Chapter 40 — Quiz

Twenty-five questions on green chemistry, flow chemistry, and the future of synthesis. ∗ marks questions answered in the answer key.

Multiple choice

1.∗ The 12 Principles of Green Chemistry were introduced by: (a) Anastas and Warner (1998) (b) IUPAC in 2020 (c) the Nobel committee (d) the Royal Society in 1985

2.∗ Atom economy: (a) higher is better (more atoms in product, less waste) (b) lower is better (c) doesn't matter for greenness (d) is the same as E-factor

3.∗ E-factor (Environmental factor): (a) mass of waste / mass of product (b) energy efficiency (c) atom-to-atom ratio (d) reaction rate

4.∗ The pharmaceutical industry typically has E-factor: (a) 1-5 (low) (b) 25-100+ (highest of any industry) (c) below 1 (d) above 1000

5.∗ Flow chemistry's main advantage: (a) better heat and mass transfer; safer for exothermic reactions; easier automation (b) larger reactor volume (c) only works at high pressure (d) only photochemistry

6.∗ Biocatalysis means: (a) engineered enzymes do selective chemistry at low temperature in water (b) only using raw bacteria (no engineering) (c) only DNA-based reactions (d) only carbohydrate chemistry

7.∗ Electrochemistry replaces: (a) stoichiometric oxidants and reductants with electrons (b) catalysts (c) solvents (d) dyes only

8.∗ AI in synthesis: (a) accelerates retrosynthesis planning by trained models (b) only used for data visualization (c) only useful for simple targets (d) cannot work on novel molecules

9.∗ A Diels-Alder cycloaddition has atom economy: (a) 100% (no byproducts) (b) ~50% (c) varies wildly (d) negative

10.∗ Green chemistry goals: (a) reduce waste, improve safety, use renewable feedstocks, lower energy use (b) maximize yield only (regardless of waste) (c) maximize cost (d) only for industrial chemistry

11.∗ Frances Arnold (Nobel 2018) won for: (a) directed evolution of enzymes for new chemistry (b) AlphaFold (c) statin discovery (d) penicillin

12.∗ Photoredox catalysis uses: (a) light + a photocatalyst (Ru, Ir, organic dyes) for single-electron transfers (b) only thermal energy (c) high pressure (d) only alkenes

13.∗ Continuous manufacturing in pharma: (a) end-to-end flow synthesis from raw materials to final tablet (b) batch processing for each step (c) only for small-molecule drugs (d) only at room temperature

14.∗ A microreactor has: (a) submillimeter channels for very fast mixing and heat transfer (b) larger volumes than batch (c) only for sensitive reactions (d) photochemistry only

15.∗ A "self-driving lab" integrates: (a) AI for retrosynthesis + lab automation for execution + AI for analysis (b) only one AI system (c) only batch chemistry (d) only flow chemistry

16.∗ Sitagliptin's modern green synthesis uses: (a) an engineered transaminase + biocatalytic asymmetric amination (b) only Pd-catalyzed asymmetric hydrogenation (c) chiral resolution (d) only chemical synthesis

17.∗ Renewable feedstocks for industrial synthesis include: (a) biomass (cellulose, lignin), CO₂, engineered microbes (b) only petroleum (c) only natural gas (d) only coal

18.∗ Solvent-free or aqueous synthesis is preferred because: (a) reduces waste, energy, and environmental impact (b) cheaper materials (c) only for organic solvents (d) all of the above

19.∗ Atorvastatin (Lipitor) modern synthesis uses: (a) engineered ketoreductase for the chiral diol (b) only Pd asymmetric hydrogenation (c) only chiral resolution (d) only chemical synthesis

20.∗ The future of organic synthesis (2030+) likely includes: (a) more biocatalysis, AI, automation, flow chemistry, photoredox, electrochemistry (b) less catalysis (back to stoichiometric reagents) (c) only batch chemistry (d) only natural product extraction

Short answer

21. Calculate the atom economy of a Diels-Alder reaction (e.g., butadiene + ethylene → cyclohexene). Show your work.

22. Compare batch vs flow synthesis. List 3 advantages and 1 disadvantage of flow.

23. Explain why biocatalysis (engineered enzymes) is increasingly used in pharmaceutical synthesis. Cite specific examples (sitagliptin, atorvastatin).

