Chapter 13 — Exercises

Fifty-five problems. The decision-tree workout. ∗ marks problems with full worked solutions in the appendix.

Section A — Mechanism prediction (apply the tree)

For each substrate–reagent–solvent combination, predict the dominant mechanism (SN1, SN2, E1, E2) and the major product. ∗ marks worked.

13.1∗ $CH_3CH_2Br + NaCN$ in DMF, 25 °C. 13.2∗ $CH_3CH_2Br + KO\text{-}tBu$ in t-BuOH, 80 °C. 13.3∗ 2-bromobutane + NaOH in DMSO, 25 °C. 13.4∗ 2-bromobutane + NaOH in water, 70 °C. 13.5 2-bromobutane + NaOEt in EtOH, 60 °C. 13.6 2-bromobutane + KO-tBu in t-BuOH, 60 °C. 13.7 $(CH_3)_3CBr + H_2O + EtOH$, 80 °C. 13.8 $(CH_3)_3CBr + NaOEt$ in DMSO, 25 °C. 13.9 Methyl iodide + NaCN in DMSO, 25 °C. 13.10 $(CH_3)_3CCH_2Br + KO\text{-}tBu$ in t-BuOH, 60 °C. (Neopentyl + bulky base.)

13.11 Allyl bromide + NaSH in DMF, 25 °C. 13.12 Benzyl chloride + NaCN in DMF, 25 °C. 13.13 Benzyl chloride in 80% aq EtOH at 70 °C. 13.14 2-bromocyclohexane + NaOEt in EtOH, 60 °C. 13.15 1-bromo-3-methylbutane + KO-tBu in t-BuOH, 80 °C.

13.16 Tosylate of $(R)$-2-octanol + NaN₃ in DMSO, 25 °C. Predict mechanism and stereochemistry. 13.17 $(R)$-2-octanol + HBr at 0 °C. 13.18 2-iodo-2-methylpropane in 50% aq EtOH at 50 °C. 13.19 1-chloro-1-methylcyclohexane in methanol, 60 °C. 13.20 Chlorobenzene + NaOMe at 25 °C. (Trick — see Chapter 23.)

Section B — Predicting products with stereochemistry

13.21∗ $(R)$-2-bromobutane + NaOEt in DMF (mostly $S_N2$). What is the configuration of the product?

13.22 $(R)$-2-bromobutane in 80% aq EtOH at 70 °C ($S_N1$ + $E1$). What stereochemistry is expected for the substitution product?

13.23 $(R)$-3-bromo-3-methylpentane in methanol at 60 °C. What stereochemistry of product?

13.24 $(2R, 3R)$-2-bromo-3-methylbutane + NaCN in DMF. Predict the configuration at C2 in the product.

13.25 $(2R, 3S)$-2-iodopentane + NaSH in DMF. Predict the major product with stereochemistry.

Section C — Predicting Zaitsev vs Hofmann

13.26∗ 2-bromobutane + NaOEt → predict the major elimination product. Is it Zaitsev or Hofmann?

13.27 2-bromobutane + KO-tBu → predict major elimination product. Hofmann?

13.28 2-bromo-3-methylbutane + NaOEt vs KO-tBu. Compare the products.

13.29 2-bromo-2-methylbutane + NaOEt at 60 °C. Major elimination product?

13.30 Hofmann elimination of $(CH_3)_3CCH_2N(CH_3)_3 \cdot OH$ at 200 °C. What's the alkene?

Section D — Cyclic substrates

13.31 Cis-1-bromo-2-methylcyclohexane + NaOEt → predict the E2 product.

13.32 Trans-1-bromo-2-methylcyclohexane + NaOEt. Different from 13.31?

13.33 A cyclohexane has a t-butyl group at one position locking the ring. The leaving group is at C2 (cis to the t-Bu). Will E2 work? Why or why not?

13.34∗ Cyclohexyl bromide + NaCN in DMF. Mechanism? Why is this slower than 1-bromohexane $S_N2$?

13.35 A bicyclic substrate with a bridgehead bromide reacts very slowly with NaOH at 80 °C. Why? What mechanism is operating, if any?

Section E — Real-world synthesis applications

13.36∗ A medicinal chemist needs to convert a 2° alcohol $(R)$-2-octanol into the inverted alkyl iodide. Outline a 2-step sequence using SN2.

13.37 Convert ($S$)-2-butanol into ($S$)-butane-2-thiol. Note: SH and OH have the same priority slot (both above the methyl and ethyl groups), so configuration label changes track the priority.

13.38 Make 2-methyl-2-butene from 2-methyl-2-butanol via E1. What conditions?

13.39 Make 1-butene (Hofmann product) from 2-bromobutane. What base?

13.40 Synthesize (R)-2-cyanobutane from racemic 2-butanol. (Hint: tosylate then SN2 with cyanide. Some racemic complications.)

Section F — Distinguishing observed vs predicted

13.41 A reaction reportedly gives 95% inverted product. The substrate is 2°. Conditions? - Mechanism: $S_N2$. - Suggested conditions: NaCN in DMF at 25 °C.

13.42 A reaction gives racemic product from a chiral substrate. Mechanism? - $S_N1$. Conditions: 80% aq EtOH at 70 °C with no added base.

13.43 A reaction gives 70% Zaitsev alkene + 25% Hofmann alkene + 5% substitution. Mechanism? - E2 dominant with mostly Zaitsev. Conditions suggest moderate-T, somewhat-bulky base.

13.44 A reaction gives a rearranged product (the tertiary methyl ether instead of the primary methyl ether expected from SN2 on a primary substrate). Mechanism? - Carbocation rearrangement → SN1. - Conditions: methanol with no strong nucleophile/base, warmed.

13.45 (challenge) A reaction shows: 1st-order kinetics, mostly inverted product (~70%). Mechanism? - This is not pure SN1 (which gives racemate) or pure SN2 (2nd-order). It could be: (a) ion-pair SN1 with slight inversion; (b) borderline SN1/SN2; (c) something else. Discuss.

Section G — Conceptual

13.46∗ Why is methyl halide always SN2, regardless of conditions? 13.47 Why doesn't a tertiary halide undergo SN2? 13.48 Why does a bulky base preferentially do E2 over SN2? 13.49 Why does heating shift the SN1/E1 ratio toward E1? 13.50 Why does polar protic solvent favor SN1 but slow SN2?

Section H — Cumulative & integrative

13.51 (challenge) Combine pKa (Ch 3), conformational analysis (Ch 5), and SN/E framework (Ch 13) to design an experiment that distinguishes SN1 from SN2 on a 2° substrate.

13.52 (challenge) A pharmaceutical process needs to install a chiral group at a tertiary center with high ee. Why is this hard? Propose a strategy.

13.53 (challenge) A natural product synthesis route requires 5 SN2 steps in sequence. Propose how the chemist would protect intermediate functionality to prevent unwanted side reactions.

13.54 (challenge) Why are many "tertiary alkyl halide → tertiary alcohol" conversions done with HBr/H2O rather than NaOH/H2O? Use the decision framework.

13.55 (challenge) Real reactions often give mixed mechanisms in moderate proportions (e.g., 70:30 SN2:E2). What experimental controls would maximize the desired mechanism?

Preview of Chapter 14

Chapter 14 — the first synthesis workshop — uses the decision framework to design multi-step syntheses. The aspirin synthesis appears as a worked example, illustrating how to choose conditions to get clean substitution (or clean elimination) at each step.