Q1
The pKa of acetic acid is approximately:
A. 5
B. 2
C. 10
D. 14
Explanation
Acetic acid (ethanoic acid) has a pKa of ~4.75 ≈ 5. This places it firmly in the "weak acid" range. pKa 2 would be a strong organic acid; pKa 10 is phenol; pKa 14 is essentially neutral water.
Trap: pKa 2 = strong acid (e.g. dichloroacetic acid). Carboxylic acids cluster at pKa 4–5.
McMurry 8e Ch 20 · Slide
Q2
Carboxylic acid acidity is primarily due to:
A. Induction only
B. Resonance stabilisation of the carboxylate anion
C. High electronegativity of oxygen only
D. sp³ carbon
Explanation
When the carboxylic acid donates H&sup+;, the resulting carboxylate anion (RCOO–) has its negative charge delocalised equally over both oxygens via resonance → highly stabilised → equilibrium favours ionisation → lower pKa (stronger acid). Both induction and electronegativity contribute, but resonance is the dominant factor.
Alcohols also have electronegative oxygen but lack resonance stabilisation of RO– → pKa ~16 vs ~5.
McMurry 8e §20.3
Q3
Fischer esterification requires:
A. Base catalyst
B. Oxidising agent
C. Acid catalyst + H₂O removal
D. NaBH₄
Explanation
Fischer esterification: RCOOH + R'OH H&sup+; RCOOR' + H₂O. Requires an acid catalyst (H₂SO₄ or HCl) to protonate the carbonyl and activate it toward nucleophilic attack. Water removal (Dean-Stark trap, excess alcohol, or molecular sieves) drives the equilibrium toward ester by Le Chatelier's principle.
Base would saponify the ester once formed. NaBH₄ is a reductant — wrong direction entirely.
McMurry 8e §21.4
Q4
Fischer esterification is best described as:
A. Irreversible
B. Exothermic and spontaneous
C. Requires an enzyme
D. Reversible (equilibrium)
Explanation
Fischer esterification is an equilibrium reaction (K~eq~ ~ 1 for many acid/alcohol pairs). Neither the forward nor reverse reaction is strongly favoured on its own. This is why practical strategies (excess alcohol, water removal) are needed to obtain good yields of ester.
Contrast with saponification (alkaline hydrolysis) which IS irreversible because the carboxylate salt formed is too stable to re-esterify under those conditions.
McMurry 8e §21.4
Q5
Aspirin is chemically:
A. An acetyl ester of salicylic acid
B. An ether
C. An amide
D. An aldehyde
Explanation
Aspirin (acetylsalicylic acid) is made by esterifying the phenolic –OH of salicylic acid with acetic anhydride. The product contains both an ester (at the phenol position) and a free carboxylic acid group. It hydrolyses back to salicylic acid + acetic acid in alkaline conditions.
Paracetamol is the amide analogue (N-acetyl, not O-acetyl). Do not confuse the two aspirin-family drugs.
McMurry 8e §21.6 · Clinical chemistry
Q6
Saponification means:
A. Acid hydrolysis of ester
B. Alkaline hydrolysis of ester (irreversible)
C. Esterification
D. Amide formation
Explanation
Saponification: RCOOR' + NaOH → RCOONa (soap) + R'OH. The product is the carboxylate salt (not the free acid), which cannot re-esterify under basic conditions → reaction is irreversible. Industrially applied to triglycerides (fats) to make soap ("sapo" = Latin for soap).
Acid hydrolysis (RCOOR' + H₂O/H&sup+; → RCOOH + R'OH) is reversible; saponification is not.
McMurry 8e §21.4
Q7
Reacting a carboxylic acid with NH₃ initially gives a salt; heating this salt gives:
A. An amide directly at room temperature
B. An ester
C. An anhydride
D. A salt then amide on heating
Explanation
Step 1 (room temperature): RCOOH + NH₃ → RCOONH₄&sup+; (ammonium salt) — acid-base neutralisation. Step 2 (heat, ~150–200°C): RCOONH₄&sup+; → RCONH₂ + H₂O — thermal dehydration gives the primary amide. Direct reaction of carboxylic acid with NH₃ does NOT give amide at RT.
Acyl chlorides and anhydrides react with NH₃ directly at RT to give amides. Carboxylic acids are less reactive and require heating.
