Chemistry • Year 12 • Module 8 • Lesson 15
Drug Synthesis & Green Chemistry
Apply atom economy and E-factor to real synthesis data, interpret a sustainability comparison graph, and reason through a pharmaceutical scenario.
1. Interpret sustainability data for three synthesis routes
A research team at CSIRO evaluated three routes for manufacturing a pharmaceutical compound at pilot scale. The table below summarises the key sustainability metrics for each route. Use the data to answer questions 1.1–1.4. 9 marks
| Route | Desired product MM (g mol−1) | Total product MM (g mol−1) | Atom economy (%) | Waste produced (g) | Product obtained (g) | E-factor | Solvent used |
|---|---|---|---|---|---|---|---|
| Route A | 180 | 240 | 75 | 6.0 | 3.0 | 2.0 | Ethanol |
| Route B | 180 | 290 | 62 | 12.0 | 3.0 | 4.0 | Dichloromethane |
| Route C | 180 | 240 | 75 | 3.0 | 3.0 | 1.0 | Water |
Note: MM = molar mass. E-factor values calculated from waste and product columns. Solvent selection is one of the 12 Green Chemistry Principles.
1.1 Verify the E-factor for Route B by showing your calculation. 2 marks
1.2 Routes A and C have the same atom economy (75%) but different E-factors. Explain what this tells you about each route. 2 marks
1.3 Using two green chemistry criteria (including solvent selection), identify and justify which route is the most sustainable overall. 3 marks
1.4 Why is Route B's solvent (dichloromethane) considered less desirable under green chemistry principles, even if its product yield were equivalent? 2 marks
2. Interpret the E-factor vs atom economy graph
The scatter plot below shows five hypothetical synthesis routes (P–T) positioned by atom economy (x-axis) and E-factor (y-axis). The most sustainable routes have high atom economy and low E-factor. 6 marks
Figure 2.1. Atom economy vs E-factor for five hypothetical pharmaceutical synthesis routes. Illustrative data, consistent with green chemistry evaluation principles (Sheldon, 2007; Green Chemistry 9: 1273–1283).
2.1 Which route is in the ideal zone (highest atom economy and lowest E-factor)? What does this tell you about how atoms are distributed in this route? 2 marks
2.2 Routes T and Q have different atom economies but similar E-factors (approximately 3.5 and 6.0). Using the graph, explain why atom economy alone is not a reliable guide to ranking these routes by sustainability. 2 marks
2.3 A chemist says: “Route P is not worth improving because its atom economy is too low.” Using data from the graph, explain why this reasoning is incomplete. 2 marks
3. Cause-and-effect chain — catalyst in pharmaceutical synthesis
Complete the cause-and-effect chain below. Each filled box is a cause; each empty box is the effect you must write. The chain traces how adding a catalyst to a pharmaceutical synthesis improves sustainability. 5 marks
| Cause (given) | → | Effect (your answer) |
|---|---|---|
| A catalyst is added to the aspirin synthesis. | → | |
| The reaction rate increases without the catalyst being consumed. | → | |
| Improved selectivity means fewer unwanted byproducts are formed. | → | |
| Less waste is generated per gram of aspirin produced. | → | |
| Overall outcome (so…): | ||
4. Case study — CSL Broadmeadows aspirin production
Read the stimulus below, then answer 4.1–4.2. 6 marks
Stimulus. CSL Limited, headquartered in Melbourne, has historically operated pharmaceutical manufacturing at its Broadmeadows site in Victoria. Aspirin-type compounds are among the oldest and most studied small-molecule pharmaceuticals; their synthesis by esterification of salicylic acid provides an industrial anchor for teaching green chemistry principles. In a process audit, a production team found that switching from an organic solvent-based crystallisation step to an aqueous recrystallisation step reduced solvent waste by 60%, improved atom economy slightly (by reducing solvent-entrainment losses), and lowered per-batch E-factor from 3.8 to 1.6. The EPA Victoria waste-reduction framework requires pharmaceutical manufacturers to report annual waste intensity per kilogram of active pharmaceutical ingredient (API) produced.
4.1 Calculate the percentage reduction in E-factor achieved by the change in crystallisation solvent. Show your working. 2 marks
4.2 Using two green chemistry principles from the lesson, explain why the switch to aqueous recrystallisation is consistent with sustainable pharmaceutical manufacturing as required by regulators such as EPA Victoria. 4 marks
Q1.1 — E-factor calculation, Route B
E-factor = mass of waste / mass of product = 12.0 g / 3.0 g = 4.0. This confirms the table value.
Q1.2 — Same atom economy, different E-factor
Both Routes A and C convert 75% of product-side atom mass into the desired compound, so they are equally efficient in terms of atomic utilisation [1]. However, Route C generates only 1.0 g of waste per gram of product versus Route A's 2.0 g — indicating that Route C has a much lower practical waste burden, possibly because it avoids extra solvents or reagents that become waste in Route A [1].
Q1.3 — Most sustainable route with two green criteria
Route C is the most sustainable overall [1]. Criterion 1 (atom economy): Route C ties Route A at 75%, the highest of the three routes, indicating that 75% of reactant atom mass is incorporated into the product rather than byproducts [1]. Criterion 2 (solvent selection): Route C uses water as the solvent — a low-hazard, non-volatile choice — whereas Route B uses dichloromethane (a halogenated solvent, higher toxicity and vapour pressure) and Route A uses ethanol (flammable, though lower risk than DCM). Water aligns with the green principle of using safer solvents [1]. Route C also has the lowest E-factor (1.0), making it the cleanest option by all metrics considered.
Q1.4 — Why dichloromethane is less desirable
Dichloromethane (DCM) is a halogenated organic solvent; it is classified as a probable human carcinogen and is volatile, making it a workplace inhalation hazard [1]. Under the green chemistry principle of safer solvent selection, chemists should replace such solvents with benign alternatives (e.g. water, ethanol, or supercritical CO2) to reduce toxicity risks, environmental contamination, and disposal costs, regardless of yield [1].
Q2.1 — Ideal zone route
Route S is in the ideal zone (atom economy ~90%, E-factor ~1.5) [1]. This indicates that approximately 90% of reactant atom mass ends up in the desired product (very few atoms are diverted to byproducts) and only 1.5 g of waste is generated for every gram of product obtained — a clean, efficient route [1].
Q2.2 — Atom economy alone is not reliable
Route T (AE ~62%) has a lower E-factor (~3.5) than Route Q (AE ~70%, E-factor ~6.0). If atom economy alone guided the decision, Route Q would seem preferable, but its higher E-factor means it actually generates substantially more waste per gram of product [1]. This demonstrates that a single metric gives an incomplete picture — both atom economy (atom efficiency) and E-factor (practical waste burden) are needed to rank routes reliably [1].
Q2.3 — Why the reasoning about Route P is incomplete
While Route P has a low atom economy (~55%), its E-factor could potentially be reduced by process changes (e.g. solvent replacement, catalyst optimisation) even without altering the underlying chemistry [1]. Atom economy is a property of the reaction equation itself; E-factor is a property of the whole process and can be improved independently. The chemist's reasoning ignores the possibility of improving the process metrics while working on improving the chemistry in parallel [1].
Q3 — Cause-and-effect chain (marking criteria only)
Accept any chemically correct effects. Suggested chain:
- Cause 1 effect: Reaction rate increases / activation energy barrier is lowered, so less energy is needed to drive the reaction.
- Cause 2 effect: The reaction can proceed efficiently without consuming a stoichiometric reagent, so overall atom use is not inflated by the catalyst.
- Cause 3 effect: The E-factor decreases because less mass of unwanted products is generated per gram of aspirin.
- Cause 4 effect: The process is more economical and produces less environmental burden per batch.
- Overall outcome: The synthesis is more sustainable (lower E-factor, lower energy use, less waste) without changing the fundamental reaction equation.
Award 1 mark per correctly reasoned effect (4 causes = 4 marks) + 1 mark for the overall outcome statement.
Q4.1 — Percentage reduction in E-factor
% reduction = (3.8 − 1.6) / 3.8 × 100% = 2.2 / 3.8 × 100% = 57.9% (accept 58%) [1 method + 1 answer].
Q4.2 — Green chemistry principles and regulatory context
Green chemistry Principle 1 — Safer Solvents: replacing organic solvent with water reduces hazardous solvent waste, workplace exposure risks and contaminated effluent that would otherwise need EPA-regulated treatment or disposal [1]. Water is benign, non-flammable, non-volatile and does not require specialised waste streams [1]. Green chemistry Principle 2 — Waste Prevention: the 60% reduction in solvent waste and the drop in E-factor from 3.8 to 1.6 directly reduces the mass of waste that the manufacturer must manage per kilogram of API, which directly reduces their waste intensity figure reported to EPA Victoria [1]. The reduced E-factor also demonstrates economic benefit (lower solvent costs) alongside the environmental benefit, showing that green chemistry and commercial efficiency are aligned goals [1].