Chapter 40 — Exercises

Forty problems on green chemistry, flow chemistry, biocatalysis, and the future of synthesis. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — Green chemistry metrics

40.1∗ (routine) Calculate the atom economy of: (a) Diels-Alder of butadiene + maleic anhydride. (b) Wittig reaction of butanal + Ph₃P=CHCH₃ → 2-pentene + Ph₃P=O. (c) Friedel-Crafts acylation of benzene + acetyl chloride → acetophenone + HCl. (d) Reductive amination of butanal + methylamine + NaBH₃CN → N-methylbutylamine.

Identify which is most atom-economical.

40.2 (routine) Compute the E-factor (mass of waste / mass of product) of a hypothetical synthesis: 10 g product from 500 g total material input.

40.3 (moderate) A pharmaceutical process has E = 80 (kg waste/kg product). After redesign with biocatalysis, E = 25. What is the percent reduction in waste?

40.4 (moderate) Why does the pharmaceutical industry have higher E-factor than petrochemicals? Identify two main reasons.

40.5 (challenge) Calculate the E-factor for sitagliptin synthesis: original (2005) had ~50 kg waste/kg product; redesigned (2009) had ~25 kg waste/kg product. What strategies achieved this?

Section B — The 12 Principles applied

40.6∗ (routine) Match each green chemistry principle to its example: (a) Atom economy → Diels-Alder. (b) Catalysis → Pd cross-coupling. (c) Renewable feedstocks → biomass-derived chemicals. (d) Safer solvents → water vs. dichloromethane. (e) Reduce derivatives → no protecting groups.

40.7 (routine) Why does each of the 12 Principles matter? Pick three and explain in 1-2 sentences each.

40.8 (moderate) Apply the 12 Principles to a hypothetical drug synthesis. Identify two violations and propose remedies.

40.9 (challenge) Design a 3-step "green" synthesis of a target molecule. Show the atom economy, E-factor, and any green features.

Section C — Flow chemistry

40.10∗ (routine) Why is flow chemistry preferred over batch for: (a) exothermic reactions, (b) reactive intermediates, (c) photochemistry?

40.11 (routine) What is a microreactor? Why is it especially useful?

40.12 (moderate) Continuous manufacturing in pharma: end-to-end synthesis of a tablet from raw materials. Why is this preferred over batch manufacturing?

40.13 (moderate) A photochemical [2+2] cycloaddition is run in a flow photoreactor. Why is flow advantageous over batch for this?

40.14 (challenge) Compare batch vs flow synthesis of a hypothetical 4-step drug synthesis. What are the trade-offs?

Section D — Biocatalysis

40.15∗ (routine) What is biocatalysis? Why is it useful for asymmetric synthesis?

40.16 (routine) Match each engineered enzyme to its function: (a) Transaminase → ? (b) Ketoreductase → ? (c) Halohydrin dehalogenase → ? (d) Cytochrome P450 (engineered) → ?

40.17 (moderate) Frances Arnold won the 2018 Nobel Prize for directed evolution. What is directed evolution? How is it used to engineer enzymes?

40.18 (moderate) Sitagliptin process: engineered transaminase + acetone-derived ketone substrate → sitagliptin precursor with high ee. Sketch the chemistry.

40.19 (challenge) Atorvastatin synthesis uses an engineered ketoreductase to reduce a β-keto ester to a chiral β-hydroxy ester. Why is biocatalysis preferred over Pd asymmetric hydrogenation here?

Section E — Photoredox catalysis

40.20∗ (routine) What is photoredox catalysis? Why has it become important in modern synthesis?

40.21 (routine) Common photocatalysts: Ru(bpy)₃²⁺, Ir(ppy)₃, organic dyes (acridinium, phenoxazine). Why are these chosen?

40.22 (moderate) A photoredox-catalyzed C-H activation: catalytic Ru complex + light + substrate → activated radical that participates in C-C bond formation. Sketch the principle.

40.23 (moderate) What is asymmetric photoredox? How does it give enantioselective products?

40.24 (challenge) Industrial-scale photoredox uses flow photoreactors. Why is flow critical for scaling up photochemistry?

Section F — Electrochemistry

40.25∗ (routine) Why is electrochemistry "green"? Identify three reasons.

40.26 (routine) Electrochemical oxidation of an alcohol to a carbonyl: what replaces traditional oxidants like KMnO₄ or PCC?

40.27 (moderate) Modern flow electrochemistry: scaled-up to industrial production. What are the advantages over batch electrochemistry?

40.28 (challenge) A pharmaceutical company replaces a chromium oxidation with electrochemistry. What is the change in waste? In environmental impact? In cost?

Section G — AI in synthesis

40.29∗ (routine) AI-driven retrosynthesis tools (Synthia, IBM RXN, AiZynthFinder): how do they work? What is their input and output?

40.30 (routine) Why is AI useful for retrosynthesis but not yet replacing chemists?

40.31 (moderate) A 2023 paper showed AI proposed a novel synthesis of a complex natural product that was 6 steps shorter than known routes. What was the role of AI vs. human chemists?

40.32 (challenge) "Self-driving lab" combines AI for proposal + lab automation for execution. Sketch how this might work for drug discovery.

Section H — Renewable feedstocks

40.33 (routine) What are renewable feedstocks? Compare to petroleum.

40.34 (moderate) Biomass-derived platform chemicals: furfural, glycerol, lactic acid, levoglucosan. How are these produced from cellulose?

40.35 (challenge) Engineered microbes (E. coli, yeast) producing platform chemicals (succinate, lactate, fatty acids, isoprenoids): why is this attractive?

Section I — Process chemistry

40.36 (routine) What is "Quality by Design (QbD)"? Why is it important in pharmaceutical process chemistry?

40.37 (moderate) What is "Process Analytical Technology (PAT)"? How does in-line monitoring improve process chemistry?

40.38 (challenge) Compare a 2010 pharmaceutical process with a 2024 process. What changes have occurred?

Section J — The future

40.39 (challenge) What will organic synthesis look like in 2050? Speculate based on current trends. Identify 3 predictions.

40.40 (challenge) What is the role of organic chemistry in addressing climate change? Identify 3 areas where chemistry can contribute.

Notes for instructors: Common stumbling blocks for Chapter 40: (1) Confusing atom economy with E-factor. (2) Underestimating the importance of solvent waste. (3) Not appreciating the scale of pharmaceutical waste (~25-100x product mass). (4) Missing the integration of multiple modern methods (AI + biocatalysis + flow + electrochemistry). Computational exercises: estimate E-factor for a real published synthesis using reagent quantities; compare to a published green-chemistry redesign.