McMurry 8e §21.8
Q8
Correct reactivity order of carboxylic acid derivatives (most → least reactive):
A. Amide > ester > acid > acyl chloride
B. Ester > amide > acid
C. Acid > ester > anhydride
D. Acyl chloride > anhydride > acid > ester > amide
Explanation
Acyl chloride > anhydride > carboxylic acid > ester > amide. Reactivity decreases as the leaving group becomes worse (Cl– is an excellent leaving group; NH₂– is very poor). Also, electron donation from N lone pair into the carbonyl (resonance) makes amides the most stable (least reactive).
A is backwards. Memorise: ClCO- reacts violently with water; amides need strong acid/base + heat to hydrolyse.
McMurry 8e §21.1–21.2
Q9
β-Keto acid decarboxylation proceeds through:
A. 6-membered cyclic transition state
B. 3-membered ring transition state
C. Radical mechanism
D. S₂ mechanism
Explanation
In β-keto acid decarboxylation (e.g. acetoacetic acid → acetone + CO₂), the keto group on Cβ and the carboxyl on Cα form a 6-membered cyclic transition state via a concerted pericyclic mechanism. This low-energy pathway is why β-keto acids decarboxylate easily at mild temperatures, whereas simple carboxylic acids do not decarboxylate.
Simple acids (no β-carbonyl) do not decarboxylate easily because they lack the 6-membered TS. This is why β-keto acids are unique.
McMurry 8e §22.7
Q10
The common name for methanoic acid (HCOOH) is:
A. Acetic acid
B. Formic acid
C. Butyric acid
D. Propionic acid
Explanation
Methanoic acid (HCOOH) = formic acid (from "formica" = ant; first isolated from ant secretions). Ethanoic = acetic; propanoic = propionic; butanoic = butyric. Memorise the C1–C4 common names as they appear constantly in biochemistry.
McMurry 8e §20.1
Q11
Penicillin is clinically important because it contains:
A. Ester
B. Anhydride
C. β-Lactam (cyclic amide)
D. Thioester
Explanation
Penicillin contains a strained 4-membered β-lactam ring (cyclic amide). The strain makes the C=O unusually reactive toward nucleophilic attack. Bacterial transpeptidases (cross-linking enzymes in cell wall synthesis) open the β-lactam, forming a covalent adduct that irreversibly inhibits them → cell wall lysis → bacterial death. β-Lactamase (penicillinase) resistance works by hydrolysing this ring.
Esters and anhydrides are too reactive to survive in vivo without purpose. The β-lactam is unusually reactive for an amide precisely because of ring strain.
McMurry 8e §21.9 · Clinical
Q12
Paracetamol (acetaminophen) contains which functional group at its N-acyl position?
A. Ester
B. Aldehyde
C. Ether
D. Amide bond
Explanation
Paracetamol = 4-hydroxyacetanilide. The acetyl group (–COCH₃) is attached to the nitrogen of aniline (an arylamine), forming an amide bond (–CO–NH–). This is also called an anilide. The analgesic/antipyretic activity depends on this amide intact; overdose leads to hepatic glutathione depletion via a reactive quinone-imine metabolite.
Aspirin is the ester analogue (O-acetyl, not N-acetyl). Know which drug has which bond type.
McMurry 8e §21.9 · Clinical pharmacology
Q13
The peptide bond in proteins is chemically:
A. An amide
B. An ester
C. An anhydride
D. An acetal
Explanation
The peptide bond is –CO–NH–, an amide. It forms by condensation of the carboxyl group of one amino acid with the amino group of the next, releasing H₂O. Resonance (lone pair of N delocalised into C=O) gives the bond ~40% double-bond character, making it planar and restricting rotation → fundamental to protein secondary structure (alpha-helix, beta-sheet geometry).
McMurry 8e §28.4 · Biochemistry
Q14
In saponification of a triglyceride with NaOH, the products are:
A. Fatty acids + glycerol
B. Soap (fatty acid salts) + glycerol
C. Fatty acids only
D. Glycerol + esters
Explanation
Triglyceride + 3 NaOH → 3 RCOONa (sodium carboxylate = soap) + glycerol (propan-1,2,3-triol). The NaOH converts the ester directly to the carboxylate salt (not the free fatty acid), hence the reaction is irreversible. Soap molecules have a long hydrophobic tail and a charged hydrophilic head → micelle formation → emulsification of grease.
If the question says "acid hydrolysis", the products would be free fatty acids + glycerol (not soap salts).
