Chapter 14 — Exercises

Forty problems on synthesis design using SN/E reactions. ∗ marks problems with worked solutions.

Section A — Single-step retrosynthesis

For each target, identify the disconnection and write the forward reaction.

14.1∗ 2-Methoxypropane (methyl propyl ether). Disconnection?

14.2 Phenyl ethyl ether (PhOC₂H₅). Disconnection?

14.3 1-iodopropane (from 1-bromopropane). Reagent?

14.4 1-azidobutane (from 1-bromobutane).

14.5 Cyclohexyl ethyl ether (from cyclohexanol and ethyl bromide). Conditions?

14.6 2-bromopropane (from 2-propanol). Three different reagents to do this. List them.

14.7 Tert-butyl methyl ether (from tert-butyl chloride and methanol). What mechanism?

Section B — Multi-step retrosynthesis

14.8∗ 2-butyne starting from 2-butanol. Show all steps.

14.9 2-butene starting from 2-butanol. Forward synthesis with conditions.

14.10 Aspirin from salicylic acid. (One step.)

14.11 Aspirin from phenol. (Multi-step, building salicylic acid first via Kolbe-Schmitt.)

14.12 1-pentanol from 1-bromobutane (extend by one carbon).

14.13 2-methyl-2-butanol from 2-methylbut-1-ene. (Markovnikov hydration, Ch 16 preview.)

14.14∗ Phenethylamine from 2-bromoethylbenzene + ammonia. Why is the product complicated?

14.15 Synthesize ethyl ether from ethanol. Show multiple routes.

14.16 Tertiary alkyl chloride from a tertiary alcohol. Conditions?

14.17 Make 1-butyne from 1-bromobutane. (Two-step: SN2 with sodium acetylide, then?)

14.18 Make 1-bromo-1-methylcyclohexane from cyclohexanone via Grignard then HBr.

14.19 Convert (R)-2-octanol into (S)-2-bromooctane via tosylation + SN2.

14.20∗ Convert (R)-2-bromobutane into (R)-2-azidobutane. (Note: this requires retention. Is direct SN2 possible? What about double inversion?)

Section C — Mechanism + condition selection

14.21 A medicinal chemist wants to install a methyl group on a tertiary alcohol's oxygen. What approach? (Option 1: Williamson with methyl halide on the alkoxide. Option 2: methylate the alcohol with diazomethane, $CH_2N_2$.)

14.22 A primary alcohol needs to be converted to a primary chloride. List 3 reagents and discuss the differences.

14.23 A secondary alcohol needs to be converted to its inverted-configuration alkyl chloride. What reagent and mechanism?

14.24 Why is the Williamson ether synthesis preferred over the alternative "alcohol + alcohol with acid" approach?

14.25 A retrosynthesis suggests a primary alcohol could come from a primary alkyl halide. What mechanism would form the alcohol? What conditions?

Section D — Sequencing and protecting groups

14.26∗ A target has both a primary alcohol and an aldehyde. You need to do a Grignard addition on the aldehyde without it being attacked by the primary alcohol's reactive O-H. How do you sequence this?

14.27 A target has a primary alcohol that needs to be tosylated (for later SN2), and a secondary alcohol that needs to remain free. How would you selectively tosylate the primary?

14.28 A multistep synthesis has, at one stage, a tertiary alkyl bromide. The next planned step is a Grignard reaction. Discuss the problem.

14.29 You need to convert a primary alcohol to an alkyl iodide while preserving an ester elsewhere in the molecule. What reagent?

14.30 Discuss the order: should you reduce a ketone before or after a substitution at a different part of the molecule? Why?

14.31 Outline aspirin synthesis from salicylic acid. Mechanism?

14.32 Why is the phenol oxygen of salicylic acid a good nucleophile? (Hint: hydrogen bonding with the COOH.)

14.33 Why is acetic anhydride preferred over acetic acid for this acetylation?

14.34 Calculate the theoretical yield of aspirin from 2.0 g salicylic acid. (MW SA = 138; MW aspirin = 180.)

14.35 What is the byproduct of the aspirin synthesis? How is it removed in lab workup?

Section F — Decision framework applied

14.36 A primary alcohol must be converted to a primary nitrile. Outline a 2-step sequence. Apply Ch 13 to predict each step's mechanism.

14.37 Convert tert-butanol to 2-methyl-2-butene. Outline a 1- or 2-step sequence.

14.38∗ Convert 1-bromobutane to butan-1-ol. (One step; what conditions?)

14.39 Convert (R)-2-bromobutane to (S)-2-pentyl iodide. (Two-step; what mechanism each?)

14.40 Convert butan-1-ol to ethyl butyl ether. (Williamson; what conditions?)

Preview of Chapter 15

Chapter 15 covers alkenes — their structure, stability, and electrophilic addition. The first major variation on the substitution/elimination theme: now the alkene attacks an electrophile, generating a cation, captured by a nucleophile. This is electrophilic addition.