Chapter 31 — Quiz

Twenty-five questions on retrosynthetic analysis and multi-step synthesis design. ∗ marks questions answered in the answer key.

Multiple choice

1.∗ Retrosynthesis is performed in the: (a) forward direction (b) backward direction (target → precursors) (c) sideways (d) randomized

2.∗ A "strategic bond" is one that is: (a) reliable to form (known reaction) and simplifying (precursor is structurally simpler) (b) random (c) only at the C-H position (d) only at quaternary carbons

3.∗ An amide retrosynthesis disconnection gives: (a) acid + amine (b) alcohol + halide (c) two amines (d) two acids

4.∗ The aldol disconnection gives: (a) β-hydroxy carbonyl ⇒ two carbonyls (one's α-C attacks the other's C=O) (b) β-keto ester ⇒ two carbonyls (c) only with strong base (d) only with esters

5.∗ A β-keto ester disconnection gives: (a) Claisen condensation partners (b) aldol partners (c) only with esters (d) only Michael partners

6.∗ A 1,5-dicarbonyl disconnection gives: (a) Michael addition partners (donor + acceptor) (b) Claisen partners (c) aldol partners (d) only with esters

7.∗ A 6-membered enone disconnection (Robinson annulation) gives: (a) a ketone + a methyl vinyl ketone (Michael + intramolecular aldol) (b) two halides (c) two amines (d) only with photochemistry

8.∗ A convergent synthesis is preferred over linear because: (a) higher overall yield (when steps are multiplicative) (b) easier (c) cheaper materials (d) all of the above

9.∗ An acetal protects: (a) C=O (aldehyde/ketone) (b) -OH alcohol (c) -NH₂ amine (d) -COOH carboxylic acid

10.∗ Boc (tert-butoxycarbonyl) protects: (a) C=O (b) -OH alcohol (c) -NH₂ amine (and converts it to -NHBoc) (d) -COOH

11.∗ Why use a TBS or TBDPS silyl ether to protect an alcohol? (a) stable in basic, nucleophilic, and reductive conditions (b) deprotected by F⁻ (TBAF) or aqueous HF (c) selective for primary OH over secondary OH (TBS easier; TBDPS more robust) (d) all of the above

12.∗ A primary amine retrosynthesis disconnection gives: (a) Gabriel: phthalimide + alkyl halide (b) reductive amination: aldehyde + ammonia (c) reduction: nitrile + LiAlH₄ (d) any of the above

13.∗ A 4° (quaternary) ammonium retrosynthesis suggests: (a) exhaustive alkylation of an amine with multiple alkyl halides (b) only direct substitution of N-X (c) Hofmann rearrangement (d) Sandmeyer

14.∗ Atom economy: (a) atoms of starting material that end up in product (b) atoms of solvent (c) atoms of catalyst (d) only weighing the product

15.∗ Modern AI-driven retrosynthesis tools (Synthia, IBM RXN): (a) suggest disconnections by training on millions of published reactions (b) replace human chemists (c) only work for simple targets (d) all of the above

16.∗ A protecting group strategy is needed when: (a) two functional groups in the target would interfere with each other in a reaction step (b) you want to slow down a reaction (c) you want to label the product (d) only for biological molecules

17.∗ A convergent synthesis requires: (a) a strategic disconnection that splits the target into two roughly-equal halves (b) two starting materials (c) high pressure (d) only ester chemistry

18.∗ When would you use a Mukaiyama aldol over an LDA-enolate aldol? (a) when other functional groups in the substrate would react with LDA (b) when the substrate is acidic (c) when stereocontrol with chiral Lewis acid is needed (d) all of the above

19.∗ A peptide synthesis often uses: (a) Fmoc protection of amino group + carbodiimide coupling (b) Boc protection + carbodiimide (c) acid chloride + amine without protection (d) all of the above with appropriate variations

20.∗ Why might an industrial synthesis differ from an academic one? (a) industrial cares about cost, scale, and atom economy more than total step count (b) academic prioritizes elegance over economics (c) industrial uses fewer steps even if yield per step is lower (d) all of the above

Short answer

21. Perform a retrosynthesis of acetaminophen (4-hydroxyphenylacetamide) from commercial materials. Show all steps.

22. Compare the overall yields of: (a) a 10-step linear synthesis at 80% per step, vs. (b) a convergent synthesis with two 5-step branches (each at 80% per step) plus a coupling step (80%). Why is convergent better?

23. Design a synthesis of N-methylbenzamide using two different routes: (a) via DCC coupling, (b) via acid chloride. Compare conditions.

24. A target has both a primary amine and a secondary alcohol. The next step requires reaction at the alcohol with a strong base (like NaH for Williamson ether synthesis). Propose a protecting-group strategy.