McMurry 8e §29.2 · Lipid biochemistry
Q15
Common name for ethanoic acid (CH₃COOH) is:
A. Formic acid
B. Propionic acid
C. Acetic acid
D. Butyric acid
Explanation
Ethanoic acid = acetic acid (from "acetum" = vinegar). Vinegar is 5% acetic acid. The acetyl group (CH₃CO–) appears throughout biochemistry: acetyl-CoA, aspirin, paracetamol, N-acetyl sugars. C1 = formic, C2 = acetic, C3 = propionic, C4 = butyric.
McMurry 8e §20.1
Q16
Acyl chlorides react with water to give:
A. Ketones
B. Esters
C. Alcohols
D. Carboxylic acid + HCl
Explanation
RCOCl + H₂O → RCOOH + HCl. Acyl chlorides hydrolyse rapidly (often violently) because Cl– is an excellent leaving group. The HCl produced is corrosive. This is why acyl chlorides are stored in anhydrous conditions and handled with care. With alcohols: RCOCl + R'OH → RCOOR' + HCl (ester); with amines: RCOCl + R'NH₂ → RCONHR' + HCl (amide).
McMurry 8e §21.3
Q17
Novocaine (procaine), a local anaesthetic, is chemically:
A. An amine-containing ester
B. An amine only
C. An amide
D. An aldehyde
Explanation
Procaine (Novocaine) is an ester-type local anaesthetic: the ester bond linking the aromatic acid (4-aminobenzoic acid) to a diethylaminoethanol chain. Ester-type anaesthetics are metabolised by plasma esterases (short duration). Contrast with amide-type local anaesthetics (lidocaine, bupivacaine) which have a –CO–NH– bond and are metabolised hepatically (longer duration). This structural distinction is clinically tested.
Lidocaine = amide type. Procaine = ester type. Allergies to ester types do not cross-react with amide types.
McMurry 8e §21.6 · Clinical pharmacology
Q18
Decarboxylation of malonic acid (HOOCCH₂COOH) gives:
A. 2 CO₂ simultaneously
B. CO₂ + acetic acid (CH₃COOH)
C. CO₂ + methane
D. No reaction — two COOH cannot both leave
Explanation
Malonic acid is a β-diacid. On heating, one COOH decarboxylates via the 6-membered cyclic TS: HOOCCH₂COOH → CH₃COOH + CO₂. The product is acetic acid (ethanoic acid). Note: only one COOH is lost per molecule under mild thermal conditions; the second COOH is not a β-keto acid and does not decarboxylate easily.
If asked about a β-keto acid, the same 6-membered TS mechanism applies but the product is a ketone or enol, not another carboxylic acid.
McMurry 8e §22.7
Q19
Which bond in an amide has partial double-bond character, making the group planar?
A. N–H
B. C–N
C. C=O
D. C–R
Explanation
Resonance in the amide: the nitrogen lone pair delocalises into the C=O system → the C–N bond acquires ~40% double-bond character. This restricts rotation around C–N (barrier ~75 kJ/mol), and all six atoms of the amide group (O=C–N with their substituents) lie in one plane. This planarity is the structural basis for the characteristic geometry of α-helices and β-sheets in proteins.
C=O is already a double bond; the question asks which bond gains partial double-bond character DUE TO resonance, i.e. the C–N.
McMurry 8e §21.8 · Biochemistry
Q20
The anhydride functional group is:
A. –C(=O)–O–C(=O)–
B. –C(=O)–NH–
C. –C(=O)–Cl
D. –O–C(=O)–O–
Explanation
Anhydride = two acyl groups linked by an oxygen: RC(=O)–O–C(=O)R'. The name "anhydride" means "without water" — it forms by condensation of two carboxylic acids with loss of H₂O. Examples: acetic anhydride (used to make aspirin), maleic anhydride. D is a carbonate ester (–O–CO–O–); B is amide; C is acyl chloride.
Carbonates (D) also contain oxygen flanking a carbonyl but the pattern is O–CO–O (one carbonyl), not CO–O–CO (two carbonyls bridged by one O) as in anhydrides.
McMurry 8e §21.5
D-1
Carboxylic acid
+
Organic compound containing the carboxyl group –COOH (a carbonyl, C=O, bonded to a hydroxyl, –OH, on the same carbon). Typical pKa ~4–5. Acidity arises from resonance stabilisation of the carboxylate anion (RCOO–): the negative charge is delocalised equally over both oxygens, lowering the energy of the conjugate base far more than in alcohols (pKa ~16). Physical properties: high boiling points due to carboxylic acid dimerisation via double hydrogen bonds; C1–C4 are water-miscible.