24. What is "directed evolution" of enzymes (Frances Arnold's Nobel-winning work)? How is it used in synthesis?

25. Speculate: what will organic synthesis look like in 2050? Identify 3 predictions and justify each.

Answer key

  1. a — Anastas-Warner 1998.
  2. a — Higher atom economy is better.
  3. a — E-factor = waste/product.
  4. b — Pharma E-factor 25-100+.
  5. a — Flow advantages.
  6. a — Biocatalysis with engineered enzymes.
  7. a — Electrons replace stoichiometric reagents.
  8. a — AI accelerates retrosynthesis.
  9. a — Diels-Alder = 100% atom economy.
  10. a — Multiple green chemistry goals.
  11. a — Frances Arnold's directed evolution.
  12. a — Photoredox uses light + photocatalyst.
  13. a — Continuous manufacturing definition.
  14. a — Microreactor description.
  15. a — Self-driving lab integration.
  16. a — Sitagliptin biocatalytic synthesis.
  17. a — Renewable feedstocks.
  18. a — Solvent-free / aqueous benefits.
  19. a — Atorvastatin biocatalysis.
  20. a — Future of synthesis.

21. Atom economy of butadiene + ethylene → cyclohexene: - Reactants: butadiene (C₄H₆, MW = 54) + ethylene (C₂H₄, MW = 28) = total MW 82. - Product: cyclohexene (C₆H₁₀, MW = 82). - Atom economy = 82/82 × 100% = 100%. All atoms from the starting materials end up in the product (no byproducts). This is why Diels-Alder is the canonical "perfect atom economy" reaction.

22. Flow vs batch: Advantages of flow: 1. Better heat transfer: small tubes (microreactors) allow rapid heat dissipation; no hot spots; safer for exothermic reactions. 2. Better mass transfer: laminar flow with mixing; faster reactions; more efficient. 3. Smaller reactive volume: only mL-scale reacting at any moment; safer for hazardous chemicals. 4. Easier automation: pumps, sensors, in-line analysis; consistent product quality. 5. Smaller footprint: continuous operation; less equipment per unit production.

Disadvantages of flow: 1. Higher initial setup cost: equipment investment. 2. Limited substrate scope: solid handling can be tricky in tubes. 3. Engineering complexity: residence time, temperature gradients, pressure drops require careful design.

23. Biocatalysis in pharma is increasingly used because: - Engineered enzymes give near-perfect stereoselectivity (often >99% ee). - Mild conditions (water, room temperature, pH 7). - Low energy / low waste. - High selectivity reduces the need for protecting groups.

Examples: - Sitagliptin (Januvia): engineered transaminase produces the chiral β-amino acid in high ee, replacing wasteful Pd asymmetric hydrogenation. - Atorvastatin (Lipitor): engineered ketoreductase reduces β-keto ester to chiral β-hydroxy ester. - Many other drugs: increasingly common for chiral steps.

The 2018 Nobel Prize to Frances Arnold (directed evolution) recognized this field.

24. Directed evolution: starting with a natural enzyme, perform random mutagenesis (or rational design) and screen for improved activity on a non-natural substrate. Iterate: mutate the best variants and screen again. Over many rounds, evolve enzymes for new chemistry.

For synthesis: directed evolution has produced enzymes that catalyze: - Stereoselective C-H bond functionalization (engineered cytochrome P450s). - Hydroxylation of specific C-H bonds in complex substrates. - C-C bond formation in non-native ways (Aldolases, transaminases for non-natural substrates). - Carbene insertion into N-H, S-H bonds (designed completely new chemistry).

The directed evolution approach has expanded the toolkit of biocatalysis dramatically. Modern engineered enzymes do reactions that are difficult or impossible with traditional catalysts.

25. Predictions for organic synthesis in 2050:

  1. Most chiral pharmaceuticals will be made by biocatalysis (engineered enzymes) rather than traditional asymmetric chemistry. The combination of enzyme engineering + AI for substrate prediction will make biocatalysis the default for complex chiral synthesis.

  2. Synthesis design will be AI-assisted by default. Tools like Synthia 2.0 will propose retrosyntheses in seconds; chemists will spend their time evaluating proposals and executing the synthesis. The synthesis design phase of drug discovery will shrink from years to weeks.

  3. Continuous manufacturing will dominate pharmaceutical production. Flow chemistry will be standard for new drugs; existing drugs will transition to flow as patents expire and processes are redesigned. Tablet-direct production from raw materials will be widespread.

Other possible predictions: - Renewable feedstocks (CO₂, biomass-derived) will dominate over petroleum. - Photoredox + electrochemistry will replace many traditional oxidations and reductions. - "Self-driving labs" combining AI + automation will execute syntheses without human intervention for routine targets. - Pharma-scale photochemistry will be common. - Personalized medicine will shift synthesis priorities (smaller scale, faster turnaround, higher value).

The fundamentals (mechanisms, retrosynthetic strategy) remain. The execution transforms.