General acid-base catalysis MCQs With Answer

Introduction: General acid-base catalysis is a core topic for B. Pharm students, covering proton transfer events that accelerate chemical and enzymatic reactions. This area explains how general acids and bases, buffer species, and amino acid side chains facilitate transition state stabilization through proton donation or abstraction. Key concepts include Brønsted catalysis, pKa relationships, proton relays, buffer catalysis experiments, kinetic isotope effects, and the role of histidine in enzyme active sites. Understanding these principles links mechanistic organic chemistry to drug metabolism, formulation stability, and enzyme inhibition strategies. Clear grasp of proton-transfer kinetics and pH-rate profiles strengthens rational drug design and biopharmaceutical analysis. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. What best defines general acid-base catalysis?

• Proton transfer mediated by any acid or base present in solution that speeds up the reaction
• Reaction rate determined only by hydronium or hydroxide ions
• Catalysis that requires a metal ion cofactor
• Enzyme catalysis unrelated to proton movement

Correct Answer: Proton transfer mediated by any acid or base present in solution that speeds up the reaction

Q2. How does specific acid catalysis differ from general acid catalysis?

• Specific acid catalysis involves only solvent H3O+ concentration affecting rate
• Specific acid catalysis uses buffer components to transfer protons
• Specific acid catalysis requires an enzyme
• There is no difference between them

Correct Answer: Specific acid catalysis involves only solvent H3O+ concentration affecting rate

Q3. In Brønsted plots, the slope (β) indicates:

• The extent of proton transfer in the transition state
• The equilibrium constant of the reaction
• The molecular weight of the catalyst
• The optical rotation of the substrate

Correct Answer: The extent of proton transfer in the transition state

Q4. A negative Brønsted β for acid catalysis implies:

• More positive charge develops on the substrate in the transition state
• Proton transfer is complete before the rate-determining step
• Only base catalysis is occurring
• The reaction is independent of acid strength

Correct Answer: More positive charge develops on the substrate in the transition state

Q5. Which experimental observation indicates general base catalysis by buffer species?

• Reaction rate increases linearly with buffer concentration at constant pH
• Rate depends only on ionic strength but not buffer
• Rate is independent of buffer concentration
• Reaction stops when buffer is added

Correct Answer: Reaction rate increases linearly with buffer concentration at constant pH

Q6. Kinetic isotope effects (using D2O vs H2O) are useful because:

• A significant isotope effect indicates proton transfer is involved in the rate-determining step
• They measure changes in pKa directly
• They identify the buffer species
• They measure ionic strength effects only

Correct Answer: A significant isotope effect indicates proton transfer is involved in the rate-determining step

Q7. Proton inventory studies vary the D2O fraction to:

• Estimate the number of protons involved in the transition state
• Measure buffer concentration precisely
• Determine enzyme tertiary structure
• Calculate molecular weight of substrates

Correct Answer: Estimate the number of protons involved in the transition state

Q8. Which amino acid commonly acts as a general base in enzyme active sites?

• Histidine
• Leucine
• Cysteine only
• Alanine

Correct Answer: Histidine

Q9. In the catalytic triad of serine proteases, histidine primarily functions as:

• A general base to deprotonate serine and later as a general acid
• An electron donor to the substrate covalently
• A metal-binding residue
• An exclusively structural residue with no catalytic role

Correct Answer: A general base to deprotonate serine and later as a general acid

Q10. Matching pKa of a general acid with substrate pKa is important because:

• Optimal catalytic proton transfer requires similar proton affinity for effective rate enhancement
• It prevents any proton transfer from occurring
• It determines the color of the solution
• It ensures irreversible binding only

Correct Answer: Optimal catalytic proton transfer requires similar proton affinity for effective rate enhancement

Q11. Buffer catalysis experiments are designed to distinguish:

• General acid-base catalysis from specific acid-base catalysis
• Enzymatic from non-enzymatic reactions solely by pH
• Optical isomers of a drug
• Solubility differences only

Correct Answer: General acid-base catalysis from specific acid-base catalysis

Q12. A linear increase in rate with buffer concentration at fixed pH implies:

• Buffer species participates directly in proton transfer during catalysis
• The reaction is zero order in buffer
• The buffer acts only to maintain ionic strength
• Buffer inhibits the reaction

Correct Answer: Buffer species participates directly in proton transfer during catalysis

Q13. Solvent effects on acid-base catalysis often include:

• Changes in dielectric constant altering proton transfer energetics
• Only changes in temperature
• No effect on proton transfer rates
• Only changes to color of reactants

Correct Answer: Changes in dielectric constant altering proton transfer energetics

Q14. In a pH-rate profile showing a bell-shaped curve, typically:

• Two ionizable groups influence catalysis, one requiring protonation and one deprotonation
• Only a single pKa controls the rate
• Reaction is independent of pH
• Reaction rate increases indefinitely with pH

Correct Answer: Two ionizable groups influence catalysis, one requiring protonation and one deprotonation

Q15. Which statement about transition state stabilization by proton transfer is correct?