McMurry & Ballantine 8e Ch 20 · Slide set OC Ch 6
D-2
Fischer esterification
+
Reversible, acid-catalysed reaction between a carboxylic acid and an alcohol to form an ester and water: RCOOH + R'OH H&sup+; RCOOR' + H₂O. Mechanism: (1) protonation of carbonyl oxygen; (2) nucleophilic addition of alcohol; (3) proton transfers; (4) loss of water; (5) deprotonation. Because K~eq~ ≈ 1, yield is improved by Le Chatelier strategies: excess alcohol, removal of water (Dean-Stark trap, molecular sieves, azeotropic distillation), or excess carboxylic acid.
McMurry 8e §21.4 · Named after Emil Fischer (1895)
D-3
Saponification
+
Irreversible alkaline hydrolysis of an ester: RCOOR' + NaOH → RCOONa + R'OH. The product is a carboxylate salt (not the free acid), which cannot re-esterify under basic conditions → reaction goes to completion. Industrially, saponification of triglycerides (fats) with NaOH gives glycerol and fatty acid sodium salts (soap). Contrast with acid hydrolysis (reversible, gives free fatty acid). The irreversibility of saponification is clinically relevant: ester-type local anaesthetics (e.g. procaine) are rapidly hydrolysed by plasma pseudocholinesterases.
McMurry 8e §21.4 · §29.2
D-4
Acyl chloride
+
Most reactive carboxylic acid derivative, containing –C(=O)Cl. Chloride is an excellent leaving group (pKa HCl ~–7), so nucleophilic acyl substitution proceeds rapidly. Reacts violently with water → carboxylic acid + HCl fumes; with alcohols → ester + HCl; with amines → amide + HCl. Common lab reagent: acetyl chloride (CH₃COCl), benzoyl chloride (PhCOCl). Prepared from carboxylic acid + thionyl chloride (SOCl₂) or oxalyl chloride. Handle under anhydrous conditions.
McMurry 8e §21.3
D-5
Amide
+
Carboxylic acid derivative containing the –CO–NH– bond. The least reactive derivative because the nitrogen lone pair donates into the C=O by resonance, building up electron density at the carbonyl carbon and reducing its electrophilicity. This resonance also gives the C–N bond partial double-bond character (≈40%), making the amide group planar (restricted rotation). Critical in: (1) peptide bonds — the planar amide unit defines protein backbone geometry; (2) β-lactam antibiotics (penicillin, cephalosporin) — strained cyclic amide; (3) paracetamol — anilide (N-aryl amide).
McMurry 8e §21.8 · Biochemistry Ch 28
D-6
Decarboxylation
+
Loss of CO₂ from a carboxylic acid (or carboxylate). Simple carboxylic acids do not decarboxylate easily. β-Keto acids and malonic acid derivatives decarboxylate readily on gentle heating via a concerted 6-membered cyclic transition state: the keto oxygen on Cβ acts as an internal base accepting the proton from the β-carboxyl as CO₂ leaves, producing an enol that tautomerises to the ketone. Metabolic examples: pyruvate decarboxylase (pyruvate → acetaldehyde + CO₂), oxidative decarboxylation of pyruvate → acetyl-CoA, and the Krebs cycle (isocitrate → α-ketoglutarate; α-ketoglutarate → succinyl-CoA).
McMurry 8e §22.7 · Biochemistry metabolism
E1
Explain why carboxylic acids are significantly more acidic than alcohols (pKa ~5 vs ~16), referencing resonance stabilisation of the carboxylate anion.
6 marks
Key principle
Acidity is determined by the stability of the conjugate base. The more stable the anion formed after H&sup+ donation, the stronger the acid (lower pKa).
Alcohol ionisation (weak acid, pKa ~16)
ROH → RO– + H&sup+;. The alkoxide anion (RO–) has its negative charge localised on one oxygen atom. No resonance stabilisation. High-energy anion → equilibrium disfavours ionisation → pKa ~16.
Carboxylic acid ionisation (stronger acid, pKa ~5)
RCOOH → RCOO– + H&sup+;. The carboxylate anion has two equivalent resonance structures: the negative charge is delocalised equally over both oxygens by π-electron overlap. Both C–O bonds become equivalent (bond length ~1.27 Å, intermediate between single and double). Lower-energy, more stable anion → equilibrium favours ionisation → pKa ~5.