25. Outline a convergent retrosynthesis of a complex target with two distinct halves connected by a strategic C-C bond. Identify the disconnection and the coupling step.

Answer key

  1. b — Retrosynthesis is target → precursors (backward).
  2. a — Strategic bond definition.
  3. a — Amide ⇒ acid + amine.
  4. a — Aldol disconnection of β-hydroxy carbonyl.
  5. a — β-keto ester ⇒ Claisen partners.
  6. a — 1,5-dicarbonyl ⇒ Michael partners.
  7. a — 6-ring enone ⇒ Robinson annulation partners.
  8. a — Convergent gives higher overall yield.
  9. a — Acetal protects C=O.
  10. c — Boc protects amine.
  11. d — All listed are correct.
  12. d — Multiple primary amine retrosyntheses are possible.
  13. a — Exhaustive alkylation of an amine gives quaternary.
  14. a — Atom economy = atoms in product / total atoms.
  15. a — AI tools learn from published reactions.
  16. a — Protecting groups handle functional group conflicts.
  17. a — Convergent requires a strategic central disconnection.
  18. d — Mukaiyama is preferred for various reasons.
  19. d — Multiple peptide-coupling strategies use protecting groups.
  20. d — Industrial vs academic synthesis differ.

21. Retrosynthesis of acetaminophen: - Step 1: Disconnect the amide (between phenol-aryl-NH and acetyl C). Precursors: 4-aminophenol + acetic anhydride. - Step 2: 4-Aminophenol can be made from phenol + nitration + reduction OR from p-nitrochlorobenzene + nucleophilic aromatic substitution + hydroxide + reduction.

Forward: 4-aminophenol + acetic anhydride + heat → acetaminophen + acetic acid. (Nucleophilic acyl substitution; the N attacks the anhydride.) The reaction is regioselective: the amine is more nucleophilic than the phenol -OH.

22. Linear: 0.80^10 = 0.107 = 10.7% overall yield. Convergent: each branch is 0.80^5 = 0.328 = 33%. Coupling at 80% gives 0.328 × 0.328 × 0.80 = 0.086 = 8.6% — but wait, this is the wrong calculation. The two branches each get to 33% of their starting material; combining requires only 80% efficiency, so the convergent outcome is 0.328 × 0.328 × 0.80 / (1.0) = 0.086 = 8.6%. Hmm, that's lower? Let me reconsider.

Actually the issue is the comparison. Linear: 10 sequential steps; result is the product of all yields = 0.80^10 = 10.7%. Convergent (two 5-step branches converging at one coupling): the two branches give 33% each (you have 33% of each). Then the coupling (80% based on the smaller fraction) gives 0.328 × 0.80 = 26.2% of the limiting branch. The other branch contributes its 0.328 portion. Net result: 0.328 × 0.80 = 26.2% for the coupling step yield...

Convergent shines when the synthesis is symmetric and you measure overall yield as the product yield from one branch's atoms. In our example: 26.2% > 10.7%. Convergent is ~2.5× higher.

Why? Because convergent processes "amortize" the step losses: each branch starts fresh, so neither has to survive 10 sequential losses. They survive only 5 each, then the coupling.

23. (a) DCC coupling: benzoic acid + methylamine + DCC → N-methylbenzamide + dicyclohexylurea (DCU). Mild conditions (room temp), high yield, no racemization at α-C if any. (b) Acid chloride: benzoic acid + SOCl₂ → benzoyl chloride; then + methylamine + Et₃N → N-methylbenzamide + Et₃N·HCl. Two-step sequence; harsher (acid chloride is reactive); some side products possible. DCC is usually preferred for sensitive substrates; acid chloride for simple cases at industrial scale.

24. Strategy: protect the primary amine first, then do the alcohol chemistry, then deprotect. - Step 1: Add Boc (using Boc₂O + base) to the primary amine. Now the amine is protected. - Step 2: Treat the now-protected amine with NaH; the alcohol is deprotonated and can react in a Williamson ether synthesis (or other base-requiring reaction). - Step 3: Remove Boc with TFA (acid). The free amine is regenerated.

This gives clean alkylation at the alcohol position without interference from the amine.

25. Example target: a complex molecule with two halves connected by a C-C bond at a stereocenter. Strategic disconnection: at the C-C bond. The two halves are: (a) a half with the stereocenter and its surrounding functionality. (b) the other half with its different functionality. Synthesis: Make each half separately (each in ~5 steps from commercial materials). Then couple the halves via aldol, Claisen, Grignard, or other reliable C-C bond-forming reaction. The coupling step is the strategic disconnection in reverse. Convergent yield: each half has ~33% overall (from 0.80^5); the coupling at 80% gives ~26% overall. Compared to a hypothetical linear ~5% (10 sequential steps).