Investigate medicinal chemistry (drug action, structure-activity relationships, functional groups, analytical techniques applied to medicines) and sustainable chemistry (the 12 principles of green chemistry, atom economy, renewable feedstocks)

What this dot point is asking

The VCE Chemistry 2023-2027 Study Design added Medicinal Chemistry and Sustainable (Green) Chemistry as new content in Unit 4 (replacing some of the pre-2024 food chemistry emphasis). VCAA expects you to understand drug action and structure-activity relationships, the 12 principles of green chemistry, and atom economy as a quantifiable sustainability measure.

The answer

Medicinal chemistry

Drug action. Medicines are chemicals that modify biochemical processes (e.g. enzyme inhibition, receptor binding). Drugs typically interact with biological targets (enzymes, receptors, ion channels) using intermolecular forces: hydrogen bonding, ionic interactions, dispersion forces, dipole-dipole, hydrophobic interactions.

Functional groups and drug structure. Common functional groups in pharmaceutical molecules:

• Amines (basic; protonated at physiological pH; salt formation for solubility).
• Amides (peptide bonds; resistant to hydrolysis; stable backbone).
• Carboxylic acids (acidic; ionised at physiological pH; salt forms used for solubility).
• Esters (often used as prodrugs; hydrolysed in vivo).
• Alcohols and phenols (hydrogen-bond donors; affect polarity and solubility).
• Aromatic rings (provide structural rigidity; affect binding).
• Halogens (modulate lipophilicity and metabolic stability).

Functional groups influence:

• Solubility (polar groups improve water solubility; non-polar groups improve lipid solubility / membrane crossing).
• Bioavailability (the fraction of administered dose that reaches systemic circulation; affected by absorption, first-pass metabolism, polarity).
• Binding affinity (how strongly the drug binds to its target; determined by complementary functional groups and shape).

Structure-activity relationships (SAR). Small structural changes can alter pharmacological properties significantly. Examples:

• Adding a halogen (e.g. fluorine, chlorine) can improve metabolic stability and binding affinity.
• Changing a functional group (ester to amide) can alter half-life and metabolic pathway.
• Modifying ring substitution can shift selectivity between related targets.

The classic SAR example: the salicylic acid → aspirin (acetylsalicylic acid) modification. Salicylic acid irritates the stomach; acetylation of the phenol-OH to an ester reduces gastric irritation while preserving the COX-inhibitor pharmacology after in-vivo hydrolysis.

Side effects and selectivity. Non-selective binding (drug interacting with unintended biological targets) causes side effects. SAR research aims to improve selectivity to reduce off-target effects.

Analytical techniques applied to medicines. Same Unit 4 analytical methods you study elsewhere, applied to pharmaceuticals:

• High-Performance Liquid Chromatography (HPLC). Separates and quantifies active pharmaceutical ingredients (APIs) from impurities. Used for batch-purity testing in manufacture.
• Mass spectrometry (MS). Identifies molecular weight; combined with HPLC (LC-MS) for structural confirmation.
• Infrared (IR) spectroscopy. Identifies functional groups; quick screening tool.
• Nuclear Magnetic Resonance (NMR) spectroscopy. Confirms molecular structure; key for structural elucidation of complex molecules.

Sustainable (green) chemistry

The 12 principles of green chemistry (Anastas and Warner, 1998) frame chemistry's sustainability agenda. Memorise the headline list:

1. Prevent waste. Design syntheses that don't generate waste in the first place.
2. Atom economy. Maximise the proportion of starting materials that end up in the product.
3. Less hazardous synthesis. Use reagents and produce products with low toxicity to humans and the environment.
4. Design safer chemicals. Make products that fulfil their function with minimal toxicity.
5. Safer solvents and auxiliaries. Avoid solvents where possible; choose safer ones if needed.
6. Energy efficiency. Run reactions at ambient temperature and pressure where possible.
7. Renewable feedstocks. Use biomass-derived rather than petroleum-derived starting materials.
8. Reduce derivatives. Avoid unnecessary protection / deprotection steps.
9. Catalysis. Use catalysts (often selective, often regenerable) rather than stoichiometric reagents.
10. Design for degradation. Products should break down into innocuous substances after use.
11. Real-time analysis for pollution prevention. Monitor processes to detect hazardous intermediates as they form.
12. Inherently safer chemistry for accident prevention. Choose substances and conditions that minimise accident risk.