Additional factors
- Inductive effect: the two electronegative oxygens of –COOH also withdraw electron density from the O–H, weakening the bond and further facilitating proton loss.
- Substituents: electron-withdrawing groups on R (e.g. –Cl, –F) stabilise the carboxylate further → lower pKa (trichloroacetic acid pKa ~0.7); electron-donating groups destabilise → higher pKa.
Marking guidance (6 marks): 1 — states acidity governed by conjugate base stability; 1 — alkoxide has localised charge; 1 — resonance delocalisation in carboxylate over 2 oxygens; 1 — two equivalent resonance structures / equivalent C–O bond lengths; 1 — quantitative comparison (pKa 5 vs 16); 1 — at least one additional point (induction, substituent effect, or correct diagram).
E2
Describe Fischer esterification: mechanism, conditions, reversibility, and how Le Chatelier's principle is exploited to drive the reaction to completion.
7 marks
Overall reaction
RCOOH + R'OH H&sup+;, heat RCOOR' + H₂O (reversible, K~eq~ ~ 1)
Mechanism (5 steps)
- Step 1: Protonation of the carboxyl C=O oxygen by H&sup+ → activated (electrophilic) carbonyl carbon.
- Step 2: Nucleophilic addition of the alcohol oxygen (lone pair) to the carbonyl carbon → tetrahedral intermediate (now has two –OH and one –OR group).
- Step 3: Proton transfers within the intermediate to protonate one of the original –OH groups.
- Step 4: Departure of water (from the original carboxyl –OH) as a leaving group.
- Step 5: Deprotonation of the oxonium ion → ester product.
Conditions
Acid catalyst (H₂SO₄, HCl, or p-TsOH); gentle heat (~60–100°C); anhydrous or water-removing conditions.
Reversibility & Le Chatelier exploitation
- Excess alcohol: shifts equilibrium right (alcohol is cheap and easily removed).
- Water removal: Dean-Stark trap (azeotropic distillation with toluene), molecular sieves, or drying agent removes H₂O as it forms → equilibrium driven right.
- Distillation of ester: if ester has low bp, continuous removal also drives forward reaction.
Marking guidance (7 marks): 1 — overall equation with equilibrium arrow; 2 — mechanism (protonation → nucleophilic addition → water loss, at least 3 clear steps); 1 — conditions (acid catalyst + heat); 1 — states reversibility / K~eq~ ~ 1; 2 — two Le Chatelier strategies explained mechanistically.
E3
Compare saponification with Fischer esterification in terms of mechanism, reversibility, product, and industrial application.
6 marks
Fischer esterification (acid-catalysed)
- Catalyst: H&sup+ (H₂SO₄)
- Mechanism: nucleophilic acyl substitution via protonated tetrahedral intermediate; water is the leaving group
- Reversibility: reversible (K~eq~ ~ 1); requires Le Chatelier strategies for good yield
- Product: ester (RCOOR') + water
- Application: industrial ester synthesis (fragrances, solvents, plasticisers e.g. dibutyl phthalate)
Saponification (alkaline hydrolysis)
- Reagent: NaOH (or KOH)
- Mechanism: OH– is the nucleophile attacking the electrophilic carbonyl C of the ester; tetrahedral intermediate; alkoxide (R'O–) leaves → carboxylic acid immediately deprotonated by NaOH → carboxylate salt
- Reversibility: irreversible — the carboxylate salt (RCOONa) is thermodynamically very stable and cannot re-esterify under basic conditions
- Product: carboxylate salt (soap) + alcohol
- Application: soap manufacture (saponification of triglycerides/fats with NaOH); glycerol by-product used in cosmetics and pharmaceuticals
Marking guidance (6 marks): 1 — correct catalyst for each; 1 — mechanism nucleophile for each (H₂O for Fischer, OH– for saponification); 1 — reversibility contrast with explanation; 1 — product (ester vs salt); 1 — industrial application ×2; 1 — explains WHY saponification is irreversible (stable salt cannot re-esterify).
E4
Explain the reactivity order of carboxylic acid derivatives from most to least reactive: acyl chloride > anhydride > carboxylic acid > ester > amide. Use electronic and steric reasoning.
8 marks
General principle
Reactivity in nucleophilic acyl substitution depends on: (1) the electrophilicity of the carbonyl carbon (how positive it is), and (2) the quality of the leaving group (ability of the departing group to accept the electron pair). Better leaving group = faster reaction.
Acyl chloride (most reactive)
Leaving group: Cl– (pKa HCl ~–7, excellent leaving group). No lone-pair donation from Cl into C=O (Cl 3p orbitals overlap poorly with C 2p). Carbonyl is highly electrophilic. Reacts violently with water, rapidly with alcohols and amines.
Anhydride
Leaving group: carboxylate (RCOO–, pKa ~5 — good but not as good as Cl–). The departing carboxylate is resonance-stabilised → reasonably good leaving group. More reactive than free carboxylic acid because the carboxylate leaves more easily than OH–.
Carboxylic acid
Leaving group: OH– (pKa H₂O ~15.7 — mediocre leaving group). Reacts, but equilibrium-controlled; requires activation (acid catalyst protonates C=O).
Ester
Leaving group: alkoxide (RO–, pKa ~16 — poor leaving group). Oxygen lone pair donates into C=O by resonance, partially deactivating the carbonyl. Slower hydrolysis; requires acid or base + heat.
Amide (least reactive)
Leaving group: amide/amine (NH₂– / R–NH–, pKa ~35 — very poor leaving group). Nitrogen lone pair donates strongly into C=O (N 2p – C 2p overlap excellent) → highest resonance contribution → carbonyl carbon is least electrophilic. Requires vigorous acid/base hydrolysis conditions. This stability is why peptide bonds are stable for years under physiological conditions.
Marking guidance (8 marks): 1 — states the two determinants of reactivity; 1 each for correct explanation of each derivative (5 marks total); 1 — uses pKa of conjugate acid of leaving group to justify order; 1 — resonance donation by N, O, Cl compared correctly.
E5
Discuss three clinically important amide-containing compounds: peptide bonds, β-lactam antibiotics, and paracetamol. For each, explain the chemical structure and its clinical relevance.
7 marks
1. Peptide bonds — protein backbone
Structure: –CO–NH–, formed by condensation of α-carboxyl + α-amino group of adjacent amino acids (releasing H₂O). Resonance gives ~40% double-bond character to C–N; all six atoms of the amide group are coplanar.
Clinical relevance: Planarity restricts the φ/ψ backbone dihedral angles available in Ramachandran space → dictates secondary structure (α-helix, β-sheet). Enzymatic hydrolysis of peptide bonds (by protease inhibitors or metalloproteinases) is a drug target (e.g. HIV protease inhibitors). Protein stability in SDS-PAGE exploits the resistance of the peptide bond to casual hydrolysis.
2. β-Lactam antibiotics (penicillin, cephalosporin)
Structure: 4-membered cyclic amide (β-lactam ring). Ring strain (~106 kJ/mol) makes the C=O far more electrophilic than an ordinary amide → reacts readily with the active-site serine of bacterial transpeptidase.
Clinical relevance: Transpeptidase cross-links peptidoglycan chains in bacterial cell walls. Penicillin opens its β-lactam ring onto the enzyme serine, forming a covalent acyl-enzyme complex that cannot be hydrolysed → enzyme permanently inhibited → cell wall lysis → bactericidal. Resistance: β-lactamase enzymes open the β-lactam ring (hydrolysis) before it reaches the transpeptidase. Combination with β-lactamase inhibitors (e.g. clavulanate) overcomes this.
3. Paracetamol (acetaminophen)
Structure: 4-hydroxyacetanilide — an anilide (N-aryl amide): acetyl group (–CO–CH₃) attached to the nitrogen of 4-aminophenol. Contains both a phenolic –OH and an amide bond.
Clinical relevance: Inhibits cyclooxygenase (COX) centrally → analgesic + antipyretic; minimal peripheral anti-inflammatory. The amide bond is metabolically stable under normal conditions. Overdose overwhelms hepatic glucuronidation and sulfation pathways → CYP2E1 converts paracetamol to the reactive N-acetyl-p-benzoquinone imine (NAPQI) → depletes glutathione → covalent binding to hepatocytes → necrosis. Antidote: N-acetylcysteine replenishes glutathione.
Marking guidance (7 marks): 2 marks per compound (structure + clinical significance) = 6; 1 mark for correct comparison across compounds (all amides, but reactivity varies due to ring strain and resonance).