• Proton donation or abstraction can lower activation energy by stabilizing charge development in the transition state
• Proton transfer always raises activation energy
• Only covalent catalysis stabilizes the transition state
• Proton transfer is irrelevant to transition state structure

Correct Answer: Proton donation or abstraction can lower activation energy by stabilizing charge development in the transition state

Q16. In general base catalysis of ester hydrolysis, the base typically:

• Abstracts a proton from a nucleophile, increasing its nucleophilicity
• Protonates the leaving group to make it better
• Forms a permanent covalent bond with substrate
• Removes electrons from the carbonyl carbon directly

Correct Answer: Abstracts a proton from a nucleophile, increasing its nucleophilicity

Q17. The Brønsted relationship links log(k) to:

• pKa of the conjugate acid (or base) of the catalyst
• Molecular weight of the catalyst
• Temperature only
• Optical rotation of the substrate

Correct Answer: pKa of the conjugate acid (or base) of the catalyst

Q18. A small Brønsted β (near zero) suggests:

• Little proton transfer in the transition state or early transition state
• Complete proton transfer in the transition state
• That the reaction is diffusion controlled
• That proton transfer is the only event in the mechanism

Correct Answer: Little proton transfer in the transition state or early transition state

Q19. Which experimental test supports a concerted proton transfer mechanism?

• Both kinetic isotope effects and linear buffer dependence consistent with simultaneous bond formation and proton transfer
• No change in rate with any buffer or isotope substitution
• Only thermodynamic data, no kinetics
• Observation of product inhibition only

Correct Answer: Both kinetic isotope effects and linear buffer dependence consistent with simultaneous bond formation and proton transfer

Q20. In drug metabolism, acid-base catalysis is relevant because:

• Enzyme-mediated proton transfers can activate or deactivate drug functional groups, influencing clearance
• It determines the color of tablets
• It only affects tablet disintegration time
• It has no role in phase I metabolism

Correct Answer: Enzyme-mediated proton transfers can activate or deactivate drug functional groups, influencing clearance

Q21. Which observation indicates that a general acid participates catalytically rather than stoichiometrically?

• Rate depends on catalytic species concentration but species is regenerated during the cycle
• The acid is consumed in a 1:1 stoichiometric reaction
• The acid is precipitated out of solution
• The acid decomposes irreversibly

Correct Answer: Rate depends on catalytic species concentration but species is regenerated during the cycle

Q22. Hammond’s postulate helps interpret Brønsted slopes because it:

• Relates transition state structure to reaction exergonicity, affecting degree of proton transfer in TS
• Directly measures pKa values
• Predicts color changes during reaction
• Is only valid for radical reactions

Correct Answer: Relates transition state structure to reaction exergonicity, affecting degree of proton transfer in TS

Q23. Which is true about buffer species acting as general acids/bases in enzymatic assays?

• Buffers can either accelerate or decelerate enzyme-catalyzed proton-transfer steps depending on their pKa and concentration
• Buffers never interact with enzyme active sites
• All buffers accelerate the reaction equally
• Buffers always denature enzymes

Correct Answer: Buffers can either accelerate or decelerate enzyme-catalyzed proton-transfer steps depending on their pKa and concentration

Q24. In acid-catalyzed keto-enol tautomerism, the acid typically:

• Protonates the carbonyl oxygen, increasing acidity of α-hydrogen and facilitating enol formation
• Abstracts an α-hydrogen directly as a base
• Forms a covalent adduct with the α-carbon only
• Prevents tautomerization entirely

Correct Answer: Protonates the carbonyl oxygen, increasing acidity of α-hydrogen and facilitating enol formation

Q25. Which kinetic pattern suggests dual general acid-base catalysis (both acid and base from buffer)?

• Rate shows dependence on both acidic and basic buffer components and on pH
• Rate is independent of pH and buffer
• Rate decreases with temperature only
• Rate is inhibited by salts but not by buffer

Correct Answer: Rate shows dependence on both acidic and basic buffer components and on pH

Q26. A primary deuterium kinetic isotope effect (kH/kD > 2) generally indicates:

• Cleavage or formation of an X–H bond is involved in the rate-determining step
• Only secondary hyperconjugative effects are present
• There is no proton movement in the mechanism
• That the reaction is photochemical

Correct Answer: Cleavage or formation of an X–H bond is involved in the rate-determining step

Q27. Proton relays in enzyme active sites (chains of H-bonded residues/waters) function to:

• Facilitate long-range proton transfers quickly and selectively
• Prevent any proton movement
• Bind metal ions irreversibly
• Provide only structural rigidity

Correct Answer: Facilitate long-range proton transfers quickly and selectively

Q28. Which descriptor best explains why histidine is commonly found in proton-transfer roles?

• Its side-chain pKa (~6–7) allows it to act as proton donor or acceptor near physiological pH
• It is the most hydrophobic residue
• It cannot form hydrogen bonds
• It is always permanently protonated at physiological pH

Correct Answer: Its side-chain pKa (~6–7) allows it to act as proton donor or acceptor near physiological pH

Q29. In designing a catalyst for a proton-transfer step, selecting a catalyst with pKa close to substrate pKa will:

• Promote efficient reversible proton transfer and optimal rate enhancement
• Always inhibit the reaction
• Make the reaction independent of temperature
• Ensure irreversible substrate binding

Correct Answer: Promote efficient reversible proton transfer and optimal rate enhancement

Q30. Which experimental result would argue against a mechanism where proton transfer is rate-limiting?

• No significant solvent isotope effect when substituting H2O with D2O
• Large primary kinetic isotope effect upon deuteration of transferring hydrogen
• Linear buffer dependence showing catalytic participation
• pH dependence consistent with protonation state changes

Correct Answer: No significant solvent isotope effect when substituting H2O with D2O