³.)

23.32 (challenge) Birch reduction of estrone (a steroid with phenolic A-ring) is a key step in some steroid syntheses. Predict the product.

Section H — Aryl Grignards and aryllithiums

23.33 (routine) Predict the product of: bromobenzene + Mg in dry ether → ? Then + benzaldehyde, then aqueous workup → ?

23.34 (routine) Why doesn't chlorobenzene easily form a Grignard? Suggest an alternative.

23.35 (moderate) Aryllithium + CO₂ → benzoic acid. Sketch this synthesis from bromobenzene.

23.36 (challenge) A student wants to make 4-cyanobenzoic acid. They consider two routes: (A) 4-bromobenzonitrile + Mg, then CO₂. (B) Benzonitrile + base, then CO₂.

Which route works? Why does (B) fail?

Section I — Multistep synthesis

23.37∗ (moderate) Design a synthesis of N,N-dimethyl-4-aminoacetophenone from 4-chloroacetophenone via SNAr.

23.38 (moderate) Design a synthesis of 4-aminobenzoic acid (PABA) from 4-nitrochlorobenzene.

23.39 (challenge) Design a synthesis of fluorouracil (a cancer drug) from 5-bromouracil + KF (SNAr on the pyrimidine ring).

23.40 (challenge) Design a synthesis of 4-(N,N-dimethylamino)cinnamaldehyde from p-chlorobenzaldehyde + dimethylamine. Hint: -CHO is an EWG that activates the ring.

Section J — Industrial / pharmaceutical applications

23.41 (moderate) Sanger's reagent (2,4-dinitrofluorobenzene) is used in protein N-terminal sequencing. The N-terminal amine attacks the ring via SNAr, displacing F⁻. Sketch the mechanism. Why is fluorine the right leaving group?

23.42 (moderate) Imatinib (Gleevec, leukemia drug) involves SNAr of a chloropyrimidine + aniline. Why is the pyrimidine more reactive than benzene? Connect to the ring nitrogens as built-in EWGs.

23.43 (challenge) Sulfa drugs (sulfanilamide, sulfadiazine) are made by SNAr of 4-acetaminobenzenesulfonyl chloride + amines. Sketch the synthesis.

23.44 (challenge) Chloroquine (antimalarial) is made by SNAr of 4,7-dichloroquinoline + diethylaminopentyl amine. Sketch.

Section K — Mechanistic comparison

23.45 (moderate) Compare and contrast EAS and SNAr in 4 key features (substrate, intermediate, regiochemistry, role of substituents).

23.46 (challenge) Pd-catalyzed C-N cross-coupling (Buchwald-Hartwig amination, Ch 37) is a modern alternative to SNAr. List 3 advantages and 2 disadvantages compared to classical SNAr. When would each be preferred?

Notes for instructors: Common stumbling blocks for Chapter 23: (1) confusing SNAr with SN1/SN2; (2) thinking F is a "bad" leaving group always (it's the best for SNAr); (3) drawing the Meisenheimer complex with the wrong geometry; (4) confusing the benzyne mechanism with EAS or SNAr; (5) ring vs side-chain halogenation conditions. Computational exercises: visualize the Meisenheimer complex's HOMO; locate the N-O resonance contributions.