Atom economy (Principle 2) is quantifiable:

A reaction with 100% atom economy converts every atom of the reactants into the product (e.g. addition reactions; rearrangements). A substitution reaction with a large leaving group has low atom economy.

Compare two routes to the same product by atom economy; the higher-AE route is greener in this respect (other principles being equal).

Renewable feedstocks. Biomass-derived chemicals (lignin, cellulose, plant oils, bioethanol, lactic acid) increasingly replace petrochemicals for some industrial syntheses. Examples: bioethanol-derived ethylene; PLA (polylactic acid) plastics from corn-derived lactic acid; bio-based surfactants.

Catalysis is the dominant green-chemistry lever: a selective catalyst reduces by-products, lowers energy requirements (lower activation energy means lower temperature), and is often recoverable. Industrial examples: zeolite catalysts in petroleum cracking; transition-metal catalysts in fine-chemical synthesis; biocatalysts (enzymes) in pharmaceutical manufacture.

Evaluating synthetic routes for sustainability. Strong responses use multiple lenses:

• Atom economy (quantitative).
• Number of reaction steps (fewer is usually better).
• Energy intensity (ambient vs high temperature/pressure).
• Solvent choice and volume (water > organic, ideally).
• Catalyst use (catalytic > stoichiometric).
• Feedstock origin (renewable > non-renewable).
• Waste generation (volume, hazard).
• Toxicity of products and by-products.

Examples in context

Example 1. Penicillin and beta-lactam SAR. Penicillin's beta-lactam ring is essential for its mechanism (inhibits bacterial cell-wall transpeptidase). Modifications around the beta-lactam (different side chains: methicillin, amoxicillin, etc.) yield drugs with different spectra of activity, resistance to beta-lactamase, and pharmacokinetics. The same core structure produces a family of drugs by SAR. This is the canonical medicinal-chemistry SAR worked example.

Example 2. PLA (polylactic acid) as a green-chemistry case. PLA is a biodegradable polyester made from lactic acid derived from corn starch (renewable feedstock; Principle 7). The polymerisation uses catalysis (Principle 9). PLA degrades to lactic acid under industrial composting conditions (Principle 10). It substitutes for petroleum-derived plastics in some food packaging. Trade-offs: requires industrial composting (not home compost); land use for corn; cost compared with conventional plastics. A strong response uses PLA to apply multiple green-chemistry principles to one real material.

Try this

Q1. Identify two functional groups common in pharmaceutical molecules and explain how each influences a drug's behaviour. [4 marks]

• Cue. Amine (basic, protonated at physiological pH, salt formation for solubility). Ester (often hydrolysed in vivo; used in prodrugs; affects half-life). Carboxylic acid (acidic, salt forms). Aromatic ring (structural rigidity, binding affinity).

Q2. Calculate the atom economy of esterification between ethanoic acid (CH3COOH, MW 60.05) and ethanol (C2H5OH, MW 46.07) to form ethyl ethanoate (CH3COOC2H5, MW 88.11) and water. [3 marks]

• Cue. AE = 88.11 / (60.05 + 46.07) x 100 = 83.0%.

Q3. Evaluate a chemical manufacturing process of your choice against three principles of green chemistry. [8 marks]

• Cue. Pick a process (Haber process for ammonia; aspirin synthesis; PLA production; biofuel production). Apply 3 principles (e.g. atom economy, catalysis, renewable feedstocks). Reach a calibrated judgement; acknowledge trade-